Premarketing Risk Assessment Special Conditions

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Premarketing Risk AssessmentSpecial Conditions

• Robert J. Temple, M.D.
• Associate Director for Medical Policy
• Center for Drug Evaluation and Research
• Food and Drug Administration

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Background

• Youve already heard a discussion of some of the
  most important general issues in pre-marketing
  assessment, including
• The size of the safety data base and
  characteristics of the drug and its effects, its
  proposed use, and the intended population that
  could affect the size
• Characteristics of an ideal safety data base,
  including adequate duration, a diverse
  population, and better dose-response information
  than we typically see. The last is particularly
  important for drugs with a high rate of
  drug-induced adverse effects or biomarkers of
  injury (CPK, TA, UA, K changes)

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Background (cont.)

• A good search for individualization factors,
  such as drug-drug interactions, drug-demographic
  relationships, and drug-disease relationships,
  including routine population PK
• Comparative data when it would be particularly
  important

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Special Considerations

• Evaluation of safety has some general principles,
  but as the paper indicates, that doesnt mean one
  size fits all. In planning and monitoring
  development there needs to be constant attention
  to results of animal and human data, to
  suggestions of problems, and to population and
  drug-specific features that raise special
  concerns. When these occur, plans need to be
  modified.
• The concept paper identifies some of these

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Special Considerations

• 1. Is maintenance dose the same as the acute
  dose?
• A. Pharmacokinetic Sometimes, long half-life
  drugs are started at high doses to get a prompt
  effect. Should the maintenance dose be lowered?
• Astemizole. The 10 mg dose was close to the dose
  causing TdP (factor of lt2). Maintenance could
  have been 3 mg (factor of about 6-7)
• Fluoxetine. Drug and metabolites have half lives
  well over a week. Seems likely maintenance dose
  could be lower

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Special Considerations

• 1. Maintenance dose
• b. PD. Perhaps the drug induces PD changes that
  would allow lower or intermittent doses, or allow
  drug holidays. The drug could produce an
  undesired effect that might be mitigated by lower
  doses.
• Alosetron. Observation of constipation in 30 of
  population starting with troublesome diarrhea
  suggests a back-off approach at first
  improvement might have avoided severe constipation

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Special Considerations

• 2. Titration It is not common for drugs that
  are titrated to have actual comparisons of
  various methods. Too slow and too fast could
  both be problems.

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Special Considerations

• 3. Subtle adverse effects Certain adverse
  effects are notoriously poorly studied in trials,
  such as effects on
• sexual function
• cognition
• motor skills (driving)
• mood
• These can become major issues (SSRI sexual
  function, depression with isotretinoin) and would
  be best studied in controlled trials as soon as
  there are hints of concern. They might, e.g., be
  dose related, respond to drug holidays, etc.

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Special Considerations

• 4. Pediatric - specific issues This is now
  becoming clear with the explosion of peds
  studies, but children pose special issues of
  growth and neurocognitive development. It is
  also particularly useful to avoid mid-day dosing

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Special Considerations

• 5. Expanding the data base, the large simple
  safety study (LSSS), a study focussing on a small
  number of specified outcomes, generally with
  reduced routine data collection.
• Not as strange an idea as it once was
• Pre-marketing studies (gt10,000 patients) to
  evaluate a new antibiotic, a new COX-2 selective
  NSAID, and an antihypertensive (omapatrilat,
  concern about angioedema)
• Similar studies are underway post-marketing
  (ziprasidone vs. olanzapine, salmeterol).
• When might this be considered?

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Special Considerations

• 5. LSSS (cont.)
• To evaluate a troublesome safety signal, e.g.,
  transaminitis with one or two bilirubin
  elevations, ambiguous extreme QT prolongations,
  that needs a larger database
• When a drug is to be used for long periods in
  asymptomatic people, to assess potential
  unexpected problems
• To evaluate a larger, less restricted population
  for potential consequences of drug-drug or
  drug-demographic interactions

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Special Considerations

• 6. Keep blood or other tissue samples for
  potential later pharmacogenomic evaluation
  (serious events, better responses). Need to pay
  attention to consent issues
• Related (not in paper) is importance of
  capturing serious events and studying the
  individuals (blood levels at least). This is
  particularly emphasized in QT paper but is ok
  more general importance

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Always Evaluated

• Some matters always need assessment, notably
• QTc effects
• Evidence of hepatotoxicity
• Polymorphic metabolism
• Drug-drug interactions, including new ones
  (inducers, inhibitors of glucuronidation,
  P-glycoprotein inhibitors)
• And, for biologics
• Immunogenicity, neutralizing Abs
• For live agents-virulence, transmissibility,
  genetic stability
• Transplantation therapies - survival, function,
  host immunocompetence

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Medication Error Prevention Analysis (MEPA)

• PRE-MARKETING ASSESSMENT TO INCREASE THE SAFE
  USE OF DRUG PRODUCTS BY MINIMIZING MEDICATION
  ERRORS RELATED TO THE NAMING, LABELING, AND/OR
  PACKAGING OF THE PRODUCT

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PRE-MARKETING ERROR PREVENTION

• PROPRIETARY and GENERIC NAME ANALYSIS
• for Sound and Look Alike similarities
• Expert and/or Focus Groups
• Verbal Orders Simulation
• Handwritten Orders Simulation
• Computer Analysis
• Orthographic/Phonetic
• Overall Risk and Benefit Assessment

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PACKAGING

• Analysis of the packaging for its error
  potential
• What are the inherent risks and benefits of
  choosing or not choosing a particular drug
  delivery package (e.g. ampule vs. syringe)?

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LABELS/LABELING

• Labeling Analysis
• Container label similarities within product
  line/class?
• Similarities with other products?
• Is Critical Information (e.g., drug name,
  strength, route of administration) clear for the
  end user?
• Are the dosing instructions in the PI clear and
  easily understood?

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Conclusion

• We look forward to discussion
• Were sure the experience of this audience can
  refine and expand the thoughts in the concept
  paper