Ethical Research Emanuel

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Ezekiel J. Emanuel; David Wendler; Christine Grady

What Makes Clinical Research Ethical?

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What Makes Clinical Research Ethical?Ezekiel J. Emanuel, MD, PhDDavid Wendler, PhDChristine Grady, PhD

WHAT MAKES RESEARCH IN-volving human subjectsethical? Informed con-sent is the answer most

US researchers, bioethicists, and insti-tutional review board (IRB) memberswould probably offer. This response re-flects the preponderance of existingguidance on the ethical conduct ofresearch and the near obsession withautonomy in US bioethics.1-4 Whileinformed consent is necessary in mostbut not all cases, in no case is it suffi-cient for ethical clinical research.5-8 In-deed, some of the most contentious con-temporary ethical controversies inclinical research, such as clinicalresearch in developing countries,9-13

the use of placebos,14-16 phase 1 re-search,17-19 protection for communi-ties,20-24 and involvement of chil-dren,25-29 raise questions not of informedconsent, but of the ethics of subject se-lection, appropriate risk-benefit ratios,and the value of research to society. Sinceobtaining informed consent does not en-sure ethical research, it is imperative tohave a systematic and coherent frame-work for evaluating clinical studies thatincorporates all relevant ethical consid-erations.

In this article, we delineate 7 require-ments that provide such a framework bysynthesizing traditional codes, declara-tions, and relevant literature on the eth-ics of research with human subjects. Thisframework should help guide the ethi-cal development and evaluation of clini-cal studies by investigators, IRB mem-bers, funders, and others.

THE 7 ETHICALREQUIREMENTSThe overarching objective of clinical re-search is to develop generalizableknowledge to improve health and/or in-crease understanding of human biol-ogy30,31; subjects who participate are themeans to securing such knowledge.32

By placing some people at risk of harmfor the good of others, clinical re-search has the potential for exploita-tion of human subjects.33,34 Ethical re-quirements for clinical research aim tominimize the possibility of exploita-tion by ensuring that research sub-jects are not merely used but are treatedwith respect while they contribute tothe social good.30

For the past 50 years, the main sourcesof guidance on the ethical conduct ofclinical research have been the Nurem-berg Code,35 Declaration of Helsinki,36

Belmont Report,37 International EthicalGuidelines for Biomedical Research In-volving Human Subjects,38 and similardocuments (TABLE 1). However, manyof these documents were written in re-sponse to specific events and to avoid fu-ture scandals.50,51 By focusing on the in-stigating issues, these guidelines tend to

Many believe that informed consent makes clinical research ethical. How-ever, informed consent is neither necessary nor sufficient for ethical clinicalresearch. Drawing on the basic philosophies underlying major codes, dec-larations, and other documents relevant to research with human subjects,we propose 7 requirements that systematically elucidate a coherent frame-work for evaluating the ethics of clinical research studies: (1) value—enhancements of health or knowledge must be derived from the research;(2) scientific validity—the research must be methodologically rigorous; (3)fair subject selection—scientific objectives, not vulnerability or privilege, andthe potential for and distribution of risks and benefits, should determine com-munities selected as study sites and the inclusion criteria for individual sub-jects; (4) favorable risk-benefit ratio—within the context of standard clini-cal practice and the research protocol, risks must be minimized, potentialbenefits enhanced, and the potential benefits to individuals and knowledgegained for society must outweigh the risks; (5) independent review—unaffiliated individuals must review the research and approve, amend, orterminate it; (6) informed consent—individuals should be informed aboutthe research and provide their voluntary consent; and (7) respect for en-rolled subjects—subjects should have their privacy protected, the opportu-nity to withdraw, and their well-being monitored. Fulfilling all 7 require-ments is necessary and sufficient to make clinical research ethical. Theserequirements are universal, although they must be adapted to the health,economic, cultural, and technological conditions in which clinical researchis conducted.JAMA. 2000;283:2701-2711 www.jama.com

Author Affiliations: Department of Clinical Bioeth-ics, Warren G. Magnuson Clinical Center, National In-stitutes of Health, Bethesda, Md.Corresponding Author and Reprints: Christine Grady,PhD, Warren G. Magnuson Clinical Center, Bldg 10,Room 1C118, National Institutes of Health, Bethesda,MD 20892-1156 (e-mail: [email protected]).

©2000 American Medical Association. All rights reserved. (Reprinted) JAMA, May 24/31, 2000—Vol 283, No. 20 2701



emphasize certain ethical requirementswhile eliding others. For instance, theNuremberg Code35 was part of the judi-cial decision condemning the atrocitiesof the Nazi physicians and so focused onthe need for consent and a favorable risk-benefit ratio but makes no mention of fairsubject selection or independent re-view. The Declaration of Helsinki36 wasdeveloped to remedy perceived lacunaein the Nuremberg Code, especially as re-lated to physicians conducting researchwith patients, and so focuses on favor-able risk-benefit ratio and independentreview; the Declaration of Helsinki alsoemphasizes a distinction between thera-

peutic and nontherapeutic research thatis rejected or not noted by other docu-ments.30,52 The Belmont Report37 wasmeant to provide broad principles thatcould be used to generate specific rulesand regulations in response to US re-search scandals such as Tuskegee53 andWillowbrook.54,55 It focuses on in-formed consent, favorable risk-benefit ra-tio, and the need to ensure that vulner-able populations are not targeted for riskyresearch. The Council for InternationalOrganizations of Medical Sciences(CIOMS) guidelines38 were intended toapply the Declaration of Helsinki “in de-veloping countries . . . [particularly for]

large-scale trials of vaccines and drugs.”The CIOMS guidelines lack a separatesection devoted to risk-benefit ratios, al-though the council considers this issuein commentary on other guidelines. Italso includes a section on compensa-tion for research injuries not found inother documents. Because the AdvisoryCommittee on Human Radiation Experi-ments was responding to covert radia-tionexperiments, avoidingdeceptionwasamong its 6 ethical standards and rules;most other major documents do nothighlight this.56 This advisory commit-tee claims that its ethical standards aregeneral, but acknowledges that itschoices were related to the specific cir-cumstances that occasioned the re-port.56 Finally some tensions, if notoutright contradictions, exist amongthe provisions of the various guide-lines.5,19,30,51,52,57,58 Absent a universally ap-plicable ethical framework, investiga-tors, IRB members, funders, and otherslack coherent guidance on determiningwhether specific clinical research pro-tocols are ethical.

