Ethical Principles for the Conduct of Human Subject Research- Pop

7/28/2019 Ethical Principles for the Conduct of Human Subject Research- Pop

1/12

Georgetown University Law Center

Scholarship @ GEORGETOWN LAW

1991

Ethical Principles for the Conduct of HumanSubject Research: Population-Based Research and

EthicsLawrence O. GostinGeorgetown University Law Center, [email protected]

Follow this and additional works at: hp://scholarship.law.georgetown.edu/facpub

Part of the Bioethics and Medical Ethics Commons, Health Law Commons, Health PolicyCommons, Public Health Commons, and the Public Policy Commons

Tis paper can be downloaded free of charge from:hp://scholarship.law.georgetown.edu/facpub/764

Tis open-access article is brought to you by the Georgetown Law Library. Posted with permission of the author.

19 L. Med. & Health Care 191-201 (1991)
http://scholarship.law.georgetown.edu/?utm_source=scholarship.law.georgetown.edu%2Ffacpub%2F764&utm_medium=PDF&utm_campaign=PDFCoverPageshttp://scholarship.law.georgetown.edu/facpub?utm_source=scholarship.law.georgetown.edu%2Ffacpub%2F764&utm_medium=PDF&utm_campaign=PDFCoverPageshttp://network.bepress.com/hgg/discipline/650?utm_source=scholarship.law.georgetown.edu%2Ffacpub%2F764&utm_medium=PDF&utm_campaign=PDFCoverPageshttp://network.bepress.com/hgg/discipline/901?utm_source=scholarship.law.georgetown.edu%2Ffacpub%2F764&utm_medium=PDF&utm_campaign=PDFCoverPageshttp://network.bepress.com/hgg/discipline/395?utm_source=scholarship.law.georgetown.edu%2Ffacpub%2F764&utm_medium=PDF&utm_campaign=PDFCoverPageshttp://network.bepress.com/hgg/discipline/395?utm_source=scholarship.law.georgetown.edu%2Ffacpub%2F764&utm_medium=PDF&utm_campaign=PDFCoverPageshttp://network.bepress.com/hgg/discipline/738?utm_source=scholarship.law.georgetown.edu%2Ffacpub%2F764&utm_medium=PDF&utm_campaign=PDFCoverPageshttp://network.bepress.com/hgg/discipline/400?utm_source=scholarship.law.georgetown.edu%2Ffacpub%2F764&utm_medium=PDF&utm_campaign=PDFCoverPageshttp://network.bepress.com/hgg/discipline/400?utm_source=scholarship.law.georgetown.edu%2Ffacpub%2F764&utm_medium=PDF&utm_campaign=PDFCoverPageshttp://network.bepress.com/hgg/discipline/738?utm_source=scholarship.law.georgetown.edu%2Ffacpub%2F764&utm_medium=PDF&utm_campaign=PDFCoverPageshttp://network.bepress.com/hgg/discipline/395?utm_source=scholarship.law.georgetown.edu%2Ffacpub%2F764&utm_medium=PDF&utm_campaign=PDFCoverPageshttp://network.bepress.com/hgg/discipline/395?utm_source=scholarship.law.georgetown.edu%2Ffacpub%2F764&utm_medium=PDF&utm_campaign=PDFCoverPageshttp://network.bepress.com/hgg/discipline/901?utm_source=scholarship.law.georgetown.edu%2Ffacpub%2F764&utm_medium=PDF&utm_campaign=PDFCoverPageshttp://network.bepress.com/hgg/discipline/650?utm_source=scholarship.law.georgetown.edu%2Ffacpub%2F764&utm_medium=PDF&utm_campaign=PDFCoverPageshttp://scholarship.law.georgetown.edu/facpub?utm_source=scholarship.law.georgetown.edu%2Ffacpub%2F764&utm_medium=PDF&utm_campaign=PDFCoverPageshttp://scholarship.law.georgetown.edu/?utm_source=scholarship.law.georgetown.edu%2Ffacpub%2F764&utm_medium=PDF&utm_campaign=PDFCoverPageshttp://www.law.georgetown.edu/?utm_source=scholarship.law.georgetown.edu%2Ffacpub%2F764&utm_medium=PDF&utm_campaign=PDFCoverPageshttp://www.law.georgetown.edu/?utm_source=scholarship.law.georgetown.edu%2Ffacpub%2F764&utm_medium=PDF&utm_campaign=PDFCoverPages


2/12

Ethical Principles for the Conductof Human Subject Research:Population-Based Research and Ethics

Larry Gostin

Ethical principles for the protection of human subjects inclinical research are now well recognized,' and rooted inthe inherent worth and dignity of the individual.Respect for persons recognizes people as autonomousagents and requres that their choices be observed. Forpersons who are not fully autonomous, the principle ofrespect for persons requires that they are protected fromrisks and adverse consequences of research, even some-times excluded from research.Beneficence (do good) and non-maleficence (do noharm) are complementary ethical principles that imposeaffirmative duties on researchers to maximize any benefitsfor subjects and minimize any risks. Thus, researchersmust go beyond mere respect for a person's choices. Theresearcher must be vigilant to ensure that the subject re-ceives all possible benefits and avoids all possible harmsfrom participating in the research.Justice requires that human beings be treated equally

unless there is a strong ethical justification for treatingthem differently. Thus, the distribution of benefits andburdens in research should be equitable. In thinking aboutjustice toward subjects, researchers need to consider equi-table selection so that individuals are chosen on the basis offactors clearly relevant to the problems being studied.Researchers also need to consider equitable distribution ofadvantages to research subjects and others who couldbenefit from the knowledge gained by the research.These ethical principles have found expression in in-ternational guidelines for the conduct of clinical research',and have been codified in national statutes and regula-tions, particularly in the developed world?Ethical principles help support autonomy and self-determination, protect the vulnerable, and promote the

welfare and equality of human beings. But traditionalethics focuses primarily on individual rights and duties,and does not always see individuals as part of wider socialorders and communities. A person dominated medicalethic is nsufficient for the task of setting moral and humanrights boundaries around the conduct of research on popu-lations.This paper provides a halting first step in organizing aset of ethical guidelines for the conduct of population-based research, surveillance and practice. These principlesare not distinct from, but an expansion of, traditionalethics. Research ethics, which matured significantly fromthe Nuremberg Code through to the Helsinki IV and theCIOMS guidelines, nourished the individual human spirit.Ethical principles should have a similarly profound impactin the development of science and the protection of humanpopulations in the 199os and beyond.The application of ethical principles to populationsEthical principles applied to larger groups of people orpopulations are designed to protect the human dignity,integrity, self-determination, confidentiality, rights, andhealth of populations and the people comprising them.The kinds of social groupings encompassed in this defini-tion include communities, cultures, social orders, andpopulations of various description including racial, ethnic,religious, cultural, and other minorities. Ethical principlesalso establish positive moral responsibilities of persons andauthorities which sponsor, conduct, or oversee research onpopulations. This includes governments, funders, and in-vestigators in the country which embarks on the researchas well as the country which hosts the research.


