Institutional review boards (IRBs) are necessary to protect study participants in US trials. However, it’s difficult to evaluate the effectiveness of IRB reviews in an evidence-based fashion, with such understanding being integral to protect participants. And the results from studies evaluating the efficacy and procedures of IRBs have been disconcerting.
According to the authors of a review article published in the Journal of Empirical Research on Human Research Ethics:
“Despite recognition of a need to evaluate effectiveness of IRB review, no identified published study included an evaluation of IRB effectiveness. Multiple studies evaluating the structure, process, and outcome of IRB review in the United States have documented inconsistencies and inefficiencies. Efforts should be made to address these concerns. Additional research is needed to understand how IRBs accomplish their objectives, what issues they find important, what quality IRB review is, and how effective IRBs are at protecting human research participants.”
In other words, IRBs, which are tasked with protecting the public, are poorly understood. Thus, it should come as no surprise that there have been notable lapses in participant safety during clinical trials. Here are five glaring examples of misconduct and missteps within clinical trials that resulted in tragedies both in the United States and abroad.
BIA 10-2474 safety trial
In January 2016, during a drug safety trial conducted in France, one person died and four became ill after taking BIA 10-2474—a drug that works on the endocannabinoid system and was intended for a range of diseases. Although the study began in June 2015, without any severe adverse effects among study participants, the injured cohort of eight patients were the first to receive several high doses of the drug.
The French government was quick to censure Biotrial, the company conducting clinical testing of BIA 10-2474. France's General Inspectorate of Social Affairs (IGAS) highlighted three major transgressions on the part of Biotrial in a French-language report.
Foremost, when the first volunteer complained of headache and dizziness and was sent to the hospital, Biotrial physicians failed to follow-up, and they continued administering scheduled doses to the rest of the participants in the cohort. The first participant went on to receive an MRI showing brain death, and four others fell ill during the interim. After eventually learning of the death, Biotrial stopped the study.
Furthermore, in violation of informed consent forms signed by the study participants, Biotrial staff neglected to inform participants of the first severely ill participant’s condition. Had these other participants been informed, they could have reconsidered their participation in the study and possibly avoided illness.
Finally, Biotrial failed to inform the IGAS of the grave repercussions of the trial for several days, which made it impossible for the agency to protect other earlier volunteers in a timely fashion, as well as protecting other participants of trials involving the same class of molecules.
In their report, IGAS also noted that Biotrial should have excluded participants with a history of cannabis use because BIA 10-2474 worked on the endocannabinoid system, and marijuana use could result in dangerous interactions. The company, however, had inconsistent and imprecise exclusion criteria.
In the wake of World War II, tranquilizers taken for sleep were all the rage, with one in seven Americans taking them. So, when a non-prescription, non-barbiturate sedative, with no purported risk for hangover or dependency came to market, people craved it.
Thalidomide was created by the Swiss company CIBA in 1953, and it was introduced to the German market without the need for prescription in 1956. Initial tests of the sedative were cursory, as was emblematic of clinical trials at the time, with preclinical studies in rodent models showing no median lethal dose, which researchers inferred to mean that it was safe for use in humans. Importantly, no tests for teratogenic potential were performed.
The drug soon became a popular treatment for morning sickness during pregnancy. In 1961, however, Dr. William McBride, an Australian obstetrician, and Dr. Widukind Lenze, a German pediatrician and geneticist, both observed that thalidomide was related to congenital malformations—including limb and bone abnormalities, gastrointestinal atresia, cardiovascular abnormalities, and gall bladder abnormalities. Most malformations occurred when thalidomide was ingested 34-49 days after the last menstrual period in women, with even one dose increasing risk. Within a year of birth, up to 40% of infants died of thalidomide exposure.
In 1960, a staggering 14.6 tons of the drug were sold worldwide. Fortunately, however, the drug never made it to the American market thanks to Dr. Frances Kelsey, a physician and pharmacologist, who was the FDA officer tasked with reviewing the drug application. She denied approval of the drug due to lack of safety data and concerns about neurological adverse effects, including peripheral neuritis, despite pressure from the drug manufacturer. For her efforts, President John F. Kennedy, Jr, bestowed her with the President's Award for Distinguished Federal Civilian Service. Talk about a profile in courage!
