CTD, Safety Tanja Braakman Genzyme Europe BV Pharmacovigilance Department

CTD, Safety 2.7.4Summary of Clinical Safety 1.xEU-RMP

2.7.4 Summary of Clinical Safety  Summary of data relevant to safety in the intended patient population; integration of individual CSRs or other reports

2.7.4 Summary of Clinical Safety  Exposure to the Drug  Adverse Events  Clinical Laboratory Evaluations  Vital Signs, Physical Findings, and Other Observations  Safety in Special Groups and Situations  Post-Marketing Data  Appendix

Exposure to the Drug  Overall Safety Evaluation Plan and Narratives of Safety Studies Special considerations, non clinical data, relevant pharmacological class effects, sources of safety data  Overall Extent of Exposure  Demographic and Other Characteristics of Study Population Age ranges ( ICH E7/ICH E11) Severity of disease, hospitalisation, impaired renal function, concomitant illnesses or medications, geographical location

Adverse Events  Analysis of Adverse Events Frequency of adverse events (drug vs comperator vs placebo) By dose (by severity, by time, by causality) Pooling of safety data  Common adverse events  Deaths  Other Serious Adverse Events  Other Significant Adverse Events (substantial intervention)  Analysis of Adverse Events by Organ System or Syndrome (potential related events)  Narratives

Clinical Laboratory Evaluations  Mean and median (central tendencies)  Range of values; number of patients with abnormal values  Clinically important abnormal lab value (discontinuations) Relationship to dose, drug concentration, disappearance with continued treatment, positive dechallenge, positive rechallenge, concomitant medication

Vital Signs, Physical Findings, and Other Observations  See previous slide  QT interval prolongation

Safety in Special Groups and Situations  Intrinsic Factors (demographic and other factors –ICH E5)  Extrinsic Factors (patient environment)  Drug Interactions  Use in Pregnancy and Lactation  Overdose  Drug Abuse  Withdrawal and Rebound  Effects on Ability to Drive or Operate Machinery or Impairment of Mental Ability

Post-Marketing Data  PSURs

1.X EU-RMP  Guideline on Risk Management Systems for Medicinal Products for Human Use (Draft)  A set of pharmacovigilance activities and interventions designed to proactively identify, characterise and prevent or minimise risks relating to medicinal products, including risk communication and the assesment of the effectiveness of risk minimisation interventions.

EU-RMP  Part I (ICH –E2E) A Safety Specification A Pharmacovigilance Plan, and  Part II Evaluation of the need for risk minimisation measures, and if there is such a need: A risk minimisation plan

EU-RMP  Safety Specification (basis of risk minimisation) Important identified risks, Important potential risks, and important missing information  Non-clinical  Clinical Limitations of the human safety database Populations not studied pre-authorisation (children, elderly, pregnant or lactating women, different disease severity) Adverse Events/Adverse Reactions (identified and potential risks, potential for overdose, presentation of risk data, potential for medication error, potential for illegal use, potential for transmission of infectious agents, interactions, epidemiology, pharmacological class effects)  Summary

EU-RMP  Pharmacovigilance Plan Routine Pharmacovigilance Practice Additional pharmacovigilance activities and action plans Action Plan for safety concern  Evaluation of the need for a Risk Minimisation Plan Risk(s) of particular nature and seriousness that minimisation actions are needed

EU-RMP  Risk minimisation plan Actions taken to reduce the risk associated with an individual safety concern  Risk minimization tools (risk communication)  Marketing authorisation  Ensuring the effectiveness of risk minimisation tools

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