POST-MARKETING SURVEILLANCE: ONE DIVISION DIRECTOR’S VIEW

1. POST-MARKETING SURVEILLANCE: ONE DIVISION DIRECTOR’S VIEW RUSSELL KATZ, M.D. DIRECTOR DIVISION OF NEUROLOGY PRODUCTS/CDER

2. POST-MARKETING SURVEILLANCE IS: • Detecting a signal • Determining causality/frequency • Doing something about it • Informing relevant parties about the problem

3. TYPES OF SAFETY SIGNALS WE SEE • Adverse Events • Medication Errors • Product Failures • Labeling Failures

4. WAYS THAT WE BECOME AWARE OF A SAFETY SIGNAL • Literature • Spontaneous Reports (AERS) • Manufacturer • Private citizen • Trials • Registries

5. ADVERSE EVENTS • Tysabri and Liver Injury • Botox and “Botulism” • Dopamine Agonists and Cardiac Valvulopathy • Pathological Gambling • Tysabri and Progressive Multifocal Leukoencephalopathy (PML) • Anticonvulsants and Suicidality

6. ADVERSE EVENTS-SPONTANEOUS REPORTS (AERS) • Tysabri and Significant Liver Injury • Several individual cases of elevated LFTs and Bilirubin • Examination of individual cases for alternative causes; two positive re-challenges • Botox and “Botulism” • Several cases consistent with known pharmacology

7. ADVERSE EVENTS-SPONTANEOUS REPORTS (AERS) • Adverse Events with “known” background rates • Tolcapone and liver failure • Felbamate and aplastic anemia

8. HOW WE EVALUATE A SAFETY SIGNAL FROM SPONTANEOUS REPORTS • Someone (clinical reviewer, safety reviewer, etc.) detects a serious (possibly unlabeled) adverse event • Task is to assess causality (also examine RCTs) • Review of individual case report usually not definitive • Incomplete information • Logically flawed

9. HOW WE EVALUATE A SAFETY SIGNAL FROM SPONTANEOUS REPORTS • EB 05 • Lower limit of the 90% Confidence Interval around the following metric: • # of cases of event of interest/ # of total ADRs for the drug DIVIDED BY • # of cases of event of interest of all drugs/ # of total ADRs for all drugs • If >2, considered a possible signal

10. HOW WE EVALUATE A SAFETY SIGNAL FROM SPONTANEOUS REPORTS • Calculation of a Reporting Rate (Not an incidence) • RR = #cases reported/patient-years of exposure • Patient-years = #prescriptions/12 (assume each prescription for 30 days) • Compare RR to background rate and other drug(s) • Assume background rate is relevant • May not be (e.g., nefazadone)

11. HOW WE EVALUATE A SAFETY SIGNAL FROM SPONTANEOUS REPORTS • Any RR approaching the background rate is presumptive evidence that the drug caused the adverse event due to underreporting (many factors influence reporting or lack thereof) • In many cases, the spontaneous reports serve as the basis for a definitive decision: i.e., spontaneous reports are not always just hypothesis generating

12. ADVERSE EVENTS-SPONTANEOUS REPORTS-LITERATURE • Dopamine Agonists and Valvulopathy • One case control study, one echocardiographic prevalence study in NEJM, 2007 • Previous studies and AERS search in 2004 led to conclusion about ergot-derived agonists • Recent AERS search for other agonists, 5HT2B agonists

13. ADVERSE EVENTS-LITERATURE • Dopamine agonists and Pathologic Gambling • Case series in the literature; mostly Mirapex (some Requip) • AERS searched for all dopaminergic drugs for impulse control disorders • Adequate background rates not available

14. VARIANT OF ADVERSE EVENT ASSESSMENT-LITERATURE • Stevens-Johnson Syndrome known to occur with carbamazepine • Literature reports of a marked increased incidence in Han Chinese patients • Additional corroboration from international spontaneous reports • Data “established” HLA B-1502 as an important risk factor for SJS

15. ADVERSE EVENTS-CLINICAL TRIALS • Tysabri and PML • Three cases observed in open-label extensions of controlled trials being done in Phase 4 • Marketing discontinued and entire database examined for any additional cases-none found • Causality assumed from mechanism

16. ADVERSE EVENTS-CLINICAL TRIALS • AEDs and Suicidality • Sponsor notified us of a signal from their controlled trials • Submission of a citizen petition raising questions about another AED • All controlled trials from 11 recently approved AEDs examined

17. ADVERSE EVENTS-CLINICAL TRIALS • Hypnotics and cancer • Individual academic performed analyses of data for recently approved hypnotics on the basis of which he concluded that they are associated with an increased risk for cancer • Resulted in detailed review of numerous databases that did not confirm his conclusions

18. ADVERSE EVENTS-REGISTRIES • Possible teratogenicity (cleft lip/palate) with Lamictal • Sponsor informed division of data from two pregnancy registries • Analyses of other registries did not reveal confirmatory findings

19. ADVERSE EVENTS-REGISTRIES • Amendments to monitoring requirements for agranulocytosis for Clozapine • Requested by an interested party based on family member’s experience • Resulted in detailed review of accumulated data to date and ultimately a change to the monitoring regimen

20. MEDICATION ERRORS • Lamictal/Lamisil • Reminyl/Amaryl • Fosphenytoin

21. HOW WE EVALUATE MEDICATION ERRORS • Here, detailed review of cases can help pinpoint how the problem arises, and point the way to possible solutions • Name confusion • Lamictal/Lamisil • Written/verbal prescription • Carton appearance; overlapping strengths • Drug locations on pharmacy shelf

