Regulatory Considerations for the Safety Assessment of Live Biotherapeutic Products in Clinical Trials

1. Regulatory Considerations for the Safety Assessment of Live Biotherapeutic Products in Clinical Trials Cara Fiore, Ph D US Food and Drug Administration Center for Biologics Evaluation and Research Office of Vaccines Research and Review June 2010, NYAS

2. CBER Regulation of Vaccines • Biologics for human use • Per authority of: • Public Health Service Act, Section 351 (1944) • Federal Food, Drug and Cosmetic Act (1938) • Regulations: Title 21 of the Code of Federal Regulations (CFR)

3. Focus • Investigational New Drugs (INDs) applications • LPBs in OVRR • Product Safety • Master Files (Type 2)

4. Stages of Review and Regulation

5. IND Principles “FDA’s primary objectives in reviewing an IND are, in all phases of the investigation, to assure the safety and rights of subjects, … FDA’s review of Phase 1 investigations will focus on assessing safety. And, in Phase 2 and 3, to help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug’s effectiveness and safety .” [21 CFR, 312.22(a)]

6. Clinical Hold • Order issued by FDA to delay a proposed clinical investigation or to suspend an ongoing investigation: • Subjects may not be given the investigational drug • No new subjects may be recruited into the study • Subjects already in the study and on therapy should discontinued unless FDA specifically permits

7. Pre-IND Meeting • Interface between pre-IND and IND phases • “Dress rehearsal” • An opportunity to discuss and identify: • Product safety issues • Potential clinical hold issues • Manufacturing process, product characterization, non-clinical animal studies for safety • Whether an IND is needed? • Data to support the IND clinical studies, e.g., dose selection for initial Phase 1 clinical study • Pre-IND meeting with FDA strongly recommended

8. Live Biotherapeutic Products (LBPs) • Biological Product • Contains whole, live microorganisms such as bacteria or yeast, • Regulated under Section 351 of the Public Health Service Act, 41 U.S.C. 262. • Drug • “Intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animal”. (Federal Food, Drug and Cosmetic Act of 1938), • LBP for such use requires an Investigational New Drug application - IND (21 CFR 312).

9. Safety - Early LBP Studies • Healthy subjects, Phase 1 • Measurements… • Clinical studies (Clinical Protocol) should be designed to evaluate clinical safety • Product information (Chemistry, Manufacturing and Controls – CMC) should be provided in IND to demonstrate product safety

10. Product Safety: CMC • Manufacture • detailed description • information on components/raw materials (source) • Product Testing • Characterization • Potency • Purity • Stability • 21 CFR 312.23 (a) (7), 21 CFR 600.3

11. Manufacturing • Raw Materials • Strain Source – cell banking • Manufacturing Process • Product Testing, Lot number of clinical material • 21 CFR 610, 21 CFR 210, “Current Good Manufacturing Practice Regulation and Investigational New Drugs” and draft guidance “INDs—Approaches to Complying with CGMP During Phase 1,” at http://www.fda.gov/cder /guidance/6164dft.htm

12. Safety – Product Testing • Characterization- Biochemical profile, serology, nucleic acid analysis • Potency- Strength/Colony forming units (cfu) per dose • Purity- Microbial limits testing (24 USP <61>) • Issues: modifications of testing, or multi – product facility • Stability- Testing program (identity, potency and purity) • Integrity of product should be demonstrated for duration of clinical investigation

13. Antibiotic Resistance and Genetics • Rationale (maintenance/selection) • Information on transferable genetic elements (i.e., insertion elements, bacteriophage or plasmids) • Considerations • Potential genetic stability testing • possible alternative approaches

14. Common CMC Pitfalls of LBP IND Submissions • Lack of information could result in a clinical hold • Manufacturing • Insufficient information on sources, manufacturing processes, facilities, stability, storage. Lot Information • Lot release specifications and test results lacking • Lack of expiry dating information • Lack of stability information • Insufficient information to assure safety = HOLD

15. Master Files (MF2) • CONFIDENTIAL Information submitted to the FDA to provide methods used in the manufacturing, processing, packaging, or storing of a product. 21 CFR 314.420. • Cross Reference - The MF holder must authorize (in writing) the FDA to incorporate the material by reference. • Can be used for multiple INDs/BLAs • “Guidelines for Drug Master Files” at http://www.fda.gov/cder/guidance/dmf.htm. • Submit to CBER

16. Summary • Follow FDA Guidelines for content of INDs. • Know your product- manufacturing, characterization, and testing. • The stage of product development must support the appropriate phase of clinical development. Maintain good working relationship with MF holder. • Quality Control and Quality Assurance are expected to be refined as product development proceeds.

17. Thanks! Elizabeth Sutkowski, Ph D, Wellington Sun, MD, MPH, OVRR/DVRPA staff Questions?

18. References and Guidances • “Guidance for Industry: Formal Meetings with Sponsors and Applicants for PDUFA Products,” http://www.fda.gov/cder/guidance/index.htm. • “Current Good Manufacturing Practice Regulation and Investigational New Drugs” and draft guidance “INDs—Approaches to Complying with CGMP During Phase 1,” at http://www.fda.gov/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/ucm064971.htm • “Content and Format of Chemistry, Manufacturing and Controls Information and Establishment Description for a Vaccine or Related Product” athttp://www.fda.gov/cber/gdlns/toxvac.htm • Shapiro. Vaccine 20 (2002): 1261-1280. “The HIV/AIDS Vaccine Researchers’ Orientation to the Process of Preparing a US FDA Application for an IND:…”

19. Ask CBER/FDA if an IND is Needed! Center for Biologics Evaluation and ResearchOffice of Communication, Training & Manufacturers Assistance Manufacturers Assistance and Technical Training Branch800-835-4709 or 301-827-1800matt@cber.fda.gov