Speaking of Big Pharm . . .

Today's N.Y. Times has a review of Marcia Angell's scathing indictment of the pharmaceutical industry, The Truth About the Drug Companies. The reviewer, Janet Maslin, writes that "Dr. Angell's case is tough, persuasive and troubling. Arguing that in 1980 drug manufacturing changed from a good business into 'a stupendous one,' thanks to changes in government regulations. She adds, 'Of the many events that contributed to their sudden great and good fortune, none had to do with the quality of the drugs the companies were selling.'"

Of particular relevance to the reimportation debate is this passage:

"The big drug companies are competing not so much to find new drugs but for the limited number of drugs to license," she argues. The enormous research-and-development budgets that are invoked to justify high drug prices, she claims, also pay for questionable forms of education for doctors and all manner of barely concealed incentives for them to prescribe certain drugs.

It was this passage, however, that caught my eye:

Why, she asks, should new drugs be tested against placebos, and sometimes tested in such high doses that their effectiveness is guaranteed? Why shouldn't they be tested in equivalent doses against drugs that already exist - and already work?

I thought it was unethical for a new drug to be randomized against a placebo if there is already an effective drug available. That is, it's ethical to use a placebo-controlled study only when those receiving the placebo are not denied the possibility of getting the established treatment or one that is possibly equivalent or better (the test drug).

To some degree, I was wrong. It is at least still a somewhat open question whether, and under what circumstances, a three-arm trial (new drug, orthodox treatment, placebo) is ethical. Back in 1994, Kenneth Rothman wrote a "Sounding Board" article for the New England Journal of Medicine ("The Continuing Unethical Use of Placebo Controls," 331:394-398 (Aug. 11, 1994); subscription required) that argued both that placebos are unethical when there's already a orthodox treatment of proved or accepted value and that the FDA hypocritically treats placebo-controlled studies as the gold standard for drug trials, even when an orthodox treatment is already available. Is this still happening?

Apparently so, if an article by two FDA staffers in the 2000 Annals of Internal Medicine is any gauge. (This one requires a subscription, too.) Here's the abstract:

In recent years, several authors have argued that placebo-controlled trials are
invariably unethical when known effective therapy is available for the condition
being studied, regardless of the condition or the consequences of deferring treatment. Some have also disputed the value of placebo-controlled trials in such a setting, asserting that the comparison of new treatment with old treatment is sufficient to establish efficacy and is all that should be of interest. This article considers the ethical concerns about use of placebo controls and describes the limited ability of active-control equivalence (also known as noninferiority) trials to establish efficacy of new therapies in many medical contexts. The authors conclude that placebo-controlled trials are not uniformly unethical when known effective therapies are available; rather, their acceptability is determined by whether the patient will be harmed by deferral of therapy. If patients are not harmed, such trials can ethically be carried out.

Furthermore, active-control trials, although valuable, informative, and appropriate in many circumstances, often cannot provide reliable evidence of the effectiveness of a new therapy.

Temple R & Ellenberg S. Placebo-Controlled Trials and Active-Control Trials in the Evaluation of New Treatments, Part 1: Ethical and Scientific Issues. Ann Int. Med. 2000;133:455-63 (Sept. 19). The Letters to the Editor (July 3, 2001) and the authors' reply also makes for interesting reading.