Risk management strategies for Rotavirus vaccines GSK Biologicals - PowerPoint PPT Presentation

Risk management strategies for Rotavirus vaccines GSK Biologicals Thomas Verstraeten 7th Annual International Rotavirus Symposium June 13, 2006

Overview • (Rotavirus vaccine) Risk management planning: general remarks • Rotarix risk management plans • Intussusception and age 2 Rota symposium Lisbon June 13, 2006

Risk Management Plans (RMPs) What are they? « A risk management plan is the presentation of a risk management system set up for a specific product in the form of a plan » 1 Set of PV activities & interventions to identify, characterize, prevent/minimize risk related to medicinal products … 1 Draft Volume 9A of The Rules governing Medicinal Products in the European Union 3 Rota symposium Lisbon June 13, 2006

Summary of risks or questions to be assessed in RMPs • Question for any vaccine: – Vaccine effectiveness – Impact on disease epidemiology • Question for any live viral vaccine: – Genetic stability of vaccine virus – Vaccine virus transmission • Question for any Rotavirus vaccine – Intussusception – Impact on RV serotype distribution • Rotarix specific question: Populations not fully investigated in completed clinical trials: – Preterm infants – Immunocompromised infants 4 Rota symposium Lisbon June 13, 2006

Summary of risks or questions to be assessed in PMS • Question for any vaccine: – Vaccine effectiveness – Impact on disease epidemiology • Question for any live viral vaccine: – Genetic stability of vaccine virus Collaborations with European rotavirus network, CDC, WHO + – Vaccine virus transmission • Question for any Rotavirus vaccine ongoing epidemiological studies – Intussusception – Impact on RV serotype distribution • Rotarix specific question: Populations not fully investigated in completed clinical trials: – Preterm infants – Immunocompromised infants 5 Rota symposium Lisbon June 13, 2006

Summary of risks or questions to be assessed in PMS • Question for any vaccine: – Vaccine effectiveness – Impact on disease epidemiology • Question for any live viral vaccine: – Genetic stability of vaccine virus – Vaccine virus transmission • Question for any Rotavirus vaccine Collaboration with the European Rotavirus Network: – Intussusception Targeted sequencing of a subset of G1P[8] strains – Impact on RV serotype distribution • Rotarix specific question: If vaccine signature identified: investigate for mutation or Populations not fully investigated in completed clinical trials: reassortant in isolate – Preterm infants – Immunocompromised infants 6 Rota symposium Lisbon June 13, 2006

Summary of risks or questions to be assessed in PMS • Question for any vaccine: – Vaccine effectiveness – Impact on disease epidemiology • Question for any live viral vaccine: – Genetic stability of vaccine virus – Vaccine virus transmission • Question for any Rotavirus vaccine Phase IIIb clinical trial (Study 052) with 100 pairs of twins 3 stools collected per week for 6 weeks post vaccination – Intussusception – Impact on RV serotype distribution • Rotarix specific question: If transmission detected: • Determine infectious viral load in stool of vaccinee and Populations not fully investigated in completed clinical trials: transmitted contact – Preterm infants •Perform mutational analysis on isolated RV – Immunocompromised infants 7 Rota symposium Lisbon June 13, 2006

Summary of risks or questions to be assessed in PMS • Question for any vaccine: Phase IIIb clinical trial (Study 054) among 1000 subjects in 2 – Vaccine effectiveness gestational age categories: – Impact on disease epidemiology • Preterm: > 31 - < 36 weeks • Question for any live viral vaccine: • Very preterm: > 27 - < 31 weeks Evaluate safety, reactogenicity and immunogenicity – Genetic stability of vaccine virus – Vaccine virus transmission • Question for any Rotavirus vaccine Phase II clinical trial (Study 022) in South Africa among 100 HIV + children – Intussusception Three dose schedule: 6, 10 and 14 weeks of age – Impact on RV serotype distribution • Rotarix specific question: Evaluate safety, reactogenicity and immunogenicity Populations not fully investigated in completed clinical trials: – Preterm infants – Immunocompromised infants 8 Rota symposium Lisbon June 13, 2006

