Table Of ContentOPENACCESS
ReviewArticle
Aspects of vulnerable patients and informed consent in
clinical trials
Aspekte schutzbedürftiger Patienten sowie der Einwilligung nach
Aufklärung in klinischen Prüfungen
Abstract
Scope:Todiscusstherationalebehindinformedconsentinclinicaltrials MariaKuthning1
focusingonvulnerablepatientsfromaEuropeanandGermanviewpoint. FerdinandHundt1
Methods:ScientificliteraturesearchviaPubMed,Medline,Google.
Results: Voluntary informed consent is the cornerstone of policies
regulating clinical trials. To enroll a patient into a clinical trial without 1 UniversityDuisburg-Essen,
having obtained written and signed consent is to be considered as a Germany
seriousissueintheconductofaclinicaltrial.Developmentofethical
guidanceforphysiciansstartedbeforeChristErawiththeHippocratic
Oath.Mainfunctionofconsent,asarticulatedinallguidelinesdeveloped
for clinical research, is to facilitate an individual’s freedom of choice,
respect autonomy, and thus to ensure welfare of the participants in
clinical trials. Minors are unable to provide legally binding informed
consent, this issue is addressed through a combination of parental
permissionandminor’sassent.Illiteracyisacriticalproblemthataffects
allcornersofourearth;ithasnoboundariesandexistsamongevery
race and ethnicity, age group, and economic class. New strategies to
improvecommunicationwithpatientsincludingtheuseofvideotapes
oranimatedcartoonillustrationscouldbetaught.Finallythetimewith
the potential participant seems to be the best way to improve under-
standing.
Conclusion:Discoveryoflifesavingandlifeenhancingnewtreatments
requires partnership that is based on good communication and trust
between patients and researchers, sponsors, ethics committees, au-
thorities,lawyersandpoliticianssothatvulnerablepatientscanbenefit
fromtheresultsofwellcontrolledclinicaltrials.
Keywords:informedconsent,vulnerablepatients,minors,illiteracy
Zusammenfassung
Ziel:DiskussionderAspektederEinwilligungschutzbedürftigerPatienten
nach Aufklärung zur Teilnahme an klinischen Prüfungen aus europäi-
schemunddeutschemBlick.
Methoden:WissenschaftlicheLiteraturrechercheviaPubMed,Medline
undGoogle.
Ergebnis:DasfreiwilligeEinverständnisisteinEckpfeilerallerRegularien
von klinischen Prüfungen. Einen Patienten in eine klinische Prüfung
aufzunehmen, ohne zuvor die mit seiner Unterschrift versehene
schriftlicheEinverständniseingeholtzuhaben,istalsschwerwiegendes
Fehlverhaltenanzusehen.DieEntstehungethischerLeitlinienbegann
bereits vor christlicher Zeitrechnung mit dem Hippokratischen Eid. In
allen danach für die klinische Forschung entwickelten Leitlinien wird
verdeutlicht,dasseineHauptfunktionderEinwilligungnachAufklärung
die Sicherstellung der Willensfreiheit ist, um auch so das Wohl der
TeilnehmerinklinischenPrüfungensicherzustellen.Minderjährigenist
esnichtmöglicheindiesbezüglichbindendesEinverständniszugeben,
diesesProblemwirddurcheineKombinationvonelterlicherZustimmung
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Kuthningetal.:Aspectsofvulnerablepatientsandinformedconsent...
sowie soweit möglich der Einwilligung des Minderjährigen adressiert.
AnalphabetismusistbetreffsderinformiertenEinwilligungeinkritischer
Aspekt,derdieganzeWeltbetrifft.ErexistiertinallenGesellschaften,
allenBevölkerungsschichtenundinjederAltersgruppe.UmdieKommu-
nikationmitdiesenPatientenzuverbessern,könnenneueStrategien
mittelsVerwendungvonVideotapesoderanimiertenIllustrationenund
Trickfilmen gelehrt werden. Letztlich scheint die mit dem potentiellen
TeilnehmerverbrachteZeitderbesteWegzusein,umdieVerständigung
zuverbessern.
