Transcript SECTION 506(b)

CLINICAL DEVELOPMENT OF
MARKETED DRUGS FOR NEW USES
RUSSELL KATZ, M.D.
DIRECTOR
DIVISION OF NEUROLOGY
PRODUCTS/CDER
DOMAINS OF INTEREST
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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 preclinical 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 preclinical 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:
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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
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Kinetics prior to controlled trial
Attempt to identify tolerated doses
More exensive safety
Juvenile animal studies