Summary of risks or questions to be assessed in PMS Well established causal relationship for 1 rotavirus vaccine • Question for any vaccine: Risk of same magnitude excluded for 2 licensed vaccines thus far (Rotateq TM and Rotarix TM ) – Vaccine effectiveness ⇒ – Impact on disease epidemiology No class effect, but: • Question for any live viral vaccine: 1. In the absence of well established etiology, IS needs to be – Genetic stability of vaccine virus excluded for every new rotavirus vaccine – Vaccine virus transmission 2. To further re-assure policy makers, further follow-up desired in • Question for any Rotavirus vaccine Post-Marketing Surveillance (PMS) – Intussusception – Impact on RV serotype distribution • Rotarix specific question: Populations not fully investigated in completed clinical trials: – Preterm infants – Immunocompromised infants 9 Rota symposium Lisbon June 13, 2006

Intussusception in PMS 1. Enhanced passive surveillance (targeted questionnaires and observed/expected analyses) Current reports: 15 cases, no clustering in time-to-onset, all resolved or improved, 3 Mi doses distributed (approx 75 IS cases expected within 1 month after vaccination)* 2. Active IS surveillance in selected European countries Limited power and dependent on use of vaccine 3. Post Authorisation Safety Study (PASS) in Mexico * Assuming annual IS rate of 25/100,000 and 2 doses/child at 2 and 4 months of age 10 Rota symposium Lisbon June 13, 2006

Power to Detect Increase in IS Cases Additional IS Cases (Power to Detect) Birth Baseline Under Different Vaccine Coverages Country Cohort IS Cases 5% 25% 50% 100% D 719 250 280 3 (27) 17 (67) 35 (89) 71 (99) 6 (38) 32 (87) 65 (99) 131 (100) D+UK 1315372 512 D+UK +I 1 850 654 721 9 (46) 46 (95) 92 (100) 185 (100) AR = 1 IS case per 10,000 infants vaccinated 11 Rota symposium Lisbon June 13, 2006

PASS in Mexico • To be performed in collaboration with the Instituto Mexicano de la Seguridad Social (IMSS) – 40 million individuals with a birth cohort of 575,000 • Will be initiated at institution of universal mass vaccination • Epidemiological analyses: – Powered to exclude AR for IS of 1/10,000 – Self-controlled case series (650 vaccinated cases) – 2 - 4 years to complete study (function of speed uptake, enrollment rates and coverage of all hospitals) 12 Rota symposium Lisbon June 13, 2006

Risk of IS and age • Murphy et al, NEJM 2001 • Simonsen et al, JID 2005 • Rothman et al, letter to the editor JID 2006 13 Rota symposium Lisbon June 13, 2006

Murphy et al, MEJM 2001 14 Murphy, NEJM 2001 Rota symposium Lisbon June 13, 2006

Simonsen et al, JID 2005 Table 2. Relative risk (Odds Ratio, OR*) of Rotashield-associated, by dose and age. OR 0-21 days OR 0-21 days OR 0-21 days 1 st dose 2 nd dose 3 rd dose Age in months and [days] 1-2 [0-59] 5. 7 [1.2-28.3] ** ** 3-4 [60-119] 10.5 [4.0-27.4] 3.5 [0.98-12.3] ** 5+ [>=120] 15.9 [4.6-54.2] 0.3 [0.03-2.5] 0.6 [0.1-4.2] Age 1-11 mo 8.6 [4.6-16] 1.7 [0.7-4.4] 0.8 [0.2-4.6] 15 Simonsen, JID 2005 Rota symposium Lisbon June 13, 2006

Rothman et al, JID 2006 Spline curve IS risk following 1st dose Rotashield No clear trend No data! 16 Rota symposium Lisbon June 13, 2006 Rothman, JID 2006

Spline curve IS risk following 1st dose Rotarix (study 023) 100 10 Relative risk compared to placebo 1 0.1 0.01 40 45 50 55 60 65 70 75 80 85 90 Age at first dose of Rotarix 17 Rota symposium Lisbon June 13, 2006

Risk of IS and age: conclusion • No evidence of an interaction between age and the relative risk of IS following Rotashield • No evidence that relative risk of IS would be lower under 2 months of age • No indication that absence of risk for IS following Rotarix would be different for other age groups 18 Rota symposium Lisbon June 13, 2006

Thank you 19 Rota symposium Lisbon June 13, 2006