Is There a Blind Spot in the Oversight of Human Subject Research?
Human experimentation has come a long way since congressional hearings in the 1970s exposed patterns of abuse. Where yesterday's patients were protected only by the good conscience of physician-researchers, today's patients are spirited past hazards through an elaborate system of oversight and informed consent. Yet in many ways, the project of grounding human research on ethical foundations remains incomplete.
As human research has become a mainstay of career and commercial advancement among academics, research centers, and industry, new threats to research integrity have emerged.
To be sure, much of the medical research we do meets exceedingly high standards. Progress in cancer immunotherapy, or infectious disease, reflects the best of what can be accomplished when medical scientists and patients collaborate productively. And abuses of the earlier part of the 20th century--like those perpetrated by the U.S. Public Health Service in Guatemala--are for the history books.
Yet as human research has become a mainstay of career and commercial advancement among academics, research centers, and industry, new threats to research integrity have emerged. Many flourish in the blind spot of current oversight systems.
Take, for example, the tendency to publish only "positive" findings ("publication bias"). When patients participate in studies, they are told that their contributions will promote medical discovery. That can't happen if results of experiments never get beyond the hard drives of researchers. While researchers are often eager to publish trials showing a drug works, according to a study my own team conducted, fewer than 4 in 10 trials of drugs that never receive FDA approval get published. This tendency- which occurs in academia as well as industry- deprives other scientists of opportunities to build on these failures and make good on the sacrifice of patients. It also means the trials may be inadvertently repeated by other researchers, subjecting more patients to risks.
On the other hand, many clinical trials test treatments that have already been proven effective beyond a shadow of doubt. Consider the drug aprotinin, used for the management of bleeding during surgery. An analysis in 2005 showed that, not long after the drug was proven effective, researchers launched dozens of additional placebo-controlled trials. These redundant trials are far in excess of what regulators required for drug approval, and deprived patients in placebo arms of a proven effective therapy. Whether because of an oversight or deliberately (does it matter?), researchers conducting these trials often failed in publications to describe previous evidence of efficacy. What's the point of running a trial if no one reads the results?
It is surprisingly easy for companies to hijack research to market their treatments.
At the other extreme are trials that are little more than shots in the dark. In one case, patients with spinal cord injury were enrolled in a safety trial testing a cell-based regenerative medicine treatment. After the trial stopped (results were negative), laboratory scientists revealed that the cells had been shown ineffective in animal experiments. Though this information had been available to the company and FDA, researchers pursued the trial anyway.
It is surprisingly easy for companies to hijack research to market their treatments. One way this happens is through "seeding trials"- studies that are designed not to address a research question, but instead to habituate doctors to using a new drug and to generate publications that serve as advertisements. Such trials flood the medical literature with findings that are unreliable because studies are small and not well designed. They also use the prestige of science to pursue goals that are purely commercial. Yet because they harm science- not patients (many such studies are minimally risky because all patients receive proven effective medications)- ethics committees rarely block them.
Closely related is the phenomenon of small uninformative trials. After drugs get approved by the FDA, companies often launch dozens of small trials in new diseases other than the one the drug was approved to treat. Because these studies are small, they often overestimate efficacy. Indeed, the way trials are often set up, if a company tests an ineffective drug in 40 different studies, one will typically produce a false positive by chance alone. Because companies are free to run as many trials as they like and to circulate "positive" results, they have incentives to run lots of small trials that don't provide a definitive test of their drug's efficacy.
Universities, funding bodies, and companies should be scored by a neutral third-party based on the impact of their trials -- like Moody's for credit ratings.
Don't think public agencies are much better. Funders like the National Institutes of Health secure their appropriations by gratifying Congress. This means that NIH gets more by spreading its funding among small studies in different Congressional districts than by concentrating budgets among a few research institutions pursuing large trials. The result is that some NIH-funded clinical trials are not especially equipped to inform medical practice.
