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© 2002 American Society for Clinical Oncology
Ethical Issues Surrounding the Conduct of Off-Shore Clinical ResearchNew York University School of Medicine, New York, NY To the Editor:The study reported by Love et al1 raises important ethical issues surrounding the conduct of off-shore clinical research by American investigators. The study design compared tamoxifen and oopherectomy with observation as adjuvant therapy of breast cancer in premenopausal patients unselected for nodal or hormonal receptor status and was activated in 1993. The first issue is that the purpose of the trial is unclear from the "Purpose" section of the abstract and is not clarified in the body of the manuscript. I would be grateful if the authors could clarify the rationale for the study at the time the study was commenced. The second issue is the selection of observation as the control arm. The consensus statement of the Fourth International Conference on Adjuvant Therapy of Primary Breast Cancer (St Gallen, Switzerland), published in both the United States2 and Europe3 in 1992, which drew heavily on the Early Breast Cancer Trialists’ Collaborative Group overview of the same year,4 provided a thorough review of the current literature and the following evidence-based treatment recommendations for premenopausal women: (1) node-negative, low risk: nil versus tamoxifen; (2) node-negative, good risk: tamoxifen; (3) node-negative, high risk, estrogen-receptor (ER) positive: chemotherapy ± tamoxifen; (4) node-negative, high risk, ER negative: chemotherapy; (5) node-positive, ER positive: chemotherapy ± tamoxifen; and (6) node-positive, ER negative: chemotherapy.
Thus, the establishment of ER status was considered part of the standard management algorithm of node-positive and high-risk node-negative at the time the study was commenced, and observation was considered an acceptable therapy only for patients with low-risk node-negative disease (defined as "patients with noninvasive tumors (ductal carcinoma-in-situ), incidentally discovered small ( The control arm of the study should, therefore, have been unacceptable to an American or European patient or peer review process at the time that the study was activated, and the experimental arm should have been considered unacceptable for ER-negative node-positive and high-risk node-negative patients. Consequently, the results of the study are of academic interest only and do nothing to challenge our current standards of care. It is of interest to me that the study was able to accrue only 100 patients per year, and that that the United States Office for Protection of Research Risk apparently only reviewed the protocol at initiation. I contend that, no matter what the availability of standard adjuvant therapies in Vietnam and China at the time the study was commenced, the trial design failed to provide an internationally acceptable level of care to at least half of the study participants. If ER assays, tamoxifen, and chemotherapy were not routinely available to Vietnamese and Chinese women, the study exploited the lack of resources available to them; if those diagnostics and therapies were available, I believe that the study was simply unethical. REFERENCES
1. Love RR, Duc NB, Allred DC, et al: Oophorectomy and tamoxifen adjuvant therapy in premenopausal Vietnamese and Chinese women with operable breast cancer. J Clin Oncol 20: 2559-2566, 2002
2. Glick JH, Gelber RD, Goldhirsch A, et al: Meeting highlights: Adjuvant therapy for primary breast cancer. J Nat Cancer Inst 84: 1479-1485, 1992
3. Glick JH, Gelber RD, Goldhirsch A, et al: Adjuvant therapy of primary breast cancer. Ann Oncol 3: 801-807, 1992 4. Early Breast Cancer Trialists’ Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic or immune therapy: 133 randomized trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 339:1-5;71-85, 1992
ResponseUniversity of Wisconsin Comprehensive Cancer Center, Madison, WI In Reply:While the challenges of conducting ethical clinical research in developing countries have been more widely discussed with respect to AIDS than cancer, the essential points made by Varmus and Satcher are very relevant to Dr Hamilton’s perspectives on our reported trial: ". . . it is essential that the debate take place with a full understanding of the nature of the science, the interventions in question, and the local factors that impede or support research and its benefits."1 Although we have written in some detail about review of specific ethical issues in our trial, Dr Hamilton’s letter provides an opportunity to further address certain issues.2 There are two recent publications that provide a framework for addressing Dr Hamilton’s points. Emanuel et al3 have proposed seven requirements for ethical clinical research; two of these, social or scientific value and favorable risk-benefit ratio, are central issues for us and for Dr Hamilton. The report of the National Bioethics Advisory Commission discusses