1. Integrated Analyses of Safety Data needed! Marie Louise Valentin, MD Director of Corporate Drug Safety

2. AgendaAgenda Integrated Safety Outputs (ISOs): Regulatory purposes Signal Detection Presentations: Consistency and Clarity Risk Management Plans (RMPs) MedDRA: – Standardised MedDRA Queries (SMQs)

3. The Issue Applications and regulatory documents only summarize the safety database Statisticians today only analyse safety data across trials, when: – Potential problems arise or – The application is for a product from a class with a known safety concern Future Health Authorities require more regular integrated safety analyses

4. Purpose of Integrated Safety Outputs Many regulatory documents require reporting of safety information: 1. IND Annual Report (FDA) 2. Annual Safety Report (EMEA) 3. Investigator’s Brochure 4. Risk Management Plans 5. DMC Data Packages 6. Investigational Medical Product Dossier (Risk/Benefit) 7. Integrated Safety Summary – CTD

5. Integrated Safety Outputs Regular Integrated Safety Reviews – To be produced at least annually – Pool or combine data across studies – Present data from several studies in a single display Gain – Provide coordinated and routine review of integrated safety data – Assist with the compilation of regulatory documents reporting safety information/ DMC data/RMP updates etc.

6. Considerations for Pooling or Combining Data Main goal More precise estimates by increasing the safety database In general, ISO produced by indication or formulation: Backgound AE may differ according to patient population Severity of disease may lead to different assessments of risk/benefit The dose, formulation and duration of treatment may differ Across indication/formulations beneficial: Investigational product developed for related indications Characterize a particular AE of interest Investigate class effects

7. The AE profile may be related to… Route of administration Dose Number of dosages Duration of exposure Time since dosing Indication Stage of disease treated Concomitant medication/disease Effect on target cell/organ e.g. B-lymphocytes Demography

8. Signal Detection No systematic tools or methods in use within the industry Need to account for all safety data, not just AE records Monitor laboratory results for an increase in abnormalities Currently done manually, more efficient and consistent with standard checks pre-defined and applied to all studies Focus on three main areas (the most common reasons to terminate projects): – Hepatotoxicity(Liver) – Nephrotoxicity(Kidney) – Haematotoxicity(Blood)

9. Operational Issues Maintenance of treatment blind – Should not be an impediment to a full ongoing review of safety data? Who should have access to data and results? Should DMCs review un-blinded data? False signals – Problem or proactive pharmacovigilance? A policy for ’Integrated Safety Outputs’ should be prepared

10. Risk Management Plans (RMP) The overall purpose of a Risk Management Plan is to describe efforts in: – Identifying – Estimating – Evaluating – Communicating – Minimising risks that may be associated with the product.

11. Risk Management Plans EMEA: Guideline on Risk Management Systems for Medicinal Products for human use – Effective date 20 November 2005 FDA: Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiological Assessment Pre-marketing Guidance Pharmacovigilance Guidance (postmarketing) March 2005

12. Risk Management Plans Be product-specific Balance assessment of risks and benefits Monitor difference between clinical trials and ”real life” Identify what is known at licensing Identify what is not known Clarify epidemiology of disease and known adverse effects

13. What we know and don’t know Know: Population treated Time treated Time to adverse events Identify specific risk groups Stratify analysis by dose, duration etc Don’t know: Interactions Populations not studied: Children, elderly, pregnancy Relevance of class effects Long term effects

14. When do we need a Risk Management Plan? When initiating trials in New active substances New indications – incl extension to a different population New routes/formulations

15. Standardised MedDRA Queries After the initial effort to implement and use MedDRA, the industry now focuses on data analysis with MedDRA – How to produce data summaries based on a more granular terminology Standardised MedDRA Queries (SMQs): – Groupings of MedDRA terms that are related to a defined medical condition – Include terms related to signs, symptoms, diagnoses, syndromes, physical findings, laboratory test data

16. Standardised MedDRA Queries Developed in a collaboration with CIOMS, industry and regulators (Council for International Organizations of Medical Sciences, WHO and UNESCO in 1949 ) Tested in industry and regulatory databases Focus on significant safety issues Currently, 16 in production and 70 in development

17. SMQ’s in Production Rhabdomyolysis/myopathy Torsade de pointes/QT prologation Acute renal failure Hepatic disorders Haemolytic disorders Severe cutaneous adverse reactions Anaphylactic reactions Acute pancreatitis Agranulocytosis Angioedema Asthma/bronchospasm Dyslipidaemia Haematopoietic cytopenias Lack of efficacy/effect Lactic acidosis Peripheral neuropathy

18. SMQs in 2nd phase of development Adverse pregnancy outcome/reproductive toxicity Anticholinergic syndrome Cardiac arrhythmias Cerebrovascular disorders Convulsions Dementia Embolic and thrombotic events Pseudomembranous colitis Retroperitoneal fibrosis Shock

19. Standardised MedDRA Queries Available in MedDRA version 9.0

20. QuestionsQuestions