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

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

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.

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

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

“…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

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

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

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

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

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