Monday, October 01, 2012

How drug companies get the clinical trial results they want | The Ethical Nag

Every prescription drug (or over-the-counter medication) in your bathroom cabinet is there because it’s been evaluated in research called a clinical trial. For a basic introduction to clinical trials, let’s turn to former editor-in-chief of the prestigious New England Journal of Medicine, Dr. Marcia Angell, who wrote the following in her frightening landmark piece called “Drug Companies & Doctors: A Story of Corruption” (New York Review of Books, 1/15/2009):

“Before a new drug can enter the market, its manufacturer must sponsor clinical trials to show the Food and Drug Administration that the drug is safe and effective, usually as compared with a placebo or dummy pill.

“The results of all the trials (there may be many) are submitted to the FDA, and if one or two trials are positive – that is, they show effectiveness without serious risk – the drug is usually approved, even if all the other trials are negative.” 

But there’s an even bigger problem with clinical trials, according to Dr. Richard Smith (editor of the British Medical Journal for 25 years). He explained the problem in his Public Library of Science journal article called “Medical Journals Are an Extension of the Marketing Arm of Pharmaceutical Companies”:*

“A much bigger problem lies with the original studies, particularly these clinical trials published by medical journals.

“Far from discounting these, journal readers see randomized controlled trials as one of the highest forms of evidence.

“A large trial published in a major journal has the journal’s stamp of approval, 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.”

Here’s an example of what Dr. Smith is talking about: a study published in the Journal of the American Medical Association reported that the drug giant Merck had hired medical ghostwriters to draft dozens of flattering ‘research’ papers about their now-discredited pain drug Vioxx. They then lined up well-known doctors who agreed to fraudulently claim to be the actual authors for submission to journals.**

The New England Journal of Medicine sold 929,400 reprints of a single Vioxx-friendly ‘research’ article it had published  – mostly sold directly to the drug’s own manufacturer, Merck, in fact. Merck’s sales reps then distributed these reprints to physicians on their daily call routes as part of their  aggressive Vioxx sales campaign.

Reprint orders from this one ghostwritten Vioxx article brought in more than $697,000 in revenue for the NEJM.

Medical journal editors who don’t want to bite the Big Pharma hand that feeds them apparently learn to hold their noses and accept this. And as Dr. Smith explains:

“The doctors receiving the reprints may not even 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.”

Consider also the systematic review published in the British Medical Journal comparing the outcomes of studies funded by the pharmaceutical industry with outcomes of studies funded from other sources.***

Researchers found that 13 of the 16 clinical trials or meta-analyses studied had outcomes favourable to the drug companies that funded the studies. In fact, 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 five studies that looked at economic evaluations, the results were favourable to the sponsoring company in every case.

The evidence is strong, warns Dr. Smith, that drug companies are generally  getting exactly the results they want from the clinical trials they pay for, and this is especially worrisome because between two-thirds and three-quarters of the trials published in the major medical journals (Annals of Internal Medicine, Journal of the American Medical Association, Lancet, and New England Journal of Medicine) are funded by industry.

But how is it possible that these companies are getting such bizarrely predictable favourable results?

Dr. Smith suggests that they’re not fiddling with the research results, which he claims “would be far too crude and possibly detectable by peer review, but rather are simply asking the “right questions”.

But how to accomplish this? Dr. Smith advises this primer for Big Pharma:

Methods Used by 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 only those that give favourable results.
  • Do multi-centre trials and select for publication only those results from centres that are favourable.
  • Conduct subgroup analyses and select for publication only those that are favourable.
  • Present results that are most likely to impress – for example, reduction in relative rather than absolute risk.


* Smith R. Medical Journals Are an Extension of the Marketing Arm of Pharmaceutical Companies. PLoS Med 2(5): e138. 2005. doi:10.1371/journal.pmed.0020138

** Joseph S. Ross, MD et al. Guest Authorship and Ghostwriting in Publications Related to Rofecoxib: A Case Study of Industry Documents From Rofecoxib Litigation. JAMA. 2008;299(15):1800-1812

*** Lexchin J, Bero LA, Djulbegovic B, Clark O (2003) Pharmaceutical industry sponsorship and research outcome and quality. BMJ 326: 1167–1170.


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