Is Industry-Funded Science Killing You?
The overrated risks and underrated benefits of pharmaceutical research "conflicts of interest"
In 2004 GlaxoSmithKline became the first major drug manufacturer to publicly disclose all the data from clinical studies of its products, including information that is usually treated as a trade secret. It was responding to a lawsuit by Eliot Spitzer, then New York's attorney general and now its governor, who accused Glaxo of hiding data about the safety and efficacy of one of its drugs. Sure enough, the company had concealed data indicating its antidepressant Paxil increased the risk of adolescent suicide. More-recent research suggests that link might not exist after all, but even if that proves true, it doesn't excuse the initial concealment.
A month later, Merck pulled its new pain reliever, Vioxx, off the market after clinical trial data showed that patients taking it had a 400 percent greater chance of heart attack than those taking the comparison drug, naproxen. Merck researchers implausibly argued that the difference was due not to damage caused by Vioxx but to the other drug's cardio-protective properties. No previous research had found that naproxen protects the heart.
For critics of the pharmaceutical industry, the Vioxx and Paxil incidents are evidence that conflicts of interest have thoroughly corrupted American medical research. "The Vioxx withdrawal serves as a reminder of the dangerous potential for conflict of interest that exists when pharmaceutical and other for-profit businesses control the dissemination of findings generated by medical research," warned a November 2004 editorial in the Dayton Daily News. In March 2005, the left-leaning Center for Science in the Public Interest (CSPI) pointed out that a Food and Drug Administration (FDA) panel that reviewed data on the risks posed by COX-2 painkillers like Vioxx included 10 researchers with financial ties to the companies that manufactured those drugs. Had the panelists with conflicts been excluded, a majority of the remaining members would have voted against approving Vioxx for distribution.
The Paxil incident prompted a June 2004 statement from the New York Attorney General's Office warning that "the ability of drug companies to pick and choose the research they provide doctors in support of their product is an outrageous conflict of interest and puts us all in harm's way." An August 2005 story about industry-funded medical research in the San Jose Mercury News quoted Sheldon Krimsky, a longtime critic of pharmaceutical companies, who asserted that "the entire system of drug testing is filled with conflicts of interest."
There's no question that some companies have behaved badly in some cases. But are these cases typical or rare?
Activists, politicians, and other critics claim conflicts of interest are pervasive in pharmaceutical research. Several years ago CSPI established an Integrity in Science Project to investigate and publicize the destructive influence of industry-sponsored science. Not to be outdone, the Union of Concerned Scientists launched its own Scientific Integrity Program to "push for reforms that will protect our health, safety, and environment."
Politicians are jumping on the bandwagon, proposing more-stringent regulations of private clinical research. Sens. Christopher Dodd (D-Conn.) and Edward Kennedy (D-Mass.) recently introduced the Fair Access to Clinical Trials Act, which would require all clinical trials to be registered in a central government database. Marcia Angell, a senior lecturer in social medicine at Harvard University, wants to ban privately funded clinical trials altogether. Instead, she proposes that drug companies be forced to pay into a government fund that would finance a new National Institute of Prescription Drug Trials to conduct all future clinical testing.
Supporters of such changes argue that conflicts of interest undermine public trust in and support for scientific research, endanger research subjects and patients, and boost medical costs by encouraging physicians and patients to use new treatments that are no better than cheaper alternatives. Yet public trust in biomedical research remains high, and that trust seems to be justified. Subjects in clinical trials hardly ever suffer serious harm, and instances in which dangerous side effects turn up after drugs are approved are relatively rare. Rather than making medicine unnecessarily expensive, pharmaceutical innovation ultimately reduces health care costs, because new drugs usually have advantages that pay off in lower medical bills.
The critics' concerns are not entirely groundless. Driven by self-interest, drug companies and researchers do occasionally hide data or run drug trials that produce data of scant clinical value. But private initiatives by medical journals, universities, and companies are already addressing these challenges, making government action unnecessary.
In 2005 The Journal of the American Medical Association reported that 5.6 percent of health spending in the U.S. goes to biomedical research, more than in any other country. In nominal dollars, funding for biomedical research in this country rose from $37 billion in 1994 to $94 billion in 2003. Even adjusted for inflation, that's an increase of almost 100 percent. The National Institutes of Health provided 28 percent of that funding; industry gave 57 percent; state, local, foundation, and other federal agencies accounted for the remainder.
