# Presentation: 276691

## Postmarketing Surveillance Conference
April 11, 2007

***Vaccine Safety Surveillance***
***A Case Study***
** *****  ***

***Postmarketing Surveillance Conference***
***April 11, 2007***

## Overview

**Complexities of Vaccine Development**
**Overview of Current Surveillance System**
**Menactra****®**** Case Study**
**Enhancing the System**
**Conclusions and Recommendations**

***Menactra® Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine***

## Vaccine Development and Safety: Commitment to Public Health

**Vaccines work best when most members of a community are vaccinated**
**Vaccines must be safe for use by as many people as possible**
**Typically given to healthy people**
**Vaccines have been shown to be remarkably safe and effective in preventing serious infectious diseases and have saved countless lives**
**Years of testing are required by law before a vaccine is licensed and distributed in the US**
**Once in use, vaccines are continually monitored for safety and efficacy**

***Source: ******www.cdc.gov***

***“******As a result, the United States currently has the safest, most effective vaccine supply in history.”***

***www.cdc.gov/od/science/iso/research_activities/vaers***

## Development of New Vaccines - Current Environment

**In the past 3 decades, more than 2/3 of all new vaccines approved worldwide have been developed in the US**
**18 new vaccines were approved between 1980 and 1996, resulting in substantial public health benefits**
**New vaccine development requires larger pre- and post-licensure studies **
**Development costs for a new vaccine increased, on average, from $231M in 1991 to $802M by 2001**
**Escalation of development costs has consequences – vaccines with small markets are not developed **
**Practical limits on the sample size of pre-licensure studies**
**Pre-licensure trials can never be large enough to rule out all rare adverse events**
**Accordingly, robust postmarketing surveillance (signal detection, hypothesis testing) is essential**

***Source: ******Warren KS. New Scientific Opportunities and old obstacles in vaccine development, 1986******Plotkin, Orenstein. Vaccines, 2004***

**As with any medical procedure, vaccination has some risks, as well as proven benefits**
**Social benefits of vaccination increase with increasing coverage**
**Social compact: in return for accepting small risk, 2 promises: **
- Continuous monitoring of vaccine safety
- Fair compensation
**An effective post-marketing surveillance system provides assurances that rare adverse events can be detected and assessed**
**Inactivated measles vaccine, rotavirus vaccine, conjugate meningococcal vaccine**
**A transparent system can also be used to answer questions / concerns of interest to public health and the public at large**

_**Effective and transparent surveillance systems**_** are the pillars for effectively monitoring immunization safety and maintaining public confidence**

***Source: ******Plotkin, Orenstein. Vaccines, 2004******www.cdc.gov***

**Post-Marketing Surveillance**

## Current US surveillance system has played a key role in monitoring immunization safety...  But how can we make a good system better?

**Limitations**

**Incomplete reporting**
**Multiple vaccines and other events create additional challenges to establish causality**
**Data limitations**
**Passive reporting**
**Undefined denominator**

**Strengths**

**National in scope**
**Able to detect very rare events and previously unrecognized events**
**Triggers further investigations**
**Can detect unusual clusters of adverse events**

**VAERS**

**1****st**** Component (Signal / Hypothesis Generation):**

## Vaccine Safety Datalink – Shared MCO databases linking vaccination records with health outcomes

**Limitations**

**Delays in data availability**
**It could take up to 18 months to generate a cleaned-up data tape compiling information from multiple sources**
**Lacks complete geographical coverage**
**Database currently not large enough to test hypotheses for very rare events**

**Strengths**

**Rigorous safety data**
**Relatively time efficient **
**Once all the data are collected, analysis can be done quickly**
**Sample size is big enough to test hypotheses for uncommon adverse events**

**Vaccine Safety Datalink (VSD)**

**2****nd**** Component  (Hypothesis Testing):**

## Menactra® Case Study

**VAERS reports of GBS following the administration of Menactra****®**** vaccine prompted a comprehensive review and data collection effort by FDA, CDC, and sanofi pasteur**
**Frequent communication and information sharing among these organizations resulted in rapid assessment and public reporting of these events **
**Public/private partnerships are key to meet vaccine safety surveillance goals and reassure the public that the system works**
**This case study also identified areas where the safety surveillance system could be enhanced**

***Menactra******®****** Case Study***

## A Comprehensive Effort

**CDC, FDA and sanofi pasteur held weekly meetings to share data, discuss case findings, review Menactra****®**** distribution data, and coordinate investigations**
**CDC utilized numerous resources and partners to collect data**
**Safety Branch and VSD partners**
**CISA centers**
**State surveillance**
**The Brighton Collaboration**
**Sanofi pasteur clinical, regulatory, and medical affairs teams worked closely with FDA to provide updated labeling and rapid communications to healthcare professionals**
**Comprehensive communications designed to prompt immediate reporting of potential cases**

