results of the public consultation on the scheer's preliminary … · 2017-06-22 · comments...

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Results of the public consultation on the SCHEER's preliminary Opinion on

"The need for non-human primates in biomedical research, production and

testing of products and devices" (2017 update)

A public consultation on this Opinion was opened on the website of the Scientific Committees from 10

February to 26 March 2017. Information about the public consultation was broadly communicated to

national authorities, international organisations and other stakeholders.

190 contributors from Academia, researchers, Member States, Non-Governmental Organisations and

industry, providing a total of 318 comments, participated in the public consultation, providing input to

different chapters and subchapters of the Opinion.

Each submission was carefully considered by the SCHEER and the scientific Opinion has been revised to

take relevant comments into account. The literature has been accordingly updated with relevant

publications.

The SCHEER thanks all contributors for their comments and for the references provided during the

public consultation.

The table below shows all comments received on different chapters of the Opinion and SCHEER's response to them. It is also indicated if the comment resulted in a change of the

Opinion.

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Comments received during the public consultation on the SCHEER preliminary opinion on "The need for non-human primates in biomedical research, production and testing of products and devices" (2017 update)

Name of

individual/ organisation

Table of

contents Submission SCHEER's response

1. Marshall,

Lindsay, Humane

Society International,

[email protected], United

Kingdom

ABSTRACT Page 9, line 34-

We agree with the statement that efforts are needed to "... gain new insights into molecular

biology, including a better understanding of signalling pathways, modelling and bioinformatics

and further research into integrated testing strategies." However, we feel that these efforts are

underway and that the Opinion could refer to the work on Adverse Outcome Pathways that has

revolutionised chemical testing and regulation. The

application of the AOP framework to other avenues of research, such as drug design and testing, has

further capability to replace animals in biomedical research. In addition, AOP may be used to support

the development of IATA [Tollefsen et al 2014] and these will be vital for the replacement of NHP.

The SCHEER agrees that these efforts are already in

place, especially in areas other than the pharma sector in which non testing methods (e.g. read

across) or some in vitro methods (e.g. OECD test guidelines for phototoxicity, skin corrosion and skin

irritation, skin sensitization using the AOP approach, or skin absorption) are already accepted by

regulators. It has to be underlined, however, that in those same sectors NHP use is not allowed. And this

is mentioned in the Opinion.

The Opinion also refers to AOP and to integrated testing strategies, therefore there is no need for any

changes.

2. Marshall,

Lindsay, Humane


lmarshall@hsi

.org, United Kingdom

ABSTRACT Page 9, line 40

We suggest that, prior to suggesting that further research is needed, the relevance and limitations of

the use of NHP models for infectious diseases and therapies could be addressed with a call for

systematic review and meta-analysis of this topic.

This is an important exercise and prevents possible duplication of NHP studies, needless use of NHP or

the further development of humanised mouse models, where these may not be required.

This part of the abstract starts with the remark that

there is an urgent need to conduct systematic reviews and meta-analysis of all areas of NHP use.

This can be performed depending on the specific question and sufficiently available data. Research in

this field for infectious diseases is already mentioned

as one of the examples (page 9, line 40-44, specifically point 1). Your suggestion is already

included in the Opinion.

3. Marshall,

Lindsay, Humane



The use of NHP in neuroscience is particularly harmful and distressing to the animals and we feel

that this area most urgently requires replacement. The use of systematic reviews here would be

The SCHEER agrees with the comment of the reader

about the potential of a small percentage of the neuroscience research (mainly electrophysiology

experiments) having an impact on primate welfare. However, studies have shown that the severity of

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lmarshall@hsi


helpful, not least to prevent duplication of studies.

Data sharing would be important, and databases such as the CocoMac 2.0 are valuable resources

that should reduce animal use. However, further

efforts should be made to develop more precise methods to examine the human brain. These could

include epidemiology, genome-wide association studies, and imaging techniques such as PET and

MEG, and to use European initiatives such as the Human Brain Project. The aim of neuroscience

research has to be a better understanding of the human brain, not a comparative study of NHP

brains.

these procedures is moderate (Pickard et al 2013).

As noticed by the reader, the Opinion recommends repeatedly that it is necessary to enforce the 3Rs, to

perform reviews, to share data and avoid duplication

of experiments, and to refine the techniques and devices to minimise any possible harm. The

suggested alternative imaging techniques that are used in NHPs and humans today unfortunately

cannot address the same issues as electrophysiology and cannot, even in combinatorial approaches,

provide the same answers. PET imaging gives metabolic but no anatomical information or

information at the single neuron or small population

of neurons level. The limitations of MEG and TMS are discussed elsewhere in the text (see section 4.6.4.4).

The Human Brain Project initiative and its potential value is of course mentioned in the text. Although

this is a personal opinion rather than a scientifically proven fact, we fully agree with the reader that the

understanding of the human brain, the specificity of its functions and the development of techniques to

study it require fundamental knowledge that has

been derived from NHP studies specifically for this purpose (section 4.6.4.1).

4. Marshall,

Lindsay, Humane



Kingdom


We feel that, whilst the development of a timetable for the passing out of NHP is a difficult task, it is

one worth accomplishing. The Netherlands are leading the way with their timetable to phase out

animals in chemical safety testing by 2025 and this sets a hugely important precedent. Producing a

timetable is likely to galvanise research and innovation and would reassure the public. Public

support of the use of monkeys in research is low

across Europe and approval for animal research in general is on the decrease [e.g. Crettaz von Roten,

2012]

The Opinion recommends ways to advance 3Rs,

acknowledging that one timetable for phasing-out cannot be given in view of a wide spectrum of

positive and negative incentives for NHP use. Risk managers, however, may decide on such a timetable,

but this is outside the mandate of the SCHEER.

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5. Marshall,

Lindsay, Humane

Society

International, lmarhall@hsi.

org, United Kingdom

ABSTRACT Page 10, line 11.

We are concerned that the Opinion appears to advocate some increased testing on NHP, for the

"emergence and re-emergence of infectious

diseases" and suggest that the likely advances that occur as a consequence of the more innovative

research stimulated by the opinion and by the publication of a timetable to phase out NHP, can

prevent this new demand for NHP. It feels that turning back to NHP as animal models is a backward

step that undoes much of the good of advances like Tox21 and EUToxRisk- initiatives that are showing

the future of animal-free science. Comments that

appear to allow continued use of NHP make it impossible to produce a phasing out timeline and

appear counterproductive to the opinion.

The Opinion highlights all the progress towards an

animal-free safety assessment framework, but for the time being we cannot ignore there are still areas

in which that NHP are a relevant animal model (e.g.

monoclonal antibody product or vaccines development). This is witnessed also by the recent

revision of the ICH guideline S6). Denying it will not result in a quicker phase out.

Nevertheless, it is clear that NHP should be only used when there are no alternatives, and the number of

animal used can be substantially limited by preliminary in vitro and in silico testing, or avoided

whenever in vitro the NHP non-reactivity can be

demonstrated (indicating NHP are not a suitable animal model). As already stated, the SCHEER's

opinion is that the use of an appropriate species or combination of species/models is essential to

obtaining the most reliable and translatable information

6. Fentener van

Vlissingen, Martje,

European College of

Laboratory

Animal Medicine

(ECLAM), m.fentener@e

rasmusmc.nl,

ABSTRACT The last part of the text in the shaded area is not

logical or in need of explanation/rephrasing: “removal of barriers and research needs”. What is

meant by removal of research needs? Is there anything in the scope of this report that would, e.g.,

remove the need for neuroscientific research or

research into emerging diseases? Do we expect brain diseases to disappear (also in view of the

increases observed), or emerging diseases? And how could that perspective materialize in this

Opinion? The citation title of the report seems not to address

basic research, which is inconsistent with Directive 2010/63. The title is identical to the 2009 report but

the Directive was only adopted after that and

provided for the inclusion of basic research in Art. 8 (the scope of purposes of NHP studies).

The SCHEER agrees with your observation and the

text has been adapted.

This is correct. Although basic research is included in

the Opinion, SCHEER chose not to change the title of the report.

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7. Rushworth,

Matthew, Federation of

European

Neurosciences Societies,


Kingdom

ABSTRACT

Scientific_Committee_on_Health_Environmental_and_Emerging_Risks_FENS_letter.pdf

Three points of concern are highlighted in the attached letter:

1/ non-invasive human neuroimaging techniques, such as functional magnetic resonance imaging

(fMRI), were proposed as potential alternatives to

research with NHPs. FMRI and related approaches do not offer simple alternatives to invasive

experiments with NHPs. As noted on page 49 of the SCHEER opinion, in an excerpt quoted from the

Bateson (2011) report, these techniques cannot tell us about the nature of brain activity and its

relationship to behaviour, the nature of anatomical connections within the brain, or the causal role of

brain regions in behaviour with anything like the

precision of investigations with NHPs. This is not simply due to a lack of scientific interest in non-

invasive techniques for investigating the human brain; these approaches have been some of the

most popular in neuroscience over the last two decades. Considerable effort in laboratories in many

European countries and beyond has been devoted to advancing their spatial and temporal resolution.

Research funders in many European countries have

invested heavily in their development and expansion. Rather the limitations of the techniques

appear intrinsic to the techniques themselves. For this reason neuroscientists do not regard such

techniques as simple alternatives to non-human primate models but rather as complementary.

Animal models reveal fundamental features of neurons and neural circuits and non-invasive

approaches with human subjects tell us how such

knowledge can be extrapolated and exploited in understanding the human brain. Both sets of

1. The SCHEER fully agrees with the commenter and the text has been modified in section 4.6.4.4 to

better reflect this concept. Comment 3: as above (section 4.6.4.1).

fMRI – Although we understand what imaging

technologies measure, what they can and cannot tell

us about brain activity, and how they are currently used in NHPs and humans, there is evidence that

certain psychophysical and electrophysiological studies in NHPs have been replaced with non-

invasive imaging studies in humans. This was noted by the Bateson Panel, which included experts in

imaging, and should be positively acknowledged in the Opinion. That is not to say we do not recognize

that human imaging and NHP electrophysiology

approaches are often used in combination in neuroscience and are valuable to gain greater insight

and understanding.

We take the point that imaging techniques have inherent limitations that are difficult to overcome,

and that other technologies may offer greater potential for advancement in the 3Rs, but because

we believe that continued development of imaging

technologies has the prospect of furthering the 3Rs, we have made this recommendation (as did the

Bateson Panel). We have edited the text to reflect this.

https://ec.europa.eu/health/sites/health/files/scientific_committees/scheer/docs/primates_co7.pdf

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approaches are powerful but in different ways. It is

through their combination that neuroscience has advanced. That many researchers use both

approaches is a testament to their complementary

strengths.

2/ the report includes some errors regarding the severity of neuroscientific procedures. For example

on page 46 of the SCHEER opinion the Pickard (2013) Report is cited, but the conclusions of that

Report are not given. It considered 10 years of research with 149 macaques and 82 marmosets

conducted in the UK. A major conclusion of the

report was that there was little or no evidence of a high welfare impact or of cumulative suffering

(section 1.2.4 on p 7 of Pickard, 2013). Confirming this, since 2013, retrospective reports (as opposed

to prospective assessments) of the actual impact of scientific procedures have been compiled in the UK

(as requested by Directive 2010/63/EU). These data show that over 90% of NHP basic research studies

have been assessed at the Moderate level or lower,

rather than Severe. In accordance with such experience in the UK we note that in many

European countries the severity classification of NHP neuroscience procedures is Moderate.

Rather than just focus on the UK situation, the

report should reflect the fact that other EU countries have decided upon a Moderate assessment for NHP

neuroscience studies.

3/The final point that we wanted to emphasize in

relation to the report concerns the importance of fundamental and basic research in neuroscience.

There is a risk of artificially separating fundamental research from research with direct and immediate

clinical translation. It is, however, essential to

2. It is specifically stated in the Opinion that this is the current situation in the UK and it only accounts

for the prospective severity classification. If there is a chance that an animal in a specific study will

experience severe discomfort, the full study will have a prospective classification as “severe”. In the

retrospective assessment this can be specified per

animal. We agree that most studies in retrospect have been assessed as less than severe

A separate, more detailed section has been added, which is not focussed on UK experience.

3. Please see the reply above

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remember that clinically oriented research with

immediate and short term impact on patients is guided by the knowledge derived from basic

research.

8. No agreement to disclose

personal data

ABSTRACT This document seems to let public sentiment and activism drive the debate rather than scientific

merit. A number of the ideas will actually hurt

development of new medicines as opposed to helping the cause of the patient.

This is a personal opinion. The commenter does not provide any suggestions for improvements of the

scientific basis of the SCHEER preliminary Opinion

and/or any scientific evidence.

9. Bailey, Jarrod,

Cruelty Free International,

jarrod.bailey@crueltyfreein

ternational.org, United

Kingdom

ABSTRACT P2 L13 A timetable for the phasing out of NHP use

in Europe is possible, we believe, given the state of current knowledge. However, even if the SCHEER

WG believes this, there is no reason not to propose a timetable of desired, non-binding outcomes and

progress points. We believe this would be immensely helpful in driving the desired move away

from NHP use to the greater adoption of alternatives.

P2 L14 As it stands the report does not clearly set out its recommendations. It would be much

improved and of more value if the recommendations within the text are more clearly highlighted as such,

as is typical with other reports. We identify in our comments what some of these recommendations

could be.

P2 L13 The Opinion recommends how to advance

3Rs, acknowledging that one timetable for phasing-out cannot be given in view of a wide spectrum of


but this is outside the mandate of the SCHEER timetable.

P2 L14 This comment refers to the last sentence in the abstract and refers to Section 5.1 which includes

specific recommendations for further work for the following topics, Advancing 3Rs (replacement,

reduction and refinement, Design and execution of experiments, Training, Improvement of techniques

and protocols and Sharing of knowledge.

10. Chlebus, Magda, EFPIA,

[email protected],

Belgium

ABSTRACT

NHP_submission_to_SCHEER_2017_final.docx

In general EFPIA finds the review to be well-

balanced, showing support overall for the appropriate use of NHPs in research, whilst

considering current trends in relation to developing improved welfare. Comments on different sections

of the report are provided in the attached

document. The main points from the letter:

Thank you for your support of the SCHEER

preliminary Opinion.


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1. The areas of research (fundamental, translational

and applied) and testing of products and devices in which non-human primates continue to be used

today

EFPIA supports the conclusion by SCHEER that the use of an appropriate species or combination of

species/models is essential to obtaining the most reliable and translatable information.

2. The currently available possibilities by type of research or testing to replace their use either with

methods not entailing the use of animals or by using other species of animals including those

genetically altered

SCHEER should be aware that requirements established for research projects as cited in 5.1.1,

may also be required in safety testing by regulators. EFPIA would like to highlight again, that it is crucial

to make sure that any additional level of scrutiny is proportionate and supports conducting safety

testing and research programmes in a timely manner in Europe rather than compromising it (by

e.g. slowing down and over-complicating decision-

making). 3. Scientific viewpoint on when their use would no

longer be necessary, considering the type of research and areas of testing with a view to the

establishment of a specific phasing-out time-table where possible

We agree with the SCHEER viewpoint that the need to consider the use of NHPs in scientific study and

pharmaceutical safety testing on a case-by-case

basis has placed additional emphasis on the requirement to use alternative methods. Adequate

monitoring of primate use, as well international coordination of work on 3Rs, dissemination of

information for better implementation have proved effective in reducing the use of NHPs, while allowing

the development of new medicines.

No reply needed.

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We agree with the SCHEER opinion that the

development of a timetable for phasing-out the use of NHPs is currently impractical, as there are often

no other available species that can help answer key

questions specific to human health, and in vitro assays remain far from replacing animals in safety

assessment. 4. Opportunities for the reduction and refinement of

their use in areas where no replacement can be foreseen in medium or long term as per the

principles of the 3Rs The SCHEER draft opinion cites a range of

opportunities for reduction and refinement, many of

which are in active use by the sector. The impact of this emphasis on the 3Rs is thought to be one

reason for the decrease in the number of NHPs used from 2009 to 2016.

Data sharing and publication of negative results remains a key issue for the 3Rs in general, but can

be difficult to implement practically and in some cases raises challenges around intellectual property.

However, the pharmaceutical industry is committed

to sharing data where possible for the progress of the 3Rs, demonstrated through the effective data-

sharing initiatives such as those developed by the NC3Rs, and IMI projects such as e-Tox .

Safety assessment of chemicals and drugs is being supported by increasing knowledge and experience

of non-animal techniques, but the availability of these techniques is variable and there is limited

regulatory acceptance of these strategies. While

these new avenues of safety assessment may reduce NHP use in some areas we should be mindful

of their limitations. 5. Identification of specific research areas where

effort should be made to advance replacement, reduction and refinement of the use of non-human

primates in scientific procedures

No reply needed and no revision to document required.

The SCHEER agrees that these efforts are already in place, especially in areas other than the pharma

sector in which non testing methods (e.g. read across) or some in vitro methods (e.g. OECD test

guidelines for phototoxicity, skin corrosion and skin

irritation, skin sensitization using the AOP approach, or skin absorption) are already accepted by

regulators. It has to be underlined, however, that in those same sectors NHP use is not allowed. And this

is mentioned in the opinion. The opinion also refers to AOP and to integrated

testing strategies, therefore there is no need for any

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It is EFPIA’s position that implementation of

Directive 2010/63 leads to a better protection of NHPs in the European member states through a

combination of measures focussed on improving

animal welfare. EFPIA supports a move towards the use of

systematic review and meta-analysis for NHP studies, where appropriate and relevant to the

study in question. In many NHP studies, particularly those involving a new concept, the available data is

limited. A blanket-approach to undertaking systematic review would prove restrictive and

costly, delaying the development of medicines while

adding little new knowledge. There is now a central repository for systematic review data, and we

recommend that any systematic review undertaken for NHP studies is logged with this source to

increase the availability and sharing of systematic reviews.

On the recommendation to develop new models, it is also important to fund work (e.g. through EU

framework programmes or national research

programmes) that would provide proof of concept of alternative solutions (such as use of the humanised

mouse). It is worth bearing in mind that many alternative

approaches, such as the humanised mouse, assume that a particular target organ or system will provide

all of the relevant toxicological data needed. Often whole animals are valued in safety testing because

a whole, living system makes it possible to identify

off-target effects which might otherwise be missed.

6. Potential implications for biomedical research (e.g., immune based diseases, neuro-degenerative

disorders, infectious diseases and serious diseases) should the use of non-human primates be banned in

the EU

changes.

This is an alternative to NHP, but it is still not animal

free.

Agreed. No revision to document required.

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We agree with the SCHEER opinion that while there

are high levels of concern about the use of NHPs in research, there is substantial scientific justification

for their continued use, and that a total ban is not

feasible.

The associated mandate for the SCHEER opinion (4.5, page 25) states that Recent years have seen

growing concern about the reliability and reproducibility of animal studies, and poor

experimental design and reporting have been implicated as major contributing factors.

A number of sources are critical of experimental

design in animal studies, but take a view that is partial in its position. For balance and perspective,

EFPIA recommends that IQ DruSafe response to these claims is also considered.

The SCHEER would like to point out that this statement cannot be found in the Opinion. Among

others, SCHEER stresses that ‘it is important that the justifications offered for individual NHP research

projects are soundly based and realistic and any potential health benefits are demonstrable’ (4.6.4.3)

and ‘The scientific justification of the use of NHPs as

recipients should still be examined on a case-by-case basis and should take into account the in silico, in

vitro and in vivo data acquired in a non-primate species’ (3.3).

11. 't Hart, Bert A., Biomedical

Primate Research

Center, Rijswijk, The

Netherlands,

[email protected], Netherlands

SUMMARY

Summary.pdf

Page 7 line 24-25. The general statement is made that “Applying the 3R’s has both

scientific and economic merit. Replacements may be more scientifically valid (questionable) and more

cost effective (true). Generalizations of this kind should be better explained.

Page 8 line 39-40. The willingness of researchers to

publish negative/null data is frustrated by the

attitude of journal editors, who prefer positive data, as these are more often cited. It may be worthwhile

considering to create a new peer-reviewed open access journal for the publication of negative/null

data.

Page 9 line 8/9. At several places in the text the expectation is expressed that usage of iPS cells will

Page 7, line 24-25 This sentence is part of the

summary and is further explained in section 3.

Page 8, line 39-40 The SCHEER agrees that this

could be a useful approach for addressing negative and null results. It has been included as a

recommendation.

Page 9, line 8/9 It is felt that this is not an overly optimistic expectation and would unlikely lead to an


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reduce the number of animal - based experiments.

This probably too optimistic as the expectation is based on only 1 publication (Giri and Bader, 2015).

It is also well possible that the demand for NHP

experiments will increase, for example for testing iPS-based regenerative treatments.

Page 9 line 27. The focusing of research with NHP in

centers of excellence is a good idea as long as these centers are adequately funded and do not depend

on animal experimentation for their survival. At this moment there are two large primate centers in

Europe, one of which is suffering from chronic

under-funding.

Page 10 line 4. The same is true for the development of alternatives for research in life

animals. One of the big stakeholders, Pharma industry, appears more interested in usage of

disease models if life animals than in supporting the development of alternative methods.

Public funding sources for the development and

validation of alternative methods are also scarce.

increase need for NHPs. No revision to document

required.

Page 9, line 27 The Opinion gives recommendations

on how to provide the most optimal possibilities to advance the 3Rs in NHP research. Funding issues can

be important but are outside the scope and mandate of the Opinion.

Page 10, line 4 The statement that Pharma industry is more interested in in vivo models rather than in

the development of alternatives is unsubstantiated and is a personal opinion.

With respect to funding, on several pages (e.g. page

10, line 7; page 20 lines 28-31, lines 40-41, page

62, lines 5-10) of the Opinion, it is mentioned that availability of funding and resources for developing

alternatives is an important factor for the development of alternatives and should be

instigated.

12. Vogel, Friedhelm,

Covance Preclinical

Services GmbH,

friedhelm.vog

[email protected], Germany

SUMMARY Page 8, lines 18-21: The sentence is incomplete; the verb is missing in the main part of the sentence.

Page 8, lines 18-21 This sentence has been revised as: “If a one-to-one replacement of a test may not

be achievable, an integrated testing strategy should be used in which in silico, in vitro, ex vivo and in vivo

experiments, and clinical research are used in combination in a weight-of-evidence approach.”

13. Hasenau,

John,

SUMMARY The Association of Primate Veterinarians (APV) a

global organization of over 375 Veterinarians



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Association of

Primate Veterinarians,

labanimalcons

[email protected], Other,

United States of America

dedicated to the welfare and clinical care of

Nonhuman Primates thanks the SCHEER working group for sharing the resent updated review and

position paper. This was a very thorough review

with evidence of dedicated effort and time in its completion. APV has no futher comments for this

report at this time.

14. Marshall,

Lindsay, Humane



Kingdom

SUMMARY p8; lines 21-23

The text assumes that in vivo tests will be required and for some applications, this may not be the case

and the text should be rewritten so that it does not suggest that in vivo research is always necessary.

This is particularly relevant for biosimilars.

Disagree. The text makes it clear animal alternatives

can be used as appropriate. No revision to document required.

15. Marshall, Lindsay ,

Humane



Kingdom

SUMMARY Line 5 There is a pressing need for independent and

systematic analysis to be conducted of the value

and necessity of NHP studies, along the lines of the recent study by the US Institute of Medicine on the

necessity of chimpanzee research. This analysis should include a consolidated review of the

retrospective assessments required for all NHP procedures under Article 39 of Directive 2010/63. In

the absence of such a review, the updated SCHER opinion should avoid making any further generalized

claims about the ‘essential’ nature of NHP

experiments or the 'need' for NHP in research.

This Opinion was written following an independent analysis of the need for NHP studies.

16. Lindsay,

Marshall,

Humane Society

International, lmarshall@hsi


SUMMARY Page 8, line 33

It is welcome to see that NHP are no longer

considered suitable for studies of xenotransplantation. We would now hope that this

statement is reflected in any and all EU-wide funding calls of relevance to this topic. We would

also envisage that any applications that request the use of NHP in xenotransplantation studies would be

required to submit revised proposals with altered

The suggested action is an issue for risk managers;

risk management is outside of the scope of the

SCHEER.

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methodology taking this into account.

17. Marshall, Lindsay,

Humane Society

International,


Kingdom

SUMMARY Page 9, line 1. We are gratified to see the acknowledgement that

"Safety assessment of chemicals and drugs is being enriched by increasing knowledge and substantial

experience of non-animal techniques" and we note

that the National Research Council (NRC) report {too large to upload; National Academies of

Sciences, Engineering, and Medicine. 2017. Using 21st Century Science to Improve Risk-Related

Evaluations. Washington, DC: The National Academies Press. doi:10.17226/24635.} describes

a future in which high-throughput in vitro assays and computational models based on human biology

are used to evaluate potential adverse effects of

chemical exposures. We believe that this 21st Century approach should be adopted in drug safety

assessment to replace the use of animals.

No reply needed.


Humane Society



SUMMARY Page 9 line 21 We could not agree more with the statement that

"There is an urgent need to conduct systematic reviews and meta-analysis of all areas of NHP use."

We would like to see a specific funding call or request for experts to facilitate this and we feel that

this could be directed from the Commission. The utility of systematic reviews and meta-analyses in

enabling reduction of animal use was a theme at

the EC conference on Non-animal approaches in December. We feel that this indicates that the

scientific community appreciates the importance of such exercises, but there may need to be more

encouragement in order to engage the appropriate groups with such an exercise.

The suggested action is an issue for risk managers; risk management is outside of the scope of the

SCHEER.

19. No agreement

to disclose personal data

SUMMARY The special public concern and ethical dilemma

about the NHP used in research as quoted in page 7 line 12, and also page 22 is not defined nor

justified.

On page 8 of the Ipsos Mori (2016) survey the

following key findings are noted: Public attitudes towards the use of animals in

research have shifted little between 2014 and 2016.

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Several public opinion surveys in UK for instance show that the NHP species used in Europe

(macaques or marmosets) are equally justified for

research as cats or dogs (ISPOS MORI 2014 and 2016)

https://www.ipsos-mori.com/Assets/Docs/Publications/sri-public-

attitudes-to-animal-research-2016.pdf https://www.ipsos-

mori.com/Assets/Docs/Polls/sri_BISanimalresearch_NONTRENDreport.pdf

please find the extracted tables on attached files.

the NHP species used in research are not a specific

concern or ethical dilemma for the public opinion, but are part of a larger group of concern = large

animals.

A majority (65%) say they can accept the use of

animals in research as long as it is for medical purposes and there is no alternative, whilst support

for an outright ban on animal research stands at 26

per cent.

Provisos remain however – whilst medical and scientific research both attract majority acceptance,

the public are less accepting of using animals in all types of research and there is a less than majority

acceptance of all forms of non-medical chemical testing.

20. Lemon, Roger, UK

Expert Group for NHP

Neuroscience Research,

[email protected]

c.uk, United Kingdom

SUMMARY Non-human primate research remains of vital importance.

We fully support the positive conclusions in the Opinion about the importance of non-human

research for further advances in science and medicine. Animal research, including research with

non-human primates (NHPs), continues to be the

basis for medical advances that have extended our life expectancy and has already raised our chances

of overcoming or ameliorating life-threatening and debilitating diseases. Current estimates show that

about 15% of the population in any major country suffer from mental and brain disorders. For the UK

for example, this means about 10 million patients. The numbers and the degree of suffering are

staggering and not really appreciated by the public,

their politicians and administrators. Politicians need to be clear when they face questions from their

constituency on how they are addressing these major challenges to mental health. One thing they



https://www.ipsos-mori.com/Assets/Docs/Publications/sri-public-attitudes-to-animal-research-2016.pdf



https://www.ipsos-mori.com/Assets/Docs/Polls/sri_BISanimalresearch_NONTRENDreport.pdf



16

must do is to promote the increased knowledge of

brain processes by facilitating research in NHPs, which provides unparalleled information on brain

function and dysfunction and remains instrumental

for advancing treatments (deep-brain stimulation, brain machine interfaces etc etc).

21. No agreement


SUMMARY

The SCHEER shares this concern about the

unnecessary use of NHPs. The Opinion therefore recommends how to advance the 3Rs, acknowledging

that one timetable for phasing-out cannot be given in view of a wide spectrum of positive and negative

implications of NHP use. Risk managers, however, may decide on such a timetable.

With regard to the 2nd concern:

Replacement of NHPs is the use of non-animal

alternatives. However, substituting NHPs with other species is a stepwise process towards non-animal

approaches when replacement is not achievable at short notice. In such cases the Opinion states that an

integrated testing strategy in which in silico, in vitro, ex vivo and in vivo experiments and clinical research

are combined in a weight-of-evidence approach could fulfil the task.

With regard to the 3rd concern: The SCHEER carefully assessed the progress in the development

of alternatives for key research areas. Similarity between humans and primates is just one of the

arguments. Unfortunately, no data are provided to illustrate the concern for unsubstantiated claims.

22. Jayne, Kimberley,

[email protected]

om, United

Kingdom

SUMMARY Please see the reply to comment 21.

17

23. Dale, Ricky,

[email protected]


24. No agreement



25. Leitch, Meg,

[email protected],

United

Kingdom


26. Hayward ,

Michelle,

[email protected]

k, United Kingdom

SUMMARY I have the following concerns:

A timetable for phasing out primate experiments is

essential to drive the implementation of replacement and provide a route to end their use.

Replacement must mean replacement! The use of other animal species, such as mice and pigs, over

primates, is misrepresentation of the definition of ‘replacement’.

Unsubstantiated claims about the necessity for primate experiments. Mentioning casual

“similarities” between humans and other primates is

NOT scientific evidence that primate species are indispensable in research.

Please see the reply to comment 21.

27. Bernard,

Johanna, Animal

Defenders International,

[email protected]

, UK


28. Stevens, Chris, n/a,

[email protected]

, United

Kingdom


18

29. Williams,

Christine, Home,

chrisholder1@

btinternet.com, United

Kingdom

SUMMARY A timetable for phasing out primate experiments is


Replacement must mean replacement! The use of

other animal species, such as mice and pigs, over primates, is misrepresentation of the definition of

‘replacement’. Unsubstantiated claims about the necessity for

primate experiments. Mentioning casual “similarities” between humans and other primates is

NOT scientific evidence that primate species are indispensable in research.


30. Denzey,

Linda, , lyndenzey@m

sn.com,

United Kingdom


31. Edwards,

Barbara, barbedwards

@btinternet.com, United

Kingdom

SUMMARY No animal should be tested on especially primate.

They are our nearest cousins in the animal world. STOP NOW before you get too cruel. We have to

have compassion in this world and it starts now with animals too.

Kind regards Barbara


32. Daniel, Helen,

[email protected],

United Kingdom


33. Edmonds,

Kate, Inner Leader ,

Kate@kateed

monds.com, United

Kingdom


34. DIXON, SUMMARY Please see the reply to comment 21.

19

GRANT, ,

[email protected],

United

Kingdom

35. No agreement

to disclose

personal data


36. Pike, Kathryn,

None, km-


Kingdom


37. Noakes, Penny,

penny_a_noakes@hotmail.

co.uk, United Kingdom


38. Kaya, Lucy SUMMARY

39. Plaskitt,

Emma, Stanford

University, eplaskitt@clra

.co.uk, United Kingdom


40. Robinson,

Elaine, robinsne@btin

ternet.com, United

Kingdom


41. Caple, Christine,

caplec@btinte

rnet.com, United


20

Kingdom

42. Edwards,

George, georgebowen


Kingdom


43. Edwards, Jean, ,

[email protected],

United

Kingdom


44. Jones, Yvonne

yadjones@aol

.com, United Kingdom


45. Burman,

Anna, , anna.burman


Kingdom


46. Geatches, Dawn, Private

citizen, dgeatches@p

osteo.net, United

Kingdom


47. Kerry , Greig, kezzagreig10

@gmail.com,

United Kingdom


48. Luscombe,

Amanda, amanda.lusco


21

mbe@btintern

et.com, United

Kingdom,

49. Crayton, James,

jamesf.crayto


Kingdom

SUMMARY Please see attached file Please see the reply to comment 21.

50. Crayton, Elaine, ,

[email protected],

United Kingdom

SUMMARY Please see attached file Please see the reply to comment 21.

51. Britton, Jenny SUMMARY Please see the reply to comment 21.

52. Lewton,

Victoria, victorialewton


Kingdom

SUMMARY


personal data

SUMMARY Please see the attached postcard Please see the reply to comment 21.

54. Vance, Amanda, N/A,

[email protected],

United Kingdom


55. Richardson,

Ingrid, , ingridcrichard

[email protected]

.uk, United Kingdom


22

56. Fairweather,

Susan, susan.fairwea

ther007@gma

il.com, United Kingdom


57. Booth, Astra,

[email protected],

United Kingdom


58. Hussenbux,

Marian, mhussenbux

@btinternet.com, United

Kingdom


59. Harris, Linda, [email protected]

et, United Kingdom


60. Payne, Terry,

PHE, terryxp5@hot

mail.com,

United Kingdom


61. No agreement


SUMMARY I find all primate experimentation abhorrent. Please see the reply to comment 21.

62. CONNOLLY,

MARIA ELLEN, NONE,

[email protected],

United Kingdom


63. Oliver, Carol, SUMMARY as per the attached Please see the reply to comment 21.

23

none,

[email protected],

United

Kingdom

64. eisenhuth,

cindy, ,

[email protected],

United Kingdom


65. Brock,

Beverley, bevbroccoli@h

otmail.com, United

Kingdom


66. fox, rachel, , rachel.fox@ya

hoo.com, United

Kingdom


67. Rigg, Stephen,

Wakefield

College, s.rigg@wakefi

eld.ac.uk United

Kingdom


68. Dixon, Nicholas,

Retired, dixon_nichola


Kingdom


69. Wilby, Clarice, SUMMARY Please see the reply to comment 21.

24

A. D.I.

supporter, wilbytlcj@virgi

nmedia.com,

United Kingdom

70. Bowring,

Nancy, nancy.bowrin


Kingdom


71. Perkins, Wendy,


Kingdom


72. Silverstone, Desirée,

[email protected],

United

Kingdom


73. Dodkin,

Christina, ,

[email protected],

United Kingdom


74. No agreement



75. Brooks,

Louise, louisebrooks1

@mac.com, United

Kingdom


25

76. Kathryn,

Wills, greyworld726

@yahoo.co.uk

, United Kingdom


77. lynda,

simpson, , mcfarlane.l@s

ky.com, United

Kingdom


78. Orriss, Miriam,

coaching Supervision

Academy Ltd, [email protected]

k.net, United

Kingdom


79. Bonnar ,

Helen,

[email protected]

k, United Kingdom


80. Bachelard,

Nikita, nikita.bachela

[email protected], France


81. Thiel,

BARBARA, n/a,


Kingdom

SUMMARY A timetable for phasing out primate experiments is

essential to drive the implementation of replacement and

Replacement must mean replacement! The use of other animal species, such as mice and pigs, over

primates, is misrepresentation of the definition of

‘replacement’.


26

Unsubstantiated claims about the necessity for

primate experiments. Mentioning casual “similarities” between humans and other primates is

NOT scientific evidence that primate species are

indispensable in research.

82. GRANT,

ELAINE,


Kingdom


83. Pagdin, Sarah,

[email protected],

United Kingdom


84. Laverick,

Faye-Danielle, fayedanielle@

gmx.de, Germany


85. rival, bri,

[email protected],

Belgium

SUMMARY No need for non-human primates in biomedical Please see the reply to comment 21.

86. Buenader, Sofía,

sofia_buenade


Argentina


87. Watts, Michael,

manwithgreyhounds@gmail.

com, United Kingdom


88. H, Tracy, Self, SUMMARY Please see the reply to comment 21.

27

tracyhrh@gm

ail.com, Other, Canada

89. Jansen van

Vuuren, Lydia,

Creative Math

For Children, creativemathf

[email protected],

Other, South Africa


90. Bonneville,

Thomas, , ukbonn@gmai

l.com, United Kingdom


91. No agreement



92. Janoutova,

Katerina, katerina.janou

[email protected]

o.uk, United Kingdom


93. Spence, Mimi,

[email protected],

United Kingdom


94. Springall,

Sandra, sandraspringa


Kingdom


28

95. Lambert,

Victoria, vjlamb@hotm

ail.co.uk,

United Kingdom


96. Ortega, F,

[email protected],

United Kingdom


97. Smith,

Barbara , smithiesinoz@

hotmail.com, Other,

Australia


98. Musk, Sue, n/a,

[email protected],

United

Kingdom


99. Karen, White,

karenwhite_6


Kingdom


100. Forlani, Rossella,

rossani8'@gmail.com, Italy


101. Meehan,

Sarah, saz22m@hot

mail.com




29

personal data

103. Maschner,

Emil, emalexalex@y

mail.com, United

Kingdom


104. Mottini, Michele,

[email protected], Italy,


105. Penman,

Mandy, Mandypen_99

@hotmail.com

, United Kingdom


106. Scotti,

Emanuela, , scottiemanuel

[email protected], Italy


107. No agreement



108. Keskla, Sirilin,


Estonia


109. Hall, Jackie, ludie1@ntlwor

ld.com, United

Kingdom


110. Heath , Sarah , ,

[email protected],


30

United

Kingdom

111. Pelger, Monica, ,

[email protected],

Netherlands


112. Peeters, Sandra, ADI,

Sandrapeeters


Kingdom


113. Nicolae, Ruxandra,

None, ruxandra@iod

es.ro, Romania


114. Louis, Anna, ,

[email protected],

United Kingdom


115. Kloppers ,

Melissa , World animal

news,

[email protected],

Other, PRIMATE

TESTING


116. Midman, Désirée,

[email protected],

Sweden


31

117. Strich,

Marian, , marian.st@g

mx.net,

Germany


118. Polenberg,

Amy, ,


USA


119. Getz, Cecilie, , Vanja_cecilie

@hotmail.com, Other,

Norway


120. Green, Rhiannon, ,

Rhiannon-green@hotma

il.com, United Kingdom


121. Graff, Gundi,

Viajes San Luis SL,

[email protected],

Spain


122. Lanzi, Alberto, alberto.lanzi@

libero.it, Italy


123. Yarnall, Matthew, ,

myarnall1978

@gmail.com, United

Kingdom


124. smith, moira, Mrs,


32

moira_c_19@

hotmail.com, United

Kingdom


personal data

SUMMARY WE need to put an end to animal testing. It's unconscionable that in this day and age of an

'advanced civilization', we continue this practice. It's

inhuman and our animals have as much feelings as we do and their right to exist and not be tortured

and used for cruel, horrific acts, is just as much justified as ours. Thank you.


126. Bastian, Mark,

[email protected]

k, United Kingdom


127. Hughes, Susan,

[email protected],

United

Kingdom


128. No agreement

to disclose

personal data


129. No agreement

to disclose

personal data


130. Smietana,

Marcin,

University of Cambridge,


Kingdom


131. Hatfield, Angela,


33

a832hatfield@

btinternet.com, United

Kingdom

132. Pannakan, Maria,

mpannakan@

gmail.com, Other,

Thailand


133. Francis, Samantha,

N/A, syoung2103@

gmail.com, United

Kingdom


134. CArroll, Jean, Jeaninlondon

@gmail.com, Ireland

SUMMARY https://www.ad-international.org/admin/downloads/adi_6e0e41470

749dda6d09631b4d792d338.pdf


135. Fetz, Peter,

[email protected],

Romania


136. Powell, Claire, clairepowell@

stjamessw16.

plus.com, United

Kingdom,



personal data


138. Hackl, Stefan, stefan.hackl8

[email protected], Austria


34

139. Spasskaia ,

Valeria, valeria.spassk

[email protected]

m, Austria


140. Mendoza ,

Magali,

[email protected]

m, Other, United States


141. Baetens, Jess,

[email protected],

France


142. Hoxha, Olta, hoxha.olta@g

mail.com, Italy


143. Dos Santos,

Nicole, nicole_ds99@

hotmail.com, United

Kingdom


144. English, Sheila,

SPEAK,

sheila.english2@btinternet.

com, United Kingdom


145. No agreement



146. No agreement



35

147. Cameo,

Michelle, mcameo@nac

kidscan.org,

Other, U.S.


148. No agreement

to disclose

personal data


149. Zycinski,

Karen , N/a,

[email protected]

m, United Kingdom

SUMMARY See attached Please see the reply to comment 21.

150. Britton,

Raymond, arunacala@bti

nternet.com, United

Kingdom


151. Andreia, Santos,

[email protected],

Portugal,


152. Petrovic, Marina, undp,

marinapetrovi

[email protected], Croatia


153. No agreement



154. Branham,

Elizabeth, elizabethebra



36

USA

155. Mallard,

Dominique, Public,

[email protected],

France


156. Aven, Bambara,

ADI, bavenphotos

@gmail.com,

Other, United States


157. Rose, Nettie,

just a person, Nettie.lynne@

gmail.com, Other, United

States of America


158. No agreement



159. Harrap,

Caroline, Ms., carolineharrap

@gmail.com, United

Kingdom


160. Hart, Michael, Hartmichael88

@yahoo.com,

Other, Usa


161. Anderson,

Rebecca,

[email protected]


37

m, Other,

United States Of America

162. Milligan,

Wendy, luvs2bfit@hot

mail.com,

Italy


163. No agreement

to disclose

personal data


164. No agreement

to disclose

personal data


165. Daniel,

Church,

[email protected],

United Kingdom


166. Florou, Maria,

[email protected],

Greece,


167. Doucette, Kathy, ,

[email protected]

m, Other, USA


168. Hagan, Dawn,

none, jacdhaa@yah

oo.com,

Other, United States


169. No agreement

to disclose

SUMMARY Stop this barbaric act NOW!!!!! Wild animals

deserve their freedom.

This is a personal opinion. The comment does not

provide any suggestions for improvements of the

38

personal data scientific basis of the SCHEER preliminary Opinion

and/or any scientific evidence. No reply needed.

170. Getz, Cecilie, , Cecilie.getz@

kvantel.no, Other,

Norway

SUMMARY Stop this insane abuse!! This is a personal opinion. The comment does not provide any suggestions for improvements of the

scientific basis of the SCHEER preliminary Opinion and/or any scientific evidence. No reply needed.

171. Czepiel, Liz, ADI,

liz.czepiel@ya

hoo.com.au, Other,

Australia

SUMMARY As an amateur researcher (medical), I only test on myself. What better way to judge results than by

experimentation on self?

This is a personal opinion. The comment does not provide any suggestions for improvements of the

scientific basis of the SCHEER preliminary Opinion

and/or any scientific evidence. No reply needed.

172. Parday, Ida, Idaparday@g

mail.com, Sweden

SUMMARY The is NO need for non-human primates in biomedical research, production and testing of

products and devices. Support human based medical research. For other product there is other

metods for use. Animaltesting is "old school" without any scienfiticall ground.

This is a personal opinion. The comment does not provide any suggestions for improvements of the

scientific basis of the SCHEER preliminary Opinion and/or any scientific evidence. No reply needed.

39

173. Dodkin,

Christina, Animal

Defenders

International/National Anti-

Vivisection Society,

[email protected]

rg, United Kingdom

SUMMARY

SCHEER_ADI-NAVS_overarching_concerns.pdf

Pg 8, lines 25–27: The Committee over generalises

and misrepresents the definition of the term “replacement”. (See comments in our response to

section 4.6.2.4)

Pg 8, lines 40–41: While greater efforts need to be taken to ensure that pain and distress experienced

by NHPs is minimised, this should not involve more

research using NHPs, especially not with studies that purposely inflict pain.

Pg 9, lines 40–41: The Committee outlines examples of where efforts are needed in specific

research areas, including infectious diseases and therapies. The Committee do not use this

scientifically collected data to further question the

scientific validity of NHP use. (See comments in our response to section 4.6.2.3)

Pg 10, lines 2–17: The Committee suggest factors

which “determine the timetable for complete replacement of NHP use”. Outlined are suggestions

to progress and find solutions to these points (expanded on in section 3.6):

Lines 4-5: Areas of primate use which should be prioritised for replacement must begin with those

Pg 8, lines 25–27 The SCHEER agrees with this

comment and has changed the text in the Opinion to: Notably, substitution of NHPs with rodents or other

laboratory animal species is not replacement as defined by Russell and Burch (1959). However, this

may be ethically desirable if the available evidence indicates that the non-primate species is likely to

suffer less harm.

Pg 8, lines 40–41 The SCHEER does not suggest that this should involve more research using NHP. The

Committee pleas for more efforts to be taken to ensure that pain and distress experienced by NHPs is

minimised as a step towards implementing the necessary refinements.

Pg 9, lines 40–41 It is correct that in the summary, issues are somewhat briefly described without all the

background information, but in section 4.6.23 more details are given.

Pg 10, lines 2–17 Thank you for these suggestions.

They do not answer the question at hand, but are taken into consideration for other parts of the

mandate as outlined below.

Lines 4-5 Thank you for the suggestion, but the

Committee did not intend to give an exhaustive list in


40

models which have reviews and demonstrated a

lack of benefit to human health. Many areas already are referenced in the Preliminary Opinion, including

NHPs in toxicity testing and neuroscience.

Lines 6–7: This rigorous, industry wide process of validation has never been carried out on animal

models. It is poor scientific practice to compare non-animal methods with animal research data,

which is of questionable relevance.

Lines 8-10: Work with regulators must be undertaken to overcome this problem, but this can

be factored into a skeleton timetable and does not

make its establishment prohibitive.

Lines 11–12: Focusing on NHP use as models for potential scenarios, in which their validity is entirely

unquantifiable, may delay the course of development and validation of non-animal methods

that are currently showing to be more human-relevant.

Lines 13–14: The Committee provide no evidence of

systematic reviews to support this suggestion. The only papers in the Scientific Rationale (Pg 32, lines

4–6) which directly discuss biosimilars and the relevance of NHPs, are discussing strategies for

moving away from the use of animals (e.g. van Aerts et al 2014), as does the EU Guidelines which

state that “the conduct of toxicological studies in

this summary and the Committee believes that not

only the developed models are important but also that funding and regulatory harmonisation are key in

the development of the alternatives.

Lines 6–7 Validation of non-animal model is not a process driven by industry: in Europe validation of in

vitro methods is coordinated and carried out by EURL-ECVAM (within the DG-Santè, at the Joint

Research Centre JRC located in Italy at Ispra) and then proposed to OECD for adoption as a test

guideline, accepted at regulatory level. The need for

validation is a long-lasting debate; however, the predictivity of in vitro methods should be evidence-

based and this is the meaning of the validation process; ideally the comparison is with human data

not with animal data.

Lines 8-10 Disagree, accepting that NHP use is still necessary under certain circumstances does not

delay the development of alternatives.

Lines 11–12 Disagree, progress has been made as outlined in the papers and regulatory documents

quoted.

Lines 13–14 Although highlighting the progress

towards an animal-free safety assessment framework, we cannot ignore that there are still

areas for which NHP remain the relevant animal model (e.g. monoclonal antibody product or vaccines

development). This is witnessed also by the recent revision of the ICH guideline S6). The bullet point on

biosimilars has been modified to better taking into

41

NHPs is usually not recommended” (Pg 32, lines 1–

4). In particular, NHP studies “rarely provide useful information if the proposed biosimilar has already

shown a high degree of in vitro similarity”

(Chapman et al 2016).

Lines 15-17: In terms of the general public, this is not the case; with the majority of the public against

the continued use of NHPs in research according to a UK Ipsos MORI poll (2016).

