Vaccine Review by CBER FDA Seminar, Denmark, April 23-24, 2013 Theresa Finn, PhD

1. Vaccine Review by CBER • FDA Seminar, Denmark, April 23-24, 2013 • Theresa Finn, PhD • Associate Director for Regulatory Policy • Office of Vaccines Research and Review (OVRR) • Center for Biologics Evaluation and Research (CBER) • Food and Drug Administration (FDA)

2. Overview • FDA, CBER and OVRR organization and overview • Vaccine Review • Legal framework • Vaccine development overview • Pre-licensure regulatory activities • Investigational New Drug Application (IND) • Clinical data development • CMC data development • Biologics License Application (BLA) • Post-licensure • Summary

3. Scope • Preventive vaccines for infectious disease indications • Pre-licensure activities and considerations are presented in very broad terms – clinical and manufacturing data needed will depend on the specific product, and proposed indication and use • Post-licensure activities are not addressed (1 slide)

4. FDA, CBER and OVRR Organization and Overview 4

5. FDA Organization Office of the Chief Scientist Office of the Commissioner Office of Medical Products and Tobacco Office of Global Regulatory Operations and Policy Office of Foods and Veterinary Medicine Office of Operations Center for Food Safety and Applied Nutrition CFSAN Center for Veterinary Medicine CVM Office of Regulatory Affairs ORA Center for Biologics Evaluation and Research CBER Center for Drug Evaluation and Research CDER Center for Tobacco Products CTP Center for Devices and Radiological Health CDRH National Center for Toxicological Research NCTR

6. CBER Organization

7. Office of Vaccines Research & Review (OVRR) • Locations: • Woodmont Office Complex • NIH Main Campus, Bldgs N29, N29A, N29B

8. OVRR Mission • To protect and enhance the public health by ensuring the availability of safe and effective vaccines, allergenic extracts, and related products.

9. Core Activities to Accomplish OVRR’s Mission • Review investigational new drug applications (INDs) for vaccines and related biological products to assess their safety and effectiveness • Review biologics license applications (BLAs) and supplements for vaccines and related biological products to determine their safety and effectiveness, and take regulatory action regarding approval • Develop and assist in the development of regulation, guidance, policies and procedures relevant to the evaluation of vaccines and related biological products • Plan and conduct research related to the development, manufacture, and evaluation of safe and effective vaccines and related products

10. Vaccine Review Legal Framework

11. Statutes Federal Food Drug & Cosmetic Act (FFD & C) Public Health Service Act (PHS) Amendments (e.g. FDAAA 2007, FDASIA 2012) Regulations Code of Federal Regulations (CFR) Legal Framework 11 11 11

12. US Code of Federal Regulations (CFR) FDA implements statutes through regulations Title 21 – Food and Drugs • 21 CFR 600-680 Biological Product Standards • 21 CFR 314.126 Adequate and well-controlled trials • 21 CFR 312 Investigational New Drug Application • 21 CFR 210-211 Good Manufacturing Practices • 21 CFR 58 Good Laboratory Practices • 21 CFR 56 Institutional Review Boards • 21 CFR 50 Protection of Human Subjects

13. Vaccine Development Overview

14. Unique Considerations for Preventive Vaccines • Target population: millions of healthy people, including young infants and children, each year • State governments mandate many vaccines for children attending public schools or day care centers • Individual risk for disease prevented by vaccination may be low (e.g., diphtheria, polio) …thus, low tolerance for vaccine-associated risks • FDA requires new vaccines to be studied in the context of concomitant use with other recommended vaccines that are given on the same, or overlapping, schedule

15. U.S.-licensed Preventive Vaccines – diverse, complex products • Toxoids • Inactivated viruses • Live viruses • Live bacteria • Polysaccharides • Polysaccharide conjugates • Purified proteins • Recombinant proteins • (Inactivated bacteria)

16. Development of New Vaccines Pre-clinical data: supportive of initiating clinical studies Clinical data: well designed and executed clinical studies to demonstrate safety and effectiveness CMC data: develop and refine manufacturing process to ensure quality product and consistency of manufacture Facility data: compliance w/cGMPs, manufacturing controls, QA/QC Goal: A safe, effective, high quality product of known stability that can be manufactured consistently 16 16

17. Key Events in Vaccine Development Pre-IND Develop rationale Identify Immunogen Develop manufacturing process Non-clinical studies IND Licensing BLA Phase 1 Phase 2 Phase 3 General investigational plan Postmarketing Phase 4 IND: Investigational New Drug Application BLA: Biologics License Application 17 17

