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The 50thAnniversary of the Declarationof

Helsinki

Progress butManyRemaining Challenges

Since 1964, through7 revisions, theWorldMedicalAs-

sociations(WMAs)Declarationof Helsinkihas stood as

an important statement regarding the ethical prin-

ciples guiding medical research with human partici-

pants.Thedeclarationisconsultedbyethicsreviewcom-

mittees,funders, researchers,and research participants;

has been incorporated into national legislation; and is

routinely invoked to ascertain the ethical appropriate-

ness of clinical trials.

There is much to praiseaboutthe revision process

and the latestrevision, which coincides with the decla-

rations 50th anniversary. The Working Group exten-

sively consulted stakeholders and justified the pro-

posed revisions. Theresult is a declarationthat is better

organized intoclearsections,more precise,and likely to

be more effective at protecting research participants.

Forthe firsttime,the declarationrequirescompen-

sationand treatmentfor research-relatedinjuries(para-

graph 15), an explicit recognition that research partici-

pantsshould notbearthecostsof research gone wrong.1

The revised declarations emphasis on the dissemina-

tionof research results, includingstudieswith negative

results, should increase the value of medical research

(paragraphs23, 35, and36).

Nevertheless, theproposed declarationcontainsper-

sistent flaws.Whilethedocumentpurportsto bea state-

mentof enduring ethical principles, thenearly continu-

ous processof revisionundermines its authority.2

More-over, thedeclarationcontinuesto assertthat consistent

with themandate of theWMA, itsprimary audience is

physicians (paragraph 2).This is a mistake.Indeed, the

documentthenoffersrecommendationsforotherhealth

professionals (paragraph9), research ethicscommittees

(paragraph 23),sponsors andgovernments(paragraph

34),andeditorsand publishers (paragraph36). Itis time

fortheWMAtorecognizethattheDeclarationofHelsinki

shouldaddressphysicians aswell other healthprofession-

als and personnel involved in research. A statement of

ethical principles does notrequire a mandate from the

people who ought to follow those principles.2

Thereviseddeclarationstreatmentof informedcon-sentremainsinadequate.It fails to recognize the possi-

bilityof waivingconsentforsomeresearchinvolvingcom-

petentadults,eventhoughsuchresearchiscommonand

widely endorsed. Similarly, the declaration avoids pro-

vidingguidance onwhenit canbe appropriateto askpar-

ticipants togivebroadconsent fortheirbiologicalsamples

tobe used in a wide rangeof futurestudies, rather than

seeking consent for each specific study. This is a press-

ingissueonwhichresearchersneedclearguidance.Inad-

dition,the declarationprohibitsindividualswho cannot

consentfrom participating inresearchthatdoes notad-

dress the condition that caused their incapacity (para-

graph30),evenwhentheresearchoffersparticipantsthe

potential for important medical benefit and there are

noorfewpotential participants whocan consent.This

approachtransformsa protection into a barrier.

ProblemsWithResearchPosingNetRisks

Research studiesand interventionsthat poseriskswith-

out compensating benefits to participantsnonben-

eficialstudiesarecrucialtoimprovingmedicalcare.Yet

the revised declaration offers conflicting and problem-

atic guidance on this topic. It rejects placing partici-

pantsatanynetrisktocollectdata,nomatterhowvalu-

able:While the primary purpose of medical research is

to generatenew knowledge,this goalcannevertakepre-

cedence over the rights and interests of individual re-

search subjects (paragraph 8, emphasis added).

Similarly, the declaration permits research com-

binedwithmedicalcareanincreasingly important cat-

egory of researchonlyto theextent that this is justi-

fiedbyitspotentialpreventive, diagnosticor therapeutic

value, leavingit unclearwhetherindividualsmay be ex-

posedtoanynetrisksinthiscontext(paragraph14).Even

morepuzzling,the declaration seemsto allow nonben-

eficial research only with individuals who areunableto

give informed consent (paragraph 28).

Clearly, thegoalof generatingnew knowledgemustnot take precedence over the rights of individual re-

searchparticipants.Researchparticipantsshould notbe

exposedto highnet risks.Yetnonbeneficialresearchcan

be ethical whenthe netrisks to participants interestsare

lowand thebenefitsto society are sufficiently large. In-

deed,inapparentconflictwithparagraphs8and14,para-

graphs16and28seemtoaffirmthatethicalresearchcan

pose some net risks to participants: Medical research

involving human subjects mayonly be conductedif the

importanceof theobjectiveoutweighsthe risksand bur-

dens to the research subjects(paragraph 16).

The declarations lack of clearand consistent guid-

anceregardingwhen netrisks areacceptablecreates un-necessary confusion and fuels the unfounded concern

that all medical research is inherently exploitative.

ProblemsWithResearchinPoor Communities

Thedeclarationrightlyrecognizes theimportance ofpro-

tectingthe worst off, including populationswholack ac-

cesstoadequatehealthcare.Thereviseddeclarationcalls

forspecial protectionfor groupsand individualswhoare

vulnerableandmayhaveanincreasedlikelihoodofbeing

wrongedorofincurringadditionalharm(paragraph19).3

VIEWPOINT

Joseph Millum, PhDDepartmentof

Bioethics, Clinical

Center, National

Institutesof Health,

Bethesda, Maryland,

and Fogarty

International Center,

National Institutesof

Health, Bethesda,

Maryland.

David Wendler, PhD

Departmentof

Bioethics, Clinical

Center, National

Institutesof Health,

Bethesda, Maryland.