It is disparaging for the Committee to claim that that these factors make it “difficult to predict a

timetable for complete replacement for each of the research areas.” Much of the information provided

throughout the Preliminary Opinion document could

be used to create a skeleton timetable which can be built on as developments are made, timelines

become clearer and barriers overcome.

Pg 10, lines 27–29: The Committee say “use of NHPs remains essential in some areas of biomedical

and biological research and for the safety

account the Guidelines from EMA and FDA.

Lines 15-17 The Committee did not identify a contradiction in the Opinion and statements on public

risk adversity in the UK Ipsos MORI poll of 2016. On page 8 of the Ipsos Mori (2016) survey the


research have shifted little between 2014 and

2016. A majority (65%) say they can accept the use of animals in research as long as it is for medical

purposes and there is no alternative, whilst support for an outright ban on animal research stands at 26

per cent.


the public are less accepting of using animals in all

types of research, and there is a less than majority acceptance of all forms of non-medical chemical

testing

The Opinion recommends ways to advance the 3Rs, acknowledging that one timetable for phasing-out

cannot be given in view of a wide spectrum of positive and negative implications of NHP use. Risk

managers, however, may decide on such a timetable,


Pg 10, lines 27–29 In the Summary no references are given, more details can be found in Section 4 on

Scientific rational.

42

assessment of pharmaceuticals” but fail to present

scientific evidence which support the notion that NHPs are essential for the benefit of humans.

References Chapman K et al (2016) Waiving in vivo studies for

monoclonal antibody biosimilar development: national and global challenges. MAbs, 8(3), 427-

435. Ipsos MORI (2016) Attitudes to animal research in

2016. Department for Business, Energy & Industrial Strategy.

van Aerts LA et al (2014) Biosimilars entering the

clinic without animal studies: a paradigm shift in the European Union. MAbs, 6(5), 1155-1162.

174. Borra, Elena,

University of Parma - Italy

Expert Group

for NHP Neuroscience

Research, elena.borra@

unipr.it, Italy

SUMMARY Summary. Paragraph 6, page 10 lines 32-36 (and in

other parts of the document) NHP research could be “forced” outside of Europe

because of a too much restrictive legislation. The

report should stress that this phenomenon is somehow already happening (see, e.g., Capogrosso

et al. 2016 Nature 539:284-288). As noted in the Opinion, this process would likely result in a

decrease in animal welfare. Accordingly, it is plausible that more stressed animals could give less

reliable data. Furthermore, in countries in which there is a lower standard of animal welfare, there

could be also lower standards of human working

conditions, a high pressure for a high publication rate and excessive competition, all factors which

could seriously affect not only the quality of the science, but also the quality of life of people. It

Your support for our analysis with regard to NHP-

research outside Europe is acknowledged. The influence on data reliability has been made more

explicit in sections 3 and 4.4. It is not clear what

Capogrosso et al. 2016 contributes to this issue.

43

might be worth stressing this aspects as well.

175. Brooks, Janet,

[email protected],

United Kingdom

SUMMARY A timetable for replacement is essential. Replaced

not by other animals. Not meaningful to implicate unsubstantiated similarities between human and

animal.


176. No agreement


SUMMARY Page 7 Line 12-15

• (12)Why are we not referencing any polls in which the general public also expects a higher degree of

safety with pharmaceuticals? There is a paradox here that has to be acknowledged when these kind

of public opinion polls are done separately.

• (13)This is a generalized statement. Are there

validated public opinion polls that support this statement or is this really what a small vocal

minority says? A small vocal minority can have lots of influence in "shaping the perception" of public

opinion.

• (14) No one would argue with but what is meant

by "harmed"? We are not aware of any mistreatment of animals in accredited research

institutions.

• This document seems to let public sentiment and

activism drive the debate rather than scientific merit. A number of the ideas will actually hurt

development of new medicines as opposed to

helping the cause of the patient.

Page 7 Line 18-19

• This doesn't make much sense since we cannot conduct human clinical trials without generating

animal safety data first and there are no validated "ex vivo organs" to replace NHPs.

(12 + 13) The SCHEER Opinions only rely on scientific sound studies (polls), and could not identify

such kind of poll focussing on safety of pharmaceuticals.

Validated ‘polls can be found on p22, line 21

and the UK MORI survey (2O16) has been added.

(14) The SCHEER does not intend to question any

research institution. The use of ‘harm’ is considered to be correct as it pertains to NHP in research,

meaning 'causing injury'. This is the term used in the Directive.

The SCHEER does not agree that the content of the

Opinion is driven by specific opinion makers (stakeholders). The Committee did consult different

opinions and based the recommendations on

scientific research. A public consultation and a public hearing were included in the process.

Page 7 Line 18-19

The SCHEER agrees that clinical trials can only be conducting after pre-clinical tests - this is currently

the only legal way that is permissible in Europe. More details can be found in section 4.6.2. on p 30, lines

44

Page 7 Line 24-25

• But, to date, there are no replacement assays that

are more scientifically valid. So, how can we say this? This is really theoretical. Although the word

"may" is included, I believe the current state of the science should be articulated more clearly and

fairly.

Page 7 Line 26 • Economic benefits for whom? The use of NHP's in

a disciplined manner is mandated by an interest in

human safety. This statement needs to be balanced by the economic and public health impact if do not

assess non-clinical safety in the appropriate species.

Page 8 Line 4 • This number needs to be put in some perspective.

For example, what are the numbers of other species

used in animal testing and what is the overall percentage of NHPs? How is this number changing

over time? If the percentage of NHPs used in biomedical research is relatively small and is not

increasing, is there really a problem?

Page 8 Line 9 • This is true, but does not reflect the whole story.

In many cases NHPs are the only relevant species to ensure safety of pharmaceuticals prior to human

testing. It's not just about following rules - it's

1-6

Page 7, Line 24-25

The SCHEER would like to remind the commenter

that not only does this Opinion describe the current state of science but it also intends to highlight the

‘desired’ ways to go forward within this context. Therefore some issues are indeed rather theoretical.

Page 7, Line 26 The line states: ‘Reduction of animal numbers has

clear economic benefit’. It is logical to reason that

the lower number of animals used, the lower the cost.

Elsewhere in the paragraph other important matters such as validity and reproducibility are indeed taken

up.

Page 8 Line 4 Additional data as well as statistical analysis on the

use of NHPs like breakdowns e.g. by primary

purposes, specific research area or severity of treatment vary among the Member State reports. In

addition, 2014 was the first year for reporting under a new format. Therefore no further statistics could be

carried out by the SCHEER to provide additional reliable information or trends regarding the use of

NHPs. A collation of the Member State reports on NHP use including comments on comprehensiveness

of the reporting and the quality of the statistics that

were published by Taylor and Rego (2016).

Page 8 Line 9 The sentence has been revised as follows:

Currently, NHPs are predominantly used in the following areas a) development and safety testing of

pharmaceuticals and medical devices, b) treatment

45

about protecting clinical trial subjects and patients!

Page 8 Line 18-23

• All of this is already being done in pharmaceutical

research. That should be clearly acknowledged.

Page 9 Line 1-3 • This is very hypothetical and there is no

widespread regulatory acceptance to such strategies. So we need to caveat this expectation

appropriately.

Page 9 Line 6-7

• This idea should be balanced against the time required to bring new drugs to market. Not every or

most NCE's are amenable to this approach. Balance this view against the impact to patients who are

waiting for new drugs.

Page 9 Line 21-22 • Why is this so urgent? This seems to be an

emotional statement. As per comments on, if NHPs

are being used only when necessary, are maintained and cared for in strict adherence with

animal welfare standards, represent only a small percentage of animals used in testing, their

numbers are not increasing, and there is a greater emphasis to ensure human safety, there does not

seem to be any urgency to make radical policy

and prevention of infectious diseases, c)

neuroscience, d) ophthalmology and e) (xeno)transplantation. The first three categories

comprise the majority of NHPs used.

While NHP are often the species of choice, their use

also meets regulatory requirements.

The numbers of other species are of no value for this Opinion.

Page 8, Line 18-23

See Section 6.6.2

Page 9, Line 1-3 This is a correct remark; the Committee never states

that this is not the case.

Page 9, Line 6-7

The SCHEER agrees that these points are opportunities to reduce (and thus hypothetical) and

not necessarily general accepted techniques.

Page 9, Line 21-22 Disagree; there is Regulatory acceptance of such

strategies throughout the EU and among ICH

members.

Disagree, the development of most NCE programmes could benefit from the use of exploratory clinical

trials.

46

changes regarding the use NHPs in biomedical

research.

Page 9 Line 23-24

• Where is the scientific evidence to support this statement? I think the scientific/medical community

should evaluate of whether there are certain models or situations where NHPs have not contributed to

scientific knowledge or human safety. They will be the first to challenge the value of these tests.

Page 9 Line 26

• Unclear. There are many situations where studies

in NHPs are considered proprietary/competitive information (safety testing for pharmaceuticals).

Page 9 Line 23-24

It is generally agreed that there is an urgent need to replace all animal models, including NHPs, to

improve scientific procedures.

Page 9 Line 26

This report was written by scientists who have

evaluated these scenarios.

Even if the data are proprietary/competitive, it does not preclude knowledge transfer, where appropriate,

or harmonised training courses.

177. Fentener van Vlissingen,

Martje, ECLAM,

[email protected],

Other, ECLAM

is a Europe wide college

of veterinary specialiasts in

laboratory animal

medicine

SUMMARY Lines 12 – 18 are in need of references. The ethical dilemma is well recognized, also among

professionals. However, ethical dilemmas need to be addressed by qualified ethical review procedures

taking into account all relevant aspects.

Lines 19 – 24 discuss the Directive in general terms

but should also refer to the further restrictions on the use of NHP in the Directive already in place

(limitation of purposes, requirement of retrospective reporting, safeguard clauses, et cetera). That is

specified on Page 12 lines 24 – 41 but should be mentioned here briefly.

Lines 35 – 39: this is a good ambition but third

countries may not be responsive to our concerns.

The ‘solution’ offered is by no means an assurance.

There is a realistic risk that in the future medical needs in Europe will be met by outcomes of

Lines 12 – 18 On page 7, only a summary is found (without references). On page 22 (scientific

rationale) more details and references can be found on this issue.

Lines 19 – 24 It is true that many issues in the

summary can be explained more in depth, but the point of the summary is to provide an abbreviated

form of the full text. The Committee believes that the scientific rational contains the necessary additional

considerations.

Lines 35 – 39: This is correct. It is not claimed by the

Committee that this is an assurance.

Indeed and this has been addressed explicitly in sections 3.1 and 4.4.

47

research that we would consider to be conducted in

a less ethical way. That, too, is a very serious ethical dilemma.

Line 46: the restrictions to the purposes of use of NHPs precludes the proper training of personnel in

some countries (also depending on how the Directive was implemented).

P. 8 line one: see comment on the abstract

regarding ‘removal of research needs’.

P. 8 lines 4 – 10: the raw data will also show that

there was no increase in the numbers of animals used. Please specify and explain how the figures

compare. (could also be done on Page 12, lines 2 -5).

P.8 lines 11 – 20 should not state the ‘replacement’ of NHP by other animal species but ‘substitution’.

Replacement by the use of human subjects would be considered real replacement but the use of other

animal species not.

P8 line 28 – 30: research in other animal species is indispensable in most influenza research.

Line 46: This is correct and addressed in section 4.5, page 27, lines 28-42.

P. 8 line one: This text has been adapted.

P. 8 lines 4 – 10:

More information is given under 4.6.1. Additional data as well as statistical analysis on the use of NHPs

like breakdowns e.g. by primary purposes, specific research area or severity of treatment vary among

the Member State reports. In addition, 2014 was the first year for reporting under a new format. Therefore

no further statistics could be carried out by the SCHEER to provide additional reliable information or

to present trends regarding the use of NHPs.

P.8 lines 11 – 20: The SCHEER agrees with this comment and has changed the text in the Opinion to:

Notably, substitution of NHPs with rodents or other laboratory animal species is not replacement as

defined by Russell and Burch (1959). However, this may be ethically desirable if the available evidence

indicates that the non-primate species is likely to

suffer less harm.

P8 line 28 – 30: Agreed, but this part addresses potential replacement strategies to limit or prevent

the use of NHP. The Opinion does not state that at the moment animal research, including NHP, is no

longer needed in studies regarding those pathogens.

48

P8 line 31 – 32: fMRI has different scientific

outcomes (perfusion rather than neuronal features)

and a much lesser resolution.

P8 line 33 – 34: this suggests that there is a reality of NHP to be considered as prospective organ

donors in medicine, although this is not the case. This makes the statement into an orphan solution

(what problem is to be solved here?).

Transplantation studies in NHP may also require NHP donor materials/organs for scientific reasons.

P9, line 1 suggests that NHP are actually used for

testing chemicals but is that substantiated by the statistical reports? There’s probably only preclinical

drug testing (efficacy and safety). This is also how the text following is focused and elaborates. So

please remove chemicals or address that in an

explanation.

P9, lines 21 – 24 would apply to areas where there is a large body of literature, e.g. where there are

both multiple studies on preclinical evaluation and multiple clinical trials. Hence, expectations should

be managed regarding how these high-level literature based studies would be useful, and their

limitations as well.

P10, lines 18 – 19: ‘substitution’ by other animal

models to be included.

P10, lines 32 – 34: grammar, this should be one sentence.

This is elaborated upon in 4.6.3.

P8 line 31 – 32: The text has been modified to clarify

as follows (p. 8, l. 33-34): “The potential to use new,

high spatial and temporal resolution imaging techniques in humans to replace some cognitive

neuroscience experiments performed in NHPs.”

P8 line 33 – 34: Disagree, the report clearly states that NHP are not considered acceptable as organ

donors.

P9, line 1 The report is not intended to imply that

NHPs are used to test chemicals. This statement is intended to explain that non-animal techniques are

used and this should ultimately lead to a reduction in NHP use.

P9, lines 21 – 24 Agreed. No revision to document required

P10, lines 18 – 19: The focus of this question is on

complete replacement by alternative methods.

P10, lines 32 – 34: The sentence has been revised in the text: Since animal welfare standards for

laboratory NHPs are on average higher in many

49

European countries than in other parts of the world,

it follows that if NHP research is forced outside of Europe there would likely be a net decrease in animal

welfare.

178. Kenna, Gerry, Safer

Medicines

Trust, Gerry@SaferM

edicines.org, United

Kingdom

SUMMARY Page 7, lines 3-5 The second sentence of the Summary does not

encapsulate accurately the conditions that must be

met by scientists who are considering undertaking animal procedures. These are: that animal

procedures are unjustified unless they can be shown to yield valuable data on diseases and /or safety

that cannot be generated in other ways; that procedures on NHPs must not be undertaken unless

they yield valuable data that cannot be obtained using less sentient animal species (e.g. rodents);

and that all animal procedures must be undertaken

in full accordance with the 3Rs principles set out by Russell and Burch.

An important consequence of this omission is that

the Preliminary Opinion has failed to highlight the need to consider the benefit (or not) of NHP data

when considering whether experimental procedures on NHPs are justified. When no clear benefit can be

expected, following a thorough and objective

evidence-based review and consideration of all the available evidence, an experimental procedure

involving NHPs is unjustified and should not be performed.

Instead, the Opinion has started from a deeply

flawed assumption (Page 7, lines 10-11) that: “NHPs are considered the best available animal

models for addressing particular research questions

because of the close phylogenetic relationship with humans.” This statement fails to take account of the

abundant data demonstrating the lack of relevance of NHP data to many human biological processes,

Page 7, lines 3-5

Clarifications are given in Section 4.

Considering the EU Animal Welfare policy in general

as well as the EU Directive 2010/63/EU on animal use for testing, whenever any animal testing has to

be conducted should be undertaken in full accordance with the 3R principals on the basis of

which an authorisation is released. Therefore there is

no omission on the points made by the commenter. In addition, the Opinion highlights all the progress

towards an animal-free safety assessment framework, but for the time being we cannot ignore

that there are still areas for which NHP remain a relevant animal model (e.g. monoclonal antibody

product or vaccines development). This is evidenced also by the recent revision of the ICH guideline S6).

Denying it will not produce a quicker phase out.



50

diseases and toxicities.

The error is especially surprising since the text of

the Opinion summarises many examples of lack of

human relevance of NHP data. These include human idiosyncratic adverse drug reactions, immune

responses, retinal biology and many neurodegenerative diseases. The Opinion also sets

out clearly why NHPs are an unsuitable source of tissues for xenotransplantation to humans.

Therefore the first part of the Summary should be

re-drafted to set out explicitly and clearly all of the

aspects that need to be considered before experimental procedures on NHPs are undertaken.

Since it is inappropriate to make the default assumption that NHPs are the best available animal

models for addressing particular research questions, for the reasons set out above, this flawed

assumption must be challenged and discarded.

Furthermore, we recommend that the Opinion

should be re-drafted to distinguish clearly between NHP data types which are considered relevant to

humans (e.g. specific disease models, such as for Graves’ disease, mentioned on Page 33, lines 17-

18); NHP data types where relevance to humans is unclear or has not been adequately established

(e.g. chemical toxicities not directly attributable to primary pharmacology); and NHP data not

considered relevant to humans (e.g. idiosyncratic

human adverse reactions).

We consider that these alterations will directly benefit scientists in academia and industry wishing

to select and use appropriate research models. They should also help to identify areas of research where

new and improved models of human disease and

whenever the NHP non-reactivity can be

demonstrated in vitro (indicating NHP are not a suitable animal model).

There is no contradiction in honestly presenting the

lack of human relevance for some cases, since the sentence ‘NHPs are considered the best available

animal models’ is related to ‘particular research questions’, and is not a general statement.

The SCHEER's opinion, as presented in the preliminary document, is that the use of an

appropriate species or combination of species/models is essential to obtaining the most reliable and

translatable information.

Clarifications are given in Section 4.

The Opinion discusses the relevance of NHP-models

in several sections. In many cases, the distinction asked for is impossible to make.

51

human toxicity are most urgently needed, and

enable funding agencies to make best use of their scarce resources. Since up to 85% of research

investment is wasted, through irreproducibility of

preclinical findings and the inexcusable failure to conduct systematic assessment of previous

research, it is imperative to improve translation to the clinic, through evidence-based identification and

use of the most human-relevant preclinical models.

179. The British Toxicology

Society, secretariat@t

hebts.org, United

Kingdom

SUMMARY The British Toxicology Society (BTS) is a learned society based in the UK, but with an international

membership. The BTS is a society for all fields of professional toxicologists and all with an interest in

toxicology. The membership includes those working in industry, in academia and in Governmental

Institutions.

Many BTS members work directly in safety assessment, including appropriate use of non-

human primates (NHPs). This is particularly the case in the several large contract research

organisations in the UK.

We note from the SCHEER Opinion that 56% of all NHP use in the EU was for the purposes of

toxicological and other safety evaluation. As that is

the special expertise of the BTS, our comments focus on that in particular. In the safety

assessment/toxicology field, use of NHPs is focused on the development of human medicines and

treatments.

The BTS welcomes the SCHEER opinion. We find it to be well written, evidence based and factual in its

descriptions of current practice.

In particular we welcome and agree with the

following points:

Thank you for your support of the SCHEER preliminary Opinion.

52

1. The need to continue to develop and assess

strategies and techniques in developing the 3Rs. 2. The adoption of the highest standards of NHP

housing and husbandry.

3. International cooperation that ensures that points 1 and 2 are global in nature to ensure a level

playing field. Many BTS members work for institutions that have facilities in Europe, North

America and Asia. Differing standards are problematic.

4. The continuation of the development of strategies to avoid the use of NHPs wherever possible. These,

however do need to be evidence based and with

patient safety at their heart. The use of cross reactivity studies prior to NHP toxicology work is a

good example of evidence based decision trees. Other, more novel technologies are constantly being

brought forward. 5. We agree that a key determinant of the timetable

for complete replacement of NHP use is the pace of regulatory validation and acceptance of alternative

test models. Rigour is clearly important but

progress is too slow. We need a new paradigm to accelerate the development of guidelines via the

OECD and ICH 6. We agree that at present it is not possible to

develop a timetable for the phasing out of the use of NHPs in biomedical research.

7. We agree that the availability of funding and resources for developing alternatives to NHP use is

critical. We point to the excellent work of the NC3Rs

over the past decade which is extensively cited in the report. BTS members have been involved in

every NC3Rs paper cited and we work extremely closely with them. We note that the NC3Rs is due to

have its funding reduced from 2018/2019. We believe it is critical for national and trans-national

funding within the EU to be directed to support the

53

work that is undertaken by organisations such as

NC3Rs. 8. We fully agree with this key statement:

“Therefore there is consensus within certain

sections of the scientific community that, where alternatives do not exist, appropriate use of NHPs

remains essential in some areas of biomedical and biological research and for the safety assessment of

pharmaceuticals. As long as sufficiently validated alternatives are not available, a total ban would

make further progress in such research and some safety studies impossible, at least in Europe.”

180. Baines, Julia,

People for the Ethical

Treatment of

Animals UK, [email protected]

rg.uk, United Kingdom

SUMMARY p.8, lines 25-27: It is incorrect to consider a second

rodent species as a replacement option for studies on NHPs. Replacement under the 3Rs principle is

defined as methods which avoid or replace the use

of animals. Use of a second rodent species instead of using NHPs is a substitution of one method for

another, not replacement and should be defined as such to avoid confusion.

p.10, lines 8-10: Lack of regulatory and guideline harmonisation should not be considered a barrier to

implementing a schedule for phasing out primate

use.

p.10, line 11: “New demands for NHP use in science, such as emergence and re-emergence of

infectious diseases where NHPs are the only relevant model” should be changed to “New

demands for NHP use in science, such as emergence and re-emergence of infectious diseases

where NHPs are considered to be the most relevant

model”. NHPs are not humans and minor differences can lead to broad function disparities, thus varying

physiological and functional outcomes. Therefore, NHPs cannot ever be considered a “relevant model”.

p.8, lines 25-27: The SCHEER agrees with this

comment and has changed the text in the Opinion to: Notably, substitution of NHPs with rodents or other

laboratory animal species is not replacement as


indicates that the non-primate species is likely to suffer less harm.

p.10, lines 8-10: Lack of harmonisation may imply slower implementation of alternatives.

p.10, line 11: SCHEER agrees with the comment before the last

sentence. In line with the Opinion, NHPs should be only used when there are no alternatives and when

they are demonstrated to be the only suitable animal model. The suggestion for change of text has been

included.

54

p.10, lines 15-16: “The risk aversive nature of society makes it difficult to move away from familiar

methods to new alternative methods where there is

less historical data to fall back on.” What is the evidence for this? A recent survey from PETA

France, PETA Germany, PETA Netherlands and PETA UK shows that over 160,000 people advocate for

the end of experiments using NHPs (http://www.peta.org.uk/blog/protesters-take-

wounded-tormented-monkey-european-commission/). Likewise, through a European

citizens’ initiative, more than 1.2 million

compassionate Europeans called for an end to animal experimentation. By signing petitions such

as these, it is clear that the public have demanded change - a move away from weak, invalid science

and towards innovative, humane science that really works.

p.10, lines 20-40: Section 6 of the summary argues

that a ban on using primates would result in a

negative impact on animal welfare, research quality, public health, access to treatments and local

economy due to research being pushed abroad. However, where tests on animals have been banned

principally for ethical reasons and significant funding made available for developing alternative

methods, a positive impact has been seen in relation to research on alternative methods. One

strategy for phasing out tests on animals is the

approach adopted by the Cosmetics Regulation (EC No. 1223/2009) which prohibits certain tests on

animals after specified cut-off dates. An impact assessment conducted by the European Commission

on the cosmetics animal testing ban stated that “[t]he provisions [of the animal testing ban] are

generally seen as a crucial accelerator of research

p.10, lines 15-16: The SCHEER recognises the power of the petition and the committee recognises polls

showing the public opinion on this (see remark 176).

The general risk adversity in EU is described in http://spire.sciencespo.fr/hdl:/2441/5konp4tce4se7d

09j4d3m31jh/resources/eerr-154-zaki-laidi.pdf

p.10, lines 20-40: This issue is discussed in Section

3 and 4.4, including the possible application of global

animal welfare policies and improvement of conditions abroad to bring research practices in line

with European standards.

55

and validation of alternative methods by all

stakeholders.”1 The assessment report went on to state that “[m]aintaining the deadline is expected

by many to lead to a continuation or even

acceleration of these developments” and the animal testing ban deadline to be imposed without

validated alternative methods for all human health endpoints was not considered a risk to consumer

safety. The cosmetics ban led to a boom in investment in the development of non-animal

methods; a similar ban on the use of primates would see the development of more humane,

human- and environment-relevant alternatives that

would better protect human health and the environment. In its current form Directive

2010/63/EU has led to little innovation with regard to the development of alternatives to testing on

animals.

Reference: European Commission 2013

The availability of alternatives is an important factor

in the determination of a phasing-out timetable as recognised in Section 3.6. Indeed, a ban may lead to

acceleration in the investment into the development of alternative methods as seen for cosmetics (EC,

2016). However, the issues here are more complex and the risk-benefit assessment may turn out

differently. This should be recognised as a potential impact by the SCHEER and therefore the text of

section 3.7 was adapted.

181. Campos, Cheryl, Adi,

[email protected]

m, Other,

South africa

SUMMARY Barbaric useless inhumane Stop experiments on primates

Only sub humans and monsters can carry out these atrocities and they hide behind the dubious curtain

of scientific research

The commenter does not provide any suggestions for improvements of the scientific basis of the SCHEER

preliminary Opinion and/or any scientific evidence.

182. Bailey, Jarrod,

Cruelty Free

International, Jarrod.bailey

@crueltyfreeinternational.or

g, United Kingdom

SUMMARY P7 L10

This should state, “The SCHEER WG considers NHPs

to be the best…” Opinions should be identified as such; we refer to

SCHER’s previous report (copied in P14, L6 of this report) where they say ‘considered’. NB: only some

sections of the scientific community believe this.

P7 L15 Opinion polls are misrepresented here, and not

reflective of what the report states (see P22 L19).

This sentence should be reiterated here. E.g. the

P7 L10 SCHEER acknowledges that not everyone

considers NHP to be the best animal model.

P7 L15 The Committee agrees that polls are easily misinterpreted. On page 8 of the Ipsos Mori (2016)

survey the following key findings are noted:

Public attitudes towards the use of animals in

56

referenced UK MORI poll (Clemence and Leaman

2016) found only 16% of respondents supported the use of macaques for, and 56% of Europeans

agreed that scientists should not experiment on

larger animals like dogs and monkeys (TNS Opinion & Social (2010). Special Eurobarometer 340

“Science and Technology” (Wave 73.1). Available: https://open-data.europa.eu/data/

dataset/S806_73_1_EBS340).

P7 L24 Applying the 3Rs also has ethical merit.

P7 L36 Where is the evidence for better welfare in

the EU? Even if so, to what degree, and what is the evidence?

P8 L4-10

Clarify: procedures or animals?

P8 L24

Could the WG strengthen and formalise these?

P9 L21 We fully agree, and hope that this will be

one of the salient recommendations. Given the

accepted urgent need for these to inform the debate, this statement should be qualified as to the

limited value the Opinion could have in their absence.

P9 L34 Insight is also needed into how much evidential weight NHP tests provide to human

risk/safety.

research have shifted little between 2014 and 2016.

A majority (65%) say they can accept the use of animals in research as long as it is for medical

purposes and there is no alternative, whilst support

for an outright ban on animal research stands at 26 per cent.


the public are less accepting of using animals in all types of research, and there is a less than majority

acceptance of all forms of non-medical chemical testing.

P7 L24 The SCHEER thanks the commenter for the comment.

P7 L36 The evidence is based on the stricter legal

requirements. It is correct that in the context of less strict requirements the welfare is better, but it is

more likely that it would be worse.

P8 L4-10 The Opinion has been changed accordingly.

P8 L24 These points are summarised in the summary

but are presented in section 5 in greater detail.

P9 L21 No reply needed.

P9 L34 The Opinion highlights all the progress towards an animal-free safety assessment

framework, but for the time being we cannot ignore

57

P9 L44 Future funding of these experiments also

needs to be more critical. Do they need to be conducted? How much human benefit is derived?

Could the same general information be derived from human investigations? Refinement is too little, and

accepts the necessity of these experiments, which

has not been proven.

that there are still areas for which NHP remain a

relevant animal model (e.g. monoclonal antibody product or vaccines development). Denying it will not

produce a quicker phase out.



whenever the NHP non-reactivity can be demonstrated in vitro (indicating NHP are not a

suitable animal model). As already stated, the SCHEER's opinion is that the use of an appropriate

species or combination of species/models is essential

to obtaining the most reliable and translatable information.

P9 L44 The commenter questions the necessity to

fund experiments that validate alternative methods where NHPs can be replaced. Validating a method

often requires an invasive procedure and/or an autopsy to prove what the indirect measurement is

measuring. This information cannot be collected from

human studies for obvious ethical reasons and although some animals might be required for the

validation step, the purpose is to replace their use and reduce the number of animals in the future

thanks to these new alternative methods. It would be contradictory to underline the necessity to replace

NHPs and not appropriately fund the development of alternative methods and new technologies. As

regards the criteria of funding, the Opinion

repeatedly states the need for appropriate review of the pertinence, necessity and quality of experiments

before allocating funding (see section 4.6.5.3 or 5.1.2.1 or 5.3). These criteria refer to all research

requiring the use of NHPs, including the validation of alternative methods.

58

P10 L2 A timetable for replacement should be

primarily driven by establishing the necessity and value of the NHP experiments. All other factors

must be secondary.

P10 L8 It is not clear what ‘harmonisation across

sectors’ is referring to. NHPs are only used for safety testing in one sector (human medicines)!

P10 L15 We agree. However, this should not inhibit

attempts to do so. Efforts should be actively made,

and could be expedited if area-specific.

P 10 L 18 See comment on P2 L13 A timetable is possible, we believe, given current knowledge.

However, there is no reason not to propose a timetable of desired, non-binding outcomes and

progress points, which would be helpful in driving the desired move away from NHP use to the greater

adoption of alternatives.

P10 L25 Phylogeny is not sufficient to support this

unreferenced opinion. It should be stated as opinion, and referenced if possible.

P10 L27 This is too general. Where do alternatives

not exist? We believe they always exist. If ‘certain sections of the scientific community’ believe there

are not alternatives to some NHP uses, they should

provide evidence, which should be assessed critically. If there were areas where NHPs are

‘better’ than alternatives, this must be proven.

P10 L2 The Opinion recommends how to advance

3Rs, acknowledging that one timetable for phasing-out cannot be given in view of a wide spectrum of

positive and negative incentives for NHP use, all

potentially influencing the establishment of the necessity and value of NHP experiments.

P10 L8: Sectors refer to the different research areas

within human medicine.

P10 L15 The SCHEER agrees with this comment.

P10 L18: The Opinion recommends how to advance 3Rs, acknowledging that one timetable for phasing-

out cannot be given in view of a wide spectrum of positive and negative incentives for NHP use. Risk

managers, however, may decide on such a timetable, but this is outside the mandate of the SCHEER.

P10 L25 In the Summary, no references are given,

more details can be found in Section 4 Scientific rational.

P10 L27: The SCHEER does not think that there are

alternatives for all research areas. In member states, research workers who propose using non-human

primates are already required to justify the use of

this species, demonstrate that no alternatives are available, nor that other species could be used

instead of non-human primates. These applications are subjected to critical evaluation as part of the

authorisation process for projects carried out by member states

59

P10 L30 In determining if alternatives are

‘sufficiently validated’, the WG must be cognisant that NHP-based approaches have never undergone

validation. There is no evidence to support the

statement “…a total ban would make further progress in such research and some safety studies

impossible…” Evidence should be provided, and critiqued, if this is to be asserted.

P10 L33 Where is the evidence for these effects?

We argue the welfare of NHPs in labs is poor in the EU, much research quality is also poor, and that

there is no evidence that public health would suffer.

P10 L37 We believe a ban is feasible, so this is

opinion. Complete honesty and transparency must be assured, and selective PR guarded against.

P10 L30 The need for validation is a long-lasting

debate; however, the predictivity of in vitro or in silico methods should be evidence-based and this is

the meaning of the validation process. Animal data

did not undergo validation in the past but the safety assessment based on animal models has been

proven to be fit-for-purpose over time (with few exceptions).

P10 L33 Evidence for this statement in the summary

is explained in section 4.4, last paragraph.

P10 L37: SCHEER has included justification within the

Opinion for not providing a timetable for a ban. Belief that a ban is feasible is also an opinion, and is one

that is contrary to that reached by the SCHEER after careful consideration of the available evidence

183. No agreement


SUMMARY p 7 - lines 11-15

The report summary states that NHP represents a serious ethical dilemma.

Different polls shows that the use of large animals represents a serious ethical dilemma, not only NHP

use. The report seems to focus only on aspects

concerning NHP which overemphasises the dilemma. (see Mori Ipsos 2014 - table 2.1 p 17 -

partial upload file do to size limitation // Eurobarometer 340 2010 - p60



research have shifted little between 2014 and 2016. A majority (65%) say they can accept the use of

animals in research as long as it is for medical

purposes and there is no alternative, whilst support for an outright ban on animal research stands at 26

percent.


the public are less accepting of using animals in all types of research, and there is a less than majority

acceptance of all forms of non-medical chemical

testing

60

184. 't Hart, Bert

A., Biomedical Primate

Research

Centre, Rijswijk, The

Netherlands, [email protected],

Netherlands

3 OPINION

Opinion.pdf

Page 14 line 13-16:

It seems a remarkable statement that because of the close phylogenetic relationship with humans the

acceptance of pain and stress is more debatable for

NHP than for other animal species. This is a rather dubious anthropocentric statement that does not do

justice to the inherent quality of all living creatures. In the same line of reasoning it is stated at page 22

line 17/16 that the usage of animals in research is an ethical dilemma, because animals cannot

consent and do not benefit themselves from the results of research. It would be an interesting

experiment to apply this reasoning to the food

industry. Consumption animals cannot consent to their fate in life as meat producers and they also do

not benefit from this role; at least I do not see any benefit for them. So, why is this dilemma

exclusively pertinent for animal usage in biomedical research?

Page 19 line 2-7:

the statements given here assumes that in research

the likelihood of scientific, medical, and social benefit can be predicted. The essence of scientific

research is that the outcome is uncertain.

Page 19 line 14-15:

what is the criterion for suitability? The successful usage of NHP in preclinical research is based on a

solid body of scientific knowledge, for example of

the immune system. This requires research into the fundamental principles of the NHP immune system.

Page 14 line 13-16:

The SCHEER agrees that this is rather anthropocentric but we cannot escape from the fact

that similarity between humans and NHP has two sides: one making them good models, but it also

creates a different acceptance to use (as shown in many polls).

The current Opinion only looks into animals used in

research and the Committee did not consider animals in food production. This is outside the scope of this

opinion.

Page 19 line 2-7:

The SCHEER agrees that the outcome of scientist research is uncertain – as far the research hypothesis

will be proven or disproven. But having said this, the research question needs to be reasonable and the

techniques applied should be well considered.

Page 19 line 14-15:

This is just a suggestion to research funders.


61

Acceptance of this line of research is exceedingly

difficult, because fundamental immunological research can also be done in mice.

185. Rushworth,

Matthew, FENS -

Federation of

European Neuroscience

Societies, [email protected]

, Belgium,

3 OPINION

Scientific_Committee_on_Health_Environmental_and_Emerging_Risks_FENS_letter.pdf

As this is the same letter as submitted for comment

7, please see the reply to comment 7.


Humane Society


.org, United

Kingdom

3 OPINION 3.3 Neuroscience Page 16, line 40.

One of the reasons for continued use of NHP in neuroscience is given as “The absence of a blood-

brain-barrier, a vascular system and an immune system…” but this appears to assume a like-for-like

replacement. We agree with earlier comments that

it is unlikely that a single in vitro test will be able to fully replace animals, but we feel that the use of an

IATA approach, bolting together several in vitro/in silico/ex vivo methods, would be more relevant. For

example, there are established methods that may be used to produce a human blood brain barrier,

with human endothelial cells, pericytes and astrocytes [Hatherell et al. 2011] or using human

iPSC [Yamanizu et al. 2017]. The functionality of

such models have been further exploited to examine drug delivery to the brain [Toman et al.

2014]. Inclusion of the vasculature is now possible with advances in microfluidics (e.g. Phan et al

2017) that permit cellular flow and fluid movement under the same shear forces as those experienced

in the human brain. In addition, novel flow cytometry-based approaches to leukocyte adhesion

assays allow simultaneous assessment of cellular

movement and tight junction protein expression in

This relates to regulatory acceptance of in vitro (tissue engineering) solutions to replacement of

NHPs – it is not clear what the comment is suggestion should be replaced, but modelling drug

delivery to the CNS using this approach might eventually be possible but I cannot see this occurring

in the immediate future, given the relative early

stage of development of these alternative approaches.


62

both normal and pathological states [Williams et al.

2016]. These assays could also be used to model the immune system responses and in addition, PET

imaging of human volunteers has been used to

show brain immune function [Kanegawa et al. 2015]. These assays have yet to be validated for

regulatory purposes, but we feel that these advances in methodology for basic research are

applicable in replacing NHP in these fields.

187. Marshall,

Lindsay, Humane


lmarshall@hsi


3 OPINION Page 16 Line 43

The use of NHP for ophthalmology research detailed in this Opinion is a concern since this field of

research was not discussed in earlier versions of the opinion and suggests an emerging use of NHP,

when attention would be better focused on

replacement, in line with recital 49 of the Directive "Such review should examine the possible

replacement of the use of animals, and in particular non-human primates, as a matter of priority where

it is possible, taking into account the advancement of science…" There are new methods employing

patient-derived iPSC that may prove to be more relevant than NHP - these have been used to define

protein defects in macular degeneration and could

be effectively employed to examine different therapeutic strategies [Singh et al 2015]

The Opinion focuses on major areas of NHP use but

does acknowledge that this simplification might oversee other areas of research where this species is

used. Ethically, their welfare should be monitored in all areas of research, regardless of whether they are

specifically mentioned in the Opinion. Ophthalmology

was not previously mentioned in the Opinion but emerging areas of research must be included if this

increases the numbers of NHP used. The sections on ophthalmology however insist on the value of in vitro

and in silico methods and the potential for replacement (see section 4.6.5.1) in agreement with

the reader. The suggested reference has now been added to the text (see section 3.3). However, it is

interesting to note that this paper made use of an

animal model (canine) to validate the therapeutic strategy discovered in vitro and found promising

results. The differences observed in serum that the authors explain as a limitation of the dog model can

also be interpreted as a physiological outcome of a therapeutic approach that must not be overseen as it

could have the same effect, and therefore therapeutic limitation, in patients. This indeed points

to the fundamental difference of exploring molecular

reactions in vitro in the absence of an immune system and a vascular system, in other words, in a

non-physiological context.

63

188. Marshall,

Lindsay, Humane

Society



3 OPINION Section 3 Opinion: Other uses:

(Xeno)transplantation Page 17 Lines 16-18

It is welcome to see that NHP are no longer

considered suitable for studies of xenotransplantation (XTP). We would now hope that

this statement is reflected in any and all EU-wide funding calls of relevance to this topic. We would

also envisage that any applications that request the use of NHP in xenotransplantation studies would be

required to submit revised proposals with altered methodology taking this into account.

We believe that XTP is not the best answer to end-

stage organ failure in humans, and that the main issues of nonspecific and toxic immunosuppression

that currently curtail the life of solid organ transplants are not addressed by XTP. New

therapies are more focused on generating tolerance to transplanted organs, in order to enable reduced

immunosuppressive treatment and prolong transplant function and the quality of life for the

recipient. There have been remarkable advances

since the last update of the Opinion and these indicate there is no longer any requirement for NHP

in organ transplantation research. These advances include tissue engineering and regenerative

medicine and the use of haematopoietic stem cells (HSC) to promote engraftment and tolerance. For

example, in 1999, a kidney transplant, accompanied with HSC graft, demonstrated acceptance and

normal organ function 5 years later [Spitzer et al.].

The mechanism behind the tolerance achieved with HSC has yet to be defined, but is likely due to the

contribution of regulatory and suppressor T cells and to some degree of chimerism permitting

acceptance of grafted tissue. Whilst these studies may have originated in animal models, they have

now moved successfully to the clinic and a recent


risk management is outside of the scope of the SCHEER.

64

review of the impact of HSC grafting on kidney

transplants reveals around 80% success, in terms of long term survival after withdrawal of

immunosuppressants [Elahimehr et al. 2016].

Clinical trials are also moving beyond the kidney – the MiSOT I trial is due to end March 2017 and is a

safety and efficacy study for bone marrow stem cell transfusion with liver transplantation. Early data

from this are promising, demonstrating the clinical feasibility of this approach, with no acute toxicity

issues noted [Soeder et al., 2015]. In addition, tissue engineering forges on - with decellularised

scaffolds showing promise in the development of

autologous bioartificial organs [Sanchez et al. 2015].

Under Directive 2010/63 it is required that

alternatives are considered before animal use is authorised and we suggest that now there are

alternatives in the field of organ transplantation, research on xenotransplantation in general, and

xenotransplantation employing NHP specifically,

should be discontinued. Spitzer et al., Transplantation. 1999 Aug

27;68(4):480-4 Sanchez et al., Biomaterials. 2015 Aug;61:279-89

Solder et al., Stem Cells Transl Med. 2015 Aug;4(8):899-904.

Elahimehr et al., Transplant Rev (Orlando). 2016 Oct;30(4):227-34

- pdf files are beyond maximum size to upload


Humane



3 OPINION General issues Page 18 Line 40 We agree that there is an urgent need to conduct

systematic reviews and meta analyses and would

like to see these form part of the time line for phasing out NHP. To be effective, we believe that

the reviews need to be balanced, to take account of negative as well as positive data and be co-

Reviews and meta-analysis are mentioned in the Opinion.

The SCHEER shares the concern on unnecessary use

of NHPs. The Opinion therefore recommends how to advance 3Rs, acknowledging that one timetable for

phasing-out cannot be given in view of a wide spectrum of positive and negative incentives for NHP

65

Kingdom authored by a range of stakeholders so that the

possibility for replacement of NHP is not overlooked.

use. Risk managers, however, may decide on such a

timetable.


Humane Society

International,


Kingdom

3 OPINION Page 19 line 17 We are gratified to see suggestions that changes

may be required in order to effectively evaluate the non-animal alternative potential of projects

proposing to employ NHP. We believe the

Commission should consider establishing an independent cross-sector expert committee on

alternative methods, with the remit of keeping replacements under review and streamlining their

uptake into all relevant EU legal instruments and guidelines. This would help ensure consistency in

risk assessment across sectors, reduce duplication, and prevent the Directive being undermined.


risk management is outside of the scope of the SCHEER.

191. Marshall,

Lindsay, Humane

Society



3 OPINION Section 3 Opinion

Page 19 line 33 Chemical safety testing has seen a revolution in

terms of the replacement of animal tests and we

believe that pharmaceutical and medical device testing can follow the same paradigm shift. The

benefits of a species-specific, AOP-based paradigm is apparent from example of skin sensitisation

[Schultz et al., 2016]. The skin sensitisation AOP was the first to be recognised and formally adopted

by the OECD and its member countries. On the basis of this AOP-driven, mechanistic understanding

of molecular and cellular key events, a series of

targeted assays were developed and validated, and have since been adopted as internationally

harmonised OECD test guidelines. When deployed as part of an integrated approach to testing and

assessment (IATA), the AOP-based non-animal methods have been clearly shown to be more

predictive of allergic skin reactions in human beings (94 per cent accuracy) than conventional animal

tests (83 per cent accuracy) [Bauch et al., 2016]. In

light of their superior predictive value, together with

It is totally true that considerable progress has been made in the development and validation of in vitro

tests and alternative methods in various fields,

especially in areas other than the pharma sector in which non testing methods (e.g. read across) or

some in vitro methods (e.g. OECD test guidelines for phototoxicity, skin corrosion and skin irritation, skin

sensitization using the AOP approach, or skin absorption) are already accepted by regulators..

However, to date, all aspects that must be assessed to ensure the safety of a substance for humans

cannot be evaluated through in vitro/alternative

methods, especially regarding systemic effects after repeated exposure. Regarding kinetic behavior, for

example. although PKPD models, and in vitro comparative metabolism testing in some cases, allow

estimation of the behavior of a substance in the human body (or at least lead to a significant

reduction in the number of animal used), it is not possible to fully avoid studies in animals and

sometimes in Non-Human Primates, if it is the most

representative species, especially for biological

66

the EU policy mandate under Directive 2010/63 to

fully apply the ‘3Rs’ principle whenever alternative approaches are available, these new AOP-based

tests for skin sensitisation have already largely

replaced their now obsolete animal-based counterparts under the EU’s chemicals regulation,

‘REACH’ [ECHA].

We believe that application of this pathways-based approach to biomedical research removes the need

for animal testing in pharmaceutical or device safety testing.

References too large to upload:

OECD. Series on Testing and Assessment No 168: Part 1: Scientific Evidence, 2012:

Bauch et al. Regulat Toxicol Pharmacol. 2012;63:489-504.

European Chemicals Agency. Skin sensitisation: New methods to replace animal testing, 2015.

drugs. More efforts should be devoted to integrate all

the kinetic and the dynamic data. Technological and scientific advances of the in vitro/in silico approaches

have to be highlighted as well as the

complementarity of the different approaches with a major goal to be able to assess the safety of different

substances. One of major objectives is to reduce as much as

possible the use of animals in experimentation especially in NHP and refine experimental protocols

so as to avoid suffering, to carry out only what is necessary and provided really transposable results to

Humans. Today the cursor between “all animal

experiments” and “all in vitro experiments” moves towards in vitro experimentation. All in vitro is not

yet achieved, but the situation is changing, technical and scientific advances are clear.

192. Marshall,

Lindsay, Humane


lmarshall@hsi


3 OPINION Neuroscience

Page 20 Line 14 We disagree that NHP are required in the quest for

better methods to image the brain and would like to refer to the NIH-funded BRAIN initiative

(https://www.braininitiative.nih.gov). This

programme aims to accelerate the development of innovative technologies with which to produce high

resolution spatio-temporal images of the human brain. Recent developments in functional MRI now

permit improved volumetric coverage and simultaneous multislice and echo-planar imaging

can be used to support higher spatial resolution imaging of the human brain [Feinberg et al.,

NeuroImage,

http://dx.doi.org/10.1016/j.neuroimage.2017.02.020].

Although we understand what imaging technologies

measure, what they can and cannot tell us about brain activity, and how they are currently used in

NHPs and humans, there is evidence that certain psychophysical and electrophysiological studies in

NHPs have been replaced with non-invasive imaging

studies in humans. This was noted by the Bateson Panel, which included experts in imaging, and should

be positively acknowledged in the Opinion. That is not to say we do not recognize that human imaging

and NHP electrophysiology approaches are often used in combination in neuroscience and are valuable

to gain greater insight and understanding.

The SCHEER takes the point that imaging techniques

have inherent limitations that are difficult to overcome, and that other technologies may offer

greater potential for advancement in the 3Rs, but we believe that further development of imaging

67

technologies has the prospect of furthering the 3Rs,

and hence we have called for this (as did the Bateson Panel). We have edited the text to reflect this

193. Marshall,

Lindsay, Humane

Society




We are concerned at the statement that novel NHP

use may be required for the testing of emerging

infectious diseases and biosimilars. This feels like a backward move that is not in accord with the

Directive.

