In early 2016, the French company Biotrial recruited 128 healthy volunteers to participate in a clinical trial for a new drug. Under small doses, none of the participants experienced any side effects. Once the quantities increased, six of the participants became very sick, which ultimately led to the death of one of them, with permanent damage to the rest. It was later discovered that the drug was known to have similar effects on dogs during pre-clinical trials, yet it moved to human testing.
After five days of taking the experimental drug that might help dull his nerve pain, Guillaume Molinet checked into the hospital. An MRI scan showed a massive stroke in the brain stem. He was declared brain dead that day, and a week later, he passed away. Five other volunteers on the highest dose of the clinical trial drug that checked into the hospital, with four exhibiting similar symptoms and showing identical brain injuries in scans. Thankfully, none of the other participants at lower doses experienced any problems, though that seemed to be more of a stroke of luck than by design.
The people running the trial appeared to lack any logic or common sense. They gave extremely high doses of the drug: almost 40 times more than needed to subdue any pain. They’d also completely ignored the fact that the drug had not really even shown indications of treating pain in the first place and moved it to human trials anyway. Despite all these missteps, everything they did was legal, but not necessarily intelligent or wise. The drug was intended to work on the endocannabinoid system in the brain. It is likely that it also worked on unintended parts in the brain which prevented an enzyme called fatty acid amide hydrolase, or FAAH, from breaking down a molecule in the brain that helps with our response to pain and anxiety.
Thalidomide was initially marketed in West Germany in 1957 as an over the counter drug for anxiety, sleeplessness, tension, and morning sickness. We may recognize the name now because of its adverse effects on pregnancy. Nevertheless, at the time, they thought it was a safe drug. Researchers found it to be a non-sedative with no risk of a hangover or dependency. They released it to market after testing with no need for a prescription. Most importantly, they perfromed zero tests for teratogenic potential, meaning anything that could cause fetal abnormalities.
In 1961, Dr. William McBride and Dr. Widukind Lenze observed a relationship between thalidomide and congenital malformations like limb and bone abnormalities and gallbladder abnormalities. The drug was pulled from most markets that year and banned from all markets by 1970. By then, it had affected an estimated 10,000 infants worldwide, not including those stillborn or miscarried during pregnancy. Thalidomide’s main hazards and side effects, not including death, include fetal impairment like bilateral limb atrophy, bilateral limb absence, missing fingers and toes, malformation of the digestive tube, malformation of the duodenum, malformation or absence of the anus, and vital organs injury.
The FDA did not approve Thalidomide in the 1950s and 1960s due to the efforts of one Dr. Frances Oldham Kelsey. She refused to approve the application because of what she felt was inadequate evidence of the drug’s safety, despite its use worldwide. She insisted on scientifically reliable evidence, which she felt the application lacked. Just a year later, Dr. McBride and Dr. Lenze made their discovery, and Dr. Kelsey was awarded the highest recognition attainable for a U.S. civil servant for her role in saving thousands from death or life-long incapacitation. In October 2000, Dr. Kelsey was also inducted into the National Women’s Hall of Fame. In 1998, Thalidomide was approved in the United States as a treatment for cancer and is on the World Health Organization’s List of Essential Medicines, and is also available as a generic medicine. However, it should not be used by anyone trying to conceive a child or by anyone breastfeeding or pregnant.
Babies born with Ornithine Transcarbamylase Deficiency Syndrome (OTCD) usually don’t reach adulthood, but Jesse had a milder version of the deficiency. OTCD is a rare metabolic disorder that builds ammonia up to lethal levels in the blood. Though he was able to manage it with a low-protein diet and a regimen of anywhere between 30 – 50 pills every day, he was incredibly interested to hear more about the trial that could treat it. Researchers at the University of Pennsylvania were developing a clinical trial to inject patients with a working version of the gene he didn’t have – attached to a cold virus to make it more spreadable.
Jesse was the 18th person to receive the injection. Previous patients had experienced flu-like symptoms, but he reacted much more severely. He then showed signs of jaundice, blood clotting, and organ failure. Four days later, he was declared brain-dead and taken off life support. After a thorough investigation, many troubling things came to light. The researchers had not retooled their eligibility criteria despite promising the FDA that they would.
