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Licence Committee - minutes

Centre 0101 (CARE Nottingham) New Research Licence – Research Project R0200

Thursday, 9 March 2017

HFEA, 10 Spring Gardens, London SW1A 2BU

Committee members

Andy Greenfield (Chair) Lee Rayfield Ruth Wilde Kate Brian Anita Bharucha

Members of the Executive Siobhain Kelly Dee Knoyle

Interim Head of Governance Secretary

Legal Adviser Sarah Ellson Fieldfisher

Specialist Adviser

Observers

Declarations of interest: • Members of the committee declared that they had no conflicts of interest in relation to this item.

The committee had before it: • 8th edition of the HFEA Code of Practice

• Standard licensing and approvals pack for committee members

The following papers were considered by the committee: • Research licence renewal inspection report

• Application form

• Patient information

• Patient consent

• Peer Review 1

• Person Responsible reply to request for further information and Peer Review 1 response

• Peer review 2

• Person Responsible reply to request for further information

• Publications

1. Consideration of application 1.1. The committee noted that CARE Nottingham, centre 0101, is located in Nottingham Business

Park. The centre currently holds a treatment (including embryo testing) and storage licence. The last inspection for the renewal of this licence was on 23 and 24 February and 31 March 2016.

1.2. The committee noted that centre 0101 has previously held several research licences and completed projects. The current research project R0188, entitled ‘To examine concordance and mosaicism in oocytes and embryos’, has been licensed since 2012. The last inspection for the renewal of the R0188 research licence was on 17 January 2017.

1.3. The committee noted that centre 0101 has submitted an application for a new research project entitled ‘mtDNA as a prognosticator for embryo viability’. This includes the additional research activities of immunosurgery and testing trophoblast and inner cell mass cells for mtDNA and chromosomes.

1.4. The research governance processes and procedures reviewed on the inspection of project R0188 were found to be generally compliant and will also apply to the proposed new research project. The centre was also assessed as having satisfied the following points:

• the research will continue to be carried out on the same premises;

• no critical areas of concern were identified during the last inspection visit to the centre;

• the centre, where applicable, has complied with all of the recommendations resulting from the last inspection visit;

• the centre has not had a ‘grade A’ incident since the last inspection visit;

• there has not been any material change in circumstances since the last inspection visit e.g. a change in the Person Responsible;

• the centre has provided the HFEA with data on embryo usage in a timely fashion.

1.5. The committee noted that the inspectorate considered it proportionate to review this new research project application using a desk-based approach. The committee noted that at the time of the assessment, there were no areas of non-compliance identified.

1.6. The committee noted that the inspectorate recommends the approval of the new research licence for a period of three years without additional conditions. The inspectorate recommends the following activities and purposes should apply to the licence: Activities

• storage of embryos

• use of embryos in research for the following purposes:

• promoting advances in the treatment of infertility

• increasing knowledge about the causes of miscarriage

• developing methods for detecting the presence of gene, chromosome or mitochondrion abnormalities in embryos before implantation

• increasing knowledge about the development of embryos

1.7. The committee noted that the CARE Fertility Group Internal Review Body is not part of the National Research Ethics Service (NRES) administered by the Health Research Authority (HRA). The PR has reviewed the project against HRA requirements and has found that it does not require approval by an Ethics Committee which is part of NRES.

1.8. The committee noted that Peer Reviewer 2 sought clarification for the justification of the proposed number of embryos to be used in research. The reviewer thought that a total of 175 embryos did not seem excessive over a 3-year project; however, no explanation or statistical framework was provided to substantiate the rationale behind these numbers. Whilst the committee had received enough information to make a decision, it agreed that it would be helpful to have this information. The committee requested that the information is provided for consideration at its next meeting scheduled in May 2017.

1.9. The committee had regard to its decision tree.

1.10. The committee was satisfied that the application was submitted in the form required and contained the supporting information required by General Direction 0008. It was satisfied that the appropriate fees had been paid. The committee noted that the application was made by the Person Responsible (PR) for the research project.

1.11. The committee noted that the centre has applied for the following activities:


• use of embryos in research

1.12. The committee considered that in order to be consistent with the other research licence it would be appropriate to also include the activity of keeping of embryos.

1.13. The committee noted that no embryos are to be created specifically for the proposed research project and therefore embryo creation is not requested as an activity on the research licence.

