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Towards Planning for Optimal Access to Effective Therapies for Rare and Ultra-Rare Conditions: A Scoping Study Mike Paulden, Tania Stafinski, Devidas Menon and Chistopher McCabe University of Alberta, Edmonton, AB

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Page 1: CADTH_2014_A2_Towards_Planning_for_Optimal_Access_to_Effective_Therapies_for_Rare_and_Ultra-Rare_Conditions_A_Scoping_Study__Mike Paulden_Tania Stafinski_Devidas Menon_Chistopher McCabe

Towards Planning for Optimal Access to Effective Therapies

for Rare and Ultra-Rare Conditions: A Scoping Study

Mike Paulden, Tania Stafinski, Devidas Menon and Chistopher McCabe

University of Alberta, Edmonton, AB

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Acknowledgements:

CIHR Emerging Team Grants Funding

Promoting Rare-disease Innovations through

Sustainable Mechanisms‟ (PRISM) Collaborators

Network

Rare and Ultra-Rare Conditions: A Scoping Study

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Rare and Ultra-Rare Conditions: A Scoping Study

US Orphan Drugs Act (1983)

• Designed to facilitate development and commercialization of

drugs to treat “rare diseases” (< 200,000 Americans)

- 7 year market exclusivity for companies

- Tax credits equal to half of the development costs

- Grants for drug development

- Fast-track approvals of drugs

Orphan Drug Approvals 1973 to 1983: 10 products

Orphan Drug Approvals 1983 to 2013: > 400

Background

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Rare and Ultra-Rare Conditions: A Scoping Study

Personalised Medicine (PM)

• Common diseases sub-divided on molecular, proteomic or

genetic characteristics

• Emergence of PM-defined orphan and

ultra-orphan diseases and associated treatments

- Kalydeco is a treatment for Cystic Fibrosis G551D mutation

(affects 4% of CF population) which costs > $300k per year

Background

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Rare and Ultra-Rare Conditions: A Scoping Study

Health system budgets are increasingly stretched:

• Aging populations driving increasing demand

• Increasingly expensive therapies for common & rare diseases

• Global economic downturn reducing tax revenues

Health systems are establishing formal value based

reimbursement mechanisms

• CDR & pCODR, NICE, HAS, iQWIG

• Decisions criticised by patients, clinicians and manufacturers

for implicit and explicit value frameworks used

Background

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Rare and Ultra-Rare Conditions: A Scoping Study

Cost of orphan drugs often > $50,000 per annum

• Mathematically exceeds conventional „value threshold‟ given

„neutral‟ equity position

Accentuates the focus on the „value‟ in value-based

coverage decision making for orphan drugs

Critical to establish the values underlying decision making

Background

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Rare and Ultra-Rare Conditions: A Scoping Study

To scope the “landscape” of proposed approaches for

assessing the value of orphan and ultra orphan drugs in

order to identify:

• Specific value propositions

• Decision process propositions

Purpose of our research

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Rare and Ultra-Rare Conditions: A Scoping Study

We conducted a scoping review

Scoping reviews map out „key concepts‟ and the main

sources of evidence in a complex area (Mays et al., 2001)

• Identifying knowledge gaps

• Potential research opportunities

Methods

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Rare and Ultra-Rare Conditions: A Scoping Study

Six steps of a scoping review:

1. Identifying the research question

2. Searching for relevant studies

3. Selecting studies

4. Charting or extracting the data

5. Tabulating and summarizing the results

6. Consulting with relevant experts on the results

(Arksey and O‟Malley, 2005)

Methods

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Rare and Ultra-Rare Conditions: A Scoping Study

Research question was formulated with input from PRISM

Investigators and Network:

What is known about societal values for new therapies for

rare and ultra-rare diseases and conditions?

• „Societal values‟ were defined as any statements regarding how

health care resources should be prioritized to reflect public

choices or social preferences

• Rare and ultra-rare diseases were defined as any conditions

that had been self-described as such

1. Identifying the research question

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Rare and Ultra-Rare Conditions: A Scoping Study

A comprehensive search strategy for identifying as many

relevant published and unpublished papers

Search parameters not limited to a particular study design

For feasibility reasons, language/date restrictions applied

(English language papers between Jan 1990 and Oct 2013)

The search strategy was applied to the following databases:

• PubMed (MEDLINE and non-MEDLINE sources), EMBASE,

Web of Science, Scopus, CINAHL, and EconLit

2. Searching for relevant studies

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Rare and Ultra-Rare Conditions: A Scoping Study

Pre-specified inclusion and exclusion criteria were used to

create a screening checklist, which was applied to discrete

citations or abstracts by two independent researchers

Any papers addressing both of the following were included:

