Use of Human Subjects

lbonnell's picture

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 saysThe 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:

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.

 

 

Comments

Colette's picture

 When experimenting with

 When experimenting with humans, there are ways in which all participants can be fully informed and whether they choose to listen or not are their responsibility. For instance, writing out a script when explaining the risks and guidelines then recording it and playing it for each participant may be one way to eliminate any biases researchers would typically have when presenting an experiment that they would like to do. It is not right or useful to target any group of people as subjects because of their likelihood to participate. This is a big ethical problem to deal with  since it would be considered taking advantage of peoples weaknesses to get what they want. I found Prof. Grobstein’s ideas of communism and “jury duty,” making everyone participate, to be an interesting approach to neutralizing participation.

 

Kwarlizzle's picture

Validity of clinical trials

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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. The people who sat up and came up with these laws didn’t come up with them because they are heartless compassion-less people. They came up with these very rigorous measures because it needed to be done – both to preserve puclic peace of mind and the researchers. I for one believe strongly in the current guidelines for clinical research. I don’t believe that a double-blind study is the ONLY or most effective way of verifying the effectiveness of a drug, but it sure is a pretty darned good and useful one. Simply put, I believe in the validity of clinical trials and don’t think they should be abolished.
However in another real sense Professor Grobstein is right about motivation ane compensation in clinical research. Something needs to be done about that, especially about the motivation. Money should not the most important motivating factor, as it seems to be with our pharmaceutical companies…

Paul Grobstein's picture

clinicial trials: some modest proposals

Lots of interesting issues posed, both in class session and below.  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.  Lots of very useful drugs have never been through the kind of clinical testing we demand today.  And it is not at all clear to me that one needs double-blind, control group testing  to evaluate either hazard or efficacy in most cases.   Such rigorous procedures are needed only when one is looking for very small effects.  Finally, I think it needs to be admitted that much clinical testing is driven not by a general concern for public health but rather by profit motives.  Under these circumstances, I might be inclined not only to pay test subjects but to insist that they be included among the authors on any resulting papers.  

Steven Walker's picture

Clinical Trial Ethics

This post is genuinely excellent. You are asking exactly the right questions, and the PLX4032 trial is the perfect example. The drug clearly works, and its efficacy is solidly supported by the science. It is being tested against a 35 year old drug (dacarbazine) that has never, even in the opinion of the FDA (the agency that approved it in 1975) been shown to provide clinical benefit, and in many clinical trials, it has never been shown to confer a survival benefit. This trial is being run solely to meet the requirements of a policy unilaterally established by Dr. Richard Pazdur (Director of the Office of Oncology Drug Products at the FDA) in 2003. Concerned at the time that such trials were difficult to enroll as Phase IV (post-approval) trials when a drug this promising received what is called Accelerated Approval based on highly promising Phase I and II results, he decided he would no longer grant Accelerated Approval until the unethical trial was run as a Phase III, pre-approval trial. We call it his Decelerated Approval Initiative. The law and the agency's regulation actually intend that a drug like PLX4032 receive Accelerated Approval after showing to a substantial degree of certainty that it is safe and effective. The idea was accelerating the delivery of progress to patients who can't wait, and while it has saved the lives of tens of thousands of HIV/AIDs sufferers, and before 2003, thousands of cancer patients, Pazdur all but eliminated it as an available approval pathway for cancer drugs in 2003. PLX4032 more than meets the standard for Accelerated Approval right now (and has for many months). But Pazdur has rigidly applied his policy to all cancer drugs whether the standard for Accelerated Approval is met or not, so the most fundamental test of ethics, that a trial that puts patents at risk must be asking a question we still need the answer to, is not met. We already have the answer. PLX4032 is clearly and obviously better than dacarbazine, and so different from the older drug that a comparison is meaningless to medical practice and progress against the disease. It is highly likely that the trial will be stopped early by the trial Data Safety Monitoring Board due to the major imbalance in outcomes that will emerge between the two arms, at that point causing it to become "unethical" under current FDA policies, but the imbalance will emerge because of quick progression and deaths in the control arm, a trial result that could be predicted with almost complete certainty before starting the trial. The details with PLX4032, and the FDA's role (which is only partialy explained here) in causing this trial to be run, are very troubling. An even more troubling fact is that these situations have been common over the last 7 years, now coming in to the light because of the NYTs coverage, and the startling gap between the safety and efficacy of the two drugs being tested in the trial. The trial is designed to measure overall survival (Pazdur's "endpoint" for this specific medical indication), which means that even when patients quickly progress on dacarbazine, they are not allowed to cross over to PLX4032, which poses an 80 percent chance of helping them. The reason? To calculate the difference in survival, the control arm patients must be denied PLX4032, and die on the schedule of patients getting only dacarbazine, the drug the FDA actually beleives based on a mountain of data, to be little more than a toxic placebo.

How is this ethical? It clearly isn't, but it is FDA's policy. Your discussion should also include questions about the responsibilities of the FDA and IRBs to make sure unethical human research is not being conducted. In fact, IRBs are not empowered to stop a trial like this one based on it being unethical on its face, as long as the patients - who have no where else to go but the grave - sign informed consents. But what about the FDA? By mandating trials like these through their policies and practices, they declare them not only ethical, but required. The clear message to drug companiesover the last seven years has been, run these trials and produce perfect statistics from the trial (as measured by an arcane, hypertechical and medically meaningless statistical metric called a p-value) or your drug won't get approved.

