Risk Management in premarketing phase

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Risk Management in premarketing phase

• Anshu Vashishtha MD PhDcharak_at_pol.net(in
  individual capacityemployer Watson
  Pharmaceuticals)

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Role of Investigator Brochure in Risk Management
in Development

• Major instrument of risk management during this
  phase is the investigators brochure(IB).
• 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.
• Most do not clearly differentiate adverse events
  and reactions.
• Do 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.

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Developmental Core Safety Information -1

• CIOMS group recommended concept of Developmental
  Core Safety Information (DCSI).
• 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.
• Clearly indicate population exposed to the drug
• 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 Investigators Brochures , Geneva
  1999

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Developmental Core Safety Information- 2

• Indicate 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.
• For all toxicity, adverse events and reactions
  indicate the frequency category observed during
  development using CIOMS guidelines (very
  common(gt1/10), common(1/10- 1/100), uncommon
  (1/100- 1/1000), rare (1/1000- 1/10000), very
  rare (lt 1/10000)
• Ensure 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 DCSI

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Concept paper lines 79-83 Size of databases
needed for products

• Size 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 exist

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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 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 concern
• If missing data could be related to an adverse
  event, consider peri-approval large simple
  safety study (LSSS) commitment to exclude concern

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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.)
• Reason Safety information derived here would
  still be relevant (eg. Hypersensitivity or dose
  related toxicity in overdose setting)

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Summary Enhancing premarketing risk management
by improving safety data presentation in
Investigator Brochure

• Developmental Core Safety Information (DCSI) to
  communicate risk information better.
• Separate listed adverse reactions and unlisted
  adverse events
• Provide data on frequency
• Provide data on exposure