An interim report from the FDA

Article Abstract:

Important questions concerning research on tacrine (tetrahydroaminoacridine), a drug proposed as effective in treating Alzheimer's disease, were raised in an investigation by the Food and Drug Administration (FDA). An article presenting the research findings by W.K. Summers and colleagues appeared in a November 1986 issue of The New England Journal of Medicine. When the FDA began to review the research that had led to the article, discrepancies were found. Since no signs of fraud appeared, the FDA closed its investigation when Dr. Summers promised to take certain steps. These included sending a letter to the Journal to acknowledge discrepancies between the way the study was conducted and the way it had been reported, and to sign an agreement showing his intent to avoid repeating specific violations of standard investigative procedure. In lieu of publishing the letter, the Journal asked the FDA to submit its view of the investigation. The Summers report was heralded in the lay media, not least because of accompanying enthusiastic editorials about it in The New England Journal of Medicine. The study purported to be double-blind (i.e. neither patients nor clinicians were aware of whether a patient received tacrine or the placebo) and controlled (patients were prospectively and randomly assigned to receive either tacrine or placebo). The FDA found that this was not the case: assignment to drug or placebo group was not random; blinding was not maintained throughout the study; and patient ratings were not recorded throughout the study, but, rather, were reconstructed later from memory. Two small, but well controlled studies, have recently shown no effects due to tacrine. At doses such as those used by Summers, the drug can cause liver damage, a fact never noted by that investigator. Without assuming that Dr. Summers deliberately misled anyone, it can be asserted that the publication of his work in a major journal raised vain hopes in people who suffer from Alzheimer's disease. The development of new drugs must proceed systematically and carefully. A response from Dr. Summers and colleagues appears in the January 31, 1991 issue of The New England Journal of Medicine. (Consumer Summary produced by Reliance Medical Information, Inc.)

Reports

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A response from Summers et al

Article Abstract:

A response is presented to an interim report by the Food and Drug Administration (FDA) appearing in the January 31, 1991 issue of The New England Journal of Medicine concerning questionable research practices by the author. The issue concerns the author's claim, in a 1986 article in the same journal, that tacrine (tetrahydroaminoacridine) helped 17 Alzheimer's patients. According to the FDA, the study was not well controlled: patients were not randomly assigned to receive either tacrine or placebo; experimenters were not always blind as to the treatment patients received; and patient ratings were performed retrospectively. Their interim report further states that the original evidence concerning tacrine's effectiveness was not found by other researchers in better controlled studies and that potentially harmful side effects of the drugs went unnoticed. Contrary to the findings in the interim report, the research plan was seen by the FDA and the authors were told they were free to perform research without prejudice in May 1989. The three points raised by the FDA are thus without basis. Elevations in liver enzymes associated with tacrine were discovered in January 1987, but this discovery was ignored. Later, the research group found the changes to be reversible if the drug was stopped immediately. The studies praised by the FDA as ''well controlled'' were studies the FDA itself had never investigated, at least one of which has received scientific criticism. The FDA report seems more like a personal attack than a scientifically motivated critique. (Consumer Summary produced by Reliance Medical Information, Inc.)

Evaluation, letter to the editor

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Tacrine as a treatment for Alzheimer's dementia: editor's note

Article Abstract:

An article in a November 1986 issue of The New England Journal of Medicine by W.K. Summers and colleagues reported encouraging results when 17 patients with Alzheimer's disease were treated with tetrahydroaminoacridine (tacrine, or THA). Because of the small number of patients studied and certain concerns about the research methodology, the editors of The New England Journal of Medicine had doubts about publishing the paper. However, reviewers supported its publication, if only to encourage additional research. Although critical feedback was received by the medical journal, no devastating complications developed. Investigation of Dr. Summers' research records by the Food and Drug Administration (FDA) revealed flaws, prompting the agency to ask him to write a letter of clarification to the Journal. The letter was duly written but, since many of the criticisms had been discussed in readers' correspondence, it was not published. Instead, the sponsoring academic institution (School of Medicine, the University of California, Los Angeles) was asked to investigate the matter; it set up an ad hoc committee to this end. No signs of fraud were found. Newer research on tacrine for Alzheimer's disease has now been reported and evaluated. An interim report on the matter from the FDA, and a response by Dr. Summers and colleagues, appear in the January 31, 1991 issue of The New England Journal of Medicine. (Consumer Summary produced by Reliance Medical Information, Inc.)

Health aspects, editorial

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