Tag Archives: New England Journal of Medicine

06/22/18

Corrupted Clinical Trials

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Dr. Jason Fung opened his article, “The Corruption of Evidence Based Medicine—Killing for Profit” with the following: “The idea of Evidence Based Medicine (EBM) is great. The reality, though, not so much.” He said if the evidence base was false or corrupted, then evidence-based medicine was completely worthless. “It’s like building a wooden house knowing the wood is termite infested.” He’s not alone in this opinion and he quoted three current or former editors of the two most prestigious medical journals in the world who corroborated his statement.

Richard Horton, editor in chief of The Lancet said: “The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue.”

Dr. Marcia Angell, former editor in chief of the New England Medical Journal (NEJM) said: “It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor.”

Dr. Arnold Relman, the former editor of the NEJM, said: “The medical profession is being bought by the pharmaceutical industry, not only in terms of the practice of medicine, but also in terms of teaching and research. The academic institutions of this country are allowing themselves to be the paid agents of the pharmaceutical industry. I think it’s disgraceful.”

Dr Fung said: “Physicians and universities have allowed themselves to be bribed.” He went on to say the examples in medicine are everywhere. For instance, medical research is typically paid for by pharmaceutical companies. “Trials run by industry are 70% more likely than government funded trials to show a positive result.” Among the issues he described were: the selective publication of clinical trials, rigging the outcomes of those trials, publication bias and industry payments to medical journals and their editors.

Clinical trials with negative results are likely to be suppressed. Using the company Sanofi to illustrate the problem, Dr. Fung noted the company completed 92 studies in 2008, but only published the results of 14. He acknowledged how it would be financial suicide to publish data that would harm your company. “But knowing this, why do we still believe the evidence based medicine, when the evidence base is completely biased?”

With antidepressants, a review of the published literature published in the NEMJ suggested 94% of the trials conducted were positive. Among FDA-registered trials, 31% were not published and only 51% showed positive results. The authors said:

We cannot determine whether the bias observed resulted from a failure to submit manuscripts on the part of authors and sponsors, from decisions by journal editors and reviewers not to publish, or both. Selective reporting of clinical trial results may have adverse consequences for researchers, study participants, health care professionals, and patients.

Before the year 2000, pharmaceutical companies doing clinical trials did not have to declare beforehand what their primary outcomes would be. So they would “measure many different endpoints and simply figured out which one looked best and then declared the trial a success.” The government changed that requirement and after 2000, 8% of clinical trials showed good results when 57% of those before 2000 showed a positive result. Evidence of the evidence base was being corrupted by commercial interest.

If a journal publishes a positive article about a Pharma drug, the company would order several hundred thousand copies of the article to distribute to doctors in their marketing efforts. “It’s insanely profitable for journals to take money from Big Pharma.” The NEMJ gets 23% of its income from reprints; the Lancet gets 41%; and the American Medical Association gets 53%! “No wonder these journals are ready to sell their readers (ordinary physicians) down the river. It pays.” A cited study noted where 50.9% of the editors of prestigious medical journals received at least some payments from the industry, and in some cases “these payments were often large.”

We found that industry payments to journal editors are common and can be substantial. Moreover, many journals lack clear and transparent editorial conflicts of interest policies and disclosures. Given our findings, we would suggest that journals take several steps. Firstly, we would strongly argue that all journals should develop and implement a transparent, publicly accessible editorial conflicts of interest policy. Secondly, editors in chief should consider excluding those with considerable industry relations from editorial positions. While such a stance could be considered drastic, editors play a crucial role in research integrity; even an appearance of conflict can serve to undermine the clinical research enterprise.

In The Chronicle of Higher Education, Batt and Fugh-Berman noted where “Disclosing Corporate Funding Is Not Nearly Enough.” In the U.S. in 2015, industry spent $102.7 billion on health-related research, while federal agencies spent $35.9 billion. “The current administration attempted to further decrease NIH funding, but those efforts were unsuccessful.” They said reliance on industry money limits the scope of research; and “it weakens researchers’ ability to act as independent critics.” Pharmaceutical companies fund, publish and promote studies that that are favorable to their marketing goals and “suppress or attack research that threatens market share.”

Perhaps most troubling is that if the final results of a study do not support commercial goals, the full study may never be published. In general, industry-funded studies are less likely to be published than non-industry-funded ones. And contrary to expectations, the reason negative studies are unpublished is not because journals rejected them, but because they were never submitted for publication. Although many universities frown on agreements that give funders the right to suppress the publication of findings, policies regarding publishing are not uniform across colleges and universities. In any case, enforcement is nil: Colleges can’t force researchers to publish studies. Industry insiders tell us that when company representatives fail to prevent a researcher from publishing unfavorable results on a drug, they may attempt to persuade the researcher to “bury” the paper in an obscure journal. Or, under the guise of reviewing a manuscript for “accuracy,” a company may soften statements or insert subtle marketing messages into the article to mitigate harm to its marketing goals. We don’t know the extent to which industry funding distorts biomedical literature — and clinical decision-making — but a substantial body of evidence now shows that allowing industry to choose what scientific questions should be asked, and how findings should be analyzed, interpreted, and disseminated, has public-health costs. We need strategies to minimize industry influence on scientific questions, and the resulting impact on policies and medical practice.

