Guinea Pig Nation
Why do some people repeatedly volunteer to suffer for science? (Hint: It's not just the money.) But their makeup may be unique, rendering them dubious stand-ins for the rest of us.
By Joann Ellison Rodgers published January 1, 2009 - last reviewed on June 9, 2016
One of a growing, if unknown, number of normal, healthy research volunteers, Marc had offered up his body, brain, and bloodstream to science—for a fee. He was rewarded with an array of experimental assaults: nasal flushes for bacteria and viruses, blood draws, injections with weakened or modified versions (or pieces) of organisms responsible for tularemia, hepatitis, canary pox, and AIDS. In a study of malaria, he contracted the disease, requiring a course of quinolone therapy.
The cadre of healthy volunteers, many of whom sign on for multiple medical and psychological experiments, often simultaneously, are responding to a legitimate social need. They are among the estimated 20 million Americans recruited into clinical trials annually by universities, medical centers, drug and biotech companies, and a host of clinical-research organizing companies that receive some $10 billion a year from pharmaceutical and medical device companies to conduct trials.
The contributions of normal healthy research volunteers, or NHRVs, are vital to the advancement of medical and psychological knowledge, and many treatments would not exist without them. The National Institutes of Health alone enrolls 3,500 to 5,500 of them each year for phase-1 trials that determine drug safety and absorption, or for "challenge" studies that temporarily create or mimic asthma, infections, allergic reactions, addictive behaviors, hallucinations, or pain in order to then attempt to treat them. Scores of thousands more volunteers, mostly college students, spend weeks in confinement to test diets or the effects of sleep deprivation—or of isolation itself.
Many come back repeatedly. One study of 440 NHRVs found that 44 percent of them had enrolled in two to five studies per year. Among another group of NHRVs, 14 percent had enrolled in at least 18 studies over the prior three-year period.
The bad old days of tricking or blatantly coercing prisoners and the illiterate into studies are over. Nonetheless, a few highly publicized deaths among NHRVs, sometimes for no clear reason, have amplified a chorus of concern among ethicists, psychologists, and medical professionals about what motivates this group of "repeat professional volunteers" for whom participation in research is close to a way of life and, for some, a living. Notably, there is no potential medical payoff for these healthy volunteers, unlike for participants in the estimated 80,000 U.S. clinical trials each year who are selected because they have specific illnesses or disease risk factors.
Are they subtly coerced by financial incentives? Paying volunteers to play with their health is nothing new; U.S. Army surgeon Walter Reed gave his 19th century volunteers $100 in gold to contract yellow fever. Yet the law puts no limit on how much privately funded researchers can pay study recruits, and some studies offer enrollees thousands of dollars. For federally funded research, the National Institutes of Health has only vague guidelines that the amount of money not be an "undue inducement."
Are they thrill seekers, or somehow "addicted" to being "used"? Are they hypochondriacs reveling in the extensive checkups that accompany such studies? In the absence of clear national standards and channels of oversight, experts say, who knows whether the volunteers are really as healthy—psychologically or physically—as they tell the experimenters they are.
Ask the volunteers themselves why they do it and the answers are almost always some combination of altruism, curiosity, excitement, and self or family interest. "It's my way of giving my body to science," says Bob Peer, a 70-year-old retired Michigan real estate appraiser, who estimates he's been in more than 100 sociological, psychological, and medical studies since 1985. "There isn't a square inch of my fanny that has its original skin," which he let doctors razor off for 40 dermatologic tests of sunscreens at $65 per half inch, leaving raw wounds that felt like "burns." Bird-flu vaccine tests? "Sure, and I didn't grow any feathers," he chirps, having enjoyed that trial a lot more than the nine years he volunteered to pose as a patient for medical students learning to do prostate exams. Peer counts MRIs, X-rays, PET scans, lung studies, and treadmill tests as "no big deal."
But the response among the "repeaters" seems also to reflect big-business marketing, a sense of indebtedness to investigators they've come to know and like, and financial rewards as high as $10,000 that may skew decision making and cloud motivation, although most payments hover at a few hundred dollars. Given the various inducements involved, and the squeamishness non-volunteers can feel about submitting their bodies to science, it's legitimate to ask why volunteers do it, says Suzanne Bartholomae, an Ohio State University scientist. She questions whether all of the individuals are "normal," "healthy," or even really "volunteers."
Questions surrounding the motivations and personalities of the repeat volunteers are not just academic. The answers could alter the validity and reliability of thousands of studies, past and future. There are, for example, the four studies, soon to be a fifth, in which Della Malone is now enrolled. The 74-year-old Baltimore administrative assistant has undergone brain scans for a study of Parkinson's and CT scans for a study of lung function, swallowed concentrated broccoli with mango juice for months in a study of cancer prevention, and is planning to take selenium in a study of aging and dementia.
