This document discusses definitions of rare diseases and considerations for drug development in rare diseases. It notes that rare diseases are defined differently in various regions but generally refer to diseases affecting fewer than 5 in 10,000 people in Canada, 1 in 2,000 in Europe, 50,000 in Japan, and 200,000 in the US. However, cumulatively over all rare disease families, about 1 in 12 people are affected by a rare disease. The document outlines challenges in rare disease drug development including small patient populations, lack of natural history data and treatment guidelines, need for alternative clinical trial designs, and difficulties detecting adverse events. It emphasizes the need to involve patients, families, regulators early in the process and consider broader views of value

1. David A H Whiteman MD FAAP FACMG
Global Clinical Sciences Leader
Shire Pharmaceuticals

2. Full Time Employee and Stockholder
Shire Pharmaceuticals
Practicing Pediatrician and Biochemical & Medical
Geneticist for 30 years prior to joining pharmaceutical
industry

3. Health Canada: Life-threatening, severely debilitating or chronic
disease that affects less than 5 in 10,000 Canadians
Broadly consistent with the EU definition:
Numerically similar result to the US, but more restrictive requiring severity
and chronicity
Being Rare alone does not define as a priority in Canada as in EU
Europe: Commission on Public Health: "life-threatening
or chronically debilitating diseases which are of such low
prevalence that special combined efforts are needed to address
them.”
Low prevalence later defined <1 in 2,000 Europeans.
Statistically rare, but NOT also life-threatening, chronically debilitating, or
inadequately treated diseases are excluded from EU definition.

4. Japan: legal definition: affects fewer than 50,000 patients in Japan:
~ 1 in 2,500 Japanese
US: "any disease or condition that affects less than 200,000 people
in the United States,“ = about 1 in 1,500 Americans
HOWEVER, CUMULATIVELY OVER ALL RD FAMILIES:-
1:12 prevalence
8% of the population
2.7M Canadians are in some way affected by 1 of ~7500 rare diseases,
- of which 80% are genetic (but not necessarily hereditary)
- of which 70% first manifest in infancy or childhood

5. Disease Population: Define Rare:
Need for good epidemiology
Natural History for comparators
Registries & Natural History Studies
Comparative Interventions / Standards of Care:
Often no prior drug development in RD: Rx guidelines for
“palliative” care are often lacking
Other diseases comparisons not necessarily appropriate
Disease Chronicity and Severity & Life-Threatening Definitions
Multiple Medical Needs
Multiple Patient and Family Psychosocial needs
HCP Resources
Access to knowledgeable HCPs
Age appropriate outcome measures
Blood and Tissue sampling/banking in children

6. “…Adequate and well-controlled studies…”
In RD the numerical power demanded in traditional drug
development studies often not feasible
Alternative Clinical Trial Designs & Modeling
Observational studies
Registries and Outcome Surveys
Very few rare diseases have validated PPRO instruments
Small n and t trials often use no obvious PPRO comparators
Use of existing generic HRQOL instruments may not appropriate
to particular rare diseases

7. Low numerical power to detect
Predicting possible adverse outcomes from targeted
biology of drug: advantages and disadvantages
Low frequency adverse events hard to
predict/determine early in the development program
Post Marketing Surveillance Studies
Registries

8. Need, at a much earlier stage, for the kind of data that is
typically obtained in large n, longer t studies
Data quality and magnitude that is traditionally considered may
not be available. Need to consider a longer term evaluation,
post marketing requirements etc.
Efficacy
Endpoints & Outcomes: reflecting the NH
Validation, Clinical Meaningfulness
6MWT
Surrogates: biochemical, clinical
Effectiveness
Real World

9. Numbers: incidence, prevalence
Natural history
Patient outcome measures
Surrogate measures validation
Stratification of disease
Post authorization monitoring beyond safety
Adaptive authorization

10. Defining Value in Rare Disease Rx Development
Requires a very broad view that respects, optimizes and balances
the interests of patients, families, health care systems, risk holders,
regulators and drug developers
International collaborations: Clinical Development Networks
Involve families, knowledgeable HCPs, regulators, HTA, & risk
carriers from the earliest in the drug development process
Often needs alternative regulatory pathways and incentives
Often needs economic incentives to attract research and
sponsors

12. Per-patient costs high:
Overall budget impact may appear less so.
Tolerance of risk holders depends on their size/budget
Compare the Cost of Not Treating:
Diagnostic odyssey costs
Medical: visits, hospitalization, tests, monitoring
Family: Social, Psychological, Monetary
Society: Multiple Family impacts: lost productivity
Production Technology Development
Sustainability and Continued Availability of an effective product