Schlussfolgerung:DieErforschunglebensrettenderundlebensverbes-
sernderneuerBehandlungenerforderteinePartnerschaft,dieaufguter
Kommunikation und Vertrauen zwischen Patienten und Forschern,
Sponsoren,Ethikkommissionen,Behörden,JuristenundPolitikernba-
siert,damitauchschutzbedürftigePatientenohneEinschränkungvon
denErgebnissenkontrollierterklinischerPrüfungenprofitierenkönnen.
Schlüsselwörter:EinwilligungnachAufklärung,schutzbedürftige
Patienten,Minderjährige,Analphabetismus
Introduction and the informing process through the investigator has
tobedocumentedinthepatients’sourcedata.
Inthispaperwearediscussingtherationalebehindin- TheICHGuidelineforGoodClinicalPractice[1]defines
formed consent in clinical trials focusing on vulnerable informedconsentasaprocessbywhichasubjectorhis
patientsfromtheEuropeanandGermanviewpoint. legalrepresentativevoluntarilyconfirmshisorherwilling-
Afterashortviewintogeneralaspectsofinformedcon- nesstoparticipateinaparticulartrialafterhavingbeen
sent,importantmilestonesofthedevelopmentforguid- informedaboutallaspectsof the trialthat are relevant
ance for physicians will be presented. A brief look into tothesubject’sdecisiontoparticipate.informedconsent
generalaspectsofvulnerablepatientswillleadtominors, isdocumentedbymeansofawritten,signedanddated
their parents and illiteracy in particular. Ethical and informedconsentform[1].Theinformedconsentprocess
practical challenges of the use of informed consent in reliesonthreeprinciples[2],[3]:
dailyroutineofphysicianshavenearlysimilarimpactand
• Adequate information is provided, generally, what a
challenges in clinical trials. While focusing ethical and
reasonable person would want to know in order to
regulatoryaspectsonEuropeandGermanyaglobalview
decide
willshowthatwecanlearnfromtherestoftheworldas
• Participantscomprehendtheinformation
well.
• Consentisgivenvoluntarily
Inobtaininganddocumentinginformedconsent,thein-
Informed consent – general vestigator should comply with the applicable regulatory
aspects requirement(s), and should adhere to Good Clinical
Practice(GCP)andtotheethicalprinciplesthathavetheir
originintheDeclarationofHelsinki[4],[5].Priortothe
Voluntaryisthecornerstoneofpoliciesregulatingclinical
beginning of the trial, the investigator should have the
trials. However, there are situations where a written in-
Ethics Committee’s (EC) written approval of the written
formed consent is impossible to obtain, such in a case
informedconsentformandanyotherwritteninformation
fromillorinjuredpatientwhoisunconsciousandunable
tobeprovidedtosubjects.Thewritteninformedconsent
to communicate or from children who do not have the
formandanyotherwritteninformationtobeprovidedto
legalcapacitytoprovideinformedconsent.Participation
subjectsshouldberevisedwheneverimportantnewin-
of vulnerable patients in clinical trials raises an ethical
formationthatmayberelevanttothesubject’sconsent
and legal dilemma which typically won’t be associated
becomesavailable.Anyrevisedwritteninformedconsent
withaverageintelligentadultsingoodmentalhealth.In
formandwritteninformationshouldreceivetheEC’sap-
Neonates, young children or comatose patients it is
proval in advance of use. The subject or the subject’s
manifested,thattheyareunabletogiveconsentfortheir
legal representative should be informed in a timely
participationinaclinicaltrial.Eitherparentsortheirlegal
mannerifnew informationbecomesavailablethatmay
representative(s)functionassurrogatesofthechildand
berelevanttothesubject’swillingnesstocontinueparti-
havetogivetheirconsentincasetheyagreetothechild’s
cipationinthetrial.Thecommunicationofthisinforma-
trialparticipation.Foranunconsciousorcomatosepatient
tionshouldbedocumented[1].Neithertheinvestigator,
alegalrepresentativehastosigntheinformedconsent
nor the trial staff, should coerce or unduly influence a
form. Similar to patients able to give consent, a signed
subject to participate or to continue to participate in a
and dated consent form has to be provided from them
trial.Noneoftheoralandwritteninformationconcerning
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the trial, including the written informed consent form, • The negative impact on the subject’s well-being is
shouldcontainanylanguagethatcausesthesubjector minimizedandlow.
