Premarketing Risk Assessment

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Premarketing Risk Assessment

• Robert J. Meyer, MD
• Director, ODE II / OND / CDER
• Chair of RA Working Group

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Group 1 - Premarketing Risk Assessment WG

• Bob Meyer Barbara Gould PM
• Mary Willy Ellis Unger
• George Rochester Mark Avigan
• David Graham Jerry Phillips
• Donna Griebel Robert Temple
• Zili Li Judy Racoosin
• Peter Lee David Cho
• Trish Rohan
• Janice Newcomb, Aileen Ciampa, Lois Chester

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Premarketing Risk Assessment

• Presentations
• Generating Risk Information
• General Considerations - Bob Meyer
• Special Considerations - Bob Temple
• Reporting Risk Information
• Analyzing and Presenting Risk Information - Ellis
  Unger

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Premarketing Risk Assessment

• For Each Topic
• FDA presentation
• Public Comment Period
• Panel Discussion (with questions from the
  attendees)

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Premarketing Risk Assessment

• What is Risk Assessment?
• Risk assessment is the process of identifying,
  estimating and evaluating the nature and severity
  of risk from a product
• Good risk assessment underlies good risk
  management and pharmacovigilance

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Premarketing Risk Assessment

• Concept Paper and Talk Does NOT cover
• Pre-clinical and clinical pharmacology aspects of
  development
• Efficacy considerations
• Post-marketing risk assessment

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Premarketing Risk Assessment

• Appropriate size of safety database
• Ideal Size depends on
• Novelty of the product
• Proposed Indication
• life-sustaining vs. symptom relief
• Intended duration of use
• Safety concern from pre-clinical, early clinical
  findings

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Premarketing Risk Assessment

• ICH E-1 has guidance on long-term treatments
  (chronic or intermittent, recurrent) for non-life
  threatening conditions
• 1500 patients total, with
• 300 - 600 for 6-months, 100 for one year

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Premarketing Risk Assessment

• ICH E-1 does NOT specify what patients should be
  regarded as contributing to this 1500 patient
  target
• For chronic use drugs, should come from multiple
  dose studies of reasonable duration (e.g., 4
  weeks or more)
• Should be exposed to doses at or above lowest
  proposed dose

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Premarketing Risk Assessment

• Rule of Three tells us that for a 1,500 patient
  database, we have a reasonable chance of
  identifying a particular event that occurs at a
  rate of 1 / 500!
• Yet, drugs commonly are used by thousands to
  millions of patients shortly after release

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Premarketing Risk Assessment

• When are ICH targets not enough?
• ICH
• Cause for concern for time related effect on
  safety
• Need to quantify low-frequency events
• Limited or unknown efficacy
• Where there is concern that a product may add to
  a background rate of morbidity/mortality

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Premarketing Risk Assessment

• When are ICH targets not enough?
• FDA
• Preventive treatments
• A very safe alternative already exists
• There is a potential for a large market and very
  fast uptake into the marketplace, particularly
  for a drug for a non-life-threatening,
  non-serious condition

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Premarketing Risk Assessment

• For acute use therapies and/or those for
  life-threatening diseases, no ICH or FDA guidance
  exits
• For life-saving products with mortality trials,
  these data alone may be enough to demonstrate
  acceptable risk/benefit
• Accelerated approval - definitive efficacy and
  full safety may come later

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Premarketing Risk Assessment

• What are the Characteristics of an ideal safety
  database?
• Controlled trials performed throughout
• Diverse population (age, race/ethnicity,
  concomitant disease, drugs.)
• Range of doses explored throughout development

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Premarketing Risk Assessment

• What are the Characteristics of an ideal safety
  database?Controlled trials performed throughout
• essential for detecting treatment relation to
  common outcomes in the population
• helps address confounding by indication
• With active comparator, opportunity to judge
  safety vs. accepted (approved) therapy

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Premarketing Risk Assessment

• What are the Characteristics of an ideal safety
  database?Diverse Population
• Only patients with obvious contraindications
  excluded in late phase trials
• Allows for better generalizability of safety
  findings
• Develop better clinical data on Rx-demographic,
  Rx - disease and Rx - Rx interactions

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Premarketing Risk Assessment

• What are the Characteristics of an ideal safety
  database?Range of doses studied throughout
  development
• Better characterize clinical exposure-response
  relationship (dose finding not complete at EOP-2)
• May help provide important E-R data for dose
  adjustments in subpopulations
• (Also may add important information on the
  assessment of efficacy - maximizing benefit vs.
  risk)

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Premarketing Risk Assessment

• To detect potential interactions not previously
  identified, sponsors should
• Be vigilant for drug-drug interactions,
  particularly for likely concomitant medications
  (e.g., binding resins and HMG-CoA reductase
  inhibitors)
• Product -demographic interactions (diverse
  population studied)

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Premarketing Risk Assessment

• To detect potential interactions not previously
  identified, sponsors should
• Product-disease interactions (study range of
  disease and concomitant diseased patients)
• Product-food interactions
• Product-dietary supplement interactions (for
  popular supplements for the disease in question)

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Premarketing Risk Assessment

• To help detect potential interactions
• An important way of providing data to inform
  about unanticipated interactions is to perform
  drug level (e.g., population PK) assessments in
  phase 3 trails
• Could help define E-R relationship for SE (help
  validate biomarkers)
• Could help define drug level relationship to any
  unusual, rare AE

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Premarketing Risk Assessment

• When would comparative safety data be useful?
• Expected with some classes of products (e.g.,
  preventive vaccines)
• Need to characterize background rates
• When there is a well established,
  well-characterized low toxicity product

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Premarketing Risk Assessment

• When would comparative safety data be useful?
• Where there is a well-established, related
  therapy
• Where there is an established therapy with effect
  on survival or altering irreversible morbidity
• When the sponsor wishes to make comparative claims

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Premarketing Risk Assessment

• Conclusion
• Pre-marketing Risk Assessment relatively mature,
  but still evolving
• Public Health, Industry and FDA would all benefit
  from optimizing Risk Assessment allowing for
  approval of safe drugs with fully informative
  labeling