Millum, J.

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21 DECEMBER 2007 VOL 318 SCIENCE www.sciencemag.org1874The aim of human subjects research is tocreate generalizable knowledge thatbenefits future patients. Consequently,it risks sacrificing the interests of researchparticipants for the greater good of society.Ethics guidelines exist to minimize this risk.Over the last decade, international biomedicalresearch in the context of substantial health-care inequalities has focused discussion onfour ethical issues: (i) standards of care; (ii)informed consent; (iii) ancillary care obliga-tions; and (iv) posttrial benefits (see table,right). It is appropriate to consider these issuesrelative to the Bucharest Early InterventionProject (BEIP) study (1), a randomized trial ofthe effects of moving institutionalized youngchildren to foster care.Four International Bioethical Issues The standard-of-care debate erupted in the1990s around placebo-controlled trials indeveloping countries of “short-course AZT”for prevention of maternal-fetal HIV transmis-sion. Short-course AZT was expected to be lesseffective than the standard AZT treatmentavailable in developed countries. Critics arguedthat using placebo controls, rather than stan-dard treatment as an active control, constituteda double standard—research forbidden on thewealthy would be carried out on the poor (2, 3).Supporters countered that it is permissible tooffer research participants in developing coun-tries less-effective interventions than thoseused in developed countries if doing so (i) isscientifically necessary to answer an importantquestion; (ii) does not deny anyone treatmentthey would otherwise receive; and (iii) isintended to develop interventions that willbenefit the developing country (4).Informed consent is fundamental to ethicalresearch. But some commentators argue thatvalid informed consent cannot be obtained indeveloping countries, whose inhabitants areimpoverished, poorly educated, deprived ofmedical services, and unfamiliar withresearch (5, 6). Others reply that this is patron-izing and inaccurate. Poverty may constrainchoices, but it does not make people coercedor incompetent, and participants in develop-ing countries seem to understand the elementsof research as well, or badly, as their wealthiercounterparts (7). Ancillary care refers to medical treatmentsprovided by researchers during the trial aboveand beyond what is required for safety or scien-tific validity. Although researchers in develop-ing countries often feel obliged to provide othertreatments that their subjects desperately need,the nature and extent of these obligations arenot well defined. The most complete accountjustifies ancillary care obligations becauseresearch participants entrust aspects of theirhealth to investigators through the proceduresthey undergo (8). Many believe that researchers have obliga-tions to provide participants posttrial benefits.These benefits are intended to prevent exploita-tion, which occurs when one party takes unfairadvantage of another (9, 10). In internationalresearch, the fear is that the developed worldwill get too much of the benefits of medicalresearch and the developing world too muchof its burdens. According to the Councilfor International Organizations of MedicalSciences (CIOMS), research in a community ispermissible only if researchers or their spon-sors ensure that interventions resulting from theresearch are made “reasonably available” to thecommunity (11).  An alternative, the “fair ben-efits” framework, proposes that posttrial bene-fits may comprise a myriad of benefits includ-ing ancillary care, training of health carepersonnel, employment, and economic stimu-lation, as well as the study intervention. Thetotal must be considered fair by the communityparticipating in the research (10).The Ethics of the BEIP StudyThe BEIP was a randomized trial comparinginstitutional and foster care for abandonedchildren currently in institutions. It took placein Romania, where there are thousands of insti-tutionalized children. Because, at the trial’sinception, Romania lacked basic foster care,the researchers developed their own, trainingfoster parents and providing social support. Thestudy found significantly improved cognitivedevelopment at 42 and 54 months for childrentransferred to foster care before 2 years of agecompared with institutionalized children.The initial reaction to the BEIP may be thatthe extreme vulnerability of abandoned, institu-tionalized children renders any research onthem unethical. Not only are they unable to giveinformed consent, there is no clear guardianacting in their best interests. This puts them atgreater risk of being selected for reasons ofconvenience rather than scientific necessity.While these are valid concerns, familiar safe-guards can protect such children. People whocannot consent can be protected by enrollingthem only in minimal-risk research, whoserisks do not exceed those of everyday