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.
New implants let paraplegics surf the web and play computer games
When I greeted Rodney Gorham, age 63, in an online chat session, he replied within seconds: “My pleasure.”
“Are you moving parts of your body as you type?” I asked.
This time, his response came about five minutes later: “I position the cursor with the eye tracking and select the same with moving my ankles.” Gorham, a former sales representative from Melbourne, Australia, living with amyotrophic lateral sclerosis, or ALS, a rare form of Lou Gehrig’s disease that impairs the brain’s nerve cells and the spinal cord, limiting the ability to move. ALS essentially “locks” a person inside their own body. Gorham is conversing with me by typing with his mind only–no fingers in between his brain and his computer.
The brain-computer interface enabling this feat is called the Stentrode. It's the brainchild of Synchron, a company backed by Amazon’s Jeff Bezos and Microsoft cofounder Bill Gates. After Gorham’s neurologist recommended that he try it, he became one of the first volunteers to have an 8mm stent, laced with small electrodes, implanted into his jugular vein and guided by a surgeon into a blood vessel near the part of his brain that controls movement.
After arriving at their destination, these tiny sensors can detect neural activity. They relay these messages through a small receiver implanted under the skin to a computer, which then translates the information into words. This minimally invasive surgery takes a day and is painless, according to Gorham. Recovery time is typically short, about two days.
When a paralyzed patient thinks about trying to move their arms or legs, the motor cortex will fire patterns that are specific to the patient’s thoughts.
When a paralyzed patient such as Gorham thinks about trying to move their arms or legs, the motor cortex will fire patterns that are specific to the patient’s thoughts. This pattern is detected by the Stentrode and relayed to a computer that learns to associate this pattern with the patient’s physical movements. The computer recognizes thoughts about kicking, making a fist and other movements as signals for clicking a mouse or pushing certain letters on a keyboard. An additional eye-tracking device controls the movement of the computer cursor.
The process works on a letter by letter basis. That’s why longer and more nuanced responses often involve some trial and error. “I have been using this for about two years, and I enjoy the sessions,” Gorham typed during our chat session. Zafar Faraz, field clinical engineer at Synchron, sat next to Gorham, providing help when required. Gorham had suffered without internet access, but now he looks forward to surfing the web and playing video games.
Gorham, age 63, has been enjoying Stentrode sessions for about two years.
Rodeny Dekker
The BCI revolution
In the summer of 2021, Synchron became the first company to receive the FDA’s Investigational Device Exemption, which allows research trials on the Stentrode in human patients. This past summer, the company, together with scientists from Icahn School of Medicine at Mount Sinai and the Neurology and Neurosurgery Department at Utrecht University, published a paper offering a framework for how to develop BCIs for patients with severe paralysis – those who can't use their upper limbs to type or use digital devices.
Three months ago, Synchron announced the enrollment of six patients in a study called COMMAND based in the U.S. The company will seek approval next year from the FDA to make the Stentrode available for sale commercially. Meanwhile, other companies are making progress in the field of BCIs. In August, Neuralink announced a $280 million financing round, the biggest fundraiser yet in the field. Last December, Synchron announced a $75 million financing round. “One thing I can promise you, in five years from now, we’re not going to be where we are today. We're going to be in a very different place,” says Elad I. Levy, professor of neurosurgery and radiology at State University of New York in Buffalo.
The risk of hacking exists, always. Cybercriminals, for example, might steal sensitive personal data for financial reasons, blackmailing, or to spread malware to other connected devices while extremist groups could potentially hack BCIs to manipulate individuals into supporting their causes or carrying out actions on their behalf.
“The prospect of bestowing individuals with paralysis a renewed avenue for communication and motor functionality is a step forward in neurotech,” says Hayley Nelson, a neuroscientist and founder of The Academy of Cognitive and Behavioral Neuroscience. “It is an exciting breakthrough in a world of devastating, scary diseases,” says Neil McArthur, a professor of philosophy and director of the Centre for Professional and Applied Ethics at the University of Manitoba. “To connect with the world when you are trapped inside your body is incredible.”
While the benefits for the paraplegic community are promising, the Stentrode’s long-term effectiveness and overall impact needs more research on safety. “Potential risks like inflammation, damage to neural tissue, or unexpected shifts in synaptic transmission due to the implant warrant thorough exploration,” Nelson says.
