Use of Human Subjects

Biology in Society Senior Seminar

Bryn Mawr College, Fall 2010

Session 6

Use of Human Subjects

 “Humans should be considered an end in themselves and not used as the means to another end.” Immanuel Kant

Questions

1. What makes clinical research ethical?
2. Should research subjects be paid?
3. Are control trials ethical?

Background 

Existing regulations and ethical guidelines including the Nuremberg Code and the Declaration of Helsinki: http://ohsr.od.nih.gov/guidelines/index.html

Bryn Mawr IRB

http://www.brynmawr.edu/grants/irb/

(1) What makes clinical research ethical? 

Many believe that informed consent makes clinical research ethical. However, informed consent is neither necessary nor sufficient for ethical clinical research. Drawing on the basic philosophies underlying major codes, declarations, and other documents relevant to research with human subjects, we propose 7 requirements that systematically elucidate a coherent framework for evaluating the ethics of clinical research studies: (1) value— enhancements of health or knowledge must be derived from the research; (2) scientific validity—the research must be methodologically rigorous; (3) fair subject selection—scientific objectives, not vulnerability or privilege, and the potential for and distribution of risks and benefits, should determine communities selected as study sites and the inclusion criteria for individual subjects; (4) favorable risk-benefit ratio—within the context of standard clinical practice and the research protocol, risks must be minimized, potential benefits enhanced, and the potential benefits to individuals and knowledge gained for society must outweigh the risks; (5) independent review— unaffiliated individuals must review the research and approve, amend, or terminate it; (6) informed consent—individuals should be informed about the research and provide their voluntary consent; and (7) respect for enrolled subjects—subjects should have their privacy protected, the opportunity to withdraw, and their well-being monitored. Fulfilling all 7 requirements is necessary and sufficient to make clinical research ethical. These requirements are universal, although they must be adapted to the health, economic, cultural, and technological conditions in which clinical research is conducted. JAMA. 2000; 283:2701-27.

 Note: (5) independent review occurs in the form of local Institutional Review Boards (IRBs)

Are these requirements necessary? Are they sufficient?

Where does compensation fit into these guidelines?

(2) Should research subjects be paid?

The standard worry expressed by ethicists is that money tempts subjects to take part in dangerous, painful, or degrading studies against their better judgment. F.D.A. guidelines instruct review boards to make sure that payment is not “coercive” and does not exert an “undue influence” on subjects. It’s a reasonable worry. “If there were a study where they cut off your leg and sewed it back on and you got twenty thousand dollars, people would be fighting to get into that study,” a Philadelphia activist and clinical-trial veteran who writes under the name Dave Onion says. The New Yorker. “Guinea-Pigging” by Carl Elliot 2008

Should research subjects be paid? If so, how much?

Should these be low-paying or high-paying jobs?

The shift to the market has created a new dynamic. The relationship between testers and test subjects has become, more nakedly than ever, a business transaction. Guinea pigs are the first to admit this. “Nobody’s doing this out of the goodness of their heart,” Miller says. Unlike subjects in later-stage clinical trials, who are usually sick and might enroll in a study to gain access to a new drug, people in healthy-volunteer studies cannot expect any therapeutic benefit to balance the risks they take. As guinea pigs see it, their reason for taking the drugs is no different from that of the clinical investigators who administer them, and who are compensated handsomely for their efforts. This raises an ethical question: what happens when both parties involved in a trial see the enterprise primarily as a way of making money? The New Yorker. “Guinea-Pigging” by Carl Elliot 2008

 Should researchers rely on professional “guinea-pigs”?

 Ideally, should science and business be two separate entities?

Over the past decade, clinical trials have moved from universities to private testing sites, the pressure to recruit subjects has quickly intensified, and ethical oversight has been outsourced to for-profit institutional review boards (IRBs). Payment to subjects has escalated, creating “shadow economies” in cities throughout North America and elsewhere. In 2005, Bloomberg Markets reported that SFBC International, a contract research organization, was paying immigrants to participate in drug trials under ethically questionable conditions in a dilapidated Miami motel. A few months later, nine apparently previously healthy subjects at an SFBC subsidiary in Montreal contracted latent tuberculosis during a trial of an immunosuppressant. In 2006, six healthy subjects required intensive care in a phase 1 trial of a monoclonal antibody at a London facility run by the contract research organization Parexel. For all the ethical debate over these cases, however, few commentators have addressed the most troubling question: Is it ethically problematic to pay poor people to test the safety of new drugs? New England Journal of Medicine. 2008, 358:22, 2316-2317.

Is this voluntary consent?

Is this taking advantage of a vulnerable population? Can this be considered exploitation?

Are researchers accountable for unforeseen complications?           

(3) Are control trials ethical? 

Based on the article "New Drug Stirs Debate on the Rules of Clinical Trials"  http://www.nytimes.com/2010/09/19/health/research/19trial.html?pagewanted=1&_r=1&sq=oncology%20research%20ethics&st=cse&scp=1

“Dude, you have to get on these superpills,” Thomas McLaughlin, then 24, whose melanoma was diagnosed first, urged his cousin, Brandon Ryan. Mr. McLaughlin’s tumors had stopped growing after two months of taking the pills.

