1

Department of Health and Human Services

Center for Drug Evaluation and Research

Joint Arthritis & Drug Safety and Risk Management Advisory Committee

February 18, 2005

Sharon Hertz, M.D.Deputy Director

Division of Anti-Inflammatory, Analgesic, and Ophthalmologic Drug Products

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Department of Health and Human Services

Center for Drug Evaluation and Research

Reason we are here• Pain drugs are critically important • Cox-2 selectives extensively studied• Over time studies have revealed new

potential uses and risks• Raise questions about whether the CV

risk is– Limited to individual products– Applies to all Cox-2 selective drugs– Extends to non-selective NSAIDS

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Department of Health and Human Services

Center for Drug Evaluation and Research

Safety AssessmentNDA Outcome Studies

Celebrex 9600 CLASS 7900

Vioxx 5400 VIGOR 8000

Bextra 5500 ----

Etoricoxib* 5800 EDGE 7100

Lumiracoxib* 7000 TARGET 18,000*Etoricoxib, lumiracoxib, and parecoxib not approved in U.S.

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Department of Health and Human Services

Center for Drug Evaluation and Research

Cox-2 Inhibitors and CV RiskSome studies appear to show an increased risk of CV events, but the findings are not consistent across the COX-2 selective NSAIDs.

There may be similar risk with some of the non-selective NSAIDs. Clinical trial data are also not consistent and suggest this may be more of an effect with some than others.

5

Department of Health and Human Services

Center for Drug Evaluation and Research

Cox-2 Inhibitors and CV Risk• Story of conflicting data

– Short term vs. long term vs. epi studies– Populations differ– Comparators differ– Similar study designs show different results

• More than one mechanism possible• Little known about non-selective NSAIDs

– Data has been inconsistent– Multiple products/generics will make study difficult

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Department of Health and Human Services

Center for Drug Evaluation and Research

Effect of ASA in Cox-2 Studies• Conflicting data - ASA appears to

mitigate risk some studies, but not all.

• Unclear effect ASA use has on GI benefit of relative Cox-2 selectivity

7

Department of Health and Human Services

Center for Drug Evaluation and Research

Where are we today?• Conflicting data and many questions• Must move forward

– Determine role of approved products on market today

– Assess need for more studies– What studies would be most helpful

8

Department of Health and Human Services

Center for Drug Evaluation and Research

Question 1, 2, 3Do the available data support a conclusion that celecoxib, rofecoxib and valdecoxib significantly increase the risk of cardiovascular events?

Does the overall risk versus benefit profile for each of these support marketing in the US? If yes, please describe the patient population(s) in which the potential benefits of celecoxib outweigh the potential risks and what actions you recommend that FDA consider implementing to ensure safe use.

9

Department of Health and Human Services

Center for Drug Evaluation and Research

Question 4If the available data support a conclusion that one or more COX-2 selective agents increase the risk of cardiovascular events, please comment on the role, if any, of concomitant use of low-dose aspirin in reducing cardiovascular risk in patients treated with COX-2 selective NSAIDs.

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Department of Health and Human Services

Center for Drug Evaluation and Research

Question 5 (1)What additional clinical trials or observational studies, if any, do you recommend as essential to further evaluate the potential cardiovascular risk of celecoxib, rofecoxib, and valdecoxib?

What additional clinical trials or observational studies, if any, do you recommend as essential to further evaluate the potential benefits (e.g., reduced gastrointestinal risk) of celecoxib, rofecoxib, and valdecoxib?

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Department of Health and Human Services

Center for Drug Evaluation and Research

Question 6Do you recommend that the labeling for these products include information regarding the absence of long-term controlled clinical trial data to assess the potential cardiovascular effects of these drugs?

If so, please describe how you recommend that information be conveyed (e.g., warning, precaution).

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Department of Health and Human Services

Center for Drug Evaluation and Research

Question 7What additional clinical trials or observational studies, if any, do you recommend as essential to further evaluate the potential cardiovascular risk of the non-selective NSAIDs?

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Department of Health and Human Services

Center for Drug Evaluation and Research

Question 8 (1)With regard to evaluation of cardiovascular risk, what studies do you recommend as essential to be completed and reviewed prior to approval of new NSAIDs?

With regard to the evaluation of the potential benefits (e.g., reduced gastrointestinal risk), what studies do you recommend as essential to be completed and reviewed prior to approval of new NSAIDs?

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Department of Health and Human Services

Center for Drug Evaluation and Research

Question 9 (1)If the pre-approval studies recommended as essential in question 8 do not demonstrate an increased risk of cardiovascular events for a new NSAID, please comment on how FDA should handle the issue of cardiovascular risk in labeling. For example, would the absence of a cardiovascular risk signal in the pre-approval database preclude the need for any warnings or precautions in the labeling for the new product?

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Department of Health and Human Services

Center for Drug Evaluation and Research

Question 9 (2)Alternatively, should all future NSAIDs carry a “class” warning or precaution about cardiovascular risk even in the absence of a signal of increased risk in the pre-approval database? If yes, please describe your recommendations for the “class” labeling regarding cardiovascular risk with particular attention to whether you recommend it apply to all NSAIDs or only COX-2 selective NSAIDs.