Presentation on theme: "Regulatory Considerations for the Safety Assessment of Live Biotherapeutic Products in Clinical Trials Cara Fiore, Ph D US Food and Drug Administration."— Presentation transcript:
1Regulatory Considerations for the Safety Assessment of Live Biotherapeutic Products in Clinical TrialsCara Fiore, Ph DUS Food and Drug AdministrationCenter for Biologics Evaluation and ResearchOffice of Vaccines Research and ReviewJune 2010, NYAS
2CBER Regulation of Vaccines Biologics for human usePer 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)
3Focus Investigational New Drugs (INDs) applications LPBs in OVRR Product SafetyMaster Files (Type 2)
4Phase 1SafetyImmuno-genicity (prelim)Phase 2Immuno-genicityDose RangingPhase 3EfficacyBLAData to support approvalInspectionPhase 4Lot ReleasePMCsBLA suppl(Post-approvalChanges)New IndicationsDosingManufactureEquip./FacilitiesINDPre-INDStages of Review and Regulation IND = Investigational New Drug Application; BLA= Biologics License Application
5IND Principles“FDA’s primary objectives in reviewing an IND are, in allphases 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)]
6Clinical HoldOrder issued by FDA to delay a proposed clinical investigation or to suspend an ongoing investigation:Subjects may not be given the investigational drugNo new subjects may be recruited into the studySubjects already in the study and on therapy should discontinued unless FDA specifically permits
7Pre-IND Meeting Interface between pre-IND and IND phases “Dress rehearsal”An opportunity to discuss and identify:Product safety issuesPotential clinical hold issuesManufacturing process, product characterization, non-clinical animal studies for safetyWhether an IND is needed?Data to support the IND clinical studies, e.g., dose selection for initial Phase 1 clinical studyPre-IND meeting with FDA strongly recommended
8Live Biotherapeutic Products (LBPs) Biological ProductContains 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).
9Safety - Early LBP Studies Healthy subjects, Phase 1Measurements…Clinical studies (Clinical Protocol) should be designed to evaluate clinical safetyProduct information (Chemistry, Manufacturing and Controls – CMC) should be provided in IND to demonstrate product safetySAFETYJustificationsCase by caseResponsibility on the sponsor
10Product Safety: CMC Manufacture Product Testing detailed descriptioninformation on components/raw materials (source)Product TestingCharacterizationPotencyPurityStability21 CFR (a) (7), 21 CFR 600.3I will go through each of these points
11Manufacturing Raw Materials Strain Source – cell banking Manufacturing ProcessProduct Testing, Lot number of clinical material21 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
12Safety – Product Testing Characterization- Biochemical profile, serology, nucleic acid analysisPotency- Strength/Colony forming units (cfu) per dosePurity- Microbial limits testing (24 USP <61>)Issues: modifications of testing, or multi – product facilityStability- Testing program (identity, potency and purity)Integrity of product should be demonstrated for duration of clinical investigation
13Antibiotic Resistance and Genetics Rationale (maintenance/selection)Information on transferable genetic elements (i.e., insertion elements, bacteriophage or plasmids)ConsiderationsPotential genetic stability testingpossible alternative approachesAntibiotic ResistancePublic Health concern (emergence)Blot hybridization data for resistance genes?
14Common CMC Pitfalls of LBP IND Submissions Lack of information could result in a clinical holdManufacturingInsufficient information on sources, manufacturing processes, facilities, stability, storage.Lot InformationLot release specifications and test results lackingLack of expiry dating informationLack of stability informationInsufficient information to assure safety = HOLD
15Master Files (MF2)CONFIDENTIAL Information submitted to the FDA to provide methods used in the manufacturing, processing, packaging, or storing of a product. 21 CFRCross 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” atSubmit to CBER
16Summary 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.
18References 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,” atRegulatoryInformation/Guidances/ucm htm“Content and Format of Chemistry, Manufacturing and Controls Information and Establishment Description for a Vaccine or Related Product” atShapiro. Vaccine 20 (2002): “The HIV/AIDS Vaccine Researchers’ Orientation to the Process of Preparing a US FDA Application for an IND:…”
19Ask CBER/FDA if an IND is Needed! Center for Biologics Evaluation and Research Office of Communication, Training & Manufacturers AssistanceManufacturers Assistance and Technical Training Branch or