Margaret Hamburg M.D.,
Commissioner, Food and Drug Administration
Department of Health and Human Services
5630 Fishers Lane, Room 1061
Rockville, MD 20852
Dear Dr. Hamburg,
This purpose of this letter is to re-petition the Food and Drug Administration (FDA) to immediately ban the weight loss drug, sibutramine (Meridia – Abbott – in the U.S.). Early results from SCOUT, a large, 10,000 person, international, randomized, placebo-controlled study mandated by the European Union (EU) and performed by Abbott as a condition of continued marketing of sibutramine in EU countries, have shown a significantly increased number of patients with heart attacks, strokes, resuscitated cardiac arrests or deaths in those who are obese and aged 55 or older with known or occult cardiovascular disease using sibutramine, compared with those given a placebo. Both groups were on the same weight management program.
The FDA has reported that 11.4% of patients getting sibutramine vs. 10 % of patients getting a placebo suffered a heart attack, stroke, resuscitated cardiac arrest or death, the primary pre-specified outcome of the study. With 5,000 patients in each group, we have calculated that this results in a statistically significantly increased risk for the drug: p=0.026 (Fisher’s Exact test) with an excess of 70 patients in the sibutramine group having one of the above outcomes. There has been a decrease over the past eight years in the use of sibutramine in the U.S. However, during the last 12 months, there were still 294,000 prescriptions filled in this country according to data from IMS. This emphasizes the urgency of banning the drug.
SCOUT had previously been described by the FDA as “the first trial to verify or refute the long-held assumption that drug-induced weight loss – in this case, with sibutramine – reduces the risk for fatal and nonfatal cardiovascular disease.”
The results of this large trial clearly refute the assumption that drug-induced weight loss with sibutramine reduces these risks. Worse, the results show that sibutramine significantly increased these risks in the 5,000 people in the trial who used the drug.
In addition to the new findings from the SCOUT study (obese people, aged 55 or older), we have found that there are now, as of June 30, 2009, a total of 84 reports of deaths from cardiovascular causes in the FDA Adverse Event Reactions (AERS) database, including 30 in people 50 or younger. Of these 30 people, 11 were 30 or younger. It must be noted that FDA’s own estimates are that no more than one in 10 adverse reactions to drugs that occur are reported to the agency. These data are incomplete as the age is missing from 22 of the 35 most recent FDA sibutramine cardiovascular death reports.
Public Citizen’s Previous Petition to Ban Sibutramine
On March 19, 2002, we originally petitioned the FDA to ban sibutramine. The petition, supplemented with additional information in September 2003, was based on the following:
- During the randomized placebo-controlled clinical trials conducted prior to sibutramine’s approval in 1997, the drug caused significant increases in blood pressure, pulse rate, and palpitations in patients taking the drug compared to patients using a placebo.
- In one study submitted by Knoll to the FDA, patients taking sibutramine were three times more likely to experience clinically significant ECG (electrocardiogram) changes than patients taking placebo.
- The FDA Medical Officer coordinating the review of the New Drug Application for sibutramine concluded on May 10, 1996 that, “sibutramine has an unsatisfactory risk-benefit ratio, and therefore this Reviewer recommends non-approval of the original submission of NDA 20-632.” He also stated that “the 10 and 15 mg doses of sibutramine satisfy the minimum weight-loss criteria and duration of study as defined in the Guidance, however, sibutramine does not improve, and in some cases it aggravates major obesity-related co-morbidities [emphasis supplied].”
- The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, on September 26, 1996, voted 5 to 4 against sibutramine’s approval when asked “Do the benefits of sibutramine outweigh the risks?” The advisory committee also voted 8 to 0 that the pressor (high blood pressure-raising) effect of sibutramine was “clinically important.”
- When announcing its approval of sibutramine in November 1997, the FDA stated that the average weight loss in obese people taking the drug for one year – beyond the weight loss in those getting a placebo – was only 6 1/2 pounds in the group taking 10 mg.
- 49 post-marketing cardiovascular deaths had been reported to FDA’s AERS database by March, 2003. 27 of the 49 (55%) were in people 50 years old or younger.
In its 2005 denial of our petition to ban sibutramine, the FDA stated: “An unbiased, objective assessment of sibutramine’s cardiovascular safety profile, particularly when used in obese patients with known or occult cardiovascular disease, can best be made through analyses of data from a large, randomized, controlled trial. The Sibutramine Cardiovascular Outcomes, or SCOUT study, is such a trial.”
In addition to pre-approval evidence of harm from randomized trials and 84 post-approval cardiovascular deaths reported to the FDA, the SCOUT study, that the FDA itself stated in 2005 would give an “unbiased objective assessment of sibutramine’s cardiovascular safety profile” is now completed and the preliminary results suggest “that sibutramine is associated with an increased cardiovascular risk in the study population.”
The November 20, 2009 FDA press release concerning the SCOUT study stated that, ”the [SCOUT] study was designed to show that weight loss with sibutramine and standard care was more effective in reducing the number of cardiovascular events compared to weight loss from a placebo and standard care.”
The fact that sibutramine actually increased the number and percentage of cardiovascular events (heart attack, stroke, resuscitated cardiac arrest or death, the pre-specified primary outcome of the study), should mandate its immediate removal from the market.
We were understandably pleased with your statement in the New England Journal of Medicine article earlier this year in which you confirmed the agency’s “overriding purpose…of protecting the public health.” You went on to say that “some benefits are not worth the risk” and concluded by pointing out that “the public must trust the agency to base its decisions on science.”
We would hope that the science behind the results seen in this study would mandate the only appropriate FDA action to protect the public health: immediate removal of sibutramine from the market.
If the agency decides not to ban this drug and, instead, chooses to merely increase the warnings, as it has previously done for two other drugs whose risks also substantially outweigh their benefits – propoxyphene (as in Darvocet) and rosiglitazone (Avandia), you will be presiding over an expanding mockery of your statement above: “Some benefits are not worth the risk” and “the public must trust the agency to base its decisions on science.”
We look forward to a prompt response to this petition.
Environmental Impact Statement
Nothing requested in this petition will have an impact on the environment.
We certify that, to the best of our knowledge and belief, this petition includes all information and views on which this petition relies, and that it includes representative data and information known to the petitioners which are unfavorable to the petition.
Sidney Wolfe, M.D.
Public Citizen’s Health Research Group
 Ann Intern Med. 2005;143:380-385.
[3 The ages of these 11 patients were: 26, 29, 22, 26, 29, 28, 30, 30, 28, 22 and 17.
 Knoll was sibutramine’s developer before Abbott took over the company in 2000.
 N Engl J Med 360;24: 2493. June 11, 2009