life. Noneof the study’s assessments of functioning werelikely to harm the children. Restricting the par-ticipation of vulnerable groups, such as prison-ers and the institutionalized, to research thatPOLICYFORUMResearch with abandoned children does notnecessarily involve exploitation.The Ethics of InternationalResearch with Abandoned ChildrenJoseph Millum and Ezekiel J. EmanuelETHICSDepartment of Bioethics, The Clinical Center, NationalInstitutes of Health, Bethesda, MD 20892–1156, USA. *Author for correspondence. E-mail: eemanuel@cc.nih.govStandard of care Must interventions always be testedagainst the treatment available indeveloped countries?Informed consent Can poor people in developing countriesgive valid informed consent to research?Ancillary care What treatments should be provided byresearchers during the trial beyond thoseneeded for safety or scientific validity?Posttrial benefits What should be provided to researchparticipants and host communities afterthe research trial?Exceptions when scientifically necessary,no harm, and research aims to benefitcommunityDepends on the aspects of their healththat participants entrust to researchersTwo main approaches: reasonableavailability of study intervention andfair benefits approved by the communityAvailable data do not show informedconsent is invalidISSUE KEY QUESTION RESPONSEFour main ethical issues in international research.Published by AAAS on December 20, 2007 www.sciencemag.orgDownloaded from addresses important questions relevant to theirsituation protects against unfair subject selec-tion (12). The BEIP study aimed to produceresults that would primarily benefit abandoned,institutionalized children.The BEIP has many of the features thathave generated special concern about medicalresearch in developing countries. Romania,the host country, is a transition economy witha relatively poor health-care infrastructure anda large number of underserved institutional-ized children. The funding and research lead-ership for the trial came from the UnitedStates. Although the results may be relevant tothe United States and other developed coun-tries, there have been no American random-ized trials comparing foster and institutionalcare, and no American children would beenrolled in the BEIP. Of greatest concern arethe standards of care affected in the trial armsand the distribution of posttrial benefits.The appropriate standard of care for a clini-cal trial depends on the research question beinganswered. Although the importance of equi-poise, i.e., uncertainty among experts, is dis-puted (13), ethics requires at least that theresearch address an important question and bescientifically valid. Trials that do not meet theseconditions lack social value. If a research studywill not generate socially useful knowledge, itwastes resources and exposes participants torisks and burdens for no good reason. The BEIP study addresses an importantquestion; the welfare of institutionalized chil-dren depends on choosing correctly betweenfurther institutional care or switching to fostercare. Prior data focused on adoption and didnot directly address this comparison, hadselection biases, and lacked a definitive ran-domized trial. Thus, the study appears to ful-fill equipoise. Moreover, although both insti-tutional and foster care can sometimes resultin maltreatment, study participation was un-likely to cause net harm to the children; nochild was put at additional risk to obtain theresults, which reduces the ethical reasons forworrying about equipoise. Guarding Against ExploitationTo judge whether this trial involved exploita-tion requires assessing whether the study’sbenefits were distributed fairly among theparties involved. A useful framework isnational research. In a developed country, theresults of research are expected to eventually beintegrated, albeit haphazardly, into that coun-try’s health system. Although participantsassume risks in research, they, and their fellowcitizens, also benefit. If all subject protectionrequirements are fulfilled (14), the research ispermissible. But in international research, thepeople that benefit may not come from thesame society as the research participants;no shared national relationship betweenresearchers, subjects, and society exists. Thus,outsourcing research may increase the potentialfor exploitation.One way to minimize the chance ofexploitation is to emulate national research.According to CIOMS, achieving this in theinternational context requires that the researchbe responsive to the health needs of the studypopulation and that the population gains fromthe research results (10, 11).The BEIP meets these two conditions. Theresearch responds to the health needs of manyabandoned children for whom the state isresponsible. Moreover, the instigation of thestudy by the Romanian Secretary of State forChild Protection and official reaction to itsresults indicate that the study had a high likeli-hood of having an impact on these children’slives; state