This cooperation between academia and industry has been essential to speeding new treatments from lab bench to hospital bedside. "By any measure, the interactions between academic research and industrial research and development, as epitomized by biotechnology, have been overwhelmingly positive," wrote Thomas Stossel, a professor of medicine at Harvard and a co-director of the Hematology Division at Boston's Brigham and Women's Hospital, in a 2005 New England Journal of Medicine article. "We should celebrate their achievements and protect the process that led to them."
But one man's beneficial cooperation is another's conflict of interest, a phrase that has acquired an inappropriately sinister connotation. As defined by the former Harvard epidemiologist Kenneth Rothman in a widely cited 1993 New England Journal of Medicine article, a conflict of interest is "any situation in which an individual with responsibility to others (which includes professional responsibilities) might be influenced, consciously or unconsciously, by financial and personal factors that involve self-interest."
Such conflicts are not at all unusual. David Korn, senior vice president for biomedical and health sciences research at the Association of American Medical Colleges, noted in 2000 that "conflicts of interest and commitment are ubiquitous in academic life (and indeed, in all professional life), and conflicting pressures inherent in the academic milieu, e.g., for faculty advancement, obtaining sponsored research funding, winning the acclaim of one's professional peers, competing for prestigious research prizes, and yes, desiring to alleviate human pain and suffering, all may be more powerful in influencing faculty behavior than the prospect of material enrichment." Such conflicts do not in themselves imply wrongdoing, Korn stressed: "Since these conflicts can never be eradicated from professional life, their existence must be accepted and not equated with professional misconduct."
Corrupt or Well-Informed?
To illustrate the dangers allegedly posed by conflicts of interest, industry critics repeatedly point to a handful of atypical cases featuring erroneous results, suppressed data, or harmful side effects. (See "Ties That Blind," page 38.) In addition to such anecdotal evidence, they cite studies that show a correlation between industry funding and results that are favorable to the sponsors. As the researchers themselves acknowledge, however, there are benign explanations for such correlations.
In 1998 The New England Journal of Medicine published an article that claimed to show how commercial interests influenced the scientific evaluation of data on the relative safety and effectiveness of calcium-channel blockers, a class of drugs used to control high blood pressure. The study found that "authors who supported the use of calcium-channel antagonists were significantly more likely than neutral or critical authors to have financial relationships with manufacturers of calcium-channel antagonists (96 percent vs. 60 percent and 37 percent, respectively)." The authors concluded that this "strong association" meant the "medical profession needs to develop a more effective policy on conflict of interest."
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 are.
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."
Krimsky claims such dangerous drugs have been allowed to reach the market because "conflicts of interest have become endemic in the system of drug evaluation," a trend that "has been exacerbated by the rise of for-profit clinical trials, fast-tracking drug approvals, government-industry partnerships, direct consumer advertising and industry-funded salaries for FDA regulators" since the mid-1990s.
There's little evidence that the FDA is more likely to approve harmful drugs than it was in the past. A 2005 report by the Tufts University Center for the Study of Drug Development found that faster approval times do not correlate with more frequent drug withdrawals. The share of drugs withdrawn for safety reasons was 3.2 percent in the 1980s, 3.5 percent in the '90s, and 1.6 percent from 2000 to 2004. The approval times for drugs that are withdrawn are not appreciably shorter than the average approval time for all drugs.
Meanwhile, the FDA removes dangerous drugs from the market much sooner than it used to. The average time between FDA approval and subsequent safety withdrawal dropped from 3.7 years in the 1980s to 1.4 years in the '90s and is now seven-tenths of a year. The bad news is that an overcautious FDA can kill people too. A 2005 study by economists at the University of Chicago calculated that the speed-up in FDA drug approvals that occurred after 1992 may have been responsible for saving the equivalent of 180,000 to 310,000 life-years (the sum of the years of life that would have been lost had the new drugs not been available). Over the same period, about 56,000 life-years at worst were lost to drugs that were eventually withdrawn for safety reasons.
