clinical development of marketed drugs for new uses russell katz, m.d. director division of...
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CLINICAL DEVELOPMENT OF MARKETED DRUGS FOR NEW
USES
RUSSELL KATZ, M.D.
DIRECTOR
DIVISION OF NEUROLOGY
PRODUCTS/CDER
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DOMAINS OF INTEREST
• Regulatory considerations• Pre-clinical/CMC• Effectiveness• Safety• New safety concerns• Pediatrics
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REGULATORY CONSIDERATIONS
• Studies intended to support a new indication or change in advertising must be done under an IND
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REGULATORY CONSIDERATIONS
• What constitutes a new claim?– Addition of description of new results in
clinical trials section or elsewhere is tantamount to granting a “claim”
– Example: imaging results imply an effect on progression; unless we have concluded this is, indeed, true, it won’t be permitted in labeling
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REGULATORY CONSIDERATIONS
• Jurisdiction– IND/NDA for new indication is held in the
division with clinical expertise• Old records may not be readily available to new
division; consultation with new division is recommended
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REGULATORY CONSIDERATIONS
• New indication may qualify for fast track/priority review status– May give rise to difficult timing issues (need
for PCNS meeting, etc.)– May permit rolling review
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PRE-CLINICAL/CMC
• 505(b)(2) applications– For old drugs, pre-clinical data may not meet
current standards (e.g., Ca, repro studies)– This has led to many difficult decisions about
what to require
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PRE-CLINICAL/CMC
• 505(b)(2) applications– Where pre-clinical data are inadequate, current
policy is to not require new data if new use does not materially increase the number/type of patients exposed
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PRE-CLINICAL/CMC
• 505(b)(2) applications– Alternatively, if new indication is for markedly
different population, considerable pre-clinical work may be required
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PRE-CLINICAL/CMC
• New indication may require new formulation (ODT, patch, CR, oral suspension, etc.)
• Example: oral AED developed for status epilepticus– Entirely new CMC; impurities?; New
metabolite pattern?• May require new toxicity studies
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PRE-CLINICAL/CMC
• New indication may require new formulation• Example: once a day dosing with CR (ADHD)
• Markedly different exposures (shape of concentration/time curve) may necessitate new pre-clinical toxicity studies
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PRE-CLINICAL/CMC
• Current use may be for short term or for an orphan indication– Toxicity studies may be of short duration or
non-existent– New use may require extensive additional pre-
clinical work
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PRE-CLINICAL/CMC
• New indication may require new formulation– May give rise to different “names” (e.g., CR,
XL) for once a day dosing but for different dosing regimens
– This is likely to result in medication errors
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EFFECTIVENESS
• Entirely new claim– Typically, a new claim will require at least two
adequate and well-controlled trials• AED developed for depression
• DOSE FINDING MAY BE NECESSARY!
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EFFECTIVENESS
• “Subsets” of approved claims– New formulations for same indication (CR)
• Unless there is clear PK/PD relationship (almost never), we will require one controlled trial
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EFFECTIVENESS
• “Subsets” of approved claims– New seizure type for AED– Disease severity (severe AD)– Long-term maintenance (MDD)– Monotherapy for PD
• Typically, a single controlled trial will be required
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EFECTIVENESS
• “Subsets” of approved claims– Effect on progression– AD, PD, ALS, MS
• Probably will require two trials, but…
• Difficult design issues
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EFFECTIVENESS
• “Subsets” of approved indications– Comparative claims– Superior efficacy– Superior safety
• Will require replication
• Very difficult design issues
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EFFECTIVENESS
• Particular problems with new claims– New claim never previously granted– Pseudospecific claim– “Questionable” new claims– New brand name
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EFFECTIVENESS
• New claim never previously granted• Example: MCI; compulsive gambling; treatment
of ADRs • Multiple questions raised
– Diagnostic criteria– Outcome measures– Duration
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EFFECTIVENESS
• New claim never previously granted– We may not be in the position to offer
definitive advice– Convening outside experts not feasible in all
cases• Was done with MCI, Vascular Dementia
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EFFECTIVENESS
• Pseudospecific claim• Example: “increased vitality” for an
antidepressant – As a general rule, we will not allow a separate
claim for one symptom of a diagnostic category
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EFFECTIVENESS
• “Questionable” new claims• Example: pediatric conduct disorder; aggression
– Not clear if these entities “qualify” for drug treatment
– Larger “societal” issues need to be addressed
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EFFECTIVENESS
• New brand names– Increasing interest in having new names for
new indication– Strong agency bias against granting new name
• Increase chance for medication errors (double prescribing, confusion with other names)
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EFFECTIVENESS
• For any different claim for a marketed drug, it may be very difficult to get studies done if the drug:– Is already being used (e.g., AED in pediatrics)– Belief exists that the drug is already effective
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SAFETY
• New formulations• Intravenous
– May require new monitoring in trials related to kinetics
• EKG, vital signs at new, higher, Cmax
• Different metabolite pattern
• Requirement for assessment of increased rate of infusion
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SAFETY
• New populations– May require extensive additional safety data
because:• New doses
• Longer durations
• Different concomitant meds (DDs)
• Previous safety data not relevant
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SAFETY
• “Slightly” new indication– Prevent menstrual migraine with an acute
treatment• For acute treatments with acute ADRs, Even a few
more doses may require extensive new safety data
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NEW SAFETY CONCERNS
• New toxicities in new populations– Usually unpredictable– May raise questions about approved population
• Reminyl-deaths in patients with MCI
• Anti-psychotics-CVAs in patients with psychosis in AD
• Gabitril-seizures in non-epilepsy pts
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PEDIATRICS
• Pediatric studies required under PREA• Most studies done in response to written requests
issued by agency• In the past, pediatric studies were “tacked on” to
adult development
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PEDIATRICS
• Current requirements– At least one controlled trial almost always
required– “Full development” plan requested
• Kinetics prior to controlled trial
• Attempt to identify tolerated doses
• More exensive safety
• Juvenile animal studies