You invest millions in researching a promising new medicine. You patent it, do some trials and it gets FDA approval. A few years later the drug is bringing in billions and your stock price is sky-high.
Then suddenly a new study finds some problems. Perhaps the drug doesn't really work all that well; perhaps there are harmful side-effects. What do you do?
The right thing to do, would be to engage with these new findings, immediately and with the intention of doing the best thing by the drug’s potential users; and, in the meantime, to alert the medical world to the situation. The less impressive reality is that more and more companies have been busted trying to delay the publication of negative findings. Their motivation is clear: another year on the market means another few billion dollars and some very happy shareholders.
Pfizer in court
The drug company Pfizer is currently in court over allegations that earlier this decade it suppressed findings that showed that their billion-dollar epilepsy drug, Neurontin, is not an effective treatment for bipolar disorder, migraine, and certain kinds of pain. The drug was widely described off-label as being appropriate for these uses.
Internal Pfizer e-mails quoted by the New York Times suggest that the company's marketers intentionally downplayed negative findings. In addition, the newspaper pointed out a discrepancy in the transparency around research: four out of five positive studies on the drug were published, while only six out of 16 negative studies were published.
"Pfizer continued with the medical marketing firms and planted marketing messages in journal articles that Neurontin was effective while they knew that their own clinical trials had failed to demonstrate it was effective,” The New York Times quotes a lawyer for the plaintiffs as saying.
Pfizer denies any wrongdoing.
The Pfizer case comes hot on the heels of a number of similar scandals to have hit the pharmaceutical industry over the past few years.
Earlier this year a study was published that found that Merck and Schering-Plough's best-selling cholesterol-lowering drug Vytorin did not reduce arterial plaque, and thereby reduce the risk of heart disease. The problem is that the findings were released only about two years after the completion of the study.
Merck has also been accused of covering up serious heart risks relating to their arthritis drug Vioxx. The New England Journal of Medicine alleged that Merck removed references to three heart attacks in a study of Vioxx before submitting an article on the drug to the journal in 2000.
Vioxx has since been withdrawn from the market due to heart risks.
Patients pay the price
It would seem that in most of these cases the health of patients was trumped by other considerations.
It makes for great headlines when corporate greed of this nature is exposed, but this is by no means the whole story. The research system may be broken in some much more subtle ways – and often in ways that could go unnoticed.
One such confounding factor is publication bias – the tendency to favour extreme findings over more moderate ones.
News is always better read the more sensational it is, and this is as true in medical journals as anywhere else: they tend to give prominence to more extreme findings. A best-seller pill that may give you heart problems, is big news – while a study finding that that same pill doesn't pose a substantial risk to your liver is less likely to raise eyebrows.
This becomes particularly problematic when scientists do review (meta-analysis) studies, in which they pool all the different studies on a given topic and attempt to draw conclusions on that topic. If all the more moderate findings were never published, the review will tend to overstate its conclusions.
In a recent study in The Oncologist, researchers found that only 17.6% of 2 082 cancer studies in the US clinicaltrials.gov study registry were published in peer-reviewed journals.
Even more remarkably, only 5.9% of industry-sponsored studies made it into print. Not surprisingly, three quarters of these reported positive findings. And even among the non-industry-funded studies, an astonishing 64.5% of the published work was positive.
In short, the study confirms the massive bias in favour of positive findings over negative ones.
Commenting on why so few negative studies make it into medical journals, Guardian columnist and medical doctor Ben Goldacre writes, "they’re not newsworthy, so journal editors reject them; they’re not much fun to write up, and they don’t look good on your CV (although they should get plaudits); and they might not flatter your idea or product, so you might not want them out there".
But, as Goldacre points out, the price for non-publication can be high. “Those missing numbers will cost lives in quantities larger than any emotive health story covered in any part of any newspaper this week," he writes. "Doctors need negative data to make rational prescribing decisions. Academics need to know which ideas have failed, so they can work out why, what to study next, and which ideas to abandon."
Medicines regulation is torn between getting effective medicines out quickly and taking the time to make sure that they’re also safe. With the Vioxx scandal, among others, it seemed the pendulum had swung too far away from caution and safety.
The backlash culminated in October 2007 when the Food and Drug Administration Amendments Act of 2007 went into effect in the US. The act was widely hailed to be the most significant FDA reform in many years. One of its key aspects was the expansion of official study registries. Before October 2007, only clinical trials looking at drug products aimed at treating life-threatening diseases had to be registered. The act expanded this to include all clinical trials involving drugs, biologics, and devices, with few exceptions.
Possibly of even greater importance, is the requirement that study findings should be indicated in study registries. Theoretically, this kind of thing should help put an end to study findings being swept under the carpet – for whatever reason.
As John Scoggins, co-author of The Oncologist article, points out though, the findings reported in study registries will be far from peer-reviewed findings. "Article submission and acceptance is a purely voluntary process that no act of congress can reliably control," he says. "The interpretation and critiquing of clinical trial results requires expert judgment. Simply registering clinical trial results does not hold the investigator to any scientific standards of quality control."
That being said, Scoggins does consider the registration of clinical trial results to be a positive step. "It provides for at least a modicum of transparency and makes suppression of negative results that much more complicated."
Whether the study registers will allow detailed enough findings for use in review studies remains unclear though, and may depend on how exactly the act is interpreted.
What if you don't publish?
The greater problem, though, seems to be how exactly researchers can be obliged to publish their findings. Ideally, the cost of not publishing should be greater than the cost of publishing – even if the findings are negative.
One of the more interesting aspects of the act is that it gives the FDA the authority to impose financial penalties on researchers who neglect to indicate their findings on study registries.
Whereas it seems results will have to be registered, Scoggins is worried about the apparent lack of quality control. "The biggest risk is the reporting if partial and misleading information. There doesn't seem to be any specific penalties for that or any method of adjudicating allegations."
According to Scoggins the problem of non-publication can best be addressed by Institutional Review Boards (these are independent ethics committees tasked with overseeing medical research). "Every research organisation has one. They have the expertise to understand the problem and the power to get results. They could require that the results of trials be submitted and could monitor the efforts of the investigators."
But whether Institutional Review Boards will be fulfilling this role anytime soon is unclear.
(Marcus Low, Health24, November 2008)
Ramsey, Scott. Scoggins, John. Commentary: Practicing on the Tip of an Information Iceberg? Evidence of Underpublication of Registered Clinical Trials in Oncology. The Oncologist. September 15, 2008.
Experts conclude Pfizer manipulated studies. New York Times. October 8, 2008.
Seriously. Is the Daily Mail any worse than your average academic journal? By Ben Goldacre. (From the Bad Science column that is published in The Guardian)
E-mail correspondence with John Scoggins from the Fred Hutchinson Cancer Research Center in Seattle.