There are 7 requirements that pro-vide a systematic and coherent frame-work for determining whether clinical re-search is ethical (TABLE 2). Theserequirements are listed in chronologi-cal order from the conception of the re-search to its formulation and implemen-tation. They are meant to guide theethical development, implementation,and review of individual clinical proto-cols. These 7 requirements are in-tended to elucidate the ethical stan-dards specific for clinical research andassume general ethical obligations, suchas intellectual honesty and responsibil-ity. While none of the traditional ethi-cal guidelines on clinical research ex-plicitly includes all 7 requirements, theserequirements systematically elucidate thefundamental protections embedded inthe basic philosophy of all these docu-ments.30 These requirements are not lim-ited to a specific tragedy or scandal or tothe practices of researchers in 1 coun-try; they are meant to be universal, al-though their application will require ad-aptation to particular cultures, healthconditions, and economic settings. These

Table 1. Selected Guidelines on the Ethics of Biomedical Research With Human Subjects*

Guideline Source Year and RevisionsFundamental

Nuremberg Code35 Nuremberg Military Tribunaldecision in United Statesv Brandt

1947

Declaration of Helsinki36 World Medical Association 1964, 1975, 1983,1989, 1996

Belmont Report37 National Commission for theProtection of Human Subjectsof Biomedical and BehavioralResearch

1979

International Ethical Guidelines forBiomedical Research InvolvingHuman Subjects38

Council for InternationalOrganizations of MedicalSciences in collaboration withWorld Health Organization

Proposed in 1982;revised, 1993

Other45 CFR 46, Common Rule8 US Department of Health and

Human Services (DHHS) andother US federal agencies

DHHS guidelines in1981; CommonRule, 1991

Guidelines for Good ClinicalPractice for Trials onPharmaceutical Products42

World Health Organization 1995

Good Clinical Practice:Consolidated Guidance44

International Conference onHarmonisation of TechnicalRequirements for Registration ofPharmaceuticals for Human Use

1996

Convention on Human Rights andBiomedicine43

Council of Europe 1997

Guidelines and Recommendationsfor European EthicsCommittees45

European Forum for GoodClinical Practice

1997

Medical Research CouncilGuidelines for Good ClinicalPractice in Clinical Trials46

Medical Research Council,United Kingdom

1998

Guidelines for the Conduct ofHealth Research InvolvingHuman Subjects in Uganda47

Uganda National Council forScience and Technology

1998

Ethical Conduct for ResearchInvolving Humans48

Tri-Council Working Group, Canada 1998

National Statement on EthicalConduct in Research InvolvingHumans49

National Health and MedicalResearch Council, Australia

1999

*CFR indicates Code of Federal Regulations. More extensive lists of international guidelines on human subjects researchcan be found in Brody39 and Fluss.40 An extensive summary of US guidelines can be found in Sugarman et al.41

ETHICAL REQUIREMENTS FOR CLINICAL RESEARCH

2702 JAMA, May 24/31, 2000—Vol 283, No. 20 (Reprinted) ©2000 American Medical Association. All rights reserved.



7 requirements can be implemented wellor ineffectively. However, their system-atic delineation is important and con-ceptually prior to the operation of an en-forcement mechanism. We need to knowwhat to enforce.

ValueTo be ethical, clinical research must bevaluable,4,35 meaning that it evaluatesa diagnostic or therapeutic interven-tion that could lead to improvementsin health or well-being; is a prelimi-nary etiological, pathophysiological, orepidemiological study to develop suchan intervention; or tests a hypothesisthat can generate important knowl-edge about structure or function of hu-man biological systems, even if thatknowledge does not have immediatepractical ramifications.4,30 Examples ofresearch that would not be socially or

scientifically valuable include clinicalresearch with nongeneralizable re-sults, a trifling hypothesis, or substan-tial or total overlap with proven re-sults.4 In addition, research with resultsunlikely to be disseminated or in whichthe intervention could never be prac-tically implemented even if effective isnot valuable.12,13,38,59 Only if society willgain knowledge, which requires shar-ing results, whether positive or nega-tive, can exposing human subjects torisk in clinical research be justified.Thus, evaluation of clinical researchshould ensure that the results will bedisseminated, although publication inpeer-reviewed journals need not be theprimary or only mechanism.

There are 2 fundamental reasons whysocial, scientific, or clinical value shouldbe an ethical requirement: responsibleuse of finite resources and avoidance of

exploitation.4 Researchresourcesare lim-ited. Even if major funding agenciescould fund all applications for clinicalresearch,doingsowoulddivert resourcesfrom other worthy social pursuits.Beyond not wasting resources, research-ers should not expose human beings topotential harms without some possiblesocial or scientific benefit.4,30,35,38

It is possible to compare the relativevalue of different clinical research stud-ies; clinical research that is likely to gen-erate greater improvements in health orwell-being given the condition beinginvestigated, the state of scientificunderstanding, and the feasibility ofimplementing the intervention is ofhigher value. Comparing relative valueis integral to determinations of fund-ing priorities when allocating limitedfunds among alternative research pro-posals.60 Similarly, a comparative evalu-

Table 2. Seven Requirements for Determining Whether a Research Trial Is Ethical*

Requirement Explanation Justifying Ethical Values Expertise for EvaluationSocial or scientific value Evaluation of a treatment, intervention,

or theory that will improve health andwell-being or increase knowledge

Scarce resources andnonexploitation

Scientific knowledge; citizen’sunderstanding of socialpriorities

Scientific validity Use of accepted scientific principlesand methods, including statisticaltechniques, to produce reliableand valid data

