Dr. Arani Chatterjee, MBBS, MPhil, PGCPM Senior Vice President, Clinical Research

1. International Conference and CME cum Workshop on Pharmacovigilance Systems and Rational Use of Drugs: An Integrated Approach Optimizing Signal Detection for Vaccines Dr. Arani Chatterjee, MBBS, MPhil, PGCPM Senior Vice President, Clinical Research Panacea Biotec Ltd. aranichatterjee@panaceabiotec.com

2. Current Positions • Senior Vice President, Clinical Research, Panacea Biotec Ltd. • Mentor, NovoTrail Pharm Innovation Hub Pvt. Ltd. • Member, Brighton Collaboration Case Definition Working Group (Diarrhea) • Member, Brighton Collaboration Case Definition Working Group (Viral Vector Vaccines) • Member, Brighton Collaboration Case Definition Working Group (Malaria and Tuberculosis Vaccines) • Member, Brighton Collaboration Case Definition Reference Group (Local reaction) • Member, Brighton Collaboration Case Definition Reference Group (Guillain Barré syndrome) • Member, Project Advisory Committee, NSTMIS (National Science and Technology Management Information System) division, Department of Science and Technology, Government of India (Project title: “Study of Bottlenecks in Industry, Academia and Institution Linkage in Pharmaceutical Sector and Development of a Database for Academia-Industry Partnership Promotion”) • Member, Expert Committee, PG Diploma in Clinical Research, Indira Gandhi National Open University • Member, Academic Board of Studies, Institute of Clinical Research, Hindustan Institute of Medical Sciences & Research, Sharda University, Greater Noida • Member, Governing Council, Institute of Clinical Research (India) • Member, Indian Society for Clinical Research • Visiting Faculty, Institute of Bioinformatics and Biotechnology, University of Pune • Visiting Faculty, Institute of Clinical Research (India)

3. Vaccine Safety • Vaccines demand special consideration because • Vaccines are generally given to healthy individuals, mostly children and infants. • Vaccines are mostly given to prevent disease; this limits tolerability of adverse events. • Vaccines are biological products which are highly complex substances derived from living materials, and sometimes comprising living organisms.

4. Vaccine Pharmacovigilance • Vaccine pharmacovigilance is defined as the science and activities relating to the detection, assessment, understanding, prevention, and communication of AEFI, or of any other vaccine- or immunization-related issues

5. Vision for continued improvement of passive surveillance data • Immediate and continuous access to accurate and automated data to optimize signal detection

6. Current Vaccine Issues • Very few companies manufacture vaccines: high costs of development, high manufacturing costs, liability concerns • Dominated by pediatric vaccines • Increasingly vaccine development is aimed at adolescent and adult diseases and populations (e.g. Influenza, Pertussis booster, HPV, Zoster, oncology vaccines, nicotine)

7. Signal Identification • Spontaneous Reports • Case definition, case ascertainment and case documentation • develop predefined check lists or formats for those adverse reactions which can be anticipated from the experience with comparable vaccines to be reported after authorisation (e.g. SIDS in temporal association with vaccines in infants) • definitions of the Brighton Collaboration should be considered if appropriate • adequate follow-up of serious spontaneous adverse reaction reports should be guaranteed

8. Signal Identification • Spontaneous Reports • Causality assessment • Vaccine induced adverse reactions following immunisation: those due to the intrinsic characteristics of the vaccine preparation and the individual response; • Vaccine precipitated: those triggered by administration of a vaccine but may also have occurred later or in other circumstances; • Other events: including GMP errors, contamination, administrative errors, vaccine storage errors; • Coincidental, only temporally related, not due to immunisation

9. Signal Identification • Spontaneous Reports • Handling of Consumer reports • AESIs/DMEs • Vaccine failures as expedited reports • Clear case definition; • Brighton Collaboration • MedDRA SMQs • Validated analytical methods; • Documentation of proper handling of immunisation; and • Evaluation of risk factors (e.g. obesity, age, smoking status)