We would suggest that, in the field of infectious

diseases, development of platforms for collaborating in and sharing data from population studies,

genome wide association studies, and clinical data, would further progress in infectious disease

research and vaccine development without recourse

to NHPs. For biosimilars, there should be no requirement for

NHP and this has been reviewed and is supported by the NC3Rs in the UK [Chapman et al 2016]. By

their nature, biosimilars are designed to mimic an existing compound and therefore testing should

focus on efficacy, and this can be achieved with in vitro assays. NHP studies are not powered to detect

differences between the original compound and the

biosimilar and therefore there is no advantage to value to using NHP. In any case, the significant

differences between human and NHP major histocompatibility and therefore antigenic peptide

It is possible that existing in vitro methods are

insufficient or inadequate to study new diseases, e.g. to identify the responsible pathogen and/or to study

pathology and intervention therapies. A recent

example has been SARS (see e.g. van den Brand JMA et al, J Comp Pathol 2014; 151: 83-112). In some

cases NHP might provide the most relevant animal model. This is also the case for new therapies using

novel biosimilars. Since it cannot be predicted which diseases will emerge and when, it is not possible to

exclude the use of NHP beforehand. The Directive specifically states that the use of NHP is allowed to

study life-threatening or debilitating human diseases

when no alternatives are available.

This is a useful suggestion and is now included in the

Opinion (4.6.3.4; Future Research). (WG: IS THIS POSSIBLE??) Although this will be helpful to limit

the use of animal models in general, it will not necessarily exclude all use of animal studies,

including NHP.

The EU guideline also calls for no in vivo animal

studies. However, other global authorities still call for such studies.

68

presentation make it highly unlikely that the risk of

adverse immune-related events would be predicted by NHP.

194. Lindsay,

Marshall, Humane

Society




Transparency is vital and we would also like to see some discussion of the alternatives to NHP that

were disregarded as unsuitable for those studies

that use NHP. This is important for public perception of science but also vitally important for science,

since in vitro methods cannot be fit for purpose (and ultimately replace NHP and other animals) if

the developers are unaware of the ultimate purpose.

Replacement of animal test is complex and as stated

in 3.3 “one model can never fully recapitulate all aspects of human diseases. The type of 19 scientific

question asked and the methodology used will

determine how useful and how 20 predictive the results obtained are. This implies that a variety of

models, animal and 21 non-animal, should be used to address different aspects of the same disease. “

therefore the validity of a model depends on the context.

195. Procyk,

Emmanuel, Biosimia,

French Non Human

Primate

Research groups,

CNRS, emmanuel.pro


3 OPINION The opinion states page 20 that «Factors related to

scientific practice and career progression [...] competition, the reputation and track record of

researchers […], and entrenchment discourage switching from NHPs to alternative (animal and non-

animal) models.” Also pages 56 and 60.

We feel that the report does not acknowledge the

fact that, at least in neuroscience and most probably in all fields, many scientists are using

both: NHPs and alternative approaches. Many NHP scientists actually work on alternative approaches to

replace where possible the use of NHPs, or work on translational research to produce therapies or

technologies directly applicable to humans (e.g.

Camus et al 2015 Neurobiology of Learning and Memory. Volume 124, October 2015, Pages 123–

129).

Scientists working with animals, rodents and monkeys, have played a key role for instance for

the development of the so-called “mini-brains” or 3D brain organoids that derived from experiments

with animals and that can now be applicable to

human cells. Although reductionist in nature, brain

The SCHEER disagrees with the view that the report

does not acknowledge that many scientists aspire to use alternative approaches.

The SCHEER agrees that further research is needed on brain organoids.

69

organoids have great potential to complement 2D

cell culture models and animal studies to investigate aspects of human brain development and pathology

(Quadrato et al 2016. Nat Med. 2016

Nov;22(11):1220-1228). This development has produced new tools that can replace animals for

testing and screening pharmacological substances before further stages of testing.

However, a critical evaluation of such techniques

shows also that they are still limited in their potential to replace whole brain questions (like

network functioning, cortical-subcortical

dissociations, evaluation on late stages of brain development, etc..) and that further studies with

entire organisms are instrumental to provide critical evaluations of in vitro systems (Betizeau M, Dehay

C. From stem cells to comparative corticogenesis: a bridge too far? Stem Cell Investig. 2016 Aug

16;3:39).

196. Sanchez, Mar, Society for

Neuroscience, mheintz@sfn.

org, Other,

United States of America

3 OPINION

SCHEER_letterhead_March_21_2017.pdf

We agree with the overall points of the report and want to emphasize that NHP research remains

essential for human health and basic scientific discovery. Research with NHPs both provides basic

information about the brain and nervous system

and advances our understanding of and working towards cures for diseases and disorders like

Alzheimer's disease, Zika virus-induced microcephaly, Parkinson's disease, multiple

sclerosis, and mood and addiction disorders. These animal models are critical to understand how the

brain works and the causes of these devastating neurologic and psychiatric disorders and diseases.

Thank you for your agreement. No reply needed.


70

Scientists must continue this valuable research to

understand these conditions and to find innovative ways to treat patients.

We also want to express our agreement with the three main points of concern expressed by the

Federation of European Neuroscience Societies (FENS) regarding this SCHEER preliminary opinion.

Please see the reply to comment Nr 7.

197. Vitale,

Augusto, European

Federation of Primatology,


3 OPINION

EFP_Comments_on_SCHEER_Opinion.docx

p.18, lines 26-35

p.19, lines 30-32 Possible changes to the text in bold and italic

3. Opinion 3.4 Opportunities for reduction and refinement

Neuroscience Technological developments have enabled

refinement of surgical and other procedures within

the neurosciences, e.g., - refining and de-sizing the devices used in invasive experiments, - improving

the anaesthetics and analgesics with faster recovery used in imaging - experiments and surgery, - non-

invasive imaging methods help reduce and refine invasive techniques such as surgery, - refinement

of food and fluid control protocols and wireless technology have a positive impact on NHP welfare.

- Use of wireless techniques to record

neuronal activity - Use of positive training techniques to

reduce stress in housing management and procedures.

- Continuous use of enrichments to refine housing conditions

Moreover, researchers and animal care staff must

The text in section 3.4 has now been modified to

include the suggested bullet points except for general considerations on enrichment and husbandry that we

feel do not specifically regard neuroscience experiments but any use of NHPs in a laboratory

setting. The text now reads: “ […]within the neurosciences, e.g.,

• refining and de-sizing the devices used in

invasive experiments, • using wireless techniques to record neuronal

activity, • Using positive training techniques to reduce

stress in housing management and procedures. • improving the anaesthetics and analgesics

with faster recovery used in imaging experiments and surgery,

• using non-invasive imaging methods that help

reduce and refine invasive techniques such as surgery,

• refining food and fluid control protocols to minimize the impact on NHP welfare.”


71

ensure that they keep abreast of the latest

techniques that enable reduction in animal numbers and suffering, and put this evidence base into

practice, both during procedures for a

particular experimental protocol, and during normal housing management.

3.5 General issues

Scientific knowledge about the welfare impact of husbandry and procedures, even after refinement

measures have been applied, needs to be assessed and factored into harm-benefit assessments.

However, a high quality of the social and

physical environment of the NHP must be always assured, beyond the scope of a

particular study.

These points are presented in detail in the section in neuroscience.

3.5 General issues

See Chapter 7 on recommendations.

198. Errett, Jill,

N/A, errettj@btinte

rnet.com, United

Kingdom

3 OPINION It is my opinion that using animals in experiments

to improve human life is unethical, unnecessary and inhumane. We are different species; what works in

an animal does not work with a human and often does harm. There are so many other methods of

exploring data (computer models etc) that to use millions of animals in painful, stressful and cruel

experiments is unnacceptable in a civilised society.

The commenter does not provide any suggestions for

improvements of the scientific basis of the SCHEER preliminary Opinion and/or any scientific evidence.


Martje,

ECLAM, m.fentener@e

rasmusmc.nl, Other, ECLAM

is the Europe wide college

of veterinary specialists in

laboratory

animal

3 OPINION P14, lines 27 -34: see comments on summary regarding training and export.

P16, lines 27-32: it would be clearer if the text would also explain that a number of brain structures

are exclusively present in primates and not other animal species. This is definitely not restricted to

the visual system.

P17, lines 11 – 12: this is very old news and also

relates to risk of disease transmission.

P14, lines 27 -34: The comment on the summary could not have been fond.

P16, lines 27-32: the SCHEER agrees, and it is not simply presence or absence, but differences in

functional importance – for example the pyramidal tract’s importance in motor control is unique to nhps

and humans. However an exhaustive list of structural similarities is outside the scope of the review – the

visual system example was just that, an example.

P17, lines 11 – 12: Agreed. No revision to document

required

72

medicine

P17, lines 15 – 18: This section should also address novel developments in regenerative medicine where

material from human donors, sometimes the patient

to be treated, may go through extensive in vitro procedures to reconstitute organ function, e.g. by

transplant of biomatrices loaded with differentiated cells coming from stem cells, e.g. iPSC (induced

pluripotent stem cells). Such new medical perspectives are currently under development and

may require the use of NHP recipients to evaluate organ function, immunotolerance, the absence of

tumor formation, et cetera.

P19, lines 2-7. Assurance that these considerations

are taken into account are also embedded in the Directive 2010/63. The evaluation by both funders

and ethical review bodies often presents a chicken-and-egg problem where different bodies are

mutually awaiting each others’ evaluations. This doesn’t really help! The fact that no animal studies

can be undertaken without prior review and project

licensing should be taken into account. Also consider that not all research will be publicly

funded.

P20, line 13-15: imaging techniques have their characteristic biophysical properties that determine

what they can visualize and with what degree of detail. Although further progress may be possible,

that will typically depend on progress in the medical

application and early adoption by this research field. It is not likely that such investments will be made

by industry with NHP research in mind but it is possible that NHPs will be necessary for the

development of this, which would provide early access to improved technologies. Hence, early

adoption of novel technology should be the

P17, lines 15 – 18:It is felt that adding this will not affect the overall message of the document.

P19, lines 2-7.The SCHEER understands the concern

formulated in the comment. The role of ethical committees is to review and to

license only appropriate project even when not publicly funded.

P20, line 13-15: Although we understand what imaging technologies measure, what they can and

cannot tell us about brain activity, and how they are currently used in NHPs and humans, there is

evidence that certain psychophysical and

electrophysiological studies in NHPs have been replaced with non-invasive imaging studies in

humans. This was noted by the Bateson Panel, which included experts in imaging, and should be positively

acknowledged in the Opinion. That is not to say we do not recognize that human imaging and NHP

electrophysiology approaches are often used in

73

ambition, here.

P20, lines 16-19: organ transplant and regenerative

medicine should be mentioned here.

P21 line 25: this is about pharmacological safety testing, not chemicals. This should be clear to avoid

misconceptions.

P21 lines 32-35 grammar (one sentence).

combination in neuroscience and are valuable to gain

greater insight and understanding.

We take the point that imaging techniques have

inherent limitations that are difficult to overcome, and that other technologies may offer greater

potential for advancement in the 3Rs, but we believe that further development of imaging technologies has

the prospect of furthering the 3Rs, and hence we have called for this (as did the Bateson Panel). We

have edited the text to reflect this

P20, lines 16-19: Not agreed. No revision to

document required.

P21 line 25: The opinion is considered to be clear as is.

P21 lines 32-35 The sentence was revised for clarity

200. Martinez, Emma, The

European Animal

Research

Association (EARA),


Kingdom

3 OPINION All explained in attached file

EARA_SCHEER_Written_Submission_24032017.pdf

On the fifth issue of the mandate of this Opinion on considering scientific viewpoints to determine a

timeline for phasing out NHP research (p10)

We would like to suggest two additional factors to be included in the list of issues determining the

timetable for the complete replacement of NHPs: • Availability of a EU authoritative knowledge source

regarding animal and non-animal methods

• EU wide efforts to promote replacement, reduction

and refinement of animal procedures (similarly to the UK National Centre for the Replacement,

Thank you for these suggestions all pertaing to a

prominent role of the EU in promoting and implementing alternative methods. Implicitly this is

already covered by several bullets. An extra bullet has been added to make this more explicit.


74

Reduction and Refinement of Animals in research)

• A collective agreement on “managed risks” of the use of alternative methods

On ‘Progress made in the last ten years in

Neuroscience Research’ section (4.6.4.3) Taking Parkinson’s disease as an example, SCHEER

Preliminary Opinion includes a reference of a gene therapy vector that produces dopamine in the brain,

which has been shown to be safe and efficacious in

pre-clinical studies of Parkinson’s disease rodents and NHPs models and in the first generation of

patients treated in Europe (p48, L16-21). SCHEER Opinion could include another reference to a new

clinical trial involving dopamine-producing cells (DA cells) of foetal origin that was launched for

Parkinson’s disease patients in 2014 (TRANSEURO, http://www.transeuro.org.uk/).

On the currently available possibilities to replace (sections 3.3 and 4.6.4.4), and to reduce and refine

(4.6.4.5) NHPs use SCHEER Preliminary Opinion has identified progress

that has been made to replace, reduce and refine the use of NHP in research by using other methods

not entailing the use of NHPs or by using other species of animals.

The alternative approaches highlighted in the

Preliminary Opinion cannot yet replace the use of NHPs and hence these alternatives remain

complimentary approaches. The specific reasons for this statement are:

• The interpretation of human fMRI data heavily relies on neurophysiological measurements in NHPs.

• Human patients’ invasive electrophysiological studies are limited in spatial and temporal scope -

the areas investigated are identified based on

clinical criteria and the recoding time is usually

The commenter suggests the addition of another example of therapy for Parkinson’s disease using

foetal-derived stem cells. The paragraph in the Opinion talks specifically about gene therapy for

neurodegenerative diseases. There is no mention of cell therapy. There are other cell therapy studies

ongoing for PD (Japan and the US) that have not been quoted either. The idea was to quote a proven,

successful, ongoing study and the limited number of

patients grafted in the Transeuro program due to great delays in the project, prevent to draw

conclusions as to its therapeutic benefit at this stage. Once again, this is a single example given, not an

exhaustive list.

Although we understand what imaging technologies measure, what they can and cannot tell us about

brain activity, and how they are currently used in

NHPs and humans, there is evidence that certain psychophysical and electrophysiological studies in

NHPs have been replaced with non-invasive imaging studies in humans. This was noted by the Bateson

Panel, which included experts in imaging, and should be positively acknowledged in the Opinion. That is

not to say we do not recognize that human imaging and NHP electrophysiology approaches are often

used in combination in neuroscience and are valuable

to gain greater insight and understanding.

We take the point that imaging techniques have inherent limitations that are difficult to overcome,

and that other technologies may offer greater potential for advancement in the 3Rs, but we believe

that further development of imaging technologies has

75

limited to one to two weeks compared to several

months in NHPs. It is unlikely that human recording studies will be able to replace experiments in NHPs

in the foreseeable future.

• The effect of non-invasive brain stimulation techniques such as transcranial magnetic

stimulation (TMS) on neural activity remains unclear. Because the pattern of sulci and gyri (brain

structure and organisation) determines the electrical current spread in the brain, all these non-

invasive techniques urgently require validation in an NHP model, which possess a brain structure and

organization similar to the human brain.

• Recent scientific breakthroughs in stem cell therapy (Grow et al., 2016) and transgenic models

of autism in monkeys (Liu et al., 2016) strongly suggest that the use of NHPs in translational

neuroscience studies is and will remain essential in the next decade.

Other area of neuroscience research where NHPs

are required that is not specifically mentioned in the

Preliminary Opinion is to develop Brain-Machine Interfaces (BMI). The current challenge of research

on BMI resides on restoring sensorimotor function in paralyzed patients. Solving this challenge will

remain a major theme in translational neuroscience (Bensmaia and Miller, 2014), which will require the

use of NHPs for further improvements.

Statements in the Preliminary Opinion that are not

referenced, contextualised or lack supporting evidence (examples in the attached letter)

the prospect of furthering the 3Rs, and hence we

have called for this (as did the Bateson Panel). We have edited the text to reflect this

Section 4.6.4.3 talks specifically about BMI as a key

area of neuroscience in the last 10 years and in the

years to come. The suggested reference has been added to the text.

More references are added to the final Opinion.


personal data

3 OPINION OPINION SECTION Page 14 Line 18

• This is repeated multiple times with no supporting data. Where did this "concern" originate from and

Page 14 Line 18

Please see the reply to comment 176, concerning p22 line 21 of the Opinion.

76

what kind of public opinion poll was used? What

context was provided? Is this really being driven by a small group who fail to see the value of animal

testing and its benefits to mankind?

Page 14 Line 27

• Recommend replacing with "unnecessary use".

Page 15 Line 3

• Use of NHPs for pharmaceutical testing is primarily performed to ensure human safety and

based on strong science, not just to check a box

with respect to the rules.

Page 15 Line 9

• I would say significant progress has been made.

Page 15 Line 14 • This makes it sound like the scientific community

just doesn't want to stop using NHPs. Strongly

recommending this be revised to "an achievable goal".

Page 15 Line 42-43

• Need to be very careful with this statement. In

many cases the pharmacological effects are not the same with homologous proteins or in transgenic

animals due to subtle but important differences in physiology.

Page 16 Line 7

• Add scientific acceptance and regulatory

Page 14 Line 27

The sentence was revised as recommended.

Page 15 Line 3

This is not contradicted by the sentence in the Opinion referred to.

Page 15 Line 9

The sentence was revised as suggested.

Page 15 Line 14: The sentence was revised as suggested. Greater

progress would be made in the replacement of NHP

experiments, if this was accepted as a desirable goal by the scientific community. WITH Greater progress

would be made in the replacement of NHP experiments, if this was accepted as an achievable

goal by the scientific community.

Page 15 Line 42-43

It is therefore the Opinion states that NHPs ‘may’ be

replaced

Page 16 Line 7

The sentence was revised as suggested.

77

Page 16 Line 41

• Also need to highlight that the in vitro models cannot assess more complicated neurologic

function, such as behavioral effects.

Page 17 Line 41-43 • This is true but the very low doses can greatly

reduce the value/decision making of exploratory INDs

Page 18 Line 1

• I think this is a very skewed view of benefit to NHP.

Page 18 Line 13-15

• This is an overreaching statement. I don't know of any cases where iPSCs have been used in lieu of

animal safety testing.

Page 19 Line 36-38

• This is true but in many cases (e.g., biologics) the

most relevant single species is the monkey.

Page 20 Line 31

It is unfair to call out regulatory bureaucracy when the whole point is to ensure robustness of the

assays, especially if they are being used to support

Important progress is still required to develop new

alternative methods and to validate them, before obtaining scientific acceptance and regulatory

recognition.

Page 16 Line 41

This is true, but the results of these "microdose" studies should not be considered alone, but they

should be considered with the results obtained from

TK, PKPD studies performed in the relevant animal species and with the data obtained in sillico when

available.

Page 17 Line 41-43 See the updated text on microdosing Section 6.6.2.5.

Page 18 Line 1 This sentence relates to safety testing without the

use of a second species.

Page 18 Line 13-15

See explanation in section 6.6.2.5.

Page 19 Line 36-38 The SCHEER agrees with this comment and will

change the text accordingly.

Page 20 Line 31:

This is just one of the factors contributing.

78

human safety.

Page 21 Line 26-29

• Not really sure what this means. What species are

being compared and what is the scientific reference to support this statement.

Page 21 Line 26-29

See explanation in section 6.6.2.3.

202. Dodkin, Christina,

Animal Defenders

International/ National Anti-


research@ad-

international.org, United

Kingdom

3 OPINION 3.3 Pg 15, Lines 30-35: See response to 4.6.2.3

Pg 15, lines 42–43: See response to 4.6.2.3

Pg 16, lines 24–25: See response to 4.6.3.4, Pg 43, lines 29 – 33 and 4.6.5, Pg 52, lines 13 – 14

Pg 16, lines 31–32: Although controlled studies of brain injury are not ethically possible in healthy

humans, controlled studies of the brains of animals do not represent the human situation or target

species.

Pg 16, lines 40–41: Validated non-animal methods for assessing the blood-brain-barrier system are

currently available which address the issues of poor

predictive ability of existing preclinical animal models (Zhang 2015) and also in the form of organ

on a chip (Marx 2015)

3.4 Pg 17, lines 25–26: This should not involve more research using NHPs, especially not with

studies that purposely inflict pain.

3.5 Article 58 of Directive 2010/63/EU requires the

Commission to conduct periodic thematic reviews of the 3Rs, particularly in primates. The Committee

must recognise this mechanism within the Directive as a tool by which certain areas of NHP use can be

3.3 Pg 15, Lines 30-35: Please see the reply to comment 253.

Pg 15, lines 42–43: Please see the reply to comment

253.

Pg 16, lines 24–25: Please see the reply to comment 259.

Pg 16, lines 31–32:See section 6.6.4 for more explanation.

Pg 16, lines 40–41: These methods are not considered to be validated sufficiently for Regulatory

purposes.

3.4 Pg 17, lines 25–26:

Please see the reply to comment 173

3.5. The Opinion recommends how to advance 3Rs,



79

identified and reviewed, resulting in a clear picture,

outcomes and steps for progressing a skeleton timetable for NHP use phase out.

Pg 18–19, lines 41–2: See response to 4.6.5.3, Pg 56, lines 31 – 32 and lines 34 – 35

Pg 20, lines 1–2: See response to 4.6.3.4 and Pg 44, lines 2–5

3.6 Outlined below are suggestions to progress and

find solutions to factors affecting the timetable:

Lines 26-29: Areas of primate use which should be prioritised for

replacement must begin with those models which have reviews and demonstrated a lack of benefit to

human health. Those already referenced in the Preliminary Opinion include NHPs in toxicity testing

(Bailey 2014), in HIV research (Akhtar, 2015;

Bailey, 2014), neurology experiments (Bailey & Taylor 2016; ADI Neurology Research Thematic

Review)

Lines 30-32: Whilst it is important to ensure that non-animal methods are relevant and fit for

purpose, it must also be taken into account that this rigorous, industry wide process of validation has

never been carried out on animal models. Non-

animal methods should be compared to data from humans where available.

Lines 42-45: The Innovate UK report (2015)

acknowledges the degree of scepticism in some sectors of the scientific community. As any

timetable is likely to provide a phase out time for


Pg 18–19, lines 41–2: This comment cannot be replied, the comment referred to was not identified

Pg 20, lines 1–2: This comment cannot be replied, the comment referred to was not identified

3.6. Please see reply to comment 173.

Lines 26-29: Please see reply to comment 173.

Lines 30-32 Please see reply to comment 173.

Lines 42-45: Please see reply to comment 173.

80

research in NHPs, where they are shown to lack

relevance, researchers would have time to re-train and embark on continued professional development

in non-animal methods in their research area.

3.7 Pg 21, 11 – 14 and 19 – 21: Although the

Preliminary Opinion recognises species differences, the Committee do not use this scientifically

collected data to further question the scientific validity of NHP use. There is also the need to

recognise high drug attrition rates (Hartung 2013) and adverse drug reactions in humans (Eddleston et

al 2016) in considering the consequences of

banning NHP use

Pg 21, Lines 41 – 44: See response to 5.2 References

ADI Neurology Research Thematic Review (and references within)

Akhtar, A (2015) Cambridge quarterly of healthcare ethics, 24(4): 407-419

Bailey, J (2014) Alternatives to laboratory

animals, 42: 287-317 Bailey, J & Taylor, K (2016) ATLA, 44, 43-69

Eddleston, et al (2016) British Journal of Clinical Pharmacology, 81, 582-586

Hao, X (2007) Cell, 129(6), 1033-1036 Hartung, T (2013) ALTEX, 30(3), 275 – 291

Innovate UK (2015) A non-animal technologies roadmap for the UK

Ipsos MORI (2016) Department for Business,

Energy & Industrial Strategy Marx, V (2015) Nature, 522(7556), 373-377

Zhang, HXM, et al (2015). Organ-On-a-Chip for Drug Testing in Brain Diseases. 19th

International Conference on Miniaturized Systems for Chemistry and Life Sciences,

Gyeongju, Korea

3.7 Pg 21, 11 – 14 and 19 – 21: The Opinion

highlights all the progress towards an animal-free safety assessment framework, but for the time being

we cannot ignore there are still areas in which that NHP are a relevant animal model (e.g. monoclonal

antibody product or vaccines development). This is witnessed also by the recent revision of the ICH

guideline S6). Denying it will not produce a quicker

phase out. Nevertheless, it is clear that NHP should be only used

when there are no alternatives, and the number of animal used can be substantially limited by

preliminary in vitro and in silico testing, or avoided whenever in vitro the NHP non-reactivity can be

demonstrated (indicating NHP are not a suitable animal model). As already stated, SCHEER opinion is

that the use of an appropriate species or combination

of species/models is essential to obtaining the most reliable and translatable information.

The validity of animal models is discussed in section 4.

81

203. Tarsitano,

Giulia, Eurogroup for

Animals,

g.tarsitano@eurogroupforan

imals.org, Belgium

3 OPINION Page 15, Lines 13 – 15. Although the Committee

correctly asserts that “Greater progress would be made in the replacement of NHP experiments, if this

was accepted as a desirable goal by the scientific

community”, it fails to highlight that scepticism of some researchers in the abilities of non-animal

methods is an important issue that has to be identified. It is crucial to point out that, across the

scientific community, there is too little incentive for a paradigm shift towards animal-free research.

Unfortunately, scientists generally perceive the development of non-animal methods as a distinct

discipline rather than an integral and integrated

part of their ongoing research. This barrier can be easily overcome by disseminating available

evidence about the reliability and effectiveness of non-animal methods.

Lines 30 – 35. By suggesting that the use of other

live vertebrates is a step towards replacement, the Committee entirely undermines the intention of the

concept. The use of animal species, such as

(genetically modified) mice and pigs, instead of primates, is a misrepresentation of replacement in

animal research. The definition of replacement includes, in some cases, ''relative replacement”,

however this indicates that the use of vertebrate cells or tissues, early life-stages or non-vertebrates

instead of live ‘protected’ vertebrates could represent a step towards replacement.

Page 16, lines 1 – 8. Although the Committee presents arguments against phasing out animal

safety testing, including them being vital for risk assessment, alongside suggesting that human

based models are “not yet a substitute for well-designed animal models”, it completely fails to

acknowledge drug trial disasters and adverse drug

Page 15, Lines 13 – 15: The SCHEER agrees with the

need of incentives toward the use of alternative methods. Indeed, this point has been already

addressed in the preliminary opinion, in the last

bullet point in answering Question 5 as well as in more details in paragraph 5.2 How to overcome

barriers?

Lines 30 – 35. The SCHEER agrees with this

comment and have changed the text in the Opinion to: Notably, substitution of NHPs with rodents or

other laboratory animal species is not replacement as


indicates that the non-primate species is likely to suffer less harm.

Page 16, lines 1 – 8. This is a general statement toward the safety assessment of pharmaceuticals,

not limited to the use of NHP but to the ‘animal models’ in general. SCHEER is aware of the limited

number of failures and market withdrawn products due to ADR, but this has to be looked at in

comparison with the number of successful and safe

82

reactions. These reactions in trial participants and

patients demonstrate how the reliance on the results of animals does not necessarily safeguard

the health of humans.

Page 18, line 41- 42 and page 19, line 1- 9. The Preliminary Opinion points out to the need to

conduct systematic reviews and meta-analysis of all areas of NHP use but pays little attention to the

studies that have already reviewed the literature in this field. It also misses the opportunity for using

the Preliminary Opinion to offer a rigorous and comprehensive review of the existing literature.

Page 21, lines 30– 31. It is essential to drive the implementation of replacement and provide a route

to end animal use by setting a timetable to phase out primate experiments. In order to achieve this

goal, a properly coordinated, supported and funded strategy for ending primate use has to be put in

place (and until this is achieved, greater and meaningful restrictions on their use should be

established). The EU Cosmetics legislation has set a

precedent for a strategy which could be utilised; it shows that industry can respond to a timetable for

the development of alternatives to animal tests: the total value of Europe’s leading cosmetics brands has

grown by 6.6% between 2012 and 2014. Despite the existing EU ban on animal testing in this sector,

of the world’s 50 leading cosmetic brands, 26 are

drugs developed following this system. It is obvious

that it can be further improved, e.g. by using powerful methodologies available thank to the

technical and scientific development of the last years,

most of which based on animal-free models (e.g. cell of human origin).

SCHEER opinion is that the use of an appropriate species or combination of species/models is essential

to obtaining the most reliable and translatable information. In addition, this is required by

international regulations.

Page 18, line 41- 42 and page 19, line 1- 9. Unfortunately, no literature was provided to show

what the SCHEER missed.

Page 21, lines 30– 31. The Opinion recommends how to advance 3Rs, acknowledging that one timetable

for phasing-out cannot be given in view of a wide spectrum of positive and negative incentives for NHP

use. Risk managers, however, may decide on such a timetable, but this is outside the mandate of the

SCHEER.

83

domiciled in Europe.

Page 21, lines 41 – 44. Analysis of Non-Technical

Summaries often contain vague project descriptions which do not properly explain what is involved in

procedures, as well as claims for the importance of NHPs research which are often exaggerated (along

with the extent to which the 3Rs are being applied). There is a widespread failure of the scientific

community to openly communicate the limitations of primate ‘models’. This skewed reporting of

researcher's scientific work suggests that there

exists a further barrier to encouraging them to be open and transparent about the research they

conduct.

Page 21, lines 41 – 44.

The SCHEER also sees a problem in communication. See the recommendation section 7.2.

204. Kenna, Gerry, Safer

Medicines Trust,

[email protected],

United Kingdom

3 OPINION Page 16, line 3: The Opinion refers to the “poor representation of pharmacokinetics by in vitro

systems”. This overlooks the well-documented success of human-relevant in vitro models in ADME

screening to reduce drug attrition due to poor PK from over 40% in the early 1990s to less than 10%

within a decade.

Page 20, lines 33-35: The Opinion refers to “the condition that is often included that an alternative

method must be formally validated and accepted by

regulatory authorities before it can be used.” Yet this assumption is not correct. I attach a paper

(Food for Thought ... on Validation. A Puzzle or a Mystery: an Approach Founded on New Science, by

Page 16, line 3: The SCHEER is aware of the human relevant in vitro models in ADME screening and

welcomes their use which has not only reduced the number of animals used, but increased the relevance

of safety assessment, recognising the pivotal role of kinetics in interpreting toxicity data. The sentence

refers indeed to another situation, that is the lack of kinetics interconnections when specific cell type are

used disconnected with other cell types. This will be

very likely overcome in the future with the use of organ-on-a chip models. The other relevant point is

that in vitro system are generally used without considering in vitro biokinetics, thus totally missing

the real cell exposure conditions.

Page 20, lines 33-35: In Europe validation of in vitro methods is coordinated and carried out by EURL-

ECVAM (within the DG-Santè, at the Joint Research

Center JRC located in Italy at Ispra) and then proposed to OECD for adoption as a test guideline,

accepted at regulatory level. The need for validation is a long-lasting debate; however, the predictivity of

84

Neil Wilcox and Alan Goldberg) which says, in the

penultimate paragraph of the second page: “Currently, ECVAM and ICCVAM are charged with

validating alternative methods through formal

processes, and there is a general assumption in the toxicological community that such formal validation

is requisite for regulatory acceptance, which is not always the case. Although regulators require

proposed safety testing methods to be valid for their intended use, and expert review is desirable,

validation through a formal process is not required by the regulatory agencies.”

in vitro methods should be evidence-based and this

is the meaning of the validation process. The validation process can be different depending on the

tests, being shorter for those methods used by the

scientific community since many years. As far as the SCHEER knows not validated methods (or at least

recommended by ECVAM in the cosmetic area) are not accepted by regulatory bodies.

205. Borra, Elena,


Expert Group



unipr.it, Italy

3 OPINION Opinion. Paragraph 3.5, p.20 lines 13-15;

Paragraph 4.6.4.4, p. 49 lines 39-40; Paragraph 5.1, p. 59 lines 40-42

MR-based techniques do not have the potential to replace electrophysiological and tract tracing studies

in NHPs. In several parts of the document the need of improving non-invasive imaging technologies to

ultimately replace the use of NHP is repeated. Though the improvement of these techniques is

desirable and could help in reducing the number of NHP used in some neuroscience experiments, these

techniques do not have the complete suggested

potential.

MRI-based approaches can be regarded at most as complementary methods. They suffer (as noted also

in the Opinion, p.49) from poor temporal resolution because of inherent limitations, since they are

based on a Blood-Oxygen-Level Dependent (BOLD) contrast technique, and not on direct recording of

neural activity. Therefore, they cannot inform us on

the dynamical aspects of operations performed by the neural assemblies and circuits, from which all

functions relevant to physiology emerge. As such, fMRI cannot help much in understanding the cause

The text in sections 3.5, 4.6.4.4, and 5.1 has been

modified to clarify the complementarity of electrophysiology and fMRI. There is no mention of

DTI in the document so although this point is shared and well taken, this discussion has not been

introduced. Suggested references have been added to the text to address these comments.

Although we understand what imaging technologies

measure, what they can and cannot tell us about

brain activity, and how they are currently used in NHPs and humans, there is evidence that certain

psychophysical and electrophysiological studies in NHPs have been replaced with non-invasive imaging


be positively acknowledged in the Opinion. That is not to say we do not recognize that human imaging

and NHP electrophysiology approaches are often

used in combination in neuroscience and are valuable to gain greater insight and understanding.


85

of brain disorders at the level of individual neurons

and small networks. Moreover, recent studies have stressed several critical factors concerning statistical

approaches used in fMRI studies (see for instance

Eklund, Nichols and Knutsson, 2016, PNAS 113:7500-7505), concluding that the widespread

use of this technique has to some extent slowed down and mislead current neuroscience research.

Second, tracking brain connections through MRI

tract tracing (DTT) while providing some encouraging results (see, e.g., Caminiti et al. 2013,

JNeurosci 33: 14501-14511), still suffers from

many serious limitations (e.g., Donahue et al., 2016, JNeurosci 36:6758–6770; Reveley et al.

2015, PNAS 112, 2820–2828; Thomas et al. 2014, PNAS 111, 16574–16579), given its inability to

properly estimate fine-grained connectivity, connectivity strength, and (long) distance

connections. These studies showed that: i) increase in sensitivity of different methods seriously

decreases specificity, and vice versa; ii) optimal

parameters of the tractography algorithm vary according to the traced pathways; and iii) the

complex arrangement of white matter fibers residing just under the cortical sheet poses severe

challenges for long-range tractography. DTT is still very far from providing estimates of nerve fibers

diameter, hence of conduction velocity, a fundamental parameter of brain function, which is

disrupted in several pathological disorders, the most

known of which is multiple sclerosis. Finally, there are several observations that MRI-based functional

connectivity is related to, but distinct from, anatomic connectivity, (e.g., Biswal et al. 2010,

PNAS 107; 4734-4739; Buckner et al. 2013, Nat Neurosci 16, 832-837).

inherent limitations that are difficult to overcome,

and that other technologies may offer greater potential for advancement in the 3Rs, but we believe

that further development of imaging technologies has


have edited the text to reflect this

86

206. Borra, Elena,


Expert Group



unipr.it

3 OPINION We have read the SCHEER Preliminary Opinion and

we recognize that the crucial role of NHPs studies in important areas of basic and applied research is

well documented and discussed, and future critical

research topics possibly involving NHPs are clearly identified. Furthermore, we agree that there is the

need of continuously refining technology and research procedures in order to improve NHP

welfare without compromising the quality of the science.

We are submitting five more comments. Italy Expert Group for NHP Neuroscience Research

The group includes scientists who are leading basic research involving NHPs at the Universities of

Rome, Bologna, Parma, Ferrara and Verona.

Thank you for your support to the SCHEER




hebts.org, United

Kingdom

3 OPINION Section 3.4 – Page 17, Line 35 Microdosing

This section makes reference to the applications of Exploratory Clinical Trials, including human

microdosing studies. While it is recognised that Exploratory Clinical Trials (including microdosing)

have the potential to reduce animal use, the current reality is that these types of studies are only

applicable under certain circumstances, have little

or no NHP use and constitute a small percentage of clinical trials. Nevertheless, we support the

suggestion in this section, and in Section 4.6.2.5 Page 37 beginning line 31, that extension of the

application of Exploratory Clinical Trials beyond the acquisition of pharmacokinetic data could potentially

reduce the number of candidate drugs that fail after entering into the full developmental process and as

a consequence reduce the number of pre-clinical

animal tests.

Section 3.4, Page 18 line 16 – Data and best practice sharing

Section 3.4 – Page 17, Line 35 Disagree, exploratory clinical trials have the capacity

of identifying clinical candidates that are unlikely to achieve a marketing authorisation, thus avoiding

further animal use, which could include studies in NHPs.

Section 3.4, Page 18 line 16 – The SCHEER agrees.

87

Here and in Section 4.6.2.5 Page 37 beginning line

20, reference is made to the benefits of sharing data and best practice in study design. For

experimental design, NC3Rs has proved to be a

hugely effective model for the sharing of best practice. We encourage the Commission to build on

this experience.



hebts.org, United

Kingdom

3 OPINION Section 3.5, Page 19 line 2 – research funders to ensure that NHP studies are only conducted where

necessary We do believe that in the UK this is already the

case. The requirement of ethical considerations being addressed in research funding applications is

interwoven with, and supported by, the UK government regulated system mandating specific

licences under the Animals (Scientific Procedures)

Act for all projects involving animal experimentation. This is further strengthened by

the review of all licences involving NHPs by both the NC3Rs and the Animals in Science committee, the

latter being a public body with the remit to advise the government department responsible for

implementation of the Animals (Scientific Procedures) Act.

It is the experience of BTS members working with facilities across the EU that practices are variable.

More should be done to standardise practices.

The SCHEER acknowledges the situation in the UK.

209. Baines, Julia, People for the

Ethical Treatment of



3 OPINION p.14, lines 13-14: “NHPs are considered the best available animal models for addressing....” NHPs are

considered by many experts in the field to not be a suitable ‘model’ for addressing human health

concerns as even minor differences between closely related species can lead to broad functional

disparities. Therefore, this sentence should be modified as highlighted: “NHPs are considered by

some to be the best available animal models for

addressing particular research questions because of

p.14, lines 13-14: Please see reply to comments 180 and 182.

88

the close phylogenetic relationship with humans.”

p.14, lines 30-31: Please see comment in the

summary section, page 10, lines 20-40. It is

postulated that tightening EU regulations may lead to research being pushed abroad, yet evidence

indicates that tighter controls and restrictions on the use of animals can have a significant positive

impact on innovation and acceleration in the development of non-animal testing methods.

p. 15, line 11: “Where NHP use is scientifically

justified…” It is assumed here that NHP use is scientifically justified without providing supporting

evidence.

p. 16, lines 11-18: We agree with the SCHEER’s statement that “NHPs are not acceptable organ

donors for both practical and ethical reasons,” however neither are other species. The shortage of

donor organs is a problem that can be solved

through simple policy changes. Countries that have instituted “presumed consent laws,” wherein an

individual’s organs and tissues are presumed available for clinical use upon death unless that

individual specifies otherwise, have seen significant increases in organs available for donation. Please

see examples from Belgium, France, Sweden, and Denmark. In light of the simple policy changes that

could easily solve the problem of “limited organ

supplies,” the use of animals in xenotransplantation research should be regarded as an area of research

where a clear alternative for solving the larger problem exists.

p. 21, lines 5-6: Although it may be difficult to

predict the availability of non-animal methods and

p.14, lines 30-31: It is recognised that tightening of

the existing strict EU regulations ...animal welfare

and ethical use. It is also true that tighter controls and restrictions on the use of animals can have a

significant positive impact on innovation and acceleration in the development of non-animal

testing methods.” See also reply to comment 180.

p. 15, line 11: Support for this statement is in

Section 4

p. 16, lines 11-18: The Opinion recommends how to advance 3Rs, acknowledging that one timetable for

phasing-out cannot be given in view of a wide spectrum of positive and negative incentives for NHP

use. Risk managers, however, may decide on such a

timetable, but this is outside the mandate of the SCHEER.

p. 21, lines 5-6: Please see the reply on tightening

EU regulations above comment above.

89

research tools for the replacement of NHPs, lack of

availability should not be considered a limiting factor in setting a timetable to phase out the use of

NHPs. It should be noted that the EU cosmetics

animal testing ban was implemented irrespective of the availability of non-animal testing methods for all

human health endpoints. Likewise, the Dutch Parliament passed a motion last year to phase out

all experiments on NHPs and commissioned a study into how this may be achieved whilst still allowing

scientific research into medical research and infectious diseases to

thrive.(https://www.tweedekamer.nl/kamerstukken

/moties/detail?id=2016Z06297&did=2016D12960) This motion was passed just months following an

announcement by the Dutch government to support a fund to stimulate the development of nonanimal

testing methods (https://www.rijksoverheid.nl/documenten/kamerst

ukken/2015/11/02/kamerbrief-voortgangsrapportage-dierproeven-en-

alternatieven) and we recommend that a similar

approach is adopted across all European member states. SCHEER note that factors such as career

progression and entrenchment can discourage switching from NHPs to alternative models,

however, such barriers may be overcome by prioritising areas of research and testing for phasing

out NHP use, setting an associated timetable and by providing funding opportunities for alternative

methods.

p. 21, lines 33-35: Please see comment in the

summary section, p. 10, lines 20-40. It is postulated that tightening EU regulations may lead

to research being pushed abroad, yet evidence indicates that tighter controls and restrictions on

the use of animals can have a significant positive

p. 21, lines 33-35:

Please the reply to comment 180.

90

impact on innovation and acceleration in the

development of non-animal testing methods.

210. Stephan, Valeska

Marija, PRIMTRAIN,

vstephan@dp

z.eu, Germany

3 OPINION 3.4 Opportunities for reduction and refinement p.18, l. 26-34

Comment: “While technological developments play an

important role in terms of reduction and refinement,

we find that progress in areas such as animal behavior management should not be neglected.

Handling and husbandry procedures have a huge impact on what influences the welfare of the animal.

The directive reflects this importance (e.g. mentioning of species-specific enriched

environments, animal training protocols) and refinement in this areas has been progressing

continuously in recent years. Hence, we believe this

opinion should reflect this as well.”

Suggestion for adjustments in the text: Neuroscience

Technological developments have enabled refinement of surgical and other procedures within

the neurosciences, e.g., - refining and de-sizing the devices used in invasive

experiments,

- improving the anaesthetics and analgesics with faster recovery used in imaging

- experiments and surgery, - non-invasive imaging methods help reduce and

refine invasive techniques such as surgery, - improving wireless technology have a positive

impact on NHP welfare. Developments in husbandry and handling

procedures have had a positive impact on the

welfare as well, e.g. - refinement of food and fluid control protocols

- systematic use of sophisticated animal training methods such as positive reinforcement training

Many of these points have been included in the final

Opinion.

91

- progress and continuous use of environmental

enrichment

211. Stephan,

Valeska Marija,

PRIMTRAIN,

[email protected],

Germany

3 OPINION p.19, l. 23-26

Comment: “While the knowledge of alternative methods in

order to reduce the number of animals used is

important when designing a research project involving NHPs. The knowledge of refinement of

techniques and procedures is just as important when it comes to the actual day-to-day work with

the animals in order to conduct research, as well as husbandry procedures as best as possible and to

reduce suffering which might be inflicted by those procedures to a bare minimum. Hence, we believe

the opinion should reflect the importance of this.”

Suggestion for adjustments in the text:

Moreover, researchers and animal care staff must ensure that they keep abreast of the latest

techniques that enable reduction in animal numbers and the refinement of existing methods and

techniques to reduce suffering, and put this evidence base into practice.

Text has been adjusted.



Jarrod.bailey


g, United Kingdom,

3 OPINION Nowhere near enough space to comment effectively

on this large section! See points made for Summary, wrt P14 L13 (P7

L10), L21 (P7 L15) & L30 (P7 L36).

P15 L13-17 Formal recommendations.

P15 L43-46 Investigate why still conducted.

P16 L1-4 Where are arguments for animal tests?

P16 L6-8 NHPs have never been validated; must

state.

Please see the replies to comment 182.

P15 L13-17 Please see Recommendation section

P15 L43-46 Probably for other regulatory authorities

P16 L1-4 Global regulatory requirements

P16 L6-8 Please see the reply to comment 173 on

the validity of NHP models.

92

P16 L10-14 Evidence needed. Refer WG to ‘Monkey-

based Research on Human Disease: The Implications of Genetic Differences’ provided.

P16 L20-25 Generalisation with no evidence.

P17 L10-18 Arguments against need for xenotransplantation; see Taylor K, Not a Solution,

BMJ 2010;340:c775, and provided ‘The SCHER Report on Non-Human primate research – Biased

and Deeply Flawed’, p430 and 432.

P18 L2-11 Microdosing needs more discussion.

P18 L34 No evidence refinements are implemented;

needs recommendation of implementation, and NHP research constantly evaluated.

P18 L41 – P19 L4 Firm recommendations.

P19 L34-38 Elaborate on replacement opportunities, and recommend?

P16 L10-14 P16 is part of the summary and more

detailed examples and references have been provided in 6.6.3, e.g., in 6.6.3.1 and 6.6.3.2. The

requested paper was already cited and discussed in

6.6.3.4.

P16 L20-25 See above, this is part of the Summary. There are most definitely ethical and safety barriers

to performing studies in humans: this is not a generalisation. The pros and cons (and thus

possibilities) of the use of human challenge models or patients and of non-animal and other animal

models have all been discussed in more detail,

including relevant references, in Chapter 6.6.3

P17 L10-18 The report is not calling for NHPs to be used in xenotransplantation.

P18 L2-11 This text was revised.

P18 L34 See recommendation section. As is made

clear in our recommendations, we encourage research workers to implement refinements.

Inspection of the current scientific literature provides good evidence that many refinements are

implemented. It is also a requirement of the Directive that available refinements are implemented

whenever possible, and this is reflected in the

national legislation of member states.

P18 L41 – P19 L4 The SCHEER elaborates on replacement opportunities, and provides

recommendations in sections 4 and 5.

93

P19 L38-41 Weak, unreferenced, generalisations.

Refer to lack of evidence to support, AND evidence against (‘Predicting human drug toxicity and safety

via animal tests...’ provided). No discussion of

human-relevant alternatives present.

P20 L9-13 Welcome.

P20 L13-15 Not valid to demand ever-increasing resolution of non-invasive methods while persisting

with invasive NHP research with high welfare costs, which often fails to translate to human benefit,

which cannot be shown to be essential, and which

suffers from confounding issues e.g. species differences, stress, and anaesthesia. Non-invasive

human methods offer best-ever spatial and temporal resolutions, especially used together;

invasive human research is possible in any case, and indeed is far from uncommon, if it were needed

when non-invasive approaches may not suffice, and calls from the neuroscience community have been

made to take more of the opportunities that exist to

conduct such research; and there is a strong scientific argument that such resolution is not

required anyway, as brain research is heading toward more global and macroscale approaches.

See our (provided) paper ‘Nonhuman primates in neuroscience research…’, e.g. p45-48, 53, 62.

P20 L25-45 See points made for Summary (P9 L21;

P10 L2).

P21 L15-17 See comment for Summary P10 L27

P21 L18-21 See comments for P16 L10-14; and Secns 4.6.2.2 and 4.6.2.3 (P31 L30-33; P32 L16-19

& L19-40)

P19 L38-41 Disagree. There is regulatory acceptance

of single species use.

P20 L9-13 Thank you.

P20 L13-15 See revised section on neuroscience 6.6.4

P20 L25-45 Please see the reply to comment 182.


P21 L18-21 Disagree.

