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Ethical Conflict in Providing Informed Consent for Clinical Trials: A Problematic Example from the Gynecologic Cancer Research Community

Department of Hematology/Medical Oncology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA

Correspondence: Maurie Markman, M.D., Department of Hematology/Medical Oncology (R35), The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA. Telephone: 216-445-6888; Fax: 216-444-9464; e-mail: markmam{at}ccf.org

	LEARNING OBJECTIVES

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After completing this course, the reader will be able to:

1. Describe the importance of the informed consent process in clinical trials.
   
2. Discuss the implications of the randomized phase III trial of maintenance paclitaxel chemotherapy in advanced ovarian cancer.
   
3. Explain the responsibilities of clinical investigators and clinicians to inform their patients of new results that may affect their willingness to participate in clinical trials.
   

	ABSTRACT

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The principle of respect for patient autonomy and the importance of informed consent are well established in the conduct of clinical research. However, in actual clinical practice, how one applies this concept is not always clear. The provocative results of a randomized trial examining "consolidation/maintenance" therapy in women with advanced ovarian cancer who achieved a clinically defined complete response to primary chemotherapy have raised difficult issues for clinicians and clinical investigators regarding their obligations to provide patients with information that may interfere with the conduct of ongoing or future research studies.

Key Words. Ovarian cancer • Paclitaxel • Randomized trials • Informed consent in clinical research

It is a well-established principle of modern medicine that research must precede the acceptance of a new therapeutic concept as a routine component of "standard clinical practice." Such research can take a variety of forms, ranging from the discovery of novel pharmaceutical agents, which are then examined in a highly structured clinical development strategy (i.e., phase I-III trials), to epidemiological observations resulting in mandated public health initiatives.

As broadly defined, the conduct of medical research in the U.S. (and elsewhere) over the past century has resulted in reductions in disease-related morbidity and mortality, and has improved overall life expectancy. Few would argue with the statement that the "good" produced by medical research during this time has been profound. The U.S. public, through its elected representatives, has been extremely generous in its support of both laboratory and clinical research efforts directed at improving the general well-being of the population and of individual patients.

Unfortunately, a "dark side" of medical research efforts has been increasingly recognized, although not always fully acknowledged. From the infamous Tuskeegee syphilis episode, to concerns with the deliberate infection of children with hepatitis at Willowbrook, and, more recently, to the inappropriate inclusion of a young man in a gene therapy trial that resulted in his death, the public has learned that blind trust of physicians and researchers must have its limits [1]. These highly publicized examples of situations where clinical investigators and research institutions have demonstrated a serious lack of judgment have served the critical task of awakening society to the dangers associated with clinical research, and to the relevance of respect for patient autonomy and the process of obtaining informed consent.

However, these discussions really only scratch the surface regarding the often severe tensions that occur regularly between a clinical investigator’s profound ethical obligations to an individual research subject and his/her responsibilities to conduct scientifically valid research. Further, the potential conflict of interest inherent in the conduct of clinical trials is often not fully appreciated. Investigators advance in the academic world through the publication of results of new studies [2]. Was an individual offered entry into a study because participation was in the patient’s or the investigator’s best interests? Was the investigator paid to participate in the trial? Does this money increase as the number of research subjects he/she enters increases? If a research subject leaves a trial prior to its completion (for any reason), does the investigator suffer financially, or academically? If yes, is this an incentive to keep the patient in the trial? Has the patient been informed regarding any of these potential conflicts? Even if the answer is "yes," how does this information impact the investigator/subject and doctor/patient relationship?

The unexpected results of a large randomized trial, conducted by two major government-sponsored cancer cooperative groups, and for which the author of this commentary served as principle investigator, have recently raised, once again, the potential for conflict between the "ethical physician" and the "clinical investigator" [3]. This trial experience involving women with advanced ovarian cancer highlights the fact that this conflict is not merely an exercise in abstract philosophy, but rather a complex bioethical dilemma that occurs regularly and must be faced by our society.

Before discussing the ethical concerns surrounding the results of this potentially landmark cancer trial, it is important to explain what the study was designed to accomplish, how it was conducted, and what was concluded. Some may question the relevance of the details of this trial in a discussion of the adequacy of informed consent. However, it is precisely because there is evidence that many physicians do not believe that the study findings require disclosure to their patients that readers of this commentary must be given the actual data and decide for themselves the appropriateness of such actions.