Psychologist Carl Tishler, a colleague of Bartholomae's at Ohio State, has found that personality characteristics of veteran NHRVs do differ from those of non-volunteers. And that may alter their response to medication, to give but one example. "Differences in personalities and psychologies have been shown to affect metabolic and immune responses, which can throw real doubt on the outcomes of clinical trials that use these volunteers," Tishler says. He contends that experimenters need to do more to understand how such differences influence brain, mind, and body reactions in drug tests or psychological research.
So little research has been conducted specifically about NHRV physiology, motivation, and personality variation that some psychologists openly suggest that the research industry and the volunteers may prefer to keep that Pandora's box closed. Nancy Kass, a bioethicist at Johns Hopkins, says she's unaware of any standard screening tool "that rules out psychopathology in 'normal' volunteers." Kass has the impression that "people have determined it's rare for someone with alarming pathology to volunteer and that it's a waste of resources to screen." It may, she notes, be "in the best interests of everyone involved to avoid the subject out of concern for eliminating volunteers even if a few are wacky."
How Normal Is "Normal"?
As far back as the late 1950s, studies have suggested that some substantial number of NHRVs have medical or psychological conditions or personality traits different from those in the general population. In a 2003 essay, Tishler and Bartholomae conclude—after reviewing the medical literature—that a substantial proportion of NHRVs "have been found to have a history of serious psychiatric illness or medical or neurological conditions, as well as characteristics, temperaments, or personality dimensions that differ from the norm of the population."
This is not to say NHRVs represent a population of Munchausen syndrome sufferers, who seek to become ill and gain sympathy and care. They may actually be more akin to bungee jumpers, or medical Evel Knievels, with temperaments that make them particularly tolerant of certain risks.
In the early 1990s, Spanish investigators assessed the relationship between personality factors and volunteering for phase-1 trials using the Sensation Seeking Scale and the Eysenck Personality Questionnaire, in 48 healthy male university student volunteers and 43 similar men who did not volunteer. "Significant differences" were found in thrill- , adventure-, and experience-seeking, boredom susceptibility, extroversion, and psychoticism, the researchers found. Overall, the personalities of volunteers were "characterized by a higher sensation-seeking trait and extroversion."
Similarly, a classic study of Army recruits decades ago found that volunteers who signed on for the most risky tasks were "significantly less anxious" than non-volunteers. And studies of prisoners, who once were allowed without limit to sign up for risky clinical trials, showed that volunteers also tended to be people who didn't see risk the way most of us do. In bioethicist Kass's study of 60 healthy volunteers, only 12 mentioned potential risks to health as a concern—and only when prompted.
There may be other significant psychological differences between NHRVs and non-volunteers besides their perception of risk and susceptibility to anxiety. Tishler and Bartholomae, among others, looked at personality characteristics of 28 male NHRVs participating in a phase-1 trial of three drugs. The drug trial required extended inpatient confinement. On the eleventh day of confinement Tishler and his team gave the volunteers questionnaires including the Minnesota Multiphasic Personality Inventory.
Among this group of very experienced subjects—who reported up to $80,000 in volunteer service income over their lifetimes—50 percent had "clinically significant elevations" on at least one of the MMPI personality scales. Findings ranged from some psychopathic deviation, to paranoia, to hysteria, to hypochondria, to depression. Tishler says, "The findings tell me that scientists might not really learn much [about the responses of the general population] if the only people signing up for a seclusion study are those whose psychological or physical makeup, temperaments, or brain chemistries are significantly different from the vast majority of those who eventually will take the drugs that were tested."
Why do such differences matter? Personality factors have deep biological roots in the brain. New Zealand investigators have shown that personality factors such as novelty-seeking, harm avoidance, and reward dependence are better than medical factors at predicting response to antidepressant drugs. Japanese scientists have found that the rate of drug absorption into the bloodstream is faster in highly neurotic volunteers than in less neurotic ones.
That those high in sensation-seeking—a personality type common to NHRVs—may respond in unusual ways to a drug owes something to variations in brain chemistry. The dopamine and serotonin systems control impulsivity and our perception of risk and reward, in addition to modulating depression. Individuals with an increased tolerance for risk or for the stress of confinement may live their lives under the disproportionate influence of dopamine, rendering them less susceptible than average to depression and anxiety.