94

P21 L22-23 Evidence & references needed.

P21 L24-26 Move to one species in testing? Needs discussion.

P21 L26-29 Needs expanding, & referencing to

provided Bailey ‘Predicting Human Drug Toxicity and Safety via Animal Tests…’ paper.

P21 L30-31 No evidence (see points for P10, L30 &

L37)

P21 L32-40 No other evidence that procedures or

care are otherwise worse outside the EU. Not established that increased cages sizes or social

housing ameliorates detrimental effects of research to any significant extent.

P21 L41-44 Need more proactive honesty wrt harms

& limitations. See comment for Secn 4.6.4.1. (P45

L33-40).

P21 L22-23 Please refer to the scientific rationale. Section 6.

P21 L24-26 Please refer to the scientific rationale. Section 6.

P21 L26-29 Please refer to the scientific rationale.

Section 6.

P21 L30-31 Please refer to the scientific rationale.

Section 6.

P21 L32-40 Please refer to the scientific rationale in

Section 6.

P21 L41-44 The comment is not clear and therefore

cannot be replied to.

213. Treue, Stefan,

EUPRIM-NET,

a EU-funded network of

European Primate

Centres (http://www.e

uprim-net.eu),

[email protected]

u, Germany

3 OPINION Pg. 19 lines 22-23: statement on “focusing NHP

research in centres of excellence”

Comment: No definition of “centres of excellence” is

provided and there is no argument or evidence provided for why focusing NHP research in centres

of excellence would be a benefit. Rather, this statement suggest that some places that study

NHPs should be closed, despite their essential

contribution to local research excellence.

Recommendation: The reference to centres of excellence should be removed. The corrected

Pg. 19 lines 22-23: A definition has been provided.

The local authorities decide what they consider to be

a centre of excellence.

More information about “centres of excellence” is given in the main body (5.1.2.1). As explained in the

text, we believe that where NHP research is necessary and justified, it should be performed to

genuinely high standards of experimental design and technical practice, ethics and animal welfare. If this

cannot be assured, for example, because of poor

veterinary and/or anaesthesia support, lack of knowledge and skills or access to imaging facilities to

maximise scientific value, then consideration should be given to relocating the work to facilities that can

95

sentence should read “It is recommended to

improve existing networks for information sharing.”

Pg. 19 lines 26-28: statement on course development

Comment: The statement incorrectly assumes that no appropriate course exists. Instead EUPRIM-NET

has developed and implemented such a course,

provisionally accredited by FELASA. Recommendation: Replace the sentence

“Consideration should be given to development … in experimental design” with “Consideration should be

given to the continuous development of a) accredited NHP-specific laboratory animal science

courses for beginners to provide a solid foundation in NHP behaviour and best practice of their care and

use, including experimental design; and b) to CPD

for all staff working with NHP (technicians, veterinarians, scientists). Both could build upon

courses developed by EUPRIM-Net and the EU COST-Action 15131 PRIMTRAIN.”

support both excellent science and welfare.

Members of the Committee are familiar with the EUPRIM-Net course, some having taught it or sent

their staff to it. The course is already mentioned on

Page 27, lines 11-12. PRIMTRAIN is already mentioned, but it is still early days for this COST

action.

Pg. 19, lines 26-28: The sentence has been adapted by the inclusion of continuous development.

Furthermore, the suggestion has been in part included in section 4.5 on page 27.

214. 't Hart, Bert

A., Biomedical Primate

Research Centre,

Rijswijk, Netherlands,

[email protected],

Netherlands

4

SCIENTIFIC RATIONALE Scientific_rationale.p

df

Page 23 line 33-37: I am really happy to see the statement that there can be a conflict among the

3R’s that requires prioritization. The conflict among each of the 3R’s is a complex issue that deserves

much more attention than it receives at this moment; please see also the review article by ‘t

Hart, Clin. Translat. Immunol. 2017.

Page 23 line 33-37: This issue has been tackled in

3.3, “one model can never fully recapitulate all aspects of human diseases. The type of scientific

question asked and the methodology used will

determine how useful and how predictive the results obtained are. This implies that a variety of models,

animal and non-animal, should be used to address different aspects of the same disease. “The validity of


96

Page 35 line 18/19. The conclusion of the paper by

van Meer lacks two nuances that are in the results

section of the paper: - For immunogenicity of fully human mAbs, which

are increasingly used, NHP are predictive as they display the same absence of

response. This is also our own experience.

- Immunity against non-human proteins can be higher or lower than in humans.

Obviously mouse Ig molecules are foreign also to

monkeys and will elicit an immune response that may or may not be greater than in

humans.

Page 38 line 6: it is not clear how iPS cell cultures can be informative about the effectiveness of a drug

in terms of … dosage. How can the PK/PD aspects of a drug be modeled in a monoculture of diffentiated

iPS cells?

a model depends on the context

Page 35 line 18/19

Agreed, but no change to report required.

Page 38 line 6:The Opinion is not suggesting that iPSCs can model PK/PD.

215. Groves, Rebecca,

Patients

Campaigning For Cures

(PCFC) , europeactionf


Kingdom

4 SCIENTIFIC

RATIONALE

Patients Campaigning For Cures (PCFC) is a non-profit NGO run by patients, their families and carers

- for patients. We promote biomedical research

based on current science and critical thinking. Please see uploaded file for our references and

resources. The document from the Scientific Committee on

Health Environmental and Emerging Risks (SCHEER) titled: 'Preliminary Opinion on the need for non-

human primates in biomedical research, production and testing of products and devices (update 2017)'

is entirely out of step with current medical

knowledge and has clearly been written by those who still hold a vested interest in 19th century

scientific principles, including the damaging 3Rs.

97

Claiming that non-human primates (and other

animals) hold predictive value for human patients was first established in 1847, by a French doctor

Claude Bernard, who went on to reject the Theory

of Evolution. Today, medical experts who work in the wider scientific community - outside the vested

interests of animal-based researchers – all agree that non-human primates (and other animals)

actually hold NO predictive value for human patients. These experts include the Editor in Chief of

The British Medical Journal, Dr Fiona Godlee, who made this the focus of her Editors Choice, in June

2104, which concluded by quoting from the paper it

cited: 'If research conducted on animals continues to be unable to reasonably predict what can be

expected in humans, the public’s continuing endorsement and funding of preclinical animal

research seems misplaced.' [1] Pharmaceutical companies also acknowledge the

failure of testing on non-human primates (and other animals) in their drug development process, and

write about this openly in the scientific literature:

http://www.forlifeonearth.org/wp-content/uploads/2013/05/Pharmaceutical-

Company-Quotes2.pdf Our expert medical Board, American and Europeans

for Medical Advancement (AFMA/EFMA) explains how current science understands exactly why

animal models fail the search for effective human treatments and cures. [2-7] The SCHEER

Committee has entirely failed to invite scientists like

these to advise their Opinion: the external experts which form the SCHEER working group are solely

limited to animal modellers and members of the misleading 3Rs community!! In today’s advanced

scientific climate, this is an absolute disgrace.

This is a general statement about the safety

assessment of chemicals including pharmaceuticals, and is not limited to the use of NHP but to ‘animal

models' in general. SCHEER is aware of the limited

number of failures and market withdrawn products due to ADR, but this has to be looked at in

comparison with the number of successful and safe drugs developed following this system.

In this context SCHEER disagrees with the commenter that ‘non-human primates (and other

animals) actually hold NO predictive value for human patients’.

It is obvious that it can be further improved, e.g. by

using powerful methodologies available thanks to the technical and scientific developments of the last

years, most of which based on animal-free models (e.g. cells of human origin).

The SCHEER's opinion is that the use of an appropriate species or combination of models is

essential to obtaining the most reliable and translatable information.

There seems to be a misunderstanding about the

process of developing the SCHEER Opinions: in general, the SCHEER does not invite any experts to

participate in the WGs. The SCHEER WG on non-human primates was set up in line with the Rules of

Procedure of the Scientific Committee; it consists of

SCHEER members and external experts selected from the SCHEER reserve list and from an Open Call for

experts.

98

To continue to ask for a human medical catastrophe to be ‘refined and reduced’ – as part of the 3Rs – is

appalling. Up-to-date science now understands that

non-human primates have never held predictive value for human patients. It does not make sense

to call for ‘alternatives’ to a method that has never existed. Viable human-based research is highly

sophisticated and advanced – this is not an ‘alternative’ to primate modelling.

Patients Campaigning For Cures (PCFC) is led by

136 members of the UK Parliament who are now

calling for a rigorous medical science debate, supported by preeminent primatologist Dr. Jane

Goodall [8]. This science hearing requires referenced position papers and will thoroughly

assess continued claims that non-human primate models advance human treatments and cures. The

debate conditions for this hearing have been endorsed by Britain's foremost human rights

defence barrister, Michael Mansfield QC: evidence

will be judged by highly qualified, independent experts from the relevant fields of scientific

expertise. PCFC would like to take this opportunity to invite

the SCHEER Committee to please free itself from the grip of outdated special interest groups and help

us call for this vital medical debate, to fairly judge which of the opposing scientific positions is correct.

This is a matter of life and death for patients who

are fighting for their health and lives.

216. Kaylor,

Sharon, individual,

[email protected],

4

SCIENTIFIC RATIONALE

A timetable for phasing out primate experiments is


Replacement must mean replacement! The use of

See reply to comment 21.

99

Other, United

States

other animal species, such as mice and pigs, over

primates, is misrepresentation of the definition of ‘replacement’.

Unsubstantiated claims about the necessity for primate experiments. Mentioning casual

“similarities” between humans and other primates is NOT scientific evidence that primate species are

indispensable in research.

217. Owen, Louise, For Life On

Earth (FLOE), floelouise@g

mail.com, United

Kingdom

4 SCIENTIFIC

RATIONALE UPDATED_Comment_by_For_Life_On_Earth__FLOE_.pdf

The document from the Scientific Committee on Health Environmental and Emerging Risks (SCHEER)

titled: 'Preliminary Opinion on the need for non-human primates in biomedical research, production

and testing of products and devices (update 2017)' is not evidence-based and should undergo rigorous

reassessment by qualified independent experts. It is

clear that the people responsible for the SCHEER Opinion either have a vested interest in animal

modeling or are tools for the industry, including its supportive 3Rs.

The science explaining why animal models

absolutely fail to achieve predictive value for humans has been published numerous times in the

peer-reviewed scientific literature. Experts

publishing on this position are far too many to name here, but include Dr Fiona Godlee, Editor in Chief of

the British Medical Journal, scientists from the drug development industry - who publish regularly on the

failure of animal models - and Dr Ray Greek. Scientists like these were clearly prevented by the

special interest groups from communicating their findings and positions to SCHEER. What is needed

The scientists working for the Scientific Committees,

in their respective roles (members, external experts),

fully meet the requirements set in the Rules of Procedures of the Scientific Committees. These Rules

of Procedures are publicly available on the website as are the CVs and declarations of interest from each

scientist working for the Scientific Committees, according to the transparency policy of the

Committees.

This is a general comment about the safety

assessment of chemicals including pharmaceuticals, and is not limited to the use of NHP but to ‘animal

models’ in general. SCHEER is aware of the limited number of failures and market withdrawn products

due to ADR, but this has to be looked at in comparison with the number of successful and safe

drugs developed following this system.

In this context SCHEER disagrees with the commenter that ‘animal models absolutely fail to

achieve predictive value for humans’. It is obvious that it can be further improved, e.g. by


100

now is for such biased special interest groups to be

recognised for what they are.

A March for Science will take place on April 22 in Washington, DC and other cities in the USA. The

march is advocating for people, society and

government to take science more seriously. According to the US magazine 'The Atlantic' four of

the goals of the march are:

1. Protect science from “manipulation by special interests.”

2. Support science education that teaches people “to think critically, ask questions, and evaluate truth

based on the weight of evidence.”

3. Encourage political leaders and policy-makers to enact evidence-based policies, and “make use of

peer-reviewed evidence and scientific consensus, not personal whims and decrees.”

4. Oppose “policies that ignore scientific evidence” or “seek to eliminate it entirely.”

Such goals have always been a part and parcel of the scientific endeavour and any committee

concerned with science should adhere to these

principles. For Life on Earth is asking the European Commission to honour the requests being made by

this march in the US.

Any Opinion about animal modeling should be based on current science that is relevant to the topic and

judged by experts in these fields. The UK is leading

using powerful methodologies available thank to the

technical and scientific development of the last years, most of which based on animal-free models (e.g. cell

of human origin).

The SCHEER's opinion is that the use of an appropriate species or combination of models is

essential to obtaining the most reliable and translatable information.

No reply needed; relevance of the comment to the SCHEER Opinion is not clear.

101

the call for this rigorous peer-reviewed scientific

debate. Preeminent primatologist Dr. Jane Goodall and 136 members of the UK Parliament, to date,

are calling for independent qualified experts in

science to judge animal modelers’ claims that experiments on non-human primates are capable of

predicting the responses of human patients.

In contrast, we note that the external experts advising this SCHEER Opinion are entirely limited to

members of the animal model community and its 3Rs support network. This SCHEER Opinion has

been formed without any input from expert

scientists who oppose the 3Rs as an outdated system, or scientists who think animal modeling

should be abandoned on scientific grounds alone. This results in SCHEER unabashedly supporting

primate modellers and the now falsified claim that experiments on nonhuman primates hold predictive

value for human patients.

Current science is explained by Drs. Greek and

Shank’s Trans Species Modeling Theory, which is founded upon current understanding of evolutionary

biology and complex system. Experiments on non-human primates (and other animals) are now

demonstrably proven to fail the search for safe and effective human treatments and cures. Claims to

the contrary need to be weighed against current science, and controversies judged by qualified

independent experts - who do not hold a vested

interest in the outcome of such a vital decision.

The scientists working for the Scientific Committees, in their respective roles (members, external experts),

fully meet the requirements set in the Rules of Procedures of the Scientific Committees. These Rules

of Procedures are publicly available on the website as

are the CVs and declarations of interest from each scientist working for the Scientific Committees,

according to the transparency policy of the Committees.

218. No agreement

to disclose

personal data

4

SCIENTIFIC

RATIONALE

SCIENTIFIC RATIONALE

Page 22 Line 20 • Is this all research? Are there opinion polls specific

for safety testing of pharmaceuticals?

Page 22 Line 20 The Committee Opinions only rely on scientific sound

studies (polls), and could not identify this type of poll focussing on the safety of pharmaceuticals.

102

Page 22 Line 21

• “Need to include the importance of protecting human safety.”

Page 23 Line 25-26

• But there are very few alternative tests today that meet this standard. The current state-of-the science

should not be exaggerated.

Page 23 Line 29-30

• Although this concept has merit the statement also implies that animals are suffering needlessly.

Where is the evidence for this?

Page 25 Line 27-29

• These references are more "opinion pieces" than

scientific publications. They lack significant credibility and based on selective or partial

information. The IQ DruSafe consortium has published a response which is not captured

anywhere in your references. See Mangipudy et al.(2014) Regul Toxicol Pharmacol 70(2): 439-41.

Also, refer to a publication by Monticello (2015) Toxicol Pathol 43(1): 57-61, which discusses an IQ

DruSafe initiative to assess the correlation of

preclinical and clinical safety data in drug development. These 2 publications must be included

for balance and perspective.

Page 25 Line 36 • What fraction of NHP use does this represent? It

was stated previously that the majority of NHP use

Validated polls can be found on p22, line 21 and the

UK MORI survey (2O16) has been added. The human safety aspect has been mentioned

several times throughout the Opinion.

Page 22 Line 21

This has been added to the text.

Page 23 Line 25-26

The SCHEER is aware of the low number of alternative tests, but are confident that this is

constantly increasing.

Page 23 Line 29-30

The forementioned reference contains good/similar suggestions on how to reduce the use of animals.

They were added to the references but the text has not been changed.

Page 25 Line 27-29

The Opinion can only rely on published reports

regarding this subject. The main problem is how data are reported, whch is something that journals at now

placing more emphasis on. This has been included in the Opinion (line 14-16, page 26).

Page 25 Line 36 Fraction has been added. Additional data as well as

statistical analysis on the use of NHPs like

103

is for pharmaceutical safety testing.

Page 25 Line 37-44 • This analysis is much too generalized and does

not take into account the objectives and methodology for each specific paper. While there

may certainly be examples of poor study

design/analysis, it is unfair to report it in such a generalized way.

Page 31 Line 30-33 • Please refer to the 2 publications. Mangipudy et

al.(2014) Regul Toxicol Pharmacol 70(2): 439-41. and Monticello (2015) Toxicol Pathol 43(1): 57-61,

which discusses an IQ DruSafe initiative to assess

the correlation of preclinical and clinical safety data in drug development.

• These 2 publications must be included for balance and perspective.for additional perspective.

Page 31 Line 44-45

• The reality is that just the opposite is happening. That is, because of their unique closeness to

humans, NHPs are often the only species used in

testing of biopharmaceuticals such as antibodies.

Page 33 Line 5-6 • No, it is not a "requirement". It is an expectation.

There is a difference.

breakdowns e.g. by primary purposes, specific

research area or severity of treatment vary among the Member State reports. In addition, 2014 was the

first year for reporting under a new format. Therefore

no further statistics could be carried out by the SCHEER to provide additional reliable information or

trends regarding the use of NHPs.

Page 25 Line 37-44 Disagree, the SCHEER judges the level of detail

sufficient for the purpose of this discussion.

Page 31 Line 30-33 Agreement to add these 2 publications after "clinical

trials", line 33.

No specific comment, no reply is needed.

Page 33 Line 5-6 The SCHEER is aware that it is not a requirement but

have mentioned that it should be considered.

104

Page 33 Line 15

• Actually, it will almost certainly hinder development of new medicines.

Page 34 Line 1-4 • One possible exception does not invalidate an

entire animal model. Using this one example to support a broad view on NHP safety testing seems

to reflect significant bias.

Page 35 Line 7-8 • Absolutely agree. However, the reality is that

NHPs are often the most relevant species for safety

testing of biopharmaceuticals. • Also, we have learned from the Tegenero

experience that the best way to test for potential cytokine storms is by using in vitro tests with

human cells.

Page 35 Line 18-19 • This statement is very misleading. There are

mostly quantitative but not qualitative differences in

the immune response between NHPs and humans.

Page 35 Line 18-19

• We do not do animal studies to assess the immunogenic potential of a biopharmaceutical. We

do the studies to test for other toxicities. This statement is not relevant to this discussion.

• Work is ongoing to try to develop other assays to

assess potential IMG in humans, but this is separate from this discussion, since animal studies are not

conducted for this purpose.

Page 35 Line 37-39 • Again a bit misleading since there are still

concerns/issues with the true predictivity of in vitro

Page 33 Line 15

The SCHEER agrees with the comment.

Page 34 Line 1-4 The main point here is that there are recognised

limitations to using NHPs. No change to the report required.

Page 35 Line 7-8 Agreed, but no change to the report required.

No specific comment. The comment is in agreement with the proposed text.

Page 35 Line 18-19 Disagree, there are reports of qualitative differences

and it has been suggested that this is why TGN1412

appeared to be non-toxic in NHPs.

Page 35 Line 18-19

Disagree, some researchers are still using NHPs to investigate immunotoxicology.

Page 35 Line 37-39 Agreed, but no change to report required.

105

teratogenicity tests. However, they are being used

more frequently as early screening tests. The ongoing revision/update to ICH S5 guidance for

reproductive toxicity testing, is likely to reference

the use of these assays.


Cruelty Free

International, jarrod.bailey


g, United Kingdom

4.1

Introduction

P22 L3-6

As discussed in the hearing, please would you insert

a paragraph explaining the methodology used by the SCHEER WG; how did it derive this Opinion? To

what extent has an independent literature review been performed or is the opinion heavily reliant on

the information provided during the public call?

Thank you. The final Opinion will indeed contain a

separate chapter discussing the data collection and

selection.

220. No agreement


4.2 Ethical

issues

What is exactly the ethical dilemma in using NHP?

This report refers to this concept at different times (Page 7 line 12 or page 22) but without clearly

defining it.

What is underlying this « ethical dilemma ». Is it

because they are non-domestic? The zoonotic risk ? The breeding and transport? Their cognitive and

emotional abilities? Furthermore, it seems that this « ethical dilemma » is for granted. From what study

is the « high levels of public concern about NHP research” coming from? Page 22 line 35.

The species of NHP used for scientific purposes are

not great apes in EU but mostly macaques bred in

captivity. A chimpanzee is not macaques in terms of consciousness, cognitive and emotional abilities.

Why is it more relevant to ban the use of macaque compared to pig or dog? Ethically speaking, is the

life of a macaque more important than the life of a pig or a dog?

The ethic remains in the arm benefit assessment

(describe page 22/Line ç or page 58). If the use of

NHP benefit to the human health, and patient life,


106

then it is worthwhile. The ethical issue relies in our

duties to guarantee the best living conditions for the animals: provide NHP with a very high standard of

housing and care, that complies with their need and

where minimal negative impact on physical of psychological health can be recorded.

221. Lindsay,

Marshall, Humane



Kingdom

4.2 Ethical

issues

Page 22, Line 27

We are concerned that the conclusions of the Bateson review are effectively cited without

challenge here. In Knight (2011), analysis of the Bateson review revealed that NHP who did not

recover as a consequence of the procedures carried out on them, or had to be euthanised after

experimental infection, were not taken into account and so the Bateson review significantly

underestimates the ‘harm’ to the animal. Directive

2010/63 explicitly states that ‘The likely harm to the animal should be balanced against the expected

benefits of the project’ and we would consider that death, as a consequence of the human

intervention(s) in the lab, is significant harm to the animal.

The experiments reviewed by Bateson were broadly

justified on the grounds of scientific value or future

medical potential, although there was little evidence of actual medical impact, despite the emphatic

assertions of the scientists using NHP. This over-exaggeration of the ‘need’ for NHP damages the

public perception of science and mars the ability of society to assess their willingness to allow or fund

such studies. We believe that, in reporting on the requirement for NHP in any study, the likely impact

has to be precisely quantifiable and demonstrate an

actual medical benefit.

The Bateson review is the most evidence-based and

systematic review to-date of the outputs and impacts of NHP research. Knight (2011) recognises this and

finds much to support. We do not agree with the criticism that the Bateson Panel underestimated the

‘harm’ caused to the animals. Euthanasia of animals as an integral part of the experiment is morally

relevant and was factored into the harm-benefit

analysis.

222. Marshall,

Lindsay,

Humane

4.2 Ethical

issues

Page 23 Line 17

We agree that there “is a need to ensure that as

new knowledge, technologies and approaches


107

Society


.org, United

Kingdom

emerge there is timely assessment and evolution of

research strategies”. We believe the Commission should consider establishing an independent cross-

sector expert committee on alternative methods,

with the remit of keeping replacements under review and streamlining their uptake into all

relevant EU legal instruments and guidelines. This would help ensure consistency in risk assessment

across sectors, reduce duplication, and prevent the Directive being undermined.

We feel that it is imperative to compile guidance on

alternatives to NHP procedures, aimed at alerting

Member State competent authorities to methods or research strategies that could be pursued instead of

a proposed NHP project to progress understanding of a disease or therapy. This guidance should be

used in all project evaluations.

risk management is outside of the scope of the

SCHEER.

223. Nichols , Brenda,


Canada

4.2 Ethical issues

Please stop hurting these animals. The commenter does not provide any suggestions for improvements of the scientific basis of the SCHEER


224. Rowena, Li, Rowena.li@ho

tmail.com, Netherlands

4.2 Ethical issues


225. Nicholetts ,

Tara, Teacher, Tarahelwn28

@hotmail.co.u

k, United Kingdom

4.2 Ethical

issues

This is disgusting. These animals have feelings;

both mental and physical, and you are depriving them of the life that they deserve. I hope you are

ashamed of yourselves. If I was as awful as you

then I would wish this sort of treatment would be upon you in a later life, but I don't think any animal

should be treated in such an appalling manner and so I just hope your dreams are full of the torture

that you cause. I hope you never forget it.



226. Lightfoot, David, world

4.2 Ethical issues

Please leave my brothers alone !!!! The commenter does not provide any suggestions for improvements of the scientific basis of the SCHEER

108

population,

davidlightfoot1944@yahoo.

co.uk, United

Kingdom,


227. Baines, Julia,

People for the




4.2 Ethical

issues

p. 22, lines 8-21 and 39-43: As acknowledged by

SCHEER, the widely acknowledged similarity of

NHPs to humans and the inability of NHPs to consent to participation in experiments introduces a

critical ethical dimension to considerations surrounding the use of NHPs in research. However,

SCHEER fail to consider the pyhlogenetic similarity between great apes and other primate species or

the remit under which the use of great apes was restricted in Europe. When the outdated Directive

86/609/EEC was being revised, the European

Parliament called for a ban on the use of great apes on the basis of phylogenetic similarity, public

opposition, advancement in non-animal methods, species differences, meaning that primate

experiments can never match the precision of human-based studies, and threat of extinction and

the associated difficulties to protect primates from threats such as human consumption if it’s perceived

that these species are used freely by Western

academic institutions (http://ec.europa.eu/environment/chemicals/lab_an

imals/pdf/fische_suite.pdf). All of these reasons can equally be applied to other branches of primates.

p. 22, lines 22-34: SCHEER mention the utilitarian

approach to the prospective harm-benefit analysis but no critical discussion is given in the opinion. At

the very least, the problems associated with this

approach should be noted, such as the difficulties in projecting potential benefits and the arguments for

primates to be given due moral consideration should be equally considered.

p. 22, lines 8-21 and 39-43: This Opinion is a

scientific opinion and not a political opinion. The

SCHEER recognises the similarities between human and non-human primates and sees that ethics,

human safety and science must be balanced when working to implement the 3Rs – including continuous

progress in adding/using more alternatives and less NHP.

p. 22, lines 22-34: The SCHEER has explained the

harm-benefit balance throughout the text and especially on p22, giving the legal context and

guidelines how this should be balanced out.

109



Jarrod.bailey


g, United Kingdom

4.2 Ethical

issues

P22 L8-9

As stated earlier: P10 L25

Phylogeny is not sufficient to support this

unreferenced opinion. It should be stated as opinion, and referenced if possible.

P22 L9-13

As stated earlier: P10 L27

This is too general. Where do alternatives not exist? We believe there are always alternatives. If ‘certain

sections of the scientific community’ (presumably

those that use NHPs) believe there are not alternatives to some types of NHP use, they should

provide evidence, which should be assessed critically. If there were areas where NHPs are

‘better’ than alternatives, this must be proven.

P21 L15-17 “…where alternatives do not exist.” Where is this

proven? Under what criteria? How are NHPs

necessary and human-relevant in any proposed area?

This is too vague, and assumes that alternatives ‘…do not exist’ for some NHP uses. We believe there

are no areas where alternatives do not exist. However, as this is controversial and there are

contrary opinions, we suggest stating something similar to: ‘where it is argued that alternatives

might not exist’, and also suggest highlighting these

areas for further analysis – rather than following with a statement that NHP use is essential.

P22 L19-21

The citation of polls of public opinion against NHP use is welcome. However, these are not cited

elsewhere, and should be, e.g. P7, L15, and p14,

P22 L8-9 Please see replies to comments 182 and

212.

P22 L9-13 Please see replies to comments 182 and

212.

P21 L15-17 Refer to comments 182 and 212.

P22 L19-21 The Committee agrees that the UK MORI

survey (2O16) is not cited – and is now added. For all clarity:


110

L21. Furthermore, the UK MORI poll should be cited

to support this statement:

Only 16% of respondents supported the use of

macaque monkeys for medical research to benefit people in a UK MORI poll in 2014 (Clemence and

Leaman 2016) and in 2010, 56% of Europeans agreed that scientists should not experiment on

larger animals like dogs and monkeys for the improvement of human health and wellbeing (TNS

Opinion & Social (2010). Special Eurobarometer 340 “Science and Technology” (Wave 73.1). Available

at: https://open-data.europa.eu/data/

dataset/S806_73_1_EBS340).

P22 L44 – P23 L1-7 The 3Rs cannot, and should not, be used here to

diminish the fact that, according to the cited Ipsos MORI poll of 2014, just 16% of people supported

the use of macaques in science to benefit people.

This should be reiterated, here.

P24 L2-9 This section needs to be updated, to improve

accuracy and to contain more recent references (the ones used are 11 years old) and opinion. It is

entirely possible to successfully send NHPs to sanctuaries, even ones used in neuroscience. The

‘welfare costs’ are unclear and we believe, in most

cases, are unlikely to outweigh the huge welfare benefits of being released from the laboratory.

There are recent examples from Italian animal group LAV (http://www.lav.it/en//16-macaques-

freedom) and at ape sanctuary Stichting AAP in the Netherlands (www.aap.nl/en). Advice is available

here https://www.nc3rs.org.uk/rehoming-ex-

following key findings are noted:

Public attitudes towards the use of animals in research have shifted little between 2014 and 2016.

A majority (65%) say they can accept the use of

animals in research as long as it is for medical purposes and there is no alternative, whilst support

for an outright ban on animal research stands at 26 per cent.

Provisos remain however – whilst medical and

scientific research both attract majority acceptance, the public are less accepting of using animals in all

types of research, and there is a less than majority

acceptance of all forms of non-medical chemical testing

P22 L44 – P23 L1-7 Please see the reply above

P24 L2-9 The reference to the report from the Netherlands

National Committee has been added. The Opinion is still in line with these reports.

111

laboratory-non-human-primates and Rehoming of

former laboratory animals. Opinion of the Netherlands National Committee for the protection

of animals used for scientific purposes (NCad) 2016,

available from https://english.ncadierproevenbeleid.nl/

229. The British

Toxicology Society,

[email protected],

United Kingdom

4.3 Housing

and husbandry

Section 4.3 Housing and husbandry

We completely agree with the points made in this section and would point to extensive cross company

visits and sharing of best practice in NHP husbandry. The three major CROs in Europe,

Covance, Charles River and Envigo, have all had extensive information sharing mutual exchanges in

the past five years involving visits to each other’s facilities.

Thank you for your support to the SCHEER


230. Baines, Julia,


Treatment of



4.3 Housing

and husbandry

p. 24, lines 11-24: SCHEER fail to recognise that

many NHPs, used for research and breeding, are held in conditions that fail to meet their ethological

needs. Standard laboratory housing for NHPs lacks

sufficient space, meaningful cognitive stimulation, and adequate social contact—causing significant

psychological and physical distress. NHPs are deprived of the ability to make meaningful choices

in their lives before they are killed at the hands of experimenters.

We recommend that a central panel of experts in primate ethology be convened to establish clear and

well-defined standards for the ethological

appropriateness of environments in which NHPs are held. It is well established that when primates are

held in impoverished conditions—deprived of companionship, sufficient space, and sufficient

environmental complexity—they experience a harmful chronic stress response and develop

behavioural abnormalities, including stereotypic and self-injurious behaviours

(http://www.fao.org/fileadmin/user_upload/animal

welfare/StereotypicAnimalBehaviour.pdf). Current

Regulations on the housing and care of NHP in

Europe have improved considerably over the last 10 years. Centres in Europe that breed NHP for research

purposes all fulfil strict requirements that meet their

ethological needs. There is no evidence that this is not the case. Also in research, animals can only be

housed single when there is strict scientific justification and approval by the competent

authorities. Implementation of training and enrichment programmes are in place in most centres

using NHP. Current animal welfare is checked by the Animal Welfare Bodies and Designated Veterinarian.

112

EU standards still allow for NHPs to be singly

housed alone, in small and sterile cages—with little consideration to the impact of such bleak conditions

on the welfare of the animals. Moreover,

meaningfully addressing the alarming rates of abnormal behaviour exhibited by NHPs in

laboratories would help address the confounding variables introduced into biomedical

experimentation for humans based on animal models through the use of psychologically

traumatized animals—and help safeguard the considerable resources funnelled into experiments

on NHPs.

At its foundation, an ‘ethologically appropriate environment’ is an attempt to approximate the

living situation of free-roaming animals with a captive environment. As Honess and Marin have

commented, “[p]roducing an environment that encourages animals to indulge in an appropriately

balanced repertoire of natural behaviours that resembles as close as possible that of wild

conspecifics will result in animals [who] are

significantly more psychologically healthy than those with restricted, disproportionate repertoires.

This will in turn result in healthier animals through a reduction of injury associated with excessive

aggression and self-injurious behaviours, lower stress levels and associated vulnerability to

opportunistic infection and neurological damage [and] a more accurate model for research (2).

For NHPs, such an attempt at approximation must take into account social housing, access to

outdoors, exercise spaces, home cage enrichment, and considerations pertaining to noise and music.

An ongoing concern is that laboratories sometimes permit single housing of NHPs for the sake of

convenience rather than necessity. For example,

113

many laboratories singly house NHPs who have had

surgical implants, such as head posts or other equipment, even though it is possible to

successfully house them socially. Ethologically

appropriate environments must include outdoor spaces, which decrease stress, aggression, and

stereotypies in NHPs, and appropriate environments for exercise, allowing for normal locomotion,

including quadrupedal walking and running, vertical climbing and clinging, leaping, and swinging.

Additionally, ethologically appropriate environments for NHPs must reduce noise and music in

laboratories and maximize enrichments. Enrichment

of the physical environment is often limited to the provision of a perch, a mirror and a toy or other

manipulanda. The evidence now available in the scientific literature suggests that such a regimen is

inadequate—not only does it fail to promote psychological well-being—it fails to prevent

pathology (3).

References: (1) Mason & Rushen 2006, (2) Honess

& Marin 2006, (3) Baker 2007

231. Stephan,

Valeska

Marija, PRIMTRAIN,

[email protected],

Germany

4.3 Housing

and

husbandry

p.24, l.18-24

Comment:

“Positive Reinforcement Training and Animal Behaviour Management are essential when working

with large animals in biomedical research (in particular with non-human primates). The COST

Action “PRIMTRAIN” provides a network for personnel working with non-human primates and

other large laboratory animals to facilitate the competence and skills needed to successfully apply

Positive Reinforcement Training and Animal

Behaviour Management. The central aim of PRIMTRAIN is to create a network in which

knowledge and experience are openly shared and state-of-the-art education and training is promoted

This has been adapted.

114

to facilitate the implementation of best possible

practice in ones own facility. In order to achieve this, regular meetings are held to share experience,

gain knowledge and develop and refine animal

training protocols; furthermore a proposal for a minimum European standard for animal training in

NHP will be suggested.”

Suggestion for adjustments in the text Improvements also include the development and

implementation of animal training protocols designed to encourage animals to co-operative

voluntarily with husbandry and scientific procedures

(e.g., Prescott and Buchanan-Smith, 2003, 2007; Prescott et al., 2005; Graham et al., 2012; Coleman

and Maier, 2010). A European network (PRIMTRAIN) is in place to develop and exchange

animal training protocols; one aim is to propose a minimum European standard for animal training for

NHP facilities.

232. Bailey, Jarrod, Cruelty Free


@crueltyfreein


Kingdom

4.3 Housing and

husbandry

No evidence is provided to show that any of the enrichments described are in place. Unless there is

evidence of wide implementation and use, this is all theoretical.

It is not conclusive that they’re a panacea. While

enrichments may be beneficial in some circumstances, enrichment may be a source of

stress (Baumans, V. 2005. ILAR J. 46, 2, 162-170), and may alter brain structure, function and

physiology (Rasmussen, S. J Am Assoc Lab Anim Sci. 50, 4, 479-483). No matter the level of

enrichment, animals in labs still experience

significant intractable stress and stressors that affect welfare and experimental data, e.g.

anaesthesia, restraint, blood sampling, food/water restriction, noise/light, cage changing/cleaning,

There is the obligation to have sufficient measures in place with respect to enrichment as stated in the EU

directive and checked by the Animal Welfare Bodies and Designated Veterinarian.

The effect of handling on animals is not the topic of this Opinion.

115

social crowding/isolation, and others (Bailey, J.

2016. Stress in Animals in Laboratories is Inherent, Unavoidable, Causes Psychological and Physiological

Harm, and Significantly Confounds Experimental

Results. IN PEER REVIEW).

Anaesthesia increases cortisol in chimpanzees for up to two days (Anestis, S. F. 2009. Stress. 12, 1, 49-

57), and repeated ketamine anaesthesia in rhesus and green monkeys leads to significant and

sustained reduction in food intake (Springer, D. A. and Baker, K. C. 2007. Am J Primatol. 69, 10,

1080-1092); monkeys experience stress during

housing transition (Clay, A. W. 2009. Am J Primatol. 71, 1, 30-39), resulting in “...significant, long-term

changes in physiological and behavioural measures of stress and anxiety” (Lilly, A. A. Am J Primatol.

48, 3, 197-223). “Room disturbances” affect white blood cell parameters in rhesus macaques

(Capitanio, J. P., Mendoza, S. P., and McChesney, M. 1996. Influences of blood sampling procedures

on basal hypothalamic-pituitary-adrenal hormone

levels and leukocyte values in rhesus macaques (Macaca mulatta). J Med Primatol. 25, 1, 26-33); in

rhesus macaques, “sustained increases in heart rate” are documented during cage change, and

room disturbances result in changes in white blood cell parameters (Line, S. W., Markowitz, H.,

Morgan, K. N., and Strong, S. Effects of cage size and environmental enrichment on behavioral and

physiological responses of rhesus macaques to the

stress of daily events. In In: Through the Looking Glass. Novak & Petto (eds). Washington, DC: 1991;

160–79., American Psychological Association; Clarke, A. S., Mason, W. A., and Mendoza, S. P.

1994. Heart rate patterns under stress in three species of macaques. Am. J. Primatol. 33, 2, 133-

148); cynomolgus macaques show increased heart

116

rate and suppressed respiratory sinus arrhythmia

simply in the presence of unfamiliar humans (Bowers, C. L., Crockett, C. M., and Bowden, D. M.

1998. Differences in stress reactivity of laboratory

macaques measured by heart period and respiratory sinus arrhythmia. Am J Primatol. 45, 3, 245-261);

and removal of cage-mates causes stress responses in many species, including marmosets (see Ferland,

C. L. and Schrader, L. A. 2011. Cage mate separation in pair-housed male rats evokes an acute

stress corticosterone response. Neurosci Lett. 489, 3, 154-158).

233. Treue, Stefan,

EUPRIM-NET, a EU-funded

network of

European Primate


uprim-net.eu),

[email protected], Germany

4.3 Housing

and husbandry

pg. 24 lines 21-24: statement about PRIMTRAIN

Comment: This in an incomplete description of the

players and the current situation.

Recommendation: Replace the sentence “A

European network … NHP facilities.” with the sentences “In the past EUPRIM-Net has developed

such training protocols and has disseminated them extensively across European NHP facilities.

Currently, EU COST-Action PRIMTRAIN continues the develop and exchange of these protocols

working towards implementing a European standard

for animal training at all NHP facilities.”

This has edited to: A new EU COST Action (PRIMTRAIN) is in place to develop and exchange

training protocols, building on the earlier work of the

EUPRIM-Net consortium. It aims to implement a minimum European standard for animal training for

NHP facilities.

234. Lindsay,

Marshall,

Humane Society



4.4 Animal

welfare

standards outside the

EU

Page 25 Lines 1-3

The approach taken by the UK to ensure that

funding of work requiring NHP adheres to high welfare standards could be adopted throughout the

EU. Where possible, national 3Rs centres could evaluate projects on a case-by-case basis. Where

no national 3Rs centre exists, then we believe that the establishment of an independent cross-sector

expert committee could review applications. This would help ensure consistency in risk assessment

across sectors, reduce duplication, and prevent the

Directive being undermined.

More recommendations were added in the final

Opinion. Implementation of the recommendations is outside of the scope of this Opinion.

117

235. MEUNIER,

MARTINE, BioSimia

France

network for non-human

primate research in

neuroscience, immunology,

and infectiology

(CNRS),

[email protected],

France

4.4 Animal

welfare standards

outside the

EU

Animal welfare outside the EUs and potential

implications for biomedical research should the use of non-human primates be banned in the EU.

The SCHEER opinion acknowledges that "if NHP research is forced outside Europe then there would

likely be a net decrease in animal welfare" (page 24 line 42) as "animal welfare standards for laboratory

NHPs are on average higher in many European countries than in other parts of the world" page 24

line 26.

As evoked page 24 lines 1-9, the existing strict EU

regulations for NHP use are currently able to impose standards to the rest of the world as European

companies or, for academic research, European public funders such as the MRC in UK or INSERM in

France, are entitled to require the same high standards whether the studies are carried out inside

or outside Europe.

We would like the committee to acknowledge that

the same would no longer hold true should the use of non-human primates be banned in the EU. How

could companies justify carrying abroad research judged unnecessary / unethical at home? Similarly,

regarding academic research, the MRC, CNRS and other public funders would no longer fund any NHP

research, and European researchers no longer carry out NHP studies whether inside or outside Europe.

How could Europe accept NHP research abroad and

contribute if it bans it in its own nations? Because NHP research has important impacts in biomedical

research and safety for new therapies, it would nevertheless continue in North America, Asia, or

Africa, possibly with decreased welfare standards.

This concern is addressed in the Opinion in section

4.4.

118

236. Fentener van

Vlissingen, Martje,

ECLAM,

[email protected],

Other, ECialistsLAM

is the Europe-wide college

of veterinary specialists in

laboratory

animal medicine

4.4 Animal

welfare standards

outside the

EU

There is also an ethical dilemma connected should

European health care use research outcomes that were obtained under conditions that we would

consider substandard. If this is the outcome of

further restrictions to NHP use in Europe, that could become hypocritical.

The current Opinion is not about restrictions but

summarises the current situation based on scientific data.

237. Baines, Julia,


Treatment of Animals UK,


Kingdom

4.4 Animal

welfare standards

outside the EU

Please see comments made in reference to section

4.3 Housing and Husbandry. p. 24, lines 26-41 and p. 25, lines 1-17: SCHEER

fail to recognise that many NHPs, used for research and breeding, are held in conditions that fail to

meet their ethological needs. SCHEER refer to UK advisory guidelines on the housing and husbandry

of NHPS (lines 2-3), such guidelines should be adopted as the minimum acceptable standard

across all EU Member States. Furthermore, Member

States must be able to improve standards beyond the minimum requirements set out in Directive

2010/63/EU and not be interpreted as ‘gold-plating’. As advances are made in animal welfare science it

is essential that the Directive allows for flexibility in national legislation that seeks to improve animal

welfare, implement measures pertaining to the 3Rs and takes into account the significant public concern

on animal experimentation.

p. 25, lines 18-22: It is repeatedly asserted within

the opinion that restricting the use of primates in Europe will lead to research moving abroad where

See replies to earlier comments regarding conditions

that meet their ethological standards (230).

The Directive provides the minimal standards for housing and husbandry.

p. 25, lines 18-22:

These are currently the only references that provide at least the evidence that research is moving abroad.

119

animal welfare standards may be lower, yet the

evidence given in support is weak. Two papers are cited as evidence of this within the opinion

(Cryanoski, 2016 and Anon, 2016). However, Anon

(2016) is an editorial based on a news feature (Cryanoksi, 2016) within the same journal issue; no

empirical evidence is given to justify the claim. SCHEER should note that when tests on animals are

banned we see a thriving expansion in innovative, humane nonanimal approaches that can have

numerous applications, as evident when the European cosmetics animal testing ban came into

effect. The tests developed and adopted as OCED

test guidelines have been implemented worldwide and, the use of animals for testing cosmetics has

been banned in India, Israel, Norway, Turkey, New Zealand, Australia, and Switzerland; similar

legislative measures are under development in Brazil, Canada, Taiwan, Argentina, Russia, South

Korea, Guatemala, and the United States.

There is no evidence that banning the use of animal

models in the very diverse and complex biomedical research area will have the same effect as has been

the case with the banning of the relative

straightforward safety & toxicity testing of non-medical products such as cosmetics.



@crueltyfreein


Kingdom

4.4 Animal welfare

standards outside the

EU

P24 L26-41

This has little or nothing to do with the question at hand, namely the scientific need for NHP research in

the EU.

While there is some discussion of cage sizes and social housing, the NHPs are, of course, still being

housed indoors and subjected to experiments.

It was noted in the SCHEER NHPs Public Hearing by an advocate of NHP research that (paraphrasing),

“One cannot sweep one’s own doorstep and ignore everybody else’s.” However (to stay with the

metaphor), sweeping one’s own doorstep is a start

when one wishes to clean up the surroundings, too. It is no excuse to leave yours dirty because others

may be dirtier still.

P24 L26-41

This provides part of the conditions that are involved in the use of NHP in research in Europe. In this

context this is an important issue.

120

P24 L42 -P25 L22

This section needs to be consistent in its opinion here. We welcome the inclusion of the arguments

that animal welfare need not deteriorate if

conducted outside of Europe because companies and funders can (and morally should) still require

the same standards of housing and care. Furthermore, whilst we appreciate the point about

cage sizes and social housing, there is no other evidence that experimental procedures or levels of

care are otherwise worse outside the EU. The animals are still subjected to experimental

procedures and live inside a laboratory in Europe. It

is by no means established that increased cages sizes or social housing ameliorates the detrimental

effects of this to any significant extent.

P24 L42 -P25 L22

With respect to the welfare: there is evidence that social housing and larger cages do improve the well-

being of NHP as judged by a decrease in atypical

behaviour and the effect on immune responses (see e.g. Benton CG, JAALAS 2013, 52:240-246). In that

respect, animals are worse off when standards were lower.


Martje, ECLAM,

[email protected],

Other, ECLAM is the Europe-

wide college

of specialist veterinarians

in laboratory animal

medicine

4.5 Experimental

Design and staff training

P27 lines 25-27 The necessary involvement of veterinary expertise should be indicated here. Vets

are typically trained to apply proper surgical techniques including aseptic technique, and the

application and monitoring of anesthesia, pain management, infection management et cetera. As

per Directive, every licensed establishment is to contract a Designated Veterinarian (art 25). And the

laboratory veterinary profession (laboratory animal

medicine) is well recognized in Europe and organized in ESLAV and ECLAM (the latter

representing the specialist level in this field).

The final Opinion has been adapted and includes veterinarians.




g, United

Kingdom

4.5 Experimental

Design and staff training

P25 L24-33 “There is no reason to suspect that NHP research is

any better in this regard than other fields of in vivo research.” In fact the paper (Taylor, K. Reporting

the implementation of three Rs in European primate and mouse research papers: Are we making

progress? (2010). Alternatives to Laboratory

Animals, 38: 495-517) shows that there has been

The SCHEER notes the Taylor paper. However, in the SCHEER's opinion it is not an appropriate supporting

reference for this sentence, given that it appears to show a very slight improvement in reporting for NHP

studies over mouse studies.

121

no significant improvement in reporting of

implementation of 3Rs parameters between 1986 and 2006 and no difference between mouse and

NHP research papers in this regard.

241. Treue, Stefan, EUPRIM-NET,

a EU-funded

network of European

Primate Centres

(http://www.euprim-

net.eu), [email protected]

u, Germany,

4.5 Experimental

Design and

staff training

pg. 26 lines 35-36 statement on the presumed duration of NHP-specific training.

Comment: This statement might reflect the UK-

situation at the time of the Weatherall Report (cited at the end of the paragraph) but does not reflect a

current common cross-European situation. Instead the available NHP-specific courses mentioned earlier

provide extensive NHP-specific training and are in wide use.

Recommendation: The sentences “First, NHP-

specific training … (Weatherall et al., 2016).” should

be replaced by “First, NHP-specific training should be provided to all prospective licensees,

concomitant with their responsibilities. The initial training needs to be followed by mandatory

Continuing Professional Development (CPD) to expand and maintain the knowledge and skills of

those working with NHPs (Weatherall et al., 2016).

pg. 27 lines 9-12

Comment: This statement is taking a UK-centric perspective and is not up-to-date.

