It is time for the diabetes community to take action regarding the conduct of clinical trials on diabetic patients in the U.S.

The Declaration of Helsinki, an international document that describes ethical principles to be used in clinical investigations, states that “In any medical study, every patient, including those of a control group, if any, should be assured of the best proven diagnostic and therapeutic method” (1). I believe that many of the placebo-controlled trials currently being performed to assess new oral diabetic therapies do not meet this ethical standard. Comparing an experimental drug with a placebo is perfectly ethical when no proven effective therapy exists and when the risk-to-benefit ratio needs to be assessed. However, when effective therapy exists, the use of placebo control subjects does not meet the ethical standard. In these situations, the efficacy and safety of the experimental medication should be tested by blindly randomizing one group to the experimental drug and the other group to an existing drug that has been shown as effective and safe.

Few would argue that using placebo for a short period of time in type 2 diabetic subjects is usually safe. Before the general utilization of HbA1c in clinical trials, when almost all diabetic drugs showed maximal efficacy within a few days, clinical trials were of short duration, and the use of placebo was unlikely to be harmful to the diabetic subject. However, when differences in A1c’s need to be assessed, clinical trials must be at least 3 months duration. In addition, if the therapy being used before the study is long-lasting, a washout period must also be included, which will further prolong the period of exposure to hyperglycemia. Furthermore, when drugs such as the thiazolidinediones, which may not be fully effective for as long as 3 months, are used to assess differences in diabetes control, clinical trials need to be at least 6 months duration.

As investigators, how long can we ethically permit hyperglycemia to continue in diabetic subjects randomized to placebo therapy? Indeed, 6 months of hyperglycemia will have an adverse effect on the quality of life, and could possibly be long enough for microvascular complications that would not have occurred with better glycemic control to occur. Undoubtedly, prolonged hyperglycemia has the potential to exacerbate macrovascular disease with increased platelet aggregation, postprandial hyperlipidemia, lower plasminogen activator inhibitor activity, higher fibrinogen levels, increased clotting factors, glycosylation of LDL particles, and more.

Another breach of ethical standard occurs in the conduct of studies designed to examine the efficacy of therapies for symptomatic diabetic distal symmetrical polyneuropathy. In most studies, a washout period of 3 weeks or more is required. Consequently, many patients cannot tolerate the symptoms and drop out. Thus, the studies are conducted on patients with mildly symptomatic neuropathy, and a positive study only proves that the drug is effective in mild diabetic neuropathy. Further pain and suffering for patients who survive the washout period can be inflicted by placing them on a placebo. In these studies, the efficacy of the experimental drug would more humanely and efficiently be tested by adding either the drug or the placebo to the patient’s existing therapy, which would be consistent throughout the study.

Therefore, as advocates for our patients and as investigators who are responsible for the welfare of diabetic subjects in clinical trials, we should encourage the Federal Drug Administration and the pharmaceutical industry to avoid (whenever possible) the use of placebo-controlled trials when a proven effective and safe alternative therapy is available.

1
World Medical Association Declaration of Helsinki: Recommendations guiding physicians in biomedical research involving human subjects.
JAMA
277
:
925
–926,
1997

Address correspondence to David S. H. Bell, Professor of Medicine, University of Alabama at Birmingham, 1808 7th Ave. S., Birmingham, Alabama 35294. E-mail: [email protected].

Ed. note: We believe that Dr. Bell has raised an important issue, and we have requested responses from representatives of the industry, the Federal Drug Administration (FDA), the FDA Advisory Committee members, and an ethicist. These responses will be published in a later issue.