Personality both affects and is affected by physiology. In studies of presumably normal students, those with the "healthiest" MMPI scores or the most dominant personalities had more active immune systems. A stronger system could increase resistance to disease or boost the response to vaccines, affecting the outcome of certain clinical trials.
Many volunteers in the three-drug confinement study lied to researchers about their health, their history of drug use, and other life events, suggesting a tendency to "purposefully conceal or distort." It was not the first study to show a tendency of NHRVs to provide fraudulent personal information, particularly about drug or alcohol use. In one such study, 45 of 282 volunteers who said they didn't smoke actually tested positive for tobacco use. Volunteers may be telling investigators what they think the investigators want to hear, rather than what they are genuinely experiencing. Perhaps they are doing the same about matters directly under study, such as drug side effects.
In It for the Money?
Yes, indeed, most healthy volunteers do it for the money, or because they can't afford routine medical care. Dollars prove a "significant motivator" for 50 to 93 percent of volunteers, Tishler and Bartholomae found. Recruits answer ads and notices in newspapers and magazines, on TV, on Web sites such as clinicaltrials.gov, centerwatch.com, and clinicalconnection.com. They also respond to flyers with messages like "Smoke Pot, Get Paid! Legal Studies." Bioethicists Trudo Lemmens of the University of Toronto and Carl Elliott of the University of Minnesota call attention to studies like one in Scotland that paid healthy volunteers £600 to drink orange juice laced with pesticides.
In 1996, Robert Helms, a former Philadelphia union organizer and long-time study volunteer, launched a now defunct publication called Guinea Pig Zero for those who, like himself, rented themselves out as human research subjects. In vivid detail, volunteers described what the clinical language of research protocols never did: the pain and bruising from botched blood draws, the indignity of prostate exams or induced hallucinations, as well as all manner of bad behaviors and irksome habits—from aggression to snoring to rudeness—among fellow volunteers. Helms openly labeled the volunteers "medical meat-puppets" and "brain sluts." What made those notes from the guinea pig underground so revealing, says ethicist Elliott, is that Helms "assumed that nobody in his right mind would enroll in a study for anything but the money."
There is, today, hot competition for recruits to clinical trials. The number of people enrolled in trials around the U.S. is estimated to have tripled between 1991 and 2001, and many hundreds of new-drug applications are filed each year with the Food and Drug Administration. Evaluating these drug candidates requires healthy volunteers for early phases of testing. In the absence of standards that limit how much volunteers can be paid, fees can be increased where recruitment is slow-going. Some for-profit companies and university-based investigators play the "everybody has their price game," say Tishler and Bartholomae, a practice that could lead to undue inducement and seems likely to attract volunteers who are different in psychological makeup and economic circumstance from non-volunteers.
Ethicists fear that many advertisements for clinical trials downplay the very real risks involved. Consider a now-infamous ad for a leukemia drug trial, posted to the Web in early 2006 by a private company contracting with drug makers to test new medicines. "You'll be paid for your time and inconvenience," it read, emphasizing the free medical care and free food, and added: "You'll have plenty of free time to read or study, or just relax—with digital TV, pool table, video games, DVD player and now FREE Internet access!" Yet this trial had rare, disastrous results that sent a shudder through the medical community. Six healthy men volunteered to take the new drug in London for £2,000 each (about $3,500), most of them immigrants. All six ended up in intensive care shortly after receiving the drug, in intense pain and with multi-organ failure—the result of immune overreaction.
Still, most volunteers deny that money is the only reasonable motivator. "I was a scientist and understood the need as a public service," says Kusinitz, now the senior science communications advisor at the FDA. "Yeah, I made about $600 in the malaria study and $20 to get nasal washes that felt like waterboarding. I was a single dad and the money was nice, and I got on Oprah when I got malaria, but believe me I didn't risk getting malaria for the money or my 10 minutes of fame." A panel that looked into the 2001 death of Ellen Roche, a serial research volunteer who died during a lung function challenge study at Johns Hopkins, concluded that she was drawn to participate for a variety of reasons: altruism and admiration for the principal investigators (her employers), in addition to the $365 offered.
A Mixture of Motives
The fact is, most repeat volunteers are like the rest of us—complex human beings who defy easy categorization with respect to background and motives. And although money is part of it, it isn't all of it by a long shot.
For a substantial number of participants, studies show, volunteering reflects an array of motives including altruism, personal or social satisfaction, and the lure of working with admired scientists. Relief of boredom counts, too, notably among retirees.
"Volunteering broadens your scope of interests," says Malone, the volunteer from Baltimore. Peer, the 70-year-old Michiganer, says, "my primary reason is to help people, and when I retired, I had a lot of time on my hands."
