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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
Acknowledgements:
CIHR Emerging Team Grants Funding
Promoting Rare-disease Innovations through
Sustainable Mechanisms‟ (PRISM) Collaborators
Network
Rare and Ultra-Rare Conditions: A Scoping Study
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
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
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
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
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
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
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
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
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
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
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)
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Press), pp. 167-179.
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