1. Risk Management in premarketing phase Anshu Vashishtha MD PhD charak@pol.net (in individual capacity employer : Watson Pharmaceuticals)

2. Role of Investigator Brochure in Risk Management in Development Major instrument of risk management during this phase is the investigator’s brochure(IB). concept of Developmental Core Safety Information (DCSI). Organization of safety information in the IB needs to be enhanced to improve risk management using CIOMS concept of Developmental Core Safety Information (DCSI). Investigators need to accurately understand likelihood of risk and frequency of risk to be able to understand and manage it

3. Limitations of safety information in IBs Variable in format.Variable in format. Most do not clearly differentiate adverse events and reactions.Most do not clearly differentiate adverse events and reactions. Do not consistently give frequency of adverse reactionsDo not consistently give frequency of adverse reactions Events mentioned may be considered listed even if they are not considered as related to the study drug.Events mentioned may be considered listed even if they are not considered as related to the study drug.

4. Developmental Core Safety Information -1 CIOMS group recommended concept of Developmental Core Safety Information (DCSI).*CIOMS group recommended concept of Developmental Core Safety Information (DCSI).* Collect all safety related information in the IB in one section.Collect all safety related information in the IB in one section. Use the information to reflect the safety portion of the anticipated label upon approval.Use the information to reflect the safety portion of the anticipated label upon approval. Clearly indicate population exposed to the drugClearly indicate population exposed to the drug Clearly indicate contraindications, warnings and precautions.Clearly indicate contraindications, warnings and precautions. *Guidelines for preparing Core Clinical Safety Information on Drugs, Second Edition Report of CIOMS Working Groups III and V including New Proposals for Investigator’s Brochures, Geneva 1999

5. Developmental Core Safety Information- 2 Indicate adverse reactions (Events that are considered associated with the drug) which will be considered listedIndicate adverse reactions (Events that are considered associated with the drug) which will be considered listed Separately indicate adverse events (reports whose relationship to study drug is unclear) ? listedness while they remain in this section.Separately indicate adverse events (reports whose relationship to study drug is unclear) ? listedness while they remain in this section. For all toxicity, adverse events and reactions indicate the frequency category observed during development using CIOMS guidelines (very common(>1/10), common(1/10- 1/100), uncommon (1/100- 1/1000), rare (1/1000- 1/10000), very rare ( 1/10), common(1/10- 1/100), uncommon (1/100- 1/1000), rare (1/1000- 1/10000), very rare (< 1/10000) Ensure regular medical review of safety information and DCSIEnsure regular medical review of safety information and DCSI For drugs approved in another jurisdiction, consider using the safety information from the approved label there as the basis for DCSIFor drugs approved in another jurisdiction, consider using the safety information from the approved label there as the basis for DCSI

6. Concept paper lines 79-83 : Size of databases needed for products Size of databases for acute products needed should depend uponSize of databases for acute products needed should depend upon – safety profile of compound – anticipated risk –Anticipated benefit –intended population For chronic products, ICH guidance generally adequate, with the possibility of exceptions for preventive products where safe alternatives already existFor chronic products, ICH guidance generally adequate, with the possibility of exceptions for preventive products where safe alternatives already exist

7. Concept paper lines 514- 516 : analysis of missing data Examine for proportionately greater frequency of loss to follow up in treated group versus placebo (may suggest safety concern).Examine for proportionately greater frequency of loss to follow up in treated group versus placebo (may suggest safety concern). Examine frequency of adverse event or lab abnormality using the time period over which data is not missing as denominator.Examine frequency of adverse event or lab abnormality using the time period over which data is not missing as denominator. Examine separately lab data and adverse events in subgroup of patients lost to follow up to evaluate indication of safety concernExamine separately lab data and adverse events in subgroup of patients lost to follow up to evaluate indication of safety concern If missing data could be related to an adverse event, consider peri-approval large simple safety study (LSSS) commitment to exclude concernIf missing data could be related to an adverse event, consider peri-approval large simple safety study (LSSS) commitment to exclude concern

8. Concept paper line 479 : pharmacodynamic and pharmacokinetic studies Add : However adverse reactions observed in these studies should be included in relevant section (adverse event, overdose etc.)Add : However adverse reactions observed in these studies should be included in relevant section (adverse event, overdose etc.) Reason: Safety information derived here would still be relevant (eg. Hypersensitivity or dose related toxicity in overdose setting)Reason: Safety information derived here would still be relevant (eg. Hypersensitivity or dose related toxicity in overdose setting)

9. Summary: Enhancing premarketing risk management by improving safety data presentation in Investigator Brochure Developmental Core Safety Information (DCSI) to communicate risk information better.Developmental Core Safety Information (DCSI) to communicate risk information better. Separate listed adverse reactions and unlisted adverse eventsSeparate listed adverse reactions and unlisted adverse events Provide data on frequencyProvide data on frequency Provide data on exposureProvide data on exposure