November 05,2004
November 5, 2004
Mr. Lester M. Crawford, D.V.M., Ph.D.
Acting Commissioner
U.S. Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
Dear Dr. Crawford:
As the Committee on Finance (Committee) continues investigating the worldwide withdrawal of Vioxx by Merck & Co., Inc. (Merck), the Food and Drug Administration’s regulatory rolerelating to Vioxx merits close scrutiny. As chairman of the Committee, I request that the FDAprovide an expedited response to this letter.
Dr. Shari Targum, a Food and Drug Administration (FDA) Medical Officer, was the author of aconsultation “to address a concern regarding risk of cardiovascular events with the use of[Vioxx].” Dr. Targum worked in the FDA, Division of Cardio-Renal Drug Products, and herconsultation was directed to the FDA Division of Anti-Inflammatory Drug Products. Both ofthese divisions fall under the FDA’s Center for Drug Evaluation and Research. Dr. Targum’sconsultation—commonly referred to as the Targum Memo—was considered by the ArthritisAdvisory Committee in February 2001. The Advisory Committee recommended labeling andfurther study of Vioxx. Several concerns are noteworthy in the Targum Memo’s Issues &Findings section, including the following:
2. Evaluation of CV events in other [Vioxx] studies that allowed ASA (085and 090): See Comments on 085 and 090. Despite lower dose, smaller sample and aspirin use, the trend is against [Vioxx].
3. Assessment of CV thrombotic risks in this database: The VIGOR study wasa large study with a longer drug exposure and follow-up than the two smallerstudies (085 and 090). The cardiovascular thrombotic event rates, while not high,were significantly different between the two groups; most striking were themyocardial infarction event rates. Thus, to this Medical Reviewer, there are morecardiovascular thrombotic events in the [Vioxx] group than in the naproxengroup; the time-to-event curves are different, favoring naproxen. This MedicalReviewer is concluding that there is an increased risk of cardiovascularthrombotic events, particularly myocardial infarction, in the [Vioxx] groupcompared with the naproxen group. More difficult is the question of a safetysignal for [Vioxx]. As there is no placebo group, it will be difficult to assess theCV thrombotic risk with [Vioxx] use compared with no therapy at all. [Merck]provides several hypotheses to explain the data (see below);
4. Assessment of [Merck]’s claim regarding CV risks: [Merck] claims:
• [Merck claims that the difference in myocardial infarctions between thetwo groups is primarily due to the antiplatelet effects of naproxen. Thishypothesis is not supported by any prospective placebo-controlled trialswith naproxen. One can further argue that, no matter what the attribution,the results (from a cardiovascular standpoint) are favorable for naproxen...
5. Suggest labeling that would properly address CV risks: It is difficult towrite labeling at this point. As discussed with Dr. Villalba, we will be glad todiscuss labeling with your Division. It would be difficult to imagine inclusion ofVIGOR results in the [Vioxx] labeling without mentioning cardiovascular safetyresults in the study description as well as the Warnings sections.(Bold and underline in original; italics added).
Dr. Targum also included several recommendations in her consultation, including:• [The Division of Anti-Inflammatory Drug Products] will need to considerthe risks vs. benefits of [Vioxx] and naproxen. We will be glad to discussthis issue further with you.
• We would like to see further analysis of the updated Time-to Event tableto answer the following questions: 1. How significant is this table; 2.What event rate is needed to detect a significant difference between[Vioxx] and naproxen.
• [The Division of Anti-Inflammatory Drug Products] should look at theVIGOR congestive heart failure results to clarify whether these events arerelated to edema, hypertension, or thrombotic events. You might ask[Merck] for further clarification.
• [The Division of Anti-Inflammatory Drug Products] might considerlooking at celecoxib data to evaluate whether there is evidence of a classeffect.
• It would be helpful if [Merck] could provide further cardiovascular safetydata regarding long-term (>2 month) exposure of [Vioxx] 50 mg andabove, both in rheumatoid arthritis and non-rheumatoid arthritispopulations.
• As we have discussed, OPDRA should be asked to look at cardiovascularsafety data for the COX-2 inhibitors.
In light of the Targum Memo, and the issues, comments, and recommendations found init, please respond to the following:
1. Provide the Committee with a copy of the administrative file(s) relating to any Vioxxlabeling change, including but not limited to the Vioxx labeling change approved in April2002.
2. State whether or not the FDA took action on the issues, comments, and specifically therecommendations made in the Targum Memo. In your response, please list each recommendation in the Targum Memo and follow it with a detailed description of thespecific action(s) taken by FDA in response to each recommendation. In addition, statewhy the cardiovascular safety results were not included in the Vioxx label warningsection as per Dr. Targum’s specific comment.
Thank you in advance for having your staff coordinate with my staff about this letter byno later than the close of business on November 8, 2004. Please provide the requesteddocuments by November 12, 2004, unless they are available sooner. Your expedited responseshould be delivered to the Committee no later than November 17, 2004, unless it is availablesooner.
Sincerely,
Charles E. Grassley
Chairman
Chairman Grassley reacts to the FDA's new drug safety initiatives and asks agency to specify what steps it took in response to knowns risks with Vioxx
M E M O R A N D U M
TO: Reporters & Editors
FR: Jill Kozeny, 202/224-1308
RE: FDA announcement today
DA: Nov. 5, 2004
Sen. Chuck Grassley, Chairman of the Senate Committee on Finance, issued thefollowing comment about the announcement today by the Food and Drug Administration of itsnew initiatives concerning the safety of medical products.