Recommendation: Replace the paragraph with the “To address such issues various European and

national entities and initiatives (e.g. EUPRIM-Net, NC3R, PRIMTRAIN, FOR-1847 (http://dfg-for-

1847.dpz.eu/en/homepage.html)) have developed and are offering courses and workshops to address

such training needs. They are suitable for different

kinds of staff working with NHP (technicians, veterinarians, scientists) and take into account

different levels of experience of primate staff (basic, advanced, senior). This includes different formats,

Not all facilities in all EU Member States send their staff on the EUPRIM-Net course, and hence some still

do experience only a half- to a full-day of initial NHP-

specific training. Therefore, we believe the sentence is accurate. We do, however, mention the EUPRIM-

Net course on Page 27 of the preliminary Opinion (11% of delegates at the 2010 Primate Welfare had

attended the EUPRIM-Net course).

Although the NC3Rs is based in the UK, its activities are international. The NC3Rs workshops mentioned

in the text, and the annual Primate Welfare Meeting,

are attended by delegates from across Europe. They are no more UK-centric than the EUPRIM-Net courses

are German-centric. We will expand the text of the EUPRIM-Net courses, however, by adding the

following sentence: “They take a blended learning approach and cover aspects of experimental design,

imaging techniques, housing and husbandry, colony management and animal behaviour management.”

Given our knowledge of some of the issues exposed

at Tubingen, we prefer not to mention the DFG-funded course.

122

such as workshops, courses, in-house training and

e-learning. It covers experimental design (ARRIVE guidelines, systematic review, refinement of chronic

implants), new imaging techniques, housing,

husbandry, colony management, NHP training and animal behaviour management.

pg. 27 line 35:

Comment: This statement provides only UK examples.

Recommendation: Include the EUPRIM-Net website (www.euprim-net.eu).

242. No agreement


4.6 Areas of

research (fundamenta

l,

translational and applied)

and testing of products

and devices

Other refinement opportunities/advances should be

added: - Increased sample analysis sensitivity = increased

sensitivity of equipment enable the scientist to use

less volume of sampling / or the same volume for more parameters. For instance flow cytometry

techniques. - New technologies: new wireless or touch screen

technologies, as for several mechatronics devices, enable the scientists to collect functional

parameters during non-invasive procedures (touch screen for cognitive tasks, external implantable

telemetry …)

- Positive reinforcement training: animals are trained to voluntary perform tasks such as blood

sample, touch screen, ultrasound... Training procedure start now in breeding farms.

- Promotion of international standards to guarantee the good use and care of animals, including NHP in

breeding or experimental facilities (AAALAC).

These aspects are covered in other parts of the

Opinion, e.g. Accreditation schemes, such as the one

administered by the Association for

Assessment and Accreditation of Laboratory Animal Care are in para 4.4.

Improvements also include the development and implementation of training protocols

designed to encourage animals to co-operate voluntarily with husbandry and scientific

procedures (reinforcement training) in para 4.3

Good experimental design and staff training

under 4.5. New techniques are addressed wherever

appropriate.

243. Borra, Elena,


Expert Group

for NHP

4.6 Areas of

research (fundamenta

l,

translational

Scientific Rationale. Paragraph 4.6.4.1. (page 46,

lines 5-8). Classification of severity in electrophysiology

studies. The statement about UK should be deleted,

for the following reasons: 1) there seems to be no

In 6.6.4 a new paragraph on severity classification has been included.

123

Neuroscience


unipr.it, Italy

and applied)

and testing of products

and devices

good reason to take the UK as an example given

the fact that classification of severity strongly relies on the specific procedures carried out on individual

animals under the Directive 2010/63/EU; 2) the

great majority of neurophysiological studies retrospectively reviewed do not exceed the

“moderate” severity limit (Pickard et al. 2013); 3) under the EU Directive there is no procedure that

can be classified by default within a certain severity category, because the impact of refinement

measures and overall lifetime experience of the animals need to be always taken into account in

prospective assessment of severity; 4) a by-default

classification of electrophysiological procedures as “severe” would clearly contrast with the general

principle of the EU Directive to minimize the harm to the animal by employing all the available

refinement measures.

We suggest, therefore, to replace the deleted statement about UK with a recommendation that,

whenever possible, the neurophysiological

procedure should be performed and authorized pending the accurate description and adoption of all

the available refinement measures, which may often allow to prospectively classify them within the limit

of “moderate”. In addition, it should be recommended to systematically collect and evaluate

retrospective assessments of actual severity experienced by each animal in order to provide

concrete basis for prospective severity classification

in future studies.

244. The British

Toxicology


hebts.org, United

4.6 Areas of

research

(fundamental,

translational and applied)

Section 4.6.2.3, Page 35, Line 35

“…..there is a strong impetus within the scientific

community to move away from animal-based reproductive and developmental toxicity testing

(Stallman Brown et al 2012). This has resulted in progress in the development of non-animal

124

Kingdom and testing

of products and devices

alternatives to move towards a predictive

mechanism based approach.”

It is true that there is a strong impetus within the

scientific community to move away from mammalian reproductive and developmental toxicity

testing, with validation work showing potential correlation in zebrafish models. However, the

reality is that progress in the development of non-animal alternatives to move towards a predictive

mechanism-based approach still remains at an early stage in order to predict and protect human safety.

We agree with the statement in Section 4.6.2.6

(page 40, beginning line 16) that there are still obstacles to be overcome in terms of regulatory

acceptance and scientific validity.

The SCHEER agrees with the comment, and thanks

the commenter for supporting our conclusions.


personal data

4.6.1 Overview on

the use of NHPs in

research and testing

The number of NHP used for scientific purposes should be counter-balanced with the number of EU

citizens or patients who benefits from the scientific outcomes provided by the NHP Models. How many

EU citizens (or Parkinson Patients) per NHP used in research ?

Obtaining accurate figures to address this point would require a separate detailed review and is

beyond the scope of this opinion. Any estimates that could be made would not be evidence-based without

such a review.

246. Visalberghi /

Manciocco, Elisabetta /

Araianna, Unit of Cognitive

Primatology,

Istituto di Scienze e

Tecnologie della

Cognizione, Consiglio

Nazionale delle

Ricerche,

elisabetta.visa

4.6.1

Overview on the use of

NHPs in research and

testing

Comment_to_the_SCHEER_on_line_Visalberghi_Manciocco.doc

It is unclear in your Preliminary Opinion whether non-invasive behavioural and cognitive studies that

use a procedure in which a monkey voluntarily chooses to stay alone in her/his familiar indoor-cage

for a period of separation of 10-30 min (while the other group members move on the other side of a

sliding door, thus remaining in auditory contact)

should be considered a procedure, or not. When we use such a methodology during the period of social

separation the monkey is presented with a cognitive task and gains rewards, an activity demonstrated to

be an enrichment for animals housed in laboratories

This depends on how the member state has

implemented the Directive and the Opinion is not

involved in the classification of severity or specific procedures.


125

[email protected]

nr.it, Italy

and zoos. Moreover, if the monkey shows signs of

distress she/he is immediately reunited to the group.

According to the interpretation given by the Italian

Authorities our short separation of a subject from the group is indeed a mild procedure. Therefore, we

are required to ask a specific authorization according to the European Directive 2010/63. Note

that our 25 capuchin monkeys are listed in the Tables in p. 28 and 29.

Since also in the EU Directive a short term separation is much more than what we do (for

example a (< 24h) restraint in metabolic cages or a

short-term deprivation of social partners, short-term solitary caging of adult rats or mice of sociable

strains) we believe that ours is not a mild procedure.

Thus, we would like this point of discussion to be

clarified.



@crueltyfreein


Kingdom

4.6.1 Overview on

the use of NHPs in

research and

testing

This section and indeed the sections that follow it are limited by a lack of clarity on exactly where the

numbers of NHP come from (which country reports), whether they constitute procedures plus

first use or just procedures and how the areas of

NHP use have been identified. Have the 2014 statistics been drilled down further to identify the

exact research areas and extent of NHP use in these or has there been a review of the literature? Safety

testing is by far the greatest use of NHP and the report should therefore address this topic in more

detail. The extent of use in ophthalmology, etc. is not based on any evidence at this point and indeed

it was implied in the Hearing that the use of NHP in

that particular area was extremely low. P26 L 41

Annex 1 should read Annex 2

The SCHEER states in the preliminary Opinion that:

"Currently, NHPs are predominantly used in the following areas a) development and safety testing of

pharmaceuticals and medical devices, b) treatment

and prevention of infectious diseases, c) neuroscience, d) ophthalmology and e)

(xeno)transplantation, with the largest fraction of NHPs used in the EU for safety assessment studies,

performed to meet regulatory demands."

Additional data on the use of NHPs like breakdowns

126

P29 L5-10

Under the Commission Implementing decision on the format of the statistical reporting, indeed it is

mandatory that all member states report these

categories. The fact that they are not yet, hindering this section of the report, is a cause for concern.

The collation of the 2014 statistics, including the 8898 figure, and concerns about the incomplete

reporting by member states is given in this paper that could be referenced (Taylor, K and Rego, L. EU

statistics on animal experiments for 2014. ALTEX 33(4), 2016).

e.g. by primary purposes by NHP species, specific

research area, severity of treatment as well as statistical analysis vary among the Member State

reports. In addition, 2014 was the first year for

reporting under a new format. Therefore no further statistics could be carried out by the SCHEER to

provide additional reliable information or even trends.

An explanation for this has been added to the

Opinion. The importance of 3Rs application in the category 'Regulatory use and routine production' has

been added.

The reference “Taylor, K and Rego, L. EU statistics on

animal experiments for 2014. ALTEX 33(4), 2016” has been added to the Opinion.


personal data

4.6.2 Development

and safety testing of

pharmaceuticals and

medical

devices

p38 a focus on the NHP models used in regenerative

therapy may have been interesting.

Marcel M. Daadi, Tiziano Barberi, Qiang Shi, and Robert E. Lanford (2014). Nonhuman Primate

Models in Translational Regenerative Medicine.

Stem Cells Dev. 2014 Dec 1; 23, 83–87

The SCHEER focused on the areas where most of the NHPs are used.

249. Marshall,

Lindsay,

Humane Society



4.6.2

Development


pharmaceuticals and

medical devices

Section 4 Justification for NHP use

Page 35 Line 19

We agree that innovative, alternative methods are required for the evaluation of monoclonal

antibodies. But we believe that these methods can be developed without the need to use NHP, or any

animals.

There are significant differences in, for example, macaque and human Major Histocompatibility

Complex (MHC) and the use of closed colonies of

NHP in most Contract Research Organisations

The paper by Chapman et al concluded that “The use

of the NHP plays an important role in assessing the

safety of mAbs”. The paper highlighted the fact that “opportunities exist through the use of scientifically-

based rationalised development programs, which take into account issues of species selection based on

pharmacology, potency and immunogenicity, and the design and timing of preclinical studies based on the

patient population, dosing regimen, and the avail-ability of other approaches”. This approach is

included in the ICH S6 (R1) guideline” on the

preclinical safety evaluation of biotechnology-derived

127

further limits their HLA allelic repertoire. This means

that the antigenic peptides presented in the context of MHC for activation and proliferation of the CD4+

T cells will be very different between NHP and

humans. This limits the likely prediction of immunogenicity in NHP. In fact, the real "acid test"

for immunogenicity is likely to come from actual early clinical development. First in human studies

are often single dose ascending design for safety and tolerability and are not powered for efficacy or

immunogenicity. Unless the monoclonal antibody is overtly immunogenic, this will only begin to be

recognised and the frequency measured in later

Phase III clinical studies. This can lead to a mandatory post marketing immunogenicity

assessment phase for compounds. We suggest that this approach (post-marketing assessment) could

be applied for all such products in order to reduce animal testing and NHP use.

The risk of adverse immune-related events is not

likely to be predicted with NHP tests. The use of

NHP in trials of the anti-CD28 monoclonal antibody (TGN1412) showed incredibly limited predictive

capacity.

In many cases, NHP are not appropriate for pre-clinical testing – the primate immune response may

rapidly clear the therapeutic antibody or the requisite cross-reactivity could have reduced

potency. In these cases, alternative approaches are

required and we suggest that the innovation that results in these alternative methods be rolled out to

permit replacement of NHP in ALL monoclonal antibody testing and evaluation.

Clarification of regulatory requirements and

harmonisation of global practices would aid in the

pharmaceuticals. Nevertheless, it is acknowledged that there are

situations where the NHP is the only relevant species for the safety assessment of new medicines for

humans.

128

decision to replace NHP. The test species for many

biotherapeutic compounds is NHP, but this is often not based on scientific rationale – of the monoclonal

antibody studies reviewed, only 10% bound to an

NHP target and of these few which did cross-react, potency was less than 10% [Chapman et al 2009].

250. No agreement


4.6.2

Development and safety

testing of pharmaceuti

cals and medical

devices

Replacement possibilities Page 36 Lines 11-23

We are gratified to see the advances in in vitro testing acknowledged and promoted here. We would

also like to see assurances taht, where these in vitro systems exist and have been shown to

perform more effectively than the equivalent in vivo tests, any proposals requesting funding to use

animals in such studies would be rejected in favour of, for example, the DILIsym setup. If such a

recommendation is not possible at this time, it

would help to incorporate this into the timeline for replacement.

This positive incentive has been made more general

and added to the list of factors on pages 10 and 20 reading: “The non-availability of funding for in vivo

studies where suitable alternatives exist”.

251. Marshall,

Lindsay, Humane



Kingdom

4.6.2



cals and medical

devices

Page 42 Line 27

We are pleased to see that NHP have been fully replaced in the neurovirulence testing of polio

vaccines. We believe that this sets a desirable precedence and is evidence that the full

replacement of NHP is entirely possible. We suggest that this is used as the 'gold standard' for vaccine

testing that does not require NHP.

This is an issue for risk managers; risk management

is outside of the scope of the SCHEER.


Martje, ECLAM,

m.fentener@e




in laboratory

4.6.2 Development


pharmaceuti

cals and medical

devices

P34 line 18 the sentence “It gives details of some NHP species, which should not be used.” should not

have a comma in it (for clarity).

The comma has been removed.

129

animal

medicine

253. Dodkin, Christina,

Animal Defenders

International/

National Anti-Vivisection

Society, research@ad-

international.org, United

Kingdom

4.6.2 Development


pharmaceuti

cals and medical

devices

4.6.2 Pg 30: The Committee must acknowledge findings from Bailey et al (2015) that “data set of

over 3,000 drugs with both animal and human data, that the absence of toxicity in animals provide[d]

little or virtually no evidential weight that adverse

drug reactions will also be absent in humans”. Value would also be added to the Preliminary Opinion

through the review of work by NCad on the opportunities for phasing out animals in toxicology

research (NCad 2016)

Pg 30, lines 4–6: There is a lack of scientific evidence to show that NHPs are essential for the

benefit of human beings and the Committee does

not provide evidence to support this assumption.

Pg 30, lines 17–23: The Committee say that animal

research is “viewed as” essential and quote a UK Government’s report that research into treating

diseases “would not have been possible” without

animal use, including NHPs. These statements are not backed up with references or scientific evidence.

4.6.2.2 Pg 31-32: The Committee must acknowledge examples where reliance on NHP data

has led to adverse reactions in humans demonstrate the poor predictivity of the primate model. See

examples highlighted in ADI’s initial submission in

2016 (Biotrial, Hepatitis C).

4.6.2.3 Pg 32–33, lines 36–1: The Committee do not highlight how Brennan et al (2015) underlines

4.6.2 Pg 30 Please refer to the Bailey papers, which are discussed in several chapters in section 6.

Pg 30, lines 4–6: NHPs as the most relevant animal model ET:

SCHEER disagrees with the comment and considers

that the successful development of ‘safe’ vaccines and bio-pharmaceuticals are suffecient proof of the

benefit to human beings.

Pg 30, lines 17–23: The UK government report is a

reference.

4.6.2.2 Pg 31-32: Disagree.

4.6.2.3 Pg 32–33, lines 36–1: Disagree

130

that primate use was not found to be relevant in the

biotherapeutic development of humanized mAbs, where researchers had previously justified their use.

Pg 33–34: There are general and specific mentions of limitations and species differences of NHPs in

Paracetamol injury, menstrual cycle, vomiting and nausea and biopharmaceuticals are highlighted.

However, the Committee do not use this scientifically collected data to further question the

scientific validity of NHP use.

4.6.2.4 Pg 35–37: The Committee over generalises

and misrepresents the definition of the term “replacement”. See ADI/NAVS over arching

concerns document

Pg 36, lines 29-35: Just this one study has

highlighted a theory that, due to the discovery of menstruation, this species might be used to study

the menstrual cycle and associated disorders with no validation process to provide evidence that it

would be a reliable model; the Committee should remove mention of the spiny mouse model.

4.6.2.5 Pg 37–38, Lines 42–11: In discussing iPSCs

technology, the Committee don’t highlight that this

method has the potential to replace primates in drug discovery, categorising its use as reduction

and refinement. Giri and Bader (2015) outline the potential for millions of animal tests to be replaced

and how it’s going to be possible to standardize these cell based assays in just a few years.

Pg 33–34: The report does highlight the fact that NHPs have limitations and should not be a default

species of choice.

4.6.2.4 Pg 35–37: The SCHEER has changed the text

in the Opinion to: Notably, substitution of NHPs with rodents or other laboratory animal species is not

replacement as defined by Russell and Burch (1959). However, this may be ethically desirable if the

available evidence indicates that the non-primate species is likely to suffer less harm.

Pg 36, lines 29-35:disagree

4.6.2.5 Pg 37–38, Lines 42–11: It is highly unlikely

that these tests will replace “millions of animal

tests”.

131

4.6.2.6 Pg 38, lines 28–33: The Committee do not

highlight species differences between NHPs and humans. (See response to 4.6.5.1.2)

Pg 40, lines 28–33: The Committee mention the

paper by Bailey et al (2015) in one paragraph, referencing general consideration in toxicology. The

opportunity is not taken to discuss the implications of this paper further, to place more weight on the

shift away from primate use, in light of the evidence that they offer little predictive value and their use is

not justified. The Committee should use this

evidence to highlight further the need of more open and independent systematic review of primate use

in this area

References Bailey, J, et al (2015). ATLA 43, 393–403

Brennan, FR et al. (2015). Regulatory Toxicology and Pharmacology, 73(1), 265-275

DIRECTIVE 2010/63/EU OF THE EUROPEAN

PARLIAMENT AND OF THE COUNCIL of 22 September 2010 on the protection of animals used

for scientific purposes Giri, S, Bader, A (2015) Drug Discovery Today,

20(1): 37-49 NCad (2016) NCad opinion Transition to non-animal

research Nowogrodzki, A (2016) Nature, doi:10.1038

4.6.2.6 Pg 38, lines 28–33: Agreed, but no change to

the report required. The report says NHPS are the most suitable model, not a perfect model.

Pg 40, lines 28–33: Please refer to the Bailey papers,

which are discussed in several chapters in section 6. There is now a recommendation for systematic

reviews in section 7.

254. Tarsitano,


Animals,


imals.org, Belgium

4.6.2


testing of

pharmaceuticals and

medical devices

Page 30, lines 4 – 6. There is a lack of scientific

evidence to show that NHPs are essential for the benefit of human beings and the Committee does

not provide evidence to support this assumption.

Scientific reviews of primate models have found them to be poorly predictive of responses in

humans, with little direct evidence of medical benefit in some areas.

Page 30, lines 4 – 6.

The SCHEER disagrees with the comment and considers that the successful development of ‘safe’

vaccines and bio-pharmaceuticals are sufficient proof

of the benefit to human beings.

132

Lines 17 – 23. The Committee states that animal

research is “viewed as” essential and that research into treating diseases “would not have been

possible” without animal use, including NHPs. These

statements are not backed up with references or scientific evidence. Claims about supposed benefits

of primate experiments should not be made unless there is scientific evidence to support them.

Pages 32 - 33, lines 36 – 1. Brennan et al (2015) is quoted as evidence that NHPs play a key role of

drug development in certain areas. However, the

Preliminary Opinion does not highlight how this paper also underlines that primate use was not

found to be relevant in some areas where researchers had previously justified their use. This

paper could also be used to target areas of NHP use which should be timetabled for phase out due to

their lack of human relevance.

Page 36, lines 8 – 10. The text indicates that

“examples given include substituting NHPs for other species (...) the context of progressing toward the

ideal position of complete replacement with non-animal alternatives”. The Committee over

generalises and misrepresents the definition of the term “replacement” as two of the examples that

follow include replacing NHPs with spiny mice in menstrual cycle and associated disorders and swine

models. Moreover, for the Committee to suggest

that the use of other live vertebrates is a step towards replacement, entirely undermines the

intention of the concept of the 3Rs as outlined in Directive 2010/63/EU. Furthermore, according to

the definition of replacement within Annex 1 of the Opinion, spiny mice and minipigs cannot be

considered under the category of replacement.

Lines 17 – 23. There are numerous reports and

ample scientific evidence to show that medical advances would not have occurred without animal

studies.

Pages 32 - 33, lines 36 – 1. The Opinion makes it quite clear that the NHP can be a useful model but is

not a perfect model.

Page 36, lines 8 – 10. The SCHEER agrees with this

comment and have changed the text in the Opinion to: Notably, substitution of NHPs with rodents or

other laboratory animal species is not replacement as defined by Russell and Burch (1959). However, this

may be ethically desirable if the available evidence indicates that the non-primate species is likely to

suffer less harm.

133

These species should thus be considered as a

“substitution” and not adhering to the 3Rs principle of Replacement.

Page 37, lines 2 – 8. It is unscientific to consider using other species whose validity has also not been

scientifically verified. Other than stating that swine models and spiny mice share similarities to humans

and outlining the areas in which they are used, no systematic review of their relevance to humans as

valid models are provided. The unscientific nature of this choice is reinforced with the acknowledgement

that the mini-pig is more convenient to reproduce

and keep.

Pages 37 – 38, lines 42 – 11. The Committee discusses iPSCs technology under the reduction and

refinement heading. Authors of the cited paper state that some animal tests can be replaced,

therefore this should be the aim in analysing the potential of iPSCs. The Committee has also missed

an opportunity to attempt to forecast the future

contributions of iPSCs in drug development, one of the areas in which an adaptable timetable could be

set.

Page 38, lines 28 – 33. In outlining how the profontal cortext in rodents is less developed,

making NHPs “the most suitable experimental animals for research on higher level cognitive and

behavioural processes”, the Committee fails to

acknowledge that the architecture and physiology of the human brain are much more complex than

those of primates and that there exist relevant differences between NHPs and humans.

Page 40, lines 28 – 33. The cited paper by Bailey et

The paper by Buse et al. (2014) has provided a good scientific review of available in vitro and animal

models to confirm that these models share similarities to humans and are valid to use.

Pages 37 – 38, lines 42 – 11. The Opinion is not intended to predict what might happen in the future.

Page 38, lines 28 – 33. The SCHEER would argue

that the differences between NHPs and other laboratory animal species in respect to development

of the cortex and particularly the prefrontal area are very large. Of course there are differences between

NHPs and humans, but the closer similarity in brain

structure between NHPs and humans may sometimes make them the only appropriate model.

Page 40, lines 28 – 33. Please refer to the Bailey

134

al (2015) could have been discussed further to

place more weight on the shift away from primate use, in light of the evidence that they offer little

predictive value and their use is not justified.

papers, which are discussed in several chapters in

section 6.


Ethical



Kingdom

4.6.2 Development

and safety


cals and medical

devices

p.30, l 38-40: Requirements to use animals, especially particular species, are not always clear or

well understood. Here, for instance, SCHEER

suggests that some medical devices are required to be supported with NHP safety testing data before

they can be marketed. Where SCHEER suggest that there are explicit requirements to use NHPs,

reference should be included to the relevant statute, policy, or other guidance document that

establishes this requirement. When referencing requirements to use NHPs, SCHEER should note

whether the requirement is strict or flexible. By

presenting this information in a clear manner, SCHEER can help researchers and drug and device

sponsors better understand NHP testing requirements and prioritise the development of

alternatives accordingly.

p.32 Justification for NHP Use: This section does not mention candidate drugs that were determined

acceptably safe and effective in preclinical tests

before ultimately failing in clinical trials. Indeed, by all estimates, the overwhelming majority of drug

candidates that “pass” preclinical testing are not safe or effective when given to humans and do not

reach the market. Until systematic reviews support NHP use as a reliable and robust approach to

demonstrating the efficacy and safety of human therapies, this will remain essential context for

claims that NHP use is essential to the process. As

this problem has been extensively explored in the literature, SCHEER should address it in this

opinion.1, 2

p.30, l 38-40: It is not possible and it is not the objective of this

document to detail the regulations which supports

the development of medical devices. This Opinion is not a guideline.

All information about this subject can be found in a specific European guidance. The European

Commission provides a range of guidance documents to assist stakeholders in implementing directives

related to medical devices. This guidance presents both the regulatory texts

relating to the development of medical devices

(MEDDEVs), consensus statements and informative documents.

p.32 Despite large investments in drug development, including in development of new technologies and

refinement of existing technologies, the overall

success rate of drugs during clinical development remains unfortunately low.

Candidates for a new drug to treat a disease might, theoretically, include from 5,000 to 10,000 chemical

compounds. On average about 250 of these show sufficient promise for further evaluation using

laboratory tests, mice and other test animals. Typically, about ten of these qualify for tests on

humans and 1 will and only one of these molecules

will become a drug. This is largely linked to the fact that researchers in

charge of drug development are looking for the most effective and safe molecule. Moreover, considering

135

SCHEER should also include counterexamples of the

harm caused by reliance on NHP models when developing human drugs and devices, such as the

profound harm caused to human clinical trial

volunteers of.3

SCHEER do not differentiate between requirements

to use NHPs in biomedical research and justifications provided retrospectively for NHP use in

biomedical research. In this section, each

illustration of NHP use falls in the latter category, as drug and device sponsors have flexibility in the

selection of test methods used during the development of new drugs and devices. As noted,

ICH guidelines allow flexibility in test method and species selection. Drug and device sponsors bear

the responsibility of generating safety and efficacy data, and can elect to conduct non-animal testing in

parallel to any required in vivo testing, in

consultation with the relevant regulatory authority. In all cases, SCHEER should ensure drug sponsors

are aware that they can and should consult with regulators if they seek to avoid the use of NHPs in

favor of alternative strategies.

the large number of drugs used, it must be noted

that medicines induce very few accidents. On the other hand, there are adverse effects that need to be

known to make good use of these drugs. Molecules

totally devoid of any adverse effects probably do not exist and the real challenge is to get the best balance

between effectiveness and risk. To obtain sufficient data to make this assessment,

there is a need for extensive data, some of which are obtained in animal experiments and in some cases in

NHPs. As described throughout this Opinion considerable efforts are made to avoid the use of

primates but also all other species. Considerable

progress has been made and is under way but it is not yet possible to develop medicines or medical

devices solely on the basis of alternative methods.

It’s true that guidelines allow flexibility and a choice

in the methodology used, this is normal since they are guidelines and not directives. This flexibility in

methodology is essential in order to adapt it to

obtain the best scientific and technical data. However animal studies have to be performed according to the

directive 2010/63/EU which it leaves no choice.

Developers of medicinal products and medical devices must carry out these studies according to the

best scientific and ethical standards. These experiments are assessed from a scientific point of

view by the scientifically competent registration

authorities who judge the quality of the studies and from an ethical point of view by the competent local

authorities who are in charge of verifying the correct application of the Directive 2010/63/EU.

This Directive established measures for the protection of animals used for scientific or

educational purposes.

136

p.38, abuse potential: The use of NHPs for addiction

studies should end. Attempts to model human

It lays down different rules pertaining to, among

other things, the evaluation and authorisation of projects involving the use of animals in procedures.

All projects using non-human primates must undergo a retrospective assessment.

Member States must ensure that the retrospective assessment has been carried out by the competent

authority which, on the basis of the necessary documentation submitted by the user, evaluate the

following points to ensure that the highest level of ethics are respected:

whether the objectives of the project were

achieved, the harm inflicted on animals, including the

numbers and species of animals used, and the severity of the procedures, and

any elements that may contribute to the further implementation of the requirement of

replacement, reduction and refinement. The SCHEER agrees with the recommendation: it has

been included in the final Opinion.

Rodents are allowed in the EU, in other jurisdictions NHPs are used.

It is agreed that more work is needed on new models for investigating abuse potential in order to replace

NHP. Progress has been made and fewer NHP are

now being used.

137

disorders such as addiction in animals is considered

to be overambitious and the validity of such models if often limited to superficial similarities, referred to

as ‘face validity’.4

Furthermore, the pharmacokinetic actions of drugs

are different among species. For example, the rate of metabolism of MDMA and its major metabolites is

slower in humans than NHPs, potentially allowing endogenous neuroprotective mechanisms to

function in a species-specific manner.5

Serious flaws in experimental design of addiction

experiments also greatly skew interpretation of their results. In the human experience with drugs,

the drug user chooses to consume the abusive substance over other methods of obtaining a feeling

of reward. Animals are not given this option. When they are, the majority of animals, including NHPs,

will choose an alternative reward, such as sugar, over the drug of abuse.6 Despite the prevalence of

addiction research, “drugs that effectively curb

opioid or psychostimulant addiction by promoting abstinence and preventing relapse have yet to be

developed” and “very little clinical development is currently ongoing”.7




g, United

Kingdom

4.6.2 Development


pharmaceuticals and

medical

devices

P30 L4-6 True? Prove or don’t state.

P30 L6-10 Proof of adoption? If not, note.

P30 L17-23 Some disagree – note. Evidence re: mAbs? – it’s opinion. Suggest delete para.

P30 L4-6 EU Directives only allow NHPs when their use is considered to be essential.

P30 L6-10 Whether scientists are fully following the

proposal does not negate the argument.

P30 L17-23 Disagree

138

P30 L35-37 See comment for Secn 3.3 (P16 L1-4).

P30 L38-45 Clarification needed.

P31 L30-33 Must include info from 3 Bailey papers on drug tox (provided). Salient finding: absence of

animal toxicity provides no evidential weight for similar in humans.

P32 L1-6 Elaborate.

P32 L7-14 Clarify (see comments for P30 L 38-45).

P32 L 16-19 Whole para must be revised. Criticises

NHP PK alternatives as ‘poor’ with 12-yo reference. See e.g WC9 abstracts for developments in this

time (http://www.altex.ch/ALTEX-

Proceedings/Proceedings.98.html?iid=4). See also lack of evidence for NHP value, e.g. previous

comments (Secn 3.3, P16 L1-4). Refer WG to: evidence against (Bailey ‘Predicting Human Drug

Toxicity…’ and ‘Monkey Based Research on Human Disease…’ – both provided) and to numerous

reviews of capacities of human in vitro methods.

P32 L20-25 Clarify – impact on need to use NHPs?

P32 L35-38 Cite absolute number – must not be downplayed by use of %. Note evidence for crucial

differences of NHPs and humans, e.g. Bailey ‘Monkey based…’ and ‘Lessons from…’ paper,

provided.


P30 L38-45 Why is there a requirement for

clarification of a regulatory requirement?

P31 L30-33 Please refer to the Bailey papers, which are discussed in several chapters in section 6.

P32 L1-6 Not agreed, and no change to report required.

P32 L7-14 Not agreed, and no change to report

required.

P32 L 16-19 Not agreed, and no change to report

required.


required.


139

P33 L15-16 Abbott paper unacceptable – news article of NHP researcher opinion.

P33 L17-18 Just 1 example here. Must be critiqued,

and weighed against others, esp. failures. See all provided Bailey papers for examples.

P33 L19-40 Reiterate failure of NHP drug tests. E.g. TGN1412 and BIA-102474; hurt/killed people while

tests in monkeys were fine.

P33 L45 – P34 L1 Cite Bailey ‘Predicting Human

Toxicity…’ here.

P34 L10-23 Recommendation?


P35 L21-24 Rodent use acceptable in EU? NHPs not needed here.

P35 L25-43 Weak para, little evidence. Revise. Use

info in, & cite, Bailey ‘Developmental Toxicity Testing…’ (provided).

P35 L45 – P36 L10 Needs to discuss replacement options. Too general & focus on OECD/ECVAM too

chemical.


P33 L17-18 Please refer to the Bailey papers, which

are discussed in several chapters in section 6.

P33 L19-40 Not agreed, and no change to report required. The results of the animal tests on BIA-

102474 are not in the public domain, so it is not

possible for you to make such a sweeping statement on what those studies revealed.

P33 L45 – P34 L1 Please refer to the Bailey papers, which are discussed in several chapters in section 6.

P34 L10-23 It is not clear what the question is.


P35 L21-24 Rodent use is only acceptable in some circumstances and many workers question the

results.

P35 L25-43

The paragraph gives the same message as the additional reference cited.

P35 L45 – P36 L10 SCHEER considers this discussion valid for the different research areas.

140



P38 L16-24 See comment for Secn 4.6.2.3. (P33

L19-40; and L45, and P34 L1)

P38 L25-33 Bailey paper ‘Nonhuman primates in

neuroscience research…’ (provided) contains many well-referenced arguments against this, which

should be included and cited.


P38 L43-P39 L3 Cannot use differences to argue for NHP use. See Bailey neuroscience paper (provided),

esp. pp58/59.

P39 L21-34 No evidence.

P40 L16-33 Combine Reprotox sections, eg see

earlier comment (Secn 4.6.2.3, P35 L25-43)

P40 L28-33 Bailey paper should be cited in other

places, eg Secn 3.3, P15; Secn 3.4, P17; Secn 3.7, P21; Secn 4.6.2.1, P30; Secn 4.6.2.2, P31; Secn

4.6.2.3, P32.

P40 L 42-45 & P41 L1-3 Arguments for not using



P38 L16-24 Please see the reply above.


required. The Bailey paper has been heavily criticised as biased.


P38 L43-P39 L3 True, but the additional argument given is that of the

higher suitability of the anatomy of primate brains

for longitudinal neuroimaging studies.


required.

P40 L16-33 Please see the reply above.

P40 L28-33 The Bailey paper is already extensively

cited.

P40 L 42-45 & P41 L1-3 Not agreed, and no change

141

NHPs in transgenics are contradicted manner by

suggesting ‘international effort’ to develop them. Should be revised.

to report required.

257. Marshall,

Lindsay, Humane

Society



4.6.3

Treatment and

prevention of

infectious diseases

We believe that adopting a pathways-based

approach to look at the mechanism of human disease and accurately map the pathogenesis of

human disease would be a more cost- and time-

effective approach to modelling infectious disease than reliance on NHP as models.

For example, different species of NHP used in

modelling tuberculosis (TB) produce confounding data as they display different pathologies and there

is no agreement over the “best” model. One study that used two different species of NHP to examine

TB infection in a mechanistic study of disease

prevention failed to provide enough novel data to justify the use of the animal model [Sharpe et al.,

2016]. The study found that ultra-low doses of aerosol can be used to infect the animals, although

it was impossible to quantify the actual dose delivered and the number of bacteria inhaled had to

be estimated. However, almost 70 years ago, rabbit models had already showed that inhalation caused

infection [Ratcliffe & Wells, 1948], so it is not clear

what additions these NHP data make to the knowledge base. Sharpe et al. went on to show that

both species of NHP were affected and that animals were equally affected if treated on separate

occasions. The animals underwent multiple anaesthesia and CT scans to visualise disease

progression but were euthanised prior to any efforts to study drug efficacy or vaccine delivery. We

believe that projects proposing this limited,

redundant basic science disease research should not require the use of NHP and could use existing

clinical data. CT scans are routinely employed as a diagnostic tool for TB and can also be used to

As with all research, animal studies (including NHP)

as well as human volunteers/patient studies form part of the whole pipeline of vaccine development.

This is also explained in the Opinion (4.6.3). The

remark on the cost- and time-effectiveness is a personal opinion and not substantiated by provided

evidence. With respect to TB, there is evidence that NHP pathology and immunology in the lung, amongst

other areas in the body, resembles that in humans (e.g. Mothé et al, 2015; Capuano SV et al, 2003).

142

assess previous infection status [e.g. Nishi &

Okazaki, 2015; Allwood et al., 2015].

The wealth of information that exists regarding TB

tells us that geography, the human genetic pool and age of the patient are all important features in

disease progression and therefore in vaccine development [Fine, 1995]. Lab strains of TB have

altered immunogenicity and often different sub-strains have more relevance for specific geographic

regions; thus research needs to use clinical data to develop effective vaccines. For TB research, there is

a specific need to understand the human lung

environment and the potential protease-dependent modifications that may occur and would impact on

TB antigenicity and therefore should inform vaccine development [reviewed in Moliva et al., 2015]. This

analysis could exploit the organ on a chip technology currently available and could use BAL

samples from disease states; available from biobanks worldwide (e.g. ukbiobank.ac.uk;

tbbiorepository.org). Indeed, the Foundation for

Innovative New Diagnostics (FIND), and the Special Programme for Research and Training on Tropical

Diseases (TDR), recently announced an initiative, in 2013, to increase access to clinical reference

materials with a view to enabling effective and efficient diagnosis of TB

[http://www.who.int/tdr/news/2013/tb_diagnostic_tests/en/].

We believe that initiatives promoting access to, and use of, clinical samples and clinical data are likely to

be more profitable than NHP usage in TB disease pathogenesis research.

References (files too large to upload)

143

Sharpe S, et al. Tuberculosis (Edinb). 2011.

Jan;96:1-12. Ratcliffe, HL and Wells, WF. J Exp Med. 1948 Jun

1;87(6):585-94.

Nishi K, and Okazaki A. Kekkaku. 2015 Nov-Dec;90(11-12):683-7

Allwood BW et al. Int J Tuberc Lung Dis. 2015 Dec;19(12):1435-40.

Fine, PE. Lancet 346:1339-1345

258. Fentener van

Vlissingen, Martje,

ECLAM, m.fentener@e

rasmusmc.nl,

Other, ECLAM is the Europe-

wide college of specialist

veterinarians in laboratory

animal medicine

4.6.3

Treatment and

prevention of infectious

diseases

P42, line 6 – grammar, sentence is incomplete. Line

22 ditto. P.46, lines 1-11, regarding severity: severity should

be pre-assessed in the context of the harm-benefit analysis as required, on a case-by-case basis, and

the risk of complications should be taken into

account in a proportional way. If harmful complications could or would lead to higher severity

classification, this should be prevented by applying, e.g., humane endpoints. However, a fixed

classification would be contra-productive to the development and implementation of further

refinements.

Opinion does involve severity classification

procedures, see also answer to 243.

259. No agreement


4.6.3

Treatment and

prevention of

infectious diseases

4.6.3.1 Pg 41–42: The Committee seek

justifications for continued use of NHP models rather than evaluating the effectiveness of those

models or their contribution to science; minimal

emphasis is placed on species differences (See comments 3.7 Pg 21, 11 – 14 & 19 – 21)

Pg 41 lines 27–30: This is not a scientific justification for continued use of these methods,

and no relevant evidence is presented to demonstrate how NHPs are effective methods to

study disease.

4.6.3.1 Pg 41–42: Not agreed. In this section 6.6.3,

the first part provides an overview of past research (including new references that have been included)

and followed by potential 3Rs strategies in this field.

This includes issues, such as species differences, other animal models and non-animal models.

Pg 41 lines 27–30: See above

144

Pg 41–42, lines 42–2: No references are supplied.

4.6.3.4 The Committee does not evaluate research

areas where animal models are failing to contribute

to therapies for disease. For example, ADI submitted a review paper (Bailey, 2010) which

concludes the validity of the chimpanzee, as well as use of other NHPs, in hepatitis C research adversely

affects scientific progress in this area.

Pg 43, lines 29–33: Continuing to focus on NHP use

as models for potential scenarios in which their

validity is entirely unquantifiable, may delay the course of development and validation of non-animal

methods that are currently showing to be more human-relevant.

Pg 43–44, lines 43–5: The Committee says that

NHPs have been essential for studies that resulted in the longer survival of HIV patients, but provide

no peer reviewed, scientific evidence to support the

claim.

We strongly suggest that the sentence and cited paper (Muenchhoff et al 2016) is reviewed and

removed from the Preliminary Opinion due to error in interpreting the paper. This paper does not find a

specific HIV macaque model with similar disease development to HIV-infected children with non-

progressive disease. The paper outlines similarities,

Pg 41–42, lines 42–2: see above

4.6.3.4 The Bailey papers were discussed in several

sections.

Pg 43, lines 29–33: The Opinion highlights all the

progress towards an animal-free safety assessment

framework, but for the time being we cannot ignore that there are still areas in which that NHP are a

relevant animal model (e.g. monoclonal antibody product or vaccines development). This is also

evidenced by the recent revision of the ICH guideline S6). Denying it will not produce a quicker phase out.


animal used can be substantially limited by

preliminary in vitro and in silico testing, or avoided whenever in vitro the NHP non-reactivity can be

demonstrated (indicating NHP are not a suitable animal model). As already stated, the SCHEER's

opinion is that the use of an appropriate species or combination of models is essential to obtaining the

most reliable and translatable information.

The remark with respect to Muenchoff has been corrected. Given the paper and the corrected

sentence, the reference still stands.

145

as well as differences, between HIV-infected

children with non-progressive disease and sooty mangabeys, naturally infected with SIV. Macaques

are only mentioned in reference to differences from

HIV-infected children.

85+ candidate vaccines found to be successful in NHP models were ineffective in human patients

(Bailey 2008). Further literature reviews on the lack of scientific contribution or benefit to humans of

NHP use are presented by Pippin (2012) and Bailey (2014), with the latter concluding SIV and HIV have

“highly different infectivity and pathology”.

Also see Rerks-Ngarm et al 2009 and U.S. Military

HIV Research Program 2011 in ADIs 2016 submission.

Pg 44, lines 23–27: The report omits a study which

compares immune response between different primate species, humans, chimpanzees, and rhesus

macaques (Barreiro et al 2010).

Where the cited review (Bailey, 2014) has shown

that differences between NHPs and humans can lead to differences in outcome of a disease or

therapy, this has been used as evidence to continue

to use NHPs over other animal models, rather than comparing their efficacy against non-animal

methods.

Pg 45, lines 14–17: There is little reason for a

timetable to include fixed dates or targets. Where

The Bailey papers were discussed in several sections.

Pg 44, lines 23–27: Barreiro et al describe an

interesting study where they stimulate monocytes with LPS in vitro. This is an interesting study in a

limited number of samples showing interesting

differences. This is no evidence (which is also not claimed) that NHP cannot be used as important

models to study specific infectious diseases. We have included the reference in the Opinion.

The Bailey papers were discussed in several sections.

Pg 45, lines 14–17: The Opinion recommends how to

advance 3Rs, acknowledging that one timetable for

146

there are potential replacements, a loose timetable

must be established, which may involve consulting scientists conducting non-animal research to assist

in estimating a time frame to overcome barriers.

References

Bailey J (2008) ATLA 36, 381–428. Bailey J (2010) Alternatives to Laboratory Animals

38(5): 387-418 Bailey J (2014) Alternatives to laboratory animals

42: 287-317 Barreiro LB et al (2010) PLoS Genetics 6(12):

e1001249

Muenchhoff M et al (2016) Science Translational Medicine 8(358):358ra125-358ra125

Pippin JJ (2012) South Texas Law Review, 54: 469-511

Rerks-Ngarm S et al (2009) New England Journal of Medicine 361(23): 2209-2210

US Military HIV Research Program (2011) http://www.hivresearch.org/news/follow-study-

rv144-hiv-vaccine-trial-shows-no-effect-disease-

progression-infected-volunteers

phasing-out cannot be given in view of a wide

spectrum of positive and negative incentives for NHP use. Risk managers, however, may decide on such a

timetable, but this is outside the mandate of the

SCHEER.

260. Tarsitano,

Giulia,

Eurogroup for Animals,


imals.org, Belgium

4.6.3

Treatment

and prevention of

infectious diseases

Pages 41– 42, lines 26 – 2. The Committee seeks to

find justifications for continuing to use animal

models for disease research rather than evaluating the effectiveness of those models or their

contribution to science. The Committee places minimal emphasis on the importance of species

differences. This section simply states that animal models need to mimic the responses of humans as

much as possible, rather than evaluating how well it does this.

Page 41, lines 27 – 30. The Committee states that because the pathophysiological aspects of many

diseases remain unknown, the continued use of animals (including NHPs) remains essential. This is

Pages 41– 42, lines 26 – 2. Please see the answer to

Comment 259.

Page 41, lines 27 – 30. As with all models, animal models are part of the whole pipeline of research.

This also includes humans, but as explained in different sections in the Opinion, this is only possible

147

not a scientific justification for continued use of

these methods, and no relevant evidence is presented to demonstrate how NHPs are effective

methods to study disease.

Pages 41 – 42, lines 42 – 2. The Committee states

that “Over the last decades, NHPs have been instrumental in gaining an understanding of the

pathogenesis of various infectious diseases and

have provided relevant models to develop new therapies, e.g., development of vaccines against

polio, yellow fever, Hepatitis B and Ebola, identification of the causative agents of infectious

diseases such as SARS, typhoid fever and mumps, and more in-depth understanding of infections such

as HIV”, however, no references are supplied.

Pages 43 – 44, lines 29 – 15. The Committee does

not evaluate research areas where animal models are failing to contribute to therapies for disease.

This is a missed opportunity for developing a timetable to phase out NHP use in fields where

reviews have shown they make poor models of particular diseases. The potential “(re)emergence”

of future disease that will affect humans, is seen as a preventative reason for not ending NHP use.

However, continuing to focus on NHPs as a model

for hypothetical scenarios, in which their validity is entirely unquantifiable, may delay the course of

development and validation of non-animal methods that are currently showing to be more human-

relevant. The Committee claims that NHPs have been essential for studies that resulted in the longer

survival of HIV patients, but provide no peer

to a limited extent. There are many practical and

ethical hurdles in the controlled follow-up of pathological development from early to late phase in

patients. A good model is selected based on fit-for-

purpose, e.g. disease development or pathology resembles that in humans.

Pages 41 – 42, lines 42 – 2. Please see also the reply to comment 259, additional references provided.

Pages 43 – 44, lines 29 – 15. Several references

regarding the knowledge derived from NHP studies were provided already, several have been added (in

section 6.6.3). It cannot be excluded that the use of NHP might

increase again when a new disease emerges where NHP are the most relevant species to study the

disease.

In the Opinion, not one but several references are

included that demonstrate the value of NHP in HIV research.

148

reviewed, scientific evidence to support the claim.

Similarly,NHPs in research are deemed indispensable because one model exists which has

similar disease development to HIV-infected

children. A model having similar disease progression to humans does not prove it to be a scientifically

valid method of studying disease, making the claim of indispensability unsupported. Indeed, the studies

cited suggest that such models have not proven beneficial to humans.

Page 44, lines 23 – 27. The report omits a study

(Barreiro et al., 2010) which compares immune

response between different primate species, humans, chimpanzees, and rhesus macaques,

concluding that “Humans respond differently than other primates to a large number of infections...

Differences in susceptibility to infectious agents between humans and other primates are probably

due to inter-species differences in immune response to infection”. Furthermore, where reviews have

shown that even small differences between NHPs

and humans can lead to major differences in outcome of a disease or therapy, this has been used

as evidence to continue to use NHPs over other animal models, rather than comparing their efficacy

against non-animal methods.

