FDA Perspectives on Clinical Trial Development of Gene Therapy

1. FDA Perspectives on Clinical Trial Development of Gene Therapy Changting C Haudenschild, M.D changting.haudenschild@fda.hhs.gov OCTGT/CBER/FDA ASGT 12th Annual Meeting May 27-30, 2009

2. FDA Organization • CBER - Center for Biologics Evaluation and Research • Office of Cellular, Tissue, and Gene Therapy • Office of Vaccines Research and Review • Office of Blood Research and Review • CDER - Center for Drug Evaluation and Research • CDRH - Center for Devices and Radiological Health • CFSAN – Center for Food Safety and Applied Nutrition • CVM – Center for Veterinary Medicine • NCTR – National Center for Toxicological research

3. Diversity of Products in OCTGT • Gene products • Replacement therapy for monogenic disease • Modification of physiological homeostasis • Cellular products: • Autologous: selected, cultured, or modified • Allogeneic: selected, cultured, or modified • Genetically modified somatic cells • Tissue and tissue based products • Xeno-transplantation products • Combination products

4. Gene Therapy Products Definition*: All products that mediate their effects by transcription and/or translation of transferred genetic material and/or by integrating into the host genome and that are administered as nucleic acids, viruses, or genetically engineered microorganisms. The products may be used to modify cells in vivo or transferred to cells ex vivo prior to administration to the recipient. • Gene transfer via vectors • Cells modified by gene transfer vectors *2006 Guidance for Industry - Gene therapy Clinical Trials- Observing Subjects for Delayed Adverse Events

5. Information Needed to Start an Early- Phase Clinical Study • Product manufacture, characterization, and safety testings http://www.fda.gov/cber/gdlns/gtindcmc.htm • Safety information to show that the proposed treatment is reasonably safe to administer in human, based on: • Pre-clinical studies conducted in appropriate animal species/models • Data from previous or ongoing clinical studies • Published scientific data

6. Information Needed to Start an Early Phase Clinical Trial • Starting dose or dose range • Rationale of route of administration • Delivery device • Biological activity data • Gene expression in target tissues • Measurable transgene product in target tissues

7. Clinical Study Design • Patient selection • Dose selection • Product administration • Safety monitoring • Collection of activity/efficacy data • Study endpoints

8. Patient Population • Define the disease indication • Specify eligibility criteria • Diagnostic/staging criteria • All patient should be on optimal medical therapy • Special consideration for treating pediatric patients • Treat adult patients first to collect safety data • Scientific justification of treating pediatric patients

9. Dosing Selection • Starting dose should be consistent with biological activity and below the dose at which adverse effects were seen in pre-clinical studies • Staggered patient enrollment • Conservative dose escalation • MTD may not be definable

10. Product Administration • Rationale for the procedure selection • Detailed procedural information with supporting data • Dose/volume/injection times • Delivery devices are subject to review • Safety monitoring plan for invasive procedures • Training plan may be needed for the use of the delivery device

11. Safety Monitoring Based on • Animal and in vitro studies • Understanding of mechanism of action of the products • Published information • Continuous improvement of safety monitoring plan

12. Safety Monitoring Plan Examples • Inflammatory response to • Product (virus vectors) • Mechanical injury due to the procedure • Immunological response to • Virus vectors • Transgene product • Modified autologous cells • *Long-term follow-up for gene therapies *Guidance for Industry – 2006 Gene therapy clinical trials – observing subjects for delayed adverse events

13. Collecting Data: Biologic Activity and Efficacy • In vivo biological activity • Duration and level of gene expression • Duration and level of transgene proteins • Clinical evaluation

14. Study Endpoints for an Early Phase Study • Evaluate specified safety • Product related • Procedure related • Select optimal dose that will be used for the late phase studies • Identify evidence of biological drug activity • Gain early evidence on effectiveness

15. Efficacy Endpoints for a Late Phase Study • Regular approval • Clinical benefits: • Increased survival • Symptomatic improvement • Accelerated Approval • Established surrogate endpoints that are reasonably likely to predict clinical benefit • Postmarketing studies are required to demonstrate clinical benefits

16. Information Needed to Start a Late-Phase Study • Product characterization and consistency • A well-controlled, scientific valid Phase 2 study is valuable and may be critical in decisions regarding dose, endpoints, time of evaluation, etc • Preliminary safety profile should be established • Biological activity, and preliminary effectiveness should be demonstrated • Pivotal study design should be supported by the data from the early phase studies

17. Meeting with FDA to Discuss a Late-Phase Study Design • Background data to support statistical design and power of the study to achieve objectives • Specific target population • Optimal dose and regimen • Proposed control arm and randomization plan • Safety motoring plans (short term and long-term) • Efficacy endpoint(s) • Statistical Analysis Plan

18. Challenges in Small Trial Design • Special design methods may be indicated for small trials • Blinding may be not feasible, or patients may be unwilling to enter a randomized trial • Double blind and placebo-control features may be not feasible • Historical control is considered • If natural history of the disease is well characterized and is relatively stable over time • If no treatment available or standard treatment is highly ineffective

19. Requirements for NDA/BLAApproval (CFR 601.25) • Safe for the use described in labeling • Demonstration of substantial evidence of effectiveness for the use described in labeling. Effectiveness is established by “adequate and well-controlled studies” (CFR 314.126) • Not misbranded

20. Early Communication with FDA • Non-binding, informal scientific discussion between FDA and sponsor • Via telecons • Via scientific meetings/workshops • Via outreach presentations • Discuss specific issue(s) of interest • Contact information: Patrick Riggins Ph.D patrick.riggins@fda.hhs.gov Branch Chief Regulatory Management Staff

21. THANK YOU