1. Responding to Vaccine Safety Events Karen Midthun, MD, Deputy Director Center for Biologics Evaluation and Research, FDA ICDRA Conference Berne, Switzerland September 19, 2008

2. INNOVATIVE TECHNOLOGY ADVANCING PUBLIC HEALTH
Vision for CBER
INNOVATIVE TECHNOLOGY ADVANCING PUBLIC HEALTH
Protect and improve public and individual health in the US and, where feasible, globally
Facilitate the development, approval and access to safe and effective products and promising new technologies
Strengthen CBER as a preeminent
regulatory organization for biologics

3. Examples of Licensed Vaccines: Great Diversity
Live, attenuated: MMR, varicella, yellow fever, rotavirus, influenza
Inactivated: hepatitis A, influenza, polio, rabies
Crude or purified antigens derived from living or killed cells: diphtheria and tetanus toxoids, polysaccharides
Conjugates: hemophilus type b, pneumococcal, meningococcal
Recombinant DNA derived: hepatitis B, human papillomavirus

4. Vaccine Production: Challenges
Biologic sources of viral or bacterial seed, cell substrate, other components
Test for adventitious agents
For inactivated vaccines, validate inactivation process
For live vaccines, demonstrate attenuating characteristics retained
Complex manufacturing processes: detailed procedures, in process testing, product characterization, lot release testing all critical for consistency and quality of product

5. Vaccine Approval Process in the U.S.
Biologics license application
FDA evaluates the clinical, non-clinical, product, and manufacturing data
Conducts a pre-approval inspection
Reviews pharmacovigilance plan and determines need for post-marketing studies
Usually obtains advice from FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) prior to approval

6. Post-Licensure Vaccine Safety Monitoring
Lot release
Biennial inspections (annual for influenza vaccine manufacturers)
Post-marketing surveillance and evaluation of adverse events following immunization
Passive surveillance, e.g., Vaccine Adverse Event Reporting System (co-managed by FDA and CDC)
Active surveillance, e.g., phase 4 studies conducted by manufacturers, government agencies

7. Post-Marketing Adverse Event Monitoring: Passive Approach
Vaccine Adverse Event Reporting System (VAERS)
National system for passive surveillance
Jointly managed by FDA and CDC
Reports received from health professionals, vaccine manufacturers, and the public

8. VAERS Advantages Limitations
National in scope, covers diverse populations
Able to detect rare adverse events
Rapid detection of possible signals (hypothesis generating)
Can assess adverse events by lot
Limitations
Underreporting
Inadequate denominator data (i.e., number of persons vaccinated)
No unvaccinated control group
No information on background rates of conditions in general population
Usually not possible to assess whether vaccine caused the reported adverse event

9. Post-Marketing Adverse Event Monitoring: Active Approach
Manufacturers’ phase 4 studies
FDA sentinel initiative
Activities in early stages or under development
CDC’s Vaccine Safety Datalink (VSD)
8 health maintenance organizations that participate in large linked database that tracks
Vaccination (exposure)
Outpatient, emergency department, hospital and laboratory data (health outcomes)
Demographic variables (confounders)
Includes approximately 3% of U.S. population
“Hypothesis testing” studies can be conducted

10. FDA and CDC Interactions on Vaccine Safety
FDA and CDC, in conjunction with HHS and other agencies, work closely together on vaccine safety surveillance activities (e.g., VAERS, VSD and other active surveillance activities) and the analysis and communication of vaccine safety concerns

11. Public Communication Regarding Vaccine Safety Updates
Labeling changes (e.g., package insert , patient information)
Presentations at FDA and CDC Advisory Committee meetings
FDA and CDC websites
MedWatch E-list
Letter to healthcare provides
MMWR and other scientific publications

12. Enhancing Vaccine Safety Activities
CBER formed a multi-disciplinary vaccine safety team with expertise in
Epidemiology
Clinical medicine
Product characterization
Manufacturing and compliance
Communications
Works in concert to improve acquisition, analysis, and communication of safety information in response to rapidly emerging vaccine safety issues

13. Vaccine Safety Team
Considers entire product life cycle and all data relevant to safety, manufacturing, and compliance
Uses these data to evaluate emerging safety issues
Coordinates FDA response to emerging safety issues with other HHS agencies (CDC, NVPO, NIH), industry
Enhances collaboration with other govt. agencies, WHO, and other entities on safety initiatives
Proactive: develop research, policy, outreach agenda

14. What kinds of post-marketing “Vaccine Safety Events” might occur?
Adverse events following immunization
Could be caused by vaccine or be coincidental
Manufacturing problems
Could impact on quality of the vaccine so that safety cannot be assured, leading to a recall and other corrective actions
Counterfeit or product tampering

15. A Case Study in Responding to a Vaccine Safety Event: Rotavirus Vaccine and Intussusception (IS)
First rotavirus vaccine (Rotashield) licensed by FDA in August 1998 for prevention of rotavirus gastroenteritis in infants
Pre-licensure data for IS
5 cases in 10,054 vaccinees
1 cases in 4633 placebo recipients
Difference in rates not statistically significant
Lack of apparent association between IS and wild-type rotavirus infection
Phase 4 study commitment at licensure
Package insert: IS included as potential AE
IS prospectively added as term in VAERS database

