valuing transformative medicines in rare diseases: …

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VALUING TRANSFORMATIVE MEDICINES IN RARE

DISEASES: METHODS AND MADNESS

Issue Panel 12

Does application of traditional HTA methodologies hamper innovation in rare diseases?

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Moderator & PanelistsPaul Hodgkins, PhD

Vertex Pharmaceuticals, Boston, MA, USA

Ron Akehurst, DSc

Professor Emeritus, University of Sheffield, Sheffield, UK

Chairman, BresMed Health Solutions, Sheffield, UK

Alastair Kent, OBE

Director, Genetic Alliance UK, London, UK

Maarten Postma, PhD

Professor of Pharmacoeconomics, Department of Pharmacy, University of Groningen, Netherlands

Issue Evolution of the regulatory pathways for transformative therapies is enabling access to medicines

earlier than ever

Innovative breakthrough medicines for several rare diseases Often transformative for patients, especially when they are the first medicines designed to treat the

underlying cause of disease Offer significant value to patients, caregivers and society

Ability to demonstrate clinical benefit and cost effectiveness at the time of regulatory approval using existing methodologies can be challenging

The issues faced in rare diseases are exemplified when a therapy may primarily offer survival benefits that are many years in the future and potentially subject to relevant uncertainty but costs accrue immediately

An appropriately timed and fit for purpose value assessment of these therapies is required Balance is needed between early access, evidence of clinical benefit, acceptable cost effectiveness

and the application of appropriate assessment framework

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Professor Ron Akehurst

BresMed Health Solutions and University of Sheffield

Why should rare and/or ultra rare conditions be

treated any differently in HTA than more

common conditions?

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Arguments put forward for a different approach to rare conditions

• Commentators are often unclear about whether they are arguing for a different

analytical process or a different valuation of particular features of a condition or

patient; arguments put forward with which I am familiar are:

– Equal Opportunity

– Evidential difficulties

– Concatenation of patient and disease characteristics which attract higher concern

– Treatment characteristics

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Equal Opportunity

• An equity argument - if there are too few patients in a therapeutic area it will not attract

investment and those who are unlucky enough to have a rare disease will be excluded

from the benefits of advancement in science; therefore we have to be willing to pay

much more for benefits in these areas than would be implied by using the usual

(implicit) cost effectiveness thresholds

– Increasingly hard to argue in a world of targeted treatments even in relatively common

diseases

– The way drug development is moving leads to given molecules being used in multiple

indications, giving a good overall sales volume (Agencies asking about this routinely)

– We do not know how big a return is “enough”

– We may (and do) have other ways to make sure these therapeutic areas are covered

through charitable activity, subsidy, tax breaks and extended exclusivity

– There is still an opportunity cost of treating these patients

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Evidential Difficulties

• Small numbers of patients and trial sizes

• Nature of conditions leads to practical and ethical difficulties in randomising – many

single arm studies

• Absence or weakness of RWE

• Current treatments often symptomatic and widely variable

• Unavailability of good outcome measures

• Lack of evidence on relevance of surrogate measures

• Not usually cited, but I would add lack of knowledge of existing patient pathways

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Evidential Difficulties – how important?

• Not qualitatively different to deal with evidential problems in rare diseases than in

common diseases; but is a more frequent issue and may justify a different

bureaucratic (but not methodological) process – weight given to specialist and patient

opinion

• Companies, researchers and charities (recent example in DMD) could do more to

address these issues

• Not reasons for a higher price

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Patient and disease characteristics

• Rare diseases are often (but not always) characterised by a combination of

characteristics which decision making committees (implicitly or explicitly) value

relatively highly; indeed they make up part of the qualifying criteria for referral to the

NICE HST in England; characteristics include:

– Disproportionate prevalence in the young

– Very big impact on length of life

– Produce a wretched quality of life

– Impact carers and families very severely

• Treatments are relatively frequently characterised by big impacts on QALYs

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Patient and disease characteristics –significance for valuation

• In my view, these characteristics should have appropriate weight in any decision in

any therapeutic area, rare or not, but being in the context of a rare disease is

irrelevant

• Further, (implicitly) weighting for these characteristics through a higher threshold for

rarity per se creates an inequity with common conditions which are, for example, also

terrible in their effects or affect mainly the young but which only qualify for the usual

threshold

• This issue is particularly marked in England (but much less so in Wales and Scotland)