Is the FDA requiring unethical human clinical research for approval of new cancer drugs? The answer is yes, and that is a huge problem for thefield of bioethics, which has largely spent the last seven years ignoring, or trying to justify and rationalize, this problem.

Steven Walker, Co-Founder
Abigail Alliance for Better Access to Developmental Drugs
www.abigail-alliance.org

adowton's picture

Participation

 I think this is a really interesting and important topic. As science and medicine progress, there is a continuous need for human participants to test things on. It makes sense...to ensure the safety of the general population, products/medications need to be piloted in test groups. The issue of who becomes a member of the test groups, and why they become a member, is the interesting part of this issue. On the one hand, I think that compensation of research subjects clearly has upsides; it increases the number of people willing to participate and it seems fair to compensate people for their time/the use of their body...but, as we established in class, there may be downsides as well. Including the fact that people may be drawn to a particular study solely for the compensation offered. Is this a problem? I think Crystal is right when she says that people who are in need of money badly enough will find many avenues to provide them with income...and some of these avenues would certainly be more risky/unsafe than participating in controlled research. 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. I think what worries me is the fact that there are probably people who, unlike Crystal, are immediately dismissive of any potential harm that may come from participating in a study. The potential for these people to enlist in multiple trials at once/in a short time, which may lead to great harm is a real one. It is this possibility that makes me back off from taking the viewpoint that: "of course people should be compensated"...I can't help but have a lingering feeling that there is an inherent coercion associated with compensating people who participate in research. On the other hand, the idea of not compensating them seems wrong too...

Crystal Leonard's picture

why I think financial compensation is ok

I'd like to comment on the issue of giving study participants financial compensation from what might be a unique perspective for the class. I am poor and several times a year I greatly consider signing up for clinical trials and other studies that I learn about. I will be the first to admit the main motivation for me is money. I've seen studies offering $2000-4000, which is A LOT of money for me. With just one little study I could pay a lot of bills. At this point I have participated in many psychology studies, but I have not actually participated in a clinical trial. To be honest, despite the very strong lure of the money, I'm scared of the potential risks. Thus far, I've decided that the money is not worth the risks and I've made do with finding other ways to pay the bills. I think a lot of people in my neck of the woods feel the same way. However, there is no doubt in my mind that most people do these studies for the money. Is this right? Maybe not. I recognize that these studies will attract those desperate to make money, which could be viewed as exploitative. However, I don't view payment alone as exploitative. If the people running the study have any scientific integrity at all they should be ensuring that the study population is representative of the general population. There should be safeguards in place to ensure that you don't have a study filled with people from the same socioeconomic class, whether that class be wealthy or poor. If this is not the case, then the whole study is flawed and those running the study are unethical. But if there are safeguards in place, I see nothing wrong with it. No one, myself included, is going to do a clinical trial without compensation. It just isn't going to happen. So why shouldn't they be compensated? 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. Regardless of my views, it is certainly a tricky subject. In my opinion there are two major ways to prevent the exploitation of the poor when it comes to compensation for clinical studies. One way would be to have greater oversight of these studies by the government. Another option, as Prof. Grobstein mentioned in class, is a redistribution of wealth, or at the very least, social programs that can help those that are desperate enough for money that they are willing to sell their body in either legitimate or illegitimate venues. In either case, it is a matter of public policy that will be hotly debated.

smaley's picture

Participant compensation

One thing that got me thinking after class was the idea that it is unethical for clinical studies, that require a certain degree of risk from their participants, to not pay those participants. While I personally believe that clinical studies should pay their participants, in order to compensate them for both their time and the risk that they are undertaking, I do not believe that it is unethical if participants are not paid. 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. While many volunteer activities do not have any risk associated with them, there are others that do, many of which require the volunteer to sign a release before they begin. In such cases, the volunteer is making the conscious decision to take that risk. Obviously there is a difference from volunteering your time, and participating in a research study, but I think that in the greater picture, they are both volunteers that have knowingly decided to participate. While payment may help get more individuals to decide to participate, which is a whole other issue, I do not feel that participants must be compensated. Instead, they are volunteering their time in order to aid in the pursuit of knowledge, and are knowingly and willingly undertaking any and all risk.      

dfishervan's picture

Control Groups

      I must admit that I may be biased when it comes to commenting on clinical trials since the two trials I have assisted on have turned out to be incredibly successful and have worked mostly with elderly study subjects who had more time available to participate in the study. That being said, I do not believe clinical trials as a whole are unethical although there are some ethical questions associated with conducting a clinical trial.

Concerning the issue control groups, I do not find their existence unethical unless the study drug/procedure shows immense improvement over the current form of treatment, in which case the study would be stopped. I must admit that my initial reaction to control groups was negative and I wondered the same things Hope mentioned in class. I wondered why a control group was necessary if we most likely had data on how patients responded to a drug that had been used for decades. However, you must remember that I was working on a study that had very positive results. 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. Also, we must remember that upon enrolling in a clinical trial, the subject’s individual health is prioritized over the study. If members of a control group in a successful clinical trial wish to withdraw and receive traditional care provided to any other person with that illness, they have that option at anytime. The drug being tested in clinical studies is not available to the public so regardless of whether or not the control group patient drops out of the study, he/she will still not have access to the drug. Of course, there are instances where doctors can appeal the IRB and request that patients receive a study drug that has tested positively and reached a certain study phase as a last resort. 

 

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