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Clinical Research in HER2 Positive Metastatic Breast Cancer – Ethical Issues of Trials Conducted in Low Resource Environments

06 May 2013
Breast cancer
Felipe Ades

Around 20% of breast cancers show amplification of the HER2 gene, which causes the overexpression of the HER2 transmembrane receptor and is associated with a more aggressive clinical course of the disease, resulting in higher propensity for visceral and brain metastatic dissemination and reduced overall survival. Trastuzumab is a humanized monoclonal antibody targeting the extracellular domain of HER2 receptor. In the metastatic breast cancer setting, trastuzumab significantly improves overall survival, and is responsible for a change in the natural course of this disease. The association of trastuzumab with cytotoxic chemotherapy has become the standard of care in the treatment of metastatic HER2 positive breast cancer after the publication of several positive trials.

A recent publication by Guan et al in the Journal of Clinical Oncology showed the results of a randomized, placebo controlled phase III pharma sponsored trial investigating the addition of lapatinib to paclitaxel in the first line treatment of HER2-positive breast cancer. The trial showed that the addition of lapatinib was associated with improvement in progression-free (median PFS: 6.5 versus 9.7 months; HR, 0.52; 95% CI, 0.42 to 0.64; P < .001) and overall survival (median OS: 27.8 versus 20.5 months; HR, 0.74; 95% CI, 0.58 to 0.94; P = .0124).

Importantly, the trial started recruiting patients in 2006, roughly 8 years after the approval of trastuzumab in the HER2 positive breast cancer metastatic setting by the Food and Drug Administration (FDA) (1) and five year after the publication of the full manuscript undoubtedly demonstrating the superiority of trastuzumab over no anti-HER2 treatment in this setting (2).

The trial was run in countries where trastuzumab is not reimbursed by the public health system and the investigators and sponsors based themselves on the outdated fourth edition of the Helsinki Declaration from 1996 that was not completely clear in defining standard of care. However, already in this edition the Declaration states that “the interest of science and society should never take precedence over considerations related to the wellbeing of the subject,” and “In any medical study, every patient — including those of a control group, if any — should be assured of the best proven diagnostic and therapeutic method.”

The two subsequent updates of the Helsinki Declaration clarified and strength the position of the scientific community on the use of placebo in clinical trials triggered by the research on vertical transmission of HIV in Africa conducted in the 90’s. Since 1994 a trial conducted in the United States showed that zidovudine was effective in reducing the HIV vertical transmission (3).  However several subsequent trials testing new drugs for that indication, were done in African countries using placebo in the control arm (4). At that time, the North American Centers of Disease Control and Prevention (CDC), the sponsor of the trial, justified the choice of placebo in the control arm by stating: “It is an unfortunate fact that the current standard of perinatal care for the HIV-infected pregnant women in the sites of the studies does not include any HIV prophylactic intervention at all” (5). A single treatment with drugs tested in Africa at that time cost several hundred times the annual per capita health care allocation of the countries where they were tested (6).

The fifth (2000) and sixth (2008) editions of the Helsinki Declaration are clear in defining the ethical issues of performing clinical trials on populations who would not benefit from the research and in the use of placebo. Paraphrasing article 17 “Medical research involving a disadvantaged or vulnerable population or community is only justified if the research is responsive to the health needs and priorities of this population or community and if there is a reasonable likelihood that this population or community stands to benefit from the results of the research.” And in article 29 “The use of placebo, or no treatment, is acceptable in studies where no current proven intervention exists” (7).


  • Is it ethical to use placebo or a “less-than-optimal control arm” in countries that do not reimburse the “best proven therapeutic method”? Should investigators base the ethical principles of their studies on outdated versions of the Helsinki Declaration?
  • Is lapatinib an affordable treatment option in countries where trastuzumab is not reimbursed for economic reasons?
  • If a trial is considered to have ethical flaws should its results be used in further scientific discussions or for drug market authorization?


  1. Trastuzumab, Genentech Herceptin approval letter - ucm091360.pdf [Internet]. [cited 2013 Apr 18].
    Available from: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm091360.pdf
  2. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 2001 Mar 15;344(11):783–92.
  3. Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O’Sullivan MJ, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N. Engl. J. Med. 1994 Nov 3;331(18):1173–80.
  4. Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries. N. Engl. J. Med. 1997 Sep 18;337(12):853–6.
  5. The development of consent requirements in research ethics. In: Faden RR, Beauchamp TL. A history and theory of informed consent. New York: Oxford University Press, 1986:151-99.
  6. Van Niekerk AA, Kopelman LM. Ethics & AIDS in Africa: the challenge to our thinking. Walnut Creek, Calif.; Oxford: Left Coast Press ; Berg [distributor]; 2005.
  7. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects [Internet]. 2008 [cited 2013 Apr 18].
    Available from: http://www.wma.net/en/30publications/10policies/b3/
Last update: 06 May 2013

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