Pentavalent Pentavalent Rotavirus Vaccine Rotavirus Vaccine European Risk European Risk Management Plan Management Plan Luc HESSEL 7th International Executive Director Rotavirus Symposium Medical and Public Affairs Sanofi Pasteur MSD Lisbon, June 12-13, 2006
From Post Post- -Marketing surveillance to Marketing surveillance to Risk Risk Management Management From The concept of Risk Management • A strategic approach to ensure optimal use of a medicinal product by individual patients and populations • A global approach � Identification and detection of risks linked to the use of the vaccine � Assessment , validation, quantification � Management through appropriate strategies to minimise risk • A paradigm change � From benefit-risk assessment to prevention of risk � From passive surveillance to active anticipation � From product safety to patient safety 2 Hessel, 7th Rotavirus Sympo, Lisbon, 12-13 June, 2006
European Risk Management System European Risk Management System • 2001: introduction of the concept of risk management plans in the EU legislation (Dir. 2001/83 EC) • June 2005: enforcement of the regulation on pharmacovigilance plans (CPMP/ICH/5716/03) • December 2005: Guideline on risk management systems for medicinal products for human use Definition of ERMS A set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risk relating to medicinal products, and the assessment of the effectiveness of those interventions 3 Hessel, 7th Rotavirus Sympo, Lisbon, 12-13 June, 2006
Risk Management Strategy: objectives and actions Risk Management Strategy: objectives and actions Detection Identify Assess Validation Communication RMS Monitor Assess Prioritise Update Quantification Minimisation Resolve / control 4 Hessel, 7th Rotavirus Sympo, Lisbon, 12-13 June, 2006
Key elements of Risk Management Plans (RMP) Key elements of Risk Management Plans (RMP) 1. Pharmacovigilance plan: a plan proposing collection of data relevant to the safety profile of a medical product once it is marketed and aiming to demonstrate safety as well as identifying harm 2. Risk minimization strategies to reduce risk to individual patients and populations 5 Hessel, 7th Rotavirus Sympo, Lisbon, 12-13 June, 2006
Characteristics of rotavirus vaccines Characteristics of rotavirus vaccines Characteristics of rotavirus vaccines • Live attenuated vaccines � Infectivity (immunosuppression), reassortment, reversion … • Oral administration � Intestinal replication and shedding • Target population: young infants from 6 weeks of age � Safety first • Co-administered with other childhood vaccines � Interferences • Prevention of infections due to several serotypes � Coverage and cross-protection � Strain replacement … and the Rotashield experience ! 6 Hessel, 7th Rotavirus Sympo, Lisbon, 12-13 June, 2006
Pentavalent RV vaccine RMP: Specifications Pentavalent RV vaccine RMP: Specifications • Identified risks � No safety signal identified in clinical trials (> 36,000 vaccinees and > 100,000 doses) • Potential risks � Extra-intestinal events reported to occur with wild-type RV � Events not previously anticipated � Intussusception (due to the history of Rotashield) � Potential for strain replacement and emergence of new reassortants � Transmission of vaccine virus from vaccinees to close contacts • Important missing information � Use in immunocompromised infants (study planned) � Safety and efficacy of PRV in developing world (studies planned) 7 Hessel, 7th Rotavirus Sympo, Lisbon, 12-13 June, 2006
Pentavalent RV vaccine RMP : action plan Pentavalent RV vaccine RMP : action plan 1. Global routine pharmacovigilance, spontaneous reporting + PSURs � unanticipated safety signals � all other adverse events 2. Post-marketing safety surveillance trial (observational study in 44,000 children - USA) � Intussusception (rule out a RR of 2.5 with a 80% power) � General short term tolerance (not pre-specified) � Potential extra-intestinal manifestations - Central nervous system : meningitis, encephalitis, paralysis, seizure - Hepatotoxic events � Significant gastro-intestinal events � Gastro-oesophageal reflux disease � … 8 Hessel, 7th Rotavirus Sympo, Lisbon, 12-13 June, 2006
Pentavalent RV vaccine RMP : Action plan Pentavalent RV vaccine RMP : Action plan Pentavalent RV vaccine RMP : Action plan 3.Incidence of intussusception (IT): Prospective evaluation of the annual incidence of IT in children <2 years: � ESPED system: « German surveillance system for rare paediatric diseases » � Birth cohort of 700,000 children will be monitored � Start January 2006 � Duration: min 2 years (6 monthly reports) 4.Transmissibility of the vaccine virus strain from vaccinees to close contacts, including immunocompromised � Study in infants born to HIV-infected mothers � Inclusion of HIV-infected and HIV-exposed infants 9 Hessel, 7th Rotavirus Sympo, Lisbon, 12-13 June, 2006
Pentavalent RV vaccine RMP: action plan Pentavalent RV vaccine RMP: action plan 5.Rotavirus strain surveillance:evaluation of the potential for strain replacement or emergence of novel reassortants � G and P genotyping of RV positive stools samples � Through European Foodborne Virus Network (11 EU countries) 6.Post-license effectiveness study � Will begin as soon as the vaccine is used with sufficient uptake to have enough power to assess its effectiveness 10 Hessel, 7th Rotavirus Sympo, Lisbon, 12-13 June, 2006
Pentavalent RV vaccine: Risk Minimisation Plan • Ready-to use liquid packaged in single dose user-friendly tubes: no admixture or misuse expected • Currently identified risks associated with PRV few and minor • Risk minimisation plan not required 11 Hessel, 7th Rotavirus Sympo, Lisbon, 12-13 June, 2006
CONCLUSION • Rotavirus vaccines are the first vaccines with such a large pre-licensure experience (since polio) • They will be the first vaccines to follow the new EU regulations on risk management • This should contribute to support the implementation of RV vaccination programmes and their acceptability by health care professionals and parents 12 Hessel, 7th Rotavirus Sympo, Lisbon, 12-13 June, 2006
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