Tag: evidence-based medicine

06/28/22

Time for a Fresh Look at Diagnosis

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Allen Frances, chair of the DSM-IV Task Force, has been a vocal critic of modern psychiatry and diagnosis. He was selected by fellow psychiatrist Awais Aftab to do the first interview for Conversations in Critical Psychiatry, a series for Psychiatric Times that aimed to engage prominent individuals who have made important and constructive critiques of psychiatry. Dr. Frances said while he considered psychiatry to be one of the noblest of professions, it had drifted away from best practice. Too many psychiatrists, he said, are reduced to pill pushing with too little time to really know their patients well. And psychiatrists have not done enough to educate primary care physicians, who prescribe 80% of psychiatric meds, on “the principles of cautious prescribing, proper indications, full consideration of risks, and the value of watchful waiting and the tincture of time.”

I despair the diagnostic inflation that results from a too loose diagnostic system, aggressive drug company marketing, careless assessment, and insurance company pressure to rush to judgement. Diagnoses should be written in pencil, and under-diagnosis is almost always safer and more accurate than over-diagnosis.

With regard to the philosophy of diagnosis, he saw three approaches that he likened metaphorically to three kinds of baseball umpires. The first kind called balls and strikes as they are. The second called them as he saw them. The third said there were no balls or strikes until he called them. Frances likened Robert Spitzer, the architect of the modern DSM, to Umpire 1, along with most biological psychiatrists (See “The Quest for Psychiatric Dragons” Part 1 and Part 2 and “Where There’s Smoke …” for more on Robert Spitzer).  “The credibility of this model has been destroyed as we have learned more about the unfathomable complexity of the human brain and the complete failure of genetics and neuroscience to provide useful answers about what causes psychiatric problems.” He thought most psychiatrists aspired to be like Umpire 2, doing their best to define mental disorders in useful ways without any pretention that it is the only way or that current constructs would withstand the test of time.

Dr. Frances expressed concern with the risks of over-diagnosis and advocated for a narrower system with higher diagnostic thresholds. He thought experts in each diagnostic area sought to expand their pet diagnoses and worried too much about missing patients (false negatives) rather than mislabeling patients (false positives). These experts were given a free rein in DSM-5, allowing mislabeling to dominate the field. This led to a checklist approach to diagnosis, which was not intended by the creators of the DSM.

The diagnostic exuberance of DSM 5 confuses mental disorder with the everyday sadness, anxiety, grief, disappointments, and stress responses that are an inescapable part of the human condition. DSM 5 ambitiously mislabels normal diversity and childhood immaturity as disorder, creating stigma and promoting the excess use of medications.

Frances thought if anything in DSM could be misused, it would be misused. “Data drawn from research studies on highly selected patients in the hothouse environment of a university research clinic generalize very poorly to the hustle and bustle of primary care.” On Twitter he pointed to a study he said “blows to bits any hope that statistical modeling” could eliminate the many inherent limitations of “Evidence Based Medicine.” This study, “Many Analysts, One Data Set” concluded that uncertainty in interpreting research results was not just a function of statistical power or the use of questionable research practices. It was also a function of the many reasonable decisions made by researchers as they conducted their research. This did not mean that analyzing data and drawing research conclusions from the data was subjective. Rather, it meant “that many subjective decisions are part of the research process and can affect the outcomes.”

Frances said “Evidence Based Medicine” often generalized poorly to everyday practice because: 1) patients in controlled studies aren’t like unselected patients; 2) research settings differ from real life; 3) biases influence data analyses. “EBM provides a necessary guide, but shouldn’t be worshipped.”

Returning to the interview for Conversations in Critical Psychiatry, he noted how there was an inherent financial, intellectual and emotional conflict of interest that leads every medical specialty to recommend over-diagnosis. He recommended that specialty groups like the APA, the American Psychiatric Association, should never be permitted sole power to determine the diagnostic guidelines for that specialty. Contributions from primary care, public health, health economics and consumers are important. With regard to psychiatric diagnosis, he thought the APA had a special conflict of interest because the DSMs were such a valuable publishing property. The income is crucial for meeting its budget. “This makes frequent revision too tempting and results in an unseemingly hyping of the product.”