10. Signal Identification • Periodic Safety Update Reports (PSURs) • Impact of changes of the manufacturing process on safety; • Batch relatedness of adverse reactions and other (quality) problems; • Vaccines failures/lack of effect; • Relevant literature information concerning stabilisers, preservatives and adjuvants and products with comparable antigens; • Concomitant administration: If concomitant vaccination (either simultaneous or mixed administration) with another vaccine is specifically mentioned in the SPC, safety aspects of the concomitant administration should be analysed; and • Safety aspects of different vaccination schedules and different dosages (adults, children)

11. Signal Quantification and Evaluation • Post-Marketing Studies • Rare but serious adverse reactions; • Reactions with delayed onset; and/or • Reactions in subpopulations • Data Management • Age (e.g. premature infants, neonates, infants, the elderly); • Number of doses; • Batch numbers; • Different vaccination schedules; and • Defined risk factors or underlying diseases

12. Vaccine Withdrawal –Case Study 1998 –Rotashield approved • Rotavirus: highly contagious infection which causes diarrhea, vomiting and fever in infants; common cause of hospitalizations & may be fatal • RotaShield: Wyeth vaccine that protected against rotavirus gastroenteritis; launched 1998 • CDC analyses indicated a safety signal in reported number of intussusception (bowel obstruction) cases temporally associated in infants that received Rotashield • Vaccine withdrawn due to safety concerns

13. Current Vaccine Safety –Case Study 2005 –MCV4 (Menactra) approved • MCV4: Sanofi quadrivalent meningococcal polysaccharide-protein conjugate vaccine • As of October 2006: 17 cases of Guillain-Barré Syndrome reported within 6 weeks of MCV4 vaccination • This was compared to the background incidence rate of GBS in 11-19 years olds using 2 databases (HCUP, VSD)

14. Current Vaccine Safety –Case Study 2006 –MCV4 meningococcal vaccine and GBS • 0.2 GBS cases per 100,000 person months (observed rate) • Background incidence rate of GBS in 11-19 years olds from 2 databases (HCUP, VSD): 0.11 GBS cases per 100,000 person-months (expected) • Risk ratios (observed vs. expected): • 1.78 (1.02-2.85) HCUP • 1.77 (0.96-3.07) VSD

15. Current Vaccine Safety –Case Study MCV4 meningococcal vaccine and GBS: Risk-Benefit Analysis • Risk:1.25 cases of GBS for every 1 million doses of MCV4 distributed to persons 11-19 years of age • Benefit: stated in terms of counterbalancing risk of invasive meningococcal disease • 1.2 cases per 100,000 persons per year; case fatality rate 10-14%

16. FDA VAERS Form

17. Vaccine Safety Surveillance VSD –Vaccine Safety Datalink Project • Population-based Data; collaborative with: • CDC (Nat’l Immunization Program) • 8 large MCOs • AHIP (America’s Health Insurance Plans) • Includes multiple merged data elements: vaccine history, medical event information, demographic data, VAERS reports • Adaptable, rapid methodology

18. CIOMS VIII Signal Detection Working Group • Comments regarding various Signal definitions were sent to CIOMS WG VIII • A vaccine-specific point-to-consider document as an annex to Signal definition in collaboration with CIOMS WG VIII has been finalized

19. Beyond VAERS • Safety throughout the Lifecycle • Enhance role of Safety Teams in safety signal response, safety communications, and policy • Analytic Epidemiology • “Adaptive toolbox” to rapidly and effectively respond to safety “signals”

20. Important links • Vaccine Pharmacovigilance Definition • http://www.cioms.ch/activities/vaccpharmadef.htm • CIOMS/WHO Working Group on Vaccine Pharmacovigilance • http://www.cioms.ch/activities/vaccpharma.htm • Guideline on the Conduct of Pharmacovigilance for Vaccines for Pre- and Post-exposure Prophylaxis against Infectious Diseases (EMEA/CHMP/PhVWP/503449/2007) • http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/11/WC500011272.pdf • Beyond VAERS: How the FDA continues to improve vaccine safety surveillance • http://www.fda.gov/downloads/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/UCM218707.pdf