1.14. The committee noted that the treatment centres donating to this research project include:

• CARE Northampton (centre 0016)

• CARE Sheffield (centre 0061)

• CARE Nottingham (centre 0101)

• CARE Manchester (centre 0185)

• CRM CARE London (centre 0199)

• CARE Tunbridge Wells (centre 0208)

1.15. The committee was further satisfied that no embryos would be used without obtaining proper consent for the use of embryos in research from patients.

1.16. The committee agreed with the point made by Peer Reviewer 2 who stated that the mismatch between the stated objectives, which make no reference to mtDNA, and the experimental strategy, which does, must be addressed.

1.17. The committee was satisfied that the activities to be licensed are necessary or desirable for the following purposes, specified in paragraphs 3A(1) and 3A(2) of Schedule 2 of the HFE Act 1990 (as amended):

• Promoting advances in the treatment of infertility The research proposes to investigate the possible association between mtDNA copy number in the trophectoderm (TE) of human blastocyst stage embryos and embryo viability, and whether or not this association is also linked to the incidence of aneuploidy in the embryo. Should such an association be established, this may prove useful in identifying embryos for transfer, through analysis of mtDNA copy number in biopsied trophectoderm cells, that are more likely to implant and lead to successful pregnancy.

• Increasing knowledge about the causes of miscarriage

Chromosomal errors in preimplantation embryos are recognized as a major contributing aetiology in early miscarriage. As the blastocyst TE is the precursor of the human placenta, and the inner cell mass (ICM) forms the developing fetus, the proposed studies will investigate the relationship between TE and ICM mtDNA copy number, POLGA methylation status and aneuploidy during the processes of embryo implantation and placental formation. The insights gained from the proposed studies may therefore shed light on the role played by TE and ICM mitochondria during either successful embryo implantation and survival or during the induction of aneuploidies that may result in early miscarriage.

• Developing methods for detecting the presence of gene, chromosome or mitochondrion abnormalities in embryos before implantation.

The chromosomal status, mtDNA copy number and POLGA methylation status will all be quantified in cells harvested from human blastocysts. While these endpoints will be investigated using established methods, the possibility exists that improved methodologies will be developed that have therapeutic application.

• Increasing knowledge about the development of embryos

Molecular genetic analyses of the chromosomal health and mtDNA status of TE and ICM cells harvested from human blastocysts will advance our understanding of human preimplantation embryo development.

1.18. The committee noted that none of the proposed activities are prohibited by the HFE Act 1990 (as amended).

1.19. The committee noted that both peer reviewers agreed that the use of human embryos in the proposed research project is necessary. The committee agreed with the following statement: Use of human embryos in research: ‘Animal studies have established the basis for the proposed research, and the techniques have been published for assessment of mtDNA copy number in pig blastocysts. Extension of the techniques to an investigation of human embryos that have been donated to research, in order to investigate possible variation in mtDNA copy number both between the two cell types of the blastocyst, and between different regions of the trophectoderm within individual blastocysts, is appropriate.

1.20. The committee was satisfied that the proposed research project does not involve the mixing of sperm with the egg of an animal.

1.21. The committee noted that the proposed research project does not involve the derivation of human embryonic stem cell lines for human application or the genetic modification of embryos.

1.22. The committee was satisfied that this is a research project and that no embryos used in the project would be implanted into a woman.

1.23. The committee was satisfied that the new research licence would not apply to more than one research project

1.24. The committee was satisfied that the PR possesses the required qualifications and experience and that the character of the PR is such as is required for supervision of the licensed activities. It was further satisfied that the PR will discharge their duties under section 17 of the Act. The committee noted that the inspectorate was satisfied that the PR had satisfactorily completed the PR entry programme.

1.25. The committee was satisfied that the premises and facilities are suitable for the conduct of the licensed activity applied for.

2. Decision 2.1. The committee agreed that, although this was a new research project, it built upon the existing

research and was not so novel as to require a shorter research licence period and therefore granted a new licence for the project entitled ‘mtDNA as a prognosticator for embryo viability’ for a period of three years without additional conditions. The following activities will apply to the licence:

• keeping embryos


• use of embryos

for the following purposes:

• promoting advances in the treatment of infertility

• increasing knowledge about the causes of miscarriage

• developing methods for detecting the presence of gene, chromosome or mitochondrion abnormalities in embryos before implantation

• increasing knowledge about the development of embryos

2.2. The committee requested that the further information to explain the statistical framework underlying the rationale for the number of embryos be provided by the centre for the committee meeting in May. It asked that the PR confirm that the stated objectives in the application should have been revised to refer to mtDNA.