16. Case Study (cont)
VAERS reports 9/1/98 – 6/2/99: 10 IS cases, temporal clustering after 1st dose and within 7 days after vaccination provided signal
CDC initiated multi-state case-control study and cohort study in 10 MCOs in June 1999
July 1999*
15 IS cases reported to VAERS, 12 within 7 days after vaccination
Background rate in infants <1 yr, 51/100,000 infant years
~1.5 million doses administered 8/98-6/1/99
14-16 cases would be expected in week after vaccination by chance alone
Population-based studies suggested higher IS rates after vaccination (not statistically significant)
CDC and AAP recommended temporary suspension of use
*MMWR July 16, 1999; 48:

17. Case Study (cont.) October 1999
Population-based studies: elevated risk of IS after vaccination*
ACIP withdrew its recommendation for vaccination
Wyeth voluntarily withdrew vaccine
What was attributable risk?
Initial estimate 1/2500 to1/5000
Consensus estimate ~1/10,000**
Did vaccine “trigger IS but result in no net increase?***
*MMWR September 3, 2004;53:
**Pediatrics 2002;110:e67-73
***Lancet 2004;363:

18. How did this impact next rotavirus vaccine?
Second rotavirus vaccine (Rotateq) licensed by FDA in February 2006
Pre-licensure: very large safety study (70,000 infants, 1:1 vaccine to placebo), no increased risk of IS
Post-licensure surveillance: VAERS, manufacturer’s phase 4 study (44,000 infants) and CDC’s VSD study (90,000 infants)
To date, no signal of increased risk of IS after Rotateq (Pediatrics 2008;121: )
Updates communicated through changes to labeling and patient information, Public Health Notification, MMWR publication

19. Guillain-Barre syndrome (GBS)
A Case Study in Responding to a Vaccine Safety Event: Meningococcal Conjugate Vaccine
Menactra licensed by FDA in January 2005 for prevention of invasive meningococcal disease caused by serogroups A, C, Y, and W135
Guillain-Barre syndrome (GBS)
No cases in ~7000 vaccinees in pre-licensure trials
5 cases reported to VAERS by September 2005, occurring within 6 weeks after vaccination and triggering concern re potential safety signal

20. Case Study (cont.)
Rapid investigation, communication, with cooperation and information sharing among FDA, CDC, manufacturer, and public transparency
Sept 2005: FDA and CDC issued alert of ongoing investigation and encouraged reporting to VAERS*
October 2005: package insert revised to reflect temporal association between vaccination and GBS
October 2005, April and October 2006: MMWR updates
October 2006: FDA/CDC statement** and MMWR***: uncertain but possible GBS risk of ~1 case/million doses
Challenges: uncertainties in background rates, VAERS reporting, number of doses given, etc.
10/06: ACIP reaffirms its recommendations for routine immunization of adolescents * **
*** October 20, 2006;55:

21. Case Study (cont) Ongoing studies of GBS after Menactra
VSD: as of 11/17/07, no cases within 6 wks after vaccination among 228, year-olds (0.35 expected)
Harvard Pilgrim in conjunction with manufacturer
Include 10 million year-olds
Time period of 3/05 to 8/08
~ 90% power to detect risk ratio of 3; 50% power to detect risk ratio of 2

22. Other Recent Examples of Vaccine Safety Issues
Possible increased risk of febrile seizures after Proquad (combined Measles, Mumps, Rubella and Varicella Vaccine)
Update on the safety of Gardasil (human papillomavirus vaccine)

23. Communications and Transparency
Early and continuing communication of possible safety signals is expected and beneficial to consumers, health care providers, science
Critical to confidence in integrity of vaccine safety system, government and industry
Enhances reporting and informs decision-making of consumers and health care providers
Initial information and medical/scientific opinion and assessments often evolve
Conveying uncertainty of risk difficult, includes potential for decreased use of safe and effective products

24. Global Collaboration CBER is a WHO Collaborating Center
Information sharing arrangements and engagement in priority areas with various regulatory authorities and WHO
Brighton collaboration for standardized case definitions of adverse events following immunization
CIOMS vaccine safety working group
Partnering with WHO and NGOs to explore additional means of providing global regulatory assistance/capacity building
International Conference on Harmonisation
Pharmaceutical Inspection Cooperation/Scheme

25. Summary
Pre-licensure clinical, product, and manufacturing data are critical foundations for evaluating vaccine safety and effectiveness
However, post-licensure surveillance is essential to assure vaccine safety
Vaccines have risks that may include rare serious adverse events not detected in pre-licensure studies
Government agencies play an important role in monitoring, analyzing, and communicating re safety of vaccines

26. Summary (cont)
Passive and active surveillance, including observational studies, after licensure are needed to detect and evaluate vaccine safety concerns
Need for robust, continuously operating and technologically advanced safety monitoring systems that include epidemiological, clinical, and laboratory assessments of causality
Public communication and engagement regarding vaccine safety concerns is critical to maintaining confidence in the vaccine safety system, optimal vaccine coverage, and the public health

27. Acknowledgments Robert Ball, MD, MPH, ScM Jesse Goodman, MD, MPH
John Iskander, MD, MPH
Douglas Pratt, MD, MPH
Marion Gruber, PhD
Mary Malarkey
Lorrie McNeill
Joan Blair

28. CBER: INNOVATIVE TECHNOLOGY ADVANCING PUBLIC HEALTH
Thank you!
We are actively engaged in assuring the safety, effectiveness, and availability of products that touch so many lives and are critical for public health and preparedness
Emerging threats, technologies, and opportunities demand constant renewal of scientific expertise and capacity
The challenges and opportunities for leadership and public health are truly global – and collaboration is key!
CBER: INNOVATIVE TECHNOLOGY ADVANCING PUBLIC HEALTH

29. CBER Contact Information
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