Drugs and Trials: Lessons From Plato

Abstract

t l t e An article appears in the medical literature reporting a previously unrecognized side effect of a drug. It may be the unexpected appearance of a rare complication such as osteonecrosis of the jaw in patients who are treated with bisphosphonates. On other occasions, it is an increased frequency of a well-recognized adverse event such as hyperkalemia in conjunction with the use of aldosterone antagonists. Usually, the assessment of risk occurs in medical journals. The new information is incorporated into practice and clinicians adjust their prescription of the drug based on their interpretation of the needs of each patient. However, more often than we care to admit, reports of an adverse event are accompanied by evidence of misconduct either by physicians prescribing the drug or the pharmaceutical company that manufactures the drug. Suddenly, the affair is prominently featured on the front pages of The New York Times and plays out in the public arena. The US Food and Drug Administration (FDA) weighs in, “black box” warnings are published, drug use is severely restricted or banned, legal proceedings are started, and sanctions are imposed. Finally, the dust settles and physicians who are prescribing the drug appropriately in clinical practice or in research trials look up and find that they can no longer prescribe an agent that they judge to be useful for their patients. Rosiglitazone is a prominent example of a recent drug in which this sorry tale unfolded in the lay media and medical press. It followed shortly after the rofecoxib fiasco that came to light in 2004. I have been involved with clinical trials of rosiglitazone as the principal investigator of an ongoing randomized clinical trial in patients with resistant focal segmental glomerulosclerosis (FSGS) that was getting underway at about the same time as the publication of a meta-analysis of the safety outcomes of trials of rosiglitazone in adults with type 2 diabetes mellitus. The Novel Therapies for Resistant FSGS Trial (FONT) (DK70341; NCT00193648) is designed to test antifibrotic therapies that may attenuate the progressive decline in renal function in patients with FSGS