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.
If you look back on the last century of scientific achievements, you might notice that most of the scientists we celebrate are overwhelmingly white, while scientists of color take a backseat. Since the Nobel Prize was introduced in 1901, for example, no black scientists have landed this prestigious award.
The work of black women scientists has gone unrecognized in particular. Their work uncredited and often stolen, black women have nevertheless contributed to some of the most important advancements of the last 100 years, from the polio vaccine to GPS.
Here are five black women who have changed science forever.
Dr. May Edward Chinn
Dr. May Edward Chinn practicing medicine in Harlem
George B. Davis, PhD.
Chinn was born to poor parents in New York City just before the start of the 20th century. Although she showed great promise as a pianist, playing with the legendary musician Paul Robeson throughout the 1920s, she decided to study medicine instead. Chinn, like other black doctors of the time, were barred from studying or practicing in New York hospitals. So Chinn formed a private practice and made house calls, sometimes operating in patients’ living rooms, using an ironing board as a makeshift operating table.
Chinn worked among the city’s poor, and in doing this, started to notice her patients had late-stage cancers that often had gone undetected or untreated for years. To learn more about cancer and its prevention, Chinn begged information off white doctors who were willing to share with her, and even accompanied her patients to other clinic appointments in the city, claiming to be the family physician. Chinn took this information and integrated it into her own practice, creating guidelines for early cancer detection that were revolutionary at the time—for instance, checking patient health histories, checking family histories, performing routine pap smears, and screening patients for cancer even before they showed symptoms. For years, Chinn was the only black female doctor working in Harlem, and she continued to work closely with the poor and advocate for early cancer screenings until she retired at age 81.
Alice Ball
Pictorial Press Ltd/Alamy
Alice Ball was a chemist best known for her groundbreaking work on the development of the “Ball Method,” the first successful treatment for those suffering from leprosy during the early 20th century.
In 1916, while she was an undergraduate student at the University of Hawaii, Ball studied the effects of Chaulmoogra oil in treating leprosy. This oil was a well-established therapy in Asian countries, but it had such a foul taste and led to such unpleasant side effects that many patients refused to take it.
So Ball developed a method to isolate and extract the active compounds from Chaulmoogra oil to create an injectable medicine. This marked a significant breakthrough in leprosy treatment and became the standard of care for several decades afterward.
Unfortunately, Ball died before she could publish her results, and credit for this discovery was given to another scientist. One of her colleagues, however, was able to properly credit her in a publication in 1922.
Henrietta Lacks
onathan Newton/The Washington Post/Getty
The person who arguably contributed the most to scientific research in the last century, surprisingly, wasn’t even a scientist. Henrietta Lacks was a tobacco farmer and mother of five children who lived in Maryland during the 1940s. In 1951, Lacks visited Johns Hopkins Hospital where doctors found a cancerous tumor on her cervix. Before treating the tumor, the doctor who examined Lacks clipped two small samples of tissue from Lacks’ cervix without her knowledge or consent—something unthinkable today thanks to informed consent practices, but commonplace back then.
As Lacks underwent treatment for her cancer, her tissue samples made their way to the desk of George Otto Gey, a cancer researcher at Johns Hopkins. He noticed that unlike the other cell cultures that came into his lab, Lacks’ cells grew and multiplied instead of dying out. Lacks’ cells were “immortal,” meaning that because of a genetic defect, they were able to reproduce indefinitely as long as certain conditions were kept stable inside the lab.
Gey started shipping Lacks’ cells to other researchers across the globe, and scientists were thrilled to have an unlimited amount of sturdy human cells with which to experiment. Long after Lacks died of cervical cancer in 1951, her cells continued to multiply and scientists continued to use them to develop cancer treatments, to learn more about HIV/AIDS, to pioneer fertility treatments like in vitro fertilization, and to develop the polio vaccine. To this day, Lacks’ cells have saved an estimated 10 million lives, and her family is beginning to get the compensation and recognition that Henrietta deserved.