3/12

Volume 19: 3-4, Fall-Winter1991

The importance of group identity, and of treatingsocial communities with dignity and respect, is ncreasinglywell recognized. Human beings gain security, happiness,and enjoyment by forming networks based upon theirspecial national or sub-national characteristics. 4 Respectand beneficence for populations requires researchers toobserve choices made by local communities, and to avoidany activity which stigmatizes, demeans, harms, or disinte-grates human populations, intentionally or inadvertently.The term "population-based research" is broadly de-fined to include all research and practice performed on, orwhich affects, groups of people or populations. This in-cludes epidemiologic research and surveillance, and inter-vention epidemiology, including field trials for drugs orvaccines.Population based research, surveillance, and practicecan have extraordinary benefits and risks. The potentialfor human good, measured in improvement of health anddecreased morbidity and mortality from population-basedresearch and practice represents one of the great triumphsof science in the zoth century. But, the potential to causeharm to human beings and the groups they comprise isalso much greater.Population-based research and practice affect not onlyindividual research subjects but integrated groups ofpeople, sometimes of considerable size. This can entaillarge scale collection, storage, transfer, and use of sensitivehealth care, demographic, social, and behavioral data.Modern field trials can also actively intervene in the behav-iors, lifestyles, social and family interactions, or environ-ments, of communities. Levine provides illustrations ofrisks to societies such as introduction of a new microor-ganism, spread of infection to persons outside the trial, andpremature or inappropriate dissemination of findings oropinions of researchers which may result in harmfulchanges in behavior, false hopes for cures, or lowered self-image. 5Foundational principles must also be developed toprotect the dignity and integrity of all populations includ-ing vulnerable populations which are non-dominant, poor,disenfranchised, compromised, persecuted, or restricted.This paper enunciates five such principles: (i) he overrid-ing imperative to protect the health and well-being ofpopulations, (ii)respect for populations and their right toself-determination, (iii) protection of vulnerable popula-tions and the need for special justifications for research,(iv) protecting the privacy, integrity, and self-esteem ofpopulations, and (v) he equitable distribution of benefitsto populations and the importance of building infra-struc-ture.First do no harmThe Geneva Declaration does not specifically cover human

subject research, but restates the first principle of medicineenunciated in the Hippocratic oath-a doctor's first duty isto his or her patient.6 In the context of population-basedresearch the investigator has a dual responsibility to indi-vidual subjects and to the populations they are part of. Thefirst principle in this area of ethics is not to harm thesubject population.The duty not to harm is grounded in the principles ofbeneficent treatment of, and respect for, populations. Ap-plication of the principle of beneficence toward individualsin biomedical research often is measured by a favorablebenefit to harm ratio. The potential benefits of a newpharmaceutical or vaccine must be well understood fromlaboratory models, the risks must be reasonable, and theadverse effects must be carefully monitored and controlled.Beneficence toward populations certainly requires afavorable balance of potential benefits and harms. But, theconcern is not merely with the physical health of thehuman subject, but also with the potential benefits andharms to the group or culture that is being studied. Humansubjects, for example, may be medically protected, but theresearch may be of little value to , or reflect poorly on, thegroup to be studied.A prerequisite of ethical research is that it is basedupon a sound objective recognized as a priority in thecountry to be studied. The research, therefore, should beclearly relevant to the public health problems in the localcommunity. Is it ethically justified to conduct research in ahost country for the overwhelming benefit of anothercountry? Research of intrinsic scientific value or a valueestablished in one country may not be valid if conducted inanother country which has little interest in, or need for,that scientific information. Research to address a pressingpublic health problem in developed countries (e.g. coro-nary heart disease) may be irrelevant in developing coun-tries which may be more concerned with diarrheal diseaseand maternal-child health. If the preponderant benefits ofa study are in the source, rather than in the host country, astrong justification would have to be made to initiate theresearch.7The ethical question isnot only whether the research isneeded in the host country, but also whether it iswanted.Respect for populations suggests that representatives whocan legitimately speak for the people ought to have controlover whether, and how, research is conducted, and howthe outcomes of research are distributed and used to ben-efit the population.Good science isalways an overarching requirement ofethical research. The quality of research is establishedwhere the scientific protocol is reviewed in both countriesusing processes that are developed in culturally and legallyappropriate ways ineach country. Good scientific research,wanted and reviewed by all relevant parties, ultimatelyprovides the best protection for human populations.


4/12

Law, Medicine & Health Care

Respect for people and populations: Individualconsent, permission and community consensusThe focus on individualism in traditional ethics is mostclear when the principle of respect for persons isexamined.The primary way to respect individuals is o abide by theirchoices, whether or not others believe their choices arewise or beneficial. "To show lack of respect for an autono-mous agent is to repudiate that person's considered judg-ments, to deny an individual the freedom to act on thoseconsidered judgments, or to withhold information neces-sary to make a considered judgment."8 Autonomy andself-determination are illuminated by the antagonistic prin-ciple of paternaligm, where decisions are made for, not by,individuals because others know better what is in thatperson's interests.

