NEJM Critique of US Medical Research – 1966 vs. 2016. A Deeply Conflicted System.

Posted on | June 6, 2016 | Comments Off on NEJM Critique of US Medical Research – 1966 vs. 2016. A Deeply Conflicted System.

 Henry K. Beecher,MGH

Mike Magee

“Assessing the Gold Standard – Lessons from the History of RCTs” , in last week’s NEJM, provided useful historical perspective, but was intentional selective and treaded lightly on the darker side of America’s medical-industrial complex, and its conflicted role in human medical experimentation.

The most significant determinant that defined the direction of medical research in the post-WW II period was not the emergence of randomized controlled trials (the “gold standard”) but money. Over a short two decades, funding of medical research, flowing primarily through the federal government, exploded. Advances by 1950 to a total expenditure of $161 million seemed significant, but they were nothing compared to the $2.3 billion in funding that existed by 1968.(44) By then, financial incentives had solidified a deep and enduring bond forged by medical research leaders who traveled unimpeded from government to academia to corporate offices and back again.

There was a great deal of discussion about ethics in clinical research that accompanied those piles of cash, but, as it turned out, the words did not routinely match the deeds. In the wake of the Nuremberg Trials, the full extremes of Nazi medical experimentation had been revealed years earlier to the full glare of a horrified global audience. It was clear from the directives that followed that medical experimentation in humans could only be justified within certain well-defined boundaries. Ten rules or principles were laid out.

This was the determination of a worldwide Allied Tribunal that was conducted under the direction of U.S. judges and prosecutors, and which, in all respects, carried the criminal procedural standards of the U.S. government. And yet, another 25 years would pass before any of the ten agreed upon standards, cited in this code, were cited in a U.S. Court.

Legal scholars attribute this lapse to the professional biases of those in the lead of medical and pharmaceutical sectors in the 25 years following the war. As one prominent medical leader stated of the Nuremberg Code, “It was a good code for barbarians, but an unnecessary code for ordinary physician-scientists.”

The American medical leadership sought refuge in semantics. To them “therapeutic research” that benefited patients while expanding physician knowledge, was an entirely different kettle of fish than Nazi “non-therapeutic” research which meant clearly to do harm to the patients. American Medicine’s noble professionalism was adequate to ensure ethical research, most doctors believed. That was until June 16, 1966, when the New England Journal of Medicine published an article titled “Ethics and Clinical Research”.

The article was written by a highly-respected Harvard physician mentor of Lou Lasagna, Henry K. Beecher, who practiced at the prestigious Massachusetts General Hospital. Dr. Beecher’s opening paragraph said, “Human experimentation since World War II has created some difficult problems with the increasing employment of patients as experimental subjects when it must be apparent that they would not have been available if they had been truly aware of the uses that would be made of them. Evidence is at hand that many of the patients in the examples to follow never had the risk satisfactorily explained to them, and it seems obvious that further hundreds have not known that they were the subjects of an experiment although grave consequences have been suffered as a direct result of experiments described here. There is a belief prevalent in some sophisticated circles that attention to these matters would ‘block progress.’”

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As for motivation for the ethical violations, he was about to catalogue in exquisite detail, he explained, “Since World War II the annual expenditure for research (in large part in man) in the Massachusetts General Hospital has increased a remarkable 17-fold. At the National Institutes of Health, the increase has been a gigantic 624-fold. This ‘national’ rate of increase is over 36 times that of the Massachusetts General Hospital…Taking into account the sound and increasing emphasis of recent years that experimentation in man must precede general application of new procedures in therapy, plus the great sums of money available, there is reason to fear that these requirements and these resources may be greater than the supply of responsible investigators. All this heightens the problems under discussion…Medical schools and university hospitals are increasingly dominated by investigators.”

From here, Beecher went on to share the review of 50 distinct American clinical studies with ethical violations. During this period, in and around the time of Beecher’s paper, other alarms were raised, only to be ignored. For example, there was a young physician from Detroit, named Irwin Schatz, who came across the study in a medical journal in 1964. It’s title was “The Tuskegee Study of Untreated Syphilis: 30 Years of Observation”. He couldn’t quite believe it and shot off a letter to the editor which read, “I am utterly astounded by the fact that physicians allow patients with a potentially fatal disease to remain untreated when effective therapy is available.”

Later records revealed that his unanswered letter had been read by one of the Public Health Service authors who wrote to her superior, “This is the first letter of this type we have received. I do not plan to answer this letter”. Schatz letter was attached. The study continued for another seven years.

What eventually catapulted the issue to the forefront was a New York Times article on July 26, 1972, titled “Syphilis Victims in U.S. Study Went Untreated for 40 Years.”(51) The whistle blower on what then remained an active human experiment was Peter Buxtan, an epidemiologist for the U.S. Public Health Service. He later said, “I didn’t want to believe it. This was the Public Health Service. We didn’t do things like that.”

In all, 399 infected patients were victimized before the plug was officially pulled on November 16, 1972 by President Nixon’s Assistant Secretary of Health, Merlin DuVal. The official apology for these crimes to humanity would have to wait another quarter century and were delivered by President Bill Clinton who said, “[t]he United States government did something that was wrong — deeply, profoundly, morally wrong.”

Congress did pass the 1974 National Research Act. It finally incorporated some of the protections recommended at Nuremberg. Voluntary consent was now required by law for all participants in U.S. medical research studies that received any federal funding. Study design had to be reviewed and pre-approved on ethical grounds by new institutional review boards (IRB’s) – a body of local professionals who would critique each proposed study and attest to its ethical construct. Finally, the Act established a National Commission for the Protection of Human Subjects of Biomedical Research that was charged to identify “the basic ethical principles which should underlie the conduct of biomedical and behavioral research involving human subjects.”

Case closed. Problem solved. Well, not exactly. In fact, the National Institute of Health has catalogued at least 11 milestone corrective legislative and rule setting events that have occurred since that time. And through it all, controversy and illegality has continued to swirl unabated. This has not only occurred in far off lands like Nigeria, but also on our own shores as well. Today’s problems are centered, not so much in the arena of treatment of research subjects, although there is always room for improvement, but rather in three derivative areas.

The first is data, or more specifically, how research data and study design is manipulated in pharmaceutical studies to exaggerate benefit and minimize risk in study results that lead to FDA approval.

The second area, not new really since it was the major concern that led to the Kefauver hearings over a half century ago, is the accuracy and purpose of the information that is regularly communicated, largely through marketing departments, to the American people and to their clinicians.

And finally, there is general agreement that the system is ripe with financial conflict of interest, heavily involving physician researchers and “thought leaders” who simultaneously direct academic medical departments, staff government drug review panels, and cash pay checks provided by the very companies whose potential products they are reviewing.