The hoopla continues over the TIDE trial, which GlaxoSmithKline hopes will vindicate its Avandia diabetes pill. You may recall that Avandia was tied in earlier studies to an increased risk of heart attacks and the TIDE trial compares Avandia with Takeda Pharmaceuticals’ Actos, which hasn’t generated the same degree of safety concerns.

However, the trial has been criticized for being unethical, since it compares one pill with known cardiac risks with a seemingly safer alternative. The FDA, in fact, may halt the trial prior to a July 13 advisory committee meeting to review Avandia (see here) and, meanwhile, Glaxo is having trouble enrolling patients (see here). And now another heavy hitter has joined the chorus of concerns and is demanding the agency end the trial.

Ruth Macklin, who is a professor of Biomedical Ethics at the Albert Einstein School of Medicine, a member of the World Health Organization’s Ethical Review Committee and, until recently, chair of the Ethics Subcommittee of the Advisory Committee to the Centers for Disease Control and Prevention’s director, has written a letter to FDA commish Margaret Hamburg to says “this study violates principles in every guidance document in research ethics.”

“One objective of the TIDE study is precisely to see how much more harm one drug causes than another drug. This is not minimizing harms. It is deliberately harming subjects of research. Presumably, if the study shows that (Avandia) causes too much harm, the FDA will determine that it should be taken off the market,” Macklin writes in a harsh criticism of the agency. “But if it shows some harm, but not much more than its comparators, there will be possible benefit - but only to the pharmaceutical manufacturer.

“Although the FDA has abandoned reliance on the Declaration of Helsinki for ethical guidance in the conduct of research, others in the global research community have not. Paragraph 20 of the 2008 Declaration says: ‘Physicians may not participate in a research study involving human subjects unless they are confident that the risks involved have been adequately assessed and can be satisfactorily managed.’ Who are the physicians who embarked on this study with the drug’s known harmful effects? How could an IRB approve such a study? And why would any patients agree to participate, especially if they have been properly informed about the advice of the American and European Diabetes Associations? Or have they?”

She goes on to cite “accumulating evidence of the increased dangers of Avandia compared with Actos and in comparison to older, standard oral treatments for diabetes; and advice by the American Diabetes Association and the European Diabetes Association, based on unanimous consensus group findings, that Avandia not be used….the agency should publicize the details of this trial, along with an explanation of why it is considered ethically justified in light of the known and predictable harm rosiglitazone causes. Better yet, stop the trial now and explain later.”

Meanwhile, the FDA is trying to create political and scientific cover for its July 13 meeting, The RPM Report writes. A former top staffer to House Energy & Commerce Chairman Waxman is doing an internal study of agency post-marketing safety procedures to assure Capitol Hill the FDA takes the issue seriously. And an Institute of Medicine workshop is convening in early June to prepare a preliminary review on the ethical issues with post-market safety studies.

This is a smart move. As RPM continues, the IoM meeting next month gives the FDA a chance to get an idea of scientific and ethical opinions on comparative safety trials in which one product is tied to a higher mortality risk. From there, the agency can go its July 13 advisory meeting in hopes focusing the discussion “without creating the appearance that its trying to defend its previous actions.”