Two patients experienced severe side effects, but it was not reported, nor was the study put on hold. Jesse’s pretrial test results indicated that his liver function was poor enough that he should not have received the drug at all – worse yet, Jesse was not informed of any of these issues, so he did not have informed consent. Jesse’s family sued, and the University settled for an undisclosed amount. In January 2000, the FDA suspended human research at UPenn’s Institute for Human Gene Therapy, and the University eventually shut the program down.
Anil Potti is the scariest kind of doctor. He is the one who promises you the world when he knows he is lying. He promised cancer treatments with an 80 percent cure rate and fabricated data that convinced medical professionals that he could save 10,000 lives a year. Anil Potti graduated from Christian Medical College in India in 1995, then completed an internship in Internal Medicine at the University of North Dakota School of Medicine in 1999. He moved on to complete training in hematology and oncology at Duke University in 2006. However, he resigned in 2010 after discovering flaws in his research and allegations of embellishments in his resume.
Potti and his team were accused of falsifying data regarding personalized cancer treatments. However, scientific journals published these findings. As of 2020, journals retracted 11 of his research publications. Furthermore, one has received an expression of concern, and two others have been corrected. Potti’s work was funded through the National Institutes of Health (NIH), the National Cancer Institute, the Howard Hughes Medical Institute (HHMI), and others. Joyce Shoffner was one of Potti’s victims. She signed up to participate in his cancer-curing clinical trial, undergoing a painful breast biopsy and following a regimen of Adriamycin-Cytoxan (AC) chemotherapy, which caused her blood clots and diabetes as well as PTSD from the trial. Keep reading for facts about clinical trials that won’t horribly wrong.
In any clinical study, researchers treat patients as gracious volunteers that are helping further science. Sometimes, there’s a financial compensation aspect to it too. One thing is for certain: they never ask trial participants for payment in exchange for treatment. At least, that’s how things are supposed to work. In this unfortunate stem cell vision treatment, they charged three women $5,000 for their trial. Sadly, they ultimately lost most, if not all, of their eyesight.
In January 2017, a study asking for elderly participants with macular degeneration offered stem cell therapy to treat their eyesight. All three women reported bleeding and retinal detachment just days after their treatment. One woman was completely blinded, while the other two lost most of their sight. The researchers have tried to erase the trial’s existence; when you visit the records of it online, it says that the study was “withdrawn before enrollment,” which is a lie.
The patients had fat cells removed from their abdomens and a standard blood draw for lab work. The fat tissue from their cores was processed with enzymes to obtain stem cells, then platelet-dense plasma was isolated from the blood. Doctors mixed the cells with the plasma and injected it into their eyes. The process took less than an hour. However, they treated both eyes at the same time. That is another red flag, as typically a clinical trial would wait to see how one eye responds to treatment before exposing the other. Though the patients had no way of knowing this, the trial had no real scientific basis. It had no hypothesis based on laboratory experiments, no control and treatment groups, no collection of data, no clear patient masking (to see who was and was not getting treatment), and no plans for follow-up.
Researchers are always searching for a cure for cancer. Leukemia is a particularly terrifying type of cancer. So Juno Therapeutics’ clinical trial tested their new cellular-level treatment that would attack malignant cells until they appeared to vanish, it came out. No wonder researchers in the cancer community were calling it the “fifth pillar” of cancer treatment. The treatment, chimeric antigen receptor (CAR)-T cell therapy, or CAR-T for short, was not specific to Juno Therapeutics’, but its results would certainly affect the entire scientific community.
The study in July 2016 caused the death of three leukemia patients from cerebral edema, or swelling in the brain. Representatives from the company admit that this is common in patients receiving CAR-T treatments, immune system reactions, and increased neurological toxicity. After the news of the deaths, the company’s stock fell by 27 percent and their practices went under FDA review. The researchers did not know how to properly gauge patient immune cells’ heterogeneity. Plus, once they injected the patient, something else happened. The rapid multiplication of the CAR-T cells led to neurotoxicity. Juno learned from its mistakes and started monitoring T-cell subtypes in other CAR-T trials. Keep reading for facts about clinical trials that won’t horribly wrong.
Like any college student, Hoiyan Nicole Wan was in search of a little extra pocket money. She heard of a clinical trial that paid $150 for a bronchoscopy to see the effects of pollution on her respiratory system, so she signed up. Wan had not planned on the researchers taking more cell samples than initially proposed, and increasing the anesthetic, Lidocaine, by about four times the maximum dosage. The college student was released feeling very weak and in pain, and two days later she was found dead.
