# Presentation: 543582

## Meeting the Challenge of Pandemic Vaccine Preparedness: FDA Perspectives

***Jesse L. Goodman, MD, MPH***
***Director, Center for Biologics Evaluation and Research (CBER), FDA***
***NVAC, Washington, DC, 11/30/05***

## FDA Task Force on Pandemic Influenza

- Commissioner’s initiative
- Announced November 10, 2005
- Will spearhead FDA’s participation in inter-agency groups:
- President’s National Strategy for Pandemic Influenza
- Department of Health and Human Services’ Pandemic Influenza Plan and related activities

## FDA Task Force on Pandemic Influenza

- Cross-functional team: 14 Centers/Offices
- Coordinate policy development, planning, priority setting, and communications.
- Focus on accelerated development and production of:
- Vaccines
- Antivirals
- Diagnostics
- Comprehensive plan to include other roles:
- Management of avian influenza outbreak (USDA)
- Ensuring the safety of  human food and animal feed

## Not Business as Usual

- Since 9/11, CBER has adapted to extraordinary circumstances through extraordinary efforts
- These include proactive measures w/ sister agencies and industry such as:
**Meetings to encourage developing new products **
**Early and intensive interactions w/ sponsors **
**Collaboration and rapid turnaround on INDs, EUA**
**Proactive trips to inspect  facilities**
**Participation in multiple product development teams **
**Expedited reviews of key product applications**
**Critical Path Research: Targeted to high priority areas for more efficient, rapid product development and availability**
- Such approaches were used in the 2004 flu season and inform all our activities (for example WNV, pandemic preparedness). Benefits and increased demands/stress.

## Meeting the Pandemic Vaccine Challenge: Overview and Actions

- Increasing manufacturing diversity and capacity
- Developing needed pathways and regulatory processes to speed vaccine availability
- Facilitating vaccine manufacturing
- Assuring safety and public confidence
- Considering pathways to prevent a pandemic
- Thinking and working globally
*Key concept: Wherever possible, parallel rather than sequenced activities.*

## Increasing manufacturing diversity and capacity

- Markets (demand and sales) are main driver
- In last few years, increased flu vaccine demand and prices stimulating interest of manufacturers
- 2004 US shortage further accelerated interest
- FDA, industry, and global interactions helpful:
- Intensive interactions to assure potential access to vaccine under IND for 2004-5 season: data reviews, regulatory information sharing and facility inspections made 5 mill doses avail, if needed

## Pathways to Speed Availability: Accelerated Approval

- FDA considers there to be a short supply
- HI anti-HA antibody levels as likely surrogate
- Accelerated approval based on immunogenicity
- GSK data generated/reviewed and approved very  rapidly – enhancing annual supply and pandemic preparedness
- ~ 900 person safety/immunogenicity study planned/reviewed/enrolled in 1 m
*Indicates that with preparation, substantive and needed data can potentially be rapidly obtained both now and even in evolving pandemic situation*
*We can consider similar approaches for most pandemic vaccines, including adjuvanted, cell and recombinant*

## Pathways to Speed Availability: Licensure of Pandemic Vaccines 

- FDA views a pandemic strain used in a licensed manufacturing process as a strain change
- For licensed manufacturers (inactivated or live vaccine), would not be treated as a *new vaccine* but as a rapid approval supplement with *some clinical data important*
*Dosing and immunogenicity, safety if at higher doses*
- Either a wild type or a reassortant virus (including reverse genetics) can be used

## Other Steps to Strengthen Supply

- Globalization:
- Information sharing agreements and relationships put into place
- Pre and post-licensure
- Encouraging global vaccine development plans
- Annual inspections of flu manufacturers
- GMP initiative
- Increased communications and enhanced preventive and collaborative approaches to vaccine GMPs

## Thinking ahead: facilitating manufacturing and availability of licensed pandemic vaccines

- Preparation of qualified seed strains and high growth reassortants representing major known and evolving pandemic antigens
- Studies of strain cross-protection within HA types, methods to predict based on sequence analysis
- Advance preparation of needed reagents for manufacturing: e.g. antigens & antisera
- Evaluation of existing assays and consideration of development of new technological approaches (e.g. to potency, Abs, sterility) that may speed manufacturing and regulatory review/release

## Thinking Ahead: Enabling New Approaches and Technologies: Overview

- Even with aggressive and successful efforts to diversify and strengthen inter-pandemic production, capacity likely still inadequate for true widespread pandemic in US, and, almost certainly, for global needs
- Antigen sparing and other new technologies should be *evaluated* now, *before *a pandemic

## Adjuvant to Extend Vaccine Supply

- Some recent clinical results promising but some past studies negative
- Adjuvants may increase immune response and, in some cases cross-protective properties - but also adverse events
*Same issues with "whole" virus flu vaccines historically*
- Adjuvant addition requires changes in manufacturing that may affect vaccine and its stability –new product (BLA)
- FDA may use accelerated approval for new adjuvanted pandemic vaccine based on rapid generation and assessment of immunogenicity, manufacturing and safety data
*If proof-of-concept studies favorable, Phase 3 studies of immunogenicity and safety should be rapidly pursued*
*How we approach pandemic vaccines should be data driven, and such data can be soundly and rapidly obtained and shared –research agenda to drive policy*

