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Comment on the Ethics of Placebo-Controlled Trials in Patients with Type 2 Diabetes Mellitus

Division of Metabolic and Endocrine Drug Products FDA/HFD 510 Rockville, Maryland 20857

The American Diabetes Association has stated that the goal of diabetes therapy should be to reduce patients’ hemoglobin A1c level to under 7% and that "treatment should be implemented as early as possible" to prevent the vascular complications (1, 2, 3). This recommendation appears inconsistent with the design of the study by Fonseca et al. (4), reported in The Journal of Clinical Endocrinology and Metabolism, in which the investigators discontinued active treatment with sulfonylureas in order to have patients participate in a trial in which many would receive a placebo (4). Studies with a similar design have been conducted by several manufacturers.

While on sulfonylureas, patients in the Fonseca study had a mean hemoglobin A1c of 8.4%, which rose to 10.7% after six months of placebo. Fasting serum glucose rose from 195 mg/dL to 264 mg/dL (4). Even leaving aside the risk of vascular complications, this rise in glycemia would predictably cause symptoms that would interfere with daily activities. If one agrees with the position of the American Diabetes Association, that it is unacceptable to allow patients with this degree of hyperglycemia to go untreated, how does one justify intentionally causing hyperglycemia by withdrawal of active treatment?

It is unethical to conduct a clinical study that is designed to demonstrate the benefits of a particular treatment in comparison with harm done to patients who do not receive that treatment. Commenting on studies of HIV infection in the third world, Marcia Angell has written that "clinical trials have become a big business" and has warned against the exploitation of vulnerable populations of patients in order "to get the work done with a minimum of obstacles." She restated that the New England Journal of Medicine "will not publish reports of unethical research regardless of their scientific merit" (5). By not requiring Fonseca et al. to comment on the ethical aspects of their study (4), the editorial board of The Journal of Endocrinology and Metabolism may inadvertently leave the impression that it feels differently about these issues.

In addition to the responsibility of medical journals not to publish the results of unethical research, it should be the responsibility of the Food and Drug Administration (FDA) to prevent unethical studies from being done. FDA should question any study design in which standard treatment is withheld and should provide guidance about designing studies that preserve the well-being of patient volunteers. In addition, FDA should state publicly that it will refuse to accept data from unethical studies in new drug applications (6).

These views reflect the personal opinion of the author and do not necessarily reflect the official position of the FDA.

Footnotes

Received September 22, 1998. Address correspondence to: Robert I. Misbin, M.D., 5727 Crawford Drive, Rockville, Maryland 20851.

References

1. Diabetes Control and Complications Trial Research Group. 1995 The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial. Diabetes. 44:968–983.[Abstract]
2. Henry RR, Genuth S. 1996 Current recommendations about intensification of metabolic control in non-insulin dependent diabetes mellitus. Ann Int Med. 124:175–177.[Abstract/Free Full Text]
3. American Diabetes Association. Standards of Medical Care for Patients with Diabetes Mellitus. 1997 Diabetes Care. 20:S5–S13.
4. Fonseca VA, Valiquett TR, Huang SM, Ghazzi MN, Whitcomb RW. 1998 Trogltiazone monotherapy improves glycemic control in patients with in type 2 diabetes mellitus—a randomized, controlled study. J Clin Endocrinol Metab. 83:3169–3176.[Abstract/Free Full Text]
5. Angell M. 1997 The ethics of clinical research in the third world. N Engl J Med. 337:847–849.[Free Full Text]
6. Misbin R. August 24, 1998 The Washington Post.

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