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.
For this podcast episode, my guest is Raina Plowright, one of the world’s leading researchers when it comes to how and why viruses sometimes jump from bats to humans. The intuition may be that bats are the bad guys in this situation, but the real culprits are more likely humans and ways that we intrude on nature.
Plowright is a Cornell Atkinson Scholar and professor at Cornell in the Department of Public and Ecosystem Health in the College of Veterinary Medicine. Read her full bio here. For a shorter (and lightly edited) version of this conversation, you can check out my Q&A interview with Plowright in the single-issue magazine, One Health / One Planet, published earlier this month by Leaps.org in collaboration with the Aspen Institute and the Science Philanthropy Alliance.
In the episode, Plowright tells me about her global research team that is busy studying the complex chain of events in between viruses originating in bats and humans getting infected with those viruses. She’s collecting samples from bats in Asia, Africa and Australia, which sounds challenging enough, but now consider the diligence required to parse out 1400 different bat species.
We also discuss a high-profile paper that she co-authored last month arguing for greater investment in preventing pandemics in the first place instead of the current approach, which basically puts all of our eggs in the basket of trying to respond to these outbreaks after the fact. Investing in pandemic prevention is a small price to pay compared with millions of people killed and trillions of dollars spent during the response to COVID-19.
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Raina Plowright, a disease ecologist at Cornell University, is taking blood and urine samples from hundreds of animals and using GPS tags to follow their movement.
Kelly Gorham
Starting this summer, the public buses in the Oberhaching suburb of Munich, Germany, won’t have to be plugged in to charge overnight anymore. Stefan Schelle, the mayor of Oberhaching, is taking advantage of the fact that an innovative startup has its offices in his community: Magment, short for “magnetizing cement,” will install its underground charging pad in the coming months. As soon as that happens, the buses will charge while they wait at the city’s main station or while stored at their overnight quarters.
In his light-filled office, Magment’s co-founder and CEO, Mauricio Esguerra, demonstrates how the new technology works: The lights on his black model car only flash when he puts the miniature Porsche directly atop the induction plate. “This works just like when you charge your iPhone on its charging pad or heat a pot on an induction range. People don’t have to be afraid of magnetic fields or anything like that,” says the 60-year-old Colombia-born entrepreneur. “The induction only gets activated when the storage battery is placed directly on top.
Patented by Esguerra, the “magnetizing concrete” is able to target the charge quite precisely. The batteries will be mounted in a box underneath the vehicles such as the retrofitted public buses. “Look, here’s one passing by,” says Esguerra, pointing out the window as a blue city bus rides past his office.
An invention finds its purpose
Esguerra grew up in Bogotá, studied physics at the Technical University Munich where he fell in love with a German woman, and started a family in her home country. For 15 years, he developed magnetic products, including the magnetizing cement, for Siemens, Europe’s largest industrial manufacturing company. The patent belonged to Siemens, of course. “But there were hardly any electric vehicles yet,” Esguerra says, “and Siemens didn’t quite know what to do with this invention.”
Esguerra changed companies a few times but, in 2015, he got an offer from Siemens. The patent for the magnetizing cement was expiring and Siemens wasn’t interested in keeping it. Would he, as the inventor, want it back? “I did not hesitate a second,” Esguerra remembers with a smile. “I’m a magnetician at heart.” That same year, he founded Magment to finally make use of the technology he created 20 years ago.
To demonstrate how his cement is made, he opens the lid of a plastic bucket filled with cement powder. Mixed in are fingernail-sized black pieces, so-called ferrites, mainly consisting of three ceramic oxides: iron, nickel and zinc. Conventionally, they are used in electronics such as cell phones, computers and cables. Molded in concrete, ferrites create a magnetic field that can transport charge to a vehicle, potentially eliminating range anxiety for EV drivers.
Molded in concrete, ferrites create a magnetic field that can transport charge to a vehicle, potentially eliminating range anxiety for EV drivers.
Magment
“Ferrites have extremely high rejection rates,” Esguerra adds. “It’s comparable to other ceramics: As soon as there is a small tear or crack, the material is rejected. We are talking about a rejection pile of 500,000 tons per year worldwide. There are mountains of unused materials.”
Exactly this fact was the starting point of his research at Siemens: “What can we do with this energy-intensive material? Back then, it was crushed up and mixed into the cement for building streets, without adding any function.” Today, too, the Magment material can simply be mixed with the conventional material and equipment of the cement industry. “We take advantage of the fact that we don’t have to build factories and don’t have high transportation costs."
In addition to saving resources, recycled ferrite also makes concrete more durable.
No plugs, no charging breaks
A young intern in the office next door winds cables around a new coil. These coils will later be lowered underground in a box, connected to the grid and encased in magnetizing concrete. The recipient box looks similar; it’s another coil but smaller, and it will be mounted underneath the carriage of the vehicle. For a car, the battery box would be 25 by 25 centimeters (about 10 inches), for a scooter five by five centimeters (about two inches).
Esguerra pushes an electric scooter into a cemented scooter rack next to his office. The charging pad is invisible. A faint beep is the only sign that it has started charging. “Childs play!” Esguerra says. “Even when someone puts in the scooter a little crooked, the charge still works. Our efficiency rate is up to 96 percent.” From this summer on, hotel chains in Munich will try out this system with their rental scooters, at a price of about 500 Euros per charging station.