***Menactra******®****** Case Study***

## Active Surveillance for GBS cases

**CDC led the “States” team responsible for active identification of GBS cases**
**Council of State and Territorial Epidemiologists (CSTE) participated in active GBS surveillance**
**State epidemiologists and Emerging Infectious Disease specialists in 7 states (New Jersey, New York, Pennsylvania, Ohio, California, Illinois, Texas), as well as other states where GBS is a reportable disease, participated in active GBS case surveillance and identification**
**American Society of Plasmapheresis (50-60% of GBS cases receive Plasmapheresis) participated in case detection efforts**
**Working with AHIP, CDC, FDA, Sanofi pasteur led efforts to expand the population under active surveillance (VSD-like)**

***Menactra******®****** Case Study***

## What has sanofi pasteur, along with CDC and FDA, done to ensure HCPs were informed and proactively looking for GBS cases...

- FDA, CDC, Medical Affairs, Regulatory Affairs

- CDC

- FDA / CDC

- FDA, Pharmacovigilance, Medical and Regulatory Affairs

**Sept 05**

**Dec 05**

- Label changes in Menactra® US Package Insert and Company’s Core Data Sheet

- GBS Surveillance Form

- Scientific Information (MMWR + Fact Sheet + Revised VIS)

- FDA / CDC / sanofi pasteur Coordination of Press Releases

- “Dear Health Care Professional” Letter

**Stakeholders Involved**

- Medical and Regulatory Affairs

***Menactra******®****** Case Study***

## Effective Public/Private Partnership

***Communication***

***Cooperation***

**Effective Public/Private Partnership**

***Action Plan***

- GBS surveillance form
- Active surveillance
- Label changes
- Data sharing (VAERS, CISA,

- Active Media Statement
- Updated MMWR and Fact Sheet
- Updated VIS
- HCP letters

- Weekly conference calls
- Coordinated press releases, statements
- Coordination regarding ongoing and planned investigations

***Menactra******®****** Case Study***

## Update through the end of January 2007: 
Total of 19 cases of GBS after Menactra® vaccine with onset interval of 2-33 days
17 cases were in the 11-19 years old age group
VSD Rapid Cycle Analysis project: 
156,542 doses administered
Zero cases observed among vaccine recipients 11-19 years old within 6 weeks of vaccination
Projection: 0-1 cases were expected
Does the number of reported GBS cases exceed the expected rate? 
Observed compared to expected rate calculations
Confounders/uncertainties: age, season, background rates

**Total of 19 cases of GBS after Menactra****®**** vaccine with onset interval of 2-33 days**
**17 cases were in the 11-19 years old age group**
**VSD Rapid Cycle Analysis project: **
**156,542 doses administered**
**Zero cases observed among vaccine recipients 11-19 years old within 6 weeks of vaccination**
**Projection: 0-1 cases were expected**
**Does the number of reported GBS cases exceed the expected rate? **
**Observed compared to expected rate calculations**
**Confounders/uncertainties: age, season, background rates**

***Menactra******®****** Case Study***

**GBS Reports in Menactra****®**** vaccine recipients****ACIP Meeting of February 21-22, 2007**

## GBS Reports in Menactra® vaccine recipientsACIP MEETING (February 21-22)

***versus***** 1.72; (95% CI 0.83-3.55)**

***versus***** 1.73; (95% ****CI 1.04-2.88****)**

**MMWR update communication on October 20, 2006 *****(data through the end of September 2006)***

**GBS Reports in Menactra****®**** vaccine recipients****ACIP MEETING (February 21-22)**

**ACIP meeting***

*  **Calculation using sale data through end of November 2006 - 6.93 million doses distributed to 11-19 y/o.*

***Source: ******www.cdc.gov***

***Menactra******®****** Case Study***

## GBS Reports in Menactra® vaccine recipients with Age Stratification

**GBS Reports in Menactra****®**** vaccine recipients with Age Stratification**
**ACIP MEETING (February 21-22)**

***Source: ******www.cdc.gov***

***Menactra******®****** Case Study***

## Enhancing the surveillance system will provide additional data

***Source: ******www.cdc.gov***

***Menactra******®****** Case Study***

**Enhancing the surveillance system will provide additional data**

## Enhanced surveillance needed to further assess potential relationship between Menactra® and GBS

**Complications**
**Rare outcome (if associated, attributable risk is on the order of 1 per million)**
**Uncertainty regarding background rates**
**Confounding with age and seasonality**
**Expanded cohort surveillance needed**
**VSD, even in current expanded form, too small**
**The potential exists to establish a much-expanded VSD-like capability**
- There are < 10 very large MCOs
- Taken together, they could contribute 100-150 M covered lives
- No economic incentive for MCOs to participate
- MCO participation would rest on public health importance, assurance of non-intrusiveness

