The FDA Review Process

1. The FDA Review Process Dan Takefman, PhD Chief, Gene Therapy Branch DCGT/OCTGT/CBER/FDA IOM Meeting 6/4/13

2. Overview • IND Review Process • Regulatory framework • Discipline review focus • FDA and RAC • Respective roles • How we interact 2

3. Basis for Review Decisions • Regulatory requirements are based on the following: • Public Health Service Act (PHS Act) • Food Drug & Cosmetic Act (FDC Act) • Regulations described in 21 CFR • IND regulations: 21 CFR 312 • Biological product regulations: 21 CFR 610, 210-211 • Protection of human subjects: 21 CFR 50 • Additional safeguards for children: (Subpart D) • Guidance documents • Internal and external science • RAC recommendations • FDA advisory committees 3

4. Relevant Guidances • Draft Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products, 2012 • Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines, 2011 • Guidance for FDA Review Staff and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs), 2008 • Guidance for Industry: Gene Therapy Clinical Trials - Observing Subjects for Delayed Adverse Events, 2006 • ICH Guidances 4

5. The IND Review Process • A Team Approach to IND Review: • Regulatory Project Manager • Chemistry, manufacturing, and controls (CMC) reviewer • Pharmacology/Toxicology reviewer • Clinical reviewer • Statistical reviewer • Within 30 days (in effect or hold) • Outstanding hold and non-hold issues conveyed by phone and detailed letter is issued. • Must satisfactorily address hold issues prior to beginning clinical trial 5

6. Yearly New GT IND Submissions(~ 370 Active INDs, 840 Total) 6

7. Regulatory Timeline Marketing Preclinical Phase 1 Phase 2 Phase 3 Phase 4 File IND Pre-BLA Meeting EOP2 Meeting Pre-IND Pre-pre-IND File BLA 7

8. 21 CFR 312.22 FDA’s primary objective in reviewing an IND are in all phases of the investigation, to assure the safety and rights of subjects…. 8

9. IND Submission: CMC Content • Safety of source materials, intermediates, and final product • Viral/microbial contaminants • Manufacturing process • Product testing for identity, purity, potency • As related to safety for early phase trials 9

10. Pre-Clinical Studies • Scientific basis for conducting clinical trial • Recommend initial safe dose & dose-escalation scheme in humans • Identification of potential target tissue(s) of toxicity/ activity • Identification of parameters to monitor clinically • Identification of patient eligibility criteria 10

11. Pre-ClinicalProof-of-Concept (POC) • POC in relevant animal models– bioactivity endpoints • Extent of functional correction • Durability of effect • Determine effective dose level range • Optimize route of administration/dose selection/dosing regimen • Collect safety data in the animal models 11

12. Toxicology Studies • Identify, characterize, quantify the potential local and systemic toxicities in relevant animal species • Identify target organs/sites for toxicity • Reversibility (acute or chronic toxicities) • Dose response relationship 12

13. Clinical Studies: Early- Phase Considerations • Optimal dose and administration • Starting dose level/dose-escalation scheme • Route of administration • Dose schedule • Define appropriate patient population • Staggering of dose escalation 13

14. Patient Safety Monitoring • Systematic observations of patients should be performed • Clinical • Radiological • Laboratory • Defined timed intervals for observations 14

15. Clinical Trial Safety Monitoring • Safety monitoring should be guided by: • Findings from Preclinical studies • Features of the underlying disease • Anticipated disease-product interactions • Long term follow-up for applicable products • Safety reporting requirements described in 21 CFR 312 15

16. Key FDA Questions In An Early-Phase IND Review Does the submission contain sufficient information to assess risks to the subjects in the proposed trial? Are source materials, manufacturing process, and final product sufficiently characterized to provide adequate assurance of safety? Were adequate preclinical studies performed? Were data submitted in sufficient detail to conduct an independent FDA review? Does the design of the clinical trial contain adequate safeguards for subject safety? Is the design of the clinical trial adequate to achieve stated aim? If sufficient data are present, are the risks to human subjects reasonable? 16

17. Overview • IND Review Process • Regulatory framework • Discipline review focus • FDA and RAC • Respective roles • How we interact 17

18. FDA and RAC • Distinct and complementary roles in the review of clinical trials involving gene transfer. • NIH RACprovides an invaluable service by allowing open public discussion of applications to initiate gene therapy trials that present novel ethical or scientific considerations. • Only FDA may authorize, at a Federal level, clinical trials using unapproved products. 18

19. FDA review • Emphasis in early clinical phases is on review of data and clinical study design to support safety. • Review is in the context of a regulatory framework. • Reviewer and sponsor interaction occurs throughout product lifecycle. • Pre-pre INDs to post marketing • Science based decision making. • Confidentiality restrictions limit what FDA can discuss in public. 19

20. RAC Review • Focus on scientific and ethical issues • Scientific perspectives • Can include ad hoc experts from around the world • Public forum • Recommendations to improve knowledge gained in pre-clinical studies and early-phase clinical trials • Activity endpoints • Understanding mechanism of action • Less detailed material to review • Minimal role in manufacturing review, but may provide recommendations to improve product/product design 20

21. FDA Interactions with RAC • Non-voting representative • Other FDA staff typically attend or watch videocast • Participates in Gene Therapy Safety Advisory Board (GTSAB) discussions • FDA can advise and clarify policies/regulations during RAC meetings • FDA does not comment on review decisions at meetings • FDA benefits from: • Public discussion of potential risks and ethical considerations • Scientific review and discussion • FDA use of the GeMCRIS database 21

22. OCTGT Contact Information • Dan Takefman • Daniel.Takefman@fda.hhs.gov • Regulatory Questions • Contact the Regulatory Management Staff in OCTGT at CBEROCTGTRMS@fda.hhs.gov • or Lori.Tull@fda.hhs.gov • or by calling (301) 827-6536 • References for the Regulatory Process for OCTGT • http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/OtherRecommendationsforManufacturers/ucm094338.htm • OCTGT Learn Webinar Series • http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/ucm232821.htm 22

23. Public access to CBER • CBER website: • http://www.fda.gov/BiologicsBloodVaccines/default.htm • Phone: 1-800-835-4709 or 301-827-1800 • Consumer Affairs Branch (CAB) • Email: ocod@fda.hhs.gov • Phone: 301-827-3821 • Manufacturers Assistance and Technical Training Branch (MATTB) • Email: industry.biologics@fda.gov • Phone: 301-827-4081 • Follow us on Twitter • https://www.twitter.com/fdacber 23