# Presentation: 307886

## Clinical Review Process:  An FDA Perspective

-      **Karen Midthun, M.D.**
**Deputy Director of Medicine**
**Center for Biologics Evaluation and Research**
**FDA**
**April 15, 2005**

## Biological Products Regulated by CBER

**Blood, blood components and derivatives**
**Vaccines (preventive and therapeutic)**
**Allergenics**
**Cell and Gene Therapies**
**Tissues**
**Xenotransplantation**
**Related Devices**

## 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**

## Types 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)**

## 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

## Vaccine Development

**Pre IND**

**Development**
**of Rationale**
**Based on Disease**
**Pathogenesis**

**Immunogen**
**Identification**

**Development of Manufacturing Process;**
**Preclinical Studies**

**IND**

**Clinical**
**Studies;**
**Additional **
**Nonclinical and CMC Work;**
**Scale-up**

**IND =Investigational New Drug Application**

## PRE-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**

## IND 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)]**

## IND 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)]**

## Meetings with FDA (21 CFR 312.47)

**Phase 1**

**Phase 2**

**Phase 3**

**License **
**Application**

**Pre-IND**
**Meeting:**
**Manufacturing**
**Product **
**Characterization**
**Animal safety &**
**immunogenicity**
**Phase 1 protocol**

**End-of-Phase 2**
**Meeting:**
**Efficacy trial **
**   ****protocol(s)**
**Phase 1/2 data**
**Update: **
**   ****Product, etc.**
**Assay data**
**Rationale**

**Pre-BLA**
**Meeting:**
**Clinical data**
**summary: **
**   ****S & E**
**Update: **
**   ****Product, etc.**
**Outline of BLA**

**IND =Investigational New Drug Application**
**BLA =Biologics License Application**

## 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)**

## Phase 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**

## Phase 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

## 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

## Phase 3 Trials (continued)

**Prospective primary and secondary endpoints**
**Monitoring**
**Case surveillance**
**Safety**
**Duration**
**Immunogenicity and correlates of protection**
**Data Monitoring Committee**
**Data analysis plan**

## 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

## 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.”**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## Usual 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**

## Clinical Hold

**Regulation: 21 CFR 312.40**
**IND goes into effect (study may proceed) 30 days after FDA receives the IND, unless sponsor is notified otherwise by FDA**
**Clinical Hold: 21 CFR 312.42**
**Order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation**

## Clinical 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 **

## Clinical Hold (3)

**Reasons - Phase 2/3:**
**Same Reasons as for Phase 1**
**Protocol design inadequate to meet objectives**

## Clinical 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**

## Clinical 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**

## Common 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)**

## Common 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**

## Common 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**** **

## 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**

## 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**

## Available 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**

## CONTACT INFORMATION

- Questions:
- _[OCTMA@cber.fda.gov](mailto:OCTMA@cber.fda.gov)_ (Consumer questions)
- _[MATT@cber.fda.gov](mailto:MATT@cber.fda.gov)_ (Manufacturers Assistance)
- Division of Vaccines and Related Products Applications:  301 827 3070
- My contact info:  midthun@cber.fda.gov