Scarce resources andnonexploitation

Scientific and statisticalknowledge; knowledge ofcondition and population toassess feasibility

Fair subject selection Selection of subjects so that stigmatizedand vulnerable individuals are nottargeted for risky research and therich and socially powerful not favoredfor potentially beneficial research

Justice Scientific knowledge; ethical andlegal knowledge

Favorable risk-benefitratio

Minimization of risks; enhancement ofpotential benefits; risks to the subjectare proportionate to the benefits tothe subject and society

Nonmaleficence, beneficence,and nonexploitation

Scientific knowledge; citizen’sunderstanding of social values

Independent review Review of the design of the researchtrial, its proposed subject population,and risk-benefit ratio by individualsunaffiliated with the research

Public accountability; minimizinginfluence of potential conflictsof interest

Intellectual, financial, andotherwise independentresearchers; scientific andethical knowledge

Informed consent Provision of information to subjectsabout purpose of the research, itsprocedures, potential risks, benefits,and alternatives, so that theindividual understands thisinformation and can make avoluntary decision whether toenroll and continue to participate

Respect for subject autonomy Scientific knowledge; ethical andlegal knowledge

Respect for potential andenrolled subjects

Respect for subjects by(1) permitting withdrawal from the

research;(2) protecting privacy through

confidentiality;(3) informing subjects of newly

discovered risks or benefits;(4) informing subjects of results of

clinical research;(5) maintaining welfare of subjects

Respect for subject autonomyand welfare

Scientific knowledge; ethical andlegal knowledge; knowledge ofparticular subject population

*Ethical requirements are listed in chronological order from conception of research to its formulation and implementation.





ation of value may be necessary inconsidering studies involving finite sci-entific resources such as limited bio-logical material or the small pool oflong-term human immunodeficiencyvirus nonprogressors.

Scientific ValidityTo be ethical, valuable research mustbe conducted in a methodologically rig-orous manner.4 Even research askingsocially valuable questions can be de-signed or conducted poorly and pro-duce scientifically unreliable or in-valid results.61 As the CIOMS guidelinessuccinctly state: “Scientifically un-sound research on human subjects isipso facto unethical in that it may ex-pose subjects to risks or inconve-nience to no purpose.”38

For a clinical research protocol to beethical, the methods must be valid andpractically feasible: the research musthave a clear scientific objective; be de-signed using accepted principles, meth-ods, and reliable practices; have suffi-cient power to definitively test theobjective; and offer a plausible dataanalysis plan.4 In addition, it must bepossible to execute the proposed study.Research that uses biased samples, ques-tions, or statistical evaluations, that is un-derpowered, that neglects critical endpoints, or that could not possibly en-roll sufficient subjects cannot generatevalid scientific knowledge and is thusunethical.4,30,62 For example, researchwith too few subjects is not valid be-cause it might be combined in a mean-ingful meta-analysis with other, as yetunplanned and unperformed clinical re-search; the ethics of a clinical researchstudy cannot depend on the researchthat others might but have not yet done.Of course the development and ap-proval of a valid method is of little useif the research is conducted in a sloppyor inaccurate manner; careless re-search that produces uninterpretabledata is not just a waste of time and re-sources, it is unethical.

Clinical research that compares thera-pies must have “an honest null hypoth-esis” or what Freedman called clinicalequipoise.30,63 That is, there must be con-

troversy within the scientific commu-nity about whether the new interven-tion is better than standard therapy,including placebo, either because mostclinicians and researchers are uncertainabout whether the new treatment is bet-ter, or because some believe the stan-dard therapy is better while others be-lieve the investigational interventionsuperior.63 If there exists a consensusabout what is the better treatment, thereis no null hypothesis, and the researchis invalid. In addition, without clinicalequipoise, research that compares thera-pies is unlikely to be of value because theresearch will not contribute to increas-ing knowledge about the best therapy,and the risk-benefit ratio is unlikely tobe favorable because some of the sub-jects will receive inferior treatment.

Importantly, a “good question” canbe approached by good or bad re-search techniques; bad research meth-ods do not render the question value-less. Thus, the significance of ahypothesis can and should be as-sessed prior to and independent of thespecific research methods. Reviewersshould not dismiss a proposal that usesinadequate methods without first con-sidering whether adjustments couldmake the proposal scientifically valid.

The justification of validity as an ethi-cal requirement relies on the same 2principles that apply to value—limited resources and the avoidance ofexploitation.4,30 “Invalid research is un-ethical because it is a waste of re-sources as well: of the investigator, thefunding agency, and anyone who at-tends to the research.”4 Without valid-ity the research cannot generate the in-tended knowledge, cannot produce anybenefit, and cannot justify exposingsubjects to burdens or risks.50

Fair Subject SelectionThe selection of subjects must befair.30,37,56 Subject selection encom-passes decisions about who will be in-cluded both through the developmentof specific inclusion and exclusioncriteria and the strategy adopted forrecruiting subjects, such as whichcommunities will be study sites and

which potential groups will be ap-proached. There are several facets to thisrequirement.

First, fair subject selection requiresthat the scientific goals of the study, notvulnerability, privilege, or other fac-tors unrelated to the purposes of the re-search, be the primary basis for deter-mining the groups and individuals thatwill be recruited and enrolled.3,30,37 Inthe past, groups sometimes were en-rolled, especially for research that en-tailed risks or offered no potential ben-efits, because they were “convenient”or compromised in their ability to pro-tect themselves, even though peoplefrom less vulnerable groups could havemet the scientific requirements of thestudy.30,37,53,54

Similarly, groups or individuals shouldnot be excluded from the opportunity toparticipate in researchwithoutagoodsci-entific reason or susceptibility to risk thatjustifies their exclusion.64 It is impor-tant that the results of research be gen-eralizable to the populations that will usethe intervention. Efficiency cannot over-ride fairness in recruiting subjects.37 Fair-ness requires that women be included inthe research, unless there is good rea-son, such as excessive risks, to excludethem.65-69 This does not mean that ev-ery woman must be offered the oppor-tunity to participate in research, but itdoes mean that women as a class can-not be peremptorily excluded.

