Wednesday, May 18, 2005

Big Pharma: right answers for wrong questions

Some people might consider the title of Richard Smith's article in PLoS Medicine [full text], "Medical journals are an extension of the marketing arm of pharmaceutical companies," provocative. I think people who follow this just think it's obvious.

Smith was editor of the British Medical Journal for 25 years. He is not talking about the ads that big drug companies run in major medical journals like BMJ but rather the scientific articles they fund and sponsor.

For better or for worse, the randomized clinical trial has become the Gold Standard for evidence-based medicine.
A large trial published in a major journal has the journal's stamp of approval (unlike the advertising), will be distributed around the world, and may well receive global media coverage, particularly if promoted simultaneously by press releases from both the journal and the expensive public-relations firm hired by the pharmaceutical company that sponsored the trial. For a drug company, a favourable trial is worth thousands of pages of advertising, which is why a company will sometimes spend upwards of a million dollars on reprints of the trial for worldwide distribution. The doctors receiving the reprints may not read them, but they will be impressed by the name of the journal from which they come. The quality of the journal will bless the quality of the drug.
Those same reprints are a major source of income for the journals and the principal reason they refuse to go Open Access (free and unhindered access to contents), despite the fact that many of the articles are taxpayer funded and the goal should be to provide important medical and scientific information to the world-wide community of doctors and scientists.

Moreover, Smith points out that a 1994 study of 56 clinical trials funded by manufacturers for non-steroidal anti-inflammatories for arthritis by Rochon et al. found none that published unfavorable results, i.e., "[e]very trial showed the company's drug to be as good as or better than the comparison treatment."
By 2003 it was possible to do a systematic review of 30 studies comparing the outcomes of studies funded by the pharmaceutical industry with those of studies funded from other sources. Some 16 of the studies looked at clinical trials or meta-analyses, and 13 had outcomes favourable to the sponsoring companies. Overall, studies funded by a company were four times more likely to have results favourable to the company than studies funded from other sources. In the case of the five studies that looked at economic evaluations, the results were favourable to the sponsoring company in every case.

The evidence is strong that companies are getting the results they want, and this is especially worrisome because between two-thirds and three-quarters of the trials published in the major journals—Annals of Internal Medicine, JAMA, Lancet, and New England Journal of Medicine—are funded by the industry. For the BMJ, it's only one-third—partly, perhaps, because the journal has less influence than the others in North America, which is responsible for half of all the revenue of drug companies, and partly because the journal publishes more cluster-randomised trials (which are usually not drug trials). [cites omitted]
The drug companies achieve their results in two ways. First, by using "asking the right question" to enhance the chances of getting the "right" answer. If the question is properly "framed" a study can pass peer review and even be of "high quality." Here is Smith's partial list of some of the strategems for "asking the right question":
Examples of Methods for Pharmaceutical Companies to Get the Results They Want from Clinical Trials
  • Conduct a trial of your drug against a treatment known to be inferior.
  • Trial your drugs against too low a dose of a competitor drug.
  • Conduct a trial of your drug against too high a dose of a competitor drug (making your drug seem less toxic).
  • Conduct trials that are too small to show differences from competitor drugs.
  • Use multiple endpoints in the trial and select for publication those that give favourable results.
  • Do multicentre trials and select for publication results from centres that are favourable.
  • Conduct subgroup analyses and select for publication those that are favourable.
  • Present results that are most likely to impress—for example, reduction in relative rather than absolute risk.
Second, drug companies succeed in using the medical journals for marketing by publishing essentially the same results in many places. This can be done in various ways, for example, by presenting partial outcomes of multicenter trials in different combinations at different times in different journals.

Smith does not believe that more skeptical peer review or "registries" of clinical trials will solve the problem. His prescription is novel:
Firstly, we need more public funding of trials, particularly of large head-to-head trials of all the treatments available for treating a condition. Secondly, journals should perhaps stop publishing trials. Instead, the protocols and results should be made available on regulated Web sites. Only such a radical step, I think, will stop journals from being beholden to companies. Instead of publishing trials, journals could concentrate on critically describing them.
Sounds right to me. The drug companies should take two of their own trials and call the journal in the morning.