Risk management strategies for Rotavirus vaccines GSK

Risk management strategiesfor Rotavirus vaccinesGSK Biologicals

Thomas Verstraeten7th Annual International Rotavirus Symposium

June 13, 2006

Rota symposium Lisbon June 13, 20062

Overview

• (Rotavirus vaccine) Risk management planning: general remarks

• Rotarix risk management plans

• Intussusception and age


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


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


Summary of risks or questions to be assessed in PMS






Collaborations with European rotavirus network, CDC, WHO + ongoing epidemiological studies








Collaboration with the European Rotavirus Network:

Targeted sequencing of a subset of G1P[8] strains

If vaccine signature identified: investigate for mutation or reassortant in isolate








Phase IIIb clinical trial (Study 052) with 100 pairs of twins3 stools collected per week for 6 weeks post vaccination

If transmission detected:• Determine infectious viral load in stool of vaccinee and transmitted contact•Perform mutational analysis on isolated RV








Phase IIIb clinical trial (Study 054) among 1000 subjects in 2 gestational age categories:

• Preterm: > 31 - < 36 weeks• Very preterm: > 27 - < 31 weeksEvaluate safety, reactogenicity and immunogenicity

Phase II clinical trial (Study 022) in South Africa among 100 HIV + children

Three dose schedule: 6, 10 and 14 weeks of ageEvaluate safety, reactogenicity and immunogenicity








Well established causal relationship for 1 rotavirus vaccineRisk of same magnitude excluded for 2 licensed vaccines thus far

(RotateqTM and RotarixTM)⇒ No class effect, but:

1. In the absence of well established etiology, IS needs to be excluded for every new rotavirus vaccine

2. To further re-assure policy makers, further follow-up desired in Post-Marketing Surveillance (PMS)


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


Power to Detect Increase in IS CasesAdditional IS Cases (Power to Detect) Under Different Vaccine Coverages

46 (95)

32 (87)

17 (67)

25%

92 (100)

65 (99)

35 (89)

50%

185 (100)9 (46)7211 850 654D+UK +I

131 (100)6 (38)5121315372D+UK

71 (99)3 (27)280719 250D

100%5%Baseline IS Cases

Birth CohortCountry

AR = 1 IS case per 10,000 infants vaccinated


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)


Risk of IS and age

• Murphy et al, NEJM 2001

• Simonsen et al, JID 2005

• Rothman et al, letter to the editor JID 2006


Murphy et al, MEJM 2001

Murphy, NEJM 2001


Simonsen et al, JID 2005Table 2. Relative risk (Odds Ratio, OR*) of Rotashield-associated, by dose and age.

0.8 [0.2-4.6]1.7 [0.7-4.4]8.6 [4.6-16]Age 1-11 mo

0.6 [0.1-4.2]0.3 [0.03-2.5]15.9 [4.6-54.2]5+ [>=120]

**3.5 [0.98-12.3]10.5 [4.0-27.4]3-4 [60-119]

****5.7 [1.2-28.3]1-2 [0-59]

OR0-21 days3rd dose

OR0-21 days2nd dose

OR0-21 days1st doseAge in

months and [days]

Simonsen, JID 2005


Rothman et al, JID 2006Spline curve IS risk following 1st dose Rotashield

No clear trendNo data!

Rothman, JID 2006


Spline curve IS risk following 1st dose Rotarix(study 023)

0.01

0.1

1

10

100

40 45 50 55 60 65 70 75 80 85 90

Age at first dose of Rotarix

Rel

ativ

e ris

k co

mpa

red

to p

lace

bo


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


Thank you

Documents

Risk management strategies for Rotavirus vaccines GSK