2.3. The committee also requested that the centre’s future renewal inspection report is submitted to the Licence Committee for consideration.

3. Chair’s signature 3.1. I confirm this is a true and accurate record of the meeting.

Signature

Name Andy Greenfield

Date 30 March 2017

New research licence inspection report, centre 0101. TRIM: 2017/001807 1

Purpose of this inspection report The HFEA licenses and monitors establishments undertaking human embryo research. This is a report of a desk based assessment, carried out to assess whether this centre will comply with essential requirements when carrying out such research. Licences for individual research projects can be granted for up to three years and this report provides information on the centre’s initial application for a research licence. The Authority’s Licence Committee uses the application and this report to decide whether to grant a licence and, if so, whether any additional conditions should be applied to the licence. The Human Fertilisation and Embryology Act 1990 (as amended) only permits research licences to be granted for a period of three years and by law research centres must have an inspection visit every two years. In September 2011, the Authority agreed to a revised compliance cycle for research centres, which included the provision for research centres to not be subjected to an on-site inspection visit prior to the renewal of a licence under the following circumstances:

• That the research will continue to be carried out on the same premises. • That no critical areas of concern were identified during the last inspection visit to

the centre. • That the centre, where applicable, has complied with all of the recommendations

resulting from the last inspection visit. • That the centre has not had a ‘grade A’ incident since the last inspection visit. • That there has not been any material change in circumstances since the last

inspection visit e.g. a change in the Person Responsible. • That the centre has provided the HFEA with data on embryo usage in a timely

fashion. The focus of this report is an application for a new research licence from centre 0101. This centre already undertakes research project R0188, which was inspected on 17 January 2017 as part of a licence renewal process. The report of that inspection is to be considered by the Licence Committee on 9 March 2017, alongside this new research licence application. The research governance processes and procedures reviewed on the inspection of project R0188 were found to be generally compliant and will also apply to the proposed new research project. The centre was also assessed as having met the above circumstances. It was therefore considered proportionate to review this new research project application using a desk based approach, but also to take into account the review of research governance arrangements at centre 0101 undertaken during the inspection of project R0188.

New Research Licence Report: Desk based assessment


Inspection details: The report covers the pre-inspection analysis, a desk based evaluation of the application and supporting information, and information received between October 2016 and February 2017. Date of Licence Committee: 9 March 2017 Centre Details: Project title mtDNA as a prognosticator for embryo viability

Centre name CARE Nottingham

Centre number 0101

Research project number

To be allocated if approved

Centre address John Webster House 6 Lawrence Drive Nottingham Business Park Nottingham Nottinghamshire NG8 6PZ

Proposed Person Responsible (PR)

Professor Simon Fishel

Proposed Licence Holder (LH)

Mrs Alison Campbell

Treatment centres donating to this research project

‘Centres within the CARE Fertility Group’: CARE Northampton (0016); CARE Sheffield (0061); CARE Nottingham (0101); CARE Manchester (0185); CRM CARE London (0199); CARE Tunbridge Wells (0208).


Contents Page Section 1: Summary report. ............................................................................................... 4

Brief description of the centre and its licensing history Summary for licensing decision Recommendation

Section 2: Summary of the research project. ................................................................... 8

Lay summary of the research project Objectives of the research Lay summary of the research undertaken since the last inspection Peer review

Section 3: Details of the inspection findings. ................................................................. 10 Section 4: Areas of practice that require the attention of the Person Responsible. ... 15

Critical area of non compliance Major area of non compliance Other area of practice that requires consideration


Report to Research Licence Committee Brief description of the centre and its licensing history: CARE Nottingham is located in Nottingham Business Park. The centre has previously held several research licences for completed projects, and has been licensed since 1 July 2012 for research project R0188: ‘To examine concordance and mosaicism in oocytes and embryos’. The centre has also held a Treatment and Storage licence with the HFEA since 21 May 1992, providing a full range of fertility services including embryo testing. The last inspection of the centre’s Treatment (including embryo testing) and Storage licence was a renewal inspection on 23 and 24 February and 31 March 2016. The last inspection at the centre of research project R0188 was a renewal inspection that took place on 17 January 2017. Summary for licensing decision: Taking into account the essential requirements set out in the Human Fertilisation and Embryology (HF&E) Act 1990 (as amended), the HF&E Act 2008 and the HFEA Code of Practice (CoP), the inspection team considers that it has sufficient information to conclude that: Administrative requirements:

• the centre has submitted an appropriately completed licence application form; • the centre has submitted the supporting information required by General Direction

0008 including evidence of ethics approval and patient information and consent; • the application has designated a suitable individual to act as the PR; • the proposed licence applies to one project of research; • the centre has submitted fees to the HFEA in accordance with requirements; • the project has been reviewed by two peer reviewers.

