Presentation on theme: "Regulation of Vaccines: Challenges and Opportunities"— Presentation transcript:
1 Regulation of Vaccines: Challenges and Opportunities Erik A. Henchal, Ph.D. Associate DirectorOffice of Vaccines Research and Review CBER/FDA
2 U.S. VaccinesRegulated 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.
3 CBER’s Approach Regulation Goal: Balanced, Flexible, Responsive Assure the safety and rights of subjectsProtect the public healthFacilitate technological innovation & product developmentInfluencesAvailable scientific knowledge, pre-clinical, clinical knowledge & experienceScientific researchCrises/ tragic eventsAppropriate Risk Management
4 OVRR Supports the Critical Path Towards Safe and Effective Vaccines Speed development of new technologies and facilitiesImproved manufacturing methodsImproved evaluation tools and reference standardsStreamlined pre-clinical and clinical evaluationsImproved international cooperationEffective vaccine review and releaseImproved safety
5 Stages of Vaccine Review and Regulation Clinical Investigational Plan Phase 4InspectionSafetyEfficacyLot ReleaseClinical Investigational PlanBLAData to support approval;InspectionINDPhase 1SafetyImmuno-genicityPhase 2Immuno-genicitySafetyDose RangingPhase 3EfficacySafetyImmuno-genicityBLA SupplementPost-approvalChanges:New IndicationsDosingManufactureEquipment/FacilitiesIND = Investigational New Drug Application;BLA = Biologics License Application
6 PDUFA MeetingsType 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
7 Vaccine LicensureVaccine 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.
8 Facilitating the Development and Evaluation of New Vaccines Anticipating and Addressing the Regulatory Issues for New ProductsGeneral regulatory issues applicable to many products or product classesCell substrate issuesImproved test methods (sensitivity, reliability, etc.)Improved standardsProduct specific issuesCorrelates of protection necessary for efficacy evaluationImproved assays (e.g., potency, efficacy)Animal models for efficacy evaluation
9 DEVELOPMENT ACTIVITIES CMC DevelopmentSAFETY INFORMATIONSource characterizationComponents info.Product CharacterizationTesting/Qualification/ Clearance of impurities, contaminantsProcess control esp. for safety processes (e.g., sterilization, virus clearance)DEVELOPMENT ACTIVITIESProduct CharacterizationFormulation DevelopmentComponent Characterization/QualificationAssay Development/ ValidationSpecification DevelopmentStability StudiesManufacturing ProcessControl & ValidationIncremental CMCBLAPhase 3DiscoveryPhase 2Phase 1Pre-clinical
10 CMC Content Source Material Cells, Viruses, Banking SystemsOrigin/ Method of collectionHistory (potential exposure)Manipulation, establishment of banks, cryopreservationTesting – Source/ source material(e.g., Microbiology, endogenous/ adventitious agents, (bovine/ porcine), identity, purity, activity, replication competent viruses)Genetic materialOriginGene modification, construction of vector, purificationTesting (e.g., sequencing)
11 CMC Content - Source Material EvaluationRisk assessment of parent cells - history, potential exposure to viral agentsScreening donors for risk factors, absence of disease markersTesting for virusesEndogenous virus testingDonors, animals, host cells, cell banks, EPCGeneral and Species specific testsFDA-approved tests if availableControlEstablishing & maintaining cell banks, viral seeds under cGMP’sClosed herds & flocks, sentinel animalsQuarantine until testing and control assures/ establishes safety
12 CMC Contents - Components All components (e.g., raw materials, excipients, reagents, ancillary products) used in productionSafety and quality of materialSource, screening, testingUse in process, (evaluated in context of use)Known/ potential toxicitiesPenicillin, MTX, residual chemicalsWhat is the amount in final product? Consider testing, qualification studyFDA-approved products (e.g., albumin) preferredClinical-grade preferredCombination products (biologic, drug, device)Develop qualification program during development
13 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 productsGood 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
15 cGMPsRecommend that cGMPs be in effect for manufacture of products used in clinical IND studies - starting with Phase 1 studiesFollow general approaches and principles that are broadly applicable, tailor cGMP application to product, process and facilityAssess risks and take appropriate actions
16 Process Validation – Considerations Reasons for ValidationQuality cannot be inspected or tested into the finished productQuality safety and effectiveness must be designed and built into the productEach step must be controlled to maximize the probability that the finished product meets all specifications“QualityBy Design”raw material propertiesFacilitate process/ product understanding & process improvement - post-approval changesImplementation/ enhancement of modern quality system for FDA & ManufacturersAdd desired stateWhile 1987 guideline provides useful information, additional considerations need further elaborationPAT started before CGMP same true for PV thinkingControl of variability from multiple sourcesraw/ materials componentsmanufacturing process operationsprocessconditionsenvironmentalDesign Space
17 Process Validation – Considerations Foundation for validationProcess and product understanding “knowledge”Well defined and designed product and manufacturing process to consistently deliver high quality productAccurate measure and control of variabilityConsider all sources of variabilityProduct lifecycle impactSupported by documentation, data
18 Expediting the Review Process: Formal Mechanisms BLA Standard Review: 10 month reviewClinical Efficacy Supplement10 month reviewCMC Supplement4 month reviewPriority Review6 monthsFast TrackAccelerated Approval
19 Fast Track Incorporates an end of Phase I meeting Allows for more frequent communications with the FDAMay allow for a “rolling” review of the BLAMay allow for an accelerated approval of the productDesigned 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.
20 Accelerated ApprovalSurrogate endpoints likely to predict clinical benefit ( , ).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.
21 ChallengesEpidemiology may preclude “field trials”, the usual source of efficacy dataMay not be able to conduct human challenge or protection studies for ethical or cultural considerations
22 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.
23 Examples of Potential Agents for “Animal Rule” Applications SmallpoxAnthraxBotulismPlagueTularemiaViral hemorrhagic feversAlphavirusesSARS
24 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.
25 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; andThe product may be effective.Granted for up to 1 year, or until termination of declaration or revocation; can be renewed.
26 CBER Available Information InternetFax Information SystemIn US toll-free: CBER-FAX ( )Outside US:Manufacturers assistance:CBER Voice Information System at:or
27 SummaryThe 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.