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

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Overview

• (Rotavirus vaccine) Risk management planning:

general remarks

• Rotarix risk management plans
• Intussusception and age

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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

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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

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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

– Intussusception – Impact on RV serotype distribution

• Rotarix specific question:

Populations not fully investigated in completed clinical trials: – Preterm infants – Immunocompromised infants

Collaborations with European rotavirus network, CDC, WHO +

• ngoing epidemiological studies

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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

– Intussusception – Impact on RV serotype distribution

• Rotarix specific question:

Populations not fully investigated in completed clinical trials: – Preterm infants – Immunocompromised infants

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

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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

– Intussusception – Impact on RV serotype distribution

• Rotarix specific question:

Populations not fully investigated in completed clinical trials: – Preterm infants – Immunocompromised infants

Phase IIIb clinical trial (Study 052) with 100 pairs of twins 3 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

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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

– Intussusception – Impact on RV serotype distribution

• Rotarix specific question:

Populations not fully investigated in completed clinical trials: – Preterm infants – Immunocompromised infants

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

• Preterm: > 31 - < 36 weeks
• Very preterm: > 27 - < 31 weeks

Evaluate 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 age Evaluate safety, reactogenicity and immunogenicity

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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

– Intussusception – Impact on RV serotype distribution

• Rotarix specific question:

Populations not fully investigated in completed clinical trials: – Preterm infants – Immunocompromised infants

Well established causal relationship for 1 rotavirus vaccine Risk 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)

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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

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Power to Detect Increase in IS Cases

Additional 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)

721 1 850 654 D+UK +I

131 (100) 6 (38)

512 1315372 D+UK

71 (99) 3 (27)

280 719 250 D

100% 5% Baseline IS Cases Birth Cohort Country AR = 1 IS case per 10,000 infants vaccinated

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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)

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Risk of IS and age

• Murphy et al, NEJM 2001
• Simonsen et al, JID 2005
• Rothman et al, letter to the editor JID 2006

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Murphy et al, MEJM 2001

Murphy, NEJM 2001

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Simonsen et al, JID 2005

Table 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 days 3rd dose OR0-21 days 2nd dose OR0-21 days 1st dose Age in months and [days] Simonsen, JID 2005

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Rothman et al, JID 2006 Spline curve IS risk following 1st dose Rotashield No clear trend No data!

Rothman, JID 2006

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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 Relative risk compared to placebo

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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

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Thank you