Standard treatment of advanced ovarian cancer includes the use of two classes of chemotherapy drugs, a platinum agent and a taxane [4]. With the currently available therapy, approximately 50% of women in this clinical setting can be anticipated to have no clinical evidence of disease (i.e., normal physical examination, no symptoms of disease, and normal blood tests and radiographic evaluation) at the completion of approximately six cycles of this two-drug combination. Unfortunately, 80% of this population with no clinically evident disease at the completion of the primary chemotherapy program will subsequently experience progression of their cancers and die of complications of the malignancy. While a variety of strategies have been proposed to prevent disease recurrence, to date, there have been no data from randomized trials to demonstrate that any approach can favorably impact either the time to initial progression of the disease or the ultimate survival in this clinical setting.

In 1997, the Southwest Oncology Group (SWOG) and the Gynecologic Oncology Group (GOG) initiated a randomized phase III trial involving women with advanced ovarian cancer who had attained a complete response (defined above) to initial standard (platinum and taxane) chemotherapy [3]. One-half of the study population was to receive a total of 3 monthly cycles of single-agent paclitaxel (control arm), with the other group being administered 12 monthly cycles of the same drug (experimental arm) following front-line treatment. Approximately 500 patients were to enter this trial, with the primary end points being both progression-free survival (PFS) and overall survival. PFS refers to the time from initiation of treatment until the first evidence of disease progression.

It is important to appreciate the difference in, and implications of, these two measurements of potential clinical benefit of a cancer treatment program, particularly in ovarian cancer. Overall survival is quite clearly defined. However, PFS is a more difficult concept. In ovarian cancer, there are a number of treatment programs that have been shown to have some effect on the clinical course of patients whose disease has recurred following completion of initial treatment [5]. Thus, even if a patient completing initial chemotherapy is subsequently found to have developed progressive disease, a second-line treatment program may produce disease regression, improve symptoms, and, possibly, substantially extend the ultimate survival.

While this fact is certainly encouraging, it is also important to realize that with the currently available therapies for ovarian cancer, once initial progressive disease does occur, it is almost certain that the patient cannot be cured of her malignancy, despite being able to experience prolongation of survival with subsequently delivered treatment programs. Thus, the implications to a patient (and to her family) of being informed that her "disease has recurred" extend beyond the mere fact that a mass has enlarged or that a serum tumor marker has increased in value. The individual now knows that she will almost certainly die of ovarian cancer. No longer can a physician talk of the treatment being delivered with the goal of "cure." Rather, currently, all second-line therapy must be considered palliative in intent. Beyond being given the initial diagnosis of cancer, it is hard to conceive of a more difficult emotional transition for an individual patient with a malignancy.

In fact, it was the profound implications associated with the development of disease progression in this clinical setting that led the investigators of this maintenance chemotherapy trial to select three cycles of monthly paclitaxel as the control arm of this study. As noted earlier, there is currently no evidence from randomized controlled trials that any consolidation (or maintenance) strategy produces a survival benefit in ovarian cancer. Thus, the standard of care at the time of the initiation of this randomized trial most appropriately should have been considered "no further chemotherapy" following the completion of a front-line treatment program.

However, if a woman was provided with the necessary facts to justify her considering entry into this trial (as ethically and legally mandated), she would have to be told that she had an 80% chance of experiencing disease recurrence if she received no further therapy. Further, she would have to be told that the drug she could be given in the "experimental" 12-month treatment arm was one she had already received and tolerated, and was a component of a regimen to which her tumor had responded (otherwise, of course, she would not be a candidate for the study). Finally, she would have to be provided with the valid scientific rationale for why an additional 12 months of treatment might be of benefit to her, either in prolonging PFS or her ultimate survival [6].

Given this information, and the availability of paclitaxel from any oncologist in the community, why would a patient agree to be entered onto a "no treatment" control arm? Further, armed with these facts, some might conclude that the principle of equipoise, upon which all randomized trials must ultimately be judged, would not be satisfied [7, 8].

However, the leaders of this multicenter trial argued that with three additional months of paclitaxel serving as a control, all patients would receive therapy beyond the standard treatment associated with an 80% recurrence rate and, as a result, might achieve some additional clinical benefit. At the same time, it was believed that the trial design (nine additional months of treatment in the experimental arm) would permit a scientifically valid analysis of the clinical utility of consolidation therapy.

