1 / 29

Vision for CBER

Responding to Vaccine Safety Events Karen Midthun, MD, Deputy Director Center for Biologics Evaluation and Research, FDA ICDRA Conference Berne, Switzerland September 19, 2008. Vision for CBER. INNOVATIVE TECHNOLOGY ADVANCING PUBLIC HEALTH

ember
Download Presentation

Vision for CBER

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Responding to Vaccine Safety EventsKaren Midthun, MD, Deputy DirectorCenter for Biologics Evaluation and Research, FDA ICDRA Conference Berne, SwitzerlandSeptember 19, 2008

  2. 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 • 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; 48:577-581

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

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

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

  21. Case Study (cont) • Ongoing studies of GBS after Menactra • VSD: as of 11/17/07, no cases within 6 wks after vaccination among 228,003 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

  22. 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

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

More Related