Clinical development of marketed drugs for new uses
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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