# Presentation: 682118

## Vaccine Safety: Vision for the Future

*Jesse L. Goodman, MD, MPH*
*Director, Center for Biologics Evaluation and Research, FDA*
*April 10, 2007*

## Purpose of Our Meeting

- Discuss approaches, methodologies and opportunities to further enhance vaccine safety, using both current and developing tools – focus is on post-licensure systems
- Share international perspectives and experiences
- Identify data and research gaps and needs
- Update and articulate a vision of an ideal vaccine safety system and help advance that vision

## Perspective: Vaccine Accomplishments

*As the specter of severe vaccine preventable diseases becomes seemingly distant in developed countries, vaccine safety concerns, always important, gain prominence *

## Partnerships in Safety

- FDA

- CDC

- NIH

***Public***

- Industry

- Healthcare
- system/providers

*Other important governmental partners/contributors: HRSA, DoD, VA, CMS*

*ACIP*

*VRPAC*

## Assuring high vaccine safety involves more than post-licensure surveillance

- VACCINE SAFETY

**PRE-APPROVAL:**
- Animal
- Clinical
- Product quality and
- manufacturing
*FDA, NIH and industry*

**PRODUCTION:**
- Manufacturing
- quality
- Inspections
- Testing and Release
*FDA and industry*

**POST-APPROVAL **
**CLINICAL SAFETY:**
- Planned (PMC) Studies
- Surveillance: AEs/VAERs/VSD
- Studies of “problems”
*RISK COMMUNICATION*
*CDC, FDA, industry*

## Result – High Safety

*Vaccines are carefully evaluated pre-licensure,  manufactured and released under tight process controls and with FDA oversight, typically studied further post-approval and monitored carefully. Information communicated and, where needed, actions taken promptly.*
- Total:  ~ 235 million vaccine doses distributed annually in US, ~ 2400 potential SAEs reported

## But Can We Do Better?

- VACCINE SAFETY

**PRE-APPROVAL:**
- Better predictive studies,
*In vitro*, animal and
- clinical
- More defined vaccines
- and components

**PRODUCTION:**
- Better technologies
- and process control
- New technologies for
- characterization
- and testing

**POST-APPROVAL :**
- Automated and more rapid
- signal detection
- Better studies
- Better determine causality of
- signals and degree of risk
- Improve risk communication
- Profile & reduce individual risk

- ?

*FDA Critical Path Initiative*

## Pre-approval: Vision

*Vision: Scientific advances predict safety risks and efficacy based on molecular, cellular, animal and human systemic and immune responses. Vaccine technologies use fully molecularly defined antigen(s) and other components that predict the clinical response. *

## Pre-approval: Needs & Opportunities

- “Purer” or molecularly defined vaccines
- Acellular pertussis
- Recombinant proteins, chemically synthesized peptides/nucleic acids/conjugates
- Currently often less immunogenic
- Better predictive models and markers
- Animal/cell models to identify rare events (e.g., gene expression responses, genetically prone transgenic mice, cytokine responses)
- Live vaccine virulence measures/models – or substitutes (e.g. OPV-IPV)

## Pre-approval: cont.

- Enhanced information from clinical trials
- Non-clinical human trial markers from clinical trials (e.g. PBMC, proteome, cytokines etc.)
- Larger/simpl*er* safety trials welcome where appropriate (e.g. Rota ~  35K)
- Focused follow up, major endpoints, short and long term
- Trade off should allow smaller intensely monitored studies (could embed within LST)
- More diverse populations (genetic perspectives may help define future needs)
- Still will never reliably detect/predict rarest AEs <= 1/10,000 (e.g. possible GBS risk ~ 1/1,000,000)

## Manufacturing and Quality: Vision, Needs and Opportunities

*Vision: A completely defined product produced consistently, with continuous process and product monitoring that detects potential risks.*
- Needs and opportunities:
- Further enhanced biologic process controls, consistency
- New process and product characterization tools e.g. NMR, mass spect
- Ability to predict what changes are meaningful

## Post-approval: Vision

*All patients’ vaccinations and health experiences are immediately and continuously accessible in automated database(s) allowing optimal detection and analysis of potential problems in vaccine safety (and effectiveness). *
- Not there yet - both major limits and opportunities in current health information systems
- Both problems and solutions to enhance vaccine safety information/analysis should link to safety initiatives for all medical products and procedures