the subject’slegalrepresentative to waive or to appear • Thetrialisnotprohibitedbylaw.
towaiveanylegalrights,orthatreleasesorappearsto • TheapprovaloftheECisexpresslysoughtontheinclu-
release the investigator, the institution, the sponsor, or sionofsuchsubjectsandthewrittenapprovalcovers
their agents from liability for negligence. The language thisaspect.
usedintheoralandwritteninformationaboutthetrial,
In emergency situations, if prior consent of the subject
including the written informed consent form, should be
isnotpossible,theconsentofthesubject’slegalrepre-
asnon-technicalaspossibleandshouldbeunderstand-
sentative,ifpresent,shouldberequested.Ifpriorconsent
abletothesubjectorthesubject’slegalrepresentative
ofthesubjectisnotpossibleandthesubject’slegalrep-
and the impartial witness, where applicable. Before in-
resentative is not available, enrolment of the subject
formed consent may be obtained, the investigator or a
shouldrequiremeasuresdescribedintheprotocoland/or
persondesignatedbytheinvestigatorshouldprovidethe
elsewhere with documented approval from the EC to
subjectorthesubject’slegalrepresentativeampletime
protect the rights, safety and well-being of the subject
andopportunitytoinquireaboutdetailsofthetrialand
andtoensurecompliancewithapplicableregulatoryre-
to decide whether or not to participate in the trial. All
quirementshastobeavailable.Thesubjectorthesub-
questionsaboutthetrialshouldbeansweredtothesat-
ject’slegalrepresentativeshouldbeinformedaboutthe
isfactionofthesubjectorthesubject’slegalrepresenta-
trialassoonaspossibleandconsenttocontinueshould
tive.Priortoasubject’sparticipationinthetrialthewrit-
berequested[1].PerdefinitionoftheICHGCPGuideline
teninformedconsentformshouldbesignedandperson-
alegalrepresentativeforsuchpatientsisanindividual,
allydatedbythesubjectorbythesubject’slegalrepre-
juridical or other body authorized under applicable law
sentativeandbythepersonwhoconductedtheinformed
toconsent,onbehalfofaprospectiveindividual,tothe
consentdiscussion[1].
individual’sparticipationintheclinicaltrial.
After the written informed consent form and any other
writteninformationtobeprovidedtosubjectsisreadand
explainedtothesubjectorthesubject’slegalrepresen- Development of guidance for
tative,andafterthesubjectorthesubject’slegalrepre-
physicians
sentative has orally consented to the subject’s partici-
pationinthetrialand,ifcapableofdoingso,hassigned
TheHippocraticOath,namedafterthephysicianHippo-
and personally dated the informed consent form, the
crates(460–370BC),isconsideredtobethefirstfunda-
witnessshouldsignandpersonallydatetheconsentform.
mentalwordingofmedicalethics.Itisanoathhistorically
Bysigningtheconsentform,thewitnessatteststhatthe
takenbydoctorsswearingtopracticemedicineethically.