Since the Nuremberg Code, international human rightsdeclarations have focused on autonomy rather than pater-nalism. International law perceives individuals as capableof exercising the power of choice. People must be free todecide whether to participate in research or to withdrawtheir participation without any influence of coercion, fraud,deceit, or constraint.9 Helsinki IVIand the CIOMS Pro-posed Biomedical Research Guidelines" focus on the needfor advance information on research methods, objectives,benefits, and risks to allow an informed choice.Autonomy and individual consent are invaluable prin-ciples which allow competent persons to keep control overhealth and research decisions. Ethical research alwaysplaces the desires and needs of the subject over those of theinvestigator." The principle of consent thus helps preventabuse by overzealous governments or researchers who aresometimes under great pressure to conduct expeditiousand successful research into the overwhelming health prob-lems facing both developed and developing countries.The limits of consent as a method of preserving hu-man dignity and health, however, are increasingly wellunderstood. As a safeguard against abuse consent is, atbest, an imperfect instrument. Informed consent, even indeveloped countries which originated the doctrine, is anideal which does not always work in practice." The in-equality of expertise and influence between researcher andsubject can be so great as to undermine the real authorityof subjects to withhold or withdraw consent. Innumerableproblems can interfere with a truly informed and volun-tary relationship between clinician/investigator and pa-tient/subject: the fine line between therapeutic practice andscientific research; the lack of access to innovative treat-ments outside of established clinical trials; the payment ofmoney or other inducements to enter and remain in re -search; the differences in linguistic and cultural under-standings between researchers and human subjects; andthe sheer complexity of written informed consent formsoften thought necessary or expedient for the purposes of

the legal system.Thus, even in well developed countries where the legalsystem and culture foster the concept of informed consent,practical realities may impede voluntariness and effectivecommunication between researcher and subject. This isparticularly true when research is undertaken in urbanghettos or poor rural areas where problems of illiteracy,and mistrust based upon race, culture, or social class mayundermine the researcher/subject relationship.The practical obstacles to obtaining voluntary andinformed consent in international collaborative researchare even more evident: the marked inequality of power andresources; the vast differences in law and culture; and thepressing problems of disease, hunger, illiteracy, and pov-erty.' 4Law and regulation in technologically developed coun-tries may require detailed written informed consent forparticipation in research even if it is conducted in anothercountry with different laws and customs.'5 Regulators inparts of the developed world sometimes forget that writtendocumentation is merely evidence of the consent, no t theconsent itself, and that documentation is an alien conceptin many cultures. Requiring a person who may be illiterateand whose first language may be different to comply withNorthern/Western conceptions of written informed con-sent is unrealistic.In some communities the very concept of respect forpersons as individuals may be at variance "with morerelational definitions of the person found in othersocieties...which stress the embeddedness of the individualwithin society and define a person by his or her relations toothers."6 In some cultures there is little perception ofconflict between self and society, except perhaps if thesociety issomeone else's.", For example, in the Indian sub-continent and West Africa great deference may be given toclinicians/healers/elders.'8 Decisions are characteristicallymade in consultation with leaders in the setting of villagemeetings."9 If permission has already been given by acommunity or family representative, the idea of an in-formed refusal by the individual may not even arise.Henderson et al. found that obedience to tribal leaders is astrong factor influencing participation in research in WestAfrica.20 Where indigenous cultural beliefs exist the re-search may take on a wholly different meaning in the localcountry than the Northern scientist understands." Ajayiillustrates this point with the socio/cultural/religious beliefsin West Africa regarding blood letting, biopsy, and post-mortem examinations.Giving impoverished people in the developing worldmoney, drugs, and food in exchange for their agreement toenter and remain in clinical trials may make it inconceiv-able that they would say no." Yet, providing reasonablecompensation to impoverished subjects who may have totake time from life sustaining work is entirely justified.


5/12

Volume i9: 3-4, Fall-Winter 1991

Despite the real problems of importing a Northern/Western concept of informed consent in Third Worldcountries, some culturally appropriate agreement to par-ticipate in research isessential. "While consent proceduresmust be adapted to accommodate cultural mores, theremust always be a requirement for consent from the indi-vidual prospective subject.", It is false to equate illiteracyor cultural differences with the inability to make decisions.Information should be presented to subjects in a mannerwhich is comprehensible and consistent with local lan-guage, custom and culture. It isequally incorrect to assumethat an individual's strong relationship with family andsociety are inconsistent with informed consent. The factthat individuals, in deciding whether to give consent, givedeference to the views of family and community leaders,and carefully consider the benefits to society, does notnegate their consent.The CIOMS Proposed Guidelines on Biomedical Re-search4 recommend that, if a person cannot give adequateinformed consent, it is desirable to obtain proxy consentthrough the intermediary of a trusted community leader."While it may be important to recognize the cultural impor-tance of community or family leaders, it isunwise to referto this process as a consent. It ismore accurately labeled as"permission." The leader may represent the interests of thecommunity more than the individual and may him orherself be susceptible to inducements which undermine thepurpose of consent.Large scale research raises a further issue as to howconsent is given on behalf of the population. Specifically,can a legitimate representative of the community giveconsent on behalf of each of its members? Clearly, commu-nity leaders cannot realistically give consent on behalf ofthe entire population, for they have no way of knowingwhat decision each person would make. "Consent" is thewrong concept because each of the traditional elements islacking: specific information on benefits and risks,voluntariness, and competency. A better conception is tosay that leaders ought to be consulted to obtain a "commu-nity consensus" on population-based research.In many situations it may be difficult to ascertain whois the legitimate representative of the community. Govern-ments or public health agencies may, or may not, beelected by the people and have their rights and best inter-ests at heart. Some leaders have no formal or recognizedlegal authority to speak for the population, but may bewidely looked to as religious, cultural or social representa-tive of te people. In seeking community consensus forlarge scale research, investigators must be knowledgeableof, and sensitive to, local perceptions of those who are intrue leadership positions.It would be antithetical to all understanding of humanrights to suggest that a leader could give "permission" foran individual or provide "consensus agreement" for the

community, as a substitute for individual consent. Rather,researchers have an ethical obligation to seek consent fromthe individual, as well as permission or consensus, whenculturally appropriate. Thus, the inter-related concepts ofindividual consent, permission, and consensus should beregarded as additive ethical obligations which are to beexamined within the context both of international humanrights norms and local cultural and ethical beliefs.An effective model of consent, permission and consen-sus has been reported by Hall in Gambia. Individual agree-ment issought through a hierarchical chain beginning withthe government, then moving to the chief of the district,and to the head of the village. Village meetings are held toexplain the study, and each individual is asked if he or sheagrees to the study in his or her household.X6