1. A specific rare or ultra-rare disease, or either more broadly

2. Values or decision factors that should be taken into account

during funding deliberations and treatment decision making

Multi-country comparisons of access to, or utilization of,

specific therapies or drug review processes were excluded

3. Selecting studies

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Rare and Ultra-Rare Conditions: A Scoping Study

Records identified through database searching

(n = 3,699)

Additional records identified through other sources

(n = 24)

Iden

tifi

cati

on

Sc

reen

ing

El

igib

ility

In

clu

ded

Records after duplicates removed

(n = 3,030)

Records screened (n = 3,030)

Full-text articles assessed for eligibility

(n = 401)

Records excluded (n = 2,629)

Studies included in synthesis (n = 43)

Full-text articles excluded: opinion pieces, news articles,

descriptive or utilization studies (n =358)

Studies discussing potential value-bearing attributes

(n=35)

Studies discussing potential process-related factors/frameworks

(n=8)

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Rare and Ultra-Rare Conditions: A Scoping Study

Information independently charted by both researchers via a

data charting form to identify key aspects or concepts

• Author(s)

• Type of paper

• Country where the paper originated

• Purpose of the paper

• Definition of „rare‟ or „ultra-rare‟ applied

• The type(s) of therapies addressed

• Decision factors or values-based statements considered

• Methods, approaches, and information sources used

• Findings and conclusions

4. Charting or extracting the data

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Rare and Ultra-Rare Conditions: A Scoping Study

Information from completed forms was tabulated to assess

the nature and distribution of papers comprising the review

Content analysis of the tabulated information was conducted

to identify „themes‟:

• Decision factors

• Preferences

• Value propositions

5. Tabulating and summarizing the results

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Rare and Ultra-Rare Conditions: A Scoping Study

A consultation exercise was carried out with key stakeholder

communities: patients, providers, industry, and government

through PRISM Network

• Network members reviewed the draft results and contributed

references, factors or arguments that had not been captured

• Feedback received was incorporated into the draft results

through a similar approach to that applied to the papers

6. Consulting relevant experts

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Rare and Ultra-Rare Conditions: A Scoping Study

• Prevalence (rarity) of disease (CoD)

• Severity (seriousness) of disease

(CoD)

• Identifiability (CoD)

• Is the disease life-threatening or

chronically debilitating? (CoD)

• Evidence of treatment

efficacy/effectiveness (CoT)

• Magnitude of treatment benefit (CoT)

• Safety profile of treatment (CoT)

• Is treatment innovative? (CoT)

• Societal impact of treatment (CoT &

CS-E)

• Impact of treatment upon distribution

of health (CS-E, CoT, CoD)

• Price (cost) of treatment (OC)

• Budget impact of treatment (OC)

• Cost-effectiveness of treatment

(Synthesis of Value & OC)

• Availability of alternatives (CoD)

• Feasibility of diagnosis (Necessary

condition for meaningful problem)

• Feasibility of treatment (Necessary

Condition for meaningful problem)

• Commercial considerations (CS-E)

• Legal considerations (CS-E)

Results: Identified decision factors

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Rare and Ultra-Rare Conditions: A Scoping Study

• Patient preferences

• Physician preferences

• The “rule of rescue”

- Argues for non-abandonment of (identifiable) patients with rare

diseases if a treatment option exists

• “The equity principle”

- Argues against special consideration for patients with rare diseases

• A “rights-based approach” (as adopted in EU legislation)

- Argues that individuals are entitled to a decent minimum level of

health care, implying that treatments for rare diseases should be

made available if patients have no other options

Results: Identified preferences/value propositions

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Rare and Ultra-Rare Conditions: A Scoping Study

Our first step is to assign each of the identified decision

factors to one of three broad categories:

1. Potential value-bearing factors

a) Disease-related factors

b) Technology-related factors

c) Socio-economic factors

2. „Opportunity cost‟-bearing factors

3. Potential decision-bearing factors

Categorizing the decision factors

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Rare and Ultra-Rare Conditions: A Scoping Study

a) Disease-related factors include:

• Prevalence (rarity) of the disease

• Severity (seriousness) of the disease

• Visibility of the disease

• Is the disease life-threatening or chronically debilitating?

1. Potential value-bearing factors

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Rare and Ultra-Rare Conditions: A Scoping Study

b) Technology-related factors include:

• Evidence of treatment efficacy/effectiveness (uncertainty)

• Magnitude of expected clinical benefit from treatment

• Safety profile of treatment (risk attitude)

• Is the treatment innovative?