Compared to plug-in charging, Magment’s benefits include smaller batteries that charge slower and, therefore, gentler, so they may last longer. Nobody needs to plug in the vehicles manually anymore. “Personally, I’ve had an EV for six years,” Esguerra says, “and how often does it happen that I forgot to plug it in overnight and then start out with a low charge in the morning? Once people get used to the invisible charging system, it will become the norm.“
There are also downsides: Most car companies aren’t ready for the new technology. Hyundai is the first carmaker that announced plans to equip some new models with inductive charging capability. “How many cars are electrified worldwide?” Esguerra asks and gives the answer himself: “One percent. And how many forklifts are electrified? More than 70 percent!” Therefore, Magment focuses on charging forklifts, e-scooters and buses.
Magment has focused most of its efforts on charging forklifts and other vehicle types that are entirely or predominantly electric, unlike cars.
Magment
On the morning of my visit to Esguerra’s office, a developer of the world’s third-biggest forklift manufacturer is there to inspect how the technology works on the ground. In the basement, a Magment engineer drives an electric forklift over a testbed with invisible charging coils, turning on the green charging light. Esguerra opens the interior of the forklift and points out the two batteries. “With our system, the forklift will only need one battery.” The savings, about 7,000 Euro per forklift, will pay for the installation of Magment’s charging system in warehouses, Esguerra calculates. “Less personnel and no unnecessary wait times for charging will lead to further savings,” he says.
To implement the new technology as efficiently as possible, Magment engineers began recording the transport routes of forklifts in warehouses. “It looks like spaghetti diagrams,” Esguerra explains. “Soon you get the areas where the forklifts pass or wait most frequently. This is where you install the chargers underground.” The forklifts will charge while in use, without having to pause for charging breaks. The method could also work for robots, for instance, in warehouses and distribution centers.
Roads of the future could be electric
Potential disadvantages might become apparent once the technology is more broadly in use. Therefore investors were initially reluctant, Esguerra admits. “Some are eager to be the first but most prefer to wait until the technology has been extensively used in real life.”
A clear hurdle today is that electrifying entire freeways with induction coils would cost at least 1 to 1.5 million Euros per kilometer. The German Department for Transportation even calculates overall costs of 14 to 47 million Euros per kilometer. So, the technology may only make sense for areas where vehicles pass or dwell the longest, like the Oberhaching train station or a busy interstate toll booth.
And yet, Magment is ramping up to compete with other companies that build larger inductive charging pads. The company just finished the first 20 meters of a testbed in Indiana, in partnership with the Purdue University and the Indiana Department of Transportation. Magment is poised to build “the world’s first contactless wireless-charging concrete pavement highway segment,” Purdue University announced.
The project, part of Purdue’s ASPIRE (Advancing Sustainability through Powered Infrastructure for Roadway Electrification) program, is financed by the National Science Foundation. “Indiana is known as the Crossroads of America, and we’re committed to fortifying our position as a transportation leader by innovating to support the emerging vehicle technology,” Governor Eric J. Holcomb said. If testing is successful, including the concrete’s capacity to charge heavy trucks operating at higher power (200 kilowatts and above), Indiana plans to identify a highway segment to install Magment’s charging pads. The earliest would be 2023 at best.
In the meantime, buses in the Californian Antelope Valley, trams at Hollywood's Universal Studios and transit buses in Tampa, Florida, are already charging with inductive technology developed by Wave, a company spun out of Utah State University. In Michigan, Governor Gretchen Whitmer announced plans to build a test route for vehicles to charge while driving, in collaboration with the Israel-based company Electreon, and this year contracted to build the first road-based charging system in the U.S. The state is providing support through an innovative grant program.
Costs remain one of the biggest obstacles, but Esguerra’s vision includes the potential that toll roads could charge a premium for inductive charging capabilities. “And in reverse, a driver who has too much energy could feed his surplus into the grid while driving,” Esguerra dreams.
Meanwhile, Wave’s upcoming big projects are moving trucks along a route in Southern California and running a UPS route between Seattle and Portland. Wave CTO Michael Masquelier describes the inductive power transfer his company champions as “similar to a tuning fork. By vibrating that fork, you sent energy through the air and it is received by another tuning fork across the room. So it’s similar to that, but it’s magnetic energy versus sound energy.”
He hopes to partner with Magment, saying that “the magnetizing cement makes installation easier and improves the energy efficiency.” More research is needed to evaluate which company’s technology will prove to be the most efficient, practical, and cost-effective.
Esguerra’s vision includes the potential that toll roads could charge a premium for inductive charging capabilities. “And in reverse, a driver who has too much energy could feed his surplus into the grid while driving,” Esguerra dreams.
The future will soon arrive in the idyllic town of Bad Staffelstein, a quaint tourist destination in the Upper Franconia region of Germany. Visitors will be taken to and from the main station and the popular thermal bath by driverless shuttles. Together with the University of Wuppertal, the regional government of Upper Franconia wants to turn its district into “the center of autonomous driving.” Magment is about to install inductive charging pads at the shuttle stations and the thermal bath, eliminating the need for the shuttles to stop for charging times. No more drivers, no cable, no range anxiety. Masquelier believes that “wireless and autonomous driving go hand in hand.” Science fiction? It will become science reality in spring 2023.
CORRECTION: An earlier version of the story erroneously mentioned that Electreon required overhead cables.