2. Arthritis Advisory Committee March 4, 2003 Presented at the Arthritis Advisory Committee meeting on March 4, 2003 by Jeffrey N. Siegel, M.D.

3. Arthritis Advisory Committee March 4, 2003 2 Adalimumab: Lymphomas Controlled portions of controlled trials: –Adalimumab: 2 cases among 1380 patients, 0.6 yrs mean exposure –Placebo: 0 cases among 690 patients, 0.5 yrs mean exposure Overall database: 10 cases among 2400 patients, 2.4 yrs median exposure, SIR 5.42 (2.6, 10.0) Controlled portions of controlled trials: –Adalimumab: 2 cases among 1380 patients, 0.6 yrs mean exposure –Placebo: 0 cases among 690 patients, 0.5 yrs mean exposure Overall database: 10 cases among 2400 patients, 2.4 yrs median exposure, SIR 5.42 (2.6, 10.0)

4. Arthritis Advisory Committee March 4, 2003 3 Etanercept: Lymphomas Controlled portions of controlled trials: –Etanercept: 1 case among 2502 patients, 0.5 yrs mean exposure –Placebo: 0 cases among 921 patients, 0.5 yrs mean exposure Overall database: 6 cases among 3389 patients, 2.2 yrs mean exposure, SIR 2.31 (0.85, 5.03) Controlled portions of controlled trials: –Etanercept: 1 case among 2502 patients, 0.5 yrs mean exposure –Placebo: 0 cases among 921 patients, 0.5 yrs mean exposure Overall database: 6 cases among 3389 patients, 2.2 yrs mean exposure, SIR 2.31 (0.85, 5.03)

5. Arthritis Advisory Committee March 4, 2003 4 Infliximab: Lymphomas Controlled portions of controlled trials: –Infliximab: 3 cases among 2421 patients, 1.0 yrs mean exposure –Placebo: 0 cases among 489 patients, 0.9 yrs mean exposure Overall database: 6 cases among 2421 patients, 1.7 yrs mean exposure, SIR 6.98 (2.56, 15.19) Controlled portions of controlled trials: –Infliximab: 3 cases among 2421 patients, 1.0 yrs mean exposure –Placebo: 0 cases among 489 patients, 0.9 yrs mean exposure Overall database: 6 cases among 2421 patients, 1.7 yrs mean exposure, SIR 6.98 (2.56, 15.19)

6. Arthritis Advisory Committee March 4, 2003 5 Concluding Remarks: Lymphomas Newer data show occurrence of lymphomas with each of the approved agents: –In controlled trials, 1-3 cases with study drugs vs. 0 with placebo –Controlled plus non-controlled extension trials showed higher rate than in general US population –Additional cases in post-marketing experience Higher reported rates in RA patients complicates analysis Newer data show occurrence of lymphomas with each of the approved agents: –In controlled trials, 1-3 cases with study drugs vs. 0 with placebo –Controlled plus non-controlled extension trials showed higher rate than in general US population –Additional cases in post-marketing experience Higher reported rates in RA patients complicates analysis

7. Arthritis Advisory Committee March 4, 2003 6 CHFCHF Deleterious effects of infliximab in CHF patients Concerning trends in CHF patients receiving etanercept Adalimumab – not known Deleterious effects of infliximab in CHF patients Concerning trends in CHF patients receiving etanercept Adalimumab – not known

8. Arthritis Advisory Committee March 4, 2003 7 ConclusionsConclusions Approved TNF blockers associated with high ACR response rates in RA, beneficial effects in progression of structural damage –For infliximab, demonstrated improvement in HAQ in long-term study A number of serious, but uncommon, adverse reactions also associated with their use For some adverse events, risks can be reduced with appropriate screening Approved TNF blockers associated with high ACR response rates in RA, beneficial effects in progression of structural damage –For infliximab, demonstrated improvement in HAQ in long-term study A number of serious, but uncommon, adverse reactions also associated with their use For some adverse events, risks can be reduced with appropriate screening

9. Arthritis Advisory Committee March 4, 2003 8 Risk Management Important to: –Maximize benefit –Minimize risk For identified risks of TNF blockers: –Collect data to accurately assess risk –Minimize risks where appropriate by patient selection and screening –Risk communication Important to: –Maximize benefit –Minimize risk For identified risks of TNF blockers: –Collect data to accurately assess risk –Minimize risks where appropriate by patient selection and screening –Risk communication

10. Arthritis Advisory Committee March 4, 2003 9 Agency Welcomes Discussion of: For lymphoma –Confounding factors in assessing causal relationships –Likelihood of causal relationship between lymphomas & TNF blockers –How to collect data that would help assess causal associations –Appropriate language for labels to communicate available information For CHF –Approaches to risk management For lymphoma –Confounding factors in assessing causal relationships –Likelihood of causal relationship between lymphomas & TNF blockers –How to collect data that would help assess causal associations –Appropriate language for labels to communicate available information For CHF –Approaches to risk management