Research activities applied for:

• use of embryos • storage of embryos

The application describes that an additional research activity will be immunosurgery and testing trophoblast and inner cell mass cells for mtDNA and chromosomes. The proposed research project does not involve the derivation of human embryonic stem cell lines for human application or the genetic modification of embryos. None of the proposed activities are prohibited by the HF&E Act 1990 (as amended). Purposes for which research activities may be licensed: The application for the proposed research licence indicates that the PR considers that the research project will meet the following purposes defined in Schedule 2 3A (1) and (2) to the HF&E Act 1990 (as amended).


A) Promoting advances in the treatment of infertility (HF&E Act 1990 (as amended) Schedule 2 3A(2)(d)).

The reason for this, as stated by the PR, is: ‘A small amount of research on mtDNA levels in trophectoderm cells has implicated mtDNA copy number as a prognosticator for embryo viability. Refining this work will elucidate its clinical relevance.’ Both peer reviewers agreed that this purpose would be addressed by the project. Peer reviewer 1 stated: ‘The research proposes to investigate the possible association between mtDNA copy number in the trophectoderm of human blastocyst stage embryos and embryo viability, and whether or not this association is also linked to aneuploidy. Should such an association be found, this may prove useful in identifying embryos for transfer, through analysis of mtDNA copy number in biopsied trophectoderm cells, that are more likely to implant and lead to successful pregnancy.’ Peer reviewer 2 stated: ‘This application is focused on human blastocyst health and will explore the association between mitochondrial DNA (mtDNA) copy number and DNA methylation at exon 2 in trophectoderm (TE) and inner cell mass (ICM) cells and blastocyst aneuploidy status as assessed by next generation sequencing (NGS). The association between these parameters will be investigated as markers of embryo developmental competence and embryo survival. Markers of embryo health have diagnostic value and are therefore relevant to the treatment of infertility.’ B) Increasing knowledge about the causes of miscarriage (HF&E Act 1990 (as amended),

Schedule 2 3A (2) e). The reason for this, as stated by the PR, is: ‘segregating embryo ploidy from mitochondria levels will help understand if mitochondria copy number has any role to play in embryo survival.’ Peer reviewer 1 did not select this purpose for comment Peer reviewer 2 stated: ‘Chromosomal errors in preimplantation embryos are recognized as a major contributing aetiology in early miscarriage. As the blastocyst TE is the precursor of the human placenta, and the ICM forms the developing fetus, the proposed studies will investigate the relationship between TE and ICM mtDNA copy number, methylation status and aneuploidy during the processes of embryo implantation and placental formation. The insight gained from the proposed studies will therefore shed light on the role played by TE and ICM mitochondria during either successful embryo implantation and survival or during the induction of aneuploidies that may result in early miscarriage.’ C) Developing methods for detecting the presence of gene, chromosome or mitochondrion

abnormalities in embryos before implantation (HF&E Act 1990 (as amended) Schedule 2 3A(2)(g)).

The reason for this, as stated by the PR, is: ‘Inherent in the experimental design.’ Peer reviewer 1 did not select this purpose for comment.


Peer reviewer 2 stated: ‘The chromosomal status, mtDNA copy number and methylation status will all be quantified in cells harvested from human blastocysts. While these endpoints will be investigated using established methods, the findings of the prosed studies have the potential for therapeutic application.’ D) Increasing knowledge about the development of embryos (HF&E Act 1990 (as amended)

