April 1, 2002

Dear Secretary Thompson:

On March 19, 2002, Public Citizen petitioned the Food and Drug Administration (FDA) of Department of Health and Human Services to remove sibutramine (Meridia) from the market and to change the standards for approving all obesity pharmacological therapies in the future.

The American Obesity Association (AOA) believes that this petition, if granted, would create a public health disaster. The petition is based on faulty reasoning, poor science and disregard for lives and well-being of 65 million persons with obesity.

The American Obesity Association is an advocacy and educational non-profit tax exempt organization. Funding has been provided from Abbott Laboratories, maker of Meridia, and the previous manufacturer, Knoll Pharmaceuticals. AOA also receives financial support from other elements of the weight loss industry, including Roche Laboratories, and Weight Watchers Intl.Inc.

Mr. Secretary your commitment to the issues of obesity and diabetes is well known and critical to the health of this nation. We urge you to consider the serious health consequences if the Public Citizen petition is granted.

1. The Petition is based primarily on old information.

The petition principally recites events occurring before FDA approval of sibutramine. This information is irrelevant.

2. The new information does not support the conclusion that the drug is unsafe.

Public Citizen petition states "since its launch in early 1998 sibutramine has now been associated with 29 deaths including 19 from cardiovascular adverse effects in people using this minimally effective drug." The implicit message of "associated" is that sibutramine has caused these deaths. Yet Public Citizen has provided no evidence of causation.

The logic in the Public Citizen petition is hardly compelling. Many cancer patients have died who took anti-cancer agents. Many HIV/AIDs patients have died who took HIV/AIDs drugs. Many stroke patients have died who took stroke medications. Many heart disease, diabetic, Parkinson and Alzheimer patients have died who have taken medicines for their conditions. Yet, Public Citizen does not imply that drugs for those patients are causally related to their medications as opposed to their disease.

Before Public Citizen can say that sibutramine is "unacceptably dangerous" it must produce evidence that the death rate of the product exceeds that for persons with obesity in general. Public Citizen has failed to make this threshold finding before condemning the product. If sibutramine has a higher death rate than persons with obesity, it should be reviewed and probably recalled. If its fatality rate is lower than that of persons with obesity, it should continue to be available to patients.

The statistical evidence at this point indicates that sibutramine fatality rate is no higher, indeed it appears much lower, than that of persons with obesity in general. The Nurses Health Study derived a death rate per 100,000 of 390 for persons with obesity.(Manson) In its release of March 20, 2002, Abbott Laboratories indicates that the fatality rate coincident with the use of sibutramine worldwide is 2.13 per 100,000.

Sudden cardiac deaths are all too common in obesity. Just recently at the meeting of the American College of Cardiology, researchers from the Cincinnati Children’s Hospital presented a study of 575 obese but otherwise healthy young women. 25% had abnormally large hearts. More than 20% were diagnosed with left ventricular hypertrophy, an enlargement of the heart’s main pumping chamber.(Winslow) Left ventricular hypertrophy is a precursor to congestive heart failure, a lethal problem that affects about 5 million Americans. The incidence of sudden death may be up to 40 times higher in severely obese subjects as compared with the general population.(Sjostrom)

It should not come as a surprise that persons with obesity die in large numbers. As you and the Surgeon General indicated as recently as December 2001 with the release of the Surgeon General's Call to Action on Overweight and Obesity over 300,000 deaths a year in this country are caused by obesity and most of these are cardiovascular events. In 1997, there were 2,314,245 deaths in the United States (CDC) which means that obesity was responsible for approximately 13% of all deaths in the United States.

On this basis it could hardly be said that there is any statistical indication that the product is not safe.

The clinical evidence available at this time does not support a connection between reported deaths and sibutramine either. A number of expert physicians on AOA’s Board of Directors and Advisory Council have reviewed the patient information provided by Abbott Laboratories and have concluded that there does not appear to be a correlation between sibutramine and those deaths.

3. The Public Citizen petition ignores data on effectiveness of sibutramine.

Public Citizen calls the weight loss effects "meager" and the drug "ineffective" but fails to state (a) what is Public Citizen’s expertise in arriving at this conclusion, (b) what is Public Citizen’s acceptable level of weight loss for a pharmacological compound, (c) why are standards established by the Food and Drug Administration, the National Institutes of Health and the Surgeon General contrary to the public interest, and, (d) why does Public Citizen reject the scientific study directly contradicting their position.

The Surgeon General’s Call to Action on Overweight and Obesity which noted that loss of between 5% and 10% "reduces the risk factors for at least some diseases, particularly cardiovascular disease, in the short term". By Public Citizen’s own statement, sibutramine falls within the Surgeon General’s acceptable range of weight loss.