The conduct of this protocol, as with all federally sponsored clinical trials, mandated a review by the SWOG (the sponsoring organization) Data Safety and Monitoring Committee (DSMC) [9]. This review process was initiated in September 2001 when slightly more than 50% of the planned study entry had been completed. In October 2001, the DSMC elected to permanently close this trial due to "extreme positive results," as an examination of the available data revealed an approximately 50% reduction in the risk of disease recurrence associated with continuation of therapy with single-agent paclitaxel for 12 months beyond the completion of initial chemotherapy, compared with only 3 months of additional treatment [3]. This difference was highly statistically significant. Of note, at the time of study closure, there was no difference in overall survival between the two treatment arms.

While patients randomized to the prolonged paclitaxel treatment program experienced a slightly higher incidence of clinically relevant, but usually reversible, peripheral neuropathy (numbness and tingling in the hands and feet), there was little difference in the overall tolerability of the treatment regimens. It should be noted that paclitaxel causes complete (and reversible) hair loss. Thus, women who received the 12-month paclitaxel regimen were not able to have their hair grow back for this additional period of time.

All patients in the study were quickly informed of the decision of the DSMC and the reasons supporting the conclusion to stop the trial. In particular, patients on the 3-month arm, whether they were currently still on therapy or had had treatment recently discontinued with no evidence of disease progression, were given the option to receive additional monthly courses of paclitaxel, presumably to a total of 12 cycles.

There are two potentially profound implications of the early closure of this randomized trial on current and future clinical trials in ovarian cancer, as well as on the routine management of this malignancy.

First, due to the absolute requirement to inform patients of study closure, as well as the reasons supporting this decision, it was virtually certain that a substantial percentage of women randomized to the three-cycle arm, when provided with this information, would elect to receive additional treatment. This makes it very difficult for an overall survival benefit (for the 12-cycle regimen) to be observed, as the treatment programs for the two study populations ultimately will be quite similar.

Thus, if follow-up data subsequently fail to show a difference in overall survival, one explanation of this outcome will be that a variety of second-line treatment programs successfully extended survival [5], negating any benefit from the delay in initial disease progression resulting from the effects of continuing single-agent paclitaxel. However, an equally plausible alternative hypothesis will be that a genuine benefit of continued treatment was not observed due to the fact that the study was prematurely closed and a large percentage of patients in the control arm ultimately received the same treatment as those in the experimental arm.

Second, and without question the more difficult concern, is how this information should influence the conduct of either ongoing, or future, clinical trials in this clinical arena. It is here we must consider a serious ethical dilemma:

Are all women who achieve a complete response to initial chemotherapy entitled to be offered 12 additional months of paclitaxel? If an ongoing trial employs PFS as a major study end point, should patients currently in that trial be permitted to receive consolidation therapy with paclitaxel when they complete their initial treatment program? If so, how will this influence the PFS end point? If they are not to be permitted to receive additional treatment, should they be told of the results of the SWOG/GOG trial? If not, why not? If a physician informs a patient participating in an ongoing front-line ovarian cancer clinical study of the results of this maintenance/consolidation trial, but advises the individual to continue on her current course of action that does not permit such therapy, is the physician obligated to also tell the patient of any potential conflict of interest associated with this recommendation (e.g., financial loss associated with the patient becoming a "protocol violation")? For future patients being considered for such studies, should investigators be obligated to inform those women that they will not be permitted to receive additional treatment if they enter this specific trial, but that another option would be for the individual to be treated "off study," with subsequent consolidation therapy administered if she attains a clinical complete response? Should an investigator who informs a newly diagnosed patient regarding the results of this consolidation trial, but subsequently councils this woman to enter a study that does not permit consolidation treatment, also be required to announce his/her potential conflict of interest in this process (e.g., being paid to enter patients, being an investigator on the study that could lead to academic advancement)?

Before the ethical issues raised by the conduct of this trial are addressed, one must first attempt to objectively define the medical implications of the findings. Do the results of this trial establish a new standard of care in the management of ovarian cancer? In the absence of data documenting a favorable impact of this consolidation chemotherapy strategy on overall survival, it would be inappropriate to declare that this management approach should be considered a mandated component of standard of care. (Unfortunately, as previously noted, due to the early termination of this trial, it may not be possible to ever know the answer to this question.)