Dr. Gladys West
Andre West
Gladys West was a mathematician who helped invent something nearly everyone uses today. West started her career in the 1950s at the Naval Surface Warfare Center Dahlgren Division in Virginia, and took data from satellites to create a mathematical model of the Earth’s shape and gravitational field. This important work would lay the groundwork for the technology that would later become the Global Positioning System, or GPS. West’s work was not widely recognized until she was honored by the US Air Force in 2018.
Dr. Kizzmekia "Kizzy" Corbett
TIME Magazine
At just 35 years old, immunologist Kizzmekia “Kizzy” Corbett has already made history. A viral immunologist by training, Corbett studied coronaviruses at the National Institutes of Health (NIH) and researched possible vaccines for coronaviruses such as SARS (Severe Acute Respiratory Syndrome) and MERS (Middle East Respiratory Syndrome).
At the start of the COVID pandemic, Corbett and her team at the NIH partnered with pharmaceutical giant Moderna to develop an mRNA-based vaccine against the virus. Corbett’s previous work with mRNA and coronaviruses was vital in developing the vaccine, which became one of the first to be authorized for emergency use in the United States. The vaccine, along with others, is responsible for saving an estimated 14 million lives.On today’s episode of Making Sense of Science, I’m honored to be joined by Dr. Paul Song, a physician, oncologist, progressive activist and biotech chief medical officer. Through his company, NKGen Biotech, Dr. Song is leveraging the power of patients’ own immune systems by supercharging the body’s natural killer cells to make new treatments for Alzheimer’s and cancer.
Whereas other treatments for Alzheimer’s focus directly on reducing the build-up of proteins in the brain such as amyloid and tau in patients will mild cognitive impairment, NKGen is seeking to help patients that much of the rest of the medical community has written off as hopeless cases, those with late stage Alzheimer’s. And in small studies, NKGen has shown remarkable results, even improvement in the symptoms of people with these very progressed forms of Alzheimer’s, above and beyond slowing down the disease.
In the realm of cancer, Dr. Song is similarly setting his sights on another group of patients for whom treatment options are few and far between: people with solid tumors. Whereas some gradual progress has been made in treating blood cancers such as certain leukemias in past few decades, solid tumors have been even more of a challenge. But Dr. Song’s approach of using natural killer cells to treat solid tumors is promising. You may have heard of CAR-T, which uses genetic engineering to introduce cells into the body that have a particular function to help treat a disease. NKGen focuses on other means to enhance the 40 plus receptors of natural killer cells, making them more receptive and sensitive to picking out cancer cells.
Paul Y. Song, MD is currently CEO and Vice Chairman of NKGen Biotech. Dr. Song’s last clinical role was Asst. Professor at the Samuel Oschin Cancer Center at Cedars Sinai Medical Center.
Dr. Song served as the very first visiting fellow on healthcare policy in the California Department of Insurance in 2013. He is currently on the advisory board of the Pritzker School of Molecular Engineering at the University of Chicago and a board member of Mercy Corps, The Center for Health and Democracy, and Gideon’s Promise.
Dr. Song graduated with honors from the University of Chicago and received his MD from George Washington University. He completed his residency in radiation oncology at the University of Chicago where he served as Chief Resident and did a brachytherapy fellowship at the Institute Gustave Roussy in Villejuif, France. He was also awarded an ASTRO research fellowship in 1995 for his research in radiation inducible gene therapy.
With Dr. Song’s leadership, NKGen Biotech’s work on natural killer cells represents cutting-edge science leading to key findings and important pieces of the puzzle for treating two of humanity’s most intractable diseases.
Show links
- Paul Song LinkedIn
- NKGen Biotech on Twitter - @NKGenBiotech
- NKGen Website: https://nkgenbiotech.com/
- NKGen appoints Paul Song
- Patient Story: https://pix11.com/news/local-news/long-island/promising-new-treatment-for-advanced-alzheimers-patients/
- FDA Clearance: https://nkgenbiotech.com/nkgen-biotech-receives-ind-clearance-from-fda-for-snk02-allogeneic-natural-killer-cell-therapy-for-solid-tumors/Q3 earnings data: https://www.nasdaq.com/press-release/nkgen-biotech-inc.-reports-third-quarter-2023-financial-results-and-business