It's tempting to think that FDA, medical journals, ethics committees, and funding agencies can fix these problems. However, these practices continue in part because FDA, ethics committees, and researchers often do not see what is at stake for patients by acquiescing to low scientific standards. This behavior dishonors the patients who volunteer for research, and also threatens the welfare of downstream patients, whose care will be determined by the output of research.
To fix this, deficiencies in study design and reporting need to be rendered visible. Universities, funding bodies, and companies should be scored by a neutral third-party based on the impact of their trials, or the extent to which their trials are published in full -- like Moody's for credit ratings, or the Kelley Blue Book for cars. This system of accountability would allow everyone to see which institutions make the most of the contributions of research subjects. It could also harness the competitive instincts of institutions to improve research quality.
Another step would be for researchers to level with patients when they enroll in studies. Patients who agree to research are usually offered bromides about how their participation may help future patients. However, not all studies are created equal with respect to merit. Patients have a right to know when they are entering studies that are unlikely to have a meaningful impact on medicine.
Ethics committees and drug regulators have done a good job protecting research volunteers from unchecked scientific ambition. However, today's research is plagued by studies that have poor scientific credentials. Such studies free-ride on the well-earned reputation of serious medical science. They also potentially distort the evidence available to physicians and healthcare systems. Regulators, academic medical centers, and others should establish policies that better protect human research volunteers by protecting the quality of the research itself.
When doctors couldn’t stop her daughter’s seizures, this mom earned a PhD and found a treatment herself.
Twenty-eight years ago, Tracy Dixon-Salazaar woke to the sound of her daughter, two-year-old Savannah, in the midst of a medical emergency.
“I entered [Savannah’s room] to see her tiny little body jerking about violently in her bed,” Tracy said in an interview. “I thought she was choking.” When she and her husband frantically called 911, the paramedic told them it was likely that Savannah had had a seizure—a term neither Tracy nor her husband had ever heard before.
Over the next several years, Savannah’s seizures continued and worsened. By age five Savannah was having seizures dozens of times each day, and her parents noticed significant developmental delays. Savannah was unable to use the restroom and functioned more like a toddler than a five-year-old.
Doctors were mystified: Tracy and her husband had no family history of seizures, and there was no event—such as an injury or infection—that could have caused them. Doctors were also confused as to why Savannah’s seizures were happening so frequently despite trying different seizure medications.
Doctors eventually diagnosed Savannah with Lennox-Gaustaut Syndrome, or LGS, an epilepsy disorder with no cure and a poor prognosis. People with LGS are often resistant to several kinds of anti-seizure medications, and often suffer from developmental delays and behavioral problems. People with LGS also have a higher chance of injury as well as a higher chance of sudden unexpected death (SUDEP) due to the frequent seizures. In about 70 percent of cases, LGS has an identifiable cause such as a brain injury or genetic syndrome. In about 30 percent of cases, however, the cause is unknown.
Watching her daughter struggle through repeated seizures was devastating to Tracy and the rest of the family.
“This disease, it comes into your life. It’s uninvited. It’s unannounced and it takes over every aspect of your daily life,” said Tracy in an interview with Today.com. “Plus it’s attacking the thing that is most precious to you—your kid.”
Desperate to find some answers, Tracy began combing the medical literature for information about epilepsy and LGS. She enrolled in college courses to better understand the papers she was reading.
“Ironically, I thought I needed to go to college to take English classes to understand these papers—but soon learned it wasn’t English classes I needed, It was science,” Tracy said. When she took her first college science course, Tracy says, she “fell in love with the subject.”
Tracy was now a caregiver to Savannah, who continued to have hundreds of seizures a month, as well as a full-time student, studying late into the night and while her kids were at school, using classwork as “an outlet for the pain.”
“I couldn’t help my daughter,” Tracy said. “Studying was something I could do.”
Twelve years later, Tracy had earned a PhD in neurobiology.