Schedule 2 3A(2)(h)). The reason for this, as stated by the PR, is: ‘Inherent in the experimental design.’ Peer reviewer 1 did not select this purpose for comment. Peer reviewer 2 stated: ‘Molecular genetic analysis of the chromosomal health and mtDNA status of TE and ICM cells harvested from human blastocysts will advance our understanding of human preimplantation embryo development.’ Prohibited research activities: The activities to be licensed are not prohibited by the HF&E Act 1990 (as amended). The creation of embryos: No embryos are to be created specifically for the proposed research project and embryo creation is not requested as an activity on the research licence. Use of human embryos: Both peer reviewers agreed that the use of human embryos in the proposed research project is necessary. Peer reviewer 1 stated: ‘Animal studies have established the basis for the proposed research, and the techniques have been published for assessment of mtDNA copy number in pig blastocysts. Extrapolation of the techniques to an investigation of human embryos that have been donated to research, in order to investigate possible variation in mtDNA copy number both between the two cell types of the blastocyst, and between different regions of the trophectoderm within individual blastocysts, is appropriate.’ Peer reviewer 2 stated: ‘The study will quantify aneuploidy rates and mtDNA copy number and methylation status in TE and ICM harvested from human blastocysts. These endpoints can only be measure through the use of human embryos for research.’ Both peer reviewers agree that the research project does not involve the derivation of human embryonic stem cell lines for human application or the genetic modification of embryos. PR considerations: The PR is suitable and will discharge his duty under Section 17 of the HF&E Act 1990 (as amended). This conclusion is based on the proposed PR’s qualifications, previous experience and current activities as PR of research project R0189 at centre 0331 and R0193 and at centre 0347.


Premises: The premises at centre 0101 were reviewed during inspection of project R0188 and are considered suitable. Recommendation to the Licence Committee: The Licence Committee is asked to note that at the time of the inspection, there were no areas of non-compliance. Peer reviews were sought from two peer reviewers. Both peer reviewers requested information supplementary to that provided in the initial application. The PR provided both peer reviewers with the requested information. The second peer reviewer has failed to provide a further response, despite repeated attempts to contact. To prevent further delay to this application the committee is asked to consider the positive recommendation of the first peer reviewer, in absence of a final recommendation from the second peer reviewer. The inspector considers that overall there is sufficient information available to recommend a research licence for a period of three years without additional conditions. The inspector recommends that the licence should authorise the following research activities:

• Storage of embryos • Use of embryos in research

For the following purposes:

• Promoting advances in the treatment of infertility (HF&E Act 1990 (as amended) Schedule 2 3A(2)(d)).

• Increasing knowledge about the causes of miscarriage (HF&E Act 1990 (as amended), Schedule 2 3A (2) e).

• Developing methods for detecting the presence of gene, chromosome or mitochondrion abnormalities in embryos before implantation (HF&E Act 1990 (as amended) Schedule 2 3A(2)(g)).

• Increasing knowledge about the development of embryos (HF&E Act 1990 (as amended), Schedule 2 3A (2) h).


Summary of the project Lay summary of the research project: Mitochondria are involved in the regulation of multiple essential cellular processes, such as apoptosis, amino acid synthesis, calcium homeostasis, and the generation of energy in the form of ATP. They have been dubbed the ‘battery of cells’. They are unique organelles in animal cells in that they contain one or more copies of their own genome. It has been shown that cells are capable of redistributing their mitochondria so as to replace damaged organelles, and adjust to variation in intracellular energy requirements. The mitochondrial content of mammalian cells ranges from a few hundred to thousands, determined by the cell’s volume and energy needs. The human mature oocyte is among the cell types with the highest content for both mitochondria and mtDNA. Oocyte mitochondrial replication begins during fetal development with cells of the oogonia containing approximately 200 mitochondria. Replication continues in synchrony with maturation, so that just before fertilisation an oocyte arrested at metaphase II contains approximately 100,000 mitochondria and between 50,000 and 550,000 copies of the mtDNA. Mammalian embryos inherit mitochondria (and thus mtDNA) exclusively from the population found in the oocyte just prior to fertilisation. Embryos at the blastocyst stage contain the precursor to the placental cells - the trophectoderm - and the inner cell mass cells, the ancestral embryonic tissue. If there is differential replication of mtDNA between the two cellular compartments of the blastocyst, it is important to determine the degree to which they regulate their mtDNA copy and if their levels are related to aneuploidy. If they are related to aneuploidy, we need to determine whether this relates to a disproportionate segregation of mtDNA to either the inner cell mass or the trophectoderm. Objectives of the research: Primary aim is to establish if the information obtained from a trophectoderm biopsy is a) consistent across the trophectoderm b) in concordance with the inner cell mass, and c) whether the cell number extracted is of relevance to scoring system.The secondary endpoint is to assess the data in relation to a) embryo ploidy and the clinical outcome following the transfer euploid embryos. Background It is now well-documented that mitochondrial DNA (mtDNA) copy number is differentially regulated in a tissue specific manner. This is true for mice, pigs and humans. It is becoming increasingly evident that mtDNA copy number is important to fertilisation outcome and development to the blastocyst stage. Oocytes with too few copies of mtDNA often fail to fertilise or arrest during preimplantation development. However, those oocytes that fertilise and progress through development have significantly higher copies of mtDNA. During preimplantation development, good quality embryos actively shed mtDNA but reinstate mtDNA replication at the blastocyst stage. By the blastocyst stage, the embryo has undergone its first phase of compartmentalisation where the inner cell mass cells remain in an undifferentiated state whilst the outer ring of cells, the trophectoderm, have initiated the process of cellular differentiation. As a consequence, we anticipate that mtDNA copy number is restricted and even further diluted out in the inner cell mass cells until they differentiate later on. Recent studies have investigated the role of mitochondria, using the level of mtDNA, as a biomarker for viability of human preimplantation embryos following IVF. It has been suggested that there is a critical threshold of mtDNA quantity within the cells biopsied from embryos, and thus a strong correlation between such levels and


