CLINICAL DEVELOPMENT OF MARKETED DRUGS FOR NEW USES

1. CLINICAL DEVELOPMENT OF MARKETED DRUGS FOR NEW USES RUSSELL KATZ, M.D. DIRECTOR DIVISION OF NEUROLOGY PRODUCTS/CDER

2. DOMAINS OF INTEREST • Regulatory considerations • Pre-clinical/CMC • Effectiveness • Safety • New safety concerns • Pediatrics

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

4. 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

5. 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

6. 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

7. 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

8. 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

9. PRE-CLINICAL/CMC • 505(b)(2) applications • Alternatively, if new indication is for markedly different population, considerable pre-clinical work may be required

10. 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

11. 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

12. 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

13. 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

14. 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!

15. 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

16. 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

17. EFECTIVENESS • “Subsets” of approved claims • Effect on progression • AD, PD, ALS, MS • Probably will require two trials, but… • Difficult design issues

18. EFFECTIVENESS • “Subsets” of approved indications • Comparative claims • Superior efficacy • Superior safety • Will require replication • Very difficult design issues

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

20. EFFECTIVENESS • New claim never previously granted • Example: MCI; compulsive gambling; treatment of ADRs • Multiple questions raised • Diagnostic criteria • Outcome measures • Duration

21. 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

22. 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

23. 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

24. 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)

25. 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

26. 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

27. SAFETY • New populations • May require extensive additional safety data because: • New doses • Longer durations • Different concomitant meds (DDs) • Previous safety data not relevant

28. 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

29. 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

30. 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

31. 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