After her post-doctoral training, Tracy started working at a lab that explored the genetics of epilepsy. Savannah’s doctors hadn’t found a genetic cause for her seizures, so Tracy decided to sequence her genome again to check for other abnormalities—and what she found was life-changing.
Tracy discovered that Savannah had a calcium channel mutation, meaning that too much calcium was passing through Savannah’s neural pathways, leading to seizures. The information made sense to Tracy: Anti-seizure medications often leech calcium from a person’s bones. When doctors had prescribed Savannah calcium supplements in the past to counteract these effects, her seizures had gotten worse every time she took the medication. Tracy took her discovery to Savannah’s doctor, who agreed to prescribe her a calcium blocker.
The change in Savannah was almost immediate.
Within two weeks, Savannah’s seizures had decreased by 95 percent. Once on a daily seven-drug regimen, she was soon weaned to just four, and then three. Amazingly, Tracy started to notice changes in Savannah’s personality and development, too.
“She just exploded in her personality and her talking and her walking and her potty training and oh my gosh she is just so sassy,” Tracy said in an interview.
Since starting the calcium blocker eleven years ago, Savannah has continued to make enormous strides. Though still unable to read or write, Savannah enjoys puzzles and social media. She’s “obsessed” with boys, says Tracy. And while Tracy suspects she’ll never be able to live independently, she and her daughter can now share more “normal” moments—something she never anticipated at the start of Savannah’s journey with LGS. While preparing for an event, Savannah helped Tracy get ready.
“We picked out a dress and it was the first time in our lives that we did something normal as a mother and a daughter,” she said. “It was pretty cool.”
A sleek, four-foot tall white robot glides across a cafe storefront in Tokyo’s Nihonbashi district, holding a two-tiered serving tray full of tea sandwiches and pastries. The cafe’s patrons smile and say thanks as they take the tray—but it’s not the robot they’re thanking. Instead, the patrons are talking to the person controlling the robot—a restaurant employee who operates the avatar from the comfort of their home.
It’s a typical scene at DAWN, short for Diverse Avatar Working Network—a cafe that launched in Tokyo six years ago as an experimental pop-up and quickly became an overnight success. Today, the cafe is a permanent fixture in Nihonbashi, staffing roughly 60 remote workers who control the robots remotely and communicate to customers via a built-in microphone.
More than just a creative idea, however, DAWN is being hailed as a life-changing opportunity. The workers who control the robots remotely (known as “pilots”) all have disabilities that limit their ability to move around freely and travel outside their homes. Worldwide, an estimated 16 percent of the global population lives with a significant disability—and according to the World Health Organization, these disabilities give rise to other problems, such as exclusion from education, unemployment, and poverty.
These are all problems that Kentaro Yoshifuji, founder and CEO of Ory Laboratory, which supplies the robot servers at DAWN, is looking to correct. Yoshifuji, who was bedridden for several years in high school due to an undisclosed health problem, launched the company to help enable people who are house-bound or bedridden to more fully participate in society, as well as end the loneliness, isolation, and feelings of worthlessness that can sometimes go hand-in-hand with being disabled.
“It’s heartbreaking to think that [people with disabilities] feel they are a burden to society, or that they fear their families suffer by caring for them,” said Yoshifuji in an interview in 2020. “We are dedicating ourselves to providing workable, technology-based solutions. That is our purpose.”
Shota Kuwahara, a DAWN employee with muscular dystrophy. Ory Labs, Inc.
Wanting to connect with others and feel useful is a common sentiment that’s shared by the workers at DAWN. Marianne, a mother of two who lives near Mt. Fuji, Japan, is functionally disabled due to chronic pain and fatigue. Working at DAWN has allowed Marianne to provide for her family as well as help alleviate her loneliness and grief.Shota, Kuwahara, a DAWN employee with muscular dystrophy, agrees. "There are many difficulties in my daily life, but I believe my life has a purpose and is not being wasted," he says. "Being useful, able to help other people, even feeling needed by others, is so motivational."