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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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; 48:577-581

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;53:786-789 **Pediatrics 2002;110:e67-73 ***Lancet 2004;363:1547-50

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;121:1206-1212) Updates communicated through changes to labeling and patient information, Public Health Notification, MMWR publication

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

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 *http://www.fda.gov/bbs/topics/NEWS/2005/NEW01238.html ** http://www.fda.gov/cber/safety/gbs102006.htm *** October 20, 2006;55:1120-1124

Case Study (cont) Ongoing studies of GBS after Menactra VSD: as of 11/17/07, no cases within 6 wks after vaccination among 228,003 11-19 year-olds (0.35 expected) Harvard Pilgrim in conjunction with manufacturer Include 10 million 11-18 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

Other Recent Examples of Vaccine Safety Issues Possible increased risk of febrile seizures after Proquad (combined Measles, Mumps, Rubella and Varicella Vaccine) http://www.fda.gov/cber/label/proquadLBinfo.htm Update on the safety of Gardasil (human papillomavirus vaccine) http://www.fda.gov/cber/safety/gardasil071408.htm

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

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

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

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

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

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

CBER Contact Information http://www.fda.gov/cber Manufacturers: matt@fda.hhs.gov Consumers, health care professionals: octma@fda.hhs.gov Phone: 301-827-1800