Clinical Review Process: An FDA Perspective

Karen Midthun, M.D.

Deputy Director of MedicineCenter for Biologics Evaluation and

ResearchFDA

April 15, 2005

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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:– 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