Pharmacovigilance in the Post-Marketing Setting: Results from the RADAR Project

1. Pharmacovigilance in the Post-Marketing Setting:Results from the RADAR Project Charles L. Bennett MD PhD MPP

2. Limited size of clinical trials Undetected toxicities at time of FDA approval Many AEs identified after several years on the market Barriers to Identifying Adverse Events

3. Presentation Overview • Comparison of post-marketing pharmacovigilance activities by: • Academic organizations • The Food and Drug Administration (FDA) • Pharmaceutical manufacturers

4. Objectives • Describe 3 types of pharmacovigilance methods • Illustrate strengths/weaknesses of each approach • Suggest novel collaborations and possibility for new public-private partnerships

5. Pharmacovigilance Organizations

6. Detect ADR signals Investigate possible ADR occurrence Analyze data Disseminate results Lessons Learned: The RADAR method Bennett CL, Nebeker JR, Lyons EA, et al. The Research on Adverse Drug Events and Reports (RADAR) Project. JAMA 2005, 293:17, 2131-40.

7. Timing and Dissemination

8. Report Completeness: RADAR vs. FDA *P < .005 for completeness of RADAR vs. FDA • Includes data from 1998- 2006. • Includes the drugs: gemtuzumab, clopidogrel, ticlopidine, gemcitabine, sildenafil, tadalafil, amiodarone, paclitaxel or sirolimus coated cardiacstents, epoetin alfa, nevirapine, • thalidomide, lenalidomide, MGDF, enoxaparin, and bisphosphonates. Bennett CL, Nebeker JR, Yarnold PR, et al. Evaluation of Serious Adverse Drug Reactions: A proactive pharmacovigilance program (RADAR) vs. safety activities conducted by the Food and Drug Administration and pharmaceutical manufacturers. Arch Int Med. 2007; 167: 1041-49.

9. Report Completeness: RADAR vs. Supplier • Includes data from 1998- 2006. • Includes the drugs: gemtuzumab, clopidogrel, ticlopidine, gemcitabine, sildenafil, tadalafil, amiodarone, paclitaxel or sirolimus coated cardiacstents, epoetin alfa, nevirapine, • thalidomide, lenalidomide, MGDF, enoxaparin, and bisphosphonates. Bennett CL, Nebeker JR, Yarnold PR, et al. Evaluation of Serious Adverse Drug Reactions: A proactive pharmacovigilance program (RADAR) vs. safety activities conducted by the Food and Drug Administration and pharmaceutical manufacturers. Arch Int Med. 2007; 167: 1041-49.

10. Major RADAR Publications

11. Postmarket Pharmacovigilance Hampton, T. Postmarket “Pharmacovigilance” Program on Alert for Adverse Events from Drugs. JAMA, August 22/29 2007, 298 (8): 851-2.

12. Example 1: Epoetin and Pure Red-Cell Aplasia Bennett CL, Luminari S, Nissenson AR, et al. Pure red-cell aplasia and epoetin therapy. N Engl J Med 2004; 351:1403-8.

13. Epoetin and Pure Red-Cell Aplasia Bennett CL, Luminari S, Nissenson AR, et al. Pure red-cell aplasia and epoetin therapy. N Engl J Med 2004; 351:1403-8.

14. Pharmacovigilance Chart: Epoetin and PRCA

15. Summary: Epoetin and PRCA • Safety of epoetin improved to normal; sales maintained • Data exchange between different entities was important • Fear of appearing self-serving limited companies’ ability to monitor epoetin safety

16. Example 2:Clopidogrel/Ticlopidine and TTP

17. Clopidogrel/Ticlopidine and TTP Ticlopidine Clopidogrel

18. Thienopyridine-Associated TTP Onset Thienopyridine-Associated TTP Onset: ADAMTS13 Deficient versus near normal levels of ADAMTS13 activity (p>0.05).

19. Thienopyridine-Associated TTP Onset Thienopyridine-Associated TTP Onset: Ticlopidine versus Clopidogrel (p=0.0016).

20. Clopidogrel/Ticlopidine and TTP • Two suspected pathogenic mechanisms: • 1. In TTP patients with near normal ADAMTS13 levels, the pathopyshiology resembles that of clopidogrel-associated TTP. • 2. In TTP patients with deficient ADAMTS13 levels, the pathophysiology resembles that of ticlopidine-associated TTP.