22. HOW WE EVALUATE MEDICATION ERRORS • Here, detailed review of cases can help pinpoint how the problem arises, and point the way to possible solutions • Name confusion • Reminyl/Amaryl • Similar written appearance • Several deaths due to hypoglycemia

23. HOW WE EVALUATE MEDICATION ERRORS • Here, detailed review of cases can help pinpoint how the problem arises, and point the way to possible solutions • Product Label • Fosphenytoin • Total units in vial (100 mg/2 mL) vs concentration (50mg/mL) • Automated displays still use old description

24. PRODUCT FAILURES • Sometimes, the causes (or the errors) are obvious • Example: • Diastat Accudial (prefilled syringes of diazepam for rectal administration) • Leakage from cracked tips • Inappropriate dialing of doses

25. PRODUCT FAILURES • Potential “failures” of generic AEDs to perform adequately (possible ADRs and/or breakthrough seizures) reported to Agency by expert community • Personal experience • Surveys • Literature

26. LABELING FAILURE-PHASE 4 STUDIES • Novantrone (mitoxantrone): approved for progressive multiple sclerosis • Two required Phase 4 studies • A study to evaluate incidence of cardiomyopathy in patients prospectively monitored • A “real-life” study to see if patients monitored according to labeling-insurance records for 400+ patients

27. LABELING FAILURE-PHASE 4 STUDIES • Novantrone (mitoxantrone): approved for progressive multiple sclerosis • Data show: • Cardiomyopathy occurs at much lower cumulative doses than previously believed • Very few patients are monitored appropriately

28. AVAILABLE ACTIONS • Early communications • Press Release, Public Health Announcement • Pergolide and valvulopathy • Diastat failures • Physician information sheets • AEDs and suicidality • Teratogenicity and Lamictal • Early communications • Botox and botulism

29. AVAILABLE ACTIONS • Labeling changes • Tysabri and PML, Liver injury • Dopamine agonists and impulsive behaviors • Novantrone • Carbamazepine

30. AVAILABLE ACTIONS • Dear Health Care Practitioner Letters • Name Change • Reminyl to Razadyne • Removal from Market • Tysabri • Pergolide (“compassionate IND” instituted)

31. AVAILABLE ACTIONS • Require studies • AEDs and generic “failures” • Restricted distribution/observational studies • Tysabri • Extensive education campaigns and other changes • Lamictal/Lamisil errors • Change carton appearance

32. FOOD AND DRUG ADMINISTRATION AMENDMENTS ACT • Title IX-Drug Safety • Sec. 901 • FDA may require studies or clinical trials at the time of approval (or after approval if new safety information)

33. FOOD AND DRUG ADMINISTRATION AMENDMENTS ACT • May require studies or clinical trials to: • Assess known serious risk related to drug use • Assess signals of serious risk related to drug use • Identify an unexpected serious risk when available data indicates the potential for a serious risk

34. FOOD AND DRUG ADMINISTRATION AMENDMENTS ACT • Before a study/trial may be required, FDA must find: • AE reporting and “active postmarketing risk identification and analysis system” are not sufficient to meet the purposes; • A post-approval study is not sufficient before requiring a clinical trial

35. FOOD AND DRUG ADMINISTRATION AMENDMENTS ACT • Required labeling changes • Agency must promptly inform sponsor of new safety information • Within 30 days, the sponsor must submit a labeling supplement or tell us why not • Rapid turnaround by Agency

36. FOOD AND DRUG ADMINISTRATION AMENDMENTS ACT • Required labeling changes • Within 15 days of conclusion of discussions, Agency can issue an order for a labeling change • Within 15 days of an order, sponsor must submit a labeling supplement, or within 5 days, sponsor may appeal the order

37. FOOD AND DRUG ADMINISTRATION AMENDMENTS ACT • Risk Evaluation and Mitigation Strategies (REMS)-Timetables Required • Pre-approval • FDA may determine REMS needed to ensure benefits outweigh the risks • Post-approval (if new safety information) • If needed to ensure benefits outweigh risks

38. NEW AGENCY SAFETY INITIATIVES • Safety First • Associate Directors for Safety • Dedicated Project Manager for Safety • Standardized Record Keeping for Safety Issues • Deadlines to be applied for action on safety issues

39. WHERE AGENCY CAN IMPROVE • No systematic surveillance outside AERS • Most assessments take too long • Have not consistently followed up requests to industry adequately (either for review of the data or requested labeling changes) • Coordination with consulting divisions can be more efficient

40. WHERE AGENCY CAN IMPROVE • May propose action with little prior notification to industry • May confuse, mislead, (anger?) relevant constituencies with early communications, public announcements

41. WHERE INDUSTRY CAN IMPROVE • Slow to respond to Agency requests • Unnecessary negotiations over labeling • Class labeling • Often don’t inform Agency of a problem (even if considerable work has been done) • May meet technical requirements for informing Agency (e.g., PSUR) but problems not flagged

42. WHERE INDUSTRY CAN IMPROVE • Even if Agency informed, may not have a proposal for a comprehensive plan • On the other hand, some proposals appear to be overly “negative” • Proposed labeling may describe adverse event which we all agree is not causally related to drug

43. THE FUTURE CHANGE WE CAN BELIEVE IN OR SOLUTIONS FOR AMERICA