Second, it is important to recognizethat subject selection can affect the risksand benefits of the study.70 Consistentwith the scientific goals, subjects shouldbe selected to minimize risks and en-hance benefits to individual subjectsand society. Subjects who are eligiblebased on the scientific objectives of astudy, but are at substantially higherrisk of being harmed or experiencingmore severe harm, should be ex-cluded from participation.71 Selectingsubjects to enhance benefits entails con-sideration of which subjects will maxi-mize the benefit or value of the infor-mation obtained. If a potential drug orprocedure is likely to be prescribed forwomen or children if proven safe andeffective, then these groups should be





included in the study to learn how thedrug affects them.63,66,67 Indeed, part ofthe rationale for recent initiatives to in-clude more women, minorities, andchildren in clinical research is to maxi-mize the benefits and value of the studyby ensuring that these groups are en-rolled.65-67,72,73 It is not necessary to in-clude children in all phases of re-search. Instead, it may be appropriateto include them only after the safety ofthe drug has been assessed in adults.

Additionally, fair subject selection re-quires that, as far as possible, groupsand individuals who bear the risks andburdens of research should be in a po-sition to enjoy its benefits,12,13,38,59,74 andthose who may benefit should sharesome of the risks and burdens.75 Groupsrecruited to participate in clinical re-search that involves a condition towhich they are susceptible or fromwhich they suffer are usually in a po-sition to benefit if the research pro-vides a positive result, such as a newtreatment. For instance, selection ofsubjects for a study to test the efficacyof an antimalarial vaccine should con-sider not only who will best answer thescientific question, but also whether theselected groups will receive the ben-efits of the vaccine, if proven effec-tive.12,13,37,59,74,76 Groups of subjects whowill predictably be excluded as benefi-ciaries of research results that are rel-evant to them typically should not as-sume the burdens so that others canbenefit. However, this does not pre-clude the inclusion of subjects who arescientifically important for a study butfor whom the potential products of theresearch may not be relevant, such ashealthy control subjects.

Fair subject selection should beguided by the scientific aims of the re-search and is justified by the prin-ciples that equals should be treatedsimilarly and that both the benefits andburdens generated by social coopera-tion and activities such as clinicalresearch should be distr ibutedfairly.3,30,37,38,66,67 This does not mean thatindividual subjects and members ofgroups from which they are selectedmust directly benefit from each clini-

cal research project or that people whoare marginalized, stigmatized, power-less, or poor should never be in-cluded. Instead, the essence of fair-ness in human subjects research is thatscientific goals, considered in dy-namic interaction with the potential forand distribution of risks and benefits,should guide the selection of subjects.

Favorable Risk-Benefit RatioClinical research involves drugs, de-vices, and procedures about which thereis limited knowledge. As a result, re-search inherently entails uncertaintyabout the degree of risk and benefits,with earlier phase research havinggreater uncertainty. Clinical researchcan be justified only if, consistent withthe scientific aims of the study and therelevant standards of clinical practice,3 conditions are fulfilled: the poten-tial risks to individual subjects are mini-mized, the potential benefits to indi-vidual subjects are enhanced, and thepotential benefits to individual sub-jects and society are proportionate toor outweigh the risks.30,36,37

Assessment of the potential risks andbenefits of clinical research by research-ers and review bodies typically in-volves multiple steps. First, risks areidentified and, within the context ofgood clinical practice, minimized “byusing procedures which are consis-tent with sound research design andwhich do not unnecessarily expose sub-jects to risk, and whenever appropri-ate, by using procedures already beingperformed on the subjects for diagnos-tic or treatment purposes.”8

Second, potential benefits to indi-vidual subjects from the research are de-lineated and enhanced. Potential ben-efits focus on the benefits to individualsubjects, such as health improvements,because the benefits to society throughthe generation of knowledge are as-sumed if the research is deemed to be ofvalue and valid. The specification and en-hancement of potential benefits to indi-vidual subjects should consider onlyhealth-related potential benefits de-rived from the research.77 Assessment ofthe research plan should determine if

changes could enhance the potential ben-efits for individual subjects. For ex-ample, consistent with the scientific ob-jectives, tests and interventions shouldbe arranged to increase benefit to sub-jects. However, extraneous benefits, suchas payment, or adjunctive medical ser-vices, such as the possibility of receiv-ing a hepatitis vaccine not related to theresearch, cannot be considered in delin-eating the benefits compared with therisks, otherwise simply increasing pay-ment or adding more unrelated ser-vices could make the benefits outweigheven the riskiest research. Further-more, while participants in clinical re-search may receive some health ser-vices and benefits, the purpose of clinicalresearch isnot theprovisionofhealth ser-vices. Services directly related to clini-cal research are necessary to ensure sci-entific validity and to protect the well-being of the individual subjects.

