“The Illusion of Evidence-Based Medicine”

Yves here. Please welcome KLG, a member of our Covid brain trust who is trying his hand at publishing articles on poor or questionable medical and bioscience practices, particularly the corruption of science. We are excited at how his contributions will extend our range of coverage and increase our expertise. Particularly in the US, medicine is an over-large share of the economy, and how it operates is of personal and societal importance.

KLG plans to post every other Wednesday. So keep an eye out!

By KLG, who has held research and academic positions in three US medical schools since 1995 and is currently Professor of Biochemistry and Associate Dean. He has performed and directed research on protein structure, function, and evolution; cell adhesion and motility; the mechanism of viral fusion proteins; and assembly of the vertebrate heart. He has served on national review panels of both public and private funding agencies, and his research and that of his students has been funded by the American Heart Association, American Cancer Society, and National Institutes of Health.

Review: The Illusion of Evidence-Based Medicine: Exposing the crisis of credibility in clinical research. Jon Jureidini and Leemon B. McHenry, Wakefield Press, 2020.

When we go to the doctor, we hope she bases her interaction with us on what has come to be called Evidence-Based Medicine (EBM), which is the “conscientious, explicit, and judicious use of current best evidence everyday practice.”  This is certainly how medical students and resident physicians think they are taught to choose how to treat their patients.

But how does theory meet practice?  Not so well according to The Illusion of Evidence-Based Medicine: Exposing the crisis of credibility in clinical research (IEBM) by Jon Jureidini (Professor of Psychiatry and Pediatrics at the University of Adelaide) and Leemon B. McHenry (Emeritus Lecturer in Philosophy at Cal State-Northridge), which was published in 2020. An accessible, short precis of their work was published in BMJ (formerly British Medical Journal) in March 2022.

The examples of clinical case studies gone awry by Drs. Jureidini and McHenry are well known if not well understood.  They concentrate most of their attention (Chapter 2: The Corruption of Clinical Research) on two studies of selective serotonin reuptake inhibitors (SSRIs) that were used to show the SSRIs paroxetine (Paxil, SmithKlineBeechum and citalopram (Celexa, Forest Laboratories) are effective interventions to treat depression in adolescents and children.  The evidence remains equivocal.  Other examples include Rofecoxcib (Vioxx, Merck), a cyclooxygenase-2 inhibitor initially approved for treatment of osteoarthritis that also caused more than 100,000 cardiac “events” in the US, 40,000-60,000 of which were fatal.  As to be expected, Naked Capitalism has covered Vioxx here  and here.

Gabapentin (Neurontin, Parke-Davis/Pfizer) was initially approved for treatment of seizures but was later improperly promoted and prescribed for off-label treatment of pain and psychiatric conditions.  Fenfluramine/Phentermine (Fen-Phen, American Home Products/Wyeth) was touted as a treatment for obesity after a public relations campaign that presented obesity as a dangerous health problem, which it most certainly can be. But those who are not skinny are not therefore by definition unhealthy, and in many cases just the opposite.  And while Fen-Phen use did lead to weight loss in those who used it, this drug combination also caused heart valve damage and potentially fatal pulmonary hypertension.  No reader of Naked Capitalism (here and here) needs to be reminded about Oxycodone (Oxycontin, Purdue Pharma) and the opioid epidemic that has caused more than 500,000 deaths).

The gory technical details are included in the book so there is no reason to repeat them here. My question is “How did ‘science’ go so far off the rails?”

Money is the short answer.  Money is also the correct answer.  Each of these drugs are/were blockbusters, with likely sales of more than a billion dollars a year, some of them many billions of dollars a year.  How does this sound familiar, “Science and Money,” in the years 2020, 2021, and 2022?  But I digress, for now.

As citizens and consumers[1], we are continuously told to “trust the science.”  I have been a student of biology, scientific worker, and an academic scientist for my entire professional life starting at the age of 19, at research universities large and small.  So, I am totally onboard with trusting the results of transparent, disinterested scientific research.