Writing for Mad in America, Zenobia Morrill summarized a review article by three researchers, “Industry-corrupted psychiatric trials.” The authors quoted from Marcia Angell’s 2008 article for JAMA, “Industry-sponsored clinical research: A broken system,” where she said:

Over the past 2 decades, the pharmaceutical industry has gained unprecedented control over the evaluation of its own products. Drug companies now finance most clinical research on prescription drugs, and there is mounting evidence that they often skew the research they sponsor to make their drugs look better and safer.”

Amstersdam, McHenry and Jureidini, the authors of “Industry-corrupted psychiatric trials,” noted it was common knowledge that pharmaceutical companies “laundered” their promotional efforts through medical communications companies that “ghostwrite articles and then pay academic consultants to sign on to the fraudulent articles.”

The firms set up advisory board meetings with key opinion leaders and marketing executives in advance of the clinical trials. Once a trial is complete, the medical ghostwriter who is employed by the medical communications firm produces a draft of a manuscript – from a summary of the Final Study Report of the clinical trial – and seeks feedback from the corporate sponsor. It is at this stage in the manuscript production that misrepresentation of the trial data frequently occurs, since the medical ghostwriter is under the direction of marketing executives to “spin” the data. The medical ghostwriter then revises a number of drafts with input from the external academic “authors” and internal industry scientists, and once the corporate sponsor is satisfied that the final manuscript draft is “on message,” it is submitted by a corporate-designated lead author to a medical journal for peer review. Once the manuscript is submitted, the medical ghostwriter disappears or is acknowledged in the fine print for “editorial assistance.”

As a result, ghostwriting by the pharmaceutical industry has become a major factor in the “crisis of credibility” in academic medicine. “The integrity of science depends on the trust placed in individual clinicians and researchers and in the peer-review system which is the foundation of a reliable body of knowledge.” If academics allow their names to appear on ghostwritten articles, “they betray this basic ethical responsibility and are guilty of academic misconduct,” according to Amstersdam, McHenry and Jureidini. Ghostwriting extends to include an academic façade for research “that has been designed, conducted and analyzed by industry.” Yet the vast majority of ghostwritten publications won’t be revealed as such.

Key opinion leaders (KOLs) or “thought leaders” are academic physicians who are carefully vetted by the industry on the basis of their receptivity to the sponsor’s products. Pharmaceutical companies say they have engaged these KOLs for expert evaluation and feedback on marketing strategy. However, they essentially are highly paid “product champions” or marketers. “Few physicians and psychiatrists can resist the flattering offer by industry to become KOLs.” Medical journals are noted to be part of the problem here as well.

Medical journals are part of the problem rather than the solution to the problem. Instead of demanding rigorous peer review of a submissions and an independent analysis of the data, medical journal editors are pressured to publish favorable articles of industry-sponsored trials and rarely publish critical deconstructions of ghostwritten clinical trials. As medical journals and their owners have become dependent upon pharmaceutical revenue, the journals fail to adhere to the standards of science. Thus the publication of “positive” studies showing drug safety and effectiveness means more pharmaceutical advertising and more orders of reprints for dissemination by the sales force. In contrast, a “negative” study showing poor tolerability or ineffectiveness results in no such revenue.

“Industry-corrupted psychiatric trials” then went on to deconstruct how three studies, “SmithKline Beecham Paroxetine Study 329,” “Forest Laboratory Citalopram Study CIT-MD-18” and “SmithKline Beecham Paroxetine Study 352” all manipulated or misrepresented outcome data. The first two to support the use of the SSRI antidepressants paroxetine (Paxil) and citalopram (Celexa) for the treatment of childhood and adolescent depression. The third study, “Paroxetine Study 352,” misrepresented and manipulated outcome data in adults diagnosed with bipolar affective disorder. Morrill said: “Misconduct of this study was revealed when academics filed complaints of plagiarism and research misconduct against KOLs at medical research universities across the U.S. as well as pharmaceutical company executives.”  Read the review article for further details on how these three research studies were deconstructed to reveal how they manipulated or misrepresented outcome data.

In closing, let me remind you again of the opinion of Marcia Angell, former editor of the NEMJ:

It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. . . . Drug companies now finance most clinical research on prescription drugs, and there is mounting evidence that they often skew the research they sponsor to make their drugs look better and safer.

