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Thursday, 26.11.2020

Jon Jureidini and Leemon B. McHenry, The Illusion of Evidence Based Medicine: Exposing the Crisis of Credibility in Clinical Research. Wakefield Press, Adelaide, 2020 (320 pages)

Reviewed by Leemon McHenry

 

INFORMATION ON CONTENTS:  The Illusion of Evidence Based Medicine is divided into eight chapters and includes appendices, notes, a bibliography, acknowledgements and an index.  Having explained the basic problem of corporate manipulation of clinical research in the first chapter, Chapter Two provides indisputable evidence of corruption of two industry-sponsored clinical trials, GlaxoSmithKline’s paroxetine study 329 and Forest Laboratories citalopram study CIT-MD-18. Both trials were highly influential in prescriptions of paroxetine and citalopram in pediatric and adolescent depression yet both trials seriously misrepresented the efficacy and safety data.  There is nothing extraordinary about these two trials; in one way or another they exemplify what is basically wrong with a system that allows industry to test its own products. Chapter Three provides the underpinning for our critique of evidence-based medicine through a general philosophical theory of what constitutes rigorous science.  The authors argue that Karl Popper’s philosophy of science, Critical Rationalism, with some limitations, restores the scientific foundation of medicine. In the four chapters that follow, the authors spell out the specifics of how this foundation is undermined: through ghostwriting, the corruption of academia, disease mongering and the failings of regulatory agencies.  In the final chapter the authors examine a number of contemporary attempts to address the basic problem, most of which have had very limited success, and then endorse a solution that removes drug trials from industry control.  After exploring the consequences of this radical proposal, the authors end by returning to Popper’s argument for scientific objectivity against a fashionable relativism, “Social Constructivism.”         

AUTHORS’ STATEMENT:  The Illusion of Evidence Based Medicine is based on a 10-year, transpacific collaboration. We worked as consultants to the Baum Hedlund law firm of Los Angeles where we had access to confidential industry documents subsequently de-classified and released into the public domain.  The critical documents that allowed us to deconstruct the clinical trials included internal email correspondence, study protocols, clinical study reports and drafts of manuscripts prepared by ghostwriters working for medical communication companies.  Our findings were presented at medical conferences and in various medical and bioethics journals.  Over time, our research developed into the present book.

       We began with a critical evaluation of GlaxoSmithKline’s study 329 and attempted to engage the named authors of this paper, the editor who accepted it for publication, the drug maker that sponsored the trial and the university where the research was based in a failed attempt to hold the stakeholders accountable.  The difference between what was reported to physicians and what was revealed in the internal documents was so alarming that it became clear that science had been usurped by marketing objectives and the academic investigators collaborating with the drug manufacturer had become nothing more than promotional agents for drug sales.  The medical journals, medical societies and the drug companies became a conspiracy to conceal the truth, but as the evidence came to light in numerous plaintiffs’ lawsuits, government investigations and academic research, it became harder and harder to maintain the fraud. 

       The published report of study 329 in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) claimed that paroxetine was generally well tolerated and effective for major depression in adolescents,” while GlaxoSmithKline claimed that paroxetine demonstrated Remarkable Efficacy and Safety.”   Unknown to the JAACAP readers, the 329 study was completely negative on all protocol-designated primary outcomes, most secondary protocol-designated outcomes and GlaxoSmithKline withheld clinically important adverse event information on paroxetine-induced suicidal and manic-like behaviors in children and adolescents.  Suicidal thoughts and behavior were miscoded under the euphemism “emotional lability.”  Study 329, now infamous in the medical world, was in fact negative for efficacy and positive for harm.  Having failed to gain regulatory approval for paroxetine in the treatment of pediatric depression, GlaxoSmithKline used the JAACAP article for illegal off-label promotion. 

       Study CIT-MD-18 was part of the same push to gain regulatory approval for the use of SSRI antidepressants in child and adolescent depression, this time for Forest Laboratories’ citalopram and escitalopram.    Forest did gain approval for escitalopram in the treatment of adolescent depression on the basis of the alleged positive results of CIT-MD-18 and another trial, SCT-MD-32.  The study report of CIT-MD-18 was published in the American Journal of Psychiatry. It concluded that citalopram was significantly more efficacious than placebo for both children and adolescents. 

       Our deconstruction of study data and court documents revealed that the claims of published article were predicated upon a combination of misleading analysis of the primary study outcome, an implausible effect size, introduction of post hoc outcomes as if they were primary outcomes, failure to report negative secondary outcomes, inclusion of eight unblinded subjects into efficacy analyses and misleading analysis and reporting of adverse events. For example, contrary to protocol stipulation, Forest increased the final sample size by adding back into the primary outcome analysis eight of nine subjects who should have been excluded from the data analysis because they were dispensed unblinded study drug. The CIT-MD-18 study was negative and therefore not supportive of Forest’s FDA adolescent indication application.   

       Like the case of study 329, the stakeholders in the CIT-MD-18 study have refused to correct the scientific record.  These are not isolated cases.  We argue that reports of industry-sponsored clinical trials have polluted the medical journals and disinformed prescribing physicians of the true risks of medicines. The basic problem with industry studies is failure to design, conduct and report honestly the outcomes of scientific experimentation.  In this respect we turn to Sir Karl Popper for a rigorous conception of science in medicine.  Popper argued powerfully that a science of real integrity is one in which its practitioners are careful not to cling irrationally to cherished hypotheses and are serious about the most stringent experiments.  But since industry-science is largely designed to escape refutation it falls into the category of pseudo-science.   

       Evidence-based medicine is meant to provide a paradigm based on a system that assesses the strengths of the evidence of risks and benefits of treatments and diagnostic tests.  However, given that the evidence is largely, if not completely, manipulated by the manufacturers of pharmaceuticals, evidence-based medicine is an illusion.

 

November 19, 2020