Pico de Orizaba

Pico de Orizaba
Taken from Huatusco, Veracruz, the closest town to Margarita's family's ranch.

Sunday, March 1, 2015

Behind the Veil: Conflicts of Interest and Fraud in Medical Research


If you want to read the very interesting and informative comments at the end of this piece:  http://chriskresser.com/behind-the-veil-conflicts-of-interest-and-fraud-in-medical-research

Recent reports have revealed that conflicts of interest and research fraud are rarely reported in the scientific literature or announced to the general public, which raises questions about the integrity of clinical trials and the reliability of public agencies like the FDA and CDC.

A couple of weeks ago I wrote an article called Why Are Scientists and the Public So Often at Odds? I described the frequent disconnect between scientists and the general public on controversial issues like nutrition, vaccination, climate change, and genetically-modified foods.

In that article, argued that both the general public and scientists were to blame for the disconnect. In some cases the public does act out of ignorance, whether intentionally or unintentionally; in other cases, scientists have ignored the very real limitations and problems with the research they rely on to reach consensus.

Why conflicts of interest and fraud harm the public’s trust of medical research.

In this article, I’m going to discuss two other reasons that the public mistrusts scientific research: fraud, and conflicts of interest.
Fraud in Medical Research: “Out of Sight, Out of Mind, and Out of the Peer-Reviewed Literature”

A large part of the subtitle above comes directly from a paper published in JAMA Internal Medicine, authored by Charles Seife. (1) In short, Seife discovered that clinical trial data determined to be fraudulent or mishandled by the FDA is rarely excluded from research studies published in scientific journals.

One of the FDA’s roles in the drug approval process is to inspect clinical trial sites to determine whether these sites are complying with FDA regulations. A typical inspection might involve auditing the records of the site, verifying that investigators adhered to the trial protocol, and comparing an investigator’s notes in hospital records with data reported to the study sponsor to ensure that there aren’t any discrepancies.

If there is a violation, the FDA classifies it in one of two ways: Voluntary action indicated (VAI) means the inspectors have found violations, but the problems aren’t serious enough to require sanction. Official action indicated (OAI) means that the inspectors have found violations significant enough to warrant official action.

Siefe and his assistants used the Freedom of Information Act to request information from the FDA, and supplemented that data with Google searches of the FDA database. They found 57 clinical trials that were directly linked to an OAI inspection.

The misconduct identified by the FDA in these cases included:
Falsification or submission of false information
Underreporting of adverse events
Failure to follow the investigational plan or other violations of protocol
Inadequate record keeping
Failure to protect the rights, safety, and welfare of patients
Use of experimental compounds in patients not enrolled in trials
Failure to supervise clinical investigations properly

The 57 trials Seife identified were in turn linked to 78 research articles published in the peer-reviewed scientific literature. 96 percent of these articles failed to mention the violations identified by the FDA inspection—despite the fact that in the majority of cases the inspection was completed at least 6 months before the article was published.

Doctors, researchers, and other health professionals rely on scientific studies to establish treatment protocols and public health policies. If the data in some of these studies are fraudulent, but the doctors and researchers have no way of knowing that, the decisions they make may be unsound and even put people at unnecessary risk.

I’d like to make the significance of these omissions even more clear by sharing a couple of examples mentioned in Seife’s paper.

One case involved a researcher who falsified lab test results to hide a patient’s impaired kidney and liver function in a trial comparing two chemotherapy regimens. The first dose of the regimen proved to be fatal to this patient, and the researcher was sentenced to 71 months in prison. Despite this episode being described in both FDA and court documents, not one of the studies in the peer-reviewed literature associated with the chemotherapy trial have any mention of the falsification, fraud, or homicide.

Another case involved a clinical site in China participating in a large trial of apixaban, an anticoagulant (i.e. anti-clotting) drug. The FDA determined that this trial site had altered patient records and falsified data. If the data from this site had been excluded, the mortality benefit for the drug would have disappeared. In other words, the “proof” that this drug saved lives was dependent on this fraudulent data. Yet none of this discussion appears in the scientific literature. In fact, studies since 2011 have consistently relied on the full data set (including the fraudulent data from the China trial site), and this was even true for an article published nearly 18 months after the fraud was discovered.

How can such egregious cases of fraud and misconduct go unreported in the scientific literature and in the media? The answer is almost hard to believe. The FDA does not notify journals when a site participating in a clinical trial receives an OAI inspection, nor does it typically make any announcement which would alert the media and general public to the issues it identified.

What’s more, the documents the FDA produces about these OAI inspections are heavily redacted, which makes it extremely difficult even for researchers like Seife who’ve invoked the Freedom of Information Act to determine which published clinical trials are tainted by misconduct. The FDA redacts these documents because it considers the identity of the drug company involved in the trial to be “confidential commercial information” that it is bound to protect.