1. Potential value-bearing factors

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Rare and Ultra-Rare Conditions: A Scoping Study

c) Socio-economic factors include:

• Impact of treatment upon distribution of health (inequalities)

- Includes age/sex/geographic considerations

• Commercial considerations

- Cost of developing the treatment

- Expected returns to manufacturer

• Other societal impacts of treatment

- Costs incurred by patients/caregivers

- Productivity losses

1. Potential value-bearing factors

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Rare and Ultra-Rare Conditions: A Scoping Study

Funding a treatment inevitably uses up resources that could

otherwise be used to fund other treatments for other patients

Economists call this the „opportunity cost‟ of the treatment

„Opportunity cost‟-bearing factors include:

• Cost of the treatment (per patient) incurred by health system

• Total budget impact of the treatment (if funded)

2. „Opportunity cost‟-bearing factors

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Rare and Ultra-Rare Conditions: A Scoping Study

Potential decision-bearing factors include:

• Availability of treatment alternatives

• Feasibility of diagnosing the disease

• Feasibility of providing the treatment

• Cost-effectiveness of the treatment

• Legal considerations

3. Potential decision-bearing factors

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Rare and Ultra-Rare Conditions: A Scoping Study

A decision making framework is required to consider the

resource constraint, and hence the opportunity cost of any

decision to provide coverage

• Preferences and value propositions must be applied not only

the treatment under consideration, but also its comparators and

the opportunity cost of each

Integrating the decision factors, preferences and

value propositions into a coherent framework

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Rare and Ultra-Rare Conditions: A Scoping Study

Value placed on any treatment by each stakeholder

𝑃𝑗𝑖 = 𝑓𝑗 𝑣1, 𝑣2, … , 𝑣𝑛

where 𝑖 represents the treatment and 𝑗 the stakeholder

Potential value-bearing factors (𝑣𝑛)

Disease-related Treatment-related Other

‘Opportunity cost’-determining factors

Price of treatment Budget impact

Patient preferences Physician preferences

Value placed on any treatment by each value proposition

𝑄𝑘𝑖 = 𝑔𝑘 𝑣1, 𝑣2, … , 𝑣𝑛

where 𝑖 represents the treatment and 𝑘 the value proposition

“Rule of rescue” “The equity principle”

Decision maker’s valuation of the orphan therapy and each relevant comparator

𝑉𝑖 = 𝑕 𝑃1𝑖 , 𝑃2

𝑖 , … , 𝑃𝐽𝑖 , 𝑄1

𝑖 , 𝑄2𝑖 , … , 𝑄𝐾

𝑖 , 𝑝𝑖 where 𝑖 represents the treatment and 𝑝𝑖 represents

the number of treatment alternatives to 𝑖

Decision maker’s valuation of the opportunity cost of the orphan therapy and each relevant comparator

𝑉𝑖′= 𝑕 𝑃1

𝑖′, 𝑃2

𝑖′, … , 𝑃𝐽

𝑖′, 𝑄1

𝑖′, 𝑄2

𝑖′, … , 𝑄𝐾

𝑖′, 𝑝𝑖

where 𝑖′ represents the opportunity cost of treatment 𝑖

and 𝑝𝑖 represents the number of treatment alternatives to 𝑖′

Potential decision-bearing factors

# of alternatives Cost-effectiveness Legal When making a coverage decision, the decision maker compares its valuations of the orphan therapy, its

relevant comparators, and the opportunity cost of each

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Rare and Ultra-Rare Conditions: A Scoping Study

Our scoping review identified a number of papers describing

decision factors, preferences or value propositions which

may be relevant for coverage decisions on orphan therapies

• Many of these are not in the legal definitions of orphan

therapies and would have to be applied to all therapies

Conclusions

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Rare and Ultra-Rare Conditions: A Scoping Study

It is important to identify the opportunity cost in any

coverage decision, since the potential value-bearing factors

apply to the “losers” as well as the “winners” of any

resource reallocation

• Price (cost) and budget impact determine this opportunity cost

– while important, they are not “potential value-bearing factors”

• For any given value framework, identifying the opportunity cost

allows for synthesis of the value to both winners and losers

(and hence consideration of the net value) of a positive or

negative reimbursement decision for a treatment

Conclusions

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Rare and Ultra-Rare Conditions: A Scoping Study

A very limited number of empirical studies were identified

• These provided little evidence to support special treatment on

the basis of prevalence, but some support for recognizing

severe illness and/or the absence of alternative therapies

• Patients bearing the opportunity cost of orphan therapies might

also have severe illnesses and/or few alternative therapies

While some studies support or reject assigning preferential

value to specific factors, a missing gap in the evidence base

concerns the assignment of preferential value to specific

combinations of these factors

Conclusions

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Rare and Ultra-Rare Conditions: A Scoping Study

Arksey, H. and O'Malley, L. (2005) Scoping studies: towards a methodological framework, International

Journal of Social Research Methodology, 8, 1, 19-32.

