Rare Disease Workshop 5: Post Marketing Confirmatory Studies in Rare Diseases Susan Boynton, VP, Global Regulatory Affairs, Shire Mary O'Donovan, Senior Director, Regulatory Affairs & Policy, Biomarin

Accelerated Approval: Requirements Under §314.510 “Approval ….subject to the requirement that the applicant study the drug further, to verify and describe its clinical benefit where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome. Post marketing studies would usually be studies already underway. When required to be conducted, such studies must also be adequate and well-controlled. The applicant shall carry out any such studies with due diligence.”

Key Aspects for Accelerated Approval - Considerations Efficacy and safety standard must still be met for full approval Confirmatory studies must meet adequate and well controlled standard when required Size, length and scope of confirmatory studies needs to compensate for limitations of pre-approval data set Goal is to verify and describe its clinical benefit. Clinical studies may need to evolve as data evolves Critical to engage FDA on post approval required confirmatory studies data early in development Feasibility challenges of post approval studies must be fully discussed and continually evaluated Reassurance that studies can be completed in a reasonable timeframe Ideally should be underway at time of AA

Rare Disease Studies in the Post Market Setting – Amplifies Design/Feasibility Challenges Placebo or Non Placebo controlled confirmatory studies? Placebo controlled trials not always appropriate or feasible Long time frames for disease progression Low frequency of events in some diseases Lack of standard-of-care treatments challenging particularly in severe and life-threatening diseases Potential early signs of clinical benefit can significantly impact feasibility of recruitment in post market setting. Rapidly progressing, irreversible (especially disabling) diseases most challenging

Rare Disease Studies in the Post Market Setting – Other Designs & Challenges Single active arm confirmatory study? How can it meet the adequate well controlled standard? Lack of parallel control group means: Magnitude and nature of clinical benefit may need to be sufficient to overcome potential for bias in assessments Given small populations, longer term observations may be necessary to measure the magnitude of benefit and verify and describe the clinical benefit What additional sources of long term robust data could be considered to support adequate and well controlled standard?

Rare Disease Studies in the Post Market Setting – Using Other Sources of Data Natural History Studies providing untreated subject data Planning is critical. Initiation early in development to ensure availability at time of confirmatory study delivery (dependent on time frame of disease) Ensure high quality data and from “matched” untreated patients Patient clinical disease outcome surveys or registries Potential option when large fraction of available population needed. Data collection on all patients at intervals Challenge: requires high quality data sources Potential for strong reliance on non-US data Overseas studies typically designed to meet international agency requirements

Rare Disease Studies in the Post Market Setting – Understanding Risk Conducting confirmatory studies in post market setting brings risk. Acknowledgement by all parties that in some cases confirmatory studies may fail. Precedence in oncology and non-oncology environment 2011 ODAC reported 10.2% failed to confirm benefit or failed to complete confirmatory trial accrual. Clear and transparent discussions (FDA, Sponsor including patient perspective) is essential during clinical development plan. Firm agreement on potential “next step” actions prior to market introduction and results of confirmatory study.

DISCUSSION How Do We Accurately Confirm Clinical Benefit Post-Marketing? Suggestions: What other alternative sources of data could be used to obtain adequate and well controlled confirmatory data? Slow progressing but debilitating diseases – how long is acceptable to wait to get confirmation? How to prevent discontinuations from long term studies once product placed on market? When is it best to start discussion around AA post marketing confirmatory study design and feasibility? How do we address the commercial challenge of long term studies. Concept of a "Disease Monitoring Program” (DMP) encompassing registry/natural history /long-term extension study in one (Emil Kakkis)