In other words, the FDA appears to believe that it’s more important to protect private, commercial interests than it is to protect public health.

Seife’s says as much in the conclusion of his paper:

However, failing to notify the medical or scientific communities about allegations of serious research misconduct in clinical trials is incompatible with the FDA’s mission to protect the public health. Such allegations are relevant to include in the peer-reviewed literature on which physicians and other medical researchers rely to help them choose treatments that they offer to patients and other research participants.

The issues highlighted here raise serious concerns not only about the trustworthiness of the data in clinical trials and published research, but the reliability and motives of the agencies tasked with protecting public health.

Which takes us to the second reason that public mistrust of scientific research is sometimes well-founded: conflicts of interest.
Conflicts of Interest in Research Are Common—and Often Unreported

In my article about the disconnect between scientists and the public, I mentioned that two-thirds of medical research is sponsored by drug companies, and industry-sponsored trials are more likely to report favorable results for drugs because of biased reporting, biased interpretation, or both. (2) This is a well-established phenomenon, and it has been explored in both the media and the scientific literature:
Can the Source of Funding for Medical Research Affect the Results? (Scientific American)
Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients (a book authored by Ben Goldacre)
How Pharmaceutical Industry Funding Affects Trial Outcomes (Social Science & Medicine)
Pharmaceutical Industry Sponsorship and Research Outcome and Quality: Systematic Review (British Medical Journal)
Association Between Industry Funding and Statistically Significant Pro-Industry Findings in Medical and Surgical Randomized Trials (Canadian Medical Association Journal)

Is it really a big surprise that the source of funding influences study results? After all, as Upton Sinclair famously said, “It’s difficult to get a man to understand something, when his salary is dependent upon him not understanding it.” The time-honored saying “don’t bite the hand that feeds you” also applies here.

Unfortunately, just as research misconduct and fraud is often not reported, conflicts of interest in academic research are rarely disclosed. According to a 2009 reportissued by the Department of Health and Human Services, very few universities make required reports to the government about the financial conflicts of interest of their researchers—and even when they are reported, the universities rarely require those researchers to eliminate or reduce these conflicts.

In fact, 90 percent of universities relied solely on the researchers themselves to decide whether to report their potential conflicts of interest, and half of universities don’t even ask their faculty to disclose the amount of money or stock they make from drug or device makers.

This isn’t likely to change anytime soon, according to Eric G. Campbell, an associate professor at Harvard Medical School that was quoted in this New York Times article covering the report. He said that “universities had no interest in putting real limits on the incomes of their star researchers for fear that those researchers would leave for institutions with fewer restrictions.”

But conflicts of interest aren’t just a problem in academia; they’re also a problem on expert advisory panels that influence public health policy. For example, back in 2008 Dr. John Briffa linked to a web page disclosing the conflicts of interest in members of the National Cholesterol Education Program, a government organization that creates the official blood cholesterol target values for the U.S..

Are you ready for this? 8 out of the 9 doctors on the panel had direct ties to statin drug manufacturers. Here’s the complete list, excerpted from a post written by Dr. Stephan Guyenet in 2008 (the companies in bold are statin manufacturers):

Dr. Grundy has received honoraria from Merck, Pfizer, Sankyo, Bayer, Merck/Schering-Plough, Kos, Abbott, Bristol-Myers Squibb, andAstraZeneca; he has received research grants from Merck, Abbott, and Glaxo Smith Kline.

Dr. Cleeman has no financial relationships to disclose.

Dr. Bairey Merz has received lecture honoraria from Pfizer, Merck, and Kos; she has served as a consultant for Pfizer, Bayer, and EHC (Merck); she has received unrestricted institutional grants for Continuing Medical Education from Pfizer, Procter & Gamble, Novartis, Wyeth, AstraZeneca, and Bristol-Myers Squibb Medical Imaging; she has received a research grant fromMerck; she has stock in Boston Scientific, IVAX, Eli Lilly, Medtronic, Johnson & Johnson, SCIPIE Insurance, ATS Medical, and Biosite.

Dr. Brewer has received honoraria from AstraZeneca, Pfizer, Lipid Sciences,Merck, Merck/Schering-Plough, Fournier, Tularik, Esperion, and Novartis; he has served as a consultant for AstraZeneca, Pfizer, Lipid Sciences, Merck, Merck/Schering-Plough, Fournier, Tularik, Sankyo, and Novartis.

Dr. Clark has received honoraria for educational presentations from Abbott,AstraZeneca, Bristol-Myers Squibb, Merck, and Pfizer; he has received grant/research support from Abbott, AstraZeneca, Bristol-Myers Squibb,Merck, and Pfizer.

