By Mary May
Many people regard participating in clinical trials as an altruistic act that could help save lives. Most people, however, are unaware of who actually participates in the earliest stage of trials performed in humans. The healthy people who participate in Phase I clinical trials for the majority of drugs in the United States are most likely low income, Black or Hispanic, and participating because of the money that is commonly paid for the most dangerous part of the clinical trial process. These groups are especially vulnerable to exploitation and policies that are designed to explicitly protect them are worth considering.
How do Phase I clinical trials work?
Clinical trials in the United States are made up of three phases (Figure 1). In Phase I, a new drug is tested in healthy volunteers to ensure it is not toxic in people. In Phase II, which occurs if the drug is deemed acceptably safe in Phase I, the drug is tested in a population of patients (anywhere from a few dozen to ~300 people) and the goal is to find out whether a drug is effective
. Finally, in Phase III, the drug is tested in a larger cohort of patients and is compared to the current standard of care to further characterize its effectiveness and safety.
Phase I trials are the riskiest because the safety of an experimental drug in humans is unknown. With the exception of trials on vaccines or in trials to treat terminally ill patients, participants do not expect to gain health benefits from exposure as they are healthy volunteers, increasing their risk to reward ratio. In many ways, the trials are designed to “produce harm in healthy volunteers” to determine how safe a drug is, according to sociologist Jill Fisher in Adverse Events.
The doctors leading Phase I trials are trying to understand what possible side effects a drug will have at a range of doses that patients could conceivably receive to understand how safe it is (Figure 2). Mild effects (headaches, diarrhea, nausea, etc.) are common and affect ~2/3 of people participating. Very rare and serious events, including hospitalization and death, effect only a small number of participants and doctors use animal studies to estimate safe and effective dosages. These serious events can be caused by the experimental drug itself or invasive procedures performed in the trial such as spinal taps or surgery.
Who participates in early clinical trials?
Up until the 1970s, up to 90% of drug trials were performed on prisoners. Today, government regulations more strictly dictate who can and cannot participate in trials. Volunteers are screened using basic criteria such as healthy weight, normal liver function, normal blood work, and the absence of infections like Hepatitis and HIV.
Representation of the population who will eventually take an experimental drug if approved is necessary for evaluating a drug’s side effects, safety, and efficacy. In Phase III clinical trials, in which volunteers might benefit medically
, minorities are underrepresented. This has led to serious issues in addressing health disparities and equality in medicine.
At the same time, in Phase I trials, in which little therapeutic benefit is expected, minorities, especially Black men, are overrepresented. Fisher estimates from her sample in Adverse Events that Black people make up 35% of Phase I participants in the US (Black people make up ~13% of the US population). Regional differences in Phase I trials are even starker: in a sampling of trial centers Black volunteers made up 70% of participants on the East Coast in the US and Hispanic volunteers made up 55% of participants in the Southwest US according to Adverse Events. Phase I trials also draw low-income individuals: in one study, 47% of participants reported yearly incomes of below $25,000 and a third did not have health insurance. In another random sample of healthy volunteers in Phase I trials, 86% of participants reported making less than $50,000 a year and 46% reported earning less than $25,000.
According to Fisher, Phase I clinical trials can pay volunteers well, especially for more invasive studies, with compensation ranging from $25 to over $10,000 for longer term studies. For people struggling to make enough money to live, becoming self-proclaimed professional “guinea pigs” can be a way to make ends meet. Many of the best paying trials involve staying in facilities for weeks to months at a time with limited ability to leave to visit family or friends and making it nearly impossible to work a job. Because of this, they disproportionately draw from those who are unemployed or who can’t get regular work because they were in jail or for other reasons.
Fisher notes that the people most likely to become serial participants in Phase I trials were Black men, followed by Hispanic men. All of the volunteers who had participated in more than 50 trials (in total six) were Black men and more than a third of the Black volunteers she interviewed had participated in more than 10 trials.
Other vulnerable groups are targeted for Phase I trials. Recruiters have a history of visiting homeless shelters seeking out people who have few other options for income. Until at least the 1990s, Eli Lilly actively recruited homeless alcoholics to participate in Phase I trials, offering them some of the lowest rates among pharmaceutical companies. In 2005 in Miami, Florida, almost all of the residents of the largest for-profit drug testing center in the US, operated by SFBC International, were poor immigrants from Latin America. Mentally ill people experiencing homelessness are also recruited for studies on experimental antipsychotics, which are deemed too dangerous to first test in healthy volunteers.
Safeguarding the health and dignity of phase I clinical trial participants
The ethics of financial incentives for participating in Phase I trials are complicated. Payment for volunteers is provided to compensate them for their time and incentivize participation but not to induce volunteers to take on any excessive risks. To avoid “undue influence,” IRBs often request payment to be minimal although FDA guidelines are vague. This makes participating unattractive for high income individuals who may be forfeiting higher pay at their job if they volunteer. In Fisher’s book, 90% of volunteers said that money was a main motivator for participating in trials, meaning even the minimal payment approved by IRBs is drawing volunteers who need it.
Fisher’s Adverse Events describes participants that view their work as both “liberating and shameful” and Roberto Abadie’s The Professional Guinea Pig quotes participants feeling “like a guinea pig more than a worker”. Professional “guinea pigs” in fact coined the term “mild torture economy” to describe their work, suggesting that the mild adverse events and requirements of Phase I trials are perhaps not so trivial. Giving these participants status as workers may help ease stigma associated with being a “guinea pig”. It would also help them advocate for better conditions at trial sites, higher payment and treatment for any trial-related injuries, something that is not required in the US at this time. In many ways, volunteers can be viewed similarly to contract workers in the so-called “gig economy” and would benefit from many of the same policy changes. Worker status, a minimum wage and benefits such as health insurance would help ensure that the people who help develop drugs can eventually benefit from them once approved.
Increasing the transparency of the clinical trial process at all points and collecting information about who enrolls would allow greater public scrutiny. Creating a registry to track who participates and studying the long-term effects of participating in many trials over multiple years would help researchers track whether participants are being harmed or exploited. The information we do have should make us confront whether we are comfortable using vulnerable people to benefit pharmaceutical companies and society as a whole.
Mary May is a sixth year PhD student in the Chemical Biology program at Harvard University.
- Read about the WHO’s recommendations on clinical trial registration here.
- This ProPublica tool lets you look up data about what payments doctors in your area might be receiving from pharmaceutical companies.
- Check out AllTrials to learn about a campaign to require (and enforce) prospective registration of all clinical trials and prompt publication of results to reduce biased data and increase transparency.
- Read about how race and participation in clinical trials for COVID19 are stoking concerns about vaccine safety as well as vulnerable populations’ access to a vaccine once developed.
This article is part of our special edition on science policy and social justice.