Well, here’s a shocker: apparently, there appears to be a difference between internal drug company documents about the research trials that they fund, and the articles reporting that research that end up in medical journals. The New England Journal of Medicine calls this ‘selective outcome reporting’, but for the sake of clarity, let’s just call it ‘lying’.
At first blush, the process of getting drug research results published seems straightforward enough. Since 2005, the International Committee of Medical Journal Editors has even required all research investigators to register their clinical trials prior to participant enrollment as a pre-condition for publishing the trial’s findings in member journals.
So in a nutshell, researchers set out to run clinical trials, as they are legally required to do, on a particular drug. They have some specific purpose in mind before undertaking this research. Will this drug ease pain? Reduce inflammation? Lower blood pressure? Treat cancer? That’s the primary outcome of the clinical trial they have in mind, which must be registered before they even begin recruiting people to participate in this study if they want to later submit their findings to a medical journal. Which of course they do.
In a study published today in the NEJM, researchers examined practices for clinical trials of a drug called gabapentin, better known by its brand name Neurontin, an epilepsy drug which was approved in late 1993 for use as an adjunctive medication to control partial seizures (meaning that it’s considered effective when added to other anti-seizure drugs). The research trials for this drug were all funded by Pfizer and Warner-Lambert’s sudsidiary drug company, Parke-Davis.
Researchers looked at 20 clinical trials of gabapentin for which there were internal Pfizer or Parke-Davis documents, 12 of which were ultimately published in medical journals. For eight of these 12 reported trials, the primary outcome defined in the ultimately published journal article differed from that described in the internal documentation protocol. Quelle surprise…
Sources of disagreement included:
- the introduction of a new primary outcome (in the case of six trials)
- failure to distinguish between primary and secondary outcomes (two trials)
- re-naming primary outcomes as secondary outcomes (two trials)
- failure to report one or more protocol-defined primary outcomes (five trials)
But it gets better. Research trials that presented findings that did not match the drug company’s protocol-defined primary outcome in the internal documents either were not reported in full or were reported with a changed primary outcome. In fact, the primary outcome was changed in the case of 5 of 8 published trials for which statistically significant differences favouring gabapentin were reported.
Of the 21 primary outcomes described in the original protocols of the published trials, six were not reported at all and four were reported as secondary outcomes. Of 28 primary outcomes described in the published reports, 12 were newly introduced.
This was particularly interesting because researchers concentrated on off-label uses for gabapentin (meaning medical conditions for which the drug was never approved to treat). These off-label uses included prevention of migraine headache and treatment of bipolar disorders.
By the mid- and late 1990s, gabapentin was being widely used for the off-label treatment of pain syndromes and psychiatric conditions – for which it had never been studied or approved. Although gabapentin was later approved for the treatment of post-herpetic neuralgia in shingles patients, in 2004 the Pfizer subsidiary Warner-Lambert settled litigation and admitted guilt in connection to charges that during the 1990s, it had violated federal regulations by promoting the drug for pain, psychiatric conditions, migraine, and other unapproved uses.
The researchers, from Johns Hopkins and UC San Francisco, concluded that there was indeed ‘selective outcome reporting’ for trials of off-label use of gabapentin, adding:
“This practice threatens the validity of evidence for the effectiveness of off-label interventions.”
Another team of researchers has reported similarly disturbing findings that were published in the Journal of the American Medical Association on September 2, 2009. This team from France looked at randomized controlled trials in three medical areas (cardiology, rheumatology and gastroenterology) that had been indexed in 2008 in 10 general and specialty medical journals.
Not surprisingly, they too found ‘selective outcome reporting’ was prevalent.
For example, of 323 trials studied, trial registration was lacking in 28%, and another 14% weren’t registered until after completion of the study. (And keep in mind that the medical journal editors themselves ruled in 2005 that registration of trials prior to participant enrollment was now a requirement of journal publication). Another 12% were registered with no or an unclear description of the primary outcome, and 1% were registered after the completion of the study and had an unclear description of the primary outcome. How could the journal editors have accepted these studies for publication?
And even among articles with trials that had been adequately registered, 31% showed some evidence of discrepancies between the primary outcomes initially registered and the outcomes later published in the medical journals.