There are also concens about data privacy concerns and the policies of companies to safeguard information processed through BCIs. “Often, Big Tech is ahead of the regulators because the latter didn’t envisage such a turn of events...and companies take advantage of the lack of legal framework to push forward,” McArthur says. Hacking is another risk. Cybercriminals could steal sensitive personal data for financial reasons, blackmailing, or to spread malware to other connected devices. Extremist groups could potentially hack BCIs to manipulate individuals into supporting their causes or carrying out actions on their behalf.
“We have to protect patient identity, patient safety and patient integrity,” Levy says. “In the same way that we protect our phones or computers from hackers, we have to stay ahead with anti-hacking software.” Even so, Levy thinks the anticipated benefits for the quadriplegic community outweigh the potential risks. “We are on the precipice of an amazing technology. In the future, we would be able to connect patients to peripheral devices that enhance their quality of life.”
In the near future, the Stentrode could enable patients to use the Stentrode to activate their wheelchairs, iPods or voice modulators. Synchron's focus is on using its BCI to help patients with significant mobility restrictions—not to enhance the lives of healthy people without any illnesses. Levy says we are not prepared for the implications of endowing people with superpowers.
I wondered what Gorham thought about that. “Pardon my question, but do you feel like you have sort of transcended human nature, being the first in a big line of cybernetic people doing marvelous things with their mind only?” was my last question to Gorham.
A slight smile formed on his lips. In less than a minute, he typed: “I do a little.”
Leading XPRIZE Healthspan and Beating Negativity with Dr. Peter Diamandis
A new competition by the XPRIZE Foundation is offering $101 million to researchers who discover therapies that give a boost to people aged 65-80 so their bodies perform more like when they were middle-aged.
For today’s podcast episode, I talked with Dr. Peter Diamandis, XPRIZE’s founder and executive chairman. Under Peter’s leadership, XPRIZE has launched 27 previous competitions with over $300 million in prize purses. The latest contest aims to enhance healthspan, or the period of life when older people can play with their grandkids without any restriction, disability or disease. Such breakthroughs could help prevent chronic diseases that are closely linked to aging. These illnesses are costly to manage and threaten to overwhelm the healthcare system, as the number of Americans over age 65 is rising fast.
In this competition, called XPRIZE Healthspan, multiple awards are available, depending on what’s achieved, with support from the nonprofit Hevolution Foundation and Chip Wilson, the founder of Lululemon and nonprofit SOLVE FSHD. The biggest prize, $81 million, is for improvements in cognition, muscle and immunity by 20 years. An improvement of 15 years will net $71 million, and 10 years will net $61 million.
In our conversation for this episode, Peter talks about his plans for XPRIZE Healthspan and why exponential technologies make the current era - even with all of its challenges - the most exciting time in human history. We discuss the best mental outlook that supports a person in becoming truly innovative, as well as the downsides of too much risk aversion. We talk about how to overcome the negativity bias in ourselves and in mainstream media, how Peter has shifted his own mindset to become more positive over the years, how to inspire a culture of innovation, Peter’s personal recommendations for lifestyle strategies to live longer and healthier, the innovations we can expect in various fields by 2030, the future of education and the importance of democratizing tech and innovation.
In addition to Peter’s pioneering leadership of XPRIZE, he is also the Executive Founder of Singularity University. In 2014, he was named by Fortune as one of the “World’s 50 Greatest Leaders.” As an entrepreneur, he’s started over 25 companies in the areas of health-tech, space, venture capital and education. He’s Co-founder and Vice-Chairman of two public companies, Celularity and Vaxxinity, plus being Co-founder & Chairman of Fountain Life, a fully-integrated platform delivering predictive, preventative, personalized and data-driven health. He also serves as Co-founder of BOLD Capital Partners, a venture fund with a half-billion dollars under management being invested in exponential technologies and longevity companies. Peter is a New York Times Bestselling author of four books, noted during our conversation and in the show notes of this episode. He has degrees in molecular genetics and aerospace engineering from MIT and holds an M.D. from Harvard Medical School.
Show links
- Peter Diamandis bio
- New XPRIZE Healthspan
- Peter Diamandis books
- 27 XPRIZE competitions and counting
- Life Force by Peter Diamandis and Tony Robbins
- Peter Diamandis Twitter
- Longevity Insider newsletter – AI identifies the news
- Peter Diamandis Longevity Handbook
- Hevolution funding for longevity
XPRIZE Founder Peter Diamandis speaks with Mehmoud Khan, CEO of Hevolution Foundation, at the launch of XPRIZE Healthspan.
Hevolution Foundation