clinical review process: an fda perspective karen midthun, m.d. deputy director of medicine center...
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Clinical Review Process: An FDA Perspective
Karen Midthun, M.D.
Deputy Director of MedicineCenter for Biologics Evaluation and
ResearchFDA
April 15, 2005
CC BBEE RR
Biological Products Regulated by CBER
Blood, blood components and derivatives
Vaccines (preventive and therapeutic) Allergenics Cell and Gene Therapies Tissues Xenotransplantation Related Devices
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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
CC BBEE RRTypes 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)
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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
CC BBEE RRVaccine
DevelopmentPre IND
Developmentof RationaleBased on DiseasePathogenesis
ImmunogenIdentification
Development of Manufacturing Process;Preclinical Studies
IND
ClinicalStudies;Additional Nonclinical and CMC Work;Scale-up
IND =Investigational New Drug Application
CC BBEE RRPRE-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
CC BBEE RRIND 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)]
CC BBEE RRIND 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)]
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Meetings with FDA (21 CFR 312.47)
Phase 1
Phase 2
Phase 3
License Application
Pre-INDMeeting:ManufacturingProduct CharacterizationAnimal safety &immunogenicityPhase 1 protocol
End-of-Phase 2Meeting:Efficacy trial protocol(s)Phase 1/2 dataUpdate: Product, etc.Assay dataRationale
Pre-BLAMeeting:Clinical datasummary: S & EUpdate: Product, etc.Outline of BLA
IND =Investigational New Drug ApplicationBLA =Biologics License Application
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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)
CC BBEE RRPhase 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
CC BBEE RRPhase 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
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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
CC BBEE RRPhase 3 Trials (continued)
Prospective primary and secondary endpoints
Monitoring– Case surveillance– Safety– Duration– Immunogenicity and correlates of
protection– Data Monitoring Committee
Data analysis plan
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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
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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.”
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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
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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
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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
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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
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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
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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
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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
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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
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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
CC BBEE RRUsual 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
CC BBEE RRClinical Hold
Regulation: 21 CFR 312.40IND goes into effect (study may
proceed) 30 days after FDA receives the IND, unless sponsor is notified otherwise by FDA
Clinical Hold: 21 CFR 312.42Order issued by FDA to the sponsor to
delay a proposed clinical investigation or to suspend an ongoing investigation
CC BBEE RRClinical 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
CC BBEE RRClinical Hold (3)
Reasons - Phase 2/3:
•Same Reasons as for Phase 1
•Protocol design inadequate to meet objectives
CC BBEE RRClinical 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
CC BBEE RRClinical 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
CC BBEE RRCommon 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)
CC BBEE RRCommon 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
CC BBEE RRCommon 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
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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
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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
CC BBEE RRAvailable 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
CC BBEE RRCONTACT INFORMATION
Questions:– [email protected] (Consumer
questions)– [email protected] (Manufacturers
Assistance)– Division of Vaccines and Related Products
Applications: 301 827 3070– My contact info: [email protected]