Public Citizen | Publications - Comments before the Food and Drug Administration's Endocrinologic and Metabolic Drugs Advisory Committee on orlistat (Xenical) for the treatment of obesity. (HRG Publication #1417)

Comments Before The Endocrinologic and Metabolic Drugs Advisory Committee
on Orlistat (Xenical) for the Long-Term Treatment of Obesity

Public Citizen would like to thank the Food and Drug Administration (FDA) and the members of the Endocrinologic and Metabolic Drugs Advisory Committee for this opportunity to comment on the new drug application for orlistat (Xenical). Our comments will address two topics; (1) secrecy; and (2) two published studies assessing orlistat's efficacy. In addition, we will pose the following question: Do the data show a measurable benefit from orlistat by reducing the health risks associated with obesity?

In preparing our comments for this meeting we requested summary safety and effectiveness data on orlistat from the FDA. Our request was refused on the grounds that this information is confidential and commercial and its release could cause Hoffman-LaRoche competitive harm in the market place, even though the Code of Federal Regulations allow, at the Commissioner's discretion disclosure of;

. . . a summary of selected portions of the safety and effectiveness data that are appropriate for public consideration of a specific pending issue; for example, for consideration of an open session of an FDA advisory committee.⁽¹⁾

We found that some FDA staff were not aware of this section of the regulations. In addition, no one knew why this regulation had been written and if it had ever been used to make safety and effectiveness data publicly available prior to an advisory committee meeting.

It is troubling that important information about orlistat has been kept secret, and the time allotted for public participation is in the hour before any presentations will reveal what is known about orlistat. Scheduling public comment later in the meeting, after presentation of what we believe are numerous studies involving large numbers of subjects⁽²⁾, without the time to carefully evaluate these data is little better than keeping the data secret.

We can only comment on two published clinical trials^(3),(4) involving orlistat, neither of which provide acceptable demonstration of the drug's efficacy based on the 1996 FDA guidelines⁽⁵⁾ for the clinical evaluation of weight-control drugs:

(1) Demonstration that the drug effect is significantly greater than the placebo effect and the mean drug associated weight loss exceeds the mean placebo weight loss by at least 5 percent.

(2) Demonstration that the proportions of subjects who reach and maintain a loss of at least 5 percent of their initial body weight is significantly greater in subjects on drug than in those on placebo.

Both studies lasted 12 weeks and both showed a statistical difference in mean weight loss between orlistat and placebo. In the first study³ this amounted to 3.9 pounds with the highest dose of orlistat, and in the other study⁴ the difference was 4.9 pounds, an average of 1.3 and 1.6 pounds per month respectively. Neither study could show that mean orlistat associated weigth loss exceeded mean placebo weight loss by at least five percent. In the first study³, at the highest dose of orlistat, the difference was a meager 1.73 percent, and in the other⁴ it was only 2.47 percent.

In summary, these two studies fail to show that orlistat fulfills one of the two requirement of the first FDA guideline and neither study reported results applicable to the second guideline.

The table below summarizes the number of subjects receiving orlistat and the mean weight loss difference between the orlistat and placebo groups. Also shown are the doses of orlistat tested, the studies' results, and the percent difference in mean weight loss between the orlistat and placebo groups.

TABLE 1 - SUMMARY OF THE TWO PUBLISHED STUDIES EVALUATING THE EFFICACY OF ORLISTAT
Study/Number of Subjects Receiving Orlistat	Mean Weight Loss Difference Between Orlistat and Placebo at the End of Study Period	Was Orlistat Weight Loss Statistically Superior to Placebo at the End of Study Period?	Did Orlistat Mean Weight Loss Exceed Placebo Mean Weight Loss by 5%?
Drent et al.³ 1995/ 140 subjects	three daily doses of orlistat were evaluated orlistat 30 mg/day = 0.63 kg or 1.39 lbs orlistat 180mg/day = 0.71 kg or 1.63 lbs orlistat 360 mg /day = 1.76 kg or 3.88 lbs	yes but only for the orlistat 360 mg/day dose p=<0.05	no orlistat 30 mg = 0.61% orlistat 180 mg =0.66% orlistat 360mg =1.73%
Drent and van der Veen⁴ 1993/ 20 subjects	orlistat 150 mg/day = 2.2 kg or 4.9 lbs	yes p=0.034	no 2.47 %

Public Citizen is fully cognizant of the health threat presented by long-term obesity and the importance of developing interventions, both drug and non-drug, to reduce the risks associated with obesity. We are also aware that few published studies have evaluated the effectiveness and safety of weight-control drugs beyond one year, and we are not aware of published studies showing that any weight-loss drug reduces the health risks of obesity. From the public health perspective, weight-control drugs have not provided a solution to chronic obesity, only drug bills that can be counted in the hundreds of millions of dollars and countless reported and unreported adverse drug reactions.

We have no doubt that if approved, orlistat will be promoted as a "magic bullet" and a "breakthrough" treatment for the chronic management of obesity just as lipid lowering drugs and antihypertensive agents are advertised to treat high cholesterol and high blood pressure. In fact, Russell Ellison, MD, Hoffman-LaRoche's Vice President for Global Drug Development was quoted in 1996 as saying "We believe that the drug is going to be important and useful in the medical management" of obesity and "that means you really have to look at chronic long-term management, just as you would look at an antihypertensive or lipid-lowering agent, and that is exactly what we intend to do."⁽⁶⁾

Pharmaceutical companies, which generate enormous profits through sales of drugs which may be used for years by millions of people must provide adequate evaluation of their products. For Hoffman-LaRoche this will mean answering the question: Do the data show a measurable health benefit from orlistat in reducing the risks associated with obesity?

2. U.S. FDA panel to review Roche's orlistat. SCRIP No. 2227 April 29, 1997, p. 19.

3. Drent ML, Larsson I, William-Olsson T, Quaade F, Czubayko F, von Bergmann K, et al. Orlistat (RO 18-0647), a lipase inhibitor, in the treatment of human obesity: a multiple dose study. Int J Obes Relat Metab Disord 1995;19:221-226.

4. Drent ML, van der Veen EA. Lipase inhibition: a novel concept in the treatment of obesity. Int J Obes Relat Metab Disord 1993;17:241-244.

5. Food and Drug Administration. Guidance for the Clinical Evaluation of Weight-Control Drugs. September 17, 1996.

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