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Treatment Characteristics

• Treatments for rare diseases at times produce very substantial transformations in the

lives of those treated in a way that has been very unusual in more common diseases

• The effects may be restoring to near normal quality of life and length of life some

children who would otherwise have died wretchedly after 2 or 3 years

• The scale of QALY gain per person may be very large in comparison to most new

therapies seen

– There is a willingness in populations to pay much more for “rescue” (move from desperate

prognosis to normal life) and I believe both that this factor is implicit in the favouring of

treatments for rare conditions and that it should be made explicit

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Conclusions (1)

• Technical issues are such as to make a strong case for a separate committee to

consider rare conditions

• None of the patient and disease characteristics we discussed as common is unique to

rare diseases and they should not mean that rare diseases are automatically allowed

a higher threshold; we should consider and weight those characteristics in all diseases

• The equity argument of underinvestment in finding treatments for rare diseases may

have some force; however, we have done virtually no work in assessing the particular

circumstances in which it might hold; what the best mix of funding for research might

be between direct subsidy, charity activity, extended exclusivity and higher price;

indeed, what is the optimum level of investment

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Conclusions (2)

• Money spent on rare diseases has to come from somewhere and the approaches

taken generally in HTA are designed to enable us to understand and reflect the

Opportunity Cost of a decision

• Any system for evaluating treatments for rare diseases must respect that fundamental

notion or create inequity; the approach we take more generally is fit for purpose in rare

diseases but we need to apply it thoughtfully

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THANK YOU!

Maarten J Postma

Prof PharmacoEconomics

Department of PharmacyUniversity of Groningen

Director of the institute for Science in Healthy Aging & healthcaRE (SHARE)University Medical Centre Groningen

Member JCVI and advisor to the AWMSG

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Maarten J Postma

Prof PharmacoEconomics

Department of PharmacyUniversity of Groningen

Director of the institute for Science in Healthy Aging & healthcaRE (SHARE)University Medical Centre Groningen

Member JCVI and advisor to the AWMSG

Cost/QALY threshold of £30,000/QALY

End-of-Life◦ Higher threshold◦ Factor 1.6 on the QALY

Orphan drugs?◦ MCDA◦ Rather qual than quan

Vaccines: more conservative cost/QALY threshold

Other countries?

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Hepatitis B◦ 2000 not cost-effective◦ 2008 cost-effective

Meningococcal Vaccination 2001◦ 3 shots not cost-effective

HPV, no full catch-up due to unfavourable cost-effectiveness




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“I am uneasy about the mantra of ‘a QALY is a QALY is a QALY.’ It means that an increase in utility from 0.3 to 0.5 is valued the same as an increase from 0.7 to 0.9. I am not sure this is fair.”

Rawlins. Value in Health 2012;15:568-9

QALY is a QALY is a QALY^

not

^

not

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0

20000

40000

60000

80000

100000

prevention cure end-of-life

20000

50000

80000

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Review of 40 studies

Various criteria1. Health impact2. Size/cost/budget3. Implementation4. Severity5. Alternative available6. Cost-effectiveness

MCDA based on Hughes-Wilson criteria◦ see below

Numerical scoring system on a scale 1 to 3

Correlations between annual costs and total scores were tested for orphan drugs

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ECRD, Berlin, 2014

ECRD, Berlin, 2014

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Vaccines: more conservative cost/QALY thresh





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An URD should be a biological entitiy and not result of “slicing”

Aspects of definite consideration

◦ Evidence is often scarce ⇨ coverage under evidence development

◦ High price ⇨ patient acces schemes

◦ Equity

◦ Societal preferences

Characteritics

◦ Severity

◦ Chronicity

◦ Unmet need





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QALY ≠ QALY

On top, the QALY is individual and doesn’t capture societal preferences

Notably, value will be inherent to just the mere fact that groups in society (with URDs) are not denied treatment

From a more pragmatic “rights-based” perspective a similar argument could be phrased as that fair chances should exist for patients with URDs in the reality private companies’ R&D costs

Alastair Kent, OBEGenetic Alliance UK

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Panel Discussion

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