Too high a price? Re-examining the ethics of Phase I oncology trials

Give more credit to patients willing to participate despite risks

For cancer patients who have exhausted all available treatment options, Phase I research trials of new oncology drugs may be their only hope. But does that hope come at too high a price?

Not necessarily, say two researchers from the department of clinical bioethics at the National Cancer Institute’s Warren G. Magnuson Clinical Center in Bethesda, MD.

Although the participation of cancer patients in Phase I trials is controversial for several reasons, the available evidence suggests that dying patients are able to understand the risks involved and often may be willing to undergo great hardship both for the potential to help others and for the chance, however remote, to fight their own disease, wrote researchers Manish Agrawal, MD, and Ezekiel J. Emanuel, MD, PhD, in the August issue of the Journal of the American Medical Association (JAMA).1

"Part of the overall controversy centers on the fact that you have to test these very toxic drugs, or at least potentially toxic drugs, generally on patients who are terminally ill," Emanuel tells Medical Ethics Advisor. "They may not be dying in the sense that they are in the last stages of life, but they have exhausted all other treatments; and barring some other treatment, they will die of their cancer."

Phase I clinical trials are the initial stages of research that permit new therapies to move from the research lab into clinical use. Classic Phase I drug trials are cohort studies in which participants are treated at increasing doses so that researchers can learn about drug toxicities, the maximum tolerated dose and the pharmacokinetics of the drugs. Phase I trials are aimed more at determining the drug’s safety than its effectiveness at treating the disease.

Some drugs demonstrate so much toxicity in Phase I studies that they never progress to Phase II and beyond. The potential for adverse events in Phase I studies is high, and the possibility that a patient will achieve a beneficial treatment result is very low.

Phase I oncology trials are particularly controversial because unlike other Phase I drug studies, they must be performed on the sick patients themselves rather than healthy volunteers, Emanuel adds.

"Cancer drugs are so toxic you can’t try them out in the same way you would the latest drugs for hypertension medicine or migraine medicine on the average healthy person," he explains. "The only people you can possibly enroll in these trials are the actual patients."

Some ethicists have proposed that Phase I oncology trials are inherently unethical because there is no reasonable probability that the subjects will benefit. There is a small but definite risk of death from toxic side effects and a very high potential for physically debilitating side effects.

Surveys of patients participating in oncology trials have found that most list the possibility of personal benefit as a primary reason for participation — an indication, some argue, that these patients are not receiving appropriate informed consent.

Similar surveys of some oncologists also indicate they have unrealistic expectations about the potential for their patients to do well in Phase I trials, which is a disturbing finding given that treating physicians usually refer patients to clinical trials.

However, researchers examining these issues have not always had an adequate understanding of the unique situations that these cancer patients face, Emanuel says.

In addition, most of the existing research on these issues is old and doesn’t take into account newer study designs that minimize risks or newer informed consent procedures and research surveys that attempt to more broadly assess cancer patients’ understanding of the research objectives and their motives for participating, he adds.

"If you examine the literature on this topic, this has been an amazingly controversial topic in the literature, yet the available literature is really bad," Emanuel says. "There are very few articles analyzing, either conceptually or empirically, the issues involved. In some ways, the best of the conceptual articles is more than 30 years old."

Examining motivation

In reviewing the available articles for the JAMA piece, Emanuel and Agrawal found interpretations of the data that, they believe, may not accurately reflect the perspective of many terminal cancer patients.

"I am not convinced, for instance, that because a participant says that his or her primary motivation for participating is to receive personal benefit, that necessarily means that the person does not understand the purpose of the study or the risks involved," Emanuel explains. "I can hope something will be the case, even though I know the odds are against it. I think every person who buys a lottery ticket falls into that category. You know you’re not likely to win. The odds are overwhelming, in fact, that you’ll lose. But choosing to participate doesn’t itself mean you lack understanding."

Some of the data obtained from studies of informed consent have not been properly understood, Emanuel notes.

"When you ask people what their primary motivation is, they almost universally say benefit for themselves, which is not surprising," he says. "On the other hand, when they are asked if they necessarily are going to benefit, the majority say they are aware they might not or probably will not. They recognize that and say that the advancement of knowledge for society is a primary benefit of the study. We think that these two beliefs can be held by people at the same time."

Clinical outcomes questioned

In addition, Emanuel says some of the empirical data about the outcomes experienced by participants in oncology trials has been misinterpreted.

Meta-analyses of Phase I studies show an overall response rate of just 5%, but that figure conceals other important information. More than 60% of the compounds evaluated had as least one objective response — tumor shrinkage of more than 50%. Additionally, more than 30% of the drugs also had a greater than 5% response rate.

There also have been individual cases in which the benefit of participation has been substantial.

"There is potential for people to experience improvements in their condition, and we know of at least one case where a patient was cured in a Phase I trial. We know of another case where there were substantial long-term benefits," Emanuel says.

Paternalism vs. autonomy

When considering Phase I oncology trials, ethicists must remember that potential participants are patients without other treatment options — they either may decide to participate in a trial, resign themselves to only supportive care, or accept whatever fall-back remedies their doctor may decide to try, but which have even less potential for benefit, says oncologist Mark J. Ratain, MD, the Leon O. Jacobsen professor of medicine and chairman of the committee on pharmacology and pharmacogenomics at the University of Chicago Cancer Research Center.

"The bottom line is, when you have advanced cancer, your chance of responding to anything is low, whether you are getting a Phase I drug, a Phase II drug or a drug some oncologist has pulled off the shelf when he is trying to do the best for his patient," Ratain explains. "The chance of the patient responding is low."

Obviously, treating physicians have an obligation to their patients to make sure they understand the high risks and low potential for benefit of Phase I studies.

But, they shouldn’t presume to determine what is in each individual’s best interest. That decision is up to the patients themselves.

"Some patients may want to pursue treatment regardless of what the chances for success are," he says. "If I had a patient, I would say what you have to do is compare the experimental drug that we are talking about today with the standard available treatment — which is no treatment. If they have rejected the concept of no treatment, then that is not an option."

People who are healthy have much different perspectives than people who are sick, Emanuel agrees. "We make the case in the paper that evaluation of the risks and benefits depends on your perspective."

More research is needed into the true risk-benefit ratios of newer drugs, given that the existing data is more than a decade old, he adds.

"There have been a lot of changes in therapeutics in cancer — more immune modulators, more targeted therapies, more vaccines — and we need to know if these risks-benefit ratios are sustained, or are they better or worse," he explains. "We need to know whether improvements in supportive care have improved or decreased the risks of Phase I treatments."

More research also is needed into appropriate informed consent techniques, Emanuel believes.

"The studies that have been done have not been done carefully," he adds. "They don’t differentiate between someone participating with a primary motive for benefit but who also recognizes that they may not benefit. These are very hard sets of questions to ask, and I don’t think we’ve seen a lot of careful surveying in this area."


1. Agrawal M, Emanuel EJ. Ethics of Phase I oncology studies: Re-examining the arguments and data. JAMA 2003; 290:1,075-1,082.


  • Ezekiel Emanuel, MD, PhD, Chair, Department of Clinical Bioethics, National Institutes of Health Warren G. Magnuson Clinical Center, Bethesda, MD 20892-7511.
  • Mark J. Ratain, MD, Leon O. Jacobson Professor of Medicine, Chairman, Committee on Clinical Pharmacology and Pharmacogenomics, Associate Director for Clinical Sciences, Cancer Research Center, The University of Chicago, 5841 S. Maryland Ave., MC 2115, Chicago, IL 60637.