## Menactra® Case Study

**The need for additional data on GBS rates triggered the creation of a *****Health Plan Consortium***

**Purpose:**
**To create an expanded, rapid and sensitive, active post-marketing safety surveillance system to inform public health and regulatory decision-makers**
**Consortium Concept:**
**An activity of the Centers for Evaluation and Research on Therapeutics (CERTs) - a national program with a congressional mandate administered by the Agency for Healthcare Research and Quality (AHRQ)**** ****and FDA**
**Dr. Richard Platt leads the Harvard CERT**
**AHIP is a key partner in organizing and administering consortium**
**Health plans are members and contribute with data**
**Advisory Committee with diverse stakeholders, including industry**
**Funding from a variety of sources**

**The *****Health Plan Consortium***** could only be developed through a multi-party public-private collaborative effort**

## Menactra® Case Study

***Health Plan Consortium***** - ****Managed Care Organizations (MCO) database study**

**The currently active study is a multi-site retrospective cohort study of the relationship between immunization with tetravalent meningococcal conjugate vaccine (MCV4) and Guillain-Barré syndrome (GBS) in adolescents over the 42-month period of March 1, 2005 to August 31, 2008. **
**Data currently being collected**
**Funded by sanofi pasteur **
**The study will use a cohort assembled from health plan members enrolled at selected health plans throughout the United States.  **
**Initial effort encompasses data from 4 major US health plans **
**Total of 40 million covered lives **

## Menactra® Case Study

***Health Plan Consortium***** - ****Managed Care Organizations (MCO) database study**

**The consortium plan is to add other health plans incrementally, reaching approximately 100 million covered lives**
**Cases will be identified using administrative data, and case validation and collection of information on risk factors and other covariates will be performed by medical record review.  **
**Quarterly data extracts and cumulative analyses**
**First quarterly report – Q3 or Q4 2007**
**A Cox proportional hazards model will be used, with age and days since vaccination as time-dependent covariates.**

## This effort exemplifies sanofi pasteur's and industry’s commitment to public health and to maintaining public confidence in vaccines 

**Strong orientation to public health**
**Unique responsibility**
- Immunizations are strongly recommended, widely used, and targeted towards healthy individuals
- Accordingly, lower risk tolerance
**Transparency**
**Direct communication and cooperation**
**Long-term public health commitment**

## Moving forward...

** ****Incidence of many vaccine-preventable diseases has been reduced by more than 97% in the US compared with pre-immunization era**
** ****Pre-licensure studies for new vaccines cannot be made large enough to rule out important but rare AEs**
** ****Diminishing returns**
** ****Public health consequences**
** ****Therefore, robust postmarketing surveillance is mandatory**
** ****Postmarketing commitment trials (manufacturer)**
** ****Population surveillance (public or public-private partnership) **

**Moving forward...**

**Conclusions and Recommendations**

***Source : CDC MMWR 46(12), April 1999******                CDC MMWR 47(53), Dec 1999******                Plotkin, Orenstein. Vaccines, 2004***

## Moving forward...

** ****Improved vaccination databases (registries)**
** ****Enlarged populations under surveillance for outcomes**
** ****Improved coordination between manufacturer, FDA, CDC, other public health agencies**
***“******All patients' vaccinations and health experiences are immediately and continuously accessible in automated databases allowing optimal detection and analysis of potential problems in vaccine safety (and effectiveness).”***** ****	****	****	****	****	****	****	****- Jesse Goodman, 4/10/07**

**Moving forward...**

**Conclusions and Recommendations**

***Source : CDC MMWR 46(12), April 1999******                CDC MMWR 47(53), Dec 1999******                Plotkin, Orenstein. Vaccines, 2004***

## Moving forward...

** ****Advances in postmarketing surveillance will require national-scale resources**
** ****Vaccine registries; very-large-population outcome databases**
** ****Further extend public/private partnerships to secure appropriate funding to institutionalize additional data collection and evaluation capabilities**
** ****The *****Health Plan Consortium*****, which was put together to address a specific acute need, can play an important role in a longer-term solution**

**Moving forward...**

**Conclusions and Recommendations**