After explaining what has gone wrong, IEBM shows us how to tackle these questions, first by pointing out that clinical research conducted with commercial objectives cannot really be scientific research, both from a commonsense perspective (i.e., how likely is the answer to be “no” when billions depend on “Yes!”?) and by the formal definition of scientific research described by Karl Popper in The Logic of Scientific Discovery and The Open Society and Its Enemiesamong other works.  These two books are often rightfully called magisterial, but I confess to never having developed a taste for Sir Karl’s philosophy of science, which seems more useful in physics than biology and the biomedical sciences (I also believe that T.S. Kuhn, who appears in IEBM with his paradigm shifts is a most overrated philosopher of science, but that is for another time).

Nevertheless, Popper’s concept of “falsifiability,” however counterintuitive and downright odd to me as a student, is exactly right as an explanation of how a scientist actually goes about her vocation.  No scientist sets out to disprove his hypothesis, but no good scientist does her experiments without the proper controls.  And these controls can and will indeed falsify a scientist’s hypothesis, as every good scientist well knows.

With these scientists, this negative result leads to a better hypothesis. The scientist who will not do the critical control experiment is not a scientist.  The scientist who ignores the negative or inconclusive result is a marketer. The problem with science conducted with a commercial outcome is that disinterest in the outcome required of a genuine Popperian scientist is essentially impossible in practice.  This is marketing, not science.

Clinical trials have been important in modern medicine since James Lind showed that citrus fruits prevent scurvy.  Double blinding followed the development of the placebo, and shortly after World War II Bradford Hill showed in a clinical trial that streptomycin in association with para-aminosalicylic acid cures pulmonary tuberculosis (and at about the same time, using similar reasoning, Hill and Richard Doll also demonstrated that tobacco causes lung cancer).  James Lind and Bradford Hill answered critical medical questions as scientists who went where their data and results sent them.  According to Drs. Jureidini and McHenry, “the randomized, placebo-controlled clinical trial was perhaps the most important discovery of modern medicine.” One might use “development” instead of “discovery,” but the message is the same.

Unfortunately, “the validity of this new paradigm…depends on reliable data from clinical trials and because the data are largely, if not completely, manipulated, by the manufacturers of pharmaceuticals, evidence-based medicine is largely an illusion.”  How do they do this, disguise marketing as science?

First, ghostwriting.  Those who write the articles describing the results of a clinical trial are often not the authors listed at the top of the first page beneath the title.  Honorary authorship has long been a thing in some research areas, and while the mechanism of ghostwriting includes getting “thought leaders” involved, the results are more significant than enhanced visibility for a junior author who attaches a senior scientist to his work in hopes of faster, better recognition (it should be noted that honorary authorship may be declining as legitimate scientific journals now require identification of the contributions of each author to the manuscript under consideration).

One of the first known cases of ghostwriting occurred when an obstetrician with five papers to his name published “Trial of thalidomide in insomnia associated with the third semester” (paywalled) in the American Journal of Obstetrics and Gynecology.  According to IEBM, this paper was actually written by a medical director of a company that wanted to market thalidomide in the US as it had been in 20 European countries and Canada.  Only the work of Frances Oldham Kelsey at the FDA (those were the days) prevented that catastrophe from being much worse than it could have been in the United States.

A more recent case of what the authors identify as ghostwriting was a key exhibit in the case against GlaxoSmithKline (the successor of SmithKlineBeechum) that resulted in a $3B fine. Follow-up reports on this publication are here with the following conclusions:

The continuation phase did not offer support for longer-term efficacy of either paroxetine or imipramine. Relapse and adverse events on both active drugs open up the risks of a prescribing cascade. The previously largely unrecognised hazards of the taper phase have implications for prescribing practice and need further exploration.

And here, with the following conclusions:

Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs. Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative. The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base.

No legitimate scientist accepts that her work can be prepared for publication by a medical communications company.  On the contrary, a legitimate scientist can only be dumbfounded to read that an outside firm “was hired to prepare eighty-five papers for publication to facilitate Pfizer’s promotion of sertraline” and that the authors assigned to papers already drafted were listed as ‘TBD” – to be determined” (p. 98).

These data are old and to be fair, as mentioned above, established journals now often require a statement of author contributions.  But with the rise of internet-based “scientific journals” over the past 20+ years, the business of scientific publication has changed beyond recognition to those of us who predate the web (more on that, especially related to COVID-19, to come).

