The medicines that we as Americans take every day to help our hearts, our muscles, and our bones, improve our health and lead to happier lives. Similarly, the drugs and devices designed to manage diabetes, cancer, HIV and other chronic diseases, have enabled those with such diseases to have better chances fighting such ailments.
Receiving the fruits of such medicines, however, is the result of years and years of clinical research and close to $1 billion. For a drug to receive approval from the Food and Drug Administration (FDA), several phases of clinical trials, including two large Phase III trials must be conducted, at the expense of the pharmaceutical company seeking approval. Consequently, a recent article published in the New England Journal of Medicine (NEJM) raised concern over how company support of such clinical trials “can affect the design” and “reporting of the results.”
Study
Because little is known about how information concerning study design interacts with information concerning funding sources to influence physicians’ interpretation of research, the authors conducted a randomized study involving simulated research abstracts to assess the role that disclosure plays in physicians’ interpretation of the results of medical research. They developed hypothetical scenarios in which three new drugs were being evaluated for the treatment of disorders commonly encountered in primary care: hyperlipidemia, diabetes, and angina.
The authors then created abstracts describing trials of these drugs in which they varied the drug being tested, the trial’s methodologic rigor, and the funding source. For each drug, one trial had a high level of rigor, one had a medium level of rigor, and one had a low level of rigor. The authors then added a variable describing the trial’s funding status. Each abstract included one of three variations: no funding source mentioned, funding by the National Institutes of Health (NIH), or funding by a pharmaceutical company, with financial involvement in that company on the part of the lead author. A total of 27 different abstracts describing a hypothetical new-drug trial were created.
This methodology is problematic in itself. The authors’ own bias was to show that industry-sponsored trials should be discounted or questioned solely on their funding. Accordingly, there is a high likelihood that the “abstracts” were drafted by the authors with cues that might have biased the outcome. Moreover, is it even legitimate to differentiate the quality of a study based on its sponsorship, particularly given that the cases were made by the authors?
The authors the randomly indentified 503 physicians who reported spending 40% or more of their time and 21 hours or more per month in activities related to patient care and spending 50% or less of their time in the intensive care unit, the emergency department, or the cardiac catheterization laboratory. The survey was given to these physicians between July 2011 and October 2011. Each participant was presented with three abstracts, each of which described a trial of a different hypothetical new drug. The survey asked physicians about their likelihood of prescribing the new drug, the level of methodologic rigor of the trial, and their confidence in the study investigators’ conclusions.
Participants were also asked if pharmaceutical company funding was likely to influence the outcome of scientific studies about the efficacy and safety of pharmaceuticals in favor of the drug in question, and if they had received any financial support from manufacturers in the previous year.
Results
Most of the respondents (75.%) reported accepting at least one type of industry suppport. Respondents generally agreed with the statement that industry funding could influence the outcome of clinical trails of pharmaceutical agents in favor of the drug question (mean score, 5.4 out of 7.0).
The authors “found clear associations between the funding disclosure variations and physicians’ perceptions of a trial’s rigor and results.” Regardless of the actual study design, physicians were less likely to view a trial as having a high level of rigor if funding by a pharmaceutical company was disclosed than if no disclosure statement was included. Similarly, in comparisons with trials for which no funding was listed and regardless of the study design, physicians were less likely to have confidence in the results of trials funded by industry and were less willing to prescribe drugs described in such trials.
These effects were even greater when industry-funded trials were compared with trials described as having NIH support. In comparisons with NIH-funded trials, respondents were also less likely to describe industry-funded trials as “important”, and were less likely to want to read the full article. However, “investigators in NIH-sponsored studies also have substantial incentives, including academic promotion and recognition, to try to ensure that their studies change practice,” said Jeffrey M. Drazen, M.D., in an accompanying Editorial in NEJM.
Irrespective of the disclosure and level of methodologic rigor, physicians who strongly agreed that funding by pharmaceutical companies can influence the results of a trial were less likely to prescribe the hypothetical drugs than were physicians with lower scores. Physicians who were older than the median age of 48 years for the sample were more likely than the younger physicians to report that they would prescribe the simulated drugs.
Discussion
In this randomized study, the authors found that respondents downgraded the credibility of industry-funded trials, as compared with the same trials randomly characterized as having NIH funding or having no source of support listed. Physicians’ skepticism of industry-funded research affected their responses to high-rigor and low-rigor trials similarly. The authors proposed that “well-publicized controversies related to industry-funded research may help explain these findings.”
For example, they noted reports of trials that withheld critical data; trials that presented positive results while withholding negative results; and industry-financed articles that were ghostwritten or published primarily as instruments of marketing.
