Clinical Review Process: An FDA Perspective

1. Clinical Review Process: An FDA Perspective Karen Midthun, M.D. Deputy Director of Medicine Center for Biologics Evaluation and Research FDA April 15, 2005

2. Biological Products Regulated by CBER • Blood, blood components and derivatives • Vaccines (preventive and therapeutic) • Allergenics • Cell and Gene Therapies • Tissues • Xenotransplantation • Related Devices

3. Focus of this Talk: Vaccines for Infectious Diseases Indications • Generally, preparations containing all or a portion of a disease-causing organism or the nucleic acid encoding one or more proteins from that organism • Intended to induce an immune response to the vaccine for the prevention or treatment of the infectious disease • Reviewed by Office of Vaccines Research and Review, in conjunction with Office of Biostatistics and Epidemiology and Office of Compliance and Biologics Quality

4. Types of vaccines • Live, attenuated: MMR, OPV, Varicella, YF, TY21A, influenza • Inactivated: HAV, influenza, IPV, rabies • Crude or purified antigens derived from living or killed cells: diphtheria and tetanus toxoids, acellular pertussis antigens, polysaccharides • Conjugate vaccines: Hib, meningococcal, pneumococcal • Recombinant DNA derived: HBV • Vectored and DNA vaccines (investigational)

5. Licensed biological products, including vaccines, must be: • Safe: “relatively free from harmful effect when prudently administered” • Pure: “relatively free from extraneous matter” • Potent: “specific ability of product … to effect a given result” • Manufactured consistently according to current Good Manufacturing Practices

6. Vaccine Development Pre IND IND Clinical Studies; Additional Nonclinical and CMC Work; Scale-up Development of Rationale Based on Disease Pathogenesis Immunogen Identification Development of Manufacturing Process; Preclinical Studies IND =Investigational New Drug Application

7. PRE-IND INFORMATION • Manufacturing process • Product characterization • Pre-clinical/non-clinical animal toxicity studies for safety • Data to support the IND clinical studies, e.g., dose selection for initial Phase 1 study • Focus: initiate first Phase 1 clinical study • Pre-IND meeting with FDA strongly recommended

8. IND GENERAL PRINCIPLES “FDA’s primary objectives in reviewing an IND are, in all phase of the investigation, to assure the safety and rights of subjects, … FDA’s review of Phase 1 submissions will focus on assessing the safety of Phase 1 investigations…” [21 CFR, 312.22(a)]

9. IND GENERAL PRINCIPLES “ …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)]

10. Meetings with FDA(21 CFR 312.47) Phase 1 Phase 2 Phase 3 License Application Pre-IND Meeting: Manufacturing Product Characterization Animal safety & immunogenicity Phase 1 protocol End-of-Phase 2 Meeting: Efficacy trial protocol(s) Phase 1/2 data Update: Product, etc. Assay data Rationale Pre-BLA Meeting: Clinical data summary: S & E Update: Product, etc. Outline of BLA IND =Investigational New Drug Application BLA =Biologics License Application

11. Clinical Development: Stages of Review and Regulation • Investigational New Drug Application • Phase 1: safety and immunogenicity • Phase 2: safety, immunogenicity, dose ranging • Phase 3: efficacy, safety, immunogenicity • Biologics License Application • Review of data to support licensure • Pre-approval inspection • Advisory Committee (VRBPAC) • Post-licensure • Post-marketing commitments and other post-licensure studies • VAERS (passive surveillance)

12. Phase 1 Clinical Trials • Initial use of investigational vaccine • Limited # of subjects, e.g., 20 in a trial • Closely monitored • Consider vaccine-specific issues, e.g. for live vaccines, shedding, risk of transmission • Often open label (may depend on experience with similar products) • Population - Inclusion/exclusion criteria • Typically evaluate healthy adults in first trial

13. Phase 2 Clinical Trials • Often randomized & controlled • Include study participants representative of those to be targeted in phase 3 trials • Further characterize safety, vaccine-elicited immune response • Determine dose(s) to be used in phase 3 • Evaluate potential for immune interference with other concurrently administered vaccines

14. Phase 3 Clinical Trials (Efficacy) • Typically double-blinded, randomized, controlled • Background epidemiology essential for sample size calculation • Case definition • Well-defined clinical criteria and validated assays for laboratory diagnosis (culture, serology, etc.) • Clinical relevance

15. Phase 3 Trials (continued) • Prospective primary and secondary endpoints • Monitoring • Case surveillance • Safety • Duration • Immunogenicity and correlates of protection • Data Monitoring Committee • Data analysis plan

16. FDA Guidance to Industry - Providing Clinical Evidence of Effectiveness (1998) • For human drugs and biological products • Two efficacy trials are the “standard” • One trial can be adequate if result compelling, which is often the case for vaccine clinical endpoint efficacy trials • e.g., robust data, multi-center trial

17. Clinical Studies: Safety Evaluation • Definition of safety (FDA, 21 CFR 600.3) • “relative freedom from harmful effect to persons affected directly or indirectly by a product when prudently administered, taking into consideration the character of the product in relation to the condition of the recipient at the time.”