Mays, N., Roberts, E. and Popay, J. (2001) Synthesising research evidence. In N. Fulop, P. Allen, A. Clarke

and N. Black (eds) Studying the Organisation and Delivery of Health Services: Research Methods (London:

Routledge), pp. 188-220.

Ritchie, J. and Spencer, L. (1994) Qualitative data analysis for applied policy research. In A. Bryman and R.G.

Burgess (eds) Analysing Qualitative Data (London: Routledge), pp. 173-194.

Pawson, R. (2002) Evidence-based policy: in search of a method. Evaluation, 8, 2, 157-181.

Oliver, S. (2001) Marking research more useful: integrating different perspectives and different methods. In S.

Oliver and G. Peersman (eds) Using Research for Effective Health Promotion (Buckingham: Open University

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Any questions?

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Rare and Ultra-Rare Conditions: A Scoping Study

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Studies included in the scoping review

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Rare and Ultra-Rare Conditions: A Scoping Study

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Studies included in the scoping review

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Rare and Ultra-Rare Conditions: A Scoping Study

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Studies included in the scoping review

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Largent, E. A., & Pearson, S. D. (2012). Which orphans will find a home? The rule of rescue in resource

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Laupacis, A. (2009). Evidence and values: requirements for public reimbursement of drugs for rare diseases -

a case study in oncology. The Canadian Journal of Clinical Pharmacology, 16(2), e282–e284.

Liang, B. A., & Mackey, T. (2010). Reforming Off-Label Promotion to Enhance Orphan Disease Treatment.

Science, 327(January), 273–274.

Luisetti, M., Balfour-Lynn, I. M., Johnson, S. R., Miravitlles, M., Strange, C., Trapnell, B. C., … Vogelmeier, C.

(2012). Perspectives for improving the evaluation and access of therapies for rare lung diseases in Europe.

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Matthews, J., & Glass, L. (2013). The Effect of Market-Based Economic Factors on the Adoption of Orphan

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Mavris, M., & Le Cam, Y. (2012). Involvement of Patient Organisations in Research and Development of

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McCabe, C., Claxton, K., & Tsuchiya, A. (2005). Orphan drugs and the NHS: should we value rarity? BMJ,

331(7523), 1016–1019.

McCabe, C., Stafinski, T., & Menon, D. (2010). Is it time to revisit orphan drug policies? BMJ, 341(sep22_4),

c4777. doi:10.1136/bmj.c4777

Meekings, K. N., Williams, C. S. M., & Arrowsmith, J. E. (2012). Orphan drug development: An economically

viable strategy for biopharma R&D. Drug Discovery Today.

Mentzakis, E., Stefanowska, P., & Hurley, J. (2011). A discrete choice experiment investigating preferences

for funding drugs used to treat orphan diseases: an exploratory study. Health Economics, Policy, and Law,

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of Pharmacoeconomics & Outcomes Research. doi:10.1586/erp.11.95

Moberly, T. (2005). Rationing and access to orphan drugs. The Pharmaceutical Journal, 275(5 November),

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Owen, A., Spinks, J., Meehan, A., Robb, T., Hardy, M., Kwasha, D., … Reid, C. (2008). A new model to

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Picavet, E., Cassiman, D., & Simoens, S. (2012). Evaluating and improving orphan drug regulations in

Europe: A Delphi policy study. Health Policy, 108(1), 1–9.

Picavet, E., Dooms, M., Cassiman, D., & Simoens, S. (2011). Drugs for rare diseases: influence of orphan

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Pinxten, W., Denier, Y., Dooms, M., Cassiman, J., & Dierickx, K. (2012). A fair share for the orphans: ethical

guidelines for a fair distribution of resources within the bounds of the 10-year-old European Orphan Drug

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Siddiqui, M., & Rajkumar, S. V. (2012). The high cost of cancer drugs and what we can do about it. Mayo

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Stafinski, T., Menon, D., McCabe, C., & Philippon, D. J. (2011). To fund or not to fund: development of a

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Sullivan, S. D. (2008). The promise of specialty pharmaceuticals: are they worth the price? Journal of

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Valverde, J.-L. (2011). Editorial. Pharmaceuticals Policy and Law, 13(3), 115–116.

Wild, C., Hintringer, K., & Nachtnebel, A. (2011). Orphan drugs in oncology. Pharmaceuticals Policy and Law,

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Winquist, E., Bell, C. M., Clarke, J. T. R., Evans, G., Martin, J., Sabharwal, M., … Coyle, D. (2012). An

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