A brief history of clinical research in humans: selected examples

BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)

The earliest recorded clinical trial is often cited as that of a special diet of legumes and water followed by Daniel in the Old Testament (Daniel 1:11, 15). During the 1530s Renaissance-era French barber-surgeon Ambroise Parи used a mix of turpentine, rose oil and egg yolk as an antiseptic for battle wounds, and enjoyed improved efficacy compared to the traditional treatments used at that time [1]. James Lind, often thought of as the father of controlled experimental design, conducted therapeutic trials of several agents (cider, seawater, elixir of vitriol, vinegar, a purgative tonic, and oranges and lemons) in the treatment of scurvy in British sailors and found that the sailors who ate oranges and lemons fared better than those who were given alternative treatments [2]. Here we have reviewed selected cases of clinical research in the last several decades that are notable either for their innovation, or more commonly for marking a period of controversy and moral outrage in the field of ethics of human research.

The Randomized Trial of Streptomycin in Pulmonary Tuberculosis Sir Austin Bradford Hill and the Medical Research Council (MRC) of the United Kingdom are often credited for carrying out the first published randomized controlled trial testing streptomycin as a treatment for pulmonary tuberculosis, reported in the British Medical Journal (BMJ) in October 1948 [3]. Hill advocated the use of random assignment of participants in a blinded manner to a treatment arm [3]. The justifications for the use of a control arm were: (1) streptomycin had not yet been established as effective for the treatment of tuberculosis and (2) due to a national shortage of streptomycin owing to the simultaneous tuberculous meningitis and military tuberculosis epidemics, the drug was not readily available for patients with pulmonary tuberculosis [4]. 109 patients were randomized to receive either standard care (bed rest) or streptomycin for four months. Results showed that mortality in the control arm was nearly four times that of the streptomycin group, establishing streptomycin as efficacious in the treatment of pulmonary tuberculosis [4]. Since these landmark findings were published in 1948, there have been several high profile human research experiments highlighting ethical controversies in clinical research conducted over the last eight decades.

The Nazi Medical Experiments During the rise of Adolf Hitler in the 1930s, civil rights and ethics suffered at the expense of the Nazi values of racial purity and Germanic/Aryan superiority. As part of the movement to purge Germany of unfit members of society, a series of horrific medical experiments in addition to euthanasia and murder were undertaken to advance Nazi medicine in areas like racial-anthropological research, brain research and neurology, military medical research, and genetics experiments [5]. The subjects were made to endure experiments involving a wide range of toxic exposures including high-altitude pressure chambers, immersion in freezing water, typhus, malaria, and mustard gas, among others [5]. These experiments are considered by many as acts of torture and murder, barely veiled under the pretense of medical research.

The Nuremberg Code is a legal and ethical framework arising from the trial of Nazi physicians at the Nuremberg war crimes trial conducted by the Allies at the close of World War II. The evidence presented at the trial, which was conducted over nearly 5 months in 1946–47, demonstrated that Nazi physicians not only conducted medical experiments under dangerous and cruel conditions, but that the experiments themselves were designed with the purpose of developing methods of extermination and ethnic cleansing [6]. In August 1947, the Nuremberg Code, a 10item guideline written to protect the rights of research participants, was published along with the final verdicts [7]. The code emphasizes the primacy of voluntary informed consent in any research endeavor [6]. It also highlights the requirements of minimizing harm to subjects, freedom to withdraw consent at any time, and scientific design aimed at achieving results for the good of society [7, 8].

The Tuskegee Syphilis Experiment From 1930 to the early 1970s, the United States Public Health Service (PHS) carried out a series of observational studies on 400 African-American men affected by syphilis. By the early 1930s, the medical community had acquired a clear understanding of the natural history of untreated syphilis in its three stages, including the devastating cardiovascular and central nervous system manifestations observed in tertiary syphilis. However, there was a commonly held belief, even among physicians, that the syphilis epidemic was a particularly serious problem in African-Americans owing to their “inherently promiscuous nature”, and that poverty and lack of education prevented them from seeking and completing treatment once infected [9].

Over 4 decades, the Tuskegee experimenters observed the natural arc of illness resulting from untreated syphilis. Among the many violations of research ethics committed in the study, the most egregious by any standards include: (1) misleading the participants about the nature of their illness, instead referring to it as “bad blood,” (2) failure to obtain informed consent, (3) offering burial stipends to the families of the deceased to secure permission for autopsies, (4) offering aspirin and iron tonic as purported “treatments,” (5) preventing men who were offered treatment by the military during the WWII draft from receiving it [9]. It was not until Peter Buxtun, a psychiatric social worker-turned-lawyer, raised protests against these violations in the mid-1960s, that there was a bona fide investigation of the study [9]. Even after such an inquiry at the Centers for Disease Control (CDC) in 1969, the study was deemed worthy of continuation with some modifications to improve its scientific integrity [9]. Finally, in 1972, an Associated Press reporter, Jean Heller, with the help of Peter Buxtun, published a series of articles [10] exposing the heinous violations of human rights and the deaths of over 100 men from the Tuskegee Study, and it was finally brought to an end. A class action lawsuit brought against the U.S. government resulted in a settlement consisting of little more than penicillin treatment for the survivors and nominal payments to the survivors and families of the deceased [11]. In 1974, after hearings on Tuskegee were held, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was founded when the National Research Act was signed into law [12], and in turn drafted the guiding principles comprising the Belmont Report [13], one of the most recognized moral frameworks governing medical research.

The Jesse Gelsinger Case The death of teenager Jesse Gelsinger after enrolling on a gene transfer protocol at the University of Pennsylvania is a recent memorable case. Gelsinger had a rare recessive X-linked genetic deficiency in the hepatic enzyme ornithine transcarbamylase (OTC), which leads to abnormal metabolism of ammonia [14]. He was diagnosed with partial OTC deficiency in his childhood, and despite adherence to the appropriate low protein diet and drug therapy, he developed many severe episodes of hyperammonemia requiring admission [15]. The University of Pennsylvania initiated a phase I trial of a functional OTC gene contained in an adenoviral vector, with the United States Food and Drug Association (FDA) approval as well as approval from the Recombinant DNA Advisory Committee (RAC), a regulatory body within the National Institutes of Health (NIH) [16, 17]. Jesse Gelsinger was the 18th patient enrolled on the phase I trial, which employed successively higher doses of adenoviral vector. He developed jaundice and confusion within 24 h of gene transfer, which rapidly progressed to multisystem organ failure and death within 4 days of receiving the therapy [15]. Autopsy studies revealed that the cause of death was an overwhelming cytokine storm and inflammatory response to the adenoviral vector [14, 15].

The case spawned a great deal of ethical controversy due to several lapses in the conduct and monitoring of the study. Previous participants had experienced liver function abnormalities which were not reported, raising the question of whether the requirement for informed consent was fulfilled [14]. Gelsinger also had baseline abnormalities in his liver enzymes, which should have disqualified him from the study at the outset [15]. Furthermore, several changes were made to the protocol that were not reported to the FDA [15], highlighting deficiencies in the conduct of clinical trials at the University of Pennsylvania. Inadequate research staff training and absent or poorly implemented procedures for clinical trial monitoring were yet other examples of misconduct in the Gelsinger case [14].

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