Intended for healthcare professionals


Phase one trials can exploit terminally ill patients

BMJ 1994; 308 doi: (Published 12 March 1994) Cite this as: BMJ 1994;308:679
  1. G McBride

    Fears are emerging in the US that terminally ill patients who take part in phase one trials of chemotherapy are being exploited. A recent pilot study carried out by the department of haematology and oncology at Chicago University's centre for clinical medical ethics suggests that patients gave their informed consent because they believed in the possibility of therapeutic benefit. The 27 patients in the study were also asked whether, as is required, other options besides participation in the trial were discussed during the informed consent process; two thirds said no.

    The purpose of phase one trials of chemotherapy - performed in the US mostly with solid tumours - is to test the toxicity of increasing doses of an experimental agent. Clearly, if the drug is sufficiently toxic or the dose sufficiently high, then some subjects will suffer. The drug is tested until the so called maximum tolerated dose is reached. If subjects fail to respond to an experimental agent after about two cycles of treatment at their assigned dose level they are usually released from the trial and sent back to their referring physicians.

    Patients were asked in interviews to state the purpose of the phase one trial that they were entering. Only a third of the 27 patients stated that it was to assess the effects of dose escalation. The other two thirds said that they didn't know or that the purpose was theraputic benefit. Clearly, despite attempts at explanations, patients' motivation to get some therapeutic benefit is so overwhelming that it obliterates the memories of much of what they have been told about the trial's purpose, said Chris Daugherty, an oncologist who carried out the study.

    * Not all patients know they are taking part in phase one trials

    There is a view that since terminally ill people who take part in these trials give their informed consent and will probably die within months anyway, any resulting ill effects or hastening of their death may be unfortunate but do not preclude such trials. Others feel that there is no alternative. Dwight Kaufman, deputy director of the division of cancer prevention at the National Cancer Institute in the US, said: “To give an experimental, possibly toxic agent that might manifest such adverse effects as leukaemia years later to a healthy person, or one cured of cancer, is unthinkable.” But Kaufman also said “terminally ill patients must be made to understand the facts: we must stress to such patients that it is unprecedented for a cure to occur - that the probability of cure approaches zero.”

    George Annas, director of the medical ethics and law programme at Boston University Schools of Medicine and Public Health, thinks that these patients need special protection. “These patients do have something to lose,” he said. “They may end up dying a more miserable death than otherwise.”

    Annas believes that the dual roles of the phase one investigator as physician and scientist present a problem: “It's difficult to separate these roles, and they can't believe that as physicians they would harm patients.

    In the US, in recent years, Annas continues, “AIDS activists have demanded experimental agents and now we all are equating research with treatment, the justification being the consent process.”

    Daugherty believes that “it's possible for all patients to understand the purpose of such trials and to give full informed consent. Certainly only the ones who understand what's involved should participate in these trials. This means that patients must become more involved in the process.” One way to do this, which he says “may not be feasible ethically or clinically,” is to allow patients to select the doses they want to take. Essentially, this means that the lower doses would be skipped, saving both time and money in a drug trial.”

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