18. Pre-licensure regulatory activities

19. Investigational New Drug Application (IND)

20. What is an IND? • Investigational New Drug Application • 21 CFR 312 • If an IND is “in effect” for an investigational new drug, it.. • Exempts an investigational new drug from premarketing approval requirements • Allows an investigational new drug to be lawfully shipped across state lines for the purpose of conducting a clinical study1 of that investigational new drug 1IND not needed to conduct non-clinical studies

21. IND Content 21 CFR 312 IND application must contain: General investigational Plan Manufacturing and product information Non-clinical pharmacology and toxicology data Summary of previous human experience Clinical protocols and investigator information 21 21

22. Primary Objectives of IND Review 21 CFR 312.22(a) • In all phases of the investigation, to assure the safety and rights of subjects • In Phase 2 and 3, to help assure that the quality of the scientific evaluation is adequate to permit an evaluation of effectiveness and safety

23. Investigational New Drug Application (IND) Clinical Data Development

24. IND: Clinical Development • Goal: To develop human safety and effectiveness data adequate to support the proposed indication and use • E.g. The prevention of disease X in persons y-z years of age

25. Phases of Vaccine Development under IND Phase 1 Phase 2 Phase 3 Preclinical • Safety • Immunogenicity • Several hundred • subjects • Safety study • Immunogenicity • Dose Ranging • 20-80 subjects • Immunogenicity • Safety • Effectiveness • Several thousand • subjects Earlier Stages Later Stages

26. Phase 1 Clinical Trials of Preventive Vaccines • Preliminary evaluation of safety and immunogenicity • Design depends on pre-clinical data, experience with similar products • Often open label • Randomized, controlled in some cases • Dose escalation, in some cases • Population • Small number of subjects (e.g., 20-80) • Adults usually studied before children • Inclusion/exclusion criteria to minimize risk • Active safety monitoring (e.g., clinic visits, diary cards, case report forms), short- and long-term • (also for phase 2 and 3) • Conservative stopping rules for safety

27. Phase 2 Clinical Trials of Preventive Vaccines • Evaluation of safety (common local and systemic reactions) and immunogenicity • Dose ranging (some studies) • Up to several hundred subjects per trial • Usually randomized and controlled • Entry criteria less restrictive, reflect target population

28. Phase 2 and 3 Clinical Trialsof Preventive Vaccines • New vaccines are evaluated in the context of the current recommended immunization schedule • Safety of concomitant immunization • Efficacy/immunogenicity of investigational vaccine administered concomitantly with other recommended vaccines • Interference in responses to other vaccines when administered with investigational vaccine (some studies)

29. Phase 3 Clinical Trialsof Preventive Vaccines • Confirm clinical benefit (efficacy/immunogenicity) • Expand knowledge of safety (including serious and less common adverse events) • Randomized, controlled • Often thousands or tens of thousands • Clinical endpoint efficacy trials usually provide a large safety database • When numbers of subjects included in efficacy trials or immunogenicity trials are insufficient to provide adequate safety data, additional controlled safety trials required • Detailed surveillance and monitoring plans (safety and efficacy/immunogenicity)

30. IND Clinical Hold • Clinical Hold: FDA may impose an order to delay a proposed clinical investigation (or halt an ongoing investigation) based on specified regulatory criteria, including unreasonable and significant risk to human subjects

31. Clinical Development: Use in Special Populations Pediatric use: Pediatric Research Equity Act (PREA) 2007 Assessments of safety and effectiveness for use in children 0-<17 years of age are required Waivers/partial waivers and deferrals Initial Pediatric Study Plan w/in 60 days of the EOP2 meeting (FDASIA 2012) Concomitant immunization studies Pregnancy (women of child bearing potential): Reproductive toxicity studies Geriatric Use (> 65 years of age) 31 31

32. Investigational New Drug Development Chemistry, Manufacturing and Controls Data Development 32

33. IND: CMC Development • Goal: Chemistry, manufacturing and controls data and testing plans adequate to support the manufacturing process, and assure stability and consistency of manufacture in an appropriate facility • The more complex the product the more complex the production, characterization and testing

34. Vaccine Manufacturing Development • Process Development • Product Characterization • Assay Development • Formulation Development • Cell Banks • Process Optimization • In - process controls • DS/DP Characterization • Formulation Optimization BLA Supplement: • Manufacturing Changes • Formulation Changes R&D Pre-clin Phase I Phase 2 Phase 3 BLA Phase 4 • Pre-clinical Safety • Immunogenicity Assay Development • Proof of concept • Process Validation • Assay Validation • Final Product Specification • Final Formulation • Stability CMC Appropriate to Development Stage 34 34 34