As an interested citizen, the publication records of scientists are freely and publicly available through the National Library of Medicine.  This is a valuable resource when reading or reading about the biomedical literature. If a scientist has too few, or just as importantly too many, publications to his or her name, or the implied expertise seems spread out over a wide area, caveat emptor.

Finally, regarding the scientific literature about psychiatric drugs and those for chronic conditions such as hypertension, high cholesterol, hyperlipidemia, and prediabetes, it is good to remember that market expansion is the goal and “what is good for Pfizer is good for Wyeth.”

Where does Big Pharma get its scientists?  Naturally from the same place that all scientists come from: The Academic-Corporate University. One can argue about when the academic-corporate university appeared, with MIT likely leading the way[2]shortly after Vannevar Bush published Science: The Endless Frontier, and many critics have addressed the question, perhaps none better than the former President of Harvard:

These growing demands [from government and business] allow universities to profit from their work in more ways than ever before. Ironically, however, the very same opportunities could easily end by harming the academic enterprise and sullying its contributions to the nation’s welfare…making money in the world of commerce often comes with a Faustian bargain in which universities have to compromise their basic values – and thereby risk their very souls – in order to enjoy the rewards of the marketplace…Thus far, however, university leaders have paid too little heed to the risks that profit-making activities often bring in their wake.  Instead, they have eagerly embraced one commercial venture after another in the hope of gaining added revenue for their institution (Bok, 2003, 199-200)

As someone who was present at the creation, which I date to the Bayh-Dole Act of 1980, all I can say is, “Amen!”  But this goes hand-in-hand with first the creeping and later the rampant neoliberalization of our world.  This has led to the commodification of academic research and the education of our students, who are now clients and customers who must be satisfied.

Few university faculty members are appreciated more by their administration than those who bring in the industry dollars, lionized at their respective institutions and by their industrial patrons, who are most generous with honoraria and consulting contracts and offers to present “continuing medical education” lectures at international meetings, which are seldom held at state parks.

The result: Distorted Research Priorities.  Which brings the us back to Karl Popper, who wrote (p.23), “My own misgivings concerning scientific advance and stagnation arise mainly from the changed spirit of science, and from the unchecked growth of Big Science (certainly including Big Pharma), which endangers great science.”

In the case of Big Pharma, this includes such “first-world problems” as “heartburn, obesity, toenail fungus, sexual performance, depression, allergies, high cholesterol and the like.”  These are likely to be blockbuster drugs.  In the era of COVID-19, we must include mRNA-based vaccines that may offer some benefit to those infected with SARS-CoV-2 but do not prevent transmission or infection or disease.  These vaccines have provided Pfizer with more than $50B over the past two years, however.

The expressly stated ambition of Big Pharma to sell drugs to healthy people has been realized, as the following ordinary conditions have been medicalized: menopause, menstruation, shyness, anxiety, erectile dysfunction, female sexual dysfunction, with psychiatry the medical specialty/discipline most vulnerable to abuse. Psychiatric drugs include those for Social Anxiety Disorder, Pediatric Bipolar Disorder, Premenstrual Dysphoric Disorder, Hypoactive Sexual Desire Disorder, Disruptive Mood Disorder, and Seasonal Affective Disorder.  Others in the pipeline include compulsive shopping, gambling addiction, smoking cessation, and writer’s block (Hmm…).  These conditions can have serious consequences, but there can also be no doubt that disease mongering by Big Pharma has contributed to their prominence.

Perhaps my favorite study of this kind is Shyness: How Normal Behavior Became a Sickness, which I read when it was published in 2007.  And for all those years I thought I was shy.  I didn’t know I was also sick (those who know me laugh at my protestations of innate shyness).  But as I have gotten older, I have learned that facultative shyness is an excellent tool in certain work and social situations.

The major ethical, social, and scientific problems associated with these distorted research priorities is that the opportunity costs are incalculable for serious medical problems, especially those that are not caused in the first place by Big Pharma disease mongering or an environment and “food system” that induces ill health and obesity in the so-called First World.  Many conditions that could be cured outright, including serious viral, bacterial, and fungal infections and assorted parasitic diseases are left unaddressed, because no matter how costly the therapy, if it results in a cure, there goes another “customer.”