A revealing study presented at the American College of Preventive Medicine annual meeting by Dr. Mohammed Hassan Murad of Mayo Clinic reviewed 202 published medical journal articles that addressed the now-recognized association between heart attack risk and another diabetes drug Avandia, made by drug giant GlaxoSmithKline. Among the journal article authors who concluded that Avandia does NOT increase the risk, 86% had financial relationships with GlaxoSmithKline. Among authors of articles offering unfavorable reviews, only 18% had relationships with GSK. * * NEWS UPDATE, New York Times, November 3, 2011: GlaxoSmithKline Settles Investigation with Record $3 Billion Fine in Avandia Settlement
Therapeutics Initiative: Evidence-Based Drug Therapy from the University of British Columbia in Vancouver published a comprehensive paper on gabapentin’s journey to blockbuster status in a report called Gabapentin for Pain: New Evidence From Hidden Data.
TI conclusions include:
- misleading promotion pushed gabapentin to blockbuster status
- scientific evidence suggests gabapentin has a minor role in pain control.
- gabapentin reduces neuropathic pain by < 1 point on a 0-10 point scale and benefits about 15% of carefully selected patients (NNT=6-8).
- a similar proportion of people suffer harm from the drug
Are you confused? If you’re a person taking any prescription drug – not just Neurontin or Avandia – that has ever been written about in any medical journal, you should be.
Your physician reads these journals, and studies have shown that prescribing habits are actually influenced by medical journal articles.
Gabapentin is a drug that was considered such a potential blockbuster when it was introduced that a unique and comprehensive marketing plan was launched, according to internal documents disclosed during the litigation for illegal off-label uses of gabapentin. A review of these documents was published in the Annals of Internal Medicine on August 15, 2006.
“The gabapentin marketing plan included: boards, consultants meetings, and accredited continuing medical education (CME) events organized by third-party vendors to deliver promotional messages. These tactics were augmented by the recruitment of local ‘champions’ and engagement of ‘thought leaders’, who could be used to communicate favorable messages about gabapentin to their physician colleagues. Research and scholarship were also used for marketing by encouraging ‘key customers’ to participate in research, using a large study to advance promotional themes and build market share, paying medical communication companies to develop and publish articles about gabapentin for the medical literature, and planning to suppress unfavorable study results. “
Their conclusions? Activities traditionally considered independent of promotional intent, including continuing medical education and research, were extensively used to promote gabapentin. The review authors suggested:
“New strategies are needed to ensure a clear separation between scientific and commercial activity.”
The same research team (very keen on gabapentin obviously) then published another paper in the Public Library of Science Medicine on April 24, 2007, that looked at the effect of ‘detail visits’ by drug company sales reps on their routine physician calls to push greater prescription numbers for gabapentin. They found that these detailing visits were of high perceived informational value and often involved messages about unapproved uses of the drug. Despite their short duration, detail visits were effective: 46% of physicians reported their intention to recommend or prescribe gabapentin in future.
The Annals of Internal Medicine report claimed that one-half to two-thirds of the marketing budget for gabapentin went to “professional education” for doctors. The study also explained one of Pfizer/Warner-Lambert’s best marketing tools: recruiting prominent medical professors to act as ‘thought leaders’ for hundreds of company-sponsored teleconference calls with doctors, dinner meetings, and conferences. In many cases, the company’s sponsorship wasn’t disclosed. These advocates, some of whom were paid up to $150,000 over several years, helped promote the drug’s ‘emerging uses’, a pleasant description of those illegal off-label uses not approved by the FDA.
The campaign was a stunning success. While prescriptions of Neurontin (gabapentin) for epilepsy remained flat at 400,000 per year through the 1990s in North America, off-label use exploded from virtually nil in the mid-1990s to more than three million prescriptions annually in 2000. By 2002, according to court documents, those unauthorized prescriptions made up 94% of the total.
Read more at:
- Reporting in Industry-Sponsored Trials of Gabapentin for Off-Label Use from the NEJM by S. Swaroop Vedula, M.D., M.P.H., Lisa Bero, PhD., Roberta Scherer, PhD., and Kay Dickersin, PhD.
- The Promotion of Gabapentin in the Annals of Internal Medicine by Michael Steinman, MD, Lisa Bero, PhD, Mary-Margaret Chren, MD, and Seth Landefeld, MD
- Characteristics and Impact of Drug Detailing for Gabapentin by the same team.