Unfortunately, it's much easier to identify people who are harmed by drugs than those who are saved by drugs. In the face of this information asymmetry, regulators tend to focus on reducing lives lost to unsafe drugs rather than preventing deaths by speeding effective new therapies to patients.
Saving Money by Spending More
What about the charge that biased reporting of scientific results boosts overall medical costs by encouraging physicians and patients to select new, expensive treat-ments that are no better than older, cheaper medicines? "The cost of pharmaceutical drugs—and health care in general—in America continues to skyrocket," Jennifer Washburn of the New America Foundation wrote in the June 2005 In These Times. "Expensive new drugs are aggressively marketed on TV and in doctors' offices the moment they hit the market. Yet physicians warn that many of these hyped prescriptions are simply 'me-too drugs' that vary only slightly from medications already on the market, despite being far more expensive."
Health care as a share of U.S. gross domestic product has tripled from 5 percent in 1960 to 16 percent today. Some analyses project the number will reach 25 percent by 2030. But this inflation is not due to spending on drugs. In a 2002 study for the National Bureau of Economic Research, the Columbia University economist Frank Lichtenberg estimated that, on average, "reducing the mean age of drugs used to treat a condition from 15 years to 5.5 years…increases prescription drug spending by $18 [averaged over the total population] but reduces other medical spending by $129, yielding a $111 net reduction in total health spending. Most of the savings are due to reductions in hospital expenditure ($80) and in physician office-visit expenditures ($24)." In other words, using newer drugs reduces other medical expenditures by more than seven times the extra amount spent on drugs.
Today 30 percent of the $2.2 trillion Americans spend on health care each year goes to hospitals. Physicians get 20 percent, and 10 percent pays for dental and other professional services. All of these are labor-intensive treatments. By comparison, prescription drugs account for about 10 percent of health care spending. "Within a generation or two," Peter Huber of the Manhattan Institute noted in the July 2006 Commentary, "they will undoubtedly account for most of it—which will be another good thing. Pharma's biochemical cures always end up far cheaper than the people-centered services they replace."
Marcia Angell rails against the pharmaceutical industry's "obscene profits." But Princeton health economist Uwe Reinhardt told USA Today in October 2006 that he had "once calculated that if you rebated all the drug company profits to patients, health spending would only go down by 1.2%." Seizing drug company profits would do nothing to address the current health care spending "crisis," but it would shut off the flow of funds to many biomedical researchers and drastically slow the discovery and development of new and more effective drugs.
As for "me-too" drugs, the implication is that companies are trying to take market share from each other without providing any "real" benefits to patients. Of course, "trying to take market share away" is better known as "competition," which ultimately results in lower prices.
Everybody's a Critic
Although critics of the drug industry exaggerate the problems created by conflicts of interest, in rare instances drug companies have withheld or misreported data, and some researchers have put their financial gain above the safety of their patients. It therefore makes sense to keep an eye on potential conflicts.
One safeguard—disclosure in journals—is here to stay. Even Stossel, a strong proponent of industry-financed research, favors disclosure. "To be sure," he wrote in a February 2005 Forbes column, "it is reasonable to require disclosure of corporate sponsorship by investigators and institutional monitoring of collaborations. But academic administrators and government officials respond to rare incidents of misconduct and to the barrage of criticism that follows by rushing to pile on restrictions."
Peer review has been the traditional means of assuring a study's validity. By requiring disclosure, journal editors are in effect admitting peer review's failure. Since their reviewers are not competent to evaluate findings based solely on the data, warning labels need to be slapped onto industry-funded studies. And peer review overlooks honest errors as well as deliberate fraud. "Peer review doesn't necessarily say that a paper is right," said Martin Blume, editor-in-chief of the American Physical Society's nine journals, in a January 2006 interview with Science. "It says it's worth publishing."
Fortunately, a new age of more-robust peer review is dawning. With the advent of online journals like those published by the Public Library of Science (PLoS), peer review is changing from a one-time appraisal of a self-contained research article to a continuous online process. Since 2003 PLoS has launched eight open-access, peer-reviewed biomedical journals. In 2006 it started a new comprehensive online journal, PLoS One, which will feature reports of primary research from all disciplines in the biological and physical sciences. The editorial board will make prompt decisions on whether papers merit publication and may refer them to outside reviewers.
