290 likes | 978 Views
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. CBER Regulation of Vaccines.
E N D
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
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)
Focus • Investigational New Drugs (INDs) applications • LPBs in OVRR • Product Safety • Master Files (Type 2)
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)]
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
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
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).
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
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
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
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
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
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
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
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.
Thanks! Elizabeth Sutkowski, Ph D, Wellington Sun, MD, MPH, OVRR/DVRPA staff Questions?
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:…”
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