In the final step, risks and potentialbenefits of the clinical research inter-ventions to individual subjects are com-pared. In general, the more likely and/orsevere the potential risks the greater inlikelihood and/or magnitude the pro-spective benefits must be; conversely,research entailing potential risks thatare less likely and/or of lower severitycan have more uncertain and/or cir-cumscribed potential benefits. If the po-tential benefits to subjects are propor-tional to the risks they face, as generallyfound when evaluating phase 2 and 3research, then the additional social ben-efits of the research, assured by the ful-fillment of the value and validity re-quirements, imply that the cumulativebenefits of the research outweigh itsrisks.30

Obviously, the notions of “propor-tionality” and potential benefits “out-weighing” risks are nonquantifiable.37

However, the absence of a formula todetermine when the balance of risks andpotential benefits is proportionate doesnot connote that such judgments are in-herently haphazard or subjective. In-stead, assessments of risks and poten-tial benefits to the same individuals canappeal to explicit standards, informedby existing data on the potential types





of harms and benefits, their likelihoodof occurring, and their long-term con-sequences.37 People routinely make dis-cursively justifiable intrapersonal com-parisons of risks and benefits forthemselves and even for others, suchas children, friends, and employees,without the aid of mathematical for-mulae.78

An additional evaluation is neces-sary for any clinical research that pre-sents no potential benefits to indi-vidual subjects, such as phase 1 safety,pharmacokinetic, and even some epi-demiology research, or when the risksoutweigh the potential benefits to indi-vidual subjects.72 This determination,which Weijer79 calls a “risk-knowledgecalculus,” assesses whether the societalbenefits in terms of knowledge justify theexcess risks to individual subjects. De-termination of when potential social ben-efits outweigh risks to individual sub-jects requires interpersonal comparisonsthat are conceptually and practicallymore difficult.78 However, policymak-ers often are required to make these kindof comparisons, for example when con-sidering whether pollution and its at-tendant harms to some people are worththe potential benefits of higher employ-ment and tax revenues to others. Thereis no settled framework for how poten-tial social benefits should be balancedagainst individual risks. Indeed, the ap-peal to a utilitarian approach of maxi-mization, as in cost-benefit analysis, isquite controversial both morally and be-cause many risks and benefits of re-search are not readily quantifiable oncommensurable scales.78-82 Neverthe-less, these comparisons are made,83 andregulations mandate that investigatorsand IRBs make them with respect toclinical research. When research risksexceed potential medical benefits to in-dividuals and the benefit of usefulknowledge to society, the clinical re-search is not justifiable.

The requirement for a favorable risk-benefit ratio embodies the principles ofnonmaleficence and beneficence, longrecognized as fundamental values ofclinical research.3,30,36,37 The principle ofnonmaleficence states that one ought not

to inflict harm on a person.3 This justi-fies the need to reasonably reduce therisks associated with research. The prin-ciple of beneficence “refers to a moral ob-ligation to act for the benefit of oth-ers.”3 In clinical research, this translatesinto the need to enhance the potentialbenefits of the research for both indi-vidual subjects and society.3,30,37 Ensur-ing that the benefits outweigh the risksis required by the need to avoid the ex-ploitation of subjects.30,37

Independent ReviewInvestigators inherently have mul-tiple, legitimate interests—interests toconduct high-quality research, com-plete the research expeditiously, pro-tect research subjects, obtain funding,and advance their careers. These di-verse interests can generate conflictsthat may unwittingly distort the judg-ment of even well-intentioned investi-gators regarding the design, conduct,and analysis of research.84-87 Wantingto complete a study quickly may leadto the use of questionable scientificmethods or readily available rather thanthe most appropriate subjects. Inde-pendent review by individuals unaffili-ated with the clinical research helpsminimize the potential impact of suchconflicts of interest.86,88 For some re-search with few or no risks, indepen-dent review may be expedited, but formuch of clinical research, review shouldbe done by a full committee of indi-viduals with a range of expertise whohave the authority to approve, amend,or terminate a study.

Independent review of clinical re-search is also important for social ac-countability. Clinical research im-poses risks on subjects for the benefitof society. Independent review of astudy’s compliance with ethical require-ments assures members of society thatpeople who enroll in trials will betreated ethically and that some seg-ments of society will not benefit fromthe misuse of other human beings. Re-view also assures people that if they en-roll in clinical research, the trial is ethi-cally designed and the risk-benefit ratiois favorable.

In the United States, independentevaluation of research projects occursthroughmultiplegroups includinggrant-ing agencies, local IRBs, and data andsafety monitoring boards.89-91 In othercountries, independent review of clini-cal research is conducted in other ways.

Informed ConsentOf all requirements, none has receivedas much explication as informed con-sent.2-4,6,7,19,30-32,35-38 The purpose ofinformed consent is 2-fold: to ensurethat individuals control whether or notthey enroll in clinical research and par-ticipate only when the research is con-sistent with their values, interests, andpreferences.2,3,30-32,35,37,92-96 To provideinformed consent, individuals must beaccurately informed of the purpose,methods, risks, benefits, and alterna-tives to the research; understand thisinformationand itsbearingon theirownclinical situation; and make a volun-tary and uncoerced decision whetherto participate.97-99 Each of these ele-ments is necessary to ensure that indi-viduals make rational and free deter-minations of whether the research trialis consonant with their interests.

Informed consent embodies the needto respect persons and their autono-mous decisions.2,3,97,98 To enroll indi-viduals in clinical research without theirauthorization is to treat them merely asa means to purposes and ends they maynot endorse and deny them the oppor-tunity to choose what projects they willpursue.

Children and adults with dimin-ished mental capacity who are unableto make their own decisions about par-ticipating in research nonetheless haveinterests and values.2,3 For instance, in-dividuals rendered unconscious due tohead trauma or a stroke typically re-tain the interests and values they hadjust before the accident. Even individu-als with severe Alzheimer disease re-tain some interests, if only those re-lated to personal dignity and physicalcomfort. Showing respect for these non-autonomous persons means ensuringthat research participation is consis-tent with their interests and values; this





usually entails empowering a proxy de-cision maker to determine whether toenroll the person in clinical research.In making this decision, the proxy usesthe substituted judgment standard:what research decision would the sub-ject make if he or she could.2,3,100

However, an individual’s preferencesand values related to clinical researchmay be unknown or unknowable, or, inthe case of children, the individual maynot have developed mature preferencesrelated to research. In such cases, re-search proxies should choose the op-tion that is in the individual’s best medi-cal interests. There is controversy abouthow much discretion proxies shouldhave in such circumstances, especiallygiven the inherentuncertaintyof the risksand potential benefits of research par-ticipation.101-105 The National BioethicsAdvisory Commission has urged thatproxies should exercise “great caution”in making judgments about a subject’sbest interest regarding research.103 Othergroups believe that proxies should havemore discretion.