With PLoS, unlike print journals, publication is not the end of the peer review process. Once an article has een published in PLoS One, community-based post-publication peer review begins, in full view of anyone who visits the site. Post-publication reviewers can post corrections, additions, or links to other relevant articles. They can engage in online debates concerning the content, conclusions, and consequences of a specific paper. Users can assign ratings to papers. (Anonymous annotations are not allowed.)
According to the PLoS good practice guidelines, post-publication reviewers should confine their criticisms to the content of papers and avoid speculation about the motivations or prejudices of authors. That may be considered good practice now, but in the future post-publication reviewers may begin to note any associations they believe relevant to the findings reported in the paper. In other words, if a researcher doesn't disclose potential conflicts, someone will do it for him.
All the Data That Are Fit to Post
Private initiatives are also achieving the goal that Sens. Dodd and Kennedy want to legislate: registration of all clinical trials. In 2004 the International Committee of Medical Journal Editors (ICMJE) adopted a policy that requires, as a condition of consideration for publication in their journals, registration of clinical trials in a public registry. Trials beginning after July 1, 2005, must be registered at or before the onset of patient enrollment. The ICMJE established criteria that each trial must meet to insure transparency and required that the registry be accessible to the public free of charge. At the time, the only website that qualified was ClinicalTrials.gov, run by the United States National Library of Medicine.
The ICMJE policy has had an effect. After the policy was announced, the number of clinical trial registrations increased by 73 percent—from 13,153 to 22,714. As of April 2007, the registry contained over 40,000 trials, with more than 200 new trial registrations occurring weekly. Now four other clinical trials registries meet the ICMJE criteria, and many more journals have adopted the ICMJE clinical trials registration policy.
Also in 2004, the Pharmaceutical Research and Manufacturers Association announced that it was launching an online registry of clinical trial results. The association's members, which include the world's leading drug companies, will provide the results of all clinical trials completed after October 1, 2002, at clinicalstudyresults.org.
And since May 2006, researchers no longer can complain that journal editors will not publish negative or inconclusive results. PLoS's journal PLoS Clinical Trials explicitly addresses the problem of publication bias: It will publish the results of randomized trials from all medical and public health disciplines. Publication does not depend on the trial's outcome, size, or implied importance. Even negative results provide useful information about the effectiveness of treatments, alerting other researchers not to waste their time and resources on therapeutic dead ends. Indeed, researchers arguably have a moral obligation to publish their results, whether positive or negative, since subjects undertake risks to generate the data.
Collaboration between academia and industry should be encouraged, not attacked. In most areas of research, including computer science, geology, and chemistry, such ties are correctly seen as a source of innovation that has dramatically improved the quality of our lives during the last half-century.
Given the potential life-or-death consequences for patients, collaboration between the pharmaceutical industry and medical researchers needs to be monitored, and adjustments should be made whenever abuses come to light. But through such private efforts as financial disclosure requirements, registration of clinical trials, and peer-reviewed publication of all clinical trial results, the scientific research enterprise has shown itself capable of protecting the validity of research results without new government regulations.
"In a transparent atmosphere, misconduct can be detected, challenged, and if necessary, purged and punished," Stossel noted in his 2005 New England Journal of Medicine article. "The intense energy currently dedicated to demonizing academic-industrial research relationships should be redirected toward developing better ways to identify and facilitate the type of partnerships that have brought more good, by far, than harm." He added, "The public wants trustworthy science, and it can get that without new ethical rules. Even more it wants results—real lives saved—and it can't get those if commercial sponsorship of research is made difficult, or impossible."
Science Correspondent Ronald Bailey (email@example.com) is the author of Liberation Biology: The Scientific and Moral Case for the Biotech Revolution (Prometheus Books). This article derives in part from research commissioned for a white paper on scientific conflicts of interest by the non-profit consumer education consortium the American Council on Science and Health. ACSH receives no-strings-attached funding from individuals, foundations, associations, and corporations. Bailey would also like to note that he owns various fairly speculative biomedical stocks that he really hopes will benefit a lot from industry-academic collaborations. The number of shares he holds in any one company amounts to a few hundred at most.