35. Clinical Trials of Preventive Vaccines: IND CMC Information • General Principles (21 CFR 312): IND should: • … describe the composition, manufacture and control of the drug substance and the drug product. • …include sufficient information to assure proper identification, quality, purity and strength of the investigation drug • …the amount of information will vary with the phase of the investigation, the proposed duration of the investigation, the dosage form, and the amount of information otherwise available

36. IND CMC Information • Phase 1: Emphasis on the identification and control of raw materials and the new drug substance • All phases: Stability data to demonstrate that the new drug substance and drug product are within acceptable chemical and physical limits for the planned duration of the proposed clinical studies

37. IND CMC Information cont’d • Drug Substance (DS) and Drug Product (DP): • Description (physical, biological, chemical characteristics) • Method of preparation • Acceptable limits and analytical methods to assure assure proper identification, quality, purity and strength • Stability data

38. IND CMC Information cont’d Manufacturing Process & Process Controls Description of the manufacturing process - Drug Substance (DS) & Drug Product (DP) Complete description covering source material, expression methods, production, etc. Description of differences in manufacturing for DS & DP in preclinical studies vs. clinical studies Adequate description of process controls for process steps, especially those that directly affect safety Data demonstrating that safety–related processes are effective when operated within manufacturing controls 38 38

39. CMC Considerations Scale-up from research to manufacturing scale Adequate data to support that the “scale-up” product is the same as the “research/pilot” product Develop data to support process, controls and critical parameters Assay development and validation Manufacturing changes during development Adequate data to support the “new” product is the same as the “old” product Assay development and validation Specifications- based on manufacturing experience 39 39

40. CMC Considerations cont’d Consistency of manufacture: Before licensure manufacturer is expected to demonstrate ability to make three consecutive lots that: Meet all lot release test specifications at the time of manufacture Meet equivalence criteria in human clinical testing (Lot -Consistency Study: immunogenicity) These lots often critical for development of specifications for critical parameters and lot release criteria Lot release Testing A panel of routine tests that assure consistency of manufacture and detect suboptimal lots Potency tests, identity, sterility, GST etc. Specifications may be refined based on additional manufacturing experience (pre- and post licensure) Stability data Container-closure system Real time stability data to support requested expiry 40 40

41. Biologics Licensure Application

42. Biologics Licensure • Section 351 of the Public Health Service Act, 42 USC 262: The Secretary shall approve a biologics license application(BLA) - on the basis of a demonstration that – • the biological product … is safe, pure, and potent; and • the facility … meets standards designed to assure that the biological product continues to be safe, pure, and potent; …. • Only those vaccines that are demonstrated to be safe and effective, and that can be manufactured in a consistent mannerwill be licensed by the FDA

43. Biologic License Application (BLA) Review Are the clinical data adequate to support the requested indication and use? Are the CMC data adequate to support the manufacturing process and ensure consistency of manufacture? Does the facility in which the vaccine is manufactured, processed, packed, or held meet standards designed to assure that the biological product continues to be safe, pure, and potent? Is the labeling adequate? 43 43

44. BLA Review • Multidisciplinary FDA review committee • medical, product, assay, manufacturing facility, statistical, epidemiology, toxicology, labeling, other consultants as needed • FDA advisory committee review • provide advice regarding adequacy of safety and effectiveness data • FDA decision • benefit-to-risk ratio considered • (after licensure CDC ACIP makes recommendations for use of vaccines)

45. Clinical Post-Marketing Requirements (PMR) • PREA PMR: required study to establish effectiveness and safety in pediatric population(s) • Safety PMR: Required at the time of approval or when post-approval when new safety information becomes available: • To assess a known serious risk related to use • To assess signals of serious risk related to use, or • To identify an unexpected serious risk when available data indicates a potential for a serious risk

46. Other Clinical PMRs • Accelerated Approval PMR: required study to verify and describe the clinical benefit if a product is approved using the Accelerated Approval pathway (21 CFR 601 Subpart E) • Animal Rule PMR: required study to verify verify benefit and evaluate safety when such studies become ethical/feasible if the product is approved using the “Animal Rule” pathway (21 CFR 601 Subpart H)

47. Clinical Postmarketing Commitments • Studies conducted by manufacturer to further evaluate safety (e.g., rare adverse events) or effectiveness (e.g. duration of vaccine-induced immunity)

48. PMRs and PMCs • Agreed upon by FDA and manufacturer • Documented in a letter • Progress of studies monitored by FDA

49. Post-licensure

50. Post-Licensure Activities • Pharmacovigilence (Safety surveillance) • Vaccine Adverse Event Reporting System • Manufacturing Supplements • E.g. changes to product, process, quality controls, equipment, facilities, responsible personnel, • Clinical Supplements • E.g. inclusion of concomitant immunization data, new age groups, indications • Labeling Supplements • E.g. add a warning, precaution or adverse reaction