In emergency settings that precludetime for identifying and eliciting theconsent of a proxy decision maker, re-search can proceed without either in-formed consent or permission of proxydecision makers when conducted un-der strict guidelines.6 Most impor-tantly, there should be clinical equi-poise—the absence of a consensusregarding the comparative merits of theinterventions to be tested.63 In such acase, the subject is not worse off by en-rolling.

Respect for Potentialand Enrolled SubjectsEthical requirements for clinical re-search do not end when individualseither sign the consent form and areenrolled or refuse enrollment.106 Indi-viduals must continue to be treated withrespect from the time they are ap-proached—even if they refuse enroll-ment—throughout their participationand even after their participation ends.Respecting potential and enrolled sub-jects entails at least 5 different activi-ties. First, since substantial informa-

tion will be collected about potential aswell as enrolled subjects, their privacymust be respected by managing the in-formation in accordance with confiden-tiality rules. Second, respect includespermitting subjects to change their mind,to decide that the research does notmatch their interests, and to withdrawwithout penalty. Third, in the course ofclinical research new information aboutthe effect of the intervention or the sub-ject’s clinical condition may be gained.Respect requires that enrolled subjectsbe provided with this new informa-tion. For instance, when informed con-sent documents are modified to in-clude additional risks or benefitsdiscovered in the course of research, sub-jects already enrolled should be in-formed. Fourth, the welfare of subjectsshould be carefully monitored through-out their research participation. If sub-jects experience adverse reactions, un-toward events, or changes in clinicalstatus, they should be provided with ap-propriate treatment and, when neces-sary, removed from the study. Finally,to recognize subjects’ contribution toclinical research, there should be somemechanism to inform them of what waslearned from the research.

For commentators used to thinkingabout respect in terms of privacy andconfidentiality alone, these different ac-tivities may seem a haphazard agglom-eration of informed consent, confiden-tiality, and other protections. In fact,this requirement integrates into a co-herent framework actions the common-ality of which often goes unrecog-nized. As such, it reminds investigators,subjects, IRB members, and others thatrespect for subjects requires the re-spectful treatment of individuals whochoose not to enroll and the careful on-going monitoring of those who do, inaddition to ensuring the privacy andconfidentiality of enrolled subjects. Thisrequirement emphasizes that the eth-ics of clinical research do not end withthe signing of a consent document butencompass the actual implementa-tion, analysis, and dissemination ofresearch. Indeed, it suggests that al-though “human subjects” is the pre-

vailing designation, the term subjectmay not fully reflect appropriate re-spect: human research participant orpartner may be more appropriate ter-minology.

Respect for potential and enrolled sub-jects is justified by multiple principlesincluding beneficence, nonmalefi-cence, and respect for persons.3 Permit-ting subjects to withdraw and provid-ing them additional information learnedfrom the research are key aspects of re-specting subject autonomy.3,37 Protect-ing confidentiality and monitoring well-being are motivated by respect forpersons, beneficence, and nonmalefi-cence.3

ARE THESE ETHICALREQUIREMENTS NECESSARYAND SUFFICIENT?Value, validity, fair subject selection, fa-vorable risk-benefit ratio, and respect forsubjects embody substantive ethical val-ues. As such, they are all necessary: clini-cal research that neglected or violatedany of these requirements would be un-ethical. Conversely, independent re-view and informed consent are proce-dural requirements intended tominimize the possibility of conflict of in-terest, maximize the coincidence of theresearch with subjects’ interests, and re-spect their autonomy.30 However, otherprocedures may also achieve these re-sults. For instance, evidence of an indi-vidual’s preferences regarding researchmay be obtained from a research ad-vance directive rather than the individu-al’s concurrent informed consent.103

Given the existence of alternative pro-cedures, informed consent require-ments can be minimized, and, in somecircumstances, consent can even bewaived.7,101,103 Research on emergencylife-saving interventions for subjects whoare unconscious or otherwise not men-tally capable of consent and for whomfamily or proxy consent is not immedi-ately available may be conducted with-out informed consent.6,107-109 Thus, all re-quirements need to be satisfied, but theymay have to be adjusted and balancedgiven the circumstances of differenttypes of research.





As interpreted and elaborated for spe-cific research protocols, the fulfillmentof each of these 7 requirements ensuresthat research is socially valuable and sub-jects are not exploited, that subjects aretreated fairly and with respect, and thattheir interests are protected. As a result,these requirements should be sufficientto ensure that the vast majority of clini-cal research is ethical.30 While it may beimpossible to exclude the possibility thatadditional requirements are needed inrare cases, these 7 requirements are theessential ones.

UNIVERSALITYOF THE REQUIREMENTSThese 7 requirements for ethical clini-cal research are also universal.35-49,110

They are justified by ethical values thatare widely recognized and accepted andin accordance with how reasonablepeople would want to be treated.110-112

Indeed, these requirements are pre-cisely the types of considerations thatwould be invoked to justify clinical re-search if it were challenged.