information in the consent form and any other written
TheHippocraticOath(gr.orkos)isoneofthemostwidely
informationwasaccuratelyexplainedtoandapparently
knownofGreekmedicaltexts,itrequiresanewphysician
understoodandthatinformedconsentwasfreelygiven
toswearuponanumberofhealinggodsthathewillup-
[1]. Prior to participation in the trial, the subject or the
holdanumberofprofessionalethicalstandards[6].
subject’s legal representative should receive a copy of
InRomanlaw(428AD)therelationshipbetweenpatient
thesignedanddatedwritteninformedconsentformand
andphysicianhasnotbeenlegallybinding.Theexchange
any other written information provided to the subjects.
betweenachievementandpaymenthasbeenregulated
Whenaclinicaltrial(therapeuticornon-therapeutic)in-
for the case of success [7], [8]. During the high middle
cludessubjectswhocanonlybeenrolledinthetrialwith
agestherelationshipphysician-patientwasregulatedby
the consent of the subject’s legal representative (e.g.,
‘healingcontracts’:a physicianhad to heal the patient,
minors, or patients with severe dementia), the subject
onlyincaseofsuccessthepaymenttothephysicianwas
shouldbeinformedaboutthetrialtotheextentcompat-
permitted[9].
iblewiththesubject’sunderstandingand,ifcapable,the
A change could be observed during the first half of the
subject should sign and personally date the written in-
17thcentury,whentherapyandpharmaceuticalmedica-
formedconsent.Anon-therapeutictrial(i.e.atrialinwhich
tion obtained more relevance and the liability of the
thereisnoanticipateddirectclinicalbenefittothesub-
physicianwasnolongerlimitedtosuccessoftreatment.
ject), should be conducted in subjects who personally
SirAjlounipresentedahistoricaldocumenton‘legalin-
giveconsentandwhosignanddatethewritteninformed
formedconsent’recordedduringtheOttomanEmpirein
consentform. Non-therapeutictrialsmay be conducted
the 17th century, but this document does not meet the
insubjectswithconsentobtainedfromalegalrepresen-
basicstandardsoftheconceptofinformedmedicalcon-
tativeincasethefollowingconditionsarefulfilled[1]:
sent,itisacontracttoensurethatthephysicianwillnot
• Theobjectivesofthetrialcannotbemetbymeansof beheldresponsiblefordeath,ratherthananattemptto
atrialinsubjectswhocangiveinformedconsentper- seek informed consent from an educated and autono-
sonally. mouspatient[10],[11],[12].
• Theforeseeableriskstothesubjectsarelow. A broad range of ethical issues concerning informed
consent became apparent as early as the 19th century;
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Figure1:Milestonesofimportantdocumentsinclinicalresearch(ownillustration)
theDirectiveofthePrussianMinisterofaGermanGov- [19]. Although it did not carry the force of law, the
ernmentregulationonhumanexperiments[13]isprob- NurembergCodewasthefirstdocumentwhichadvocated
ably the earliest official regulation of informed medical voluntaryparticipationandinformedconsent.
consentintheWesternworld.Itwasissuedafterpatients The Declaration of Geneva [20] was adopted by the
wereinjuredinnon-therapeuticresearch[13];thesein- General Assembly of the World Medical Association at
juriesevokedcriticalpublicandprofessionaldiscussion Geneva in 1948 and amended in 1968, 1984, 1994,
andadebateinthePrussianparliament[13].Minorsand 2005and2006.Itisa‘declarationofphysicians’dedi-
individuals not competent due to other reasons were cationtothehumanitariangoalsofmedicine.TheDeclar-
generallyexcludedfromnon-therapeuticresearch,since ation of Helsinki (DoH) [5]: In 1964, the World Medical
theycouldnotgiveavalidinformedconsentintheunder- Associationestablishedrecommendationsguidingmed-
lyingmodelofautonomy.Otherpronouncementsonthe ical doctors in biomedical research involving human
importance of consent in medical research are to be subjects.Thedeclarationprovidesguidanceforinterna-
foundintheearly20thcenturyinGermany[14],[15]. tional research ethics and defines rules for research
TheGenevaDeclarationoftheRightsoftheChild1923 combinedwithclinicalcareandnon-therapeuticresearch.
