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, C max 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