"The public must be able to have faith in the Food and Drug Administration. It's obviousthat the leadership of the agency must take on what look like deep-rooted problems when itcomes to putting public health and safety first and public relations second. Today'sannouncement is welcome, albeit late in coming. These initiatives need to take hold in ameaningful way and be more than an attempt to inoculate the agency in the face of alarmingrevelations."
Sen. Grassley also released a letter he sent to the Food and Drug Administration askingwhat actions the agency took in response to known risks about Vioxx. The text of the letterfollows here.
November 5, 2004
Mr. Lester M. Crawford, D.V.M., Ph.D.
Acting Commissioner
U.S. Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
Dear Dr. Crawford:
As the Committee on Finance (Committee) continues investigating the worldwide withdrawal of Vioxx by Merck & Co., Inc. (Merck), the Food and Drug Administration’s regulatory rolerelating to Vioxx merits close scrutiny. As chairman of the Committee, I request that the FDAprovide an expedited response to this letter.
Dr. Shari Targum, a Food and Drug Administration (FDA) Medical Officer, was the author of aconsultation “to address a concern regarding risk of cardiovascular events with the use of[Vioxx].” Dr. Targum worked in the FDA, Division of Cardio-Renal Drug Products, and herconsultation was directed to the FDA Division of Anti-Inflammatory Drug Products. Both ofthese divisions fall under the FDA’s Center for Drug Evaluation and Research. Dr. Targum’sconsultation—commonly referred to as the Targum Memo—was considered by the ArthritisAdvisory Committee in February 2001. The Advisory Committee recommended labeling andfurther study of Vioxx. Several concerns are noteworthy in the Targum Memo’s Issues &Findings section, including the following:
2. Evaluation of CV events in other [Vioxx] studies that allowed ASA (085and 090): See Comments on 085 and 090. Despite lower dose, smaller sample and aspirin use, the trend is against [Vioxx].
3. Assessment of CV thrombotic risks in this database: The VIGOR study wasa large study with a longer drug exposure and follow-up than the two smallerstudies (085 and 090). The cardiovascular thrombotic event rates, while not high,were significantly different between the two groups; most striking were themyocardial infarction event rates. Thus, to this Medical Reviewer, there are morecardiovascular thrombotic events in the [Vioxx] group than in the naproxengroup; the time-to-event curves are different, favoring naproxen. This MedicalReviewer is concluding that there is an increased risk of cardiovascularthrombotic events, particularly myocardial infarction, in the [Vioxx] groupcompared with the naproxen group. More difficult is the question of a safetysignal for [Vioxx]. As there is no placebo group, it will be difficult to assess theCV thrombotic risk with [Vioxx] use compared with no therapy at all. [Merck]provides several hypotheses to explain the data (see below);
4. Assessment of [Merck]’s claim regarding CV risks: [Merck] claims:
• [Merck claims that the difference in myocardial infarctions between thetwo groups is primarily due to the antiplatelet effects of naproxen. Thishypothesis is not supported by any prospective placebo-controlled trialswith naproxen. One can further argue that, no matter what the attribution,the results (from a cardiovascular standpoint) are favorable for naproxen...
5. Suggest labeling that would properly address CV risks: It is difficult towrite labeling at this point. As discussed with Dr. Villalba, we will be glad todiscuss labeling with your Division. It would be difficult to imagine inclusion ofVIGOR results in the [Vioxx] labeling without mentioning cardiovascular safetyresults in the study description as well as the Warnings sections.(Bold and underline in original; italics added).
Dr. Targum also included several recommendations in her consultation, including:• [The Division of Anti-Inflammatory Drug Products] will need to considerthe risks vs. benefits of [Vioxx] and naproxen. We will be glad to discussthis issue further with you.
• We would like to see further analysis of the updated Time-to Event tableto answer the following questions: 1. How significant is this table; 2.What event rate is needed to detect a significant difference between[Vioxx] and naproxen.
• [The Division of Anti-Inflammatory Drug Products] should look at theVIGOR congestive heart failure results to clarify whether these events arerelated to edema, hypertension, or thrombotic events. You might ask[Merck] for further clarification.
• [The Division of Anti-Inflammatory Drug Products] might considerlooking at celecoxib data to evaluate whether there is evidence of a classeffect.
• It would be helpful if [Merck] could provide further cardiovascular safetydata regarding long-term (>2 month) exposure of [Vioxx] 50 mg andabove, both in rheumatoid arthritis and non-rheumatoid arthritispopulations.
• As we have discussed, OPDRA should be asked to look at cardiovascularsafety data for the COX-2 inhibitors.
In light of the Targum Memo, and the issues, comments, and recommendations found init, please respond to the following:
1. Provide the Committee with a copy of the administrative file(s) relating to any Vioxxlabeling change, including but not limited to the Vioxx labeling change approved in April2002.
2. State whether or not the FDA took action on the issues, comments, and specifically therecommendations made in the Targum Memo. In your response, please list each recommendation in the Targum Memo and follow it with a detailed description of thespecific action(s) taken by FDA in response to each recommendation. In addition, statewhy the cardiovascular safety results were not included in the Vioxx label warningsection as per Dr. Targum’s specific comment.
Thank you in advance for having your staff coordinate with my staff about this letter byno later than the close of business on November 8, 2004. Please provide the requesteddocuments by November 12, 2004, unless they are available sooner. Your expedited responseshould be delivered to the Committee no later than November 17, 2004, unless it is availablesooner.
Sincerely,
Charles E. Grassley
Chairman
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