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The Case of Neurontin: Skewed Research in the Service of Selling
Annette B. Ramírez de Arellano, DrPH
When pharmaceuticals are intent on proving that one of their products is safe and effective, they may engage in practices that are professionally suspect and morally unethical. The recent news on Neurontin is a case in point.
Neurontin, manufactured by Pfizer and Parke-Davis, is the brand name for the drug gabapentin. It is approved to treat epilepsy and post-herpetic neuralgia but may also be used off-label, i.e., for uses not approved by the Food and Drug Administration (FDA). The latter include the treatment of migraines, bipolar disorder, and restless leg syndrome.
In addition, some physicians prescribe Neurontin off-label for a wider range of higher-prevalence conditions, including hot flashes, insomnia, and certain types of tinnitus (ringing in the ears). Over time, off-label uses have exceeded approved uses, so they are an increasingly important share of the market. In 2004, sales of the drug peaked at $2.7 billion. But that same year Pfizer was found to be urging physicians to prescribe Neurontin for off-label uses, which is illegal. As a result, the company had to pay $430 million in criminal fines and civilian penalties. But this was not the end of the Neurontin saga.
Because companies have a vested interest in having the FDA approve some of the off-label uses, they conduct research to see if the drug works for some of these other conditions. If they can convince the federal regulators that there is adequate evidence of safety and efficacy, FDA can then extend its approval for these additional uses, thereby broadening the drug’s market. Otherwise, advertising or promoting these uses is prohibited. Sometimes, not even intending to submit studies to the FDA to extend the approved uses, the companies do studies to publish the alleged new benefits of drugs.
The legal case against Neurontin uncovered some of the strategies that Pfizer and Parke-Davis employed to offset or otherwise scuttle publication of unfavorable findings. The deceptive tactics that were first revealed to the public in 2008 included delaying reports that found no evidence of the drug’s efficacy, “spinning” or reinterpreting negative data, and bundling negative findings with positive studies to neutralize results. In some cases, legitimate researchers saw their findings rewritten and recast to, in the words of one of company’s medical writer, “make [the overall picture] sound better than it looks on the graphs.”
A recent study published in the New England Journal of Medicine, based a more comprehensive analysis of these same documents, found that published results of randomized clinical trials on off-label uses of Neurontin conducted by Pfizer and Parke-Davis were skewed to show efficacy, and that the data were manipulated to support the desired findings. This practice, called “selective outcome reporting,” used two techniques: non-reporting of negative outcomes, and changing the outcomes of the trials to produce the desired results.
The latter practice entails modifying the purposes of the research after it has been conducted. Most drug trials include primary and secondary outcomes. Primary outcomes are, by definition, more important than secondary ones. For example, the primary outcome may be reducing the incidence of a particular condition, while a secondary outcome may be mitigating some of the symptoms.
The Guardian describes the practice of modifying the outcomes as follows:
You might do a trial on a blood pressure pill, for example, stating that you will look to see if it can reduce heart attacks, but find that it doesn’t. Then you might retrospectively change the purpose of the study, ignore heart attacks, pretend it was only ever about blood pressure, and glowingly report a reduction in blood pressure as if this was what you were always interested in.
This is tantamount to embarking on a cross-country trip between Los Angeles and Washington, DC, but deciding that you have arrived when you reach Wichita, Kansas, and declaring that is was your destination all along!
The researchers examining the research protocols for Neurontin identified 20 clinical trials, of which 12 were reported in publications. In eight of these 12 published trials, the primary outcomes defined in the report were different from those in the original research protocol. The discrepancies included introducing a new primary outcome, failing to distinguish between primary and secondary outcomes, and failing to report on one or more primary outcomes. Of the 21 primary outcomes in the research protocols, six were not reported at all and four were reported as secondary outcomes. And of the 28 primary outcomes in the published reports, 12 were newly introduced. And these changes were not neutral, but rather led to a more favorable presentation of Neurontin’s efficacy for unapproved indications.
While there may be legitimate reasons for modifying primary and secondary research outcomes, these changes need to be documented in the research protocol and in the statistical analysis to which findings are subjected, and should be included in any published report on the clinical trials. This was not consistently done in the Neurontin trials. The authors of the study therefore express their concern that “the reporting practices observed in [their] analysis do not meet the ethical standards for clinical research or maintain the integrity of scientific knowledge.”
These practices undermine the trust we place on science and published studies and make a mockery of the systems that generate evidence for decision-making purposes. While reliable data on clinical trials may seem arcane, they are at the core of much of what we do and don’t do in health care. To quote The Guardian: “Our failure to ensure full, undistorted publication of all trial data is the single most important issue in medicine today, because this is the only way we can know whether a treatment does good, or harm.”