successful implantation of human embryos. So far only a limited number of studies have been performed but based on these a commercially available test is available as a diagnostic tool. Further studies have also implied that reproductively older females contain higher levels of mtDNA associating the role of mitochondria in the aging process of oocytes in such women. Aneuploid embryos are understood to possess abnormally elevated mtDNA that is independent of age. However, the replication of mtDNA observed in the blastocyst stage is specific to the trophectodermal cells, but some studies have observed that undifferentiated embryonic stem cells, which arise from the inner cell mass, have very few copies of mtDNA but, when induced to differentiate, they increase mtDNA copy number in a manner synchronous with differentiation in a stage-specific manner. Peer Review Comments The application for an initial licence for this research project has been sent out to two peer reviewers. Both had further questions regarding the project, which the proposed PR has responded to. One peer reviewer has subsequently recommended that the research licence is approved. The second peer reviewer had yet to provide a final recommendation when this report was completed and sent to the PR, despite several attempts at contact by the Executive. If a response is received before the papers are considered by the Licence Committee, either the report will be updated accordingly or an Executive summary will be submitted to the committee along with the peer reviewers comments. Donation and use of embryos The initial licence application proposes the use of 25 frozen embryos in year one of the project, 50 fresh embryos and 50 frozen embryos in year two of the project and 50 fresh embryos in year three of the project. Initially, peer reviewer 1 did not consider the proposed number of embryos to be used in research to be justified and requested further clarification on the study design from the PR. After reviewing the PR’s responses the peer reviewer stated: ‘I am happy to recommend that the proposed research should be licenced to proceed.’ Peer reviewer 2 did not consider the proposed number of embryos to be used in research to be justified, stating: ‘A total of 125 fresh embryos and 50 frozen embryos (ie 175 embryos in total) will be used in the proposed studies. This number does not seem excessive over a 3 year project, however no explanation or statistical framework is provided to explain the rationale behind these numbers. It is not clear whether these numbers refers to cleavage stage embryos donated for research and if so what the expected blastocyst rates/numbers for analysis are, or conversely whether the numbers outlined relate to the number of blastocysts to be donated /analysed for research. No indication is provided of the demographics of couples donating the research embryos. In the absence of this information it is impossible to access whether the numbers of embryos proposed for analysis are justified. Further clarification is needed.’ The PR responded stating: ‘From the study protocol, this will be a binary comparison between ICM and TE biopsy, there will either be a correlation (analysis per cell basis) or there will not be. There will be no statistical evaluation of the secondary outcome data as this will require much more detailed level of computation – based on 3) below – depending on the information from the primary – research only - outcome.’ Peer reviewer 2 has not commented on the clarification provided by the proposed PR.


Section 3: Details of the inspection findings ► Principle: 3. Have respect for the special status of the embryo when conducting licensed activities. ►What we inspected against: RLCs R23, R24, R26, R27, R28, R29, CoP Guidance Note 22. What the centre does well. Discussions with the proposed PR, along with document review, provided assurance that the special status of the human embryo will be respected at centre 0101 in the proposed research project:

• the centre has processes to ensure that embryos obtained for the purposes of research, will not be kept or used for any other purposes (RLC R23);

• research staff are well informed regarding the restrictions of the HF&E Act 1990 (as amended) and effective supervision of the project by the LH and PR will prevent the use of donated embryos in unlicensed activities;

• each embryo used in the research project will be uniquely labelled (RLC R26); • clinical and research roles will be separated, guided by documented procedures

(RLC R27); • Keeping embryos in culture for more than is necessary to recovery from thawing is

not a proposed activity within this research project, therefore embryos will not develop after 14 days or the primitive streak has appeared (if earlier) (RLC R28).