Her autopsy revealed that the Lidocaine levels she received were lethal, causing her heart to stop beating and her organs to shut down. She had a heart attack the day of the study, in fact, after initial struggles with breathing and then going to the emergency room. Her parents settled with the university. They did not release the full details. However, it does call for a full scholarship for a Chinese-American student for eight years, an annual lecture on the ethical and safety issues in medical research involving humans, and a memorial in Ms. Wan’s name. Keep reading for facts about clinical trials that won’t horribly wrong.
Ellen Roche was a 24 year old technician at Johns Hopkins Asthma and Allergy Center, where she heard of a trial recruiting healthy volunteers to help doctors discover the reflex that protects the lungs of healthy people against asthma attacks. The researchers would provoke a mild asthma attack by having her inhale hexamethonium, a medication used for treating high blood pressure in the 1950s and 1960s. She signed up for the study and quickly developed a cough, though the researcher administering the trial chalked it up to a common cold. Her condition worsened over the next week. Doctors put her on a ventilator. Ellen Roche’s lung tissue dissolved and her blood pressure plummeted. Then, her kidneys began to fail. She died on June 2, 2001, a month after entering the study.
Medical officers from the trial now admit that the hexamethonium was either solely responsible or played a contributory role to her illness, but that doesn’t make accepting her death any better. In fact, to make things worse, participants learned the FDA did not even approve of the drug after the trial. In their consent forms, they merely referred to it as a “medication” instead of clearly indicating that it was experimental or listing the risks. Keep reading for facts about clinical trials that won’t horribly wrong.
Since chimpanzees share more than 99% of DNA with humans, and mice share more than 98%, they are susceptible to many similar health problems as humans like cancer, diabetes, and heart disease. Researchers are legally and morally obligated to ensure the health and well-being of the animals in their care. They never set out to harm them; animal testing is essential in drug approval. Animal trials have helped scientists learn about disease stages and how to treat or even cure them. Currently, animal use is even a mandated part of drug development. Current federal laws in the U.S. require proof of safety and effectiveness in animal trials before they move into human trials. In our last entry, we’ll look at a clinical trial where successful animal testing didn’t translate to safe human testing.
Theralizuman is also as TGN1412, CD28-SuperMAB, and TAB08. Thomas Hunig developed it at the University of Wurzburg in 2006. The purpose of the drug was originally to treat B cell chronic lymphocytic leukemia (B-CLL) and rheumatoid arthritis by binding to receptors on the T-cell. The six human participants were assumed that the worst symptoms they’d experience were likely a headache and nausea, but the trial soon spiraled into one of the most infamous medical trials in British history. Shortly after receiving their doses, all patients began experiencing severe pain and vomiting uncontrollably. One patient lost his fingers and toes, another had to have this foot partially amputated. The trial is “the Elephant Man Trial” because one patient’s head swelled up so much that his girlfriend teased him about looking like an elephant.
Doctors now know to call the symptoms men experienced cytokine storm. It is where their temperatures soared, their organs failed, and some of their bodies swelled past recognition. One of the participants, Rob Oldfield, had fluid seeping into his lungs and had to breathe through a mask. Ryan Wilson spent four months in the hospital and battled pneumonia, septicaemia and dry gangrene. His father had warned him the night before the trial: “Don’t do it. Your body is a temple.” The volunteers still suffer from weakened immune systems and other side effects.
Though knowing what went wrong with the trial is difficult, there are a few theories about why it was so ill-fated. One theory claims that the period of drug injection was to blame. Researchers spent over an hour and a half injecting the drug carefully into the animals. However, injecting the entire dosage into the human participants took a mere six minutes. Another theory suggests that animal testing did not translate to human testing accurately because it was done on a macaque instead of a bonobo, so the animal-to-human DNA match was only 94% instead of 98%.
Oddly, one source said that the first infusion in six patients was five hundred times smaller than that found safe in the animal studies, but the volunteers still suffered life-threatening organ failure. Clearly, a disconnect between animal and human studies happened here, resulting in a hugely unfortunate incident for those involved. Parexel, the drug company that ran the clinic where the trial was carried out, was found to have acted within all proper protocols. However, a final report did indicate that the trial had not adequately considered the safe dosage for humans. The company that developed the drug, TeGenero Immuno Therapeutics went bankrupt later that year.