Protection of vulnerable people and populationsNot every human being can give a competent and volun-tary consent to research. Some people have diminishedautonomy due, for example, to young age, mental illnessor mental retardation. Others, such as prisoners, or, insome countries, the military, are so impeded in their free-doms and so subject to authority, that their consent is notentirely voluntary. For some individuals such as pregnantwomen, there can be increased risks associated with re-search; the woman herself may be subjected to heightenedrisk due to her condition, and the fetus may be utinecessar-ily exposed to harm. Respect for people with diminishedcapacity, those who are not entirely free to choose, orthose with a heightened risk may require protection frompotential harms of research. People may be so vulnerablethat strict criteria must apply before they can even partici-pate in a clinical trial.Traditional micro-ethical principles, therefore, requirea special justification before research is conducted on vul-nerable individuals. In general, vulnerable subjects areselected only if the research is directly relevant to theperson or class of persons-e.g., the very issue to bestudied is prevalent in, or unique to, the group. 7Ethical principles would similarly require a specialjustification for research on vulnerable populations. Vul-nerable populations could be defined as a class of individu-als or groups who are non-dominant, substwvient, orsubject to restrictions in the culture where they live. Itcould include a minority race, religion, ethnic group, indig-enous people, or aliens. These groups may have retainedsocial, cultural, economic and political characteristicswhich are distinct from those of other segments of nationalpopulations.,' Examples of epidemiologic research on non-dominant social groups include studies of prostitutes forsexually transmitted infections, drug users for needle-borneinfections, women and children for vertical transmission ofdisease, and gays or hemophiliacs as risk groups for HIV


6/12


infection. Vulnerable populations might also include per-secuted non-minorities such as women in cultures wherethey are wholly subservient to their spouses.Non-dominant populations should be regarded as vul-nerable for much the same reasons that apply to individu-als. Non-dominant populations are inherently likely to beexploited. Poverty makes a population more susceptible tofinancial or other inducements; their culturally or politi-cally insular position may undermine their autonomy andability to resist the suggestion of authorities that theyparticipate in research; their illiteracy and lack of adequatecommunication networks makes it difficult to disseminatecomprehensive and comprehensible information; their hun-ger and poor health may heighten the risks and burdens ofresearch. Under such circumstances, the principles of re-spect and beneficence toward populations militates againstimposing burdens without a special justification.

Special circumstances justifying research onvulnerable groupsWhat are the special circumstances that might justify re-search on vulnerable groups? Aparticularly favorable ben-efit to burden ratio would be one prime factor. If it couldbe established that the health advantages to the populationclearly outweigh the minimal risks or burdens, this wouldhelp protect the population.Second, the problem to be studied should be clearlyrelevant to the unique or special health problems of thepopulation. A study of tropical disease, for example, in anendemic area may be completely justified, even though thepopulation is highly vulnerable. The principle of justice, ofcourse, would require that the vulnerable population hasaccess to the present and future benefits of the research.Third, every effort should be made to maximize therights of the population to self-direction and protectionfrom harm. The voices of vulnerable populations shouldbe heard and respected not only on issues of subject selec-tion, but also on the ethical conduct and outcomes of theresearch. Thus, genuine representatives of the population(as well as the individuals who comprise the population)must agree to participate, must have the right to withdrawat any time, and must be consulted in the use of theinformation generated from the study. If the study maycast aspersions on, or in some way disintegrates, the com-munity, this must be discussed as part of the process ofconsent, permission, and consensus.The relevant criteria, then, are whether there is afavorable benefit to burden ratio, whether the problem isrelevant to the special health problems of the population,and whether the population chooses the research. To many,however, research may be justified when it provides apotential for overwhelming benefit for humankind, even ifthe benefit to the research population is in doubt. Consider

the real ethical quandary over HIV anti-viral or vaccineresearch in Africa, particularly if undertaken on especiallyvulnerable groups such as prostitutes. Field trials may beaccomplished more expeditiously in endemic areas be-cause of the greater incidence of infection. The scientificadvantages are that reliable results could be obtained morequickly and at less expense. The local population, how-ever, may never see the benefit of a safe and efficaciousdrug or vaccine due to the prohibitive cost, and an expen-sive anti-viral might be low on the health care priorities ofthe host country. Similarly, in z vaccine trial for HIV,beneficent treatment of persons would require that sub-jects were counselled to avoid high risk behavior. Thiswould undoubtedly result in a relatively smaller measuredinfluence, requiring a larger sample size to demonstrate theefficacy of the vaccine.Cost and expediency alone are seldom sufficient ethi-cal justifications for subject selection. The key questionsare how much benefit and harm might accrue to thepopulation? Are there adequate laboratory or animal mod-els to predict efficacy and risk? What are the reasons thatother, less vulnerable, subjects cannot be used, and canthey be used in parallel?First World research in Third World countriesIn international collaborative research First World investi-gators conduct research in poorer Third World countries.Because of the inherent inequality in economic and politi-cal power, these local communities may also be thought ofas vulnerable populations and subjected to ethical rulesthat are similar to those applied to vulnerable individualsand groups within the same country. It is a legitimateethical inquiry to ask why investigators choose to do theirresearch abroad rather than at home. First, and mostcynically, governments, sponsors and investigators may beprepared to impose risks and burdens on Third Worldpopulations which they are reluctant to impose on theirown populations. A particularly risky, intrusive, or politi-cally controversial piece of research may be perceived to beeasier to conduct thousands of miles from home. A keyinternational principle for research on human beings isthat "a nation should not allow or support, in othercountries, research which does not conform to ethics re-view standards at least equivalent to those in force withinthe nation."19 Clearly, if research could be conducted aseffectively on home populations, there should be specialjustifications before carrying it ou t on poorer populationsabroad. Indeed, similar reasoning would prohibit researchon the poor, illiterate, and unhealthy dweller of the ghettoif the research could just as effectively be carried out in anaffluent suburb.Second, researchers might choose poorer populationsfor their research because of financial, management, and


7/12

Volume 19:3-4, Fall-Winter 1991

administrative reasons. AThird World population may beregarded as more available, manageable, and less expen-sive than in a developed country. Naked financial or ad-ministrative considerations are rarely sufficientjustifications for imposing risks and burdens on poorerpopulations. However, if appropriate subjects in the domi-nant populations have been saturated, some believe it isappropriate to utilize more vulnerable populations.Whether a recruitment problem itself provides a sufficientjustification for research on non-dominant populationsdepends upon the context.Third, the conditions in Third World populations mayresult in higher seroprevalence and greater incidence oftransmission of disease. Clearly a study conducted undersuch conditions might be completed more quickly andmore reliably, providing some justification for the deci-sion. But, if populations at home have similar characteris-tics, they would be more appropriate subjects for research.