In the United States, most patients have to pay out of pocket for drugs to treat obesity since insurance reimbursement is so poor. As Public Citizen has noted these drugs are not cheap. It is not unreasonable to think that many patients continue to pay out of pocket because the product is effective for them. It is reasonable to believe that many patients have found the product helpful in reducing their risks of serious comorbid conditions like type 2 diabetes and heart disease.

Most striking, however, is Public Citizen’s failure to indicate that a long-term clinical trial directly contradicts their assertions. Over 15 months ago, the highly respected British medical journal, The Lancet, published the results of the STORM trial. (James)

This trial involved eight European centers which compared the effects of weight loss program including sibutramine with a placebo group. The trial showed that almost all patients who stayed with the study achieved at least a 5% weight loss with sibutramine and over half could lose more than 10% weight within six months. Of the sibutramine treated patients who completed the 2 year study, 43% maintained 80% or more of their original weight loss compared to 16% in the control group. The study carefully looked at cardiovascular events. The authors concluded, "The potential benefits from this management system could be moderated by any adverse change in blood pressure induced by sibutramine. In this trial, patients with hypertension were not excluded, their blood pressures and pulse rates essentially remained unchanged despite the substantial weight loss. 20 patients (including two hypertensives) were, however, withdrawn because of excessive blood-pressure rises. . . . Increases in blood pressure increase the risk of cardiovascular disease, but this effect of sibutramine will be counteracted by the drug’s beneficial impact on lipid abnormalities and other indices of risk - e.g. insulin resistance. Analyses of the metabolic and cardiovascular responses in different sibutramine trials by means of risk equations based on the Framingham Heart Study suggest a decrease in absolute risk of events of coronary heart disease; those with greater risk- e.g. from hypertension, diabetes or lipid abnormalities, show the greatest reduction in risk. The overall long-term benefit of sibutramine therefore now needs to be assessed not only in obese patients, but also in those with lipid disorders with and with hypertension where the impact of sibutramine on those with low concentrations of HDL cholesterol would be particularly interesting. However, it is prudent to monitor routinely the blood pressure of patients receiving sibutramine so any unusual cardiovascular response can be identified."

Patients in both groups had substantial decreases over the first six months with respect to triglycerides, VLDL cholesterol, insulin, C peptide and uric acid but these changes were sustained in the sibutramine group but not in the placebo group. HDL concentrations increased in both groups. Only 3% of patients were withdrawn from the study because of increases in high blood pressure.

4. Public Citizen does not allege that physicians are misprescribing or overprescribing sibutramine.

It is important to note what Public Citizen does not allege. Public Citizen does not allege that the maker is marketing the product for off-label uses. Public Citizen does not allege that physicians are prescribing the product to patients for whom the product is not intended or for uses beyond the labeling. Public Citizen does not allege that patients are misusing the product.

While there is no way of knowing how precisely physicians are prescribing sibutramine, we believe that the pattern is very conservative. The litigation around the fen-phen combination is still on-going but moving to conclusion. Most physicians who are actively involved with obesity treatment are very aware of this litigation. It appears that sales of both approved obesity agents are well below the levels of fen-phen and Redux. This supports our belief that dispensing patterns are very moderate.

5. The Public Citizen petition encourages discrimination against person with obesity.

The Public Citizen petition reaches far beyond sibutramine. The petition if granted would put persons with obesity in a ghetto with a sign reading, "Do Not Help Them. Do Not Treat Them." It would effectively bar any development which modern science might develop for the 65 million Americans with obesity.

The petition insists that approval of future products for the treatment of obesity, whose chemical composition and clinical experience are unknown, be approved only after each and every product has demonstrated a long-term reduction in mortality and morbidity due to weight loss. Such clinical trials are unnecessary and would be of such long duration and of such great cost that no pharmaceutical or biotechnology company could afford to pay for them. Therefore, the drug companies would stop any research and development if this petition were granted because no product could meet such a burden. Academic researchers pursuing a pharmacological intervention would see no usefulness in pursuing this avenue of research.

Public Citizen would impose this burden solely on drugs for the treatment of obesity. We cannot imagine Public Citizen would demand that each and every cholesterol-lowering product show that lowering cholesterol is beneficial to health. Or that every product for hypertension establishes that reducing blood pressure which reduces heart disease prolongs life. Or that every product for cancer treatment demonstrates that treating cancer prolongs life. Or that every product for HIV/AIDs demonstrates improvement in total mortality and morbidity of infected persons. This special standard for drugs to treat persons with obesity is itself a form of discrimination.