By 1961, the drug was pulled from most markets, and it was flat out banned worldwide by 1970. Nevertheless, thalidomide use left an estimated 10,000 infants worldwide affected, with even more uncounted stillborn or miscarried pregnancies. Although it’s hard to find any positives in this unspeakable tragedy, the clinical trial landscape did improve thereafter, according to the authors of a review published in Therapeutic Advances in Hematology.
“A lasting impact of these tragic events has been in the positive change in the drug regulation process,” wrote the authors. “Problems with animal models and inefficiencies in the pharmaceutical agent approval process were rectified by new legislation which revamped the FDA regulatory process, expanded patient informed consent procedures and called for more transparency from drug manufacturers.”
Therapeutic trials for drugs targeting advanced cancers is a perilous endeavor. Even so, when five patients with leukemia died of cerebral edema in 2016 after being treated with Juno Therapeutics’ take on chimeric antigen receptor (CAR)-T cell therapy, shockwaves reverberated throughout the oncology community, with the safety of all CART-T cell therapies called into question.
Of note, autopsies of two of the decedents exhibited a complete breakdown of the blood-brain barrier. However, engineered T cells and other immune cells were absent from biopsied tissue.
In retrospect, the deaths were likely specific to Juno’s version and administration of the therapy and not generalizable to other CAR-T therapies. For one, the treatment was highly personalized, and patient immune cells were highly heterogeneous, a variable that may not have been properly gauged by researchers. Furthermore, there could have been issues with handling of the cells, per Juno representatives, as well as rapid multiplication of CAR-T cells once injected, thus leading to neurotoxicity. Learning from their mistakes, Juno started monitoring T-cell subtypes in other CAR-T trials.
Animal models aren’t equivalent to human models, and sometimes what is safe for an animal is unsafe for a human—at least, that’s the lesson from a 2006 phase I clinical study involving CD28 superagonist antibody TGN1412, which was intended to treat autoimmune disease. Although the first infusion in 6 patients was 500 times smaller than that found safe in animal studies, all 6 volunteers suffered life-threatening organ failure.
Per the author of a review article published in the Journal of Young Pharmacists, this tragedy “was an alarming call for the researchers and also for the trial approving regulatory authorities on toxicity-related unpredictability of new drugs in human subjects especially for biological with a novel mechanism of action like TGN1412. Though there is always a risk involved with clinical trials, these risks can be potentially reduced if more scientific research toward development of animal models closely mimicking drug behavior in humans can be developed.”
This particularly egregious example of a clinical study gone terribly wrong is surreal. In 2003, a judge ordered 26-years-old Dan Markingson, who was suffering from psychosis and homicidal tendencies, to be involuntarily committed at the recommendation of University of Minnesota physician Stephen Olson, MD. Dr. Olson then persuaded the judge to release Markingson—on the condition that he be enrolled in Dr. Olson’s treatment program.
However, instead of treating Markingson inpatient, Dr. Olson enrolled the young man in a clinical study of Seroquel, in which Dr. Olson was serving as an investigator. Importantly, Markingson lacked the capacity to consent to study participation. (Why the unethical recruitment? Hefty financial incentives by Seroquel’s manufacturer and trial sponsor, AstraZeneca.)
Even more troubling, Dr. Olson delegated the administration of prescription drugs to a social worker named Jeanne Kenney, who was also responsible for monitoring potentially deadly adverse effects, including akathisia. In turn, Kenney assigned these responsibilities to a social work intern.
As Markingson’s mother observed that her son was decompensating, she tried to have him removed from the study. However, Dr. Olson and a co-investigator of the study declined to do so. Shortly thereafter, Markingson committed suicide.
Unfortunately, it gets worse. The University of Minnesota denied accountability and shielded itself with statutory immunity.
But, there was one good thing to come out of this tragedy: The state of Minnesota banned the recruitment of study subjects from the criminal justice system.