The overriding justification for research in ThirdWorld countries is hat the disease studied iseither rare ornon-existent in the country of origin. This justification isasrigorous as that used for research on vulnerable individualsand groups within a country. The ideal circumstances forinternational collaborative research are when the scientificinquiry is focused on a genuine health problem of the localpopulation, there is a low risk and a good prospect ofbenefit to the research subjects, and the outcome of theresearch will be available to promote the health of ThirdWorld populations.

Can exclusion of vulnerable populations frombeneficial research be unethical?Ethical principles requiring special justifications for re-search on vulnerable individuals were based upon an as-sumption that is not entirely true today. In the past it waspresumed that all research subjects bear risks and burdens,making it a sacrifice to be selected. But, special benefits(sometimes of considerable worth) may be afforded toresearch subjects, which may make vulnerable persons andpopulations particularly eager to be selected. A fine linecan be drawn between pure research and innovative treat-ment. For some poor groups, the only access to innovativetherapies is by participation in research. To exclude vul-nerable populations from participation in research may beto deny them their only realistic hope and promise ofeffective treatment and services.

A drug or vaccine that has not betn tested on poorer,more vulnerable populations may also prove more risky orless beneficial to them in future. The generalizability ofresearch to vulnerable populations may require that thosepopulations be involved in clinical trials. A decision toexclude vulnerable populations from research impedes sci-entific understanding about their health problems and the

most promising interventions to meet their health needs.Over-protection of vulnerable populations, therefore,may be paternalistic and ultimately harmful. A balanceneeds to be struck between protecting vulnerable peopleand providing them the benefit of therapeutic innovation.Overly strict ethical and legal limits placed on vulnerablepersons to enter research can impede humanitarian investi-gation of problems relevant to their medical needs.Protecting the privacy of people and populationsThe concept of privacy is as complicated as human affectitself. Research subjects may claim a right to privacy onthree levels: the right to have space in the physical, per-sonal, or social sense (e.g., the absence of intrusive surveil-lance or questioning); a right to control the disclosure ofinformation about their health, behavior or life circum-stances (e.g. sexual or drug use history); and the right tomaimain intimacy and confidences in their personal, fam-ily or social relationships (e.g. their interactions with sexualpartners, spouses, and professional counselors).

Ifsensitive information is linked to an individual it cancause him or her harm both of a tangible and intangiblekind. It can result in the person being subjected to discrimi-nation by employees, educators, landlords, or insurers(tangible harms);3, or it can result in a sense of personalviolation, shame, or hurt (a wrong).3'The ethical foundation for privacy is respect for theperson. Respecting human beings means giving them theright to choose who has access to confidential informationand under what circumstances.L It means recognizing thelegitimacy of personal secrets and allowing the individualto define what is secret and to control how secrets areused.,,The importance of privacy isunderscored by the prom-ises that researchers make, implicitly or explicitly, to keepinformation confidential. Research subjects come to thinkabout investigators partly as clinicians, and they reason-ably anticipate that their confidences will not be unreason-ably disclosed. Each culture has its own mores aboutconfidential information and relationships. It is ncumbentupon researchers from other countries to learn about andbe sensitive to local customs, and religious and personalbeliefs about the sanctity of confidential information.From a researcher's perspective, maintaining confi-dentiality has a utilitarian value. Recruiting and keepinghuman subjects will become much more difficult if re-searchers cannot ensure that information obtained as aconsequence of the study will not be disclosed outside ofthe research team.There are, of course, constant pressures to disclose theconfidences of research subjects. Researchers may chooseto disclose information in furtherance of their scientificpurpose; they may be required to report the information to


8/12


government agencies or sponsors; or they may receive acourt order or subpoena to divulge the information for theadministration of justice.Abreach of confidentiality does not occur if a compe-tent adult gives informed consent, specifying the informa-tion that may be disclosed and to whom. Clear rules,

however, are needed to govern effectively when disclosurecan ethically occur in the absence of consent.Three kinds of justification can be offered for divulg-ing confidences obtained in the course of research. First,disclosure may be thought necessary to present a morecredible or authoritative scientific report. A case studywhich does not disclose certain identifying characteristicsmay omit scientifically relevant information. In epidemiol-ogy, often the very object of the research is to obtaindemographic, health or behavior related data. Restrictionson publication or other dissemination may defeat the verypurpose of the research. A prior understanding aboutdissemination of information between the investigator andthe individual and/or population can overcome confidenti-ality problems.Second, disclosure may be thought necessary to pro-tect the health and safety of others. The United StatesTarasoff case 4 created a legal duty on psychiatrists todisclose to a third party if a psychiatric patient poses animmediate and grave danger. The "duty to warn" mayextend to third parties or populations who face a seriousand imminent health risk-such as a sexual or needlesharing partner of a person infected with HIV, an environ-mental risk from hazardous waste, or the risk of diseasefrom food or water contamination. Knowledge gained inepidemiologic research, then, may be necessary to curtail aserious health risk to a population. Requirements to reportinstances of child abuse or communicable diseases to pub-lic health authorities also illustrate the need for disclosurefor the protection of others. It is important in evaluating a"duty to warn" whether the health risk is serious andprobable, or whether it is based upon a low probability ofharm or even irrational fear or prejudice.Finally, researchers may believe that disclosure is inthe best interests of the research subject, such as when thesubject needs medical treatment. One controversial issue iswhether a mature minor deserves confidentiality when sheseeks an abortion without informing the father or herfamily. Ordinarily, the principle of respect for personsrequires the researcher to follow a competent person's ownjudgment about where his or her best interests lie.Ethical principles of privacy and confidentiality areapplicable to individual invasions, but need strengtheningto safeguard adequately the privacy of populations. Th epotential for violating privacy rights is formidable wherethere is wide scale collection, transfer and use of informa-tion. Systematic gathering, reporting, and sharing of infor-mation about a group can be highly detrimental to the

