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Published Online, 6 March 2007, www.theannals.com, DOI 10.1345/aph.1H234b.
 The Annals of Pharmacotherapy: Vol. 41, No. 3, pp. 530. DOI 10.1345/aph.1H234b
© 2007 Harvey Whitney Books Company.
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Authors' Reply

James W Anderson, MD

Professor of Medicine & Clinical Nutrition, Endocrine Division, Room MN520 Medical Science Building, University of Kentucky, Lexington, Kentucky 40506, fax 859/323-5707, jwandersmd{at}aol.com

Susan M Schwartz, PhD

Director, Weight Control, GlaxoSmithKline Consumer Healthcare, Parsippany, New Jersey

Jonathan Hauptman, MD

Director, Clinical Research and Metabolic Diseases, Hoffmann-La Roche Ltd. Nutley, New Jersey

Mark Boldrin, MS

Statistical Leader, Hoffmann-La Roche Ltd.

Maureen Rossi, MS

Drug Safety Surveillance Team Leader, Hoffmann-La Roche Ltd.

Vidhu Bansal, PharmD

Director, Medical Affairs, GlaxoSmithKline Consumer Healthcare

Cecilia A Hale, PhD

Senior Statistician, GlaxoSmithKline Consumer Healthcare

Published Online, March 6, 2007. www.theannals.com, DOI 10.1345/aph.1H234b

AUTHORS' REPLY: We appreciate the interest of Rowell and Amarshi in our recent publication and provide these clarifications. The Food and Drug Administration (FDA), the National Institutes of Health (NIH) Clinical Guidelines, and clinical practice mandate that energy-restricted, low-fat diets be used in clinical trials. As stated in the NIH Clinical Guidelines on Overweight and Obesity, weight-loss drugs "should never be used without concomitant lifestyle modifications" and are not meant as a substitute for lifestyle modifications.1 Additionally, the FDA Guidance for the Clinical Evaluation of Weight-Control Drugs (www.fda.gov/cder/guidance/obesity.pdf) states, "For the long-term efficacy studies, it is preferable to instruct all subjects in the relevant life-style modifications.... As a minimum, a modestly restricted diet and regular exercise should be actively encouraged." We are not aware of any weight-loss drug approved for long-term use that has not used a reduced calorie diet as part of the study design.2

The protocol recommended a 30% fat restriction, which is in agreement with NIH Clinical Guidelines, the American Heart Association,3 and clinical practice. Specifically, NIH Clinical Guidelines recommend that for weight loss and maintenance, "total fats should be 30% or less of total calories." Importantly, we would argue that 30% of calories from fat is the optimal level for maximizing efficacy and tolerability, based on the mechanism of action,4 and is the recommended level for the prescription product.

Concerns were raised about the power of the tests for secondary parameters and use of standard errors. We used widely accepted and commonly used statistical analyses and data presentation. Studies are typically sized for the primary endpoint. Observation of statistically significant treatment differences for several secondary parameters indicates that the study was sufficiently sized for these endpoints. Baseline means were presented with SDs to describe the populations from which the samples were drawn while SEs were presented for mean changes from baseline and mean treatment differences to describe the variability of these means. As explained in their reference by Gaddis and Gaddis, inference about a mean is based on the standard error of the mean: "The width of the CI depends on the SEM and the degree of confidence."5

As for any drug, additional studies are encouraged, but it should be recognized that orlistat's efficacy and safety have been established in more than 100 clinical studies and that it is the most extensively studied weight-loss drug.

We believe that this study, as designed, addressed appropriate objectives and resulted in scientifically sound conclusions.

References

  1. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults—the evidence report. Washington, DC: National Institutes of Health, NIH publication no. 98-4083, September 1998.
  2. Padwal R, Li SK, Lau DCW. Long-term pharmacotherapy for obesity and overweight (review). Cochrane Library 2005;1-57.
  3. Lichtenstein AH, Appel LJ, Brands M, et al. Diet and lifestyle recommendations revision 2006. A scientific statement from the American Heart Association nutrition committee. Circulation 2006;114:82-96.[Abstract/Free Full Text]
  4. Hauptman JB, Jeunet FS, Hartmann D. Initial studies in humans with the novel gastrointestinal lipase inhibitor Ro 18-0647 (tetrahydrolipstatin). Am J Clin Nutr 1992;55:309S-13S.[Abstract/Free Full Text]
  5. Gaddis GM, Gaddis ML. Introduction to biostatistics: part 2, descriptive statistics. Ann Emerg Med 1990;19: 309-15. Epub 17 Mar 2005. DOI10.1016/S0196-0644(05)82052-9[CrossRef][Medline]




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