What they could do better. Nothing identified.

►Principles: 5. Provide prospective and current patients and donors with sufficient, accessible and up-to-date information in order to allow them to make informed decisions. 6. Ensure that patients and donors have provided all relevant consents, before any licensed activity is undertaken. ►What we inspected against: Information, counselling and consent; CoP Guidance Note 22, RLCs R18, R19, R20, R21, R22. Consent for storage; CoP Guidance Note 22, RLCs R31, R32, R33, R34, R35, R36, R37, R38, R39. What the centre does well. Provision of information and counselling to those consenting to donate to research All embryos to be used in the proposed project will be donated to the project at CARE Fertility Group centres before being transferred to centre 0101 to store and subsequently


use. All the donating centres use a common research consenting process, whereby trained staff operate to procedures for offering counselling and giving gamete providers suitable information before they are asked to give consent (RLCs R18, R19 and R21). Documented procedures guide the process if consent for research is withdrawn (RLC R18). The patient information document describing the research project and the associated research consent form were reviewed by the inspection team and were considered to be compliant (RLCs R19 and R22). Consent for storage Stored embryos are to be obtained only from centres to which an HFEA licence applies (RLCs R32, R33). An effective bring-forward system is applied to stored embryos donated for use in project R0188 to ensure those embryos are stored only within the storage period the gamete providers have consented to. This bring-forward system will also be applied to embryos stored for the proposed research project (RLCs R35, R36, R37, R38 and R39). What they could do better. Nothing identified.

►Principle: 8. Ensure that all premises, equipment, processes and procedures used in the conduct of licensed activities are safe, secure and suitable for the purpose.

►What we inspected against: Premises and facilities; RLC R10 What the centre does well. Premises and facilities Embryos donated to the proposed research project will be stored in the cryostorage facility at centre 0101. The proposed research will involve embryo biopsy and immunosurgery, which will be performed in the embryology laboratory at centre 0101. These premises, facilities and equipment were reviewed as part of the inspection of project R0188 on 17 January 2017 and were considered secure, clean, well maintained and suitable for licensed activities (RLC R10). What they could do better. Nothing identified.


►Principle: 10. Maintain proper and accurate records and information about all licensed activities

►What we inspected against: Information and record keeping; RLCs R13, R14, R15, R16, R17, General Direction 0002. What the centre does well. Discussions with the proposed PR indicate that proper records of embryo usage in the proposed research project will be maintained, as they currently are for embryos used in research project R0188 (RLC R15). The proposed PR has, in previous years in his role as the PR of projects R0189 and R0193 at centres 0331 and 0347, submitted annual research information and data sheets to the HFEA (RLC R14 & General Direction 0002). What they could do better. Nothing identified.

► Principle: 11. Report all adverse incidents (including serious adverse events and reactions) to the HFEA, investigate all complaints properly, and share lessons learned appropriately

► What we inspected against: Incidents; RLC R40 What the centre does well. A global CARE Fertility standard operating procedure has been developed to guide actions and respond to adverse incidents (RLC R40). The inspection team who reviewed the renewal application for project R0188 considered that this procedure functions in a compliant manner. What they could do better. Nothing identified.


►Principle: 12. Ensure that all licensed research by the centre meets ethical standards, and is done only where there is both a clear scientific justification and no viable alternative to the use of embryos.

►What we inspected against: HF&E Act 1990 (as amended), Schedule 2 (3(5) and 3A). What the centre does well. Evidence was provided in the application that the research project has been approved by the CARE Fertility Group Internal Review Body, having been judged on the basis of its potential benefit to the field and the appropriateness of the research in relation to the HF&E Act, the HFEA CoP and the ethics of medical research. This body also provided the ethics approval for project R0188 at centre 0101, project R0189 at centre 0331 and project R0193 at centre 0347. The composition of the CARE Fertility Group Internal Review Body, as stated in the licence application, satisfies the research ethics committee composition requirements of the World Health Organisation’s Guidance for Ethics Review of Health-Related Research with Human Participants, these being that;

• Members include individuals with scientific expertise, members who have expertise in legal matters and/or ethics; and lay people whose primary role is to share their insights about the communities from which participants are likely to be drawn.

