For researchers who conduct clinical trials, phase I studies are a hard sell: The drug or therapy is being tested in humans for the first time, the study has no hypothesis to test, and none of the accepted goals include a benefit to the patient. Instead, patients are asked to be willing participants in research that mayor may nothelp cancer patients in the future.
"The history of human experimentation can be traced back as long as the history of medicine," said Neil Abramson, M.D., of the Baptist Cancer Institute in Jacksonville, Fla., who chaired a symposium on the practical and ethical issues of phase I research at this year's annual meeting of the American Society of Clinical Oncology (ASCO). "When is it right to experiment and when is it wrong to experiment?"
For phase I research, the answer to that question is repeatedly debated and analyzed in the medical community.
"There are certain ethical principles that bioethicists and others argue need to be kept in mind when we ask patients or even a normal volunteer to participate in clinical research," Christopher K. Daugherty, M.D., of the University of Chicago, said at the ASCO symposium. "These principles include that we ought not to deceive others, we ought not to harm others or allow harm to come to others, and we ought not to use others as means to an end."
Daugherty noted that these principles are not unique to cancer research, but in the context of clinical research, patients are in fact used as means to an enda violation of one of the principles. This is allowable if the benefits outweigh the harms or if voluntary and informed consent is given by the patient. "In the phase I setting, it's at issue whether the benefits outweigh the harms," he said.
For many patients, however, the true benefits of phase I trials are misunderstood. In survey data collected over the course of 10 years from more than 500 participants in phase I clinical studies at the University of Chicago, Daugherty and his colleagues found that when patients were asked about the purpose of their clinical trials, 61% of patients gave responses related to the effectiveness of the drug, and when they were asked what their goals were for participation in the clinical study, 56% of them said that they hoped for cure or remission of their disease. This belief is sometimes referred to as the "therapeutic misconception."
The reality is that only 3% to 5% of patients will have a partial response or better in a phase I trial; some studies suggest that the percentage may actually be lower. A natural assumption from the misperception of benefit is that the informed-consent process is not truly informing patients of the purposes of a phase I study. However, among those same patients in Daugherty's study, 95% of them said that they understood most or all of what was told to them during the informed consent process.
A study published in December 2002 in the New England Journal of Medicine looked at 272 consent documents from phase I clinical studies and found that, overall, the forms themselves were unlikely to be a source of misinformation about the purpose of phase I studies. Most of the forms explicitly stated that the trial was a research study and that the purpose was to determine the safety of the drug, and nearly all of the forms discussed the patient's right to withdraw from the study.
At the same time, the consent form document does not represent the full extent of the informed-consent process, said Mace Rothenberg, M.D., of the Vanderbilt-Ingram Cancer Center in Nashville. "You don't simply give the form to the patient, have them read it, and say, `OK, I've fulfilled my responsibility.' It's a process. That process involves discussing it, answering questions, making sure patients understand all things in the consent form, seeking out answers, and making sure patients have enough time [to make an informed decision]," Rothenberg said.
Also essential to the ethical conduct of phase I studies is ensuring that a patient has a realistic understanding of his or her prognosis, Daugherty added. In a study of 160 patients in phase I trials, 31% of patients reported that their doctor never discussed prognosis with them or gave them a quantitative estimate, and 30% of patients reported that they were told that their cancer was terminal.
"Our knowledge is never 100% when we're asked to make big decisions in our lives, and we can't expect that to be true in phase I clinical trials either," Rothenberg said. "But there's really a threshold at which we say we know enough to be comfortable with our decision. And that's what we have to recognize in the consent process.... But looking back, will these patients say they were informed?"
Outside of the ethical questions surrounding phase I studies and the basic goals of a phase I studyto determine the toxic effects and adverse events, identify the highest dose with an acceptable toxicity profile, and assess the pharmacologic behavior of the drug in a patient's bodythere are several practical issues for clinical researchers to overcome.
For starters, the patient population of a phase I study is highly selective, Daugherty noted: Patients have to have lived long enough, been nonresponsive or have progressed on several other therapies, and they generally have to live close to an academic medical center.
In addition, the investigators themselves can be inherently biased. "I have a phase I research team that I work with," Rothenberg said. "Those studies have to be paid for by the National Cancer Institute or the drug's sponsor. Those people's salaries are paid for by funds that come through those mechanisms. If we don't put patients on phase I trials, we don't get paid and those people will lose their jobs." Investigators who succumb to pressures created by this situation can introduce biases into the clinical research process.
The increase in the number of biologic and cytostatic drugs being tested in humans has also created some problems for clinical researchers. These types of drugs often do not have the same toxic effects as traditional chemotherapy drugs, making it difficult to assess the true maximum tolerated doseor whether such high doses are even necessary.
In a recent study in the Journal of the National Cancer Institute (Vol. 96, No. 13, p. 990), researchers reviewed the methods used in 60 phase I studies of 31 targeted therapies. They found that only six of the trials limited enrollment to patients who actually expressed the target of interest, and they found that 36 of the 60 trials used the traditional endpoint of toxicity as the primary cutoff for increasing the dose of the drug.
"The assumption is that more is better," Rothenberg said at the symposium. "We know now that that's not always the case."
There is ongoing debate about how to adjust or rethink the current phase I model to best meet the needs of these new types of compounds, but regardless of the outcome, testing drugs will still depend on the continued interest of cancer patients in enrolling in clinical trials.
"Although some patients are treated with a great many drugs before referral for phase I, no patient has received all known anticancer drugs," Abramson, Daugherty, and Rothenberg wrote in a summary of the symposium. "By presenting phase I clinical trials to the patient as one of several options, the patient is empowered to make the choice that is right for him or her."
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