policy was likely to adopt the BEIPconclusions. This impact is not guaranteed:social and economic circumstances or govern-ment policies might change, resources may notbe made available for foster care, or the conclu-sions of the research may be disputed. Certaintyabout implementation cannot be required to eth-ically proceed with a study. Instead, researchersmust judge the likelihood that their work willgenerate health benefits, and proceed on thebasis of its expected benefit. The expectedbenefits to Romania’s abandoned childrenappear to provide ample justification for the BEIP.Finally, judging whether exploitation hasbeen avoided by using the responsiveness toneeds and reasonable availability criteria canbe problematic. These criteria consider bene-fits to the participants’community. But it is theparticipants—not the community—who bearthe risks of research and are therefore mostvulnerable to exploitation. Even when a suc-cessful intervention will be available to a pop-ulation after the trial’s completion, supplying itto the research participants themselves maynot be possible.Unfortunately, in many cases harm to par-ticipants is inherent in generating valid scien-tific results. In some trials, data on the effec-tiveness of an intervention cannot be obtainedwithout some risk to the subjects, perhaps ofserious or fatal outcomes. For instance, for avaccine trial to be successful, some participantsmust acquire the disease the vaccine is intendedto prevent. Otherwise, no intervention can beshown to be superior. But the preventive bene-fits of the vaccine do no good for participantswho became infected during the study. Similarissues arise in many cancer and cardiovasculartrials. The BEIP raises the same concern; thechildren who remained in institutional carecannot now receive the benefit of early fostercare, which the trial showed to be superior forsome developmental outcomes. This consideration does not make the BEIPstudy unethical, just as it does not make vaccinetrials unethical. However, it does indicate thatresearchers need to pay special attention to howresults get implemented when the benefits can-not accrue to participants. For instance, trialdesigns that move participants into the arm thatis doing better during the course of the trial canbe employed. According to the researchers,limited funds foreclosed this option. Alter-natively, as done in the BEIP, researchers canpresent valid scientific results as soon as possi-ble to those parties who can act on them. Theseparties have responsibilities to the participants,too; because the children were involved inresearch for the benefit of Romanian society,the representatives of society should ensure thatthe children get the care they deserve.The BEIP researchers did not create and arenot responsible for Romania’s institutionaliza-tion of abandoned children. They conductedresearch to determine what interventionswould benefit these children. This is not ex-ploitation, but shows how research can helpbenefit participants, as well as the wider popu-lation of abandoned institutionalized children.References and Notes1. C. A. Nelson III et al., Science 318, 1937 (2007).2. M . Angell, N. Engl. J. Med. 337, 847 (1997).3. P. Lurie, S. M. Wolfe, N. Engl. J. Med. 337, 853 (1997).4. R. K. Lie, E. J. Emanuel, C. Grady, D. Wendler, J. Med.Ethics 30, 190 (2004).5. G. Annas, M. Grodin, Am. J. Publ. Health 88, 560–563(1998). 6. N. A. Christakis, Hastings Cent. Rep. 18, 35 (June-July1988).7. C. Pace, C. Grady, E. J. Emanuel, SciDevNet, 28 August2003; www.scidev.net.8. H. S. Richardson, L. Belsky, Hastings Cent. Rep. 34, 25(January-February 2004). 9. A. Wertheimer, Exploitation (Princeton Univ. Press,Princeton, NJ, 1999), p. 10.10. The participants in the 2001 Conference on EthicalAspects of Research in Developing Countries, HastingsCenter Rep. 34, 17 (May-June 2004).11. International Ethical Guidelines for Biomedical ResearchInvolving Human Subjects (Council for InternationalOrganizations of Medical Sciences, Geneva, 2002),Guideline 10. 12. U.S. National Commission for the Protection of HumanSubjects of Biomedical and Behavioral Research, TheBelmont Report: Ethical Guidelines for the Protection ofHuman Subjects of Research (U.S. Government PrintingOffice, Washington, DC, 1979).13. F. Miller, H. Brody, Hastings Cent. Rep. 33, 19 (May-June2003). 14. E. J. Emanuel, D. Wendler, C. Grady, JAMA 283, 2701(2000).15. We thank C. Grady, F. Miller, G. Persad, A. Schulz-Baldes,D. Wendler, and A. Wertheimer. The opinions expressedare the authors’ own. They do not reflect any position orpolicy of the National Institutes of Health, U.S. PublicHealth Service, or Department of Health and HumanServices.10.1126/science.1153822www.sciencemag.org SCIENCE VOL 318 21 DECEMBER 2007 1875POLICYFORUMPublished by AAAS on December 20, 2007 www.sciencemag.orgDownloaded from 

The Ethics of International Research with Abandoned Children

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