However, the fact that overall survival is not prolonged, or that we currently do not know if this will be the end result, does not alter a physician’s obligation to inform his/her patient of relevant data that may influence the individual’s decision regarding her own management.

Federal guidelines for the conduct of ethical clinical research clearly define the requirement that investigators provide patients with information that may influence their willingness to continue to participate in, or enter into, a clinical trial [10]. It is difficult to imagine that any objective observer could conclude that data revealing that the risk of progression of ovarian cancer may be reduced by 50% if treatment with single-agent paclitaxel is continued for an additional 12 months fail to meet the criteria for information that must be disclosed to study participants.

Further, a strong argument can be advanced that all oncologists, including clinical investigators, have an ethical obligation to inform appropriate patients (i.e., those who have met the study entry criteria) regarding the results of this trial, and to discuss how its findings may influence the individual patient’s future management.

Despite the legitimate concern that this additional information has the potential to confuse rather than enlighten patients, and may add an additional emotional burden, it is appropriate to argue that the optimal management choice can only be made when all relevant information regarding possible options has been provided to, and considered by, the patient and her family. Due to the morbidity, mortality, and emotional/psychological impact associated with malignant disease, and its treatment, individual choice is of particular importance in this group of medical conditions.

Certainly, there is nothing in this informational process that precludes a physician (e.g., a specialist with particular expertise in the area or a family physician with a long-term relationship as a trusted advisor) from providing a recommendation (even a forceful one) regarding what he/she considers to be the optimal course of action. This opinion may be based on general information about the disease and its therapy or specific concerns for the particular patient (e.g., added risk for serious toxicity associated with a specific management approach). However, it is the individual patient who must decide what course of action is best for her. In the case of maintenance treatment for ovarian cancer, the "right answer" to this question is what the patient decides is "right for her."

While this individual autonomous decision has the potential to invalidate PFS as a relevant end point in future randomized trials in advanced ovarian cancer if some women elect to receive consolidation therapy and others do not, it is the clinical research community that has the responsibility to establish a new mechanism to continue drug development in this area, rather than patients who must serve the wishes and needs of clinical investigators.

	REFERENCES

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1. Beecher HK. Ethics and clinical research. N Engl J Med 1966;274:1354–1360.
2. Levinsky NG. Nonfinancial conflicts of interest in research. N Engl J Med 2002;347:759–761.[Free Full Text]
3. Markman M, Liu PY, Wilczynski S et al. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 2003;21:2460–2465.[Abstract/Free Full Text]
4. McGuire WP, Hoskins WJ, Brady MF et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and IV ovarian cancer. N Engl J Med 1996;334:1–6.[Abstract/Free Full Text]
5. Markman M, Bookman MA. Second-line treatment of ovarian cancer. The Oncologist 2000;5:26–35.[Abstract/Free Full Text]
6. Markman M, Hakes T, Barakat R et al. Follow-up of Memorial Sloan-Kettering Cancer Center patients treated on National Cancer Institute Treatment Referral Center protocol 9103: paclitaxel in refractory ovarian cancer. J Clin Oncol 1996;14:796–799.[Abstract/Free Full Text]
7. Schafer A. The ethics of the randomized clinical trial. N Engl J Med 1982;307:719–724.[Medline]
8. Emanuel EJ, Patterson WB. Ethics of randomized clinical trials. J Clin Oncol 1998;16:365–366; discussion 366–371.[Free Full Text]
9. Smith MA, Ungerleider RS, Korn EL et al. Role of independent data-monitoring committees in randomized clinical trials sponsored by the National Cancer Institute. J Clin Oncol 1997;15:2736–2743.[Abstract/Free Full Text]
10. Department of Health and Human Services. Regulations for the Protection of Human Subjects (45 CFR 46), Section 46.116: General Requirements for Informed Consent. Code of Federal Regulations: Department of Health and Human Services.

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This Article Abstract Full Text (PDF) CME: Take the course for this article: Ethical Conflict in Providing Informed Consent for Clinical Trials: A Probl... eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Markman, M. Search for Related Content PubMed PubMed Citation Articles by Markman, M.