1. 1 TNF Blocker Safety: Lymphoma and Liver Failure Tim Coté MD MPH, Chief, Therapeutics & Blood Safety Branch, DE/OBE/CBER/FDA March 4, 2003

2. 2 Postmarketing Surveillance Clinicians and others can report adverse events associated with drugs Passive surveillance Greatest strength is as a means of signal generation

3. 3 Characteristics of Postmarketing Reports: Voluntary for clinicians but mandatory for companies Often incomplete -Unreported cases and -Sketchy narratives Coded into MedDRA terminology with high sensitivity Causality assessments are tenuous by design Cannot generate incidence rates

4. 4 Lymphomas with TNF Blockers Rich body of medical literature associating immunodisregulation and lymphoma; biologically plausible that TNF blockers might cause lymphoma Hundreds of thousands of patients on these drugs, increasing the public health importance of this Committee’s consideration. We have published a series of 26 lymphomas arising among people on TNF Blockers, but causality unclear.

5. 5 Lymphomas and TNF Blockers: Current Understanding RA and NHL are associated; this complicates the problem. Placebo-controlled studies have been small. Manufacturer’s pre- and post- marketing cohort studies have short follow-up times relative to carcinogenesis.

6. 6 Update: Lymphomas Reported to FDA following TNF blockers, 1/99-12/02

7. 7 Reports of 158 Lymphomas Reported Among Persons Taking TNF Blockers, 1/99-12/02 Source: Reports to FDA MedWatch program

8. 8 Patient Characteristics: Lymphoma among patients treated with TNF blockers InfliximabEtanerceptBoth Age: Median Range 66 24-85 62 29-85 64 24-85 % Female55%63%59% Indication RA Crohn’s Other 73% 21% 6% 86% 0% 14% 79% 12% 11%

9. 9 Histology of 158 Lymphomas among Patients with TNF Blockers, Reported to FDA 1/99-12/02 78 (49%) Lymphoma NOS 26 (16%) non-Hodgkin’s Lymphoma, NOS 23 (15%) B-cell lymphoma, NOS 20 (13%) Hodgkin’s Disease 6 (4%) T-cell Lymphoma 3 (2%) Mantle cell lymphoma 1 (1%) Plasmacytoma 1 (1%) Burkitt’s Lymphoma

10. 10 Conclusions: Lymphoma among TNF blocker recipients They are poorly characterized. It has not been established if they are the same grade as the general population. Histologically, they may be consistent with lymphoma secondary to immunodeficiency. Clinical trials found increased NHL risk, but based on few observations. Assessment is complicated by RA-confounded increases. The number of cases of lymphoma among persons taking TNF Blockers is growing. FDA needs input from the AAC to assess causality and/or propose means to better evaluate causality.

11. 11 Liver Failure Signal for Leflunomide, thus of interest for TNF Blockers In clinical trials, some patients on Infliximab showed elevated increased liver enzymes.

12. 12 Infliximab-mediated ALT Increases PlaceboInfliximab RA Patients on MTX 25/85 (29%) 127/342 (37%) CD Patients w/o MTX 68/187 (36%) 160/385 (42%) -Increased ALT was predominately <2x ULN --No clinical sequelae

13. 13 Analysis of Liver Failure Reports to FDA

14. 14 Extraneous causes of hepatic impairment among 43 pts on TNF Blockers.

15. 15 Conclusion: Liver Failure with TNF blockers Liver Failure with TNF Blockers appears to be a rare event While there are a large number of people on TNF blockers, chance occurrence is unlikely (1/10 6 in general pop); causality cannot be ruled out. Some concern remains warranted Further clinical data on remaining cases are pending.