## Post-approval: Needs - surveillance

- Access to more patients and better data (vs. proprietary issues, costs)
- Given diversity of sources, innovative more “Google” - like approaches to retrieval of key data may have great potential vs. single unified systems
- Better background rates, comparable “control” populations
- More consistent event/disease nomenclature, IT architecture, data interchangeability/quality
- Differences between adult and child immunization
- Increase in “non-medical” data sources – e.g. pharmacy, supermarket, employer vaccination

## Post-approval: Areas of Opportunity

- Data: Health systems: e.g. VA, DoD, CMS, managed care
- More in this meeting
- Global data: regulatory, review, inspectional, health systems, international surveillance/pharmacovigilance
- Better analytic tools and methods

## Post-marketing Safety- Other Approaches

- “Roll-out” – e.g. slower/initial uptake in high disease burden population(s)
- but n to detect and analyze is still the same n
- Large(r) simpler studies (as for premarket)
- More pts. for same/less $$: focus on key data
- Major endpoints (medical care, hospitalization, death)
- Enhanced VSD type studies
- New reporting strategies:                                     cell phone, internet

## Post-marketing Safety- Other Approaches continued

- “Personalized Vaccination”: Identifying patients “at risk” for rare AEs and either not vaccinating, changing dose, or using alternate vaccine strategy
- Population defined risk factors
- Genetic risk factors
- Whole genome, someday
- Risk loci/signatures/SNPs/Immune                   response genes

## Communications and Transparency

- Respect and autonomy of patients should be a guiding principle
- Early, open and continuing
-    communication of possible
-    safety signals is expected and            beneficial to consumers/HCPs/science
- Critical to confidence in integrity of the vaccine safety system, government and industry, and the safety of vaccines
- Enhances reporting and informs consumer/HCP decision-making
- Initial information and medical/scientific opinion and assessments often evolve and can be wrong

*      ****Not an option!***

## Modern Vaccine Safety: Meeting Challenges to Detect, Analyze and Communicate Early

- Rotavirus- earlier vaccine approved in 1998
- Though no excess pre-licensure, intussusception (IS) noted as possible AE: term specifically added to VAERs
- Post-license: likely excess IS noted through VAERs and ACIP recommendation withdrawn in 98 (likely 1 in 5-11k)
- Next generation vaccine, licensed 2006
- Larger pre-licensure studies: > 70,000, no excess IS
- Larger post-licensure studies: sponsor 44k+ VSD 90k
- Careful VAERS monitoring/analysis in place – in first year 17 cases reported w/in 21 days  vs. 52 “expected”
- Transparency: though below expected, label and patient info updated 1/07, FDA provided early Public Health notification 2/12 & FDA/CDC publish MMWR 3/16

## Meeting Challenges to Detect, Analyze and Communicate cont:

- Meningococcal conjugate vaccine - licensed 1/05 - prevents life threatening disease
- No GBS seen pre-licensure in ~ 7k recipients but 5 cases reported to VAERS by 9/05 triggering concern re: potential safety signal
- Rapid investigation, communication, with cooperation/info sharing among FDA, CDC, manufacturer and public transparency
- FDA statement 9/05 – MMWR & label update 10/05
- Current information: uncertain but possible GBS risk ~1.25 cases/million doses (CI = 0.058--5.99)
- Challenges: uncertainties in background rate, VAERs reporting - studies continuing, no cases seen in VSD
- Continued joint FDA/CDC monitoring/analyses and updates x 3 in MMWR, last 10/06, label update 9/06

## Transparency and “Risk Literacy”

- Risk literacy – very difficult and non-intuitive to understand risk and causal association statistically vs. individually
- There are risks in conveying uncertainties, including potential decreased use of safe vaccine
- Major behavioral science, educational system and risk communication scientific needs

## Conclusion

- While today’s vaccines are very safe and safety systems and activities are stronger and more transparent than ever, there are opportunities to apply advances in laboratory, manufacturing, clinical and population sciences, and in health informatics, to meet our highest expectations.

## Vision

*   **Completely defined vaccines are found safe in sensitive, predictive pre-clinical and clinical studies, are manufactured to the highest possible quality using new technologies, and given to individuals with a low likelihood of serious adverse events. Populations are actively monitored for vaccine adverse event signals which are analyzed accurately allowing potential risks (and benefits) to be communicated rapidly and effectively. *

## Thanks!

*   **We look forward        to sharing information and insights concerning tools for vaccine safety - and to working together to achieve our shared vision – both during *
*    **this workshop and in the future.*