18. Clinical Studies: Safety Evaluation (cont.) • Thus, safety is relative and risk tolerance may be influenced by: • Risk of vaccine-preventable disease vs. risk of adverse event associated with vaccine • these risks may change over time • Alternative treatments (e.g., other vaccines) • e.g., recommendation for use of IPV instead of OPV • Intended population

19. Clinical Studies: Safety Evaluation (cont.) • Size of safety database for routinely administered childhood vaccines • Size of target population (U.S. birth cohort, about 4 million per year) • Predominantly healthy population • Vulnerable population • Vaccination often mandated

20. Clinical Studies: Immunogenicity • Ability to induce an immune response • Humoral • Cell-mediated • Factors that affect immunogenicity • Maternal antibody • Nature and dose of vaccine • Route of administration • Adjuvant • Host factors (age, nutritional status, genetics, coexisting conditions

21. Clinical Studies: Immunogenicity (cont.) • Results typically reported and analyzed • Percent responders • Geometric mean titers • Reverse cumulative distribution curves • Functional antibody assays (e.g., neutralizing, opsonophagocytic) may be needed in addition to binding alone (e.g., ELISA) • Assay validation critical

22. Immune Correlate of Protection • A predictor of vaccine efficacy based on a particular type and quantity of immune response associated with protection from disease or infection • Allows assessment of protection for an immunized individual

23. Immune Correlate of Protection (cont.) • May be identified from a successful efficacy trial • May be suggested from other sources, e.g. post-infection immunity • Useful for interpreting immune response data from “bridging studies” • Identifying an immune correlate of protection is not required for licensure

24. Clinical Studies: Other Considerations • If new vaccine recommended on the same schedule as other routinely recommended vaccines (e.g., infants, travelers) • Obtain safety and immunogenicity data in pre-licensure studies to support simultaneous administration

25. Clinical Studies: Other Considerations(cont.) • Bridging studies • Support manufacturing change • Extrapolate efficacy and safety data to a different population • Support a new dosing schedule • Clinical lot consistency studies • Support physicochemical assessment of manufacturing consistency

26. Review of a BLA and Post-licensure Activities • Multi-disciplinary review (microbiologists, chemists, toxicologists, medical officers, statisticians, etc.) of the product, manufacturing, clinical data • Advice usually sought from FDA’s VRBPAC • Labeling must be supported by the data • Post-licensure commitments may be requested at time of licensure • Post-licensure, monitoring of the products continues through lot release, VAERS, and biennial inspections

27. Usual Timelines for Review • IND: original submission reviewed within 30 days of receipt, study may proceed at 30 days unless placed on clinical hold by FDA • IND amendments: new protocols may proceed immediately, although FDA strongly encourages end-of-phase 2 and pre-BLA meetings; an IND can be placed on hold at any time for safety reasons or for clinical design issues regarding phase 2 or 3 studies • BLA: standard review completed within 10 months, priority review within 6 months

28. Clinical Hold • Regulation: 21 CFR 312.40 • IND goes into effect (study may proceed) 30 days after FDA receives the IND, unless sponsor is notified otherwise by FDA • Clinical Hold: 21 CFR 312.42 • Order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation

29. Clinical Hold (2) • Reasons - Phase 1: • Unreasonable & significant risk • Clinical investigators not qualified • Inadequate investigator’s brochure • Insufficient information to assess risk • Investigational drug is intended to treat a life-threatening disease that affects both genders, and men or women with reproductive potential who have the disease are excluded because of risk or potential risk of reproductive or developmental toxicity

30. Clinical Hold (3) • Reasons - Phase 2/3: • Same Reasons as for Phase 1 • Protocol design inadequate to meet objectives

31. Clinical Hold (4) • Before imposition of clinical hold, FDA will, unless patients exposed to immediate and serious risk, attempt to discuss and resolve deficiencies with the sponsor • Clinical hold order will identify studies to which hold applies and briefly explain basis

32. Clinical Hold (5) • Notification: • By telephone or fax • Clinical Hold Letter: • Within 30 calendar days of hold notification • Additional Comments (Non-Hold) Letter • Review of Complete Hold Response • Letter within 30 days of receipt of response

33. Common Pitfalls • Product issues • Lots to be used in clinical study not identified • Lots release test results to submitted • Adequate information to assure proper identification, quality, purity, and strength not generated or submitted (e.g., inadequate testing for adventitious agents or inadequate information on source materials)

34. Common Pitfalls (2) • Nonclinical data • Experimental details lacking, e.g., information on lot, dose, route, and assays • Data lacking to support dose proposed for clinical trial

35. Common Pitfalls (3) • Clinical protocol issues • Lack of detail on how subjects will be monitored (e.g., diary card, case report forms, follow-up plans, etc.) • Stopping rules not addressed • Eligibility criteria not clearly delineated • Protocol deficient in design to meet its objectives

36. Vaccine Development: Conclusions • Vaccines have unique considerations for product & clinical development • Overall planning and coordination: • Product characterization & manufacturing (cGMP) • Anticipate needs of future trials, e.g., critical assays • Accumulate sufficient safety, immunogenicity & efficacy data during development • Clinical bridging studies, e.g., population; product scale-up • Prospective application of Good Clinical Practices • Utilize available FDA documents/resources

37. US Code of Federal Regulations • 21 CFR 50 - Protection of Human Subjects • 21 CFR 56 - Institutional Review Boards • 21 CFR 58 - Good Laboratory Practices • 21 CFR 210, 211 - Good Manufacturing Practices • 21 CFR 312 - Investigational New Drug Applications (INDs) • 21 CFR 314.126 - Adequate and Well-Controlled Trials • 21 CFR 610 - General Biological Product Standards

38. Available Resources • FDA documents /Federal Register (FR) notices /FDA regulations • http://www.fda.gov/cber/publications.htm • 1-800-835-4709 or 301-827-1800 • International Conference on Harmonisation (ICH) Documents (U.S., E.U. and Japan) • WHO. Guidelines on Clinical Evaluation of Vaccines. 2001. • Baylor N, Midthun K: Regulation & Testing of Vaccines. Vaccines 4th ed, 2004, WB Saunders

39. CONTACT INFORMATION • Questions: • OCTMA@cber.fda.gov (Consumer questions) • MATT@cber.fda.gov (Manufacturers Assistance) • Division of Vaccines and Related Products Applications: 301 827 3070 • My contact info: midthun@cber.fda.gov