Page 45, lines 14 – 17. There is little reason for the establishment of a timetable to include fixed dates

or targets. Where there are potential replacements,

a loose timetable must be established, which may involve consulting scientists conducting non-animal

research to assist in estimating the time frame to overcoming any current barriers in their methods.

Page 44, lines 23 – 27. Reference has been added.

Page 45, lines 14 – 17 Given the many uncertainties and difficulties to overcome in both animal and non-

animal models and also in patient studies, a realistic

loose timetable is not yet feasible.


4.6.3 Treatment

p.42, l 30-40: SCHEER identified the Zika virus as an example of a virulent pathogen studied in

p.42, l 30-40: The Opinion can never provide a total overview of the various diseases and all models. As

149

Ethical


[email protected]


and


diseases

primates. However, SCHEER has under-estimated

the opportunities for replacement. Evidence was presented at the 2016 Society for Neuroscience

meeting on the use of 3D brain microphysiological

systems as a replacement model. The system has already shed light on how the Zika virus attacks

foetal human brain cells (http://www.npr.org/sections/health-

shots/2016/11/13/501257433/minibrains-could-help-drug-discovery-for-zika-and-for-alzheimers).

p.43, l 46 and p.44, l 1-5: SCHEER credits the use of NHPs with developments in the area of infectious

disease prevention. It is useful to reflect that the scrutiny brought by the U.S. NIH and IOM to the

issue of chimpanzee use in behavioural and biomedical research revealed that such use was

“largely unnecessary”1 and “rarely accelerated new discoveries or the advancement of human health for

infectious diseases.”2 The NIH and IOM reports

reflect an impoverished review process in the oversight of experiments involving animals and

underscored the necessity of conducting comprehensive and systematic reviews to ensure

that information gleaned from animal studies in a particular area of research is, in fact, advancing our

knowledge. In light of the conclusion of the NIH and IOM reports that chimpanzees—our closest relatives

with whom we share more than 98% of our DNA—

have not helped advance our understanding of infectious diseases in humans, it seems highly

suspect that other NHPs, with whom we share approximately 93% of our DNA, would offer more

reliable data.

explained in several parts in the Opinion, animal

models form part of the pipeline. Depending on the research question, a specific model can be selected.

Although there are several in vitro models, none of

the in vitro models can mimic all the immune responses and physiological interactions that are

needed for specific questions. It is never claimed that for certain questions ex vivo or in vitro models

cannot be used.

p.43, l 46 and p.44, l 1-5: Chimpanzees have been used and are being used for a very limited number of

complicated diseases and should not be compared with the models in other NHP. In those cases where

they have been used new discoveries have been reported, e.g. in the HIV research and in the

Hepatitis B vaccine development. Comparison of percentages of total DNA (98% vs. 93%) only is not

valid and if done at all should be based on the

comparison of specific systems e.g. the immune system and underlying genetics.

http://www.npr.org/sections/health-shots/2016/11/13/501257433/minibrains-could-help-drug-discovery-for-zika-and-for-alzheimers



150

Considering the differences of the laboratory

environment from human society, it is clear that animal experiments will never capture the

complexity of human infectious disease.

Experimental animals are kept in pathogen-free conditions and cofactors that may be present in

human patients, such as other microbial infections, are absent, likely altering the acquisition and course

of the virus. Scientists have admitted that even after costly animal experiments, human data is still

needed to determine if a drug is fit for the clinical setting appear to be the only reliable way to

determine whether an HIV vaccine candidate will

have activity or efficacy in humans.3, 4

p.44, l 16-32: SCHEER recognise that small species differences can influence the outcome of a disease

or therapy. This section should also consider that immune system and genetic differences between

NHPs and humans weaken NHP infectious disease research. For example, human T cells, lacking the

siglecs (or “brakes”) of some NHP T-cells, respond

differently to infection and to treatment.5 Also, the primate TRIM5-alpha gene codes for a restriction

factor that impacts responsiveness to retroviruses such as simian immunodeficiency virus (SIV),

conferring some NHPs with greater resistance to infection, a function mostly lost in human TRIM5-

alpha.6

Importantly, infected NHP colonies are a public

health risk. Roberts and Andrews (2008) state, “During the past 60 years, individuals responsible

for NHP importation programs have observed morbidity and mortality typically associated with

infectious disease outbreaks. These outbreaks have included infectious agents such as tuberculosis,

Herpesvirus sp., simian hemorrhagic fever, and

Animal models will indeed never capture all aspects

of human infectious disease, but we need to learn and understand how certain aspects work. In vitro

models can also not provide this. Animal models form

part of this process that includes in vitro, ex vivo, in vivo and clinical research.

p.44, l 16-32: Science learns from both similarities and from differences. As such, animal models have

provided much insight in the human immune system. Comparative studies between small animal models,

NHP and humans provides new insights in our combat against human disease.

The suggested risk for the human population is not a

topic for this Opinion.

151

filovirus infections such as the Ebola and Marburg

viruses. Some outbreaks have affected both animal and human populations. These epizootics are

attributable to a variety of factors, including

increased population density, exposure of naïve populations to new infectious agents, and stress”.7

Funding should be allocated toward the be allocated

toward the improving animal-free methods of research, particularly microfluidic technologies and

mathematical models.

The Opinion does include the need for funding to

develop alternatives.


personal data

4.6.3 Treatment

and prevention of

infectious

diseases

p 42 - line 10-13

The report doesn't address the interest of studiyng natural hosts of pathogens in order to elucidate

specific mechanisms which could lead pathogenecity

(see Ploquin 2016 DOI:10.1097/COH.0000000000000238)

It has been included.



jarrod.bailey@crueltyfreein


Kingdom

4.6.3

Treatment and


diseases


P41 L28-30 No evidence given of ‘indispensability.’ Generalisation. Must provide for each area of use.

Many disagree. See e.g claims of hepatitis C researchers in Bailey paper #2 on HepC (provided).

Also see failure of NHP HIV/AIDS research summarised in Bailey AIDS paper (provided), in

contrast to claims of necessity by NHP researchers.

Notably, vaccines and drugs can be tested for immunogenicity, efficacy and safety in vitro, for

example using Sanofi Pasteur’s (developed by VaxDesign) ‘Modular Immune In Vitro Construct’ or

‘MIMIC’ system, based on multi-individual cultured entire human immune systems

http://www.vaxdesign.com/mimic-technology.

P41 L31-32 V negative, given reference to use of

human challenge models elsewhere, e.g. P42.

P41 L18-23 Sharing of data and tissues is in the

recommendations (CHECK)

P41 L28-30 Several references demonstrate that NHP are still important in infectious disease research. No

references other than the companies' websites have been provided to substantiate the claim that MIMIC

can provide all details needed to assess safety, immunogenicity and efficacy testing. To claim that

this is for vaccines and drugs is also a generalisation.

However, a very recent paper on MIMIC to demonstrate a potential for replacement has been

included.

P41 L31-32 Do not agree.

152

P41 L32-36 Past contribution and current capability of human-specific methods greatly

underappreciated here. Prospective studies are

routine, allowing study of early infection (see Bailey paper on HepC #2 (provided), and further, late-

stage is possible too in humans, as some patients present late. Augmented by in vitro culture

methods, these approached permit the study of infection and pathology throughout the pathogenic

organisms’ life cycle, all, crucially, without the confounding species differences and in a human

context.

P41 L41-42 Evidence to support?

P41 L42-45 – P42 L1-2 Evidence to support claim?

Areas of NHP use not sufficient. Must prove NHPs were predictive and essential, providing human-

relevant data that was reliable and could not have been obtained otherwise. And, it must be viewed

critically. Further, where have any NHP experiments

contributed to the development of treatments or cures for the diseases given as examples?

P41 L32-36 This is further discussed in the replacement section.

P41 L41-42 References were added to the final Opinion.

P41 L42-45 – P42 L1-2 There are many examples

that NHP have contributed to the understanding of many human diseases and the development of new

therapies. As is the case with scientific research in general, it is always a combination of systems, i.e. in

vitro models, in vivo animal models and patient

studies that result in improved knowledge and development and implementation of new treatments.

Examples that were mentioned in the Directive (P41 L42-45 P42 L1-2) are supported by both historical

and recent scientific publications. Examples of scientific publications were NHP have been

recognized to have greatly contributed to the understanding of the disease and development of

treatments for the diseases mentioned in the Opinion

include amongst others : Prince AM & Brotman B, ILAR J (2001) 42:85-88;

Buynak EB et al, Proc. Roy. Soc. Exp. Biol. Med. (1976) 151:694-700 ; Sabin AB, JAMA (1956)

162:1589-1596, Fouchier RA et al, Nature (2003) 423:240; Geisbert TW et al, J. Infect. Dis. (2015)

212 Suppl. 2:S91-97; Watson AM & Klimstra WB,

153

P42 L29-40 Section claiming human studies with

virulent pathogens are not possible for ethical

reasons ignores human in vitro methods, such as Sanofi Pasteur’s MIMIC system, which permits the

study of varied and individual human immune responses to pathogens

[http://www.vaxdesign.com/mimic-technology], as well as other associated approaches.

It is notable that human challenge models are

possible for less virulent pathogens including

Plasmodium falciparum and TB. This should be highlighted and included as a recommendation that

NHPs are not used for non-virulent pathogen research.

P43 Whole section defaults to NHP necessity – must

be challenged.

P43 L32-33 Baboon use retrograde – please

remove.

P43 L37-39 Malaria in vitro cell lines very capable – see Bailey HepC 2 paper, p482 (provided).

P43 L43-46 & P44 L 1-5 It seems strange to argue

that, in the face of catastrophic-scale failure of NHPs—both chimpanzees and macaques—to

develop effective human HIV/AIDS vaccines (some

100 vaccines have appeared safe and effective in NHPs, but every single one has failed in humans),

NHP HIV/AIDS research has otherwise been ‘essential’ and remains ‘indispensable.’ This is a

bold claim, and needs detailed evidence, which should be critically assessed. See comments for

Secn 4.6.3.1, P41 L28-30. The Opinion should cite &

Viruses (2017) 9:77.

P42 L29-40 Please see above. However, for many

virulent pathogens, the use of MIMIC (and other

systems) are not yet possible because of lack of knowledge that can only be gained through human

studies and controlled animal studies.

On-virulent must be defined better, both pathogens mentioned are virulent. Use of human challenge

models can be used for specific questions but not for

all.

P 43 Do not agree.

P43 L32-33 Do not agree.

P43 L37-39 Malaria in vitro growth of Plasmodium vivax is not possible currently.

P43 L43-46 & P44 L 1-5 The combat against HIV

does not only involve vaccine development but also the gain of knowledge on disease development and

the development of new therapies. This has been

very successful and resulted in a currently much longer survival. However, given the side-effects and

the risks for drug-resistance, the development of a good vaccine is still essential.

154

discuss Bailey’s paper on NHP HIV/AIDS research

(provided).

P44 L16-32 Only possible inference from Bailey NHP

genetics paper (provided) is that species differences in pathogenesis and host response, drug efficacy

and safety and so on, are due to intractable genetic differences—even minor ones—that often affect

disease outcome/pathology and mode of action/efficacy of therapies, which invalidates the

use of other species as models. Inter-species extrapolation of data is therefore virtually

impossible, or extremely unreliable at best.

P45 L14-19 See prior comments re: non-binding

timetable of desired outcomes, for impetus/targets (Abstract, p2 L13; Summary P10 L2; Secn 3.6 P20

L25-45).

P44 L16-32 There is no peer-reviewed evidence

provided that these small genetic difference have the claimed impact on all aspects of all diseases and that

this makes the models invalid.


264. Treue, Stefan, EUPRIM-NET,


European Primate

Centres

(http://www.euprim-

net.eu), [email protected]

u, Germany

4.6.3 Treatment

and prevention of

infectious diseases

page 45 line 6: reference to Vierboom et al., 2016

Recommendation: Include the highly relevant reference to Haus et al., 2014 (Haus T, Prinz K,

Pauling B, Roos C. Genotyping of non-human primate models: perspectives and challenges for the

implementation of the "three R's". Primate Biol.

2014;1(1):1-9. doi: 10.5194/pb-1-1-2014.) This publication is attached.

pg. 45 lines 9&10:

Comment: The current state is not adequately presented.

Recommendation: After the sentence “Sharing of biological material … of animals used.” The following

information should be added: “From 2006-2015 the

EUPRIM-Net BioBank of NHP materials and their affiliated institutes provided more than 600 organ

and tissue samples and more than 700 gene samples to almost 100 European research projects,

page 45 line 6 Thank you for the relevant information. This has

been included.

pg. 45 lines 9&10:

A reference is needed to be able to include this.

155

underlining the scientific interest in and the need for

such NHP material.


personal data

4.6.4 Neuroscience

P. 47; Line 12. Please include the article published in Nature, 2016

(Capogrosso et al.) ; the file of the article is too large; Title: A brain–spine interface alleviating gait

deficits after spinal cord injury in primates

Brain-machine interfaces have already been discussed and referenced sufficiently in the SCHEER

Opinion.


Humane



Kingdom

4.6.4 Neuroscience

The use of NHP in neuroscience is particularly harmful and distressing to the animals and we feel

that this area most urgently requires replacement.

The use of systematic reviews here would be helpful, not least to prevent duplication of studies.

Data sharing would be important, and databases such as the CocoMac 2.0 are valuable resources

that should reduce animal use. However, further efforts should be made to develop more precise

methods to examine the human brain. The aim of neuroscience research has to be a better

understanding of the human brain, not a

comparative study of NHP brains.

There are various, ongoing efforts to map the human brain, including the NIH-funded Human

Connectome project (http://www.humanconnectomeproject.org) and the

EU’s own Human Brain Project (https://www.humanbrainproject.eu/en_GB). These

not only represent a promising start to the

replacement of NHP in these studies, but are also giving us the advanced technologies that are

required for full replacement of NHP in neuroscience.

The Human Connectome project launched in 2009

and aims to map the anatomical and functional connectivity of the human brain. Recent studies to

emerge from the NIH Brain Initiative demonstrate

refinements to non-invasive functional MRI (fMRI):

Please see the reply to comment 3 from the same commenter.

Here the commenter expands on the NIH

connectome project results. The Opinion mentions these efforts because it believes in its potential for

replacement. However, the validation of the

measurements performed in humans with any new

156

ultra high magnetic fields (7T) provides high spatial

and temporal resolution images. The application of simultaneous multi-slice (SMS) echoplanar imaging

(EPI) gives improved volumetric coverage [Feinberg

et al., 2017] with a reduced scan time and improved efficiency, compared to fMRI. Ultrahigh

resolution MRI has also been used to map metabolites in the human brain and produce

anatomically detailed pictures [Nassirpour et al., 2016]. Further modifications of advanced

techniques such as diffusion-weighted MRI (DWI) have produced distortion-fee maps of the human

brain with clear delineation of cortical structures [In

et al., 2017]. These novel techniques support the requisite high resolution imaging that is needed for

full replacement of NHP.

There have been many significant and important advances in research into non-animal models of the

human brain. These models show functionality and importantly, exhibit pathology-specific

characteristics (e.g. Marchetto et al., 2016). They

pave the way for new explorations of human brain activity and are the start of effective models of

neurodegenerative disease (Choi et al., 2015). Ever more sophisticated culture techniques employing

bioreactors, three dimensional scaffolds and co-culture of multiple cell types further increase the

complexity of in vitro models and therefore enhance their similarity to human brain tissue. Qian et al.

(2016) developed a spinning bioreactor to culture

human cerebral organoids that they propose will be of value in antiviral drug testing (e.g. ZIKA virus).

Alongside advances in cell culture are advances in microfluidic technologies that enable the culture of

the ‘Brain-on-a-chip’ (reviewed in Yi et al., 2015). We believe that the rapid advances that have

occurred over the last eight years, and the

technologies will require the use of animals before

their replacement. There are limitations to all new technologies and the literature is not unequivocal on

the precision of the measurements obtained and

their significance and references have been added to the text to clarify this point (see, for example,

Buckner et al 2013, Thomas et al 2014, Eklund et al 2016).

The commenter highlights the importance of in vitro and in silico models that are also quoted as having

great promise in the Opinion (sections 3.3; 4.6.2.4; 4.6.3.3; 4.6.4.1; 4.6.4.2; 4.6.5.1.1). The main use

of these systems is to unravel mechanisms of cellular

biology that could lead to the identification of pathways and of targets upon dysfunction. Another

valuable resource is the screening of potential drugs, which has already led to the replacement of many

animal species in fields like cancer. However, in the treatment of the disease and its consequences

(which is different from drug screening), even the most sophisticated organoids lack the capacity to

integrate the full anatomical connection and the

contributions of the physiology of a living organ such as the vascular system and the immune system.

Importantly, function does not limit itself to the functionality of a cell or a network at a molecular

level but extends to the outcome behaviour/action or phenotype. Similarly, GWAS analysis and the study

quoted are incredibly useful in narrowing down

157

continuation of this progress, means that these in

vitro systems now have the capacity to replace NHP in studies of brain complexity and function.

Genetic studies, including powerful genome-wide association studies (GWAS) have further

revolutionised the field of neuroscience. Recently, GWAS were used to demonstrate the link between

the single nucleotide polymorphism rs2312147 on the VRK2 gene and susceptibility to schizophrenia

[Chang et al., 2016]. Such investigations are the building blocks for a future of multi-faceted brain

research that does not rely on NHP.

This is merely a snapshot to indicate that it is no

longer relevant or necessary to continue to use NHP in neuroscience.

Refs too large to upload

candidates and pathways of cell function and

dysfunction but although genetics can explain susceptibility links, epigenetics often mitigates how

determinant the genetic component will be and the

cumulative life experiences of a being cannot be mimicked in a disk or a chip (see Kumsta R et al

2013; Keverne et al 2014). This is why, with our current state of knowledge, animal and non-animal

approaches must provide complementary answers to different scientific questions, reducing, where

possible, the number of animals used.

267. Lindsay, Marshall,

Humane Society


.org, United

Kingdom

4.6.4 Neuroscience

The Opinion states that the ‘absence of a blood-brain-barrier, a vascular system and an immune

system constitute major limitations when investigating complex pathological processes’ but

we would like to point out recent advances that are addressing these shortfalls. We agree with earlier

comments that it is unlikely that a single in vitro

test will be able to fully replace animals, but we feel that the use of an IATA approach, bolting together

several in vitro/in silico/ex vivo methods, would be more relevant. For example, there are established

methods that may be used to produce a human blood brain barrier, with human endothelial cells,

pericytes and astrocytes [Hatherell et al. 2011] or using human iPSC [Yamanizu et al. 2017]. The

functionality of such models have been further

exploited to examine drug delivery to the brain [Toman et al. 2014]. Inclusion of the vasculature is

now possible with advances in microfluidics (e.g. Phan et al 2017) that permit cellular flow and fluid

See above, but consider the Opinion phrase “constitutes a major limitation” – to which could be

added, “until such time as in vitro approaches using sophisticated tissue engineering reach more

advanced stage of development”.

158

movement under the same shear forces as those

experienced in the human brain. In addition, novel flow cytometry-based approaches to leukocyte

adhesion assays allow simultaneous assessment of

cellular movement and tight junction protein expression in both normal and pathological states

[Williams et al. 2016]. These assays could also be used to model the immune system responses and in

addition, PET imaging of human volunteers has been used to show brain immune function

[Kanegawa et al. 2015]. These assays have yet to be validated for regulatory purposes, but we feel

that these advances in methodology for basic

research are applicable in replacing NHP in these fields.

268. PROCYK,

Emmanuel, BioSimia

France network for

non-human primate

research in neuroscience,

immunology,

and infectiology

(CNRS), emmanuel.pro


4.6.4

Neuroscience

Severity classification of electrophysiology studies in

the awake behaving monkey.

The SCHEER opinion states page 46 Section 4.6.4.1:

"In the UK, the prospective severity classification for such invasive, long-term studies is often

‘severe’, given the seriousness of the adverse effects or complications which can occur in a

minority of animals and the requirement under

Directive 2010/63/EU for severity classification to take into account the lifetime experience of

animals, the duration, frequency and multiplicity of harmful techniques, the potential for cumulative

suffering within a procedure and the application of refinement techniques (Pickard et al., 2013)."

The report emphasizes the UK usage of prospective

severity classification and omits a major conclusion

of the Pickard Report, namely, that there was little or no evidence of a high welfare impact or of

cumulative suffering (section 1.2.4 on p 7 of Pickard, 2013). It is precisely because serious

Please see earlier replies to similar comments (e.g.

243).

159

adverse effects such as seizures and brain infections

are very rare (< 6% of cases according to Pickard et al. 2013) that the prospective severity

classification of electrophysiological recording

experiments is ‘moderate’ in most EU countries, in particular in France, Germany, and the Netherlands.

269. Procyk,

Emmanuel, BioSimia

France network for

non-human primate

research in neuroscience,

immunology,

and infectiology

(CNRS), emmanuel.pro


4.6.4

Neuroscience

Human Neuroimaging

Section 4.6.4.4 Replacement possibilities Improving the spatial and temporal resolution of

current human neuroimaging techniques is not an alternative to research with non-human primates as

presumed by the report (pages 9, 20, 49, 59). This is because e.g. fMRI measures blood flow changes

taking seconds related to local variations of multiple biological elements (Logothetis 2008 What we can

do and what we cannot do with fMRI. Nature 453,

869–78).), it will never measure actual neural responses that take milliseconds, that are based on

rapid and transient synchronization events (Buzsaki et al. 2012 The origin of extracellular fields and

currents), and that contain multiplexed and multidimensional data (Rigotti et al Nature. 2013

May 30; 497(7451): 585–590) inaccessible through the BOLD signal. In addition the true relationships

between BOLD and increases or decreases of

activity is not direct and remains to be investigated (Schridde et al. 2008 Negative BOLD with large

increases in neuronal activity. Cerebral Cortex 18, 1814–1827).

Both human neuroimaging and monkey

neurophysiology are truly powerful tools but they are complementary. When used in complementary

ways they deliver true advances in the acquisition

of knowledge.

We suggest that the report emphasizes more the importance of both techniques for neuroscience at

Thank you for your support and for enriching the

document. The text has been modified in relevant sections to clarify the complementarity of fMRI and

electrophysiology and references have been added. Although we understand what imaging technologies

measure, what they can and cannot tell us about brain activity, and how they are currently used in

NHPs and humans, there is evidence that certain

psychophysical and electrophysiological studies in NHPs have been replaced with non-invasive imaging


be positively acknowledged in the Opinion. That is not to say we do not recognise that human imaging

and NHP electrophysiology approaches are often used in combination in neuroscience and are valuable

to gaining greater insight and understanding.


inherent limitations that are difficult to overcome, and that other technologies may offer greater

potential for advancement in the 3Rs, but we believe that further development of imaging technologies has


have edited the text to reflect this.

160

the present time (Procyk et al 2016. Midcingulate

Motor Map and Feedback Detection: Converging Data from Humans and Monkeys. Cerebral Cortex

February 2016;26:467–476; R. Passingham. How

good is the macaque monkey model of the human brain? Curr Opin Neurobiol. 2009 Feb; 19(1): 6–

11), but that scientific and funding efforts should be made to pursue research for new technologies that

would possibly replace both and be used in humans only.


Expert Group


Research, [email protected]

c.uk, United Kingdom

4.6.4 Neuroscience

The Opinion is clear that NHP research has tremendous benefits in the field of Neuroscience.

We note that the Opinion recognises the contributions that NHP research has made in the

past, including direct impact on human medicine (p22 line 27, p45 line 32). Research with NHPs,

because of their physiological similarity to humans, has been a cornerstone of basic neuroscience

research and it has led to advances in the treatment of neurological diseases. For example, deep-brain

stimulation technique has been used in the

successful treatment of over two hundred thousand patients with Parkinson’s disease. This medical

breakthrough would not have been developed had it not been for research on the physiology of a brain

structure called the basal ganglia in NHPs. Further examples include the contribution of NHP

neuroscience to the understanding and treatment of stroke and spinal injury, and to neuropsychiatric

disorders such as anxiety. While only a small

proportion of animal research in Europe involves NHPs, its importance is clear.

We note that the major contribution of NHP

The Opinion tries to give a balanced view on the pros, but also the cons, of NHP research in

neuroscience. This section was revised slightly to

improve on that.

161

research to the success of Deep Brain Stimulation

for the treatment of Parkinson's Disease has been challenge by Cruelty Free International (Bailey &

Taylor, 2016, ATLA).

Deep Brain Stimulation (DBS) of the subthalamic

nucleus (STN), a small nucleus belonging to the basal ganglia of the brain, is a very specific

application of DBS: it does not concern the more general aspects of DBS, which has been used for a

wide variety of neurological conditions, but to the specific combination of DBS of the STN in Parkinson

patients.

Bailey and Taylor could not have read the landmark paper in The Lancet in 1995 from Benabid’s group

on bilateral DBS of the STN which has been cited more than 800 times (Limousin et al 1995 Lancet),

which pioneering study led the way to modern DBS of the STN. This paper cites all the key monkey

studies that led up to the use of DBS of the STN; 10 of the 25 references given are to monkey studies

and the summary of the paper states that it was the

monkey research that led to the Benabid study “In monkeys rendered parkinsonian, lesions and

electrical stimulation of the subthalamic nucleus reduce all major motor disturbances.” This

statement, from the acknowledged leaders in the clinical use of DBS clearly supports the NHP

contribution.

The ‘MPTP model’ of PD used in monkeys stemmed

from discoveries in human pathophysiology, but it was research in the NHP model that was absolutely

pivotal in showing that STN in parkinsonism was the source of pathological overactivity and

demonstrating that blocking this activity resolved many of the parkinsonian features of the MPTP state

(Bergman et al 1990, Science; Aziz et al 1991,

162

Movement Disorders). The award of the prestigious

Lasker Prize in 2014 to two of the leading scientists who carried out key research in the monkey and in

the human, Mahlon Delong and Alim Louis Benabid,

also reflects the importance of the experimental work

Therefore we can dismiss the claim by Bailey and

Taylor that the contribution from monkey research is ‘debatable’: all the evidence is heavily against

them.

We attach a further Citation Analysis which

demonstrates that all of the most highly cited reviews of DBS of the STN repeatedly reference

research in NHPs.





Kingdom

4.6.4 Neuroscience

The Opinion should reflect the continuum between fundamental research and translational research.

The Opinion should clarify that the very nature of

experimental work means that one cannot predict the outcome at the outset of the research. To give

two major examples, the fundamental work of Wolfram Schultz on the NHP dopamine reward

system, which has just been recognised in the 2017

Brain Prize, is having a major impact on how we understand many neurological and psychiatric

conditions, while the discovery of mirror neurons by Gallese, Rizzolatti and colleagues in NHPs has

revolutionised ideas about human social neuroscience. Fundamental research on neural

mechanisms in the sensory, motor and cognitive systems has brought new understanding of the

human brain and its disorders. While we fully

support the need for ‘robust peer review procedures’ of proposals for research involving

NHPs (p46 line 38), it is not always possible to decide beforehand which projects have a ‘high

The report makes clear in several sections that fundamental research is still needed in many areas of

biomedical research and that some of this work may require the use of non-human primates.

163

likelihood’ of producing ‘scientific, medical or social

benefit’. Nonetheless, as prior examples have shown time and again, fundamental research is

instrumental and has broad benefits for human

society. It is not always useful to try and define a clear boundary between 'basic' and 'applied'

research.

272. Lemon,

Roger, UK Expert Group


Research , [email protected]

c.uk, United

Kingdom

4.6.4

Neuroscience

Non-invasive or invasive approaches in humans

complement but cannot replace the advances made with NHP research.

In the Preliminary Opinion non-invasive human

neuroimaging techniques, such as functional magnetic resonance imaging (fMRI), were proposed

as potential alternatives to research with NHPs.

However these approaches do not offer simple alternatives to invasive experiments with NHPs. As

noted on page 49, in an excerpt from the Bateson (2011) Report, these techniques cannot tell us

about the nature of brain activity and its relationship to behaviour, the nature of anatomical

connections within the brain, or the causal role of brain regions in behaviour with anything like the

precision of investigations with NHPs. Despite huge

scientific interest, effort and investment in these non-invasive techniques over the last two decades,

it is now widely recognised, that because of the intrinsic nature of these techniques, their spatial

and temporal resolution will remain limited compared to conventional invasive

neurophysiological and neuroanatomical techniques. The same is true for the small number of invasive

studies in ill neurosurgical patients: they are not a

replacement for what can be achieved with primate models. These techniques should not be viewed as

simple alternatives to NHP models but rather as complementary. These models reveal fundamental

Thank you for your support and for enriching the

document. The text has been modified in relevant sections to clarify the complementarity of fMRI and

electrophysiology.

Please see the reply to comment (fRMI-Bateson)

164

neuronal mechanisms while non-invasive

approaches tell us how such knowledge can be extrapolated and exploited in understanding the

human brain. Both sets of approaches are powerful

but in different ways and it is through their combination that neuroscience has advanced. Many

of us use not only the NHP model but also non-invasive imaging techniques in humans and

intracranial recordings in human patients, and this testifies to their complementary strengths.

273. Lemon,



Research ,


Kingdom

4.6.4

Neuroscience

The Opinion should cite the outcomes of the Pickard

Report and the evidence for assessment of severity as Moderate for most NHP neuroscience studies

throughout the EU. The revised Opinion should take a more evidence-

based approach to the question of severity of the

procedures used in NHP neuroscience. On page 46, lines 1-11, of the SCHEER Opinion, the Pickard

Report (2013) is cited, but the conclusions of that Report are not given. A major conclusion of the

Report was that there was little or no evidence that cumalative severity resulted in macaques or

marmosets experiencing a Severe level of harms (section 1.2.4 on p 7 of Pickard, 2013). Thus rather

than being cited as supporting the UK policy on a

‘Severe’ prospective assessment for NHP studies as the current draft opinion suggests, the cited

Report’s evidence points to a Moderate level of severity.

Confirming this, since 2013, retrospective reports

(as opposed to prospective assessments) of the actual impact of scientific procedures have been

compiled in the UK (as requested by Directive

2010/63/EU). These statistics from the UK Home Office show that over 90% of NHP basic research

studies have been assessed at the Moderate level or lower, rather than Severe. Thus retrospective

The Opinion does involve severity classification procedures, see also answer to 243. A new section on

severity classification was added to the Opinion.

165

assessment of severity is revealing that the actual

harms experienced by NHPs in laboratories are significantly lower than predicted by the regulators.

Rather than just focus on the UK situation, the Opinion should also reflect the rationale of France,

Germany, Belgium and The Netherlands, who have decided, after detailed investigation, upon a

Moderate prospective assessment for NHP studies.

274. Pickard, John, University of

Cambridge, prof.jdp@med

schl.cam.ac.uk, United

Kingdom

4.6.4 Neuroscience

page 46 lines 1-11 I congratulate the SCHEER Committee on its

excellent report. However, I wish to draw your attention to potential misreporting of our Review of

the Assessment of Cumulative Severity and Lifetime Experience in Non-human Primates used in

Neuroscience Research (Pickard et al., 2013) in the

paragraph on p46 which reads: ‘Electrophysiology studies in the awake, behaving

state are generally assessed as imposing ... the potential for cumulative suffering within a procedure

and the application of refinement techniques (Pickard et al., 2013)’.

The phrasing of this paragraph seems to imply that

our Review (Pickard 2013) found that there was

evidence for ‘cumulative severity’ in long-term NHP studies and advocated designating all such studies

as ‘severe’. Our Review found no such evidence and made no such recommendation.

May I draw your attention to Paragraphs 1.2.4,

1.2.5 and 1.3.7 from our Review: Paragraphs 1.2.4 (Page 7) Adverse events and

cumulative experience within individual events and

procedures The Review found little evidence for adverse

cumulative severity (‘additive stacking up’, ‘additive potentiation’) in the following events /

Thank you for your support of the SCHEER preliminary Opinion.

A new section on severity classification was added to

the Opinion.

166

procedures…

Paragraph 1.2.5 (page 8) Overall Cumulative

Severity and Experience

The Review found little evidence for additive effects between procedures, whether through incomplete

recovery between events (additive stacking up) or potentiation of adverse effects and suffering by

earlier procedures. Some animals were reported to show diminished responses to repeated procedures

(habituation), for example, in macaques, 86 per cent for restraint and handling, 71 per cent for the

training chair, and 1 per cent for surgery.

Specifically, there was little evidence in the majority of nonhuman primates to suggest that the nature of

pain, suffering, distress and lasting harm caused by (all elements of) the procedure, and its intensity,

the duration, frequency and and the suffering within a procedure after applying all appropriate (Directive

2010/63/EU) should have increased the severity assessment over that for single events/procedures

alone.

I would also draw your attention to our

recommendation made in regard to the designation of severity limits: Para 1.3.7 (Page 13) Designation

of severity limits ‘The process of ascribing a severity classification or

limit in advance of the project authorization depends upon assessing the cumulative suffering

and impact on lifetime experience of the likely harm

that will be informed by the retrospective reports of similar projects. The assignment of severity

categories should be evidence-based. The nomenclature relating to the evaluation of severity

should be clarified and criteria set to provide consistency in allocation, both prospectively and

retrospectively. The Review regrets that the

167

opportunity was not taken in Directive 2010/63/EU

to extend the vocabulary that is used to describe severity limits. There is clearly a distinction to be

made between Moderate, Multiple Moderate without

significant impact on welfare, and Severe.

Clarification of the phrase in the EU Directive: [the assignment of the severity category] shall be based

on the most severe effects likely to be experienced by an individual animal after applying all

appropriate refinement techniques. This phrase introduces the concept of the

probability that a particular severity limit might be

reached in contrast to the previous use of the worst case to define the severity limit. The probability of

what might happen has to be established through an iterative process based on the documented

outcomes of individual investigators and institutions obtained through retrospective reporting.’

Congratulations again on an excellent report.

275. Vitale, Augusto,

European Federation of

Primatology,


4.6.4 Neuroscience

EFP_Comments_on_SCHEER_Opinion_3.docx

p 46, lines 1-11

p.51, after line 17

Electrophysiology studies in the awake, behaving

state are generally assessed as imposing an impact on the welfare of the animals due to the number of

procedures involved, their likely effects on the monkeys, and their repetition over many months or

years (e.g., surgeries under anaesthesia, chronic restraint and penetration of microelectrodes, food or

fluid control). However, behavioural studies could not show any substantial impact on the behavior of

A new section on severity classification was added to the Opinion.


168

the animals as a possible result from the procedures

(Hage, 2014). To assess the true impact on the welfare of the animals and be able to apply specific

refinements, more comprehensive studies are

needed. Severity classification, as required under the

Directive, have to be conducted on a case-by-case basis and take several factors into

account (e.g. severity of procedure, lifetime experience of the animal).

4.6.4.5 Reduction and refinement possibilities

Refinements possibilities relate also the improving of housing conditions and

management procedures. Progress in animal training techniques and protocols have

allowed for more advanced and stress-free animal handling in experimental, husbandry

and veterinary procedure with a significant impact on the animals welfare, and on the

quality of the science. Developments in cage-

based training systems show promising results, which may allow for un-restrained

training of animals in sophisticated cognitive tasks, lowering the stress which may be cause

by handling and being separated from peers.

General comment and addendum to the section

“In ethological studies, a case-by-case analysis of severity procedures must be

conducted. In particular, it must be considered that in particular cases the level of

invasiveness could fall under the threshold definition of “procedure”: for example, when

individuals voluntarily separate themselves

169

from the social group to participate in short

and rewarded behavioural tests.”


Martje,

ECLAM, m.fentener@e




in laboratory

animal medicine

4.6.4 Neuroscience

P45 lines 40-43: it should be indicated that neuroscientific research with NHPs will continue to

be important for both further development of

functional imaging techniques and similarly for modeling neurological functions in vitro and in silico.

The SCHEER agrees with the comment and the continued need for NHP research in parallel with in

humans, in silico, and in vitro so that use of NHPs

can eventually be replaced in some of these areas of research.

277. Dodkin,

Christina, Animal

Defenders International/

National Anti-Vivisection

Society, research@ad-

international.o

rg, United Kingdom

4.6.4

Neuroscience

4.6.4 The Bailey & Taylor (2016) review of the

contribution of NHP use to neuroscience, would be a logical starting point for reviewing the use of NHPs

in neuroscience, as this is a only available review of their relevance as models for human conditions, and

the availability of non-animal methods.

Pg 46, lines 12-14: The Committee have failed to

acknowledge species differences between artificially

created NHP models and naturally occurring human Parkinson’s Disease (See ADI’s 2016 submission).

The implications of using NHPs to model neurological disease must be addressed, such as

species differences in Parkinson’s symptoms (Porras & Bezard 2012) and the options for non-animal

methods of studying the disease (Giri & Bader 2015; Shen 2016). Pathways-based research has

also been suggested as a more advanced human-

specific model of the disease (Langley 2014).

4.6.4

The Bailey & Taylor 2016 paper was cited in the preliminary Opinion. Please note that it is not the

only such review of the use of NHPs in neuroscience and available alternatives.

Pg 46, lines 12-14: The Opinion quotes examples of

models of neurodegenerative disease in NHPs that

have led to discoveries of disease mechanisms and treatments. There is no formal discussion of the

individual models that exist for each disease as this would be beyond the scope of this document.

The commenter quotes Porras & Bezard’s paper, an

elegant manuscript that supports the use of the MPTP NHP model by explaining how versatile it can be and

how many features of the human disease it can

recapitulate. This paper, and the Opinion (see section

170

There is no critique of the value of NHP models to Alzheimer’s research; for example, primate

“Parkinson’s” lack Lewy body formation which is

specific to humans, even when made to live with Parkinson’s like syndrome for 10 years (Halliday

2009). Langley et al (2016) (published since the SCHEER 2016 request) evaluates the deficiencies of

the animal model in Alzheimer’s research.

3.3), state that no animal model can fully mimic all

aspects of human disease but all models can be useful in addressing specific questions. The

knowledge of the model used, the species used and

the mechanisms by which the disease is induced are the key factors determining how relevant that answer

obtained is. The reader suggests animal models are artificial. All models are artificially created, in silico

and in vitro models are not less artificial and have an extremely important role in advancing our

understanding of human physiology. The reader quotes several interesting papers (Langley 2014, Giri

& Bader 2015), providing “keys gates for low cost

and high quality drug discovery and development” but not directly addressing issues of human brain

disease modelling or the replacement of animal studies when looking at phenotype. In full

agreement, however, and as pointed out by the Opinion in relevant sections, these techniques are

increasingly used for the replacement of animal species in drug screening beyond the field of

neuroscience. Finally, the reader touches upon a

paper that is in support of a complementary approach using organoids, in vitro models and

genetically engineered NHPs to produced more refined models of psychiatric disease in particular

(Shen 2016).

The last remark of this comment confuses the absence of one (out of several that do exist like DA

neuron loss in SNC, DA terminal loss in the striatum

as a gradient in caudate and putamen, and changes in alpha-synuclein expression levels) of the

pathological landmarks of PD in MPTP primates with a quoted paper (Langley 2014) criticising transgenic

mouse models of Alzheimer’s disease. The pertinence of all animal models of human disease is beyond the

scope of discussion of this document but there is

171

4.6.4.2 Pg 47, lines 3–7: This statement is not

logically sound; it implies that animal models are not sufficient for studying human brain disease and

justifies their continued use by suggesting research with more animal models (as well as non-animal) to

offset the limitations they pose.

4.6.4.3 Pg 47–48: Years of animal research have not demonstrated results which led to effective

treatments in humans. Systematic reviews must be

factored into the establishment of a timetable so that models shown to be poor can be phased out

first.

published evidence of the value of primate models of

AD (Van Dam D, De Deyn PP 2017).

(4.6.4.2 Pg 47, lines 3–7: The reader misinterprets

the statement that only implies that human disease being complex, it is impossible to reproduce all its

features by using a single animal, or for this case, non-animal model. The same limitations will be

encountered when using patient-derived IPS cells or organoids that are short-lived and variable from

batch to batch. As repeatedly stated in the Opinion, complementary approaches, in vivo, in vitro and in

silico, in animals and humans, are required to

unravel complex brain processes and the adaptations that the brain exerts after acute (i.e. stroke), chronic

(neurodegenerative diseases like AD, PD, HD, etc…) or neurodevelopmental diseases.

4.6.4.3 Pg 47–48: The reader claims that “Years of animal research have not demonstrated results which

led to effective treatments in humans.” This is taken

as a personal opinion as there is no factual basis to this statement. A rebuttal of the Bailey review from

2016 is provided elsewhere as an answer to criticism of the Opinion by the authors and members of

Cruelty Free International on the basis of the misquoted evidence presented in this review. Once

again, the Langley paper quoted refers to the limitations of transgenic mouse models of

Alzheimer’s disease which is beyond the scope of the

Opinion. The value of NHP research in the understanding of how the brain functions and its

implications for human disease are supported by many scientific publications in peer-reviewed journals

(as an example see Capitano & Emborg 2008; Roelfsema & Treue 2014; Philippes et al 2014) and

white papers issued from international organisms like

172

The Committee do not acknowledge the results of

the systematic review by Bailey & Taylor (2016) on the lack of contribution made by the continued use

of NHP in neuroscience research.

Langley et al (2016) reviews animal models of

Alzheimer’s Disease describing high drug attrition

rates for compounds which were encouraging in animal tests but failed in clinical trials and how no

new therapies have been developed in the past ten years due to overdependence on animal models.

The paper describes the range of human-specific approaches than can be used, including human

iPSCs, a 3D human stem cell model, computational modelling and structural and functional clinical brain

imaging techniques.

4.6.4.4 Pg 49, lines 19–40: Limitations of MRI are

cited from a paper that is 7 years old. The potential for human-based (f)MRI, following recent

developments, has been discussed by Bailey & Taylor 2016.

the Foundation for Biomedical Research

(www.monkeyresearch.org). The proposed in vitro, in silico and imaging approaches are acknowledged

to have an immense potential in refining and

replacing some NHP studies and are repeatedly quoted throughout the Opinion as complementary

approaches, in agreement with the reader.

The SCHEER has taken the findings of the Bateson

review of UK-funded studies into account. The Bateson review focused on publicly-funded UK

studies conducted mainly in academia.

The SCHEER is confident in our assessment of

imaging technologies and their current and future contribution to the 3Rs.

4.6.4.4 Pg 49, lines 19–40: Once again, the Bailey

and Taylor review (2016) is quoted regarding fMRI studies in humans being able to replace

electrophysiological studies in NHPs. fMRI only indicates perfusion changes in neuronal populations.

The temporal and spatial resolution of this technique

173

4.6.4.5 Pg 50, lines 29–43: The Committee must acknowledge that these are methods where the full

replacement of animals can be implemented, as concluded in the review by Bailey and Taylor

(2016): “humane human-relevant neuro -cognitive (and associated) research is much more capable,

widespread, important and powerful than those who use NHPs accept”

4.6.4.6 Pg 51, lines 43–44: It would be highly

questionable to validate new methods against animal models which also have known limitations

and have not been validated. A more scientifically rigorous approach would be to use available target

species (human) data to validate non animal methods.

References

Bailey J & Taylor K (2016) ATLA, 44, 43–69 Giri S & Bader A (2015) Drug Discovery Today,

20(1): 37-49 Halliday G et al (2009) Movement Disorders,

24(10): 1519-1523 Langley GR (2014) Drug Discovery Today, 19(8):

1114-1124

does not make it possible to reflect a direct increase

in neuronal activity, especially at the single cell level. New references have been added and the text in the

Opinion has been modified to reflect these limitations

and address this comment (see section 4.6.4.4). Interpretation of fMRI signals in humans has heavily

relied on NHP fundamental research experiments to explain the changes observed (Logothetis 2001,

2008). A combinatorial approach is required to avoid biased interpretations (see Buzsaki et al 2012,

Thomas et al 2013, Eklund et al 2016).

4.6.4.5 Pg 50, lines 29–43: This comment regarding imaging non-invasive studies in humans and their

potential to replace neurocognitive experiments in NHPs has already been addressed in the previous

comment (4.6.4.4 Pg 49, lines 19–40).

4.6.4.6 Pg 51, lines 43–44: If the validation methods

necessitate invasive (for example electrophysiological or histopathological) approaches it is impossible to

perform such experiments in humans in an ethical and timely fashion. Similarly, if the absence of a

lesion or the over-proliferation of unwanted cell types (like in FUS or direct cell reprogramming, see

4.6.4.6) that are mechanically triggered and

expected by the method itself need to be assessed, it is unethical to perform such validation in humans. In

this case, the use of animals is still required for validation. However, if the validation methods were

completely non-invasive (i.e. a cognitive test or an MRI), they could and should of course be performed

in humans.

174

Langley GR et al (2016) Drug Discovery Today,

22(2), 327 – 339 Porras G et al (2012) Cold Spring Harbor

Perspectives in Medicine, 2(3): a009308

Shen HH (2016) PNAS, 113(20): 5461-5464

In Europe validation of in vitro methods is

coordinated and carried out by EURL-ECVAM (within the DG-Santè, at the Joint Research Center JRC

located in Italy at Ispra) and then proposed to OECD

for adoption as a test guideline, accepted at regulatory level. The need for validation is a long-

lasting debate; however, the predictivity of in vitro methods should be evidence-based and this is the

meaning of the validation process. Comparison is carried out by using data on humans, as suggested

by the commenter. The validation process can be different depending on

the tests, being shorter for those methods used by

the scientific community since many years. As far as the SCHEER knows not validated methods (or at

least recommended by ECVAM in the cosmetic area) are not accepted by regulatory bodies. SCHEER

recommended in the preliminary opinion: It is also necessary to reduce the timescale and bureaucracy associated with the process of formal validation and to overcome the lack of regulatory harmonisation both within and across sectors. The use of alternatives will be greatly encouraged for regulatory purposes when they are justified in internationally accepted guidelines. (see section 5.2)

278. Tarsitano, Giulia,



imals.org,

Belgium

4.6.4 Neuroscience

Page 45, lines 22 – 30. Historical use of NHPs, particularly without supporting scientific evidence

that this use has been of benefit to humans, is of little relevance to debating their continued use.

Page 45, lines 22 – 30: the commenter suggests that “Historical use of NHPs, particularly without

supporting scientific evidence that this use has been of benefit to humans, is of little relevance to debating

their continued use.” The published, peer-reviewed references provided in this section of the Opinion

state to the contributions of the understanding of

how the brain works which is at the basis of unravelling disease/brain dysfunction and treating it.

The same cumulative knowledge approach is envisaged when using non-animal models. It is

unclear whether this statements points to the fact that the reader does not believe in the importance of

fundamental research, i.e. understanding how the

175

Page 45, lines 40 – 41. It is not possible to validate

whether alternative methods to NHP use could also

have led to these findings, such unsubstantiated claims should not be made by a scientific

committee.

Page 46, lines 12 – 14. Research on species differences between NHP simulated and true human

Parkinson’s Disease have not been acknowledged in the Preliminary Opinion. Similarly, there is no

critique of the value of NHP models to Alzheimer’s

research; a report by Langley et al (2016) titled 'Towards a 21st-century road-map for biomedical

research and drug discovery: consensus report and recommendations in Drug Discovery Today which

includes a review of animal models of Alzheimer’s Disease against human-relevant non-animal

methods evaluating the deficiencies of the animal model to Alzheimer’s research' should be integrated

in the Preliminary Opinion.

Page 47, lines 3 – 7. The Committee reports that

“There is consensus in the scientific community that one animal model can never fully recapitulate all

aspects of human brain diseases. (...) This implies that a variety of models, animal and non-animal,

must be used to address different aspects of the

normal brain works, as a key to treating disorders.

