Regulation of Vaccines: Challenges and Opportunities Erik A. Henchal, Ph.D. Associate Director Office of Vaccines Research and Review CBER/FDA

U.S. Vaccines Regulated by FDA Center for Biologics Evaluation and Research (CBER) Office of Vaccines Research and Review (OVRR) Authority resides in Section 351 of the U.S. Public Health Service Act and the Federal Food, Drug and Cosmetic Act. Thorough review of laboratory and clinical data to ensure the safety, efficacy, purity and potency of these products.

CBER’s Approach Regulation Goal: Balanced, Flexible, Responsive Assure the safety and rights of subjects Protect the public health Facilitate technological innovation & product development Influences Available scientific knowledge, pre-clinical, clinical knowledge & experience Scientific research Crises/ tragic events Appropriate Risk Management

OVRR Supports the Critical Path Towards Safe and Effective Vaccines Speed development of new technologies and facilities Improved manufacturing methods Improved evaluation tools and reference standards Streamlined pre-clinical and clinical evaluations Improved international cooperation Effective vaccine review and release Improved safety

Stages of Vaccine Review and Regulation Clinical Investigational Plan Phase 4 Inspection Safety Efficacy Lot Release Clinical Investigational Plan BLA Data to support approval; Inspection IND Phase 1 Safety Immuno- genicity Phase 2 Immuno-genicity Safety Dose Ranging Phase 3 Efficacy Safety Immuno-genicity BLA Supplement Post-approval Changes: New Indications Dosing Manufacture Equipment/ Facilities IND = Investigational New Drug Application; BLA = Biologics License Application

PDUFA Meetings Type A: Immediately necessary for an otherwise stalled drug development program (i.e. critical path meeting). Scheduled within 30 days of written request. Type B: pre-IND; certain end of phase I; end of phase 2 and pre-BLA meetings. Scheduled within 60 days of written request. Type C: Any other meeting. Scheduled within 75 days of written request. See Guidance for Industry: Formal Meetings With Sponsors and Applicants for PDUFA Products http://www.fda.gov

Vaccine Licensure Vaccine development and commercialization are complex processes. Licensure based upon demonstration of safety and effectiveness, and ability to manufacture in a consistent manner. The FDA is committed to fostering the efficient, and rapid development of vaccines needed for the public health.

Facilitating the Development and Evaluation of New Vaccines Anticipating and Addressing the Regulatory Issues for New Products General regulatory issues applicable to many products or product classes Cell substrate issues Improved test methods (sensitivity, reliability, etc.) Improved standards Product specific issues Correlates of protection necessary for efficacy evaluation Improved assays (e.g., potency, efficacy) Animal models for efficacy evaluation

DEVELOPMENT ACTIVITIES CMC Development SAFETY INFORMATION Source characterization Components info. Product Characterization Testing/Qualification/ Clearance of impurities, contaminants Process control esp. for safety processes (e.g., sterilization, virus clearance) DEVELOPMENT ACTIVITIES Product Characterization Formulation Development Component Characterization/ Qualification Assay Development/ Validation Specification Development Stability Studies Manufacturing Process Control & Validation Incremental CMC BLA Phase 3 Discovery Phase 2 Phase 1 Pre-clinical

CMC Content Source Material Cells, Viruses, Banking Systems Origin/ Method of collection History (potential exposure) Manipulation, establishment of banks, cryopreservation Testing – Source/ source material (e.g., Microbiology, endogenous/ adventitious agents, (bovine/ porcine), identity, purity, activity, replication competent viruses) Genetic material Origin Gene modification, construction of vector, purification Testing (e.g., sequencing)

CMC Content - Source Material Evaluation Risk assessment of parent cells - history, potential exposure to viral agents Screening donors for risk factors, absence of disease markers Testing for viruses Endogenous virus testing Donors, animals, host cells, cell banks, EPC General and Species specific tests FDA-approved tests if available Control Establishing & maintaining cell banks, viral seeds under cGMP’s Closed herds & flocks, sentinel animals Quarantine until testing and control assures/ establishes safety

CMC Contents - Components All components (e.g., raw materials, excipients, reagents, ancillary products) used in production Safety and quality of material Source, screening, testing Use in process, (evaluated in context of use) Known/ potential toxicities Penicillin, MTX, residual chemicals What is the amount in final product? Consider testing, qualification study FDA-approved products (e.g., albumin) preferred Clinical-grade preferred Combination products (biologic, drug, device) Develop qualification program during development