But when Mr. Ryan, 22, was admitted to the trial in May, he was assigned by a computer lottery to what is known as the control arm. Instead of the pills, he was to get infusions of the chemotherapy drug that has been the notoriously ineffective recourse in treating melanoma for 30 years

Even if it became clear that the chemotherapy could not hold back the tumors advancing into his lungs, liver and, most painfully, his spine, he would not be allowed to switch, lest it muddy the trial’s results.”

Are control experiments ethical?

Is there an alternative to controlled trials? What would it be?

What does volunteering mean when the patients feel they have no choice?

In general, do trial experiments provide a false sense of hope to individuals with terminal illnesses?

 “Defenders of controlled trials say they are crucial in determining whether a drug really does extend life more than competing treatments. Without the hard proof the trials can provide, doctors are left to prescribe unsubstantiated hope and an overstretched health care system is left to pay for it. In melanoma, in particular, no drug that looked promising in early trials had ever turned out to prolong lives.”

 “But critics of the trials argue that the new science behind the drugs has eclipsed the old rules — and ethics — of testing them. They say that in some cases, drugs under development, PLX4032 among them, may be so much more effective than their predecessors that putting half the potential beneficiaries into a control group, and delaying access to the drug to thousands of other patients, causes needless suffering.”

 Recent News Articles:

•  U.S. apologizes for syphilis experiment in Guatemala   http://www.reuters.com/article/idUSTRE6903RZ20101001
•  A Drug Trial Cycle: Recovery, Relapse, and Reinvention http://www.nytimes.com/2010/02/24/health/research/24trial.html?ref=target_cancer
• ‘Bodies’ exhibition accused of putting executed Chinese prisoners on show http://www.dailymail.co.uk/news/worldnews/article-1241931/Bodies-Revealed-exhibition-accused-putting-executed-Chinese-prisoners-show.html

Summary of class session discussion

The discussion began with an overview of guidelines for clinical research and questions about what makes clinical research ethical. One issue raised involved children: whether or not it's ethical to have children in clinical trials, if a proxy is an acceptable way to gain informed consent, and why children are necessary for clinical research.

The discussion then shifted to the ethics of compensation. We agreed that business and science should not be mixed but there isn't much to be done about it at this point. Is offering compensation taking advantage of those who need money? Not all poor people are motivated by money; some just want to help and it is insulting to suggest that individuals who are poor only participate in clinical trials for money. Is participating in clinical research voluntary or simply a way to make money? How can researchers get people from all socioeconomic backgrounds to participate in clinical trials? Perhaps the government could make participating in clinical trials a civic duty. It would be ideal if everyone did research to further human understanding and well-being, but it seems that companies and universities are only doing it to make money. Those who have more funding are better able to do research than those who don't. This raises questions about the integrity of the research. The information and the studies done could be biased based on who is conducting the research (i.e. a university vs. a pharmaceutical company). One way to better ensure that research isn't motivated by money is to turn to communism.

Then the discussion turned to the ethics of control trials. Sometimes people die because they are depending on the care of the treatment group but instead end up in the control group. However, controls are needed to compare the effects of the treatment. Moreover, the side effects are unknown, so it would not be beneficial to give treatment to all participants. Control trials may be unethical in some regards, but a drug can't be approved without them. Paul informed us that most of the drugs we currently use weren't tested in control trials, and that control trials are a modern practice. We decided that controls are necessary if researching small differences in effectiveness.

Conversations and Implications

Before any participant can enroll in a study, they need to give their informed consent in order for the study to perform any required experiments on them and to use the data that is obtained from them. Such consents must describe the exact role of the participant, or else it would not be considered an informed consent, and therefore would be invalid. After signing such a consent, it is safe to assume that each participant knows exactly what is required of them, and they are willingly volunteering their time, and bodies, to this study. I have a hard time seeing how this is fundamentally any different from any other type of volunteer activity. -smaley

When experimenting with humans, there are ways in which all participants can be fully informed and whether they choose to listen or not is their responsibility. -Colette

Those who are extremely desperate are going to find ways to make the money somehow, and the alternatives are often more dangerous than participating in a legitimate, well-designed clinical trial. -Crystal Leonard

 So, in this light, perhaps the presence of research in need of human subjects is a good thing because it provides a (relatively) safer place to go for money. -adowton

Among the thoughts on my mind is that many of the problems being addressed are of our own making and reflect culturally idiosyncratic (perhaps not sustainable?) presumptions about biomedical research, human risk, and money. -Paul Grobstein

 In one sense Prof Grobstein is right – a lot of the things we consider indispensable conditions of clinical trials are largely a result of the culture in which we find ourselves and the rigors that allopathic medicine considers necessary and/or acceptable.

But I would like to point out that these decisions and the place in which we find ourselves sin regard to ethics and clinical trials did not appear in a vacuum. They came about as a result of things that went awry (Thalidomide is the one big example) and the culture in which we find ourselves: lawsuits, expecting medicine to fix everything by hook or by crook and alla that. -Kwarlizzle

In clinical trials, the possibility of ending up in a control group is a risk that the study subject is aware of when enrolling in a study. In cases where the study drug shows no improvement over or proves to be worse than the traditional treatment, we do not question whether control groups are ethical and certain study subjects will be glad that they ended up in a control group.- dfishervan

• Informed consent is an important component to clinical research. Particpants must be educated in risks and benefits.
• Compensation is not acceptable if it being used lure subjects to a study. Compensation is acceptable if it is payment for time at the lab.
• Clinical trials are an effective way to determine the efficacy of a drug. However it is possible that there are alternatives to clinical trials.