The value of NHP research in the understanding of how the brain functions and its implications for

human disease are supported by many scientific

publications in peer-reviewed journals (as an example see Capitano & Emborg 2008; Roelfsema &

Treue 2014; Philippes et al 2014) and white papers issued from international organisms like the

Foundation for Biomedical Research (www.monkeyresearch.org).

For the rest of the comments, please see replies to

comment 277 (identical comments).

http://www.monkeyresearch.org/

176

same disease.” This statement is not logically

sound; firstly, it implies that animal models are not sufficient for studying human brain disease;

secondly, it justifies their continued use by

suggesting research with more animal models (as well as non-animal) to offset the limitations they

pose. Animal models should be shown to be valid for human specific diseases before their continued

use is justified.

Page 47 – 48. The Committee misses the opportunity to establish a basic timetable for

phasing out specific areas of NHP use in

neuroscience research where years of animal research, particularly in NHP models, have not led

to effective treatments in humans. A number of systematic reviews exist of the contribution of

animal models to specific areas of neuroscience which conclude NHPs, or animals in general, to

make poor models; these reviews must be factored into the establishment of a timetable so that models

shown to be poor can be phased out as a first step.

Page 48, lines 36 – 47. Although the Committee

acknowledges the results of the Bateson et al. (2011) review of NHP research, this is not used as

weighted evidence to seek alternatives to the use of NHPs. Similarly, despite mentioning the paper

elsewhere in the Opinion (Page 49, lines 10 – 11), the Committee does not acknowledge a systematic

review by Bailey and Taylor (2016) on the lack of

contribution made by the continued use of NHP in research.

Page 49, lines 19 – 40. Limitations of MRI are cited

from a paper that is 7 years old. The potential for human-based MRI, among other methods, to

replace NHPs in research is discussed by Bailey and

177

Taylor (2016) in light of the most recent

technological developments.

Page 50, lines 29 – 43 The Committee discusses the

use of non-invasive methods used with NHPs, including TMS, structural and functional MRI. The

Committee must acknowledge that these are methods where the full replacement of animals can

be implemented, as indicated in the review by Bailey and Taylor (2016).

Page 51, lines 43 – 44. The Committee mentions

how new or developing methods might need to be

validated in animals, in particular NHPs. However, it would be highly questionable to validate new

methods against animal models which also have known limitations and have not been validated. A

more scientifically rigorous approach would be to use available target species (human) data to

validate non-animal methods.



Animals UK,


Kingdom

4.6.4 Neuroscience

The presumed necessity of NHPs in neuroscience

research by SCHEER is based more on assumption and habit than on significant evidence. The

argument that primates should be used for

neuroscience research because their brains more closely resembles ours than do the brains of mice or

rats is not sufficient proof that the NHP is a particularly good model. Further, the argument that

primate research has led to significant findings in the past when more sophisticated technologies were

not available is not significant justification for its continued use when alternative methods now exist.

While humans and NHPs share many neurological similarities, in such complex systems, small

discrepancies lead to broad functional disparities, thus varying physiological responses and outcomes.

This comment is unfortunately not backed up by any

data.

All those working with any model recognise that it does not completely recapitulate the situation in

man, which is one of the reasons why continued efforts are needed to develop better models – of all

178

In the brain, humans and chimpanzees have

differential expression of approximately 34% of genes,1 not taking into account differences in splice

variants or protein translation.

SCHEER cite neurodegenerative disease research as

benefiting from the use of NHPs, when for this field especially, NHP experimentation has not translated

to treatments for humans beyond initial clinical stages. For Alzheimer’s disease (AD), the clinical

failure rate for new drugs is 99.6% and there have been no new discoveries aimed at slowing the

progression of the disease for 10 years.2 For

Parkinson’s disease (PD), SCHEER claim that the gene therapy drug ProSavin® has been “safe and

efficacious in pre-clinical studies in rodents and NHPs,” when in fact these data fall within the range

of placebo controls and are inferior to response to the commonly used levodopa.3, 4 If history is any

indication, ProSavin® will also fail to be a viable option for PD patients because animal trials

overwhelmingly fail to predict human response.

Likewise, consider stroke; there have been over a thousand treatments investigated in animal

models,5 but so far there is only one drug on the market, which is associated with serious side

effects. Experts in the field admit that "animal models of stroke mimic at best less than 25 percent

of all strokes".6 This again illustrates the need to

shift away from animal models and focus on human-centred methods.

Failures of clinical trials can partially be attributed

to the unnatural ways in which neurodegenerative disease animal models are created. No non-human

species develops AD, PD, Huntington’s disease, or

types (in vitro, in silico etc as well as in vivo,

including NHPs).

The reader quotes figures on the failure of drug

treatments in the clinic in particular for AD where no non-human primate model has been used. There is a

confusion in the reader's viewpoint on general issues of animal testing that go beyond the use of NHPs and

therefore beyond the scope of the Opinion. As for PD, the reader discredits the results of an ongoing clinical

trial that has proven recovery on UPDRS scores (and

safety) in the clinic. Referring to the publication that reports on this clinical trial "A significant

improvement in mean UPDRS part III motor scores off medication was recorded in all patients at 6

months (mean score 38 [SD 9] vs 26 [8], n=15, p=0·0001) and 12 months (38 vs 27 [8]; n=15,

p=0·0001) compared with baseline." The comparison between oral levopoda discontinued used and

constant production of dopamine in the brain through

a viral vector is not relevant to assess patient benefit. The reader concludes this comment with a

personal view on the probable outcome of the ongoing clinical trial according to their own

experience. New results on the follow-up of this trial are now available and a publication supporting the

efficacy of this treatment 7 years after intervention will be released later this year if the reader would

like to keep informed on the scientific, evidence-

based facts."

Most animal models of stroke are rodents, and the issues of poor translation have been reviewed

elsewhere.

179

amyotrophic lateral sclerosis naturally, so physical

and chemical lesioning and systemic administration of toxins are used to mimic symptoms of these

diseases. Not only do these methods demonstrate

lack of construct validity in animal models, but toxins act as acute stressors and as such

necessitate a response in these animals that is not present in human patients. The acute and

immediate nature of many neurodegenerative disease models, along with the common use of

young instead of aged animals, fails to capture the progressive nature of the disorders they aim to

mimic.

SCHEER has severely underestimated the

opportunities for replacement of NHPs in neuroscience research. Following a review of AD

research, an interdisciplinary panel recommended that funding be allocated away from animal studies

and toward more promising techniques involving patient-derived induced pluripotent stem cell

models, ‘omic’ technologies (genomics, proteomics,

etc.), in silico models, neuroimaging, and epidemiological studies.2 “Mini-brains,” or 3D brain

microphysiological systems, utilize iPSC-derived human cells to reproduce synaptic connections,

neuron-glial interactions, and microenvironments that are uniquely human.7 Technologies such as

these have the opportunity to provide rapid knowledge about the human brain that NHP

research has failed over many decades to achieve.

Again this is a generalisation to all animal models

and outside our remit to address.

The Opinion has tried to balance the value of

different models, both in vitro, in silico, ex vivo and in vivo – the committee recognises all have a part to

play, and we disagree that we have severely underestimated the value of these other approaches.

However we consider that at the present time, NHPs are still required for some areas of research. As

alternative approaches are validated, the use of NHPs

will reduce.


Marija,

PRIMTRAIN, vstephan@dp

z.eu, Germany

4.6.4 Neuroscience

4.6.4.1 Introduction p.45, l. 40-43

Comment:

“Within this opinion, the need to progress in the development of advanced imaging techniques as an

alternative method for the use of NHP in research is emphasized repeatedly. It is necessary to point out,

p.45, l. 40-43 The text and reference have been added to address

this comment.

180

that the work with NHP in fundamental

neuroscience has had a huge impact on the progress of this technique in the past and will have

most likely in the future (e.g. Logothetis 2001).”

Suggestion for adjustments in the text

Fundamental neuroscience research has also helped, along with data from rodents and man,

construct new experimental in silico and in vitro models and to develop new computational

technologies to simulate how the brain works. Substantial work in the field of imaging techniques

has been achieved due to the work with NHPs in

fundamental neuroscience research.

p. 46, l.1-11 Comment:

“Electrophysiological studies in awake, behaving NHPs play a critical role in (fundamental)

neuroscience. While there is an impact on the welfare of the animal, the opinion should reflect

that it is not clear as in how far the welfare is

affected. For example, studies have been done to assess the welfare of the animals via behavioural

observations and did not find clear indication of the impact of the procedures. It should also reflect the

legislative rulings and regulatory decisions in others countries then the UK. The directive is clear on the

careful assessment of each project in terms of the severity assessment and it should be made clear

that the assessment as it is currently characterized

here is not as clear cut and straightforward as the opinion makes it out to be.”


Electrophysiology studies in the awake, behaving state are generally assessed as imposing an impact

on the welfare of the animals due to the number of

p. 46, l.1-11 A new section on severity classification was included

in the Opinion. Please see replies to earlier comments, e.g. 243;

181

procedures involved, their likely effects on the

monkeys, and their repetition over many months or years (e.g., surgeries under anaesthesia, chronic

restraint and penetration of microelectrodes, food or

fluid control). However, behavioural studies could not show any substantial impact on the behavior of

the animals as a possible result from the procedures (Hage, 2014). To assess the true impact on the

welfare of the animals and be able to apply specific refinements, more comprehensive studies are

needed. Severity classification, as required under the Directive, have to be conducted on a case-by-

case basis and take several factors into account

(e.g. severity of procedure, lifetime experience of the animal). These factors may vary from case to

case and therefore, severity classifications for the described paradigm are in the range between “mild”

and “severe”. A court ruling from Germany over experimental paradigms similar to the one

described above, which was based on veterinary, as well as scientific assessment in accordance with the

requirements under Directive 2010/63/EU, classified

the experimental paradigm as “mild” to “moderate” (OVG: 1 A 180/10; 1 A 367/10 (2012)).

281. Stephan,

Valeska Marija,


z.eu, Germany

4.6.4

Neuroscience

4.6.4.4. Replacement possibilities

p.49, l.39-40 Comment:

“Within this opinion, the need to progress in the development of advanced imaging techniques as an

alternative method for the use of NHP in research is emphasized repeatedly. It is necessary to point out,

that the work with NHP in fundamental neuroscience has had a huge impact on the

progress of this technique in the past and will have

most likely in the future (Logothetis, 2001).”

Suggestion for adjustments in the text: Significantly improving the spatial and temporal

The text of the Opinion has been modified to address

this comment.

182

resolution of non-invasive imaging technologies

should a high priority given the potential for replacement in NHP research. Considering the

substantial role NHPs played in the past in the

development of non-invasive imaging techniques, it is to be expected that they are likely to play an

important part in the future as well.


Marija, PRIMTRAIN,

[email protected],

Germany

4.6.4 Neuroscience

4.6.4.5 Reduction and refinement possibilities p. 51, following l.17

Comment: “Husbandry, experimental and veterinary

procedures play an important part in terms of the welfare of the animals. The routine handling in the

experimental as well as husbandry setting is likely to have a significant impact on the welfare of the

animals. Therefore refinements in this areas are

just as important as technological developments to reduce suffering and increase welfare. A key

technique in this context is animal training. This should be reflected in this opinion.”

Suggestion for addition to the text:

Progress in animal training techniques and protocols have allowed for more advanced and stress-free

animal handling in experimental, husbandry and

veterinary procedure with a significant impact on the animals welfare. Developments in cage-based

training systems show promising results and may allow for un-restrained training of animals in

sophisticated cognitive tasks in the future (Calapai, 2016).

Also, the training is an additional means of

enrichment and intensifies human-animal

interaction in a positive way.

Section 6.5 addresses animal training.

283. No agreement

to disclose

personal data

4.6.5 Other

uses

Page 55 = in the report the chapter "barriers

against implementation..." is part of the chapter

"other issues " , and this looks weird and not

The text has been modified.

183

coherent / it should be a separate chapter or

included in " chapter 5 = recommendation for further work"


Humane



Kingdom

4.6.5 Other uses

NHP use in xenotransplantation should be ruled out, with further consideration instead being given to (a)

wider public health strategies for

encouraging/mandating human organ donation, and (b) the urgent development of gene-editing, stem

cell and tissue engineering research.

This is outside the scope of the Opinion.


Martje, ECLAM,

[email protected],

Other, ECLAM



in laboratory animal

medicine

4.6.5 Other uses

P52, lines 42-44: The VC is neural structure

P53, lines 4-13: some other species could warrant more in-depth discussion, e.g. birds with binocular

vision and color discrimination, also cats (although

there are serious ethical restraints there as well).

P45 – 55 (on transplantation). There should be

more deliberation on regenerative medicine where it stands. It is anticipated that human or even

patient-derived cells will be engineered to replace

organs or organ function. One area of application would be the loading of tissue matrices with

differentiated stem cells, e.g. cells derived from iPSC. There are, however, a lot of unknowns

regarding tissue survival and prolonged functioning, immune responses (or tolerance), enhanced risk of

cancer development (because the regulation of proliferation and differentiation of cells was

disturbed during reprogramming). This type of

research, when approaching the preclinical stage,

p.52, lines 42-44: Indeed, the VC is a neural structure but this text is a quote from a paper and

cannot be modified.

P53, lines 4-13: Indeed, this paragraph could be expanded to discuss ophthalmology wok on other

species, although, as pointed out, ethical concerns

about the use of cats would need to be detailed. Hence, the accent has been put on the possibilities of

replacement through in vitro models.

P45 – 55 Generally agreed, but no change to report

required.

184

might well need the use of NHPs for efficacy and

safety evaluation of xenotransplants (human to NHP) or allo- or autotransplants (NHP to NHP). An

example of a recently published study is enclosed

(front page of: Transplantation of human embryonic stem cell-derived retinal tissue in two primate

models of retinal degeneration, Hiroshi Shirai et al, PNAS | Published online December 22, 2015 | E81–

E90, www.pnas.org/cgi/doi/10.1073/pnas.1512590113).

286. Dodkin,

Christina, Animal

Defenders International/

National Anti-


[email protected]

rg, United Kingdom

4.6.5 Other

uses

4.6.5 Page 52, lines 13 – 14 The Committee states

that NHPs are likely to be required to study the effects of stem cell therapy and organoid

transplants. Approximation of future research should not be used as justification for the continued

use of NHPs currently, when other non-animal

methods are currently available and more may be developed in the interim.

4.6.5.1. 4.6.5.1.1 Pg 52, lines 23 – 25: Even if NHPs

represent a more relevant model to human ophthalmology research than other non-human

4.6.5 Page 52, lines 13 – 14 This was not the

SCHEER intention. As stated in the preliminary opinion, NHP should be only used when there are no

alternatives, and the number of animal used can be substantially limited by preliminary in vitro and in

silico testing, or avoided whenever in vitro the NHP

non-reactivity can be demonstrated (indicating NHP are not a suitable animal model). The SCHEER's

opinion is that the use of an appropriate species or combination of species/models is essential to

obtaining the most reliable and translatable information.

The need for validation is a long-lasting debate,

based on the fact that animal models were never

validated; however, the current safety assessment so far has properly worked in the great majority of

cases. To have even better results, the predictivity of in vitro methods should be evidence-based and this

is the meaning of the validation process; generally the comparison is with human data not with animal

data and this is of great value and benefit to human beings.

Pg 52, lines 23 – 25: The report says they are a

more relevant model, not a perfect and validated model.

185

species, this does not make them a validated

model.

Pg 52, lines 32 – 39: It is poor scientific practice to

suggest that NHP models, which are not validated, can be replaced with other animal models that are

also not validated (lines 32 – 33). However, it is encouraging to see that lines 34 – 39 place greater

emphasis on the importance of non-animal methods. There is the missed opportunity here of

using this as a starting point to develop a timetable for phasing out animal use for this research.

4.6.5.1.2 Pg 53, lines 6 – 13: Listing the ways that

NHPs are more similar to humans than the “many animal models” that have been used in ophthalmic

research, does not make them a validated model.

4.6.5.1.3 Pg 53, lines 22 – 24: Stating how more

NHP models are being developed is not a scientific reason to continue their use. Sharing similarities

with the human ophthalmic system does not make them a scientifically validated model. It also does

not mean that other non-animal methods could answer these research questions.

4.6.5.2 Pg 54, lines 6 – 7: Other than outlining how

they have been used, the statement that NHPs have

been essential for developing organ transplantation is not supported by scientific evidence.

References

Bailey, J. and Taylor, K. (2016). Non-human Primates in Neuroscience Research: The Case

Against its Scientific Necessity, ATLA, 44, 43–69.

Pg 52, lines 32 – 39

NHPs will not be replaced by un-validated models. What constitutes a validated model is outside the

scope of this report.

The Opinion recommends how to advance 3Rs, acknowledging that one timetable for phasing-out

cannot be given in view of a wide spectrum of positive and negative incentives for NHP use. Risk



4.6.5.1.2 Pg 53, lines 6 – 13 The report says they

are a more relevant model, not a perfect and validated model.

4.6.5.1.3 Pg 53, lines 22 – 24 The report says they

are a more relevant model, not a perfect and validated model.

4.6.5.2 Pg 54, lines 6 – 7 Disagree.

186

287. Tarsitano,


Animals,


imals.org, Belgium

4.6.5 Other

uses

Page 52, lines 13 – 14. The Committee states that

NHPs are likely to be required to study the effects of stem cell therapy and organoid transplants.

Approximation of future research should not be

used as justification for the continued use of NHPs when other non-animal methods may be developed

in the interim.

Page 52, lines 23 – 25. Even if NHPs represent a

more relevant model to human ophthalmology research than other species, this does not make

them a validated model.

Page 52, lines 32 – 39. It is poor scientific method to suggest that NHP models, which are not

validated, can be replaced with other animal models

that are also not validated. Lines 34 – 39 place greater emphasis on the importance of non-animal

methods, however this is not used as a starting point to develop a timetable for phasing out animal

use for this research.

Page 53, lines 6 – 13. Listing the ways that NHPs

Page 52, lines 13 – 14 This was not the SCHEER's

intention. As stated in the preliminary Opinion, NHP should be only used when there are no alternatives,

and the number of animal used can be substantially

limited by preliminary in vitro and in silico testing, or avoided whenever in vitro the NHP non-reactivity can

be demonstrated (indicating NHP are not a suitable animal model). The SCHEER's opinion is that the use

of an appropriate species or combination of species/models is essential to obtaining the most

reliable and translatable information. The need for validation is a long-lasting debate,

based on the fact that animal models were never

validated; however, the current safety assessment so far has properly worked in the great majority of

cases. To have even better results, the predictivity of in vitro methods should be evidence-based and this

is the meaning of the validation process; generally the comparison is with human data not with animal

data and this is of great value and benefit to human beings.

Page 52, lines 23 – 25 The report says they are a

more relevant model, not a perfect and validated model.

Page 52, lines 32 – 39 There is no intention to develop a timetable to phase out animal studies, as

stated at the 'Conference Non-animal approaches -

the way forward'.

Page 53, lines 6 – 13 Please see comments above.

187

are more similar to humans than the “many animal

models” that have been used in ophthalmic research, does not make them a validated model.

Page 53, lines 22 – 24. Stating how more NHP models are being developed is not a scientific

reason to continue their use. Sharing similarities with the human ophthalmic system does not make

them a scientifically validated model. It also does not mean that other non-animal methods could

answer these research questions.

Page 54, lines 6 – 7. Other than outlining how they

have been used, the statement that NHPs have been essential for developing organ transplantation

is not supported by scientific evidence.

Page 55, lines 32 – 35. The Preliminary Opinion indicate a number of opportunities for replacement.

In this regard, the Committee should lay out in clear terms areas of research where NHPs should no

longer be used.

Page 55 – 56, lines 40 – 7. The barriers framework

outline by Schiffelers et al (2014) are discussed in the NCad report as a realistic means to achieving a

phasing out toxicology research. The Committee has missed the opportunity to use this to construct

something similar with research involving NHPs.

Page 56, lines 10 – 13. The Committee states that scientific limitations of alternative methods are a

micro-level barrier. However, the Committee does not acknowledge the scientific limitations of

continuing to use animal models over non-animal

Page 53, lines 22 – 24 Please see comments above.

Page 54, lines 6 – 7. Disagree

Page 55, lines 32 – 35. Disagree, that is outside the scope of this report.

Page 55 – 56, lines 40 – 7.

It is assumed that this remark refers to a timetable for phasing out research using NHPs. In Section 3.6,

the Opinion recommends how to advance 3Rs, acknowledging that one timetable for phasing-out

cannot be given in view of a wide spectrum of positive and negative incentives for NHP use. Risk



Page 56, lines 10 – 13.SCHEER acknowledges the scientific limitations of animal models, but this

paragraph in the Opinion discusses barriers for the implementation of alternatives.

188

methods.

Page 56, lines 22 – 24. The risk-aversive nature of

society is seen as a macro-level barrier. In terms of the general public, this is not the case; with the

majority of the public against the continued use of NHPs in research according to the UK Ipsos MORI

2016 poll ''Public attitudes to animal research''. However, the reluctance of the scientific community

has been acknowledged, with research funding bodies recognising that overcoming scepticism of

some in the scientific community can break down

barriers to the funding and development of non-animal technologies.

Page 56 – 57, lines 42 – 1. The Committee states

that “In particular, it is important that the problems with validation are addressed so that the paradox of

in-vitro models being expected to meet criteria that were never meet criteria that were never met by

most animal tests is resolved.” However, this is in

direct opposition to their claim that the implementation of a timetable for replacement of

NHPs relies upon “The progress to validate new non-animal models against existing animal models”

(Section 3.6).

Page 57, lines 7 – 8 and 24 – 26. The Bateson report is given as an example of the kind of reviews

that should be carried out, yet one particular

recommendation is not followed by SCHEER. The Bateson report states how the benefits of NHP

research are often overstated, but this is something which is repeatedly carried out by the Committee,

with little evaluation of the scientific harms.

Page 56, lines 22 – 24.

Please see the reply to comment 173

Page 56 – 57, lines 42 – 1.

The SCHEER believes that, unfortunately, both statements are true: validation often still occurs

against the ‘golden standard’ of animal tests whereas we all know such tests have flaws but will still used

until we have better methods. We know these flaws

and try to correct for these in safety and risk assessment.

Page 57, lines 7 – 8 and 24 – 26. Unfortunately, no reference was made to particular

statements in the Opinion where this is the case.

Therefore it is difficult to reply to this comment.

Bateson – The SCHEER disagrees. We have been critical of the contribution of NHP research in a

number of areas (e.g. ). Furthermore, we call for further systematic reviews (and meta analyses) to

identify where NHP research has and has not

189

contributed significantly to advancement of scientific

knowledge and/or medicine. (Recognising the value of the systematic approach, but also that the Bateson

Review had a specific remit, i.e. 10 years of UK

publicly-funded NHP research).

288. Baines, Julia,




Kingdom

4.6.5 Other

uses

p. 52, Ophthalmology: SCHEER fail to address the

welfare implications of ophthalmological research conducted in NHPs, which are severe. In these

experiments, craniotomies are often performed for implantation of electrodes. Needles may be inserted

through the sensitive scalp, skull, dura, and meninges of NHPs. Restraint devices are often used

to immobilize NHPs into rigid position for long periods of time. NHPs are often deprived of food

and/or fluid and trained exhaustively so that they

will perform tasks. Combes and Shah have elaborated on how NHPs may be affected by these

experimental paradigms, noting that NHPs “have an acute awareness of their surroundings, and are

sensitive to the presence/absence and well-being of other members of their group. As such, NHPs are

more likely than other animals to suffer from fear and anxiety by anticipating what is going to happen

to them in the laboratory, especially when subjected

to preliminary training”.(1) Regarding physical restraint, the authors state, “[i]n highly aware and

intelligent animals such as the macaque, this will cause discomfort at the very minimum, and, at

worst, considerable distress” (Combes and Shah 2016). Without an adequate review of the harms of

NHP ophthalmological research and translation to the clinical setting, the views presented in the

opinion are premature.

Sophisticated in vitro technologies, coming-of-age

in silico modelling, and human studies offer researchers methods for studying the human eye

p. 52, Correct. The welfare aspects are not

addressed specifically in this section. The section overall shows the attempt to come to alternative

methods.

It is outside the scope of this report to decide how

funding should be applied.

190

without harming other species. These methods have

been thoroughly reviewed in Combes and Shah (2016). Diverting intellect and funds from cruel,

invasive experiments on NHPs to these more

humane methods will more rapidly improve their replacement value and applicability to human

disease.

p. 54, Transplantation: We agree with SCHHER’s statement that “NHPs are not acceptable organ

donors for both practical and ethical reasons,” however neither are other species. The shortage of

donor organs is a problem that can be solved

through simple policy changes. Countries that have instituted “presumed consent laws,” wherein an

individual’s organs and tissues are presumed available for clinical use upon death unless that

individual specifies otherwise, have seen significant increases in organs available for donation. Please

see examples from Belgium, France, Sweden, and Denmark. In light of the simple policy changes that

could easily solve the problem of “limited organ

supplies,” the use of animals in xenotransplantation research should be regarded as an area of research

where a clear alternative for solving the larger problem exists.

References: (1) Combes and Shah 2016

p. 54, It is outside the scope of this report.


Marija, PRIMTRAIN,

[email protected]

4.6.5 Other uses

4.6.5.3 Barriers p.56, l. 29-31

Comment: “The EU Directive stretches the importance of the

3R principle when working with animals in research. Dissemination and further the implementation of

the 3Rs among the scientific community is an

important task. However, it should be pointed out, that of the three example initiatives, only one

(PRIMTRAIN) is currently receiving funding.”

The examples mentioned are already included in the

Opinion.

191


There have also been a small number of European initiatives funded to further the implementation of

3Rs principles in NHP research including

EUPRIMNet, ANIM.AL.SEE and PRIMTRAIN.

290. Stephan,

Valeska Marija,


z.eu, Germany

4.6.5 Other

uses

p.57, l.2-4

Comment: “The importance of the development of alternative

methods in order to phase out NHP research in the future is pointed out throughout this opinion.

However, it should be made absolutely clear that in order to develop alternatives which may replace

animal research in the future, research with NHPs (and other animals) will be needed. A prime

example is the development and progress of

imaging techniques (see above). Hence, the opposite of development of alternatives is not

animal-based research.”

Suggestion for adjustments in the text: In recent years, there has been some improvement

in the resources and funding available for developing alternatives and implementing 3Rs

initiatives. However, the amount of funding should

be increased in order to be able to replace animals with non-animal approaches in the future.

p. 57, l.31-33

Comment: “Additional examples for successful cooperation in

the field.”


This opinion includes several examples where such cooperation has been very effective such as the

NC3Rs working groups on NHP use in mAb development and vomiting and nausea, the

p.57, l.2-4 Research needs are addressed in Section 7.3.

p. 57, l.31-33

Thank you, the text has been amended accordingly.

192

EUPRIM-Net initiative, which facilitated the

implementation of the 3Rs among NHP researchers from different lines of research or PRIMTRAIN,

which focuses on refinement of training procedures

and animal behavior management.

291. Fentener van

Vlissingen,

Martje, ECLAM,

[email protected],

Other, ECLAM

4.6.6

Barriers

against the implementati

on of alternatives

and opportunities

to progress

P. 55, lines 42 – 43: how can the case of

‘conservatism’ regarding regulatory testing be

extrapolated to scientific research, and in particular basic and biomedical research? These seem to be

quite different contexts and hence scientific research and governing principles in this area would

warrant in depth analysis for their own merit, also to identify further opportunities for the development

and implementation of alternatives.

P. 55, lines 42 – 43: Indeed, this section focuses on

barriers against the implementation of alternatives

associated with regulatory acceptance and use of 3R models in pharmaceutical and chemical testing.

Some extrapolations to scientific research are made, however, such as the barrier of the scientific

limitations of alternatives, translational issues, ‘scientific practice’ and lack of resources for scientific

research on alternatives.

292. Dodkin,

Christina, Animal

Defenders



[email protected]

rg, United Kingdom

4.6.6

Barriers against the

implementati

on of alternatives

and opportunities

to progress

4.6.5.3 Barriers against the implementation of

alternatives and opportunities to progress

Pg 55 – 56, lines 40 – 7: The barriers framework

outline by Schiffelers et al (2014) are discussed in the NCad report (2016) as a realistic means to

achieving a phasing out toxicology research. The Committee have missed the opportunity to

implement timetable measures in failing to use this to construct something similar with research

involving NHPs.

Pg 56, lines 10 – 13: Within the framework for understanding barriers and drivers, the Committee

states that scientific limitations of alternative methods are a micro-level barrier. However, the

Committee does not acknowledge the scientific limitations of continuing to use animal models, in

general, over non-animal methods, which is outlined in many reviews and analyses (e.g., Akhtar

2015;Bailey 2014; Bailey 2015; Bailey and Taylor

2016; Bailey, Thew & Balls 2015; Hartung 2013;

Pg 55 – 56, lines 40 – 7: The Opinion recommends

how to advance 3Rs, acknowledging that one timetable for phasing-out cannot be given in view of

a wide spectrum of positive and negative incentives for NHP use. Risk managers, however, may decide on

such a timetable, but this is outside the mandate of the SCHEER.

Pg 56, lines 10 – 13: The SCHEER does not agree: scientific limitations have been addressed throughout

the report.

193

Langley et al 2016; Pippin 2012;).

Pg 56, lines 22 – 24: The risk-aversive nature of

society is seen as a macro-level barrier. In terms of

the general public, this is not the case; with the majority of the public against the continued use of

NHPs in research according to a UK Ipsos MORI poll (2016). However, the reluctance of the scientific

community has been acknowledged, with research funding bodies recognising that overcoming

scepticism of some in the scientific community can break down barriers to the funding and

development of non-animal technologies (Innovate

UK 2015).

Pg 56, lines 31 – 32 and lines 34 – 35: It is encouraging that the Committee acknowledges the

need to carry out systematic reviews of areas of NHP use. However, the Committee have not

recognised some of the systematic reviews already carried out which indicate that NHP use should end

in certain areas, such as Bailey and Taylor (2016)

on NHPs used in neuroscience.

Pg 56 – 57, lines 42 – 1: This is in direct opposition to their claim that the implementation of a

timetable for replacement of NHPs relies upon “The progress to validate new non-animal models against

existing animal models” (Section 3.6)

It would be highly questionable to validate new

methods against animal models which also have known limitations and have not been validated. A

more scientifically rigorous approach would be to use available target species (human) data to

validate non animal methods.

Pg 56, lines 22 – 24 Please see the reply to comment

287.

Pg 56, lines 31 – 32 and lines 34 – 35: the Bailey & Taylor 2016 paper has been cited. Please note it is

not the only such review of the use of NHPs in neuroscience and available alternatives.

Pg 56 – 57, lines 42 – 1: Please see reply to comment 287.

The need for validation is a long-lasting debate,

based on the fact that animal models were never validated; however, the current safety assessment so

far has properly worked in the great majority of cases. To have even better results, the predictivity of

in vitro methods should be evidence-based and this is the meaning of the validation process; generally

the comparison is with human data not with animal

194

Pg 57, lines 7 – 8 and 24 – 26: The Bateson report is given as an example of the kind of reviews that

should be carried out yet one particular recommendation is not followed in the drafting of

this Preliminary Opinion. The Bateson report states how the benefits of NHP research are often

overstated, but this is something which is repeatedly carried out throughout the Preliminary

Opinion, with little evaluation of the scientific

harms, such as using a model that does not always respond the same as the target species which can

lead to high drug attrition rates (Hartung 2013).

Pg 57, lines 33 – 35: We agree that greater

collaboration is needed between stakeholder groups, including animal protection groups, is

needed.

References

Akhtar A (2015) Cambridge quarterly of healthcare ethics, 24(4): 407-419

Bailey J (2014) ATLA 42, 287–317 Bailey J & Taylor K (2016) ATLA, 44, 43–69

Bailey J et al (2015) ATLA 43, 393–403 Hartung T (2013) ALTEX, 30(3), 275 – 291

Innovate UK (2015) A non-animal technologies

roadmap for the UK Ipsos MORI (2016) Department for Business,

Energy & Industrial Strategy

data and this is of great value and benefit to human

beings.

Pg 57, lines 7 – 8 and 24 – 26: The SCHEER has taken the findings of the Bateson review of UK-

funded studies into account. The Bateson review was focused on publicly-funded UK studies conducted

mainly in academia. We are confident in our assessment of imaging

technologies and their current and future contribution to the 3Rs.

Unfortunately, no data are provided to illustrate the

concern for unsubstantiated claims. In several cases the SCHEER has included additional references.

Pg 57, lines 33 – 35: Thank you for your support.

195

293. Baines, Julia,


Treatment of



4.6.6

Barriers against the

implementati

on of alternatives

and opportunities

to progress

2_European_Commission_2013.pdf

We agree with the barriers identified by SCHEER, particularly the need to conduct thorough

systematic reviews of all areas of NHP research and

the imbalance in funding between animal-based and animal-free research. However, without stiff

legislative mandate, experimenters driven by bias and habit will find little reason to overhaul their

current methodologies. When tests on animals are banned we see a thriving expansion in innovative,

humane non-animal approaches that can have numerous applications, as evident when the

European cosmetics animal testing ban came into

effect—which it should be noted, was implemented irrespective of availability for non-animal

replacement methods for all human health endpoints. In the advent of the testing ban, Europe

invested heavily in the development of nonanimal testing methods with fantastic returns. For

example, scientists may now use high-tech, sensitive tests such as 3-D tissue models produced

from human cells to evaluate whether chemicals

irritate the skin and eyes. These humane tests are a great success story, not only in reducing suffering

to animals but these tests have been found to produce more accurate, human-relevant results in

comparison to tests on animals.(1) An impact assessment published by the Commission

recognised that the provisions of the cosmetics animal testing ban “are generally seen as a crucial

accelerator of research and validation of alternative

methods by all stakeholders”.(2) In addition, the report states that “The search for alternative

Indeed, a ban may lead to acceleration in the investment into the development of alternative

methods as seen for cosmetics (EC, 2016). This should be recognised as an impact by SCHEER and

therefore the text of section 3.7 was adapted.


196

methods is by now also more and more recognised

as the search for better science and forms part of an overall shift of paradigm in safety assessment.”

References: (1) JRCEC 2013, (2) European

Commission 2013

294. Treue, Stefan,

EUPRIM-NET,


European Primate


uprim-net.eu),

[email protected]

u, Germany

4.6.6

Barriers

against the implementati

on of alternatives

and opportunities

to progress

pg 57 line 17-26 Communication paragraph

Comment: This statement is taking a UK-centric

perspective and ignores other European initiatives.

Recommendation: Replace the sentence “The Concordat on Openness initiative in the UK is a

welcome development, which is being replicated in other EU countries.” By the sentence “The Basel

Declaration (http://www.basel-declaration.org), GIRCOR in France (http://www.recherche-

animale.org), the Concordat on Openness initiative

in the UK, the Tierversuche Verstehen Initiative in Germany (http://www.tierversuche-verstehen.de)

and several other such efforts across Europe are a welcome development.

g. 57 line 31-35: The statement singles out UK

efforts, ignoring pan-European efforts.

Recommendation. Replace the wording “such as the

NC3Rs working groups on NHPs use in mAb development and vomiting an nausea” with “such as

the pan-European EUPRIM-Net interdisciplinary platform for cooperation and collaboration, in place

since 2006. Through its activities is has advanced cooperation to the benefit of NHP welfare and

science. Given appropriate funding these efforts can be continued across Europe.

The SCHEER believes the sentence is correct - the Concordat on Openness led by UAR in the UK was the

first such initiative and other EU member states then followed; the Concordat is the most advanced in

terms of impact achieved thus far. We have, however, added the examples from other countries:

“The Concordat on Openness initiative in the UK is a welcome development, which is being replicated in

other EU countries (e.g. Tierversuche Verstehen

Initiative in Germany and GIRCOR in France).”

295. 't Hart, Bert

A. , Biomedical

Primate

Research

5

RECOMMENDATIONS FOR

FURTHER

WORK

Page 60 line 35/36

the sweeping statement is made that the 4Cs will be the solution for current problems caused by

competition among and reputation of scientists. This

requires an explanation.

The SCHEER is not claiming that this is a panacea. However, it can help with advancing the process.

197

Centre,

[email protected], Netherlands

296. No agreement


5

RECOMMENDATIONS FOR

FURTHER

WORK

Other recommendations for further work/

implementation of 3R should be added and part of a EU strategy for NHP:

- Good living condition from birth to the end of the

procedure. What is EU strategy for the supply NHP models? What about breeding NHP in Europe?

Transport of macaques batches from Asia or Mauritius damages the animal welfare. The

opportunity to promote the breeding of NHP in Europe can be a strong effect of refinement as well

as strategic or sanitary issues. Also, some few animals can be replaced at the end of a procedure.

EU should support the existing or new sanctuaries

needed to rehome those NHP after the study. Re-use / rehome section (P24 / L5), should mentioned

this need. - The NC3R is an effective organization which

implement the main good practices, guidelines or analysis (see Page 10, page 25, line 3, P26 Line 6,

page 27, Page 60, line 13-14/ . It also gives financial support to research on the 3R, but this

initiative remains a UK one’s, and may narrow the

EU vision of NHP use. The EU should promote the creation of other national equivalent

institutions/platforms to spread/collect/adapt good practices in different cultures and languages.

- Re-using animals will have a strong impact on reducing the total number of NHP used in research.

P60 L4-6, not only the pain and stress should be further investigating but also the real cumulative

severity of the procedures experienced by the NHP.

Even if they are non- domestic animals, they are bred in captivity and show remarkable adaptive

behaviors in experimental conditions. The real effect of repeated procedures, in a re-use process

The recommendation section has been revised taking into account all comments from the public

consultation

198

should be further analyzed.

- Training the Ethical committee and Animal welfare body members to the “arm benefit assessments”

procedures.

297. Elena, Borra, University of

Parma - Italy




5 RECOMMEND

ATIONS FOR

FURTHER WORK

Recommendations for further work. Paragraph 5.1.1 page 58 lines 39-41.

In the different parts of the Opinion, there should

be a more balanced acknowledgment of the key role of fundamental, in addition to translational/applied,

research. The following sentence (p. 58) should be rephrased and/or tempered: “it is important that

research funders and ethics committees establish robust peer review procedures to ensure that only

those projects with a very high likelihood of producing scientific, medical or social benefit go

ahead”. One possibility is to state: "it is important

that research funders and ethics committees establish robust peer review procedures to ensure

that only those projects with a very high likelihood of producing scientific or translational

(medical/social) benefit go ahead, regardless of whether they are classified as basic or

translational/regulatory research".

We would like to stress that History of Medicine

shows in an unequivocal way that the fundamental drive to most medical advancement has been and

remains basic science. Basic research has an implicit translational impact, especially in behavioral

neurophysiology, where the consequences of brain lesion in humans are the main source of inspiration

for studies in NHP. We recommend to add an additional sentence emphasizing the crucial role of

NHP basic research in neuroscience advancement.

We would also like to stress that for both knowledge gained and translational impact, it is not useful to

try to distinguish ‘basic’ from ‘applied’ research.

The recommendation section has been revised taking

into account all comments from the public

consultation.

199

298. Borra, Elena,


Expert Group



unipr.it, Italy

5

RECOMMENDATIONS FOR

FURTHER

WORK

Recommendations for further work. Paragraph 5.1.2

page 59 lines 15-16 (and in other parts of the document).

Centers of excellence. In the EU there is a plurality of groups producing cutting edge science using

NHPs. Improving the networks for information sharing and training opportunities is a very

important aspect. Furthermore, in recent years there have been numerous developments to ensure

a high level of skills in NHP labs through coordinated and specialized training initiative

(EUPRIM-NET, EU COST-Action CA15131-

PRIMATRAIN). However, the suggestion of “centralizing” research on NHP in centers of

excellence is problematic. In fact, a small number of center of excellence would not allow the rich

interplay between NHP laboratories and other local neuroscience communities. Furthermore, the

feasibility of this proposal could be prevented by several local factors, different in the various EU

countries.


into account all comments from the public consultation.


Humane



Kingdom

5.1 Advancing

3Rs

Recommendations 1. Independent expert review of NHP use,

concluding on its value, translational relevance and

necessity in the context of alternative approaches. To include analysis of retrospective assessments

conducted under Directive 2010/63. 2. Detailed consideration of NHP use during the

review of Directive 2010/63, including consideration of ethical aspects, with proposals for amendment to

strengthen the protection provided to NHPs through that legislation, to speed the development of and

recourse to alternatives to NHP procedures with a

view to the urgent phase-out of the latter. 3. Review of pharmaceutical legislation and

guidance to identify where NHP use may be being driven by ‘box-ticking’ regulatory requirements


into account all comments from the public consultation.

200

rather than genuine scientific justification.

4. Compilation of guidance on alternatives to NHP procedures, aimed at alerting Member State

competent authorities to methods or research

strategies that could be pursued instead of a proposed NHP project to progress understanding of

a disease or therapy. This guidance should be used in all project evaluations.

5. Commitment from EU and Member State pharmaceutical sector regulators to examine the

concept of 21st century toxicology, and to present recommendations on how the approach can be

integrated into drug safety testing. Integration of all

available, validated (where applicable) in silico, in chemico and in vitro toxicological methods into rules

and guidelines for medicinal product authorizations, and commitment to updating these on a regular

basis as new methods are developed. 6. Rules be developed (e.g. in the context of

amendments to Directive 2010/63) on the mandatory sharing of data on NHP projects to avoid

duplication of effort.

7. Development of platforms for collaborating in and sharing data from population studies, genome wide

association studies, and clinical data, to further progress in infectious disease research and vaccine

development without recourse to NHPs. 8. Widespread use of organ-on-a-chip technologies,

advanced imaging techniques and genome wide association studies to replace NHP use in

neuroscience research.

NHP use in xenotransplantation be ruled out, with further consideration instead being given to (a)

wider public health strategies for encouraging/mandating human organ donation, and

(b) the urgent development of gene-editing, stem cell and tissue engineering research

201

300. Lemon,


for NHP



Kingdom

5.1

Advancing 3Rs

Advancing both animal welfare and scientific

discovery can and should co-occur. We also recognise the need to couple good science with

optimal welfare for experimental NHPs, through

application of the 3Rs. As active scientists, many of us are leading 3Rs projects that are improving

welfare in our laboratories. We cite the recent paper by Gray et al (2016), in the peer-reviewed

journal ENeuro, which tested the welfare impact of different types of fluid control in macaque monkeys

involved in neuroscience research, and which concluded that these protocols had little welfare

impact and certainly much less than predicted on

purely subjective criteria. The PDF of the paper is attached.


consultation. Several recommendations take into

account animal welfare.

301. Farningham,

D, MRC Harwell,

Centre for Macaques,

United Kingdom

5.1

Advancing 3Rs

We wish to address the opportunities referred to in

Section 5 of the opinion; “Advancing the 3Rs”. Refinement is an imperative in any area of animal

research and particularly so in sensitive species such as non-human primates. In addition to the

issues raised within the opinion, we propose that there is a strong case for the breeding unit to

contribute to both welfare and science. Animals that are well habituated to humans and are socially

adaptable will make better scientific subjects having

the potential for a better experience during subsequent experimental use.

Cognitive neuroscience in particular requires

animals that will work daily with users and the human/animal relationship is vital to ensuring this

works well, at minimum cost to the animals. This can be assisted by the breeding unit staff spending

time on a daily basis interacting with the animals.

This should start with simple habituation, working with individual groups of animals, hand feeding and

building trust between animals and technicians. As the animals become familiar with staff, positive

The recommendation section has been revised

taking into account all comments from the public consultation.

202

reinforcement training can be introduced; animals

entirely of their own volition learning to carry out simple tasks in return for valued food rewards.

Groups of animals can be trained by working with

the hierarchy, starting with the highest ranking animals and working downwards. Animals

participate willingly in this experience. It builds the human animal bond, provides useful practical tools

and provides staff with a greater understanding of the individuals in their care.

Animals that are well adjusted and comfortable in

the presence of humans are much more likely to

come forwards and perceive interactions with humans a positive experience. This gives them with

the confidence to work with scientists within the laboratory.

Beyond this, there is potential for the breeding

facility to prepare animals for future use by for example providing the opportunity to carry out

simple tasks such as a button press which releases

food or liquid reward. In the breeding setting these tasks can be made available on a voluntary basis for

the animals to access as they wish. Such tasks can assist by pre-training animals for tasks that may be

needed in the laboratory. The evidence is that this does assist with future learning in the laboratory.

The breeding unit provides a natural complexity of

environment that lends itself to studies of animal

welfare. Breeding facilities should have as a primary objective the incorporation of scientific

programmes to study and understand behaviour and social interaction. The Centre for Macaques is

working with colleagues in Newcastle and elsewhere to bring new and existing technologies to bear to

address these issues. Such studies should result in

203

increased understanding of the captive environment

within the breeding unit, better welfare and with considerable potential for broader application.

The Directive stresses the importance of lifetime experience. Good early experience will help reduce

subsequent stress and improve the lives of these animals. This is an example where by working

together we can assist scientists in achieving robust scientific outcomes answering important scientific

questions. The focus of the 3Rs is rightly mostly directed towards the experimental paradigm;

however there is a good case for advances in

husbandry and care in the broadest context providing additional benefits.

302. Tarsitano,


Animals, g.tarsitano@e

urogroupforanimals.org,

Belgium

5.1

Advancing 3Rs

Page 58, lines 3 – 16. It is important for the

Committee to highlight how, in conducting harm-benefit assessments on a case-by-case basis for

NHP research proposals, the Commission guidance includes that “there will be a need to seek external

advice on specific issues” if the application is beyond the scope of the project evaluators

expertise. This could include experts in non-animal technologies in related areas or even consultation

with organisations which, by working to promote

non-animal methods, may have access to networks of scientific experts.

This section on replacement is also lacking vital

advice that those using primates in research should also undergo training in non-animal methods, as is

recommended for reduction and refinement of animal procedures. As highlighted in the report by

Innovate UK and a number of biomedical research

institutions, the support and building of skills in multidisciplinary science and technology can help to

drive the development of non-animal technologies. With the acceptance that research is starting to shift

The recommendation section has been revised,


204

away from the use of primates, those currently

using them should be learning new skills to continue research in their field, without animal use.

303. Stephan,

Valeska Marija,

PRIMTRAIN,

[email protected],

Germany

5.1

Advancing 3Rs

5.1.2.2 Training

p.59, l.22-24 Comment:

“While the knowledge of alternative methods in

order to reduce the number of animals used is important when designing a research project

involving NHPs. The knowledge of refinement of techniques and procedures is just as important

when it comes to the actual day-to-day work with the animals in order to conduct research, as well as

husbandry procedures according to best practice and to reduce suffering and stress. Hence, we

believe the opinion should reflect the importance of

this.”

Suggestion for adjustments in the text Moreover, researchers and animal care staff must

ensure that they keep abreast of the latest techniques that enable reduction in animal numbers

and the refinement of existing methods and techniques to reduce suffering, and put this

evidence base into practice.

5.1.2.3 Improvement of techniques

p.59, l.38-42, p.60, l.1-2 Comment

“As mentioned before, we find refinement of existing techniques, procedures and methods to

play an important part in the work with NHP and are of the opinion that this document should reflect this

importance.”


