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Update on the Safety of TNF Blockers

Update on the Safety of TNF Blockers. Li-ching Liang, M.D. FDA / CBER/ OTRR Arthritis Advisory Committee March 4, 2003. Update on Safety Outline. Update safety data from clinical trials and post-marketing reports Focus on several issues with new data Adalimumab and Tuberculosis

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Update on the Safety of TNF Blockers

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  1. Update on the Safety ofTNF Blockers Li-ching Liang, M.D. FDA / CBER/ OTRR Arthritis Advisory Committee March 4, 2003

  2. Update on Safety Outline • Update safety data from clinical trials and post-marketing reports • Focus on several issues with new data • Adalimumab and Tuberculosis • Malignancies/Lymphoma with all approved TNF blockers

  3. AdalimumabSafety Database • At end of Phase 2 meeting, Agency recommended large safety database • Abbott studied for safety: • 2070 pts. in controlled trials (mean exposure 7 mo.) • >2400 pts. in open-label studies (median exposure 24 mo.) • Interpretation of open label data difficult due to lack of concurrent control group though larger experience and duration of such trials are beneficial

  4. Adalimumab and TB: Early Clinical Trial Experience • 8 cases seen of initial ~542 pts. treated (1.5%) • After discussions with FDA, screening and prophylaxis measures begun: • Europe -> chest x-ray • USA -> PPD • For PPD+ patients, prophylactic anti-TB treatment per CDC Guidelines

  5. TB: Later Experience • Reduction but not elimination of TB following screening: • 5 cases in subsequent 1900 patients • Other factors may have reduced the TB rate: • lower doses used • fewer patients from highly endemic areas

  6. Adalimumab: Tuberculosis Most reported TB cases from Europe More frequent in patients receiving higher than licensed dose (40 mg q2wk) Most cases extrapulmonary Most occurred in first 8 months of therapy in controlled trials May reflect reactivation of latent infection Box Warning

  7. Malignancies • Because of immunomodulatory properties of TNF-blockers, concerned about malignancies with long-term treatment. • Assessment difficult because hard to maintain a comparator control arm in long-term studies • One approach: Compare observed malignancy rates to the expected rate in general population (e.g. using 1995-99 SEER Database adjusted for age, gender, race, geography) to calculate SIR - Standardized Incidence Ratio

  8. Malignancies & RA • Interpretation of data is complicated: • Lymphoma incidence reported to be several fold higher among RA patients, especially those with higher levels of disease activity and inflammation* • Most patients enrolled in trials have highly active disease • Most receive concomitant DMARDs with immunosuppressive properties *Baecklund E. et al. BMJ 1998; 317:180-1. *Wolfe, F. Arthritis Rheum 1998; 41 (9): S188.

  9. Malignancies with AdalimumabControlled Portions of Controlled Trials

  10. Lymphomas with AdalimumabControlled Portions of Controlled Trials

  11. Observed vs. Expected Cancer Rates Adalimumab Clinical Development Program (thru 8/02)* Based on SEER database * T

  12. Summary of 10 Lymphoma Cases By TypeAmong Adalimumab-Treated Patients (REAL Classification) • B cell lymphoma: Diffuse Large B-cell lymphoma (5) • B cell lymphoma: Mantle cell lymphoma • B cell lymphoma: Marginal Zone lymphoma • B cell lymphoma: Follicular center lymphoma • T cell lymphoma: Peripheral T cell lymphoma • Hodgkin’s Lymphoma

  13. Etanercept Malignancies and Lymphomas

  14. Etanercept Malignancies in Placebo-Controlled Portions of Clinical Trials (6 month trials)Etanercept: Malignancies in Controlled Portionsof Clinical Trials

  15. Etanercept: Types of Malignancies in Controlled Portions of RA Trials

  16. Etanercept:Lymphomas in Clinical Trial Database • 3389 patients representing 7364 pt-yrs of data • Median exposure of 2.2 yrs. • 6 lymphoma cases reported in all clinical trials • additional 3 cases reported after f/u period • 2.6 cases expected* • SIR 2.31 (95%CI 0.85, 5.03) * Based on SEER database

  17. Infliximab Malignancies and Lymphomas

  18. Infliximab: All malignancies in controlledportions of controlled trials (includes ASPIRE data)

  19. Basal cell CA (6) Squamous cell CA (4) Breast CA (3) Lymphoma (3) Follicular cell center NK lymphoma (IG) Angiocentric Melanoma (2) *Total of 23 malignancies in 22 patients 1blinded data where all malignancies counted as if observed in infliximab-treated subjects Rectal adenoCA Bladder CA Hypernephroma Pancreatic CA Endometrial CA Infliximab: All malignancies seen in the controlledportions of controlled trials (including ASPIRE)*

  20. Infliximab: Lymphomas in controlled portions of controlled trials

  21. Infliximab: All malignancies in all clinical trial experience

  22. Infliximab: Lymphomas in all clinical trial experience

  23. Lymphoma with TNF BlockersConclusions • Lymphomas observed with all 3 TNF blockers • Small numbers/short exposure in controlled portions of clinical trials • For entire database, calculated SIRs are between ~2 and 7 compared to SEER database • A more appropriate comparison would be to RA population but accurate incidence rates unavailable

  24. Lymphoma with TNF BlockersConclusions • 1-3 cases of lymphomas are diagnosed in treated groups for each TNF product, vs. 0 in control groups (6 lymphomas vs. 0 across all controlled studies) • Biological plausibility of lymphomas associated with immunomodulatory agents, along with these data presented, raise concern about causality

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