The authors recommended that companies seeking to enhance the appropriate use of important new products or to expand the appropriate uses of existing products “must address the attitudes” revealed in the survey “so that the credibility of the results of industry-supported trials are more likely to be based on methodologic rigor than on funding sources.” Of course, the authors provided no suggestions of how to do so, since that was “not the subject of this research.”
It was noted that journal reviewers and editors, those who conduct systematic reviews, or even interested physicians can refer to the ClinicalTrials.gov database to see whether trial data as reported reflect the planned study design. They suggested that such a “retrospective check could alleviate concerns about the possibility that trial outcomes were changed after the data were gathered and analyzed.” But the website may be incomplete.
The authors also suggested that because NIH-funded trials had the highest level of credibility, increased funding by NIH or the new Patient-Centered Outcomes Research Institute (PCORI) might reduce clinicians’ skepticism and lead to more data-driven changes in practice. Interestingly, the authors failed to unravel two important aspects of such funding. First, the government has minimal to no funds available for any hard clinical research; most funding is for basic research that amounts to Phase I of clinical trials, and pre-clinical trial research. Second, funding from PCORI has its own tremendous conflict and bias: trying to reduce the cost of healthcare, making no distinction between what is truly effective and really seeking only what is “cost-effective.”
The recent partnerships between NIH and industry, such as the new National Center for Advancing Translational Sciences (NCATS) may be a reasonable middle ground.
What is ironic about this article, is the authors’ failure to acknowledge that the reason physicians are discounting research because of financial support is because the editors of such journals have created their own problem. It is precisely because journals are publishing articles that demonize industry, that we have results such as this. As we noted back in May, nearly 90% of articles published in high-tier medical journals emphasize the down-side of the medical products industry – with precious little evidence, false evidence and almost no effort at balanced discussion.
In addition, the suggestion that media attention has also raised concerns from physicians is misplaced. The overwhelming majority of large settlements have involved off-label promotion, not clinical trials or fraud related to such trials. Thus, this article is merely feeding into the perception that anything and everything physicians do with industry is evil.
Specifically, the authors maintained that some practitioners “may be swayed by potential bias in industry-supported publications to use certain medications more widely than would be appropriate, whereas other practitioners may be skeptical about the validity of company-funded research.” To address these concerns, medical journals that publish the results of clinical trials have increased their transparency by including disclosures of financial support and/or conflicts of interest.
The authors, however, maintain that “some financial disclosure may not fully address the problem of potential bias in published research results.” For example, they point to one study that showed that physicians ignored disclosure statements, whereas other studies have shown that disclosure of substantial conflicts of interest can lead clinicians to discount the reported results of a trial. On the other hand, the authors also point to some studies, which show that disclosure can “enhance the trustworthiness of the discloser.”
What this study really shows is that the critics of industry-physician collaboration and those leading the “conflict-of-interest” mania have caused physicians to discount valid, truthful and scientific research, based not on the quality of the design, but by its funding. Such questioning threatens the very knowledge our physicians depend on to improve their practice and care, which may ultimately harm patients.
This research is problematic because it ignores the fact that physicians could be discounting valid and truthful scientific research because of such disclosures, which in the end, will only hurt patients and slow implementation of new evidence-based medicine and treatment guidelines. As the authors themselves recognize, “pharmaceutical industry has supported many major drug trials that have been of particular clinical importance.”
Moreover, they recognized that “Excessive skepticism concerning trials supported by industry could hinder the appropriate translation of the results into practice.” In fact, they pointed to results of a large, well-designed trial describing a new use for a widely prescribed class of drugs, in which readers believed that the results of the trial did not justify a change in clinical management, citing industry funding as a key reason for this conclusion. Despite their recognition, the authors continued to feed fuel to the fire of this “excessive skepticism.”
Conclusion
What is disappointing about this research is its failure to clearly acknowledge the adverse consequences this study will have on researchers. While admitting that skepticism of research can “reduce the credibility and acceptance of even high-quality research that is industry-supported,” the authors offer no further elaboration on how to prevent such events from taking place. Instead of citing ways researchers can rely on research and disclosures to prevent this kind of credibility reduction for high-quality research, the authors self-servingly hold true to their own bias and reason for writing this article: trying to prove that anything involving industry is bad; guilt by association.
Ultimately, we have now come into an era where the editors and critics who once called for transparency are getting a taste of their own medicine. Doctors, who try to rely on research from clinical trials to treat their patients, are now questioning the very truthful, valid, and scientific research such editors are publishing. Is transparency really helping us?