Whilst there has been progress with refinement of neuroscience studies involving NHPs, the basic

The recommendation section has been revised,


205

paradigm still involves in many cases invasive

techniques, prolonged restraint, fluid or food control. Scientist should continue refining these

paradigms (e.g. improved schedules for fluid or

food control, restraining techniques, and animal training protocols), as well as continue the work on

refining technical approaches (such as wireless recordings). Experiments should also make full use

of modern imaging, biotelemetry, virtual models and other technologies, and sharing of data and

resources (animals, tissues and equipment) between researchers and institutions, to reduce and

refine NHP use.

Furthermore, there needs to be a focus on

significantly improving the spatial and temporal resolution of non-invasive imaging technologies to

refine and ultimately replace the use of NHP by non-invasive functional studies of the human brain.

304. Bowring,

Nancy, Private,

[email protected],

United

Kingdom

5.1.1

Replacement

Experiments on animal is not only inhumane and

cruel but totally ineffectual, as so many experiments have shown. They can be harmless to

animals but lethal to humans. These experiments should have been made obsolete many years ago.



305. Dodkin,

Christina,

Animal Defenders



[email protected]

rg, United

Kingdom

5.1.1

Replacement

5.1.1 Replacement

Pg 58, lines 3-16: It is important for the Committee to highlight how, in conducting harm-benefit

assessments on a case-by-case basis for NHP research proposals, the Commission guidance

includes that “there will be a need to seek external advice on specific issues” if the application is

beyond the scope of the project evaluators expertise. This could include experts in non animal

technologies in related areas or even consultation

with organisations which work to promote non-

The recommendation section has been revised, taking into account all comments from the public

consultation

206

animal methods, who may have access to networks

of scientific experts.

This section on replacement is also lacking vital

advice that those using primates in research should also undergo training in non-animal methods, as is

recommended for reduction and refinement of animal procedures. As highlighted in the report by

Innovate UK and a number of biomedical research institutions, the support and building of skills in

multidisciplinary science and technology can help to drive the development of non-animal technologies.

With the acceptance that research is starting to shift

away from the use of primates, those currently using them should be learning new skills to continue

research in their field, without animal use.





5.1.1 Replacement

The definition of replacement given in Annex 1 of the opinion is correct. However, SCHEER are

inconsistent in their use of this terminology. Mice, pigs and zebra fish are repeatedly referred to as a

potential replacement for primates within the opinion. This is not replacement but substitution. All

suggestions of replacing NHPs with other species should be removed.

The SCHEER agrees with this comment and have changed the text in the Opinion to: Notably,

substitution of NHPs with rodents or other laboratory animal species is not replacement as defined by

Russell and Burch (1959). However, this may be ethically desirable if the available evidence indicates

that the non-primate species is likely to suffer less harm.


Ethical



Kingdom

5.1.2 Reduction

and

refinement

Both at the recent oral hearing on the SCHEER preliminary opinion and elsewhere, calls have been

made to review the process of prospective severity

assessment on project licences for neuroscience experiments using NHPs such that the category of

suffering assigned to these experiments would be lowered from "severe" to "moderate".(1) This call is

made in response to a 2013 report from the UK Animal Protection Committee (APC) which found

that the majority of procedures conducted on NHPs under a severity protocol were retrospectively self-

assessed as being of moderate severity.(2)

However, the APC report has subsequently been

A new section on severity classification was included in the Opinion.

207

criticised. The report notes that there was little

evidence for additive effects of procedures on severity, but this may be challenged on the grounds

that the assessment of cumulative severity was

made by those at the establishment, performed in a way that was not blind to the treatments and

involved an analysis of historical records rather than real-time sampling. Furthermore, the welfare

assessment methods employed often focused on physical aversive affects, negating the impact on

psychological or emotional well-being. Some self-assessments also noted that fluid and food

restriction had no adverse effects and that the task

to which the monkeys were trained was enriching itself. If this were the case then there would be no

need to restrict food/fluid in order to motivate the animal to complete the task. It is evident from the

report that retrospective assessment of pain and suffering by those invested in the studies reveals a

high level of desensitisation and a lack of ethical self-examination by experimenters, resulting in

ethical degradation of the NHPs. The report itself

notes that there was a degree of underestimation of severity and a poor understanding of the nature of

suffering by experimenters. Indeed, the UK Animals in Science Committee raised serious questions

about the quality of data collected and conclusions drawn from the report, recommending that further

work is required before drawing assumptions about the presence or absence of negative affective states

in NHPs.(3) A systematic review of the accuracy and

independence of retrospective severity assessment on the available data from 2014/15 has not been

conducted since the requirement to report actual severity to the regulator was implemented in

January 2015 (http://www.parliament.uk/business/publications/w

ritten-questions-answers-statements/written-

208

question/Commons/2016-11-11/52550/).

Therefore, retrospective severity assessment cannot be considered a reliable indicator without

independent oversight and changing the severity

classification of NHP neuroscience research based on the flawed APC report would be foolhardy. We

urge SCHEER to recommend independent oversight of the retrospective severity assessment process.

References: (1) ASC 2016, (2) APC 2013, (3) ASC

2014

308. Dodkin,

Christina, Animal

Defenders



[email protected]

rg, United Kingdom

5.2 How to

overcome barriers?

5.2

Pg 60, lines 35-36: To support the statements about barriers such as concerns over researcher

reputation and entrenchment, the Preliminary

Opinion should cite the Innovate UK report which also acknowledges that “A major barrier will be the

degree of scepticism in some sectors of the scientific community about the ability to model

complex biological processes using NATs, which can discourage wider engagement in the development,

validation and translation of alternative approaches. Changing perceptions and building confidence will

be as important as building capacity” (Innovate UK

2015).

Pg 60, Lines 37 – 39: The Committee suggest that in communications about NHP use, the scientific

community should provide accurate description of benefits, harms and limitations of research.

However, in our analysis of Non-Technical Summaries in the UK we have found vague project

descriptions which do not properly explain what is

involved in procedures, subjective, sweeping and unfounded statements about the potential benefits

and apparently poor knowledge of alternative methods. This skewed reporting of their own work


consultation.

The reference has been added to section 4.6.5.3.

The SCHEER sees this comment as support for our

recommendation.

209

suggests a further barrier to encouraging

researchers to be open and transparent about the research they conduct.

References Innovate UK. (2015). A non-animal technologies roadmap for the UK: Advancing

predictive biology.

309. Tarsitano , Giulia,



imals.org, Belgium

5.2 How to overcome

barriers?

Page 60, lines 35 – 36. To support the statements about barriers such as concerns over researcher

reputation and entrenchment, the opinion should cite the Innovate UK report which also

acknowledges that “A major barrier will be the degree of scepticism in some sectors of the

scientific community about the ability to model complex biological processes using NATs, which can

discourage wider engagement in the development,

validation and translation of alternative approaches. Changing perceptions and building confidence will

be as important as building capacity”.

Lines 37 – 39. The Committee suggests that in communications about NHP use, the scientific

community should provide accurate description of benefits, harms and limitations of research.

However, analysis of Non-Technical Summaries in

the UK found vague project descriptions which do not properly explain what is involved in procedures

and apparently poor knowledge of alternative methods.


consultation.

310. Baines, Julia,




Kingdom

5.2 How to

overcome barriers?

Throughout its opinion, SCHEER indicates an

“urgent need” to conduct systematic reviews and meta-analyses of NHP use without asserting the

need for proactive policies and practices that make these studies possible (e.g. p. 56). We encourage

SCHEER to consolidate its references to this need in a central, expanded recommendation to promote

and implement systematic reviews. In addition to a

central recommendation, we encourage SCHEER to

This is beyond the scope of the mandate received by

the Commission.

210

indicate sections of its opinion in which claims are

made that are not substantiated by currently available systematic reviews. For example, section

3.7 (p. 21 l. 7) asserts that NHPs are “the best

available animal models for addressing particular research questions,” including drug efficacy and

safety, due to general biological interspecies similarities. This assessment is ascribed to

“consensus within certain sections of the scientific community,” without noting that very few

systematic reviews of preclinical animal models have been conducted. Where systematic reviews of

preclinical models have been carried out, they have

undermined the validity of previous consensus.(1) We ask SCHEER to make note of this in its opinion,

and to specifically identify areas where consensus on animal model appropriateness is not supported

by systematic review or meta-analysis. These areas should be prioritised for retrospective assessment.

SCHEER must take a firm stance on the necessity of

mandatory compliance with ARRIVE and other

guidelines that facilitate thorough review of NHP use. SCHEER mentions the value of the ARRIVE

guidelines, minimum reporting standards for published studies, but the ARRIVE guidelines are

voluntary and poorly enforced by journal editors.(2) The ARRIVE guidelines alone are insufficient, as

they do not address the prevalence of NHP studies that are not published, publication bias, and other

problems that have been evaluated extensively in

the literature.(3) (4) Without explicit direction by SCHEER (or Member States) to meet the specific

reporting needs outlined in these publications, they will remain unmet. Thorough review of the impact

of experimentation on NHPs, or lack thereof, will not be possible.

Without explicit mandate for companies to share

211

and systematically review published and

unpublished results of NHP studies with the goal of eliminating the use of NHPs in unnecessary studies,

it is unclear how such assessments will be expected

to translate into reducing the use of NHPs. We encourage SCHEER to address the need for this

mandate in its revised opinion. Cross-company and cross-sector data sharing, proposed elsewhere in

SCHEER’s opinion as a path forward (p. 18, line 16), should be integrated into the opinion as an essential

requirement for a substantive retrospective assessment of all NHP studies carried out to date.

As a part of this stance, we encourage SCHEER to

propose that researchers using NHPs are required to complete training in approaches to rigorously

analyse previously performed experiments using NHPs before beginning new experiments.

Standardized approaches to this practice have been described in the literature and widely discussed as a

cornerstone of avoiding unnecessary duplication of experiments on animals.(5) (6)

References: (1) Sena et al 2010, (2) Baker et al

2014, (3) Sena et al 2014, (4) de Vries et al 2014, (5) Leenaars et al 2016a, (6) Leenaars et al 2016b

311. Baines, Julia,




Kingdom

5.3 Research

needs

In light of the growing body of evidence that data

resulting from studies on NHPs cannot be readily extrapolated to humans and the development of

nonanimal testing methods and technologies that can replace the use of animals, it is essential that

plans are drawn up to phase out the use of NHPs for scientific purposes. In 2016 the Dutch Parliament

passed a motion to phase out all experiments on NHPs at Europe’s largest primate-testing laboratory,

the Biomedical Primate Research Centre in Rijswijk

and commissioned a study into how this may be achieved whilst still allowing medical research to

thrive. This motion was passed just months following an announcement by the Dutch

The Opinion recommends ways to advance 3Rs,




212

government to support a fund to stimulate the

development of nonanimal testing methods and we recommend that a similar approach is adopted

across all European member states. We agree with

SCHEER regarding the need to conduct thorough systematic reviews of all areas of primate research.

However, without stiff legislative mandate, there is little drive for experimenters to overhaul their

current methodologies. We recommend that SCHEER propose a moratorium on the use of

primates for scientific purposes in light of a thorough approach to the systematic review of all

areas of primate research.


Martje,

ECLAM, m.fentener@e


6 7 ABBREVIATI

ONS AND

GLOSSARY OF TERMS

P52, lines 42-44: VC is an abbreviation not explained (Visual Cortex)

In case the comment on 4.5 is taken, ESLAV and ECLAM should be included as well:

ESLAV: European Society of Laboratory Animal

Veterinarians

ECLAM: European College of Laboratory Animal Medicine

The text has been appropriately revised.

313. Dodkin,

Christina, Animal

Defenders



[email protected]

rg, United Kingdom

9.1 Annex 1:

Definitions and

examples of

replacement, reduction

and refinement

Annex 1- Definitions and examples of replacement,

reduction and refinement

The definition given in Annex 1 of the Preliminary

Opinion (and the paper from which this is cited), states that in some cases “relative replacement”

involves “replacing the use of live ‘protected’ vertebrates with vertebrate cells or tissues, early

life-stages or non-vertebrates” as a step towards replacement. Examples of whole animal use as

relative replacement cited include “non-protected immature forms of vertebrates; invertebrates, such

as Drosophila and nematode worms.” The

Preliminary Opinion uses adult vertebrates, e.g.

The text has been appropriately revised.

213

spiny mice and pigs, as examples of species that

could replace NHPs. Therefore this is an incorrect use of this definition. When referring to replacing

NHPs with other animals it must be made clear that

this definition of replacement is not the same as the one described by the 3Rs in the Annex. Consider

using the term “substitute” rather than “replace”.

314. Tarsitano, Giulia,



imals.org, Belgium

9.1 Annex 1: Definitions

and examples of

replacement, reduction

and refinement

The definition given in Annex 1 of the SCHEER opinion (and the paper from which this is cited),

states that in some cases “relative replacement” involves “replacing the use of live ‘protected’

vertebrates with vertebrate cells or tissues, early life-stages or non-vertebrates” as a step towards

replacement. Examples of whole animal use as relative replacement cited include “non-protected

immature forms of vertebrates; invertebrates, such

as Drosophila and nematode worms.” The Opinion uses adult vertebrates, e.g. spiny mice and pigs, as

examples of species that could replace NHPs. Therefore this is an incorrect use of this definition.

When referring to replacing NHPs with other animals it must be made clear that this definition of

replacement is not the same as the one described by the 3Rs in the Annex. Consider using the term

“substitute” rather than “replace”.

The SCHEER agrees with this comment and have changed the text in the Opinion to: Notably,

substitution of NHPs with rodents or other laboratory animal species is not replacement as defined by

Russell and Burch (1959). However, this may be ethically desirable if the available evidence indicates

that the non-primate species is likely to suffer less harm.

214

Comments received by email

No. Name of

individual/organisation Submission SCHEERs response

1 Christina Dodkin

Animal Defenders International

research@ad-

international.org

Dear Sir/Madam,

I am emailing with regards to the public consultation on the preliminary opinion of the use of NHPs in biomedical

research. On Friday I submitted several submissions via the appropriate form, along with a number of supporting papers.

However, some of these exceeded the maximum size allowed, but are necessary additions to the references.

Therefore, please find a separate email sent directly to you

from “WeTransfer”, which should enable you to download the

files. They correspond to the following relevant sections of our submission:

Ipsos Mori poll, Attitudes to animal research UK, 2016 –

Summary, Opinion, 4.6.6 Marx, 2015 – Opinion

Hartung, 2013 – Opinion, 4.6.6 Zhang – Opinion

Giri, 2015 – 4.6.2, 4.6.4

NCad report, 4.6.2, 4.6.6 Muenchhoff, 2016 – 4.6.3

Barrierio, 2010 – 4.6.3 Shen, 2016 – 4.6.4

Please acknowledge receipt of this email and that you

received the files via WeTransfer, and confirm that these papers will be considered along with our comments.

Kind regards,

Christina Dodkin

Research Director

The references were considered by the SCHEER and where relevant added to the final Opinion.

mailto:[email protected]


215

Research Department

National Anti-Vivisection Society Animal Defenders International

2 Jarrod.Bailey

Cruelty Free International

jarrod.bailey@crueltyfreei

nternational.org

Dear Sir/Madam,

It is with gratitude and appreciation for your understanding that I attach (as a Word document and a PDF, possibly

located at the foot of this message) the remainder of our

responses to the Draft Opinion, to be added to those responses to earlier sections that were submitted via the

website.

With thanks and best regards,

Jarrod Bailey, Ph.D., FOCAE Senior Research Scientist

Cruelty Free International

SCHEER NHPs - Additional CFI Responses to Opinion.pdf

4.6.4 NEUROSCIENCE

P45 L33-40 Balance against Batson Review’s comment on decade of NHP neuroscience research: “…little direct evidence

was available of actual medical benefit in the form of changes

in clinical practice or new treatments”?

P46 L12-22 Evidence? Balance against eg review of

Alzheimer’s models (Langley, provided) for critique.

P45 L33-40 This has been quoted in the Opinion

(see section 4.6.4.3).

P46 L12-22 This review focuses on transgenic mouse models of Alzheimer’s disease which is out of the

scope of the Opinion. For a reference in support of NHP models of AD please see (Van Dam D, De Deyn

PP 2017).



https://ec.europa.eu/health/sites/health/files/scientific_committees/scheer/docs/primates_comail2.pdf

216

P46 L30-31 Modified how?

P46 L35-36 Rephrase: a single surgical procedure is not

always moderate. If it is likely to induce long lasting moderate suffering, then it would be classified as severe

according to the Directive.

P46 L37-42 Recommendation? Factor in critique of AD & PD NHP use.

P47 L3-10 Must know what non-NHP approaches can provide.

P47 L29-39 The use of fMRI and PET imaging in NHPs must

be considered in more detail as it currently raises the question of why it cannot be done in humans. It is indeed our

experience that often non-invasive imaging in NHPs is done in retrospect or parallel to equivalent human studies to

demonstrate the transferability of data between the two

species. The value of this is not acceptable in our view. See Bailey neuroscience paper.

P46 L30-31 The text in section 4.6.4.1 has now been

modified to illustrate some of the caging adjustments that can be envisaged.

P46 L35-36 The text has now been modified to

clarify this point (see section 4.6.4.1).

P46 L37-42 The models quoted in this section are examples of some of the available models, not an

exhaustive list. The final paragraph aims to

ackowledge the fact that other models can also be severe and appropriate assessment should precede

their use. This is also listed in the recommendations of the Opinion (see section 5.1.1).

P47 L3-10 This paragraph assumes knowledge of how the animal and the non-animal models are

constructed and what their limitations are so that

appropriate questions can be addressed by their use.

P47 L29-39

Both fMRI and PET are performed routinely in humans in the clinic. The reader refers to a personal

belief that timing of the experiments in NHPs is inappropriate but does not substantiate this claim

with facts. In pharmacological PET experiments,

irrevocable proof of a receptor ligand interaction might require displacement experiments with hot

and cold radioligands, with repeated arterial input functions (i.e. blood drawing) that are not routinely

performed in patients. However, the pertinence of a given radioligand for a disease (e.g. anti-tau or anti-

alpha-synuclein radioligands) is often tested in

217

P47 L32-39 Sweeping & no substantiation. See e.g. in Bailey

neuroscience paper (provided), p58 & 59.

P47 L43-44 Evidence?

P48 L1-15 It does not follow, and has not been critically

assessed or demonstrated here, that the NHP work in BMI

development was essential. This section should cite examples

of human BMI research in the Bailey neuroscience paper

(provided), e.g. p50.

humans first to see if patient stratification is possible

(e.g. AD, MCI, FTD). If the result is positive, the pharmacology of the ligand is the characterized in

detail in animals, in vivo and post-mortem, to prove

the specificity of the target. The timing of clinical and pre-clinical experiments can therefore vary

according to the stage of radioligand characterization. This clarification however goes

beyond the scope of the Opinion and is only provided to the reader as guidance.

P47 L32-39 References have been added to the text

to substantiate the statement.

A reference has been added.

P48 L1-15 The reader quotes the Bailey review, that in the

working group’s opinion interprets the advances in

the use of BMI in humans too optimistically. First, the reader does not acknowledge that BMI is largely

based on equipment (from amplifiers to electrodes) and algorithms developed for NHP research

experiments. Single unit recording techniques that are the basis of the BMI control by humans is based

on fundamental work of research performed in NHPs by researchers like A Schwartz, J Donoghue, R

Andersen and M Nicolelis. Moreover, the patients

that have for the time being benefited from BI are severely paralysed and it cannot be assumed that

the same approaches will work in all types of human disability. In the same light, electrode improvement

is an active field of research that greatly benefits for biomaterial and informatics advancements and any

pre-clinical studies that can show an improvement in

218

P48 L16-21 One e.g. of possible success (Current status?

Caveats/concerns?) of gene therapy cannot be used to justify NHP use; its essential contribution is not proven here in any

case. Further: how many gene therapy trials have gone on to fail in

humans, following ‘success’ in NHPs? This must be established. How essential was NHP use? How predictive are

they of human success?

P48 L22-35 Listing egs of NHP use is of no value. The need

for NHP use is evaluated by looking at all areas of use, including where this is a failure wrt humans, and—for those

examples where there is correlation—to critically ask if those NHP data were essential, and not able to be provided by

alternatives.

P48 L36 What progress?!

P48 L36-40 Bateson finding of ‘little benefit’ is critical – but is

almost ignored. ‘Good quality’ ‘cited’ nature is immaterial.


long-term stability of new electrodes could greatly

benefit patients. All claims in the Opinion have been substantiated with references.

P48 L16-21 The reader provides a personal opinion

about the value of a successful clinical trial that has diminished parkinsonian symptoms in patients

without any adverse events. The NHP work carried out to assess the safety and efficacy (including

scaling-up issues like volume, titer and rate of viral delivery) of introducing a GMO in a human brain for

life is deemed as not essential but they do not

substantiate this claim and do not consider the regulatory requirements for such type of therapeutic

intervention to be considered for clinical use.

P48 L22-35 This is a personal opinion.

P48 L36 This is a personal opinion.

P48 L36-40 This is a personal opinion.

P48 L44-47 The recommendations in this section are

further summarised in section 5.

P49 L5-9 The reader quotes a misinterpretation of

219

P49 L5-9 Such human studies are considered by many

scientists to be too rare, and that more opportunities for research should be sought and taken advantage of. See

Bailey neuroscience paper (provided), e.g. p47-50.

P49 L10-11 Citation of Bailey neuroscience paper (provided)

here ignores huge amounts of information it contains, and instead cites it simply to argue against one point it makes

regarding the greater use of human single-neuron studies (see earlier point, above).

Cite correctly as ‘Bailey and Taylor, 2016’ and include in

bibliography.

P49 L11-12 Not the case. See Bailey neuroscience paper, p49. Also, this ignores confounding NHP-human species

differences; see e.g. Bailey neuroscience paper, p 61.

P49 L19-38 These ‘limitations’ are not as great as some

would make out, as we argue in the Bailey neuroscience paper (provided). To compound this, these limitations are not

balanced by the information in our paper, leading to

significant bias. This must be address by the SCHEER WG in its revision of the Opinion. For egs of progress, see Bailey

the role of electrophysiological recordings in

humans. Neurosurgeons practicing this type of recordings do not hesitate to express caveats to the

extrapolation of findings in acutely or chronically

injured brains (parkinsonian, epileptic or tetraplegic) to the normal functioning of the rain or its

malfunction in other types pf brain disorders such as Alzheimer’s disease or multiple sclerosis (for

references carefully review Fried 2014, Mamelak 2014, Ojemann 2014). However, the Opinion

acknowledges that this approach, where patient consent is given, is complementary and of value to

the advancement of the understanding of the brain

in specific disease conditions. Any further discussions go beyond the scope of this document.

P49 L10-11 This document is not meant to be a

rebuttal, point by point, of the Bailey and Taylor 2016 review. This paper has been acknowledged and

discussed to a greater extent than other publications. Moreover, this section 4.6.4.4 has been

modified to further discuss fMRI. TMS, BMI, and PET

have also been considered. The citation has now been corrected in the body of the text and added to

the reference list.

P49 L11-12 Other points of view exist in the literature that support the idea that although inter-

species differences exist, NHPs are closer to humans (for e.g. Izpisua Belmonte et al 2015).

P49 L19-38 Bias in quoting the literature in the Bailey and Taylor review has been identified by this

WG. Many comments to the Opinion have been received by expert scientists in the field of

electrophysiology and fMRI that expressed a strong disagreement to the claims that the latter (or any

other available imaging method) can replace the

220

neuroscience paper, p45-48.

P50 L29-43 Refinements noted are techniques also used in

human neuroscience.

P50 L44-46 and P51 L1-17 There is no evaluation of the methods or extent of use in EU. Reference to the Prescott et

al. 2010 fluid paper is not a recommendation of a particular refinement protocol but a discussion of the issue in general.

4.6.5 OTHER USES

P52 L7-14 Citing areas of NHP use is no validation.

P52 L23-41 What about NHP-Human differences?!

P54-P55 None of this section reviews, however briefly, how

riddled with problems the field of xenotransplantation has

been. It’s been going on for decades, and problem after problem has come about, despite numerous promises, often

based on NHP experiments, that xenotransplantation was ‘around the corner.’ It’s been a huge failure, and should not

be dressed up as having been productive in any way. Also,

information obtained with electrophysiology. Instead

they suggest these approaches are highly complementary and the text in section 4.6.4.4 has

been amended accordingly. Once again, the aim of

this document is not a point-by-point rebuttal of a single published review.

P50 L29-43 No reply needed.

P50 L44-46 and P51 L1-17 Two further references

are provided alongside Prescott et al 2010 that the

reader might want to consider (Hage et al 2014 and Gray et al 2016). Importantly, this research is

issued from the same laboratories that implement food or fluid control for operant conditioning showing

the will of neuroscientist to assess the impact of such procedures in NHP welfare.

P52 L7-14

P52 L23-41 It is not possible to report on all NHP models in this

Opinion and the report focused on areas where use

of NHPs was greatest. However, we felt it necessary to highlight other areas where more work needs to

be done.

P54-P55 The Opinion is not calling for NHPs to be used in xenotransplantation, quite the reverse. The

problems in this area are acknowledged.

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there’s no consideration of approaches to the problem that

DO work and that obviate xenotransplantation, such as opt-out donor schemes. See Taylor, K. Not a solution, BMJ

2010;340:b5595:

See eg prior comment, Secn 3.3., P17 L10-18

P53 L4-13 This is another list of rodent-human differences,

implying that NHP-human differences are fewer/less in

degree, and so NHPs must be used. What about NHP-human differences? What about what all the alternatives to NHPs are

able to provide, together? What about a critical look at what NHP models have essentially and uniquely contributed to

human progress in these areas - if anything?

P53 L15-16 Where is the evidence to support these statements? It must be provided, and critiqued, or the

statement removed.

P53 L22-24 So what if an NHP model is under development?

Should it be? Why? How likely is it to be useful and human relevant?

P53 L4-13 The point made is this paragraph is that

although there are differences across species and even across individuals of the same species,

including humans, the way the eyes are used and therefore their anatomical organization, is

significantly different in rodents and this might prevent certain types of research looking at such

specific structures that only exist in primates. In

parallel, and in line with the commentator’s opinion, this section also describes the need to pursue

research in in vitro cultures and combinatorial approaches of in silico, in vitro and in vivo

techniques in the species most relevant to the question to be studied.

P53 L15-16 The reason why NHP are essential in

studying this disease is explained in the lines that

follow: the presence of the genes and proteins coding for USH1 and their localization to the

membrane in primates and not rodents. This statement already includes a reference

P53 L22-24 Once again, the relevance resides on the

discovery of the anatomical localisation of the USH1 proteins and how their mutation leads to a

dysfunction in humans that is not seen in existing

rodent models of the disease. This means that rodent models of this disease are not pertinent

should not be used only because they are available. A model in primates would make it possible to test

therapeutic strategies to potentially cure this condition in humans without exposing patients to

treatments that are neither inefficacious nor unsafe.

222

P55-57 (Whole section) Main barriers: lack of real will; insistence that alternatives must be perfect perfect; passive

view that animals are a gold standard that never gets fully critically assessed. In this paragraph of the Opinion, excuses

are made for NHP methods, and examples of use offered as validation. It is not a balanced, rounded discussion.

P56 L31-39 There is an urgent need for systematic reviews,

which are critical to this debate. Opinions such as this

(SCHEER) don’t help if they assume value of NHP research non-critically, based on opinions of those who use NHPs and

areas of use. This reduces impetus for such reviews and analyses, and the perceived urgency of the need for change.

Urgent recommendation?

P56 L40-43 We agree. This is a very important point. Will SCHEER be recommending this is addressed?

P57 L1-4 “However, this is still small in comparison to the figures involved in animal based-research.” We agree with

this statement. The following paper provides evidence to support this assertion. A recent survey of EU member states

found that reported funding of alternative (3Rs) methods totalled € 18.7 million in 2013, provided by only seven

countries (Austria, Belgium, Denmark, Finland, Germany, Sweden, and the UK). There were indications that the

contributions of some of these countries have increased since

the implementation of the new Directive. However, funding of alternatives is between 0 and 0.036% of national science

R&D expenditure and nearly half of the countries that responded reported that they do not specifically contribute.

Please include this paper. Taylor, K. EU member state government contribution to alternative methods. (2014).

ALTEX, 31: 215-222.

The relevance to humans can only be determined

once the model is established and used.

P55-57 (Whole section)

The purpose of this section 4.6.5.3 is to describe barriers to the implementation of alternatives for

NHPs and solutions. The SCHEER does not recognise the allegation that excuses are being made for NHP

methods.

P56 L31-39 The SCHEER indeed agrees with the urgent need for systematic review and has

formulated a recommendation on this

(recommendation 6 in final Opinion). The SCHEER strongly believes that this Opinion critically assesses

the value of NHP-research.

P56 L40-43 Yes, please see recommendation 21 in

the final Opinion.

P57 L1-4 Thank you, the reference has been added.

223

P57 L17-26 Caution needs to be applied here. In essence, the argument for greater openness and transparency is laudable,

and we agree with it. However, we would argue that this is

used as an opportunity for ‘PR’ about NHP experiments by some who conduct and advocate them. Consequently, what

should be encouraged is a greater focus on the harms, limitations, welfare and ethical issues, and where the benefits

may be overstated and generalised.

P57 L27-35 We agree – initiatives for 3Rs cooperation such as those initiated by the NC3Rs are welcome and have proven

to be successful. Will SCHEER make this a formal

recommendation?

5 RECOMMENDATIONS FOR FURTHER WORK

Entire section.

Could these be presented as numbered, formal

recommendations? The absence of formal recommendations

in the Opinion limits its utility and impact.

5.1 ADVANCING 3RS

P58 L3-5

We welcome the assertion that “Decisions about the need for

NHPs in research projects or regulatory testing should be

made case-by-case based on strong scientific rationale and

the availability of alternative approaches.”

However, we believe the following type of caveat must be

included: “Any proposed scientific rationale for NHP use must be overtly and significantly critical in nature. What is the

human relevance? What are the confounding species

differences? Does the specific information/data being sought really need to be determined? If so, how likely is it to

P57 L17-26: SCHEER believes the emphasis in this

paragraph is on communication on benefits, harms and limitations, realism on outputs, ethics. A specific

recommendation was formulated. No change

needed.

P57 L27-35 There is a general recommendation on

application of the 4C’s, which is in the spirit of NC3Rs.

Entire section on Recommendations: The recommendations are now presented as

numbered, formal recommendations.

5.1 ADVANCING 3RS

P58 L3-5 The suggested caveat has been added as a recommendation

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translate to humans and, ultimately, to human benefit? Why

can’t a combination of alternatives be used instead?” And so on.

P58 L5-9 The suggestion that a one-species paradigm in drug testing is

possible has some scientific merit (it would, at least, be an

improvement on the current two-species paradigm, though we believe testing is possible without the use of any

animals), and, consequently, some support within industry and regulatory bodies. The text here should be clarified,

however: ‘One species’ (Line 5) should clearly state something similar to ‘One (non-primate) species’.

P58 L3-16

Can the suggestions in this paragraph be made into formal recommendations by the SCHEER WG?

P58 L17-20

It is too speculative, without evidence, to state that “…other areas of research, partly new, may require increased NHP use

in the future, e.g., emerging infectious diseases.” We agree with the suggested requirement for a ‘solid HBA’

here, however.

P58 L 26-33

See comment on P57 L27-35 We agree – initiatives for 3Rs cooperation such as those

initiated by the NC3Rs are welcome and have proven to be successful. Will SCHEER make this a formal recommendation?

P58 L34-37

We support this recommendation (could it be formalised?)

This process must be as critical as possible. Avoiding NHP use must be seriously and thoroughly investigated and desired.

P58 L5-9

This project is on going and it is not possible to clarify at the moment.

P58 L3-16 The recommendations have been listed by number

in response to this comment.

P58 L17-20

Please refer to infectious disease section. There is evidence for infectious disease section 4.6.3.4.

P58 L 26-33

See comment on P57 L27-35 The recommendations have been reformatted as

formal recommendations.

P58 L34-37

The recommendations have been reformatted as formal recommendations.

P59 L40-42

225

P59 L40-42

We agree that there needs to be focus on improving the spatial and temporal resolution of non-invasive imaging

technologies.

However, this has been done for some time, and continues to be done, even though these resolutions are at unprecedented

levels, giving these techniques unprecedented power and capability. We also do not support the premise that it is only

until these methods have appropriate spatial and temporal resolution that NHPs use can be avoided. Human single cell

recording can be a superior ‘replacement’ in many cases. This is discussed in the Bailey neuroscience paper (provided).

Also see previous comments, e.g. Secn 3.5, P20 L13-15

P60 L25-27

See comment on P29 L5-10

Under the Commission Implementing decision on the format of the statistical reporting, indeed it is mandatory that all

member states report these categories. The fact that they are

not yet, hindering this section of the report, is a cause for concern. The collation of the 2014 statistics, including the

8898 figure, and concerns about the incomplete reporting by member states is given in this paper that could be referenced

(Taylor, K and Rego, L. EU statistics on animal experiments for 2014. ALTEX 33(4), 2016).

5.3 RESEARCH NEEDS

P61 L14-15

It is of paramount significance that the majority of EU citizens oppose NHP research, even if there were clear human

benefit. The replacement of them is therefore, of course, a

The SCHEER agrees that there needs to be a focus

on improving the spatial and temporal resolution of non-invasive imaging technologies.

However, this has been done for some time, and continues to be done, even though these resolutions

are at unprecedented levels, giving these techniques unprecedented power and capability.

We also do not support the premise that it is only

until these methods have appropriate spatial and temporal resolution that NHPs use can be avoided.

Human single cell recording can be a superior

‘replacement’ in many cases.

This is discussed in the Bailey neuroscience paper (provided). Also see previous comments, e.g. Secn

3.5, P20 L13-15

P60 L25-27

The SCHEER agrees with this comment. The

reference has been added.

5.3 RESEARCH NEEDS

The SCHEER recommendations include the need for reviews and analyses of NHP use.

226

‘desirable goal’. However, as stated in the Opinion, many NHP

researchers do not accept this goal. We think it is an important step to have recognised this fact.

We welcome the SCHEER WG’s recommendations towards EU

strategic funding help to achieve this. Such efforts must include objective, unbiased, transparent and critical reviews

and analyses of NHP use, as stated above; and there must be coordinated efforts to replace NHPs, as in NC3Rs projects in

the UK for example.

P61 L20-26

We would argue we are already there in being able to completely replace NHPs in safety testing, especially given

how much evidence there is for the lack of human-relevance of NHPs. The suite of alternatives doesn’t have to be perfect

(arguably, even that good) - it just has to be better than the

NHPs, which we believe is not difficult.

3 Shameen Afif-Rider

AstraZeneca Group of Companies

[email protected]

m

Please see the attached comments and examples from

AstraZeneca regarding the use of NHPs in biomedical

research.

Shameen Afif-Rider BS, LATG, CPIA, RAC

Associate Director, Regulatory Governance

AZ Comments on SCHEER Opinion on the use of Nonhuman Primates 3-24-2017.docx

The AstraZeneca Group of Companies have contributed

directly to the March 2017 submission by the EFPIA Research and Animal Welfare Group on the SCHEER Opinion, and we

appreciate the opportunity to provide comments and product

specific evidence as requested.

We concur with the EFPIA perspective that the SCHEER

The comments are noted and acknowledged. The

Opinion acknowledges the continuing use of NHPs in

some areas of research while promoting more work to seek alternatives.




227

review was well balanced and showed overall support for the

use of NHPs in research, whilst considering current trends in relation to developing improved welfare. We recognize and

support the need to carefully consider NHP research;

conducting said research only when there are no viable alternatives available, reducing the numbers of animals used

without compromising scientific integrity, and refining techniques and procedures performed on animals to minimize

stress and discomfort to the animals. AstraZeneca would like to demonstrate that NHPs are only

used when there are no alternatives by sharing the work we have done to find alternative methods and species to support

our monoclonal antibody product development. While this

can be particularly challenging with regard to monoclonal antibody development, we have had success developing one

of our novel bispecific single-chain antibodies without using NHPs in general toxicology or safety studies. This Bispecific

T-Cell Engager (BiTE) molecule was developed to link to a certain surface antigen found on cancer cells and killing those

cells. While the cell surface antigen is expressed in humans and NHPs, in vitro tissue culture studies revealed that our

molecule did not bind to the NHP or mouse antigen, making

the evaluation of this molecule in NHPs ineffective. Without a pharmacologically relevant animal model available to

evaluate the toxicity of this molecule, our scientists implemented a unique nonclinical safety strategy which

utilized an in vitro pharmacology approach to assess nonclinical safety and select an appropriate first time in

human dose for our molecule. As a first step, a minimal anticipated biological effect level (MABEL) was determined

from results of in vitro human tissue culture studies.

Specifically, in vitro cytotoxicity and cytokine release studies using human peripheral blood mononuclear cells (PBMCs),

cells that express the antigen of interest, and our molecule were used to establish a concentration-response for biological

activity. Next, exposure parameters were established in a cynomolgus monkey PK study and used to scale PK

parameters to humans following allometric correction. This

228

PK study was limited in scope, did not include necropsy of the

animals and refinement considerations were applied using only 6 males in a cross-over design. After the study samples

were collected, the animals were returned to the facility

colony. Finally, results from these studies were used collectively to select an appropriate starting dose for Phase 1

clinical studies of our novel molecule for the treatment of patients with cancers expressing certain antigens. This

approach was submitted in a US IND application and was fully accepted by the FDA. As a result, no animals were used in

GLP-compliant general toxicity studies. Performing in vitro human tissue culture studies replaced the use of about 60

nonhuman primates without compromising the prediction of

safety in this case.

Another example of our success is with the development of a neutralizing antibody fragment that binds a marketed small

molecule blood thinner and its active metabolite with high affinity. It is intended to reverse the antiplatelet effects of

the blood thinner in patients who experience acute major bleeding or who require urgent surgery or intervention.

Nonclinical safety studies required to support clinical

development would typically be conducted in NHPs and would require multiple groups given the antibody fragment with and

without the small molecule blood thinner, however the team chose to carefully evaluate the nonclinical safety package

data from the marketed blood thinner, and determined that there were no differences in the toxicological profile between

rodents and NHPs. Additionally, given the low risk of QT prolongation with a biologic, and high specificity of our

neutralizing antibody fragment to the small molecule blood

thinner and its active metabolite, the nonclinical team was able to successfully present and defend a reduced nonclinical

package to support Phase I & II clinical studies to the regulatory authorities (FDA, EMA and PMDA) without affecting

the quality of the nonclinical risk assessment. This included an extended single dose study in rats and a complex in vitro

tissue cross-reactivity study in human tissues. This minimal

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package to support Phase I & II clinical studies in the US,

Europe and Japan highlights the global desire across AstraZeneca to reduce the number of animals used, seek

alternatives to the use of NHPs without affecting the quality

of the nonclinical risk assessment. While the examples above are not applicable to all biologic

products, they show that pertinent in-vitro studies, and careful evaluation of available data can result in successful

approval of products, within the scope of most current nonclinical safety testing requirements. Evaluation of

biologics in the NHP is still necessary in many cases for the foreseeable future. These examples demonstrate that the

choice of species for biologics where there is often a specific

need for NHP use is case by case driven and that alternative approaches are acceptable when science driven.

Sincerely,

The AstraZeneca Group of Companies

4 No agreement to disclose personal data

Dear SCHEER Secretariat

Please find attached a response to the Preliminary Opinion on

The need for non-human primates in biomedical research, production and testing of products and devices (update 2017)

In submitting our response we would ask that we are made aware in advance of which sections of our response you

would like to make public by placement on the SCHEER website.

SCHEER response letter.docx

Summary Section 2


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Whist other areas of our Institute are actively engaged in development of alternatives such as cell culture (we house

the European Collection of Animal Cell Cultures) we are also

engaged in replacement (Section 2 of Summary) strategies such as para-clinical studies to develop a BCG challenge

model that can be used in human volunteers to assess new tuberculosis (TB) vaccines. NHP studies have been invaluable

in developing this approach by providing data on the doses and timings involved whilst paralleling the techniques used in

preliminary human trials. Our work on vaccine delivery strategies has provided data that will inform on the design of

clinical application (White et al, 2015, Sharpe et al 2016)

2.1 Background

We note the assessment under “Use of non-human primates today” (P12) that refers to the use of NHPs as essential for

studying the pathophysiology of infectious diseases such as HIV/AIDS and would add that our in experience macaques

represent the only model with the capability to evaluate combinations of infections such as TB/HIV which is a huge

problem in the developing world.

Summary Section 3

Furthermore, Section 3.4 encourages researchers to increase the yield of data per animal and experimental session and to

share data and tissues with other researchers. To this end we have created an extensive archive of samples of tissues,

blood cells and sera from completed experiments such that these can be interrogated as new techniques evolve. These

archives have already provided materials for a number of

post-graduate projects with academic collaborators to investigate gene expression and to identify the role of

important T-cell subsets (Rhodes et al 2016, Tanner e al 2017) without the need for further in vivo studies.

The SCHEER agrees with this remark regarding NHP on HIV/TB combinations. NHP are the best, if not

only, animal model that provides the opportunity to study the combination of HIV and Tb infections. This

is an existing, well-recognised problem in a large group of patients in several poorer areas in the

world and as such macaques provides the opportunity to study the interaction of these

diseases and development of new interventions.

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Section 3.3 Opthalmology

In addition, every effort is made to provide spare tissues such as eyes and brains to academic institutes and we fully

support the statement that currently no rodent, in vitro or in

silico model appear to recapitulate the complex structural and functional interactions of retinal cells. As a by-product of on-

going studies, we are able to supply samples in areas such as research into healthy retinal ageing which is of critical

importance our academic collaborators confirm that not only is there currently no suitable animal model, but many

assumptions based on mouse models have been shown to be wrong and human post mortem retinae suffer from significant

delays between death and processing and variations due to

lifestyle issues such as smoking and diet. (Weinrich et al 2017)

We welcome the statement (p10) that factors to be taken into consideration when establishing a phasing out time-table

include new demands for NHP use in science such as emergence and re-emergence of infectious diseases where

NHPs are the only relevant model and would add that this ability to respond in a timely manner necessitates

maintaining breeding colonies of known provenance, relevant

expertise and biocontainment infrastructure. In fact it is difficult to see how a rigid timetable for cessation could be

applied that would be ethically and morally acceptable in the context of the continuing threat worldwide to human health.

Section 3 Opinion 3.1

Your point that further restrictions or even a ban on the use of NHPs in Europe would result in work being undertaken in

areas with lower standards is well made and we have direct

evidence of this through scientific review of a submission of work conducted in China where our reviewing scientist

applied the ARRIVE guidelines and found through further questioning that the work was conducted to very low

standards that were ethically unacceptable. To the credit of the European journal concerned this submission was rejected

and the funders were informed of the reasons for this.

Section 3.3 Opthalmology

The comments on Ophthalmology are only supportive:” Section 3.3 Opthalmology: In addition,

every effort is made to provide spare tissues such as

eyes and brains to academic institutes and we fully support the statement that currently no rodent, in

vitro or in silico model appear to recapitulate the complex structural and functional interactions of

retinal cells. As a by-product of on-going studies, we are able to supply samples in areas such as

research into healthy retinal ageing which is of critical importance our academic collaborators

confirm that not only is there currently no suitable

animal model, but many assumptions based on mouse models have been shown to be wrong and

human post mortem retinae suffer from significant delays between death and processing and variations

due to lifestyle issues such as smoking and diet. (Prof G J, University College London: personal

communication).” Unfortunately, there are no references to add to the Opinion to show their

support but we would like to thank you for your

support to ophthalmology research in your continuous efforts to provide post-mortem material.

232

However, the paper subsequently appeared in a US-based

journal. Thus, whilst the long term goal may be to influence standards outside of Europe there should also be continued

pressure on international journals to accept the ARRIVE

guidelines and reject submissions where ethical standards are lower.

3.5 General issues

We agree in principle with the statement on P18 that there is an urgent need to conduct systematic reviews and to create a

database that could minimise duplication. However, we are concerned about who makes a judgement on what is allowed

(line 42) and feel that this responsibility lies with the

scientists proposing new research, the sponsors who fund it and the regulator. In our experience of work funded in the

UK and Europe there is a rigorous process of justification both at an institutional level and as an integral part of the funding

process. We would also say that, in our experience of EU funded programmes, the process of robust ethical and

scientific evaluation continues during delivery of the project.

We have reservations concerning meta-analyses in that

these should be conducted by experts in the field of review rather than by experts in meta-analysis or those with a

particular agenda, otherwise there is a danger of misinterpretation by not comparing like with like, resulting in

a preponderance of negative conclusions. We hope that the SyRF initiative about to be launched by NC3Rs will go some

way to address this issue. The creation of a database that is freely available is a good idea as it would allow negative

findings to be more readily disseminated but we wonder

about who would fund or resource such an initiative.

We agree with the statement on P19 that there should be centres of excellence for NHP research and that existing

networks should be improved for information sharing and to keep abreast of the latest techniques. We feel that we have

a good relationship with colleagues in Netherlands, Germany

3.5 General issues

The SCHEER agrees and has expressed this in this Opinion. See, for example, P50 lines 21-26 of final

Opinion.

The SCHEER agrees with this point of view. No

change needed.

233

and France that enables us to do this to some extent but we

regret that funding has not been extended for the excellent EUPRIM-net initiative which served to promote the sharing of

good practice in both husbandry and science, whilst funding

focused areas of research that would promote application of the 3Rs

4.6.2.6 Identification of specific research areas We feel that NHP studies will continue to contribute to the

area of paediatric medicine (P39) in terms of infectious disease research and would add that we and our European

colleagues with on-site breeding colonies are ideally placed to

investigate the potential not only for infant vaccination strategies, but also for consideration of stratified medicine in

the treatment and prevention of infectious diseases.

4.6.3 Treatment & prevention of infectious diseases

4.6.3.2 Justification for NHP in infectious disease research

We welcome the positive statements on P42 and would

emphasise that we and other EU NHP centres are ideally placed to select from our breeding colonies the most suitable

species or geographical sub-group that most accurately reflects human disease (Sharpe et al 2015, 2017). Continued

research in this area also maintains the capability to respond rapidly and appropriately to new or re-emerging health

threats.

4.6.3.3 Progress made in last 10 years

We and our European colleagues have already embraced rapidly evolving technologies such as advanced medical

imaging and our use of in-life scanning has served to refine TB studies in terms of reduced numbers required, reduced

challenge doses and levels of disease and length of studies required to demonstrate efficacy. (Rayner et al 2014,

Dennis et al 2015, Sharpe et al 2015)

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4.6.3.1 Introduction In terms of refinement, in addition to those mentioned above,

we have striven to refine our NHP models to provide the most

clinically relevant route of infection and challenge dose to that which occurs in humans (Sharpe et al 2015, Marriott et

al, 2016, Sibley et al 2016)

5.3 Research needs In summary we endorse the view that the replacement of

animal experiments is a desirable goal and welcome the concept of strategic research funding initiatives to achieve

this. With regard to infectious disease research we feel that

imposing specific time-constraints to attain this target would pose a serious threat to human health world-wide and that

the approach taken should be to address the most important challenges to human health with strategies to provide

relevant models of the complex human/pathogen interaction and comparing these to current clinical and pre-clinical data

rather than to focus on replacement of a particular species

References

Please see in the attached letter.

The Opinion recognises that there are already many efforts in place to refine the NHP models that are

still needed in research. This can be further

improved by additional research funding initiatives in this field. The Opinion also specifically states that

NHP are still essential in various research fields, including in the area of infectious diseases, and that

therefore at this moment no phasing-out time-table for the use of NHP can be provided.

results of the public consultation on the scheer's preliminary … · 2017-06-22 · comments...

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