Dr. Hunninghake has received honoraria for consulting and speakers bureau from AstraZeneca, Merck, Merck/Schering-Plough, and Pfizer, and for consulting from Kos; he has received research grants from AstraZeneca,Bristol-Myers Squibb, Kos, Merck, Merck/Schering-Plough, Novartis, andPfizer.

Dr. Pasternak has served as a speaker for Pfizer, Merck, Merck/Schering-Plough, Takeda, Kos, BMS-Sanofi, and Novartis; he has served as a consultant for Merck, Merck/Schering-Plough, Sanofi, Pfizer Health Solutions, Johnson & Johnson-Merck, and AstraZeneca.

Dr. Smith has received institutional research support from Merck; he has stock in Medtronic and Johnson & Johnson.

Dr. Stone has received honoraria for educational lectures from Abbott,AstraZeneca, Bristol-Myers Squibb, Kos, Merck, Merck/Schering-Plough,Novartis, Pfizer, Reliant, and Sankyo; he has served as a consultant for Abbott, Merck, Merck/Schering-Plough, Pfizer, and Reliant.

Another 2009 report, also from the Department of Health and Human Services, revealed similar issues with expert panels that advise the Centers for Disease Control (CDC) on vaccine safety. The report found that 64 percent of experts who served on advisory panels in 2007 to evaluate vaccines for flu and cervical cancer had potential conflicts of interest that were never identified or resolved. The report also revealed that the CDC failed nearly every time to ensure that experts adequately disclosed that they were being paid by vaccine manufacturers.

Can you see how these conflicts of interest might be a problem, when the advisory committees mentioned above strongly influence the sales of both statin drugs ($30 billion a year) and vaccines ($20 billion a year)?

Sadly, these financial relationships between experts who influence or formulate guidelines and drug companies whose drugs are being considered are not the exception, they’re the rule. A study published in JAMA shows that 59 percent of the experts participating in guideline creation have such financial ties. (3)

Another related problem is the “revolving door” between public agencies like the CDC and FDA or institutions like the U.S. Congress, and pharmaceutical companies. A year after leaving her position as the director of the CDC in 2009, Dr. Julie Gerberding took a position as president of Merck Vaccines. Another former CDC employee, Dr. Thomas Verstraeten, took a position with GlaxoSmithKline (a vaccine manufacturer) while he was still involved in completing a major study on the possible negative side effects of thimerosal (a mercury-containing compound used in some vaccines) at the CDC. Finally, over half of the lobbyists employed by the pharmaceutical industry in 2008 had worked in Congress or another branch of the federal government, and 35 had been former members of Congress. (4)

These conflicts of interest do not necessarily lead to fraud or misconduct. There are surely many honest and unbiased researchers and physicians investigating controversial topics like cholesterol targets and statin drugs, vaccines, and genetically-modified foods. However, studies have confirmed what common sense and an understanding of human nature would also suggest: conflicts of interest can and do influence both individuals and institutions. For example, the financial interests of researchers are positively associated with outcomes favorable to the sponsor in medical studies, and research institutions can be influenced by industry sponsorships such as grants, endowed chairs, and other gifts. (5, 6, 7, 8)
Concluding thoughts

My purpose here is not to attack the credibility of scientific research as a whole, or scientists as a group. But science is a human endeavor, and like all human endeavors, it is subject to the vagaries of human ethics and behavior. There is good science, and bad science; there is honest science, and dishonest science.

If you’ve been following my work for several years, you’ll know that my blog used to be called “The Healthy Skeptic”. I called it that because I believe that skepticism is healthy when it comes to science. Yet all too often I see this skepticism being applied in a biased or inconsistent manner.

For example, I’ve noticed that some people who are indignant about conflicts of interest in government agencies responsible for bank bailouts or among experts responsible for establishing blood cholesterol targets are completely unwilling to consider how similar conflicts might affect research on, say, vaccines or genetically-modified foods.

I’ve also encountered people who are skeptical of any challenge to the status quo, but don’t apply their skepticism with the same rigor to the the status quo itself. On the other side of the coin are those that accept unconventional or alternative ideas (regardless of whether there is evidence to support them), and tend to reject anything that could be remotely construed as conventional or mainstream.

Someday, perhaps we’ll be able to extricate the financial interests of Big Pharma from the behavior of medical scientists and regulatory agencies. Until then, our responsibility—whether we are clinicians, patients, researchers, or members of the media—is to acknowledge the influence these relationships may have on scientific research, and take that influence into account when considering controversial issues—especially when large amounts of money are at stake.

Now I’d like to hear from you. Were you aware that research misconduct rarely gets reported on in the media or scientific literature? Are you surprised by the extent to which conflicts of interest are present on advisory panels responsible for creating guidelines? How do you feel about this subject after reading this article? Let us know in the comments section.

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