12/31/14

Anti-Anti-Black Box Warning

395675_sThe New England Journal of Medicine recently published two very different articles on the 2004 black box warnings the FDA put on antidepressants because of their relationship to suicidality. They illustrate the truth that there are no brute, utterly uninterpreted facts. “The modern scientist, pretending to be merely a describer of facts, is in reality, a maker of facts” (Cornelius Van Til).

Richard Freidman concluded from his review of the literature that the black box warnings led to less treatment for depression. Not only had prescription rates for antidepressants fallen, so had the rate of diagnosing new cases of depression. He acknowledged that data indicating these trends were only correlational and could not establish a causal link between the warning and these changes. Yet he thought it plausible that in the face of the debate over FDA warning and resultant media coverage, “patients might be reluctant to disclose symptoms that could lead to a diagnosis of depression and subsequent antidepressant treatment, and physicians might be hesitant to prescribe these drugs.”

He also noted a study by Lu et al. that found there was a statistically significant increase in psychotropic-drug poisonings after the FDA warning.  This measure was used by the study as a proxy measure for suicide attempts. “Insofar as such poisonings represent a reasonable proxy for suicide attempts, it’s possible that the downward trend in antidepressant use resulted in an increase in such attempts.” He qualified that statement by saying that we cannot be certain that any given poisoning was intentional or accidental. Then he pointed to a gradual increase in suicide rates among 10 to 34 year olds between 1999 and 2010. “So there is little evidence that actual suicide rates have changed in the wake of the advisory.”

In his opinion, the “very small risk associated with antidepressant treatment” is offset by the far greater risk posed by untreated depression. Given that the 2007 modification of the black-box warning was not enough to prevent “a chilling effect on depression treatment,” he did not think further modifications would be helpful. He recommended that the FDA consider removing the warnings entirely.

I believe we cannot ignore the weight of these epidemiologic data or the very real possibility that the FDA advisory has unintentionally discouraged depressed patients from seeking treatment and doctors from prescribing antidepressants.

However, as Mad in America pointed out, Dr. Marc Stone challenged virtually all of the interpretations made by Dr. Freidman in his article. Stone meticulously demonstrated how the investigators in the reported studies failed to distinguish the alleged effect of “the boxed warning from the effect of general public awareness of the suicidality issue.” He further noted that it cannot be assumed that 2005 decreases in antidepressant prescription rates were a reaction to the warning and resultant controversy.

While the number of prescriptions did decrease in every age group up to 54 years of age, they increased in every older subgroup. “Why were prescribing trends unaffected among adults 55 or older?” Stone suggested that the time period was a transitional one, where several popular antidepressants went off patent, while generics sharply increased. From 2004 through 2008, promotional expenditures for antidepressants decreased by 35%.

It is possible that the modest reduction in antidepressant prescribing reflected drug makers’ reduced marketing of brand-name antidepressants to everyone except patients who would soon be eligible for the new Medicare prescription-drug benefit.

Stone also noted that the Lu et al. study cited by Freidman rested its claim that “poisoning by psychotropic agents” could be a proxy measure for suicide attempts on an invalid application of another study: “That study did not investigate whether the relationship between proxy and attempted suicide remained stable over time.” Superior data from the CDC indicated that incidents of attempted suicide from poisoning and all other causes peaked in 2003 or 2004 and then declined.  In addition, the rate of accidental poisoning, such as drug overdoses, increased significantly in 2005 and 2006. Dr. Stone concluded:

These data should be sufficient to dispel any serious concerns, but nearly 10 years after the labeling changes, the idea that the boxed warning had adverse consequences persists in the minds of many health professionals, in the media, and among the general public.

Psychologist Philip Hickey also wrote a critique of the Lu et al. study. He quoted several statements from the National Institute of Health (NIH) press release about the study and then proceeded to devastatingly show how the statements were false. Both the link provided by Hickey and a search of the NIH site failed to find the noted press release. It seems to have been removed.  He concluded that the Lu et al. study was meant to be PR and spin, not science.

The fundamental message in the study, and in the NIH press release, is:  If you reporters print bad things about antidepressants, this will lead to reduced usage of these products, which in turn will lead to more suicides, and you will have blood on your hands!

But why is there a PR campaign for antidepressants occurring now? Julia Calderone’s article in Scientific American, “The Rise of All-Purpose Antidepressants,” may have provided a clue. She noted that doctors commonly use antidepressants to treat conditions they are not approved for by the FDA—so-called off label use. “Studies show that between 25 and 60 percent of prescribed antidepressants are actually used to treat [off label] conditions.”  So the message is, if you reporters print bad things about antidepressants, doctors could lose one of the main drug options they have for altering brain chemistry.

Antidepressants are ineffective in treating all but the most serious cases of depression. There have also been reliable studies showing that the placebo effect accounts for virtually all of the drug effect of antidepressants. Could the placebo effect also be at work in the off-label use of antidepressants? They have been shown to have serious side effects warranting the inclusion of the black box warning. If anything, the warning should be extended to include adults, the age group most often using antidepressants.