Soon after the publication of the DSM-5 in 2013, Allen Frances published an article in World Psychiatry, “The past, present and future of psychiatric diagnosis.” He said psychiatric diagnosis is facing a serious crisis caused by diagnostic inflation. “The elastic boundaries of psychiatry have been steadily expanding, because there is no bright line separating the worried well from the mildly mentally disordered.” Drug companies have used their marketing muscle to sell psychiatric diagnoses by convincing potential patients and prescribers that life problems were really mental disorders caused by chemical imbalances and curable by pills.

We are now in the midst of several market-driven diagnostic fads: attention-deficit/hyperactivity disorder (ADHD) has tripled in rates in the past twenty years; bipolar disorder has doubled overall, with childhood diagnosis increasing forty-fold; and rates of autistic disorder have increased by more than twenty-fold. In the US, the yearly prevalence of a mental disorder is reported at 20–25%, with a 50% lifetime rate, and Europe is not far behind. A prospective study of young adults in New Zealand has reported much higher rates and another of teenagers in the US found an astounding cumulative 83% rate of mental disorders by age 21.

He said the DSM-5 was prepared without adequate consideration of clinical risk/benefit ratios and did not calculate the large economic cost of expanding the reach of psychiatry. It has been unresponsive to widespread professional, public and media opposition “based on the opinion that its changes lacked sufficient scientific support and often defied clinical common sense.”  A petition endorsed by fifty mental health associations, that called for an independent review, “using methods of evidence-based medicine, was ignored.” It was time for a fresh look at diagnosis.

On the podcast The Recommended Dose with Ray Moynihan, Frances said the tendency over the last forty years has been to turn the stuff of life into mental disorder. “The best customer for a drug, is someone who is basically well.” We get advertisements for drugs as frequently as we get advertisements for cars or brands of beer. When it comes to most psychiatric problems, people get better on their own in a few weeks. “My concern is that we’re way overmedicating the problems of everyday life and that parallel to that, we are terrifically neglecting people who are really sick.”

One of the areas he gave as an example of transforming ordinary life into mental illness is with mild forms of depression, that really aren’t depression, but are being diagnosed as major depressive disorder. “The drug companies have convinced the world that major depressive disorder is one entity, and that it is always a chemical imbalance, and that it always requires a chemical solution in the form of a pill.” Eleven percent of Americans are taking an antidepressant. Grief in particular is often over diagnosed and over treated with medication. Then there is anxiety; children who have temper tantrums; and so on. “In general, we have taken every day experiences, that are part of the human condition, and we’re over diagnosing them as mental disorders, and we’re way too often providing a pill, when there’s not really a pill solution for every problem in life.”

Children have been over medicalized with Attention Deficit Disorder, which should be properly diagnosed at around 2 or 3 percent of the U.S. population. In the U.S., by the time a child is 18, they have a 15 percent chance of getting the diagnosis. “This is absolutely ridiculous. We are turning immaturity into a disease.” There are also unwarranted increases in diagnosing childhood Bipolar Disorder. And there is a terrific overuse of antipsychotics in children with behavior problems. “I think we are doing a massive, worldwide experiment on immature brains, bombarding them with very powerful chemicals, with no knowledge whatever about what the long-term outcome will be; and without informed consent.”

He thinks the DSM-5 set off on in the wrong direction. Psychiatrists were worrying about underdiagnosis, when they should have been concerned with overdiagnosis. He said we have gone overboard in the developed world in giving too much treatment to people who can afford it, while neglecting people who can’t.

Then he was asked to comment on the role of good evidence that comes from systematic reviews, from summaries of evidence. Frances said evidence is absolutely crucial in making medical decisions, even though you can’t trust all of it. It takes time to gather enough reliable evidence to be confident. “But without evidence it’s a crapshoot that will be governed by commercial, for profit elements that so determine how people are treated.

I think the biggest role for change will come from the evidence-based guidelines and from a press that is educated to advertise to the people reading the article, not just the possible miracle medical benefit, which is always exaggerated, but also the possible realistic risks of side effects.

The biggest problem for the doctor is too little time. The more time you have to get to know the patient, the less likely you’ll be inaccurate in your diagnosis. “It’s the easiest thing in the world to give a diagnosis and to write a pill prescription. It’s the hardest thing in the world, often, to get rid of a diagnosis once it’s been established. . . A wrong diagnosis made in ten minutes can haunt for life.” Medication, given casually, can do great harm and you should be as careful in taking medication as you would be for a major life decision.

 

Originally posted on 5/19/2020

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.

