When Ethical Constraints Seemingly Undermine the Protocols of Clinical Trials

ORLANDO—Like mom and apple pie, high ethical standards in medicine is a concept few people would argue against. But the impulse to apply strict standards can sometimes backfire, as seen in potential scenarios offered by experts here at the American Association for Cancer Research Annual Meeting, in a session titled “International Impact of Ethics and Regulation on Cancer Research.” Today, for example, some researchers say it is an ethical imperative to make positive clinical trial outcomes public as soon as they are observed, to allow other patients access to the study treatment. But Harry Bartelink, MD, PhD, President of the Federation of European Cancer Societies and Head of the Department of Radiotherapy at the Netherlands Cancer Institute, said that could mean no follow-up to validate the conclusions from early, positive trial data. He pointed to a 2003 publication by Dr. Paul Goss and colleagues on a study that found significantly increased disease-free survival among breast cancer patients taking letrozole after tamoxifen compared with those taking tamoxifen alone in a randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer (NEJM 2003; 349:1793–1802). The trial had a large number of patients, more than 5,000, and the trial's safety and monitoring committee recommended the findings be made public, Dr. Bartelink said. “The positive side is that patients could then immediately access this treatment and benefit from improved disease-free survival, including patients in the trial who had not been receiving letrozole. But the negative points are that follow-up was extremely short—no patient completed five years of letrozole therapy—and there is minimal information on late side effects.” Also, Dr. Bartelink said, since patients were switched from the tamoxifen-alone arm to the tamoxifen-letrozole arm after the news of improved disease-free survival was released, the trial could end up being negative. For one thing, that might mean long-term negative results would not be published in the same journal as the original article on the early positive results. “Meanwhile, other trials from the NSABP will significantly be disturbed,” he said. Dr. Bartelink noted that the rules for publishing positive data early were made by the trial coordinators themselves. “We have to be careful about assigning our own [clinical trial] rules,” Dr. Bartelink said. “Properly we should only design rules saying that if there is serious toxicity, then you should stop the trial, and otherwise you would continue.” Stored Tumor Material Reinforcing ethical precepts with legislation and regulations can sometimes impede scientific investigation all the more. Dr. Bartelink warned that in the near future, medical-privacy rules written by the European Parliament could prohibit the use of stored tumor material without a patient consent form for each specimen.Figure: Harry Bartelink, MD, PhD, warned that in the near future, medical-privacy rules written by the European Parliament could prohibit the use of stored tumor material without a patient consent form for each specimen. The document, the European Clinical Trial Directive, was written by politicians without consulting scientists, Dr. Bartelink said. He urged scientists not to take a wait-and-see attitude about such legislation but to become proactive in designing rules on research.The document, the European Clinical Trial Directive, was written by politicians in the European Parliament without consulting scientists, Dr. Bartelink said. He could see the immediate impact on his own institute, which is very active in microarray studies based on stored tumor material—material from patients who never consented to its use for research. “At this time we don't need informed consent to use this material, but I am sure that will change in the future,” Dr. Bartelink said. He urged scientists not to take a wait-and-see attitude about such legislation but to become proactive in designing rules on research. European Clinical Trial Directive Another speaker at the session discussed another section of the European Parliament's Clinical Trial Directive, Section 20, which was implemented into the national laws of all European member states last year and put into force in May. Dieter Hossfeld, MD, PhD, Chair of the Department of Oncology/Hematology at University Clinic Hamburg-Eppendorf in Germany, said the aims of Section 20 are laudable: promotion of multinational clinical trials in Europe, harmonization of clinical trial procedures there, and increased protection of patients. But the potentially negative implications for clinical research are tremendous, he said, since the directive may result in studies of new drugs being initiated, financed, and performed almost exclusively by pharmaceutical companies. This is due to the section's definition of “sponsor” to be whoever takes over total organizational, monitoring, legal, safety, and financial responsibilities of the investigation, Dr. Hossfeld said. “This definition would place such a heavy workload and expense on clinical investigators that many medical oncologists and institutions in Europe believe the directive may end academic clinical research in Europe. And then who will question the need for non-commercial investigator-initiated trials?” Dr. Hossfeld said society has to face the question of whether to continue overestimating patient autonomy and individual rights over the benefit of medical progress to society as a whole. Researcher vs. Healer A basic conflict between the individual rights and the good of society can be seen in any clinical trial, Dr. Hossfeld said, noting that the National Bioethics Advisory Commission of the US National Institutes of Health has stated that “treatment means solely to enhance the well-being of an individual patient.” But he said research, according to the Belmont Report, “is intended to test a hypothesis, to draw conclusions, which then permit to develop or contribute to generalizable knowledge.” (The report is a 1979 document by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research spelling out specific ethical principles and guidelines.) Despite these competing aims, Dr. Hossfeld said, it has been reported that a substantial minority of US oncologists believe that clinical trials exist to ensure state-of-the-art therapy for study participants. “The physician's dilemma when participating in clinical research, namely whether he should present himself as a researcher or a healer, is closely related to the difficult topic of informed consent,” Dr. Hossfeld said. The conflict between these roles comes to a head when the physician has to tell a patient what the trial is designed to benefit: medical knowledge, or that particular patient? Strictly following the premise that the trial is designed to benefit society rather than the individual, some physicians believe it is unethical to promise study subjects that they will personally benefit in any way from participating in the trial. But another speaker, David Korn, MD, Senior Vice-President for Biomedical and Health Sciences Research for the Association of American Medical Colleges, said this starkly realistic attitude alone could do the patient harm.Figure: Dieter Hossfeld, MD, PhD, said society has to face the question of whether to continue overestimating patient autonomy and individual rights over the benefit of medical progress to society as a whole.“I agree it is wrong to promise utility to a patient in a Phase I trial,” Dr. Korn said, during a discussion period. “But I have also heard researchers argue against eliminating all hope for improvement. “Everyone has to have some hope, and I think it is evil to try to eliminate that hope.” Low Attendance at Ethics Session The “International Impact of Ethics and Regulation on Cancer Research” session was somewhat of a letdown in view of the poor attendance, with fewer than 100 people in a room set up for 1,500. A member of the audience pointed this out to the session chair, AACR 2003–2004 President Karen Antman, MD. “In light of the attendance of this event it seems to be more of an issue to patients and patient advocates than to researchers,” said Simon Parker, a volunteer for the Canadian Cancer Advocacy Network. “Why aren't more people here?” “I am also disappointed in the participation,” Dr. Antman answered. “We actually thought this would be an area for hot debate and that there would be more people attending.” She offered that the many simultaneous sessions might have drawn away a larger audience that would have otherwise attended a session on ethics.

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