the additional important but usually neglected issue of posttrial benefits in a world with vast inequities in wealth and resources.4 The overall goal of our study was to define an adjuvant therapy for women with the most common presentations of breast cancer in Vietnam, which, if demonstrated to be effective, could be widely applied there. At the time our study began and until recently, the standard of care in Vietnam for operable breast cancer was mastectomy alone. Our study has resulted in a change in that standard of care. The American and European standards presented in the publications to which Dr Hamilton refers are not universal standards and cannot be used to define "an internationally accepted level of care." Medical standards of care vary among societies for a variety of scientific, economic, and cultural reasons. The primary responsibility for ethical review of trials such as ours falls on the country in which the research is taking place. Our trial was initially reviewed and annually rereviewed by the Vietnamese Ministry of Health and leaders of the National Cancer Institute Hospital in Hanoi; it was also reviewed by the leaders of the Vietnamese Women’s Union. A second level of review occurred in my American institution, which provided initial approval and then required annual review along with a written statement from the extramural data monitoring committee, which was responsible for dealing with issues of changing science. The Office for Protection of Research Risks, which it is not an institutional review board, has no role in specific project/trial review; rather, its role is to ensure that for foreign projects the stated reviews do occur. The statement by Mr Mbidde at the end of the Varmus and Satcher article1 is relevant to our trial: "Ours was a study of Vietnamese women conducted by Vietnamese investigators and approved by Vietnamese authorities concerned about prudent and efficient use of medical resources." It has been usual and ethical global practice to evaluate new therapies against the local standard of care, which, in the case of breast cancer in Vietnam, has included no systemic adjuvant therapy. Why has this been a reasonable standard? First, there have been no rigorous data about adjuvant interventions in this or similar populations. For biologic and socioeconomic reasons, therapies have different risks and benefits in different populations; thus, it cannot be assumed that Vietnamese women would benefit from Western therapies. Vietnam is a poor country with a predominantly rural population. Poor nutrition, chronic or recurring infections (tuberculosis is endemic in Vietnam), and limited access to diagnostic and supportive therapies (surgical pathology, mammography, antibiotics, blood transfusions, and antiemetics) have characterized the health status and medical care for many Vietnamese women. Until very recently there has been no reliable system in any Vietnamese hospital for assaying breast tumors for estrogen receptors. Developing such capacity has now, in light of our data, become possible, and I and my pathology coinvestigators have trained two Vietnamese pathologists in the United States who then became surgical pathologist trainers themselves in a workshop/course for which we provided the complete financial support, in Hanoi in March, 2002. Moreover, the state of the art with respect to hormonal adjuvant therapy at the beginning of our trial was addressed in the introduction section of our article.5 Tamoxifen was not proven therapy in premenopausal women, and the results of the oophorectomy meta-analysis were unexpected, hypothesis-generating, and based on only subsets of patients studied in the original trials.6 Furthermore, Asian physicians have long expressed concerns about excessive toxicities with standard chemotherapy regimens; rigorous data have now been developed to confirm these concerns; myelotoxicity of anthracycline/cyclophosphamide adjuvant chemotherapy is significantly greater in Asian women.7 Whether this is on a morphometric or pharmacogenetic basis is not understood. In practice in Asia, however, this excessive toxicity has long led to use of reduced doses and altered drug administration schedules, whose impact might be expected to decrease, if not completely negate, any therapeutic benefit.8 These considerations all led to a recognition by ethical review committees and other authorities in the United States and in Vietnam, that for Vietnam, a standard of care with respect to adjuvant therapy which differed from that in Western countries was a fact of life and not unwise. The research we facilitated actually offered better than the standard of care for women in the no-adjuvant treatment arm because of attention to details of initial diagnosis and treatment, regular follow-up, and organized and no-cost therapy for those patients who developed recurrent disease. The safety data developed from the trial are critical in the efforts now to change clinical practice for Vietnamese