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But the study did not actually demonstrate that researchers had been inappropriately influenced by their ties to industry. The authors acknowledged as much, saying, “We believe that the authors we surveyed expressed their own opinions and were not influenced by financial relationships with pharmaceutical manufacturers.” If financial relationships had no clearly discernible influence on the clinicians, what were the study’s authors concerned about? Appearances. “We wonder how the public would interpret the debate over calcium-channel antagonists,” the authors mused, “if it knew that most of the authors participating in the debate had undisclosed financial ties with pharmaceutical manufacturers.”
Reviewing the data from that study, Thomas Stossel, the Harvard hematologist, noted that consultants working for companies that were not producing calcium-channel blockers were as likely to favor the drugs as those that consulted for companies that did produce them. Do scientists who do consulting work for one company have an interest in promoting its competitors’ products? Stossel suggests a more logical explanation is that the researchers who consult with drug companies are better informed.
That argument seems credible, especially since, according to a 2002 meta-analysis of blood pressure treatments in the Journal of the American College of Cardiology, calcium-channel blockers have turned out to be at least as safe and effective as alternative drugs. Calcium-channel blockers are still widely used to control blood pressure. A 2005 study published in The Lancet found that a combination of calcium-channel blockers and angiotensin-converting enzyme (ACE) inhibitors was safer than a more conventional treatment combining diuretics with beta blockers. People with high blood pressure who take calcium-channel blockers are significantly less likely to develop diabetes than those treated with cheaper diuretics.
At the time of the 1998 New England Journal of Medicine article, activists claimed drug companies were duping physicians and patients into using more expensive treatments that were no more effective than earlier, cheaper medicines. Nine years later, further research shows the situation is more complicated: There is no one-size-fits-all treatment for hypertension. Based on what we know now, the more benign interpretation—that companies consulted with the most knowledgeable experts rather than that researchers favored companies that paid them—is more plausible.
Suspiciously Effective Medicine
A number of other studies have concluded that research results are biased by industry funding. Thirty-seven of those investigations were summed up in a review article by three Yale Medical School researchers that was published in The Journal of the American Medical Association (JAMA) in 2003. This meta-analysis found that “industry-sponsored studies were significantly more likely to reach conclusions that were favorable to the sponsor than were non-industry studies.” But it also noted that “there are several possible reasons for this finding. It is possible that, given limited resources, industry only funds potentially winning therapies.”
That explanation was bolstered by a 2006 study, also published in JAMA, that analyzed the outcomes of 202 randomized trials evaluating cardiovascular drugs reported between 2000 and 2005. Forty percent of the randomized drug trials funded by nonprofit organizations favored newer agents, compared to 54 percent of the jointly sponsored trials and 65 percent of the industry-funded trials.
The authors of the analysis suggested an explanation for these differences: “When the first trial report of a truly novel therapy is null or negative, it becomes less likely that any funding source will support subsequent studies. On the other hand, when the first trial of a truly novel therapy is positive, the likelihood of further trials is increased. These subsequent trials understandably and perhaps appropriately are more likely to be funded by for-profit organizations.”
In other words, government and foundations are more likely to fund earlier stages of drug development, where the risk of failure is higher. Companies jump in to sponsor drug research at later stages of development, when success is more likely. Thus it is not surprising that industry-funded research is more likely to reach positive conclusions. If a drug company’s trials regularly turned up negative findings, that would signal serious flaws in its drug discovery process.
Another concern related to conflicts of interest is that publication bias dangerously skews the medical literature by favoring studies that reflect well on new therapies. “Studies with positive findings are more likely to be published than studies with negative or null results,” said American Medical Association trustee Joseph M. Heyman at the organization’s 2004 meeting. “We are concerned that this pattern of publication distorts the medical literature, affecting the validity and findings of systematic reviews, the decisions of funding agencies, and, ultimately, the best practice of medicine.”
Any tendency to put negative results into a file drawer and
forget them can bias reviews of treatments reported in the medical
literature, making them look more effective than they really
Because of the fear that industry funding and commercial motives skew research results, most prominent life science journals now require financial disclosures from researchers whose work they publish. JAMA’s disclosure policy is one of the more demanding, requiring authors to “provide detailed information about all relevant financial interests and relationships or financial conflicts within the past 5 years and for the foreseeable future (e.g., employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), particularly those present at the time the research was conducted and through publication, as well as other financial interests (such as patent applications in preparation) that represent potential future financial gain.” These disclosures, which must be included with each manuscript before it’s submitted to peer reviewers, are typically published on the last page of the article.
The Public’s Trust
Advocates of such precautions argue that they will help restore public trust in biomedical research. But public trust is already at a very high level. A 2006 Harris poll found that physicians and scientists are among the professional groups most trusted by Americans. Indeed, medicine is the single most trusted profession, with 85 percent of Americans saying doctors can be trusted to be truthful. Trust in scientists is only slightly lower, at 77 percent.
More tellingly, a 2006 survey of cancer patients participating in five research trials found that the vast majority (more than 90 percent) were unconcerned about any financial ties their doctors might have with drug companies. According to the poll results, published in The New England Journal of Medicine last November, large majorities of the patients said they would have enrolled in the trial even if the drug company had paid the researcher for speaking or consulting, if the researcher had received royalty payments, or if he owned stock in the drug company. More than 80 percent of the patients believed it was ethical for researchers to receive speaking or consulting fees from the company. Most patients said they opposed bans on relationships between researchers and drug companies, and some said they would be more likely to participate in a trial if a drug company were involved. Even among the respondents with at least some post-graduate training, less than a third said they wanted to know about potential financial conflicts.
That trust appears to be justified. It’s hard to get firm numbers, but the Boston-based medical information and publishing firm CenterWatch, which tracks clinical trials, estimates that more than 40,000 are in progress, involving more than 20 million subjects. There are very few documented examples in which research subjects were seriously harmed. Looking at studies that led to the approval of one-third of all new drugs between 1987 and 2001, CenterWatch found that one in 30 subjects experienced a serious side effect. The 2001 report also noted that “each year, an average of 3.6 deaths attributed to study drug effects are reported to the FDA for approved drugs.” The FDA does not collect systematic data for injuries and deaths in studies of drugs that don’t get approved.
And “unlike industry-sponsored clinical trials that are regulated by the FDA,” CenterWatch noted, “government-funded studies conducted by individual investigators at academic medical centers frequently have risks that go unreported” to the federal Office for Human Research Protection.
CenterWatch President Ken Getz summed up the evidence in a 2002 interview with the San Francisco Chronicle: “It is not a patient-beware situation. The vast, vast majority of clinical trial participants have very positive experiences.”
What about the patients who use drugs after they’re approved? “Between 1997 and 2004,” the pharmaceutical industry critic Sheldon Krimsky noted in a 2005 op-ed piece in the Newark Star-Ledger, “12 major prescription drugs, with a market value of billions of dollars, were recalled by the FDA.”