group and its members. The use of sophisticated computertechnology to store and use personal data among countlesssources only heightens the concern over privacy, stigmati-zation, and discrimination within populations. Capronemphasizes that information can be obtained from, andtransferred to, government agencies (such as census, vitalstatistics, revenue collection, health, social services, anddefense), schools, health care services and police."Data suggesting that particular groups are more likelyto be infected with, and hence, capable of transmittingcommunicable or sexually transmitted diseases can rein-force prejudice and irrational fear of members of thatgroup. Data which create or reinforce negative culturalstereotypes can be extremely hurtful. Examples of suchdata include research purporting to demonstrate that HIVoriginated in Africa,36 that homosexuals, drug abusers,and prostitutes spread sexual and blood borne disease,that mentally ill people are dangerous, or that certain raceshave less intelligence. Derogatory information associatedwith a group can result in real harms such as discrimina-tion against members of the group in employment, hous-ing, or insurance. Derogatory information can also causeintangible hurt to groups such as lowering their self-esteemand racial or cultural pride. Derogatory information abouta sub-population can stigmatize and wound its people asmuch as breaches of confidentiality can affect an indi-vidual. The information collected from groups, just as theinformation about individuals, need not be blatant orintentional to cause harm or hurt. Even the best intentionedand careful research can trigger concerns about privacy.Consider, for example, the widespread practice in theUnited States and elsewhere of reporting HIVseroprevalence data broken down by race and ethnicity.Although the data are collected for a valuable purpose anddo not identify individuals, the method of reporting em-phasizes the disproportionate impact on African Ameri-cans and Hispanics. Avalid reason may, in fact, exist for sopublicly characterizing race and ethnicity as risk markers(but not risk factors) for HIV, rather than using moreneutral classifications such as socio-economic status orgeographic area. The practice is so well entrenched, how-ever, that no one asks whether the public health justifica-tion is significant enough to outweigh the potential impacton the dignity and self-esteem of the populations affected.

Even publicly available information, which the micro-ethical principle of confidentiality often does not safe-guard, takes on a new meaning when it is joined withinformation from a variety of sources. Some information,while technically "public" in the sense that it is theoreti-cally available by, say, a freedom of information request ora national census, may hurt a person or a group by itspublic disclosure. Isolated facts by themselves may beinnocuous, but when analyzed together with a chain ofinformation, may reveal personal or group secrets. Thus,


9/12

Volume 19: 3-4, Fall-Winter 99z

even if people agree to the release of particular informationas an isolated event, they have not given meaningful con-sent unless they are aware of the totality of the collectionand use of the information.The ethical principle of privacy of populations, then,would view an entire pattern of collection and use ofinformation, and not merely be concerned with unautho-rized disclosure of an individual's research record.Could individuals in a study each give consent todisclosure of information, and yet the study would violatethe right of the collective to privacy? The answer is yes ifone believes that populations have a right to defend theirreputation and dignity as much as individuals do. It isconceivable, even where the information revealed abouteach member of the group is non-consequential or is notpersonally identifiable, that the group can be harmed.Blind seroprevalence studies, for example, raise few con-cerns about individual confidentiality because the name ofthe person is not identifiable. But the very purpose of thestudy is o obtain information about the population. To besure, much of the information collected in goodepidemiologic surveillance is potentially beneficial to thehealth of the community. Still, the power (whether inten-tional or inadvertent) to use the information in ways whichundermine the dignity of the culture is always present. Theright of populations to have some say in the collection andspread of data that they believe reflect badly on theiridentity isan important ethical principle.Distributive justice in international collaborativeresearch

The concept of justice is hardly foreign to the frame-work of ethics. "Justice" is an often used bu t seldomclearly defined term. It is frequently taken to mean that thebenefits and burdens of research should be fairly distrib-uted. This definition begs the question, for it does notexplain what is fair or appropriate in allocating benefitsand burdens. The legal concept of equal protection, moreprecisely, states that similarly situated individuals or classesof individuals should be treated equally, unless there is arelevant and compelling reason to treat them differently. 37This section suggests an entitlement to benefits, ser-vices, and resources which some traditional ethical think-ers may feel goes too far. Those who initiate, sponsor, andconduct research (including governments, funders, indus-try, and investigators) have an obligation to share thebenefits of research not only with subjects while they areparticipating in a clinical trial, but with those subjects afterthe trial, as well as their communities.Consider a case where researchers from the First Worldare undertaking a large field trial for a candidate vaccine ordrug in the Third World. What responsibilities do theyhave to the subjects and the wider community during the

trial, and what responsibilities do they have once the trial isover? Traditional ethical principles would certainly re-quire protection of subjects while they are in the clinicaltrial, at least from any harms that may arise directly fromtheir participation. This would mean that qualified clini-cians would carefully observe any adverse effects of theresearch on subjects and provide immediate treatment.Once the drug or vaccine is shown to be efficacious, thestudy should cease so that those in the control group couldbe beneficially treated.Taking ethical obligations further, do researchers havean obligation to confer benefits on research subjects whichare not strictly relevant to the study? Many Northern/Western researchers working in technologically develop-ing countries provide prevention and health care ser,-icesfor the local community.Investigators have a duty not merely to prevent harmto subjects, but to affirmatively protect their health andwell-being by providing, within reasonable limits, preven-tion and health services. Research subjects should not beviewed as mere tools for the purposes of the research, butas whole persons with diverse health needs. In accordancewith the principle of distributive justice, a primary ethicaljustification for selecting vulnerable populations for studyis that benefits are conferred in exchange for their partici-pation. This can include the direct benefits of the drug orvaccine provided in the study design, as well as risk reduc-tion and health care services. Persons on the margins ofsurvival give up productive time to contribute to the scien-tific endeavors of the research team. They can reasonablyexpect minimal services in return.