women throughout the country. In sum, in our trial, we met Emanuel’s requirements with respect to value and assessment of risks and benefits; and in addition, even for a trial with chemotherapy treatment, a strong case could have similarly been made for a no-adjuvant therapy arm.3 To Dr Hamilton’s suggestion that our trial was exploitative of Vietnamese women, I would suggest that, on the contrary, our trial was the most effective way to prevent exploitation by pharmaceutical entrepreneurs who are aggressively marketing chemotherapeutic drugs in South East Asia, in the absence of data on the impact of these treatments. A difficult issue to which we have tried to be sensitive from the beginning of our work in Vietnam is highlighted by the National Commission’s report: access of the broad population of Vietnam to benefits of the knowledge or treatment studied in a clinical trial.4 The intervention we studied could be applied very widely, whereas chemotherapy programs cannot. The total costs of an adjuvant chemotherapy program vary of course in different settings, but costs of the pharmaceuticals alone make such treatment prohibitive or significantly burdensome for women in a country with a per capita annual income of $365. In contrast, a cost-effectiveness analysis of the intervention we tested, in women unselected for estrogen-receptor status, suggested that this costs $350 per year of life saved.5 The apparent narrow scope in Dr Hamilton’s statement about "our current standards of care" is unfortunate in that it seems to apply only to the United States and Europe. Based on data from Parkin et al9 and our assessment of the frequency of hormone receptor–positive tumors in premenopausal Asian women, about 450,000 premenopausal Asian women will be diagnosed annually with estrogen receptor–positive tumors. The newest St Gallen consensus includes oophorectomy plus tamoxifen as the first or second option for adjuvant therapy for women in this category.10 I believe that Asian, indeed all women, are better off for the existence now of our rigorous data supporting that standard of care. I have always felt, and after September 11 have felt even more strongly, that "our" standards of care need much more frequently to take into account the circumstances of the large majority of fellow travelers on planet earth. Finally, far from being irrelevant to Western women, this trial has produced other findings very relevant to women with breast cancer everywhere.11-13 REFERENCES
1. Varmus H, Satcher D: Ethical complexities of conducting research in developing countries. N Engl J Med 337: 1003-1005, 1997 2. Love RR, Fost NC: Ethical and regulatory challenges in a randomized control trial of adjuvant treatment for breast cancer in Vietnam: Westerman Prize winning entry of American Federation for Medical Research. J Invest Med 45: 423-431, 1997[Medline]
3. Emanuel EJ, Wendler D, Grady C: What makes clinical research ethical? JAMA 283: 2701-2711, 2000 4. United States National Bioethics Advisory Commission: Ethical and policy issues in international research: Clinical trials in developing countries. Bethesda, MD, 2001
5. Love RR, Duc NB, Allred DC, et al: Oophorectomy and tamoxifen adjuvant therapy in premenopausal Vietnamese and Chinese women with operable breast cancer. J Clin Oncol 20: 2559-2566, 2002 6. Early Breast Cancer Trialists’ Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 339:1-15;71-85, 1992 7. Beith JM, Goh BC, Yeo W, et al: Inter-ethnic differences in the myelotoxicity of Adriamycin/cyclophosphamide for adjuvant breast cancer. Proc Am Soc Clin Oncol 21: 64a, 2002 (abstr 252)
8. Bonadonna G, Valagussa P, Moliterni A, et al: Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: The results of 20 years of follow-up. N Engl J Med 332: 901-906, 1995 9. Parkin DM, Pisani P, Ferlay J: Estimates of the worldwide incidence of 25 major cancers in 1990. Int J Cancer 80: 827-841, 1999[CrossRef][Medline]
10. Goldhirsch A, Glick JH, Gelber RD, et al: Meeting highlights: International Consensus Panel on the treatment of primary breast cancer. J Clin Oncol 19: 3817-3827, 2001 11. Love RR, Duc NB, Dinh NV, et al: Young age as an adverse prognostic factor in premenopausal women with operable breast cancer. Clinical Breast Cancer 2: 294-298, 2002[Medline]
12. Love RR, Duc NB, Dinh NV, et al: Mastectomy and oophorectomy by menstrual cycle phase in operable breast cancer. J Natl Cancer Inst 94: 662-669, 2002 13. Love RR, Duc NB, Havighurst TC, et al: HER-2/neu overexpression and response to oophorectomy plus tamoxifen adjuvant therapy in estrogen receptor-positive premenopausal women with operable breast cancer. J Clin Oncol (in press)
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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1 cm) invasive tumors detected by mammography or by microscopic examination of tissue removed because of benign breast disease or because of in situ breast carcinoma", as well as those with certain low-risk histologies). 