21. Comparison of findings for ticlopidine- versus clopidogrel-associated TTP *Ticlopidine received its original FDA approval in 1991; current sales are $100,000. **Clopidogrel received its original FDA approval in 1998; current sales are $5.6 billion.

22. Comparison of findings for ticlopidine- versus clopidogrel-associated TTP

23. Comparison of findings for ticlopidine- versus clopidogrel-associated TTP

24. Comparison of findings for ticlopidine- versus clopidogrel-associated TTP

25. Pharmacovigilance Chart: Clopidogrel/Ticlopidine and TTP

26. Summary: Clopidogrel/Ticlopidine and TTP • Prospective data collection and basic science support were important • Mechanism characterized • Reporting was timely (1 year post approval)

27. Example 3: Erythropoietin/darbepoetin in cancer • Since 2003, Market-expanding indications explored: • Anemia of cancer • Anemia caused by radiotherapy • Prevention of anemia prior to chemotherapy initiation • Raising hemoglobin levels beyond the correction of anemia

28. Effect of ESA on survival: studies before 2003 vs. after 2003

29. Effect of ESA on survival: studies before 2003 vs. after 2003

30. Effect of ESA on survival: studies with and without survival endpoint

31. Effect of ESA on survival: studies with and without survival endpoint

32. Pharmacovigilance Chart: Erythropoietin/darbepoetin in cancer

33. Summary: Epoetin/darbepoetin in cancer • Both on- and off-label data was important • Took 16 years to notice safety concern • Basic science research on-going

34. Example 4:Erythropoietin in chronic kidney disease • Project: • Evaluate meta-analyses, randomized controlled clinical trials, and observational trials regarding the safety of erythropoietin in dialysis patients • Purpose: • Determine if safety signals have been under-reported or muted due to heterogeneity of trials and meta-analyses, specifically when major adverse events were not included as a primary or secondary outcome

35. Risk of all-cause mortality in the higher hemoglobin target group compared with the lower hemoglobin target group Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet 2007; 369:381-88.

36. Risk of mortality as an efficacy endpoint versus a safety endpoint Safety: 0.67(0.37, 1.19) Efficacy: 1.27(1.08, 1.49)

37. In Summary: • Per the Lancet meta-analysis: risk of all-cause mortality in higher versus lower Hb target group: RR (95%CI): 1.17(1.01, 1.35) • Our meta-analysis: risk of all-cause mortality as an efficacy endpoint versus a safety endpoint in higher versus lower Hb target group: RR (95%CI): 1.27(1.08, 1.49)

38. Unadjusted 1-year mortality rates by hematocrit group according to epoetin dose quartile Zhang Y, Thamer M, et al. Epoetin requirements predict mortality in hemodialysis patients. Am J Kidney Dis, 2004 Nov;44(5):866-76

39. Pharmacovigilance Chart: Erythropoietin in chronic kidney disease

40. Clinical Trials Registries Case Reports Referral Centers Databases Independent Pharmacovigilance Center Information Synthesis; Epidemiology; Basic Science; Immunology; Pathology Dissemination Academic FDA Company Other Presentations/Abstracts at National Medical Conferences Company Alerts, Including Dear HCP Letters and Package Insert Updates Eisenberg Center- Consumer Union Reports VA MedSafe Publications in Peer-Reviewed Medical Journals CERTs MedWatch Reports Company Communication w/RADAR DEcIDE Centers Cochrane Collaboration FDA Alerts Evidence-Based Practice Center Reports New Paradigm for Pharmacovigilance

41. Future Pharmacovigilance Efforts R-01 Funded Hematology and Oncology RADAR SERF-TTP Chicago Acute Liver Failure Texas: UT Southwestern Dallas FDA Funded (20%) Pediatric University of North Carolina CERT FDA U-01 Funded CERT Data Coordinating Center Cardiovascular Duke CERT Ocular Toxicities Oregon Health and Sciences No Funding Physicians CERT Communication Center Nurses Q-T Cardiac Arrhythmia Arizona CERT Pharmacists GI Vanderbilt CERT CERT Funded Cleveland Clinic Cleveland Cardiology/GI/Peds/ID University of Pennsylvania Philadelphia

42. Conclusions • Current pharmacovigilance methods have limitations • Quality vs. Quantity • Timing and dissemination • Novel public-private collaborations are needed to improve ADR detection/reporting and improve patient safety