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

• Studies intended to support a new indication or change in advertising must be done under an IND

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 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 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

• 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/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/CMC

• 505(b)(2) applications– Alternatively, if new indication is for markedly

different population, considerable pre-clinical work may be required

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/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/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/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

• 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!

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

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

• “Subsets” of approved claims– Effect on progression– AD, PD, ALS, MS

• Probably will require two trials, but…

• Difficult design issues

EFFECTIVENESS

• “Subsets” of approved indications– Comparative claims– Superior efficacy– Superior safety

• Will require replication

• Very difficult design issues

EFFECTIVENESS

• Particular problems with new claims– New claim never previously granted– Pseudospecific claim– “Questionable” new claims– New brand name

EFFECTIVENESS

• New claim never previously granted• Example: MCI; compulsive gambling; treatment

of ADRs • Multiple questions raised

– Diagnostic criteria– Outcome measures– Duration

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

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

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

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)

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

• 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

SAFETY

• New populations– May require extensive additional safety data

because:• New doses

• Longer durations

• Different concomitant meds (DDs)

• Previous safety data not relevant

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 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

• 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

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