So, what is the solution to the fraudulence of so much EBM?  In my view, this is where Drs. Jureidini and McHenry could have gone further.  Their admirable list of proposals for reform includes:

….liberation of regulators from drug company funding; taxation imposed on pharmaceutical companies to allow public funding of independent trials; and, perhaps most importantly, anonymised individual patient level trial data posted, along with study protocols, on suitably accessible websites so that third parties, self-nominated or commissioned by health technology agencies, could rigorously evaluate the methodology and trial results.  With the necessary changes to trial consent forms, participants could require trialists to make the data freely available.  The open and transparent publication of data are in keeping with our moral obligation to trial participants—real people who have been involved in risky treatment and have a right to expect that the results of their participation will be used in keeping with principles of scientific rigour.  Industry concerns about privacy and intellectual property rights should not hold sway.

They rightly note that failures of regulation have contributed to this impasse. While true, it is not clear that the regulatory capture of the FDA, which has become a client of Big Pharma, can be reversed under a neoliberalism ideology in which markets rule, and everything is part of the one, true “Market.”  Whatever the motivation of individual scientist-regulators at the FDA, they are overwhelmed at every step by money and the power that comes with money. According to IEBM (p. 184), in 2018 there were 797 Big Pharma lobbyists at a cost of $133M, with Pharmaceutical Research and Manufacturers of America (PhRMA) accounting for $21M, followed by Pfizer at $9M and Amgen at $8M.  These numbers have undoubtedly increased in the past four years, and given that Pfizer forecasts 2021-2022 vaccine revenues of $65B, their lobbying costs have a good return on investment.

So, can this be made to work?  During my early days in a biomedical research laboratory, pre-Bayh-Dole Act of 1980, it was widely accepted that academic research built the foundation for the development of drugs and other biomedical and clinical interventions, while Big Pharma optimized synthesis, production, approval, and distribution, with marketing bringing up the rear.  Although some will accuse me of romanticizing this past, during those days the system worked. Those who stayed in academic science were committed and content to do this essential research during sustained careers and those otherwise inclined moved to one of the then Big Five pharmaceutical firms (a combination of Upjohn, Merck, Ciba-Geigy, Hoffman-LaRoche, Pfizer, Eli Lilly, and Burroughs-Wellcome) to figure out how to best manufacture drugs, vaccines and the like.

As an example, Eli Lilly received approximately $320 million in the first year of the Salk vaccine against polio, adjusted for inflation, which is about 100-fold less than what Pfizer collected in the first year of their mRNA vaccine against SARS-CoV-2. Although soon supplanted by the Sabin vaccine, which I remember taking as a blue or purple spot on a sugar cube at my elementary school, the Salk vaccine worked by providing sterilizing immunity, not unlike the smallpox vaccine those of us of a certain age also took, frequently from a school nurse, one after another as the entire elementary school filed through her office.

The question remains: “What to do?”  An answer is beyond the scope of this post and I hope to address this later, but it seems obvious that there can be very little legitimate, for-profit clinical research based on independent investigator-initiated fundamental research through FDA approval.  After the research, yes, with for-profit competition in manufacturing, distribution, and marketing (to physicians and medical professionals instead of patients/consumers – this is not a matter of “free speech”).  Unless and until we return to something fairer, better, and more functional than this Era of American Capitalism, when General Electric accounted for a full percentage point of the GDP of the United States and bragged in its annual report that it employed over 400,000 men and women in well-paying union jobs that did comprise a true middle class (which was also when Eli Lilly was large and profitable in the same manner), we must come up with another solution.  This other solution is more likely, whatever form it will take.

Finally, I must point out that all is not amiss in the research community.  Although basic biological and biomedical research is not exactly healthy under the neoliberal dispensation, especially in the United States, the problems there are not the same that afflict clinical research. There is room for hope. One problem, and one solution, at a time!

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[1]I have read in several places that “consumer” is neoliberal for “citizen.”  Indeed, this is the truth and I thank others for pointing this out, and I apologize for not giving proper credit here.

[2]MIT pioneered the Big Business-University nexus beginning early in the 20^thcentury, to its benefit and arguably for the benefit of society in the beginning.