## New Delivery Approaches

- Limited data suggest that intradermal delivery might reduce amount of vaccine needed
- Can be given into the skin by syringe or by various to date unproven devices, patches, injectors
- FDA in most cases could evaluate use rapidly as clinical supplements to licensed vaccines; would require dose, immunogenicity and some safety data

## Enabling New Technologies: Cell Culture & Recombinant Vaccines

- Significant potential advantages in flexibility
- FDA has licensed many other cell culture and recombinant based vaccines and has no special regulatory concerns with these technologies for flu
- We are encouraging their development and providing intensive interactions with sponsors –VRPAC on MDCK
- Several in development but *l****imited manufacturing, clinical experience to date***
- Potential for considering accelerated approval: based on immune response - cannot compromise on safety

## Considering Potential Future Pathways to Preparedness?

- For a pandemic to be a pandemic a prerequisite is the lack of population immunity
- Can we conceptualize pandemic preparedness in a routine prevention rather than crisis mode?
- Should we consider earlier building of immunity against evolving virulent pandemic threat strains?
- Should we consider the potential for integration of such preparedness into routine influenza immunization?
- Transparency, public dialogue, a non-crisis environment, and acceptance/demand would be important for any such approaches to be considered

## Relevant Lessons of Swine Flu

- Communication re: benefit/risks of vaccine critical
- Includes balanced communication of uncertain risk of pandemic as vaccine benefit depends on it
- Public's safety concerns and expectations are important and significant (and even more so today) and can affect, even derail, vaccination plans
- Confidence in vaccines, governments, industry and public health systems will be on line

## Relevant Lessons of CT Efforts

**Vaccine production complex, time consuming, not always predictable- *****vaccines are not widgets.***
***Short-cuts seldom are. ***
- Most delays have been in making a workable product, not clinical studies
***Less expensive seldom is.  ***
- FDA and other global regulatory counterparts can play important and facilitating roles
- Help facilitate production, maximize the efficiency of investments
***Rapidly ***_***and ***_***objectively evaluate scientific findings re: safety, manufacturing and efficacy in face of urgency***

## Why is global regulatory convergence desirable?

- It should be possible to generally agree upon a reasonable science based dataset needed to assess various potential pandemic vaccine types
- This may make development faster and more efficient for manufacturers and government
- In urgent situations it may be possible to share regulatory resources, information and reviews, as well as safety and effectiveness monitoring in use
- Convergence, including defining and where possible resolving true differences is desirable
***Plans and priorities: ***
***1) CBER concept papers/pandemic vaccine guidance***
***2) FDA/WHO/HC global regulators meetings (Q1&Q2 '06)***

## Pandemic Vaccines: Inactivated

| Agency | Approach | Basic Requirements | Comments |
| --- | --- | --- | --- |
| FDA 
Licensed product

New product | Supplement for pandemic strain

BLA- poss. accel. approval
 | Strain characterization, immunogenicity, dose selection

Above + manufacturing, safety, immunogenicity | FDA will accept immunogenicity c/w CPMP: provides EMEA level safety data
Some peds & elderly safety and immunogenicity experience desirable, may be largely PM. 
 |
| "               "  | Possible EUA option (BioShield) | Inadequate avail Rx
"known and potential benefits outweigh K&P risks"  | Could potentially  allow use in public health emergency with less available data, public disclosure |
| EMEA – Licensed or new | All treated as new vaccine – mock dossier | Same + manufacturing and safety database to detect 1% AE. 
New process, full non-clinical data | Also c/w CPMP not EU annual strain change
6 months safety f/u
Post-marketing safety, immunogenicty, efficacy |

## Pandemic Occurs: New Strain

| Agency | Approach | Basic Reqs. | Comments |
| --- | --- | --- | --- |
| FDA | Strain change supp, rapid approval | Strain characterization, immunogenicity, dose selection as needed
 | Some bridging clinical immunogenicty desirable 
– experience with closely related strain could minimize or eliminate. 
Can be obtained concurrently w manufacturing
Post-licensing safety and immunogenicty in larger and special populations |
| EMEA ("mock dossier" already approved) | Pandemic variation rapid approval | Strain characterization
Animal immunogenicity | Post-licensing protocols for safety, immunogenicity, efficacy in place |

## Summary

- We are working with partners to diversify and strengthen influenza vaccine manufacturing, and provide flexible and rapid regulatory pathways – *progress has been made*
- Scientific data needs for evaluating antigen sparing approaches and non-egg based technologies are critical for policy decisions and best addressed before a pandemic – *several key studies underway*
- Further advance preparation and improvement of strains, reagents, assays and standards would be beneficial
- Consider benefits and risks of early intervention vs.             virulent potential pandemic strains, including             potential integration into routine public health
- Regulatory convergence being encouraged

***CBER: INNOVATIVE TECHNOLOGY ADVANCING PUBLIC HEALTH***