Once a person enters a research project, particularly ifhe or she ispoor and lacks adequate access to medical care,the investigator assumes some duty of care to safeguardthat person's health and welfare. Doctors involved in atrial cannot turn their backs on obvious illness and healthcare needs of trial participants.From a utilitarian perspective, researchers have aninterest in maintaining the health and welfare of subjects.Subjects who are healthy and satisfied are far more likelyto be cooperative and reliable partners in research.In addition to the arguments based upon equity andutility, it can also be argued that researchers should adhereto explicit or implicit promises. Unless the research teammakes it otherwise clear, subjects expect that their basichealth care needs will be met by health care professionalsinvolved in the study. Subjects may not perceive the finedistinctions made by researchers between treating directadverse effects of the drugs provided in the study design,and more general health care needs.Ethical duties may extend after the study is complete.Is it ethical to summarily withdraw all health care servicesthat the community has benefited from and come to ex-pect, once the study is over? Some ongoing responsibility


10/12


for subjects and communities extends beyond the temporallimits of the study. If research is viewed from the subjects',rather than solely from the investigators', perspective, asense of loss and unmet expectations naturally occur theday after the research is completed and services are with-drawn. Sponsors and researchers who leave behind somecontinuing capacity to meet needs, even if at a reducedlevel, will help ensure receptivity to future research ideasand longer term health research planning.Let us assume the results of the field trial are positiveand the drug or vaccine is shown to be safe and effective.What is he responsibility of the research team to make thedrug or vaccine available to the local population? Astrongethical responsibility exists to provide the efficacious agentto the subjects of the research. This requires that the agentis available as long as it is clinically appropriate. TheWorld Health Organization consultation on candidate HIVvaccines said that justice requires that the "population inwhich the vaccine is tested is entitled to first priority inreceiving the vaccine after its safety and efficacy have beenestablished. " 31 One might argue that it also includes theancillary medical support and supervision necessary tomonitor the adverse effects and toxicity of the agent.Do other people in the local community have anethical claim to the drug or vaccine? The choice of onesubject over another in the community is often randomand certainly unrelated to any morally rational choice. Itwould be inequitable if certain members of the populationwere to receive a benefit from which others were excluded.If Third World populations are to be used to create ahealth benefit for humankind, careful consideration shouldbe given to making that benefit available to those whocannot afford it.Why, it may be asked, are there affirmative ethicalduties owed to local populations? The agreement requiredfor international collaborative research is entered into notmerely with subjects bu t with entire communities. Govern-ment and community leaders in host countries are con-sulted and provide permission for research. Theunderstanding between collaborators may be that the com-munity receives improved health services, as well as bear-ing any fruits that the research provides. By agreeing tobecome involved, research subjects and their communitiesanticipate that any knowledge, therapeutic agent, or vac-cine that is advanced in the study will be used to improvetheir health.Persons who sponsor and conduct research in ThirdWorld communities obtain a substantial benefit from theresearch. Investigators gain access to otherwise unavail-able populations for research. Those populations bear therisks and burdens of research, the fruits of which will go tobenefit many others. Industry may benefit financially fromgovernment subsidies in the development of a product. Insome countries, industry isalso permitted to set the price at

whatever level it wishes. The commercial developers ofnew drugs or vaccines stand to make substantial profits inthe marketplace. Arguments for making the product avail-able more widely to the local population, then, are basedupon the mutual exchange of benefits, and the equities ofaccess to essential health improvements irrespective of theability to pay.Research conducted in the Third World sometimescan be inequitable in its allocation of benefits and burdens.All areas of the world benefit, for example, from thedevelopment of an efficacious vaccine or pharmaceutical.But a significant burden of experimentation rests on poorerThird World countries. At the same time, economic pov-erty and underdeveloped medical services realistically pre-vent Third World countries from buying and distributingbeneficial preventive or therapeutic agents." It would beunjust if the populations which bear significant burdens ofresearch were to reap the fewest rewards.Developing sound and enduring infra-structuresDeveloping infra-structures in the host countries is animportant objective of international collaborative research.Host countries can richly contribute both to local publichealth needs and to research objectives if their scientistsand health care professionals are provided the resourcesand capacity to function as equal partners. Infra-structurebuilding requires the development of high quality trainingand education, laboratory and other vital equipment, andprevention, health care, and hospital services.The development of infra-structures provides stabilityfor meeting ongoing public health and scientific needs.This is advantageous not only to host investigators andtheir institutions, but also to their collaborating partners inthe North/West who will gain from ongoing relationships.A sound infra-structure that can endure through lengthystudies and enable future research to flourish emerges as anessential component of international public health plan-ning and research.Ethical imperialism and ethical relativism"Ethical imperialism appears to be the imposition on onesociety of solutions culturally appropriate to another soci-ety, on the pretext that they represent ethical absolutes."40Certainly, no single country has the right to set universalstandards to which other countries must comply. But, thefoundation of international human rights from Nurembergto Helsinki and beyond is the conviction that there is anirreducible set of international ethical standards commonto all societies, which local law, politics, or custom cannotbend.4'Foundational principles for population-based researchinclude: (i) the overriding imperative to protect the health


11/12

Volume 19: 3-4, Fall-Winter 199z

and well-being of populations; (2) the right of populationsto self-determination, including the right to refuse partici-pation; (3) protection of vulnerable populations and theneed for special justifications for research; (4) protectingthe privacy, integrity, and self-esteem of populations; and(5) the equitable distribution of benefits and burdens ofresearch. How these principles operate in practice requiresan understanding of the mores of other people and places.40The purpose of this paper is to define a set of ethicalprinciples which extend beyond the person dominatedethics of Helsinki to a view of ethics based upon theintegrity of populations. In so doing, a deeper respect for,and toleration of, cultures steeped in the tradition of socialrelationships can be nurtured.References

The author would like to thank the researchers and ethicalthinkers on the WHO/CIOMS steering committee who assistedin the formulation of this paper, particularly ZbigniewBankowski, Jay Bryant, Bernard Dickens, David Heymann, JohnLast, and Robert Levine.