Like constitutional provisions andamendments, these ethical require-ments are general statements of valuethat must be elaborated by traditions ofinterpretation and that require practi-cal interpretation and specification thatwill inherently be context and culturedependent.110-113 For instance, while in-formed consent is meant to ensure thatresearch subjects are treated with re-spect, what constitutes respect variesfrom culture to culture.110,114 In someplaces, it will be necessary to elicit theconsent of elders before individual sub-jects can be approached for informedconsent.115 Similarly, who is consid-ered vulnerable for the purposes of fairsubject selection criteria will vary by lo-cale. While in the United States specialefforts are necessary to ensure that ra-cial minorities are not just targeted forresearch with high potential for risks,53,73

in other places fair subject selection mayrequire special focus on religious groups.Similarly, local traditions and eco-nomic conditions will influence whenfinancial payments may constitute un-due inducements. Also, whether re-

search has a favorable risk-benefit ratiowill depend on the underlying healthrisks in a society. Research that is un-acceptable in one society because its risksoutweigh the risks posed by the dis-ease may have a favorable risk-benefitratio in another society where the risksposed by the disease are significantlygreater. Adapting these requirements tothe identities, attachments, and cul-tural traditions embedded in distinct cir-cumstances neither constitutes moralrelativism nor undermines their univer-sality110-112; doing so recognizes thatwhile ethical requirements embody uni-versal values, the manner of specifyingthese values inherently depends on theparticular context.110-112

NECESSARY EXPERTISEThese ethical requirements emphasizethe type of training and skills neces-sary for clinical investigators and thoseconducting independent review (Table2). Not only must clinical investigatorsbe skilled in the appropriate methods,statistical tests, outcome measures, andother scientific aspects of clinical trials,they must have the training to appreci-ate, affirm, and implement these ethi-cal requirements, such as the capacityand sensitivity to determine appropri-ate subject selection criteria, evaluaterisk-benefit ratios, provide informa-tion in an appropriate manner, andimplement confidentiality procedures.Similarly, because independent reviewof clinical research must assess its value,validity, selection criteria, risk-benefit ra-tios, informed consent process, and pro-cedures for monitoring enrolled sub-jects, the necessary skills must rangefrom scientific to ethical to lay knowl-edge. Consequently, the independentethical review of research trials shouldinvolve individuals with training in sci-ence, statistics, ethics, and law, as wellas reflective citizens who understand so-cial values, priorities, and the vulner-ability and concerns of potential sub-jects (Table 2).

ACTUAL CASESConsidering actual cases illuminateshow the requirements can guide ethi-

cal evaluation of clinical research. Onepersistently controversial issue is theuse of placebo controls.14-16 A new classof antiemetics, serotonin antagonists,such as ondansetron hydrochloride andgranistron hydrochloride, were devel-oped about 10 years ago. To evaluatethese drugs, investigators conductedplacebo-controlled trials randomizingcancer patients receiving emetogenicchemotherapy to either placebo or theserotonin antagonists.116-118

In evaluating the ethics of this clini-cal research, all requirements need to befulfilled, but 3 requirements seem par-ticularly relevant: value, scientific valid-ity, and risk-benefit ratio. There is nodoubt that the dominant antiemetictherapies of the time, such as prochlor-perazine, metoclopramide hydrochlo-ride, and high-dose corticosteroids areeffective. However, they are not com-pletely effective, especially for stronglyemetogenic chemotherapy such as plati-num, and they have significant adverseeffects, especially dystonic reactions.Alternative antiemetic therapies thatwould be more effective and have feweradverse effects were viewed as desirableandofvalue.However, therewasnovaluein knowing whether the serotoninantagonists were better than placebo incontrollingemesis, sinceplacebowasnotthe standard of care at the time of theresearch.14,63 Evenif theserotoninantago-nists were shown to be more effectivethan placebo, it would be a further issueto evaluate their effectiveness andadverse-event profile compared with theextant interventions. Thus, a placebo-controlled trial of the serotonin antago-nists for chemotherapy-induced emesisdoes not fulfill the value requirement.

Comparative studies evaluating thedifference between 2 active treat-ments are common in cancer therapyand valid as a study design.14-16 Someargue that active-controlled studies arescientifically more difficult to con-duct than placebo-controlled trials.119

However, any ethically and scientifi-cally valid randomized trial requires thatthere be an honest null hypoth-esis.30,63 The null hypothesis that the se-rotonin antagonists are equivalent to





placebo was not reasonable at the timeof the clinical research.14,63 Indeed, co-eval with the placebo-controlled stud-ies were randomized controlled trialswith serotonin antagonists vs active an-tiemetic therapy.120,121 Thus, a placebo-controlled trial was not the only scien-tifically valid method.

Those who supported the notion ofa randomized, placebo-controlled trialof serotonin antagonists argued thatthere was no serious risk from using aplacebo because emesis is a transitorydiscomfort that results in no perma-nent disability.119,122 However, emesisis not pleasant. Indeed, the entire ra-tionale for developing serotonin an-tagonists is that chemotherapy-induced emesis is a sufficiently serioushealth problem that development anduse of effective interventions in clini-cal practice are justifiable and desir-able.123 As one published report of a ran-domized placebo-controlled trial ofondansetron stated to justify the re-search: “Uncontrolled nausea and vom-iting [from chemotherapy] frequentlyresults in poor nutritional intake, meta-bolic derangements, deterioration ofphysical and mental condition, as wellas the possible rejection of potentiallybeneficial treatment. Many patients aremore afraid of uncontrolled nausea andvomiting than of alopecia.”118

Furthermore, the placebo-con-trolled trials for antiemetics includ-ed“ ‘rescue’ medication if patients hadpersistent nausea or vomiting.”118 Thisindicates both that there was an alter-native standard treatment for chemo-therapy-induced emesis and that eme-sis was sufficiently harmful to requireintervention.14,15,123,124 Permitting pa-tients to vomit while being adminis-tered placebo causes them unneces-sary harm.14,123,124 Thus, a placebo-controlled trial of antiemetics forchemotherapy-induced emesis does notminimize harm in the context of goodclinical practices and so fails the favor-able risk-benefit ratio when an avail-able clinical intervention can partiallyameliorate some of the harm.123

Importantly, the evaluation of theseplacebo-controlled trials of antiemet-

ics did not need to address informedconsent to determine whether they wereethical.122 Indeed, even if patients hadsigned an informed consent docu-ment that indicated they could be ran-domized to placebo and that there werealternative effective treatments, the pla-cebo-controlled research on serotoninantagonists would still be unethical.