• Committee membership includes members who are not affiliated with organisations that sponsor, fund, or conduct research reviewed by the research ethics committee.

• Committees are large enough to ensure that multiple perspectives are brought into the discussion. To this end, quorum requirements provide that at least five people, including at least one lay member and one non-affiliated member, are present to make decisions about the proposed research.

The CARE Fertility Group Internal Review Body is not part of the National Research Ethics Service (NRES) administered by the Health Research Authority (HRA). The PR has reviewed the project against HRA requirements and has found that it does not require approval by an ethics committee which is part of NRES. The research project does not include any activities that are prohibited by the HF&E Act 1990 (as amended). Two peer reviewers were approached to review and provide comment on the project. Both peer reviewers requested further information from the PR before making a recommendation. Peer reviewer 1 is supportive of the project and recommends approval of this initial research licence application. Peer reviewer 2 has failed to provide a response to the further information they requested. Justifications that the activities to be licensed are necessary or desirable to meet the statutory purposes have been provided by the PR and the peer reviewers, as discussed in detail in the ‘Summary for Licensing Decision’. The PR and peer reviewer 1 have also


provided reasons why the use of human embryos is necessary and the proposed number of embryos to be used is justified. What they could do better. Nothing identified.

► Principle: 13. Conduct all licensed activities with regard for the regulatory framework governing treatment and research involving gametes or embryos within the UK, including:

• maintaining up-to-date awareness and understanding of legal obligations; • responding promptly to requests for information and documents; • co-operating fully with inspections and investigations by the HFEA or other

agencies responsible for law enforcement or regulation of healthcare.

► What we inspected against: Licensing; RLCs R1, R2, R3, R5, R6. The Person Responsible; HF&E Act 1990 (as amended) Section 16 & 17, RLCs R8, R9. What the centre does well. Licensing Recent inspection of the proposed licensed premises indicate that the proposed research project can be performed within the premises specified in the application. These activities will be carried under the supervision of the PR and LH (RLC R1, R2). The Person Responsible The PR has a key role to play in implementing the requirements of the HF&E Act 1990 (as amended) and is the person under whose supervision the licensed activities are authorised. The PR has the primary legal responsibility under Section 17 of the HF&E Act 1990 (as amended) to secure:

• that suitable practices are used in undertaking the licensed activities; • that other persons working under the licence are suitable and; • that the conditions of the licence are complied with.

The proposed PR has suitable qualifications and experience for the activity authorised by the licence (HF&E Act 1990 (as amended), Section 16 2 ca). The PR has successfully completed the HFEA PR Entry Programme (R/1058/7) and is currently the PR of projects R0189 at centre 0331 and R0193 at centre 0347. The researchers are aware of the conditions of the research licence applied for. What they could do better. Nothing identified.


Areas of practice that require the attention of the Person Responsible The section sets out matters which the Inspection Team considers may constitute areas of non compliance. These have been classified into critical, major and others. Each area of non-compliance is referenced to the relevant sections of the Acts, Regulations, Standard Licence Conditions, Directions or the Code of Practice, and the recommended improvement actions required are given, as well as the timescales in which these improvements should be carried out. ► ‘Critical’ area of non compliance

A ‘critical’ area of non compliance is an area of practice which poses a significant risk of causing harm to a patient, donor, embryo or to a child who may be born as a result of treatment services. A ‘critical’ area of non-compliance requires immediate action to be taken by the Person Responsible.

Area of practice and reference

Action required and timescale for action

PR Response Executive Review

Nothing identified.


► ‘Major’ area of non compliance A ‘major’ area of non compliance is a non critical area of non compliance:

• which poses an indirect risk to the safety of a patient, donor, embryo or to a child who may be born as a result of treatment services

• which indicates a major shortcoming from the statutory requirements; • which indicates a failure of the Person Responsible to carry out his/her legal duties • a combination of several “other” areas of non-compliance, none of which on their own may be major but which

together may represent a major area of non-compliance.




Nothing identified.


► ‘Other’ areas of practice that requires improvement Areas of practice that requires improvement is any area of practice, which cannot be classified as either a critical or major area of non compliance, but which indicates a departure from statutory requirements or good practice.




Nothing identified.


Additional information from the Person Responsible

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