i. National Commission for the Protection of HumanSubjects of Biomedical and Behavioral Research. The BelmontReport: Ethical principles and guidelines for the protection ofhuman subjects of research. Office of Protection from ResearchRisks, U.S. Public Health Service: Bethesda, Md., April 18,1979; R.J. Levine, Ethics and Regulation of Clinical Research.Yale University Press: New Haven, 2d ed. 1988.2. Nuremberg Code 1947, printed inTrials of War Crimi-nals Before the Nuremberg Military Tribunals Under ControlCouncil Law No.,o, vol. Ii(Washington, DC : U.S. GovernmentPrinting Office, 1949, at 18 - 82); World Medical AssociationDeclaration of Helsinki: Recommendations Guiding MedicalDoctors in Biomedical Research Involving Human Subjects,adopted by the i8th World Medical Assembly, Helsinki, Fin-land, 1964, revised by the z9 th WHA, Tokyo, Japan, 1975, andthe 35th WHA in Venice, Italy, 1983. Reprinted in MedicalEthics Declarations. World MedicalJournal. 1984; 31:4; WorldHealth Organization and Council for International Organiza-tions of Medical Sciences. Proposed International Guidelines forBiomedical Research Involving Human Subjects. Geneva, 1982.3. Law Reform Commission of Canada. Biomedical Ex -perimentation Involving Human Subjects: Working Paper 61.Ottawa, 1989; U.S. Department of Health and Human ServicesRules and Regulations, 45 CFR 46C (Revised as of March8,1983); French Consel d'Etat. De l'ethique au droit. Paris1988. 4. L.Gostin,"Collective and Individual Rights: Towards

Resolving the Conflict." In: L. Gostin (ed), Civil Liberties inConflict, Routledge: London and New York, 1988.5. R.J. Levine, supra note xat 5z.6. Geneva Declaration 1948, amended 1968, reprinted inMedical Ethics Declarations. World Medical Journal 1984;3 1:3.7. 0.0. Ajayi, "Taboos and Clinical Research in WestAfrica,"]. Med. Ethics i98o;6o6i-63.8. The Belmont Report, supra note i.9. Nuremberg Code, supra note i, first principle.io. Declaration of Helsinki, supra note a, article 1,9.ix WHO/CIOMS, supra note 1, at 23-24.12. Council of Europe. Recommendation No. R(9o)3 Con-

cerning Medical Research on Human Beings (6 Feb. 199o).13. G.J. Hill, "Research on humans published in ]AMA"(letter).]J. Amer. Med. Assn. 1987; 258:1604.14. E.O. Ekunwe and R. Kessel, "Informed Consent in theDeveloping World," Hastings Cen. Rep. 1984; 14:23-24.15. U.S. Department of Health and Human Services, Rulesand Regulations, 45 CFR 46, para. 46.116 (Revised as of March8, 1983). Yet, some highly developed countries expressly reject

the concept of informed consent. Sidaway v. Bethlehem RoyalHospital Governors 119851 A.C. 871.16. N.A. Christakis, "The Ethical Design of an AIDS Vac-cine Trial in Africa." Hastings Center Rpt. 1988;18:31-37.17. 0.0. Ajayi, supra note 7; D. Adityanjee, "InformedConsent: Issues Involved for Developing Countries." Med. Sci.& Law 1986; z6 : 305-307; WHO/CIOMS, supra note 2; R.J.Levine, "Validity of Consent Procedures in Technologically De-veloping Countries. In: Human Experimentation and MedicalEthics," Z. Bankowski, N. Howard-Jones, eds. Geneva: CIOMS,1982, pp.16-30.18. Indian Council of Medical Research. Policy statementon ethical considerations involved in research on human subjects198o; New Delhi, ICMR.I9. .J. Hall, "Public Health Trials in West Africa: Logis-

tics and Ethics." IRB 1989; 1x:8-io.2o. Henderson et al., "Assessment of Vaccination Cover-age, Vaccination Scar Rates and Small Pox Scarring in FiveAreas of West Africa." Bull. WHO 1973;84:183-194.21. 0.0. Ajayi, supra note 7.22. D. Adityanjee, supra note 17; 0.0. Ajayi, supra note 7.23. World Health Organization. Criteria for internationaltesting of candidate HIV vaccines, 27 February - 2 March,

1989.24. WHO/CIOMS, supra note 2.2 5.WHO/CIOMS, supra note a, paras. 14-15.26. A.J. Hall, supra note 19.27. R.J. Levine, supra note 5.-8. entre for Human Rights, United Nations. The Rightsof Indigenous Peoples. U.N.: Geneva, 199o.29. J. Miller, "Towards an International Ethic for Re-search with Human Beings." IRB 1988; io:9-i i.3o. L. Gostin, "The AIDS Litigation Project: A NationalReview of Court and Human Rights Commission Decisions,Part II: Discrimination." J. Am. Med. Assn. 199o;263:2o86-2093; PANOS Institute. The Third Epidemic: Repercussions ofthe fear ofAIDS. i99o, PANOS, London.31. T.L. Beauchamp, J. hildress, Principles of BiomedicalEthics. Oxford University Press, New York. -nd ed. 1 83.3z. R.J. Levine, supra note 5; H.C. Kelman, "Privacy andResearch with Human Beings." J. Soc. Issues 1977; 33:x69-195.33. S. ok, "The Limits of Confidentiality." Hastings Ctr.Rpt. 1983;13:24-31.34. Tarasoff v. Board of Regents of California (1976) 17

Cal.3d 452. (Tarasoff II), vacating 13 Cal.3d 117 (Tarasoff I).35. A.Capron, "Protection of Research Subjects: Do Spe-cial Rules Apply in Epidemiology." Paper presented at the IEFConference on Ethics in Epidemiology, June 1'-]3, 1989, Bir-mingham, Alabama.36. E. Tabor, R.J. Gerety, J. Cairns, A.C. Bayley, "DidHIV and HTLV Originate inAfrica?" (letter).JAMA z99o; 264:691-692.37. L. Gostin, "The Future of Public Health Law." Amer.J. Law & Med. 1987;12:461-49o.38. WHO, supra note 2.39. N.A. Christakis, "Responding to a Pandemic: Interna-ZOO


12/12

Law, Medicine & Health Caretional Interests in AIDS Control." Daedalus 1989; 118:113-134. 4o . F. Gilks and J.B.O. Were, "Ethical Imperialism" (let-ter) N. Engi. J.Med. 1990; 32.:20o41. M. Angell, "Ethical Imperialism? Ethics in Interna-

tional Collaborative Clinical Research." N. Engl. J. Med. j99o;319:o81-io83.4z. M. Barry, "Ethical Considerations of Human Investi-gation in Developing Countries: The AIDS Dilemma." N.Engl,J. Med. 199; 319:1083-1o86.

Ethical Principles for the Conduct of Human Subject Research- Pop

Documents

Transcript of Ethical Principles for the Conduct of Human Subject Research- Pop