Released by FDA: 5/9/01.  Posted by FDA:  5/22/01

Kenneth Palmer, M.S. 
Associate Director, Drug Regulatory Affairs 
Sanofi-Synthelabo Inc. 
90 Park Avenue 
New York, New York 10016

RE:    NDA #20-839 
         Plavix (clopidogrel bisulfate) Tablets 
         MACMIS ID #9466

Dear Mr. Palmer:

As part of its routine monitoring program, the Division of Drug Marketing, Advertising, and Communications (DDMAC) has become aware that Sanofi-Synthelabo Inc. (Sanofi) is promoting its product, Plavix (clopidogrel bisulfate) tablets, in violation of the Federal Food, Drug, and Cosmetic Act (Act) and its implementing regulations. Specifically, we refer to Sanofi’s dissemination of a visual aid (69-201499) for Plavix, submitted under cover of Form FDA 2253, that contains promotional claims that are false or misleading.  Our specific objections follow.

Overstatement of Efficacy

The clinical evidence for the efficacy of Plavix is derived from the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) trial.   The CAPRIE trial demonstrated an overall risk reduction of a combined outcome cluster of events (ischemic stroke (IS), myocardial infarction (Ml), and other vascular death).

Your visual aid is misleading because it selectively presents the most favorable relative risk reductions for Plavix versus Aspirin for two of the three individual components (IS and Ml) of the combined outcome cluster.   Specifically, two full pages of the visual aid (pages 5 & 10) depict a 19.2% relative risk reduction for Plavix versus aspirin for an individual component (Ml) of the combined outcome cluster.   MI was the individual component of this combined outcome cluster that resulted in the most favorable relative risk reduction for Plavix versus aspirin.   Additionally, page 11 of the visual aid includes a similar presentation of the relative risk reduction (5.2%) for IS.   However, you limit your presentation of the difference in relative risk reduction for Plavix versus Aspirin for the third component of this combined outcome cluster (other vascular death) to a single statement on the bottom of page 11 of the sales aid (Vascular death not attributed to MI or stroke would not be expected to be reduced by antiplatelet therapy).   This component resulted in the least favorable risk reduction for Plavix versus aspirin (no difference).   Therefore, the visual aid is misleading because it overstates the efficacy of Plavix by selectively presenting the most favorable relative risk reduction data for two of the individual components of the combined outcome cluster.

Furthermore, important contextual information that is necessary to interpret these claims, including the actual event rates of these individual outcome events is presented in footnotes at the bottom of the page in a much smaller font size than the relative risk claims.   For example, on page 10 of your visual aid, you present the claim “Myocardial Infarction -- 19.2% relative risk reduction vs aspirin 325 mg...”  along with a very prominent related graphic presentation.   However, the absolute risk, as reflected in the actual event rates of patients experiencing an Ml (2.9% for Plavix vs 3.47% for aspirin 325 mg), is presented in a footnote at the bottom of the page in a very small font size. Thus, your presentations are misleading because they distort and misrepresent the actual differences between the groups, implying a much larger difference than was actually demonstrated.

In addition, the actual event rates for MI and IS presented in these footnotes are inconsistent with the rates provided in the PI.   Specifically, the event rate for Ml (3.6%) is not consistent with the rate provided in the PI(3.47%), and the event rates for IS presented in the footnote (4.9% for Plavix and 5.3% for aspirin) are not consistent with the rates provided in the PI(4.56% for Plavix and 4.81% for aspirin).

Unsubstantiated Superiority Claim

On page 4 of the visual aid you present the claim, “Significant overall risk reduction vs. aspirin 325 mg in CAPRIE, a 3 year study of 19,185 patients.”   This claim is misleading because it suggests that Plavix is superior to aspirin when such has not been demonstrated by substantial evidence.   As previously stated in our December 18, 1998, untitled letter, the CAPRIE trial does not provide substantial evidence to support the implication that Plavix has superior efficacy over aspirin.   Therefore, claims suggesting that Plavix is significantly better than aspirin are misleading because they are not based on substantial evidence.

Misleading Efficacy Presentation

The mechanisms of action (MOA) for Plavix and aspirin are presented on page 6 under the header “Plavix and Aspirin work differently.”   This graphic presentation includes the effects of Plavix on the inhibition of platelet aggregation on one side of a single platelet and the effect of aspirin on the inhibition of platelet aggregation on the other side of the same platelet.   Directly underneath the graphic depiction of the platelet is an arrow that leads to the concluding text “Inhibition of Platelet Aggregation: Reducing the Risk of MI, Ischemic Stroke, and Vascular Death.”   This presentation suggests that concurrent use of Plavix and aspirin will produce an additive effect on the inhibition of platelet aggregation.   However, the safety and efficacy of taking Piavix in combination with aspirin has not been demonstrated by substantial evidence.  Therefore, this MOA presentation is misleading because it suggests that the combined use of Plavix and aspirin is safe and effective when such has not been demonstrated.

Fair Balance

This promotional piece fails to present risk information with a prominence and readability reasonably comparable to the presentation of information on the effectiveness of the drug.   Claims promoting the effectiveness and safety of Plavix are presented in large bolded print throughout the visual aid (12 pages).   In contrast, the majority of your risk information about Plavix is limited to one page of the visual aid. This risk information is further minimized by use of paragraphing and the absence of a signal to alert readers to its importance.   Furthermore, the pages of the visual aid that do not include risk information fail to specify the location of this information in the piece.

In order to address these objections, you should immediately cease distribution of these materials immediately and all other promotional materials for Plavix that contain the same or similar claims or presentations.   You should respond in writing by May 23, 2001, with your intent and plans to comply with this request.   Your response should include a list of materials discontinued, and the date on which these materials were discontinued.

If you have any further questions, please direct them to me by facsimile at 301-594-6771 or at the Food and Drug Administration, Division of Drug Marketing, Advertising, and Communications, HFD-42, Rm 17B-20, 5600 Fishers Lane, Rockville, MD 20857.

We remind you that only written communications are considered official.   In all future correspondence regarding this particular matter please refer to MACMIS ID #9466 in addition to the NDA number.

Sincerely,

Andrew S.T. Haffer, Pharm.D. 
Regulatory Review Officer 
Division of Drug Marketing, 
     Advertising, and Communications