# Presentation: 354162

## Pandemic Influenza Vaccines:FDA Preparedness Activities

**Sara Gagneten, Ph.D.****CBER/FDA**
**April 20, 2005**

## Acknowledgement

**Many individuals at CBER/FDA have made contributions to pandemic preparedness and have contributed to this slide presentation**
**Roland Levandowski, M.D., Antonia Geber, M.D., and Karen Goldenthal, M.D.**

## Objectives

**Overview of FDA approval process**
**Licensing of influenza vaccines**
**Pathways for licensing of pandemic vaccines ******** ****CBER activities**
**Preparedness: reagents, surveillance, guidance ******** ****CBER activities**
**Conclusions**

## Stages of Review and Regulation

**Clinical Investigational Plan**

**Phase 1**
**Safety**
**Immuno-genicity**

**Phase 2**
**Safety**
**Immuno-genicity**
**Dose Ranging**

**Phase 3**
**Safety**
**Efficacy**
**Immuno-genicity**

**BLA**** **
**Data to support approval;**
**Inspection**

**Phase 4**
**Inspection**
**Safety**
**Efficacy**
**Lot Release**

**BLA **
**Supplement**
**Post-approval**
**Changes:**
**New Indications**
**Dosing**
**Manufacture**
**Equip./Facilities**

-                   **IND**** **

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

## Inactivated Influenza Virus Vaccines

**Vaccines are trivalent. Strains (influenza A/H1N1, influenza A H3N2, influenza B) are selected to match circulating viruses**
**Contain at least 15 ****μg/dose of each HA (standardized by SRID)**
**Vaccine efficacy **
**	****- Potency of vaccine **
**	****- Match of vaccine HAs with circulating **
**	****  ****viruses**

## Routine Licensing Actions for Inactivated Influenza Vaccines

**Each year, any of the three vaccine strains from the previous year’s vaccine may be replaced with a new strain**
**Strain changes are based on evaluation of circulating wild-type influenza strains and recommendations of WHO, CDC and VRBPAC**
**A BLA supplement to an existing license is submitted for strain changes, and does not require clinical data for FDA approval**

## Range of Regulation of Pandemic Vaccines

**1. Vaccine produced using a licensed manufacturing process ******** ****immune response (IR) data**
**2. Vaccine produced using a licensed manufacturing process but formulated to contain less antigen ******** ****immune response data****, a novel adjuvant or a different delivery method ******** ****clinical safety, IR, or efficacy data depending on novelty of adjuvant**
**3.****	****Vaccine produced using an unlicensed novel manufacturing process ******** ****safety, IR, efficacy data**

## 1. Licensure of a Pandemic Vaccine Manufactured Using a Licensed Process

**The new pandemic strain would be reviewed as a supplement for strain change**
**Either a wild type or a reassortant virus could be used to produce the vaccine**
**Clinical studies to determine optimal dose and schedule for a pandemic vaccine should be conducted during interpandemic period**

## CBER Activities: Clinical Safety and Immunogenicity Studies

**Review of the design for clinical trials; e.g., H5N1 vaccine in healthy adults, children and the elderly**
**Review and analysis of clinical data**

## 2. Licensure of a Pandemic Vaccine with Both Licensed and Novel Components

**Data supporting certain antigen sparing strategies (same product, less antigen) would be reviewed as a clinical supplement**
**Adding a new adjuvant to vaccine formulation would likely require more extensive clinical and manufacturing data compared to the case above (novel adjuvant = new product)**

## CBER Activities: Antigen Sparing Studies

**Review and analysis of clinical data for:**
**Dose ranging studies in adults and the elderly**
**Studies using alternative routes of administration**

## 3. Licensure of a Novel Investigational Pandemic Vaccine

**An investigational vaccine made according to a new process requires product and pre-clinical data, to support the initiation of clinical trials**
**Clinical studies are required to demonstrate safety and efficacy of the new vaccine produced with current circulating strains**

## CBER Activities: Novel Vaccine Studies

**Guidance to sponsors on new cell substrates for virus propagation **

## Preparation of Reagents

**Generation of wild type or reassortant reference viruses **
**Preparation of antigen and antisera for potency assays**

## CBER/FDA Activities: Preparation of Reagents

**Development of reagents for laboratory detection of novel strains; e.g., H5, H7, H9, in collaboration with CDC, NIH, and NVPO**
**Development of reagents (i.e., anti-HA antisera and purified antigen preparations) for formulation and evaluation of H5 and H9 antigen-containing vaccines**

## Surveillance Preparedness

**Preparation for collection of clinical data at the time of the pandemic:**
**To assess the incidence of rare adverse events in the setting of mass immunization**

## CDC/FDA Collaborative activities: Surveillance

**Safety monitoring of SAEs for pandemic vaccines through VAERS**
**Plans developed with recent IND experience**

## Regulatory Pathways for Licensure of Pandemic Vaccines

**Endpoints:**
**Traditional approval:**** for a new vaccine clinical endpoint efficacy data are required as part of the data base to support approval**
** ****Accelerated approval:**** for a new vaccine licensure is conditionally approved based on surrogate endpoints (i.e., IR), with a post-marketing commitment to perform a clinical endpoint efficacy study to verify and describe its clinical benefit**

## CBER Activities: Guidance to Sponsors and Manufacturers

**Meet with sponsors of clinical trials to provide guidance for the licensure of pandemic influenza vaccines**
**Provide input in pandemic influenza meetings on pathways to licensure and input on the identification of product, pre-clinical and clinical study priorities for pandemic vaccines**

## CBER Activities: Preparation of Guidance Documents

**Draft guidance document defining pathways to licensure of pandemic or epidemic vaccines (in preparation)**
**Draft guidance document for the use of an unapproved product under an Emergency Use Authorization (EUA)**
**	****(“attacks”, “national security”)**

## Summary

**Supportive studies for licensure range from minimal, for the manufacture of pandemic vaccines produced using a licensed process, to extensive for vaccines produced using novel processes.**
**CBER pandemic preparedness activities include guidance and oversight of clinical studies, regulatory guidance to sponsors, preparation of reference reagents for vaccine production and evaluation, and surveillance.**

## FDA Perspectives

**When the pandemic arrives, there won’t be time to develop new manufacturing processes and the ability to increase the existing capacity will be limited.**
**Therefore, the main sources of vaccine will be manufacturers with processes licensed in the interpandemic period.**
**Either wild-type virus or high growth reassortants may be used to manufacture vaccine.**

## FDA Perspectives (cont.)

**Rapid initiation of clinical trials with licensed vaccine containing the actual pandemic strain could help to evaluate the immunogenicity of the vaccine formulation and the need for more than one dose of vaccine.**
**Epidemiological studies to evaluate the impact of the pandemic vaccines on disease burden would be of great importance, as would surveillance for vaccine-associated adverse events.**