"Don't fall into the trap of making simple generalizations about why people join studies," warns Kass, whose own research supports a wide mix of motives. "In our studies, one reason absolutely was money, but for a very large number, repeat volunteering is driven by intellectual curiosity and socializing," and no amount of money would work if they felt they weren't of value. "They liked being in the halo of the medical profession," she adds.
A third of the 60 volunteers Kass studied had college degrees, half were employed full-time, and nearly one in three had been in more than 10 studies. Notably, those without college degrees were almost 19 times as likely as grads to have participated in 10-plus studies. In response to direct questions about what was best about the experience, four themes emerged among all volunteers: making contributions to science, making money, meeting people (staff and other volunteers), and relaxation.
When prompted to discuss the money, 55 percent said it was a "good" aspect, 46 percent the "best" aspect. Paradoxically, perhaps, college grads were more than three times as likely as the less educated to cite money as a big motivator, as were whites over nonwhites. Nearly one quarter of the volunteers said it was an easy way to live, enjoy free meals, or make money. "Like a vacation," one put it, suggesting that for some, spending time outside their quotidian environments is an attraction. Nearly one quarter liked learning about their health, science, or medicine, and they appreciated preventive care such as cholesterol screening. Asked to name "the bad things," only 5 percent said the study did not pay enough, while 37 percent mentioned pain, scarring, diarrhea from bacterial challenge studies, and multiple blood draws.
That non-whites and those without a college degree are less likely to be motivated by money suggests yet another, subtle influence—the desire for social power. Some people are easily wooed by those they perceive as socially desirable, and volunteers' behavior certainly raises the likelihood that they hold the scientific and medical professions in high esteem. They may be motivated by the desire to be part of a group or activity they believe is highly valued by those they admire. The higher people score on a test of approval-seeking, the more likely they are to volunteer for studies. Particularly among repeat volunteers, it's likely they enjoy being part of a team, in an intellectual atmosphere, and fear losing the approval of researchers and team members if they don't return for a next round of studies.
Not Such an Odd Decision
For bioethicists, the major concern is whether participants have been coerced, financially or otherwise, to risk their health and occasionally their lives. Yet Ruth Faden, director of the Berman Institute for Bioethics at Johns Hopkins, asks why society should consider the risks NHRVs sign up for any less rational than the willingness of people throughout history to take on other "dirty work" or dangerous assignments; they see it as a way to better themselves or society. "It's paternalistic for people who don't mine coal or become police officers or soldiers or rescue workers to automatically consider those who do as vulnerable, irrational, or exploited," Faden points out.
Indeed, she notes, it's as likely as not that veteran volunteers are just fine and the issue with their motivation lies not with them but us. She recalls driving to the train station one day behind a trash truck when a large garbage load fell to the road and the men on board swooped down to pick it up. "I thought to myself, 'I'd hate to do that and I'm glad I don't have to.'" But then it occurred to her that she didn't necessarily have the right or the right perspective to question the motives of those who perform such jobs. "Maybe," she suggests, "whatever collective squeamishness we have about creepy or risky work results less from any real problem among those who do it than from the fact that we all benefit from what they do—but fail to appreciate them or pay them a fraction of what they are worth." — Joann Ellison Rodgers
Know Your Rights
- Protect yourself.
Check out websites devoted to research volunteer protection and education, including the Alliance for Human Research Protection (ahrp.org) and the federal Office for Human Research Protections (hhs.gov/ohrp), as well as the Center for Information and Study on Clinical Research Participation (ciscrp.org). Look especially at the latter group's Clinical Trial Volunteer's Bill of Rights. Make sure that studies are approved by an institutional review board.
Google the investigator and the funding source, remaining alert for controversy.
Have someone else read the informed consent forms along with you, preferably someone with only your interests at heart and not a fellow guinea pig.
"Consider best and worst case scenarios, and put yourself in those scenarios,"says Ohio State's Suzanne Bartholomae. Ask about all potential side effects, not just the major physiological and psychological risks.
Be alert to subtle forms of coercion. Clinical trials constitute a big business; universities and pharmaceutical and other companies pay doctors to recruit patients and have volunteer quotas to meet.
Don't volunteer for the person you work for, and resist social or peer pressures.
- Comparison Shop.
ClinicalConnection.com offers free email updates about trials in your area, along with a message board for swapping information.
- Examine Your Motivations.
Emotional or financial stress can override good judgment. "If you are willing to lie or deceive the investigator to get into the study, you may not be able to make a sound decision, whatever your motivation," notes Bartholomae. Ask yourself if you would do it for nothing.