The health benefits of weight loss are well established. The Surgeon General's Call to Action recites the health benefits. "Randomized controlled trials, " it states, " have shown that weight loss (as modest as 5 to 15% of excess total body weight) reduces the risk factors for at least some disease, particularly cardiovascular disease, in the short term. Weight loss results in lower blood pressure, lower blood sugar, and improved lipid levels. While few published studies have examined the link between weight loss and reduced disease or death in the long term, current data as well as scientific plausibility suggest this link. Studies have shown that reducing risk factors for heart disease, such as blood pressure and blood cholesterol levels, lowers death rates from heart disease and stroke, Therefore, it is highly probable that weight loss that reduces these risk factors will reduce the number of deaths from heart disease and stroke." AOA supports greater research but also believes, with the Surgeon General, that current data and scientific plausibility create a powerful link between weight loss and health benefits.

The Surgeon General referenced the recently concluded Diabetes Prevention Program (DPP) which clearly demonstrated significant reductions in the risk of developing type 2 diabetes among persons with obesity with impaired glucose tolerance. The reductions in risk were greater in the lifestyle modification groups although pharmacological intervention showed reductions in risk as well.

(The weight loss target in the DPP was 7%, just above sibutramine’s level of 6.5%. Presumably Public Citizen would consider this level "meager" as well.)

For Public Citizen, the only acceptable obesity agent would be one that achieves a much greater than 6.5% weight loss and shows lifetime effectiveness. That would be nice but as one axiom states, "The perfect is the enemy of the good."

Society cannot insist that only the proverbial "magic bullet" - a total cure- is the only acceptable product for the treatment of obesity. AOA insists that obesity agents in the future be judged by the same applicable scientific standards that the FDA applies to other therapeutic categories. An unobtainable "magic bullet" is the pitch of frauds and scams; it is neither responsible policy making nor good science.

It is conceivable that a drug with no weight loss at all would be desirable. Consider a possible agent which might prevent weight gain and would maintain a person’s weight with minimal side effects. Would not the prevention of more cases of obesity be a desirable public health goal? Would not such an agent help meet the Department of Health and Human Services objectives for obesity and overweight set out in Healthy People 2010?

6. Petition is demeaning to persons with obesity.

Throughout the petition, Public Citizen identifies sibutramine and the entire class for the treatment of obesity as "diet drugs." The Public Citizen use of this term is condescending. It is meant to imply a superficial effort to lose weight driven by vanity. It trivializes a life-or-death disease. How different the petition would read if Public Citizen used "medicines for the treatment of the often fatal disease of obesity" rather than "diet drugs."

The petition also assumes that persons with obesity are not smart enough to make health care decisions with their physicians. In many areas of health care, especially with life-threatening long term chronic conditions such as obesity, there are therapeutic trade-offs. These trade-offs require information and communication between the patient and the physician and other health care professionals. Hormone replacement therapy (HRT) is one such example. Another is the recent controversy over the appropriate use of mammography. Persons with obesity and their physicians are not ignorant or uninformed. The trade-offs involved in sibutramine are well understood and should be left to the patient and physician to decide an appropriate course of treatment.

Conclusion

The Public Citizen petition fails to raise a threshold question of whether sibutramine is safe or not and should be rejected.

The Public Citizen petition regarding a standard for future approvals of any product for the treatment of obesity is unfair in setting a standard which is not comparable with other therapeutic areas and whose effect would be to leave millions of persons without products developed by the revolution in biomedical research in the last three decades.

We urge the Secretary to immediately and unequivocally reject this petition.

Respectfully submitted,

Morgan Downey
Executive Director

References:

• CDC, Mortality and Morbidity Weekly Report, Mortality Patterns- United States 1997.
• James WP,Astrup A, Finer N, Hilsed J, Kopelman P, Rossner WH.
• Effect of sibutramine on weight maintenance after weight loss: a randomized trial. The Lancet Vol. 356, Dec 23/30 2000;9248: 2119-2125.
• Manson JE, Willett WC, Stampfer MJ, Colditz GA, Hunter DJ, Hankinson SE, et al. Body weight and mortality among women. N Engl. J. Med. 1995;333(11)677-685.
• Sjostrom, LV, Mortality of Severely Obese Subjects, Am J Clin Nutr, 1992, Feb:55 (2 Suppl):516S-523S).
• Surgeon Generalšs Call To Action to Prevent and Decrease Overweight and Obesity 2001, DHSS.
• Winslow, R, Obesity is Causing Health Problems among the Young, Wall St. Journal, March 20, 2002, B1.