1. Factors to Consider in Assessing the Accelerated Approval Pathway Mark Thornton, MD, MPH, PhD President, Sarcoma Foundation of America Sr. Clinical Consultant, Biologics Consulting Group, Inc.

2. Factors to Consider in Accelerated Approval for Rare Diseases Extremely high unmet medical need Extreme rarity Absence of any prior clinical study of formally collected clinical data Slow disease progression with significant irreversible symptoms Significant delay between the onset of irreversible disease and clinical diagnosis Lack of readily measurable, recognized clinical endpoints due to unusual clinical disease manifestations

3. Historical Perspective How we got here – The rare cancer perspective

11. Factors to Consider Guidance for Special Flexibility for Ultra-Rare Diseases Under FDASIA

12. Special Flexibility for the Ultra-Rare Extremely high unmet medical need –Feedback from groups representing ultra-rare, life threatening diseases indicate acceptance of greater safety risks and lessened assurance of the efficacy of the product Leveling the playing field; not lowering standards Extreme rarity –The EU has bravely tried to carve out a definition of ultra-rare (< 1:50,000, or approx. 6000 U.S.) versus Orphan, in opposition to the forces who are motivated to maintain the status quo. –Industry has found ways to make sizable profits from populations of 200,000 down to 6,000 range. Much harder to hope for any ROI in much smaller populations, especially if regulatory uncertainty exists.

13. Special Flexibility for the Ultra-Rare Absence of any prior clinical study of formally collected clinical data –Disconnect between disease-focused clinical assessment for many rare diseases and the regulatory precedents set for endpoints used in more common diseases makes determining how to evaluate a disease or treatment effect difficult. Slow disease progression with significant irreversible symptoms –If the clinical manifestations of the disease are not reversible and the goal of therapy is disease stabilization, achieving sufficient power to detect the difference between placebo and treated patients is extremely difficult (e.g., Fabry disease and loss of renal function)

14. Special Flexibility for the Ultra-Rare Significant delay between the onset of irreversible disease and clinical diagnosis –Slow and inconsistent changes early in progression difficult to study using clinical endpoints –Common in rare neurological disorders, leading to late, rapid decline (e.g., Adrenoleukodystrophy and Batten’s disease) Lack of readily measurable, recognized clinical endpoints due to unusual clinical disease manifestations –For example, autosomal recessive dystrophic epidermolysis bullosa, where the disease process is not measured using any reasonable intermediate clinical endpoints, short of major clinical events easily confounded by supportive symptomatic care

15. Regulatory Creep and the Need for Advocacy Decelerated Approval and A Cautionary Tale

16. A History of Accelerated Approval: Overcoming the FDA’s Bureaucratic Barriers in order to Expedite Desperately Needed Drugs to Critically Ill Patients (Jacob W. Stahl, Class of 2005 Harvard Law School)

17. A History of Accelerated Approval: Overcoming the FDA’s Bureaucratic Barriers in order to Expedite Desperately Needed Drugs to Critically Ill Patients (Jacob W. Stahl, Class of 2005 Harvard Law School) - Continued

18. How AA begat AAv2.0 AIDS patient, and to a lesser extent cancer patient, advocacy resulted in fundamental change in regulatory behavior in the 1990’s Over 20 years vigilance, sense of urgency dimmed from advocates Regulators caution, conservatism and avoiding sins of commission shifted the pendulum –The spirit of AA has been stifled in proportion to strict or flexible adherence of Prentice criteria for surrogate endpoints –“The surrogate is not validated” remark has killed many programs, and is a sin of omission difficult to quantify –Especially painful in the ultra-rare setting Setting reasonable standards for qualification of biomarkers in the ultra-rare setting is the main intent of the advocacy behind FDASIA –Less regulatory uncertainty = Greater industry risk-taking in ultra-rares

19. A Cautionary Tale Rare HIV subgroup product –Product X and Company A (late 2012, post-FDASIA) Indication is a severe/fatal neurologic disease due to an opportunistic non-HIV virus (U.S. incidence of 2000) AA requested based on surrogate (decline in the responsible non- HIV virus); pivotal trial needing 60 patients (a survival trial would require 250 patients) Given patient participation rates in clinical trials of 1-2%, only 20-40 patients might be available per year FDA found surrogate unacceptable (“The surrogate is not validated”), and required a survival trial; EMEA gave the OK for the surrogate, with post-marketing confirmation of the surrogate Hope dimming that company will continue development The lesson is that even with HIV, AA can be an elusive goal if the indication is too rare, and intent of laws can be easily diluted. Is this the tip of the iceberg?

20. Solutions? Where to from here?

21. Food for Thought – Advocating for Compliance and Accountability to the Law Institute a Rare Disease Oversight Committee at FDA akin to the Clinical Hold Oversight Committee of the mid-1990’s –Congressional accountability provisions of the first PDUFA altered clinical hold behavior profoundly (at first) Establish a patient volunteer/SGE Rare Disease Ombudsman position (possibly within OOP or OSHI?) –Companies trying to develop products for ultra-rare settings could have a safe harbor to voice possible actions counter to the intent of FDASIA –FDA Division would have opportunity to explain reasons for denial of surrogate before being reported to Congress