Current Challenges in the Designation and Development of Orphan Products

1. Current Challenges in the Designation and Development of Orphan Products DIA Annual Meeting Marlene Haffner, MD, MPH June 27th, 2012 Philadelphia, Pennsylvania

2. Rarity Paradigm • Limited public awareness (invisible) • Scarcity of clinical expertise and reference centers – disease is poorly understood • Delay in diagnosis • Small patient population • Geographic dispersion • Life threatening/chronic • Heterogeneous conditions • Difficult to stratify/stage • Limited treatment availability Imited treatment availablil

3. Obtaining your designation • Orphan Products “tip sheet” • http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/ucm135122.htm • Aka – www.fda.gov/orphan - how to apply for orphan products designation

4. Obtaining Designation • Carefully consider when to obtain designation • Once designated, information is public • Designation document not available under FOIA until approved • Review if other products for same disease in development – check website of OOPD – www.fda.gov/orphan Then go to designation website

5. Identify the disease • Clearly define what is the disease • Is the disease/symptom the disease or… • Polyps in Familial adenomatous polyps vsadenomatous polyps • Bone pain in MPS vs bone pain • Is the disease real • Do you wish to designate a subset of the disease? • Why?

6. What determines subset validity • NOT because that is what you wish to study • Because the drug is not useful for the “larger” disease • It is too toxic • Genetic markers make it ineffective – HER2 +, KRAS mutant – except in the subset • What is mechanism of action of the drug • More effective treatments for other segments of the disease – surgery for stage 1 • Pediatric manifestations of a disease are valid

7. Determining the prevalence • No easy answer • Multiple sources • Scan the literature • SEER data • If data and your analysis are not parallel – why? Explain completely • Who can benefit?

8. FDA Involvement • EARLY, EARLY, EARLY • Two key FDA Offices – OOPD, Associate Director of OND for Orphan Products/CDER • Involve the Review Division • OOPD does not review products for approval • They do meet with the review division when asked by sponsor • Assoc Director in OND – Anne Pariser • Involved in policy and consistency • Small office but growing

9. Finding the population • Get involved in NORD • Get involved in patient groups • Facilitate patient group interaction • Develop teaching materials for patients • Is there a known “Natural History?” If not, may need to develop one • Evaluate patient needs – may not be the same as sponsor perceived needs

10. Planning the Product Development • Meet with the review Division – include the OOPD and Assoc for Orphans/CDER • Have a thorough and well thought out plan • Involve Key Opinion Leaders in your strategy; consider involving patients or care givers • Be aware of Natural History and heterogeneity of the disease • Requires very careful planning. May have only 1 opportunity • Think about geographic dispersion – multicenter trials

11. The clinical trials • Most are double blind, well-controlled trials – even in relatively small populations. Best method • Historical most desired, but often not feasible • Varying stage of disease • Natural history not known • Varying methods of existing treatment • Advances in treatment • Single pivotal trial – rarely. Drug info known • Non-placebo – in life threatening conditions • These are chronic diseases

12. Adequate and Well-Controlled Studies • A&WC studies require • Research goal/objective • Valid comparison with a control • Concurrent (strongest) or historical • Appropriate selection of subjects • Method of assignment to treatment and control • Measures to minimize bias • Well-defined and reliable methods of assessing response • Adequate analysis of results • 21CFR314.126 Adequate and well-controlled studies

13. Natural History vs Registry • Registry ≠ NH Study • Registries can include: • Communication • Post-marketing commitments/requirements e.g., • Intervention assessment • Safety • NH Study • Specific purpose • Intended to be comprehensive, granular • Intended to describe the disease

14. Natural History Studies • Track course of disease over time • Identify demographic, genetic, environmental and other variables that correlate with disease and outcomes in the absence of treatment • “Pillar of epidemiologic research on rare conditions”3 • Many potential uses/functions of NH study data in addition to drug development, e.g. • Patient care, best practices • Research priorities identification • “centers of excellence” development, clinical trial readiness

15. Rare diseases are a highly diverse collection of disorders • -Design and conduct of clinical development programs are highly individualized • -Dependant on disease and population under study, understanding of the intervention and its expected impact on the disease • One size does not fit all – MUST understand the disease and, if possible, the genetics of the disease Challenges in Rare Disease Drug Development

16. ?