11/19/14

Evidence-Based Treatment … Lacks Evidence

21828750_sEvidence-based medicine (EDM) began in the early 1990s and was seen as a revolutionary movement that would improve patient care. It grew to become the buzz-word for all medical and behavioral health care—make sure treatment is evidence-based! And yet, there is little evidence that EDM has achieved its aim. Health care costs have soared and there is a distinct lack of “high-quality evidence suggesting that EBM has resulted in substantial population-level health gains.”

Given that EBM firmly favours an empirical approach over expert opinion and mechanistic rationale, it is ironic that its widespread acceptance has been based on expert opinion and mechanistic reasoning, rather than EBM ‘evidence’ that it actually works.

The article from which the above critique was taken suggested that the lack of evidence for the overall benefit of EBM was a consequence of it not being implemented effectively. A cornerstone of EBM methodology—the randomized trial—has been corrupted by vested interests.  The authors, Every-Palmer and Howick, defined EBM as “the conscientious and judicious use of current best evidence in conjunction with clinical expertise and patient values to guide health care decisions.” They singled out the field of psychiatry for specific concern, where “the problems with corruption of randomized trials are dramatic.”

Most of the medical psychiatric evidence base has been funded by the pharmaceutical industry, often without the relationships being disclosed. “Between two-thirds and three-quarters of all randomized trials in major journals have been shown to be industry funded.” One of the consequences of this has been publication bias: positive results are published; negative results are not. The best current estimate is that half of all completed clinical trials have never been published in academic journals. Some trials are never registered.

There is also evidence that industry-funded studies exaggerate the treatment effects in favor of the product preferred by their sponsor. One study reviewed industry-funded studies of atypical antipsychotics and found that 90% of the trials showed superiority of the sponsor’s drug. The studies had been designed “in a way that would virtually guarantee the favoured drug would ‘win.’”

Among their recommendations, Every-Palmer and Howick suggested that all clinical trials should be registered and reported. There needs to be more investment in independent research. Evidence-ranking schemes also need to be modified to account for industry bias. These suggestions would be helpful corrections for the corruption of the randomized trial methodology, but what if there are additional problems? For example, merely correcting problems with the misuse of randomized trials would not address concerns related to clinical expertise or patient values.

If current medical science is reaching its limits with some complex illnesses, as Every-Palmer and Howick said was one possibility for the lack of progress with EBM, then further gains will be hard to come by. This would seem to be true with mental illness and addiction, which are diagnosed with the Diagnostic and Statistical Manual (DSM), 5th edition. DSM diagnoses are consensus-based decisions about clusters of symptoms and do not have any objective laboratory measure. Thomas Insel, the Director of the National Institute of Mental Health (NIMH), said that diagnosis with the DSM was equivalent to “creating diagnostic systems based on the nature of chest pain or the quality of fever.”

A further compounding error could be when the role of clinical judgment is neutralized as a result of an overreliance upon the trump of scientific—real or imagined—evidence. Kiene and Kiene noted how the reputation of clinical judgment in medicine has undergone a “substantial transformation” over the last century with the rise of modern research methodology.  “A primary mission [in medical progress] therefore became ‘to guard against any use of judgement’, and it was executed through clinical trials.”

Giovanni Fava pointed to the increasing crisis in psychiatric research and practice because “Psychopathology and clinical judgment are often discarded as non-scientific and obsolete methods.” He noted how the concept of evidence-based medicine has achieved widespread endorsement in all areas of clinical medicine, including psychiatry. But randomized trials were not intended to answer questions about the treatment of individual patients. “The results may show comparative efficacy of treatment for an average randomized patient, but not for pertinent subgroups formed by characteristics such as severity of symptoms, comorbidity and other clinical nuances.”

An aura of authority is given to collections of “best available evidence”, which can in turn lead to major abuses that produce “inappropriate guidelines” for clinical practice. The risk is especially serious as a result of the substantial financial conflicts of interest in medical societies and with the authors of the medical guidelines for clinical practice within those societies.

Special interest groups are thus using evidence-based medicine to enforce treatment through guidelines, advocating what can be subsumed under the German language term of “ Leitkultur ”, which connotes the cultural superiority of a culture, with policies of compulsory cultural assimilation. In psychiatry, such process has achieved strong prescribing connotations, with a resulting neglect of psychosocial treatments.

Given the existing crisis within psychiatry, especially with the questionable validity and reliability of diagnosis within the DSM, evidence-based treatment guidelines that were developed and disseminated within such a culture require radical revision or should be used with extreme caution. The evidence for their efficacy is lacking.