What are cGMPs? Current Good Manufacturing Practices (cGMP) cover a broad range of principles, methods, and practices that are implemented during product development and documented to ensure consistent manufacture of quality products Good Laboratory Practices (GLPs) support the conduct of nonclinical laboratory studies; purpose is to ensure the quality and integrity of the safety data; support IND and BLA’s

cGMPs CMC Review Inspection Submitted On-site Companion Personnel Source Material Components Manufacturing Process Process Controls Analytical Procedures Specifications Stability Personnel Quality Control Facilities Equipment Laboratory Control Component Control Production Control Distribution Records Labeling

cGMPs Recommend that cGMPs be in effect for manufacture of products used in clinical IND studies - starting with Phase 1 studies Follow general approaches and principles that are broadly applicable, tailor cGMP application to product, process and facility Assess risks and take appropriate actions

Process Validation – Considerations Reasons for Validation Quality cannot be inspected or tested into the finished product Quality safety and effectiveness must be designed and built into the product Each step must be controlled to maximize the probability that the finished product meets all specifications “Quality By Design” raw material properties Facilitate process/ product understanding & process improvement - post-approval changes Implementation/ enhancement of modern quality system for FDA & Manufacturers Add desired state While 1987 guideline provides useful information, additional considerations need further elaboration PAT started before CGMP same true for PV thinking Control of variability from multiple sources raw/ materials components manufacturing process operations process conditions environmental Design Space

Process Validation – Considerations Foundation for validation Process and product understanding “knowledge” Well defined and designed product and manufacturing process to consistently deliver high quality product Accurate measure and control of variability Consider all sources of variability Product lifecycle impact Supported by documentation, data

Expediting the Review Process: Formal Mechanisms BLA Standard Review: 10 month review Clinical Efficacy Supplement 10 month review CMC Supplement 4 month review Priority Review 6 months Fast Track Accelerated Approval http://www.fda.gov/cber/guidelines.htm

Fast Track Incorporates an end of Phase I meeting Allows for more frequent communications with the FDA May allow for a “rolling” review of the BLA May allow for an accelerated approval of the product Designed to facilitate the development and expedite the review of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.

Accelerated Approval Surrogate endpoints likely to predict clinical benefit (314.510, 601.40). Post-licensure studies required (usually ongoing) to demonstrate effects on clinical outcomes. Restrictions on use or distribution possible. Potential problems obtaining controlled data. Withdrawal if agreements violated/not safe & effective. Can approve through regular mechanisms with validated surrogate.

Challenges Epidemiology may preclude “field trials”, the usual source of efficacy data May not be able to conduct human challenge or protection studies for ethical or cultural considerations

Animal Rule 21 CFR 314.600 FDA may approve a product for which … Human safety has been established, and “Animal Rule” requirements are met – based on adequate and well-controlled animal studies, the results of which establish that the product is reasonably likely to provide clinical benefit in humans. Not an approach that will necessarily expedite approval.

Examples of Potential Agents for “Animal Rule” Applications Smallpox Anthrax Botulism Plague Tularemia Viral hemorrhagic fevers Alphaviruses SARS

Animal Rule Considerations Well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the product. The effect is demonstrated in more than one animal species (unless there is already a sufficiently characterized model) expected have a response predictive for humans. The animal study endpoint is clearly related to the desired benefit in humans: enhancement of survival or prevention of major morbidity. Kinetics and pharmacodynamics of the product or other relevant data or information in animals and humans allows selection of an effective dose in humans.

Emergency Use Authorization (EUA) Secretary of HHS can declare an emergency after Secretary of Defense, Homeland Security, or HHS determines an emergency (or potential for) exists. Secretary of HHS can authorize use of an unapproved product or unapproved use of an approved product if: Agent can cause serious or life-threatening disease or condition; No adequate and sufficiently available approved alternative; Product’s known and potential benefits must outweigh known and potential risks; and The product may be effective. Granted for up to 1 year, or until termination of declaration or revocation; can be renewed.

CBER Available Information Internet www.fda.gov/cber Fax Information System In US toll-free: 1-888-CBER-FAX (1-888-223-7329) Outside US: 301-827-3844 Manufacturers assistance: MATT@CBER.FDA.GOV CBER Voice Information System at: 1-800-835-4709 or 301-827-1800

Summary The U.S. FDA is facilitating the development, production and regulatory review of vaccines. Many opportunities exist to seek FDA review of developmental plans. Risk management throughout the vaccine development life cycle is critical. Flexible regulatory approaches are available, especially for serious or life threatening conditions or unmet medical needs.