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CLINICAL DEVELOPMENT OF MARKETED DRUGS FOR NEW USES. RUSSELL KATZ, M.D. DIRECTOR DIVISION OF NEUROLOGY PRODUCTS/CDER. DOMAINS OF INTEREST. Regulatory considerations Pre-clinical/CMC Effectiveness Safety New safety concerns Pediatrics. REGULATORY CONSIDERATIONS.

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clinical development of marketed drugs for new uses

CLINICAL DEVELOPMENT OF MARKETED DRUGS FOR NEW USES

RUSSELL KATZ, M.D.

DIRECTOR

DIVISION OF NEUROLOGY

PRODUCTS/CDER

domains of interest
DOMAINS OF INTEREST
  • Regulatory considerations
  • Pre-clinical/CMC
  • Effectiveness
  • Safety
  • New safety concerns
  • Pediatrics
regulatory considerations
REGULATORY CONSIDERATIONS
  • Studies intended to support a new indication or change in advertising must be done under an IND
regulatory considerations1
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
regulatory considerations2
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
regulatory considerations3
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
pre clinical cmc
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
pre clinical cmc1
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
pre clinical cmc2
PRE-CLINICAL/CMC
  • 505(b)(2) applications
    • Alternatively, if new indication is for markedly different population, considerable pre-clinical work may be required
pre clinical cmc3
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
pre clinical cmc4
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
pre clinical cmc5
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
pre clinical cmc6
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
effectiveness
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!
effectiveness1
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
effectiveness2
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
efectiveness
EFECTIVENESS
  • “Subsets” of approved claims
    • Effect on progression
    • AD, PD, ALS, MS
      • Probably will require two trials, but…
      • Difficult design issues
effectiveness3
EFFECTIVENESS
  • “Subsets” of approved indications
    • Comparative claims
    • Superior efficacy
    • Superior safety
      • Will require replication
      • Very difficult design issues
effectiveness4
EFFECTIVENESS
  • Particular problems with new claims
    • New claim never previously granted
    • Pseudospecific claim
    • “Questionable” new claims
    • New brand name
effectiveness5
EFFECTIVENESS
  • New claim never previously granted
  • Example: MCI; compulsive gambling; treatment of ADRs
  • Multiple questions raised
    • Diagnostic criteria
    • Outcome measures
    • Duration
effectiveness6
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
effectiveness7
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
effectiveness8
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
effectiveness9
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)
effectiveness10
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
safety
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
safety1
SAFETY
  • New populations
    • May require extensive additional safety data because:
      • New doses
      • Longer durations
      • Different concomitant meds (DDs)
      • Previous safety data not relevant
safety2
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
new safety concerns
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
pediatrics
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
pediatrics1
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
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