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. Phase 1
Safety
Immuno-genicity (prelim)
Phase 2
Immuno-genicity
Dose Ranging
Phase 3
Efficacy
BLA
Data to support approval
Inspection
Phase 4
Lot Release
PMCs
BLA suppl
(Post-approval
Changes)
New Indications
Dosing
Manufacture
Equip./Facilities
IND
Pre-IND
Stages of Review and Regulation IND = Investigational New Drug Application; BLA= Biologics License Application

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, (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
SAFETY
Justifications
Case by case
Responsibility on the sponsor

10. Product Safety: CMC Manufacture Product Testing
detailed description
information on components/raw materials (source)
Product Testing
Characterization
Potency
Purity
Stability
21 CFR (a) (7), 21 CFR 600.3
I will go through each of these points

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 /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
Antibiotic Resistance
Public Health concern (emergence)
Blot hybridization data for resistance genes?

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
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
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,”
“Current Good Manufacturing Practice Regulation and Investigational New Drugs” and draft guidance “INDs—Approaches to Complying with CGMP During Phase 1,” at
RegulatoryInformation/Guidances/ucm htm
“Content and Format of Chemistry, Manufacturing and Controls Information and Establishment Description for a Vaccine or Related Product” at
Shapiro. Vaccine 20 (2002): “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 Research Office of Communication, Training & Manufacturers Assistance
Manufacturers Assistance and Technical Training Branch or