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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.

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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
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
Focus
  • Investigational New Drugs (INDs) applications
  • LPBs in OVRR
  • Product Safety
  • Master Files (Type 2)
ind principles
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
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
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
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
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
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
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
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
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
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
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
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
Thanks!

Elizabeth Sutkowski, Ph D,

Wellington Sun, MD, MPH,

OVRR/DVRPA staff

Questions?

references and guidances
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
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