Another controversial issue in-volves research in developing coun-tries.9-13,57,59 Recently, a rhesus rotavi-rus tetravalent (RRV-TV) vaccine waslicensed in the United States after ran-domized trials in developed countriesdemonstrated a 49% to 68% efficacy inpreventing diarrhea and up to 90% ef-ficacy in preventing severe cases of di-arrhea.125-127 However, shortly after ap-proval, the vaccine was withdrawn fromthe US market because of a cluster ofcases of intussusception, representingan approximately 1 in 10000 added riskof this complication.128 Should random-ized controlled trials of RRV-TV vac-cine proceed as planned in developingcountries or wait for a new vaccine can-didate to be developed? (C. Weijer, MD,PhD, written communication, March24, 2000) In evaluating the ethics ofthese proposed trials, the require-ments of value, scientific validity, fairsubject selection, and risk-benefit ra-tio are particularly relevant.

Despiteoral rehydration therapy,morethan 600000 children in developingcountries die annually from rotavirus di-arrhea.129 In some countries, the deathrate from rotavirus is nearly 1 in 200.Clearly, a rotavirus vaccine with even80% efficacy that prevented more thanhalf a million deaths would be of greatvalue. But is research using the RRV-TVvaccine ethical when the risk of intus-susception stopped its use in the UnitedStates? The RRV-TV vaccine was the firstand only licensed rotavirus vaccine andhas already been administered to nearly1 million children; potential alternativerotavirus vaccines are still years awayfrom phase 3 research. Thus, given thepotential benefit of preventing deathsfrom rotavirus in developing countries,a trial of RRV-TV vaccine now—even ifa better vaccine becomes evaluable in a

few years—is worthwhile. There is valueto the research on the vaccine for devel-oping countries only if there is reason-able assurance children in the countrywould be able to obtain it if it proved ef-fective.12,13,59

Vaccines effective in developed coun-tries may or may not be as effective orsafe in developing countries. Host, vi-ral, and environmental factors and sea-sonality of the disease can alter the ef-ficacy and safety profiles of a vaccine.130

Thus, there is good scientific rationalefor determining whether the RRV-TVvaccine can achieve sufficient levels ofprotection against diarrhea with an ac-ceptably low incidence of complica-tions in children in developing coun-tries. In this case, given the lack of anestablished method of preventing ro-tavirus infections in these countries, aplacebo-controlled trial would be valid.

Two factors suggest that, in theRRV-TV vaccine study, subjects in de-veloping countries are being selected forreasons of science and not being ex-ploited. First, the most appropriate sub-jects for a rotavirus vaccine trial are in-fants and children who have a highincidence of rotavirus infection and whoexperience significant morbidity andmortality from the infection. In such apopulation the efficacy of the vaccinewould be most apparent. Second, sincethe RRV-TV vaccine has been with-drawn from the US market, children indeveloping countries are not being se-lected to assume risks to evaluate a vac-cine that will ultimately benefit chil-dren in developed countries (Weijer,written communication). As long as theRRV-TV vaccine would be made avail-able to the population recruited for thestudy if proven safe and effective, chil-dren in the developing countries are be-ing selected appropriately.12,13,59

The final element is evaluation of therisk-benefit ratio. In the United States,the RRV-TV vaccine posed a risk of in-tussusception of about 1 in 10000, whilerotavirus causes about 20 deaths annu-ally or in fewer than 5 in 1 million chil-dren. Thus, in developed countries therisk-benefit ratio is not favorable—1 death from rotavirus diarrhea pre-





vented at the risk of 20 to 40 cases of in-tussusception. Because of underlying dis-ease burden, the risk-benefit ratio indeveloping countries is much different.If rotavirus causes the death of 1 in 200children while the RRV-TV vaccinecauses intussusception in 1 in 10000children, about 50 deaths from rotavi-rus diarrhea are prevented for each caseof intussusception. Consequently, therisk-benefit ratio of the RRV-TV vac-cine is favorable for individual subjectsin developing countries while it is unfa-vorable for subjects in developed coun-tries. This difference in risk-benefit ra-tios is a fundamental part of thejustification for conducting the re-search on an RRV-TV vaccine in a de-veloping country when it could not beethically conducted in a developed coun-try (Weijer, written communication).Obviously, to be ethical, randomizedcontrolled trials of an RRV-TV vaccinewould also have to adhere to the otherrequirements—independent review, in-formed consent, and respect for en-rolled subjects.

CONCLUSIONThese7requirements forconsideringtheethics of clinical research provide a sys-tematic framework to guide researchersandIRBsintheirassessmentsofindividualclinical research protocols. Just as con-stitutional rulingsare rarelyunanimous,this framework will not necessarily en-genderunanimousagreementontheeth-ics of every clinical research study. Rea-sonable disagreement results from 3sources: differences of interpretationsof the requirements, of views about theneed foradditional requirements, andofapplicationtospecific studies.Neverthe-less,thisframeworkdoesprovidethenec-essary context for review bodies to gen-erate traditionsof interpretation,under-stand disagreements, and highlight thekinds of considerations that must be in-voked to resolve them. Like a constitu-tion, these requirements can be reinter-preted, refined,andrevisedwithchangesin science and experience. Yet these re-quirements must all be considered andmet to ensure that clinical research—wherever it is practiced—is ethical.

Disclaimer: The views herein are those of the au-thors and do not represent the views or policies of theDepartment of Health and Human Services or the Na-tional Institutes of Health.Acknowledgment: We thank Robert J. Levine, MD,Steven Joffe, MD, Franklin Miller, PhD, Robert Truog,MD, James Childress, PhD, Francis Crawley, PhD, andAlbert Kapikian, MD, for their criticisms of the manu-script as well as Alan Sandler, DDS, Ruth Macklin, PhD,Eric Meslin, PhD, and Charles Weijer, MD, PhD, forhelpful discussion and suggestions on the ideas con-tained in the manuscript.

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