Ezekiel J.Emanuel,

MD,PhD

Officeof theProvost,

Universityof

Pennsylvania,

Philadelphia, and

Departmentof Medical

Ethics and Health

Policy, Perelman School

of Medicine,University

of Pennsylvania,

Philadelphia.

Viewpoint

Related article

Corresponding

Author: Ezekiel J.

Emanuel, MD,PhD,

Departmentof Medical

Ethics and Health

Policy, Universityof

Pennsylvania, 122

CollegeHall,

Philadelphia, PA19104

(vp-global@upenn

.edu).

Opinion

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It thendelineates 3 conditions for researchwith vulnerable groups:

(1)theresearchmustberesponsivetotheirhealthneeds;(2)itmust

be impossible to carry out with nonvulnerable groups; and (3) the

group should stand to benefit fromthe knowledge, practices, or in-

terventions thatresult fromthe research(paragraph 20).

Thedeclarationis confusedand mistakenaboutvulnerability and

appropriateprotections.4,5First,thegroupthedeclarationhasinmind

that is in need of special protections is vulnerable because they arepoorand have limited access to medical services, notbecause they

areat higher riskof harms. Failureto make thisclearunderminesthe

protections. What is necessary to protect poor populations is very

different from what is necessaryto protect participants whoare at

higherrisk ofharm,cannot consent, or, becauseof their position,eg,

being a student,are atincreased risk of coercion.

Secondand moreimportantly,the declarationis confusedabout

whatconstitutesappropriateprotections andthe appropriatemeans

to achieve those protections.

Tobe clearand comprehensive,the declaration should state that

populations who are vulnerable to exploitation should always re-

ceive a fair level of benefits. Providingfair benefits is thegoal.The

means to achieve it vary. In only a limited number of clinical trials,

the requirement that vulnerable groups should benefit from the

knowledge, practice, or interventions that result from the re-

search (paragraph 20) along with the requirement that partici-

pants haveposttrial access to interventions identified as beneficial

(paragraph 34) can provide fair benefits, but only with respect to

phase 3 trialsin which an experimentalintervention is found to be

more effective. When research does not prove an intervention ef-

fectivephase 1 and 2, and negative phase 3 research trials

participantsfrom poorcountrieswith limited access tomedicalser-

vicesare unlikely to benefit at allfrom these requirements. In these

cases, a research project might supply clean water, new clinics, or

build local medical andresearch capacity. If this level of benefits is

fair, then theresearchwill not be exploitative.

ProblemsWithPlacebos

Therevised declaration fails to address the testingof interventions

thatmay be beneficialto some groups but are expected tobe less

effective thaninterventionsthatare available elsewherethebest

proven interventions. It asserts that placebos may be used only

when thepatients whoreceive them will notbe subject to addi-

tional risksof serious or irreversible harmasaresultofnotreceiving

thebestproven intervention (paragraph33, emphasisadded). Howtointerpret this last clauseis unclear. Thedanger is that itmay pre-

clude vital research that promises to improve the condition of the

worst off. Forexample, pasttrialsof single-dose nevirapine given to

mothersduringlabor andtheir infantswithin 72hours ofbirth dem-

onstrated that this approach was a highly cost-effective means of

reducing mother-to-child-transmission of HIV.6 However, it was

known at the time that single-dose nevirapine would not be as ef-

fective as more comprehensive and much more expensive treat-

ment regimens that also targeted transmission during pregnancy.

Yet trialsthat used less than thebest-knowntreatment were ethi-

caland had thepotential tobenefit mothers whootherwise would

receive nothing. A future and better declaration should allow such

trials under strict conditions, especially when no patients are de-

prived of treatment they would otherwise receive and the re-

searchhas the potentialto save lives and improve thecare of poor

populations.7

Conclusion

Therevised Declarationof Helsinkirepresents a significant improve-

ment over previous versions. Creating an international document

to guide research around the world is an enormously difficult and

complicatedtask.Nevertheless,importantproblems andsomecon-

fusion remain in this 50th-anniversary declaration. The definitive

guidance on research ethics and even better protection for re-

search participants await responsesto the Declaration of Helsinkis

remaining challenges.

ARTICLEINFORMATION

Published Online: October 19,2013.

doi:10.1001/jama.2013.281632.

Conflict of Interest Disclosures: All authors have

completedand submitted theICMJE Form for

Disclosure of PotentialConflicts of Interest.Dr

Emanuel reported receiving payment for speaking

engagements unrelatedto this work.

Disclaimer: Theviews expressedare the authors

own. Theydo notrepresent thepositionor policy of

the National Institutesof Health, US PublicHealth

Service, or theDepartmentof Healthand Human

Services.

REFERENCES

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2. Emanuel EJ.Reconsidering theDeclarationof

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3. HurstSA. Vulnerabilityin research andhealth

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Bioethics. 2008;22(4):191-202.

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Aspects of Research in DevelopingCountries.Moral

standards for research in developingcountries:

from reasonableavailability to fairbenefits.

Hastings CentRep. 2004;34(3):17-27.

5. MillumJ. Sharing thebenefitsof research fairly:

two approaches.J Med Ethics. 2012;38(4):219-223.

6. MarseilleE, Kahn JG,MmiroF,et al.Cost

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care debate: can research in developingcountries

be both ethical andresponsiveto thosecountries

health needs?Am J Public Health.

2004;94(6):923-928.

Opinion Viewpoint

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