isthenamegiventoaseriesofrelatedchildren’srights TheDeclarationofHelsinkiwasrevised[21]mostrecently
proclamations[16].ThefirstwasadoptedbytheInterna- in2008[22].
tionalSavetheChildrenUnion,Genevaandendorsedby In 1974 the National Commission for the Protection of
the League of Nations General Assembly on November HumanSubjectsintheUnitedStatesdevelopedtheNa-
26th,1924astheWorldChildWelfareCharter[17]. tionalResearchActfortheProtectionofHumanSubjects
In1931theGermanMinister‘ReichsministerdesInnern’ of Biomedical and Behavioral Research, which was
releasedaDirectiveonHumanExperimentation:‘Richt- chargedtoidentifythebasicethicalprinciplesthatshould
linie des Reichsministers des Inneren vom 28. Februar underlie the conduct of biomedical and behavioral re-
1931’. The Deutsche Reich forbids innovative therapy search involving human subjects and to develop
unlessthesubjectorhislegalrepresentativehasunam- guidelineswhichshouldbefollowedtoassurethatsuch
biguously consented to the procedure in the light of research is conducted in accordance with those prin-
relevantinformationprovidedinadvanceandtheprotec- ciples. The commission drafted the Belmont Report, a
tionofvulnerablepersonsandtheresponsibilityaswell foundationaldocumentfortheethicsofhumansubjects’
as the necessity of a trial protocol are regulated [18] researchintheUnitedStates[23].
(Figure1). TheBelmontReportfrom1979isanimportanthistorical
Asdirectresultofthemedicalexperimentsonthousands documentinthefieldofmedicalethics.Itstressedthat
of concentration camp prisoners, the Nuremberg Code eachpatientgroupshouldbeevaluatedseparatelyand
was established in 1949, stating that “The voluntary a subject’s wishes should be taken into account to the
consent of the human subject is absolutely essential”, greatestextentpossible.Athirdpartyshouldbeappointed
making it clear that subjects should give consent and to act on behalf of the subject and thus substitute his
thatthebenefitsofresearchmustoutweightherisks[4], consent. The report recommended the role of Ethics
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Table1:Importantdocumentsinclinicalresearch
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Committees in ensuring that sufficient information will capacityandviceversa.Finallythephysicianjudgesand
bedisclosedtothesubjects.Moreoveritisstressedthat decidesaboutthecompetenceofanadultpotentialtrial
investigatorsshouldavoidtheuseofvulnerablesubjects subject.
whenpossible[23],[24]. Still,therapeuticresearchforthesediseasesinpatients
The International Conference on Harmonization (ICH) unabletogiveconsentismeaningfulandequallyimport-
publishedguidelinesgoverningclinicaltrials.Animportant ant,suchaswhichinterventionsareeffective,whichhave
one is the ICH Tripartite Guideline E6 from 1996, last no impact, and which do more harm than good. The
published in 2002 [1], a Note for Guidance on Good guarantee for the protection of the individual intended
ClinicalPractice(GCP,CPMP/ICH/135/95).Compliance tobetreated,belongstoanotherindividual,whichisre-
with this standard provides public assurance that the latedtoacommunityandthereforeisnotviolatedincase
rights,safetyandwell-beingoftrialsubjectsareprotected; thehumanbeinghastocomplyregardlessofhisinterests
consistentwiththeprinciplesthathavetheirorigininthe [26]. This makes clear that self-interest is not the only
DeclarationofHelsinki,andthattheclinicaltrialdataare criterion for the guarantee for protection of the human
credible(Table1). dignity in the area of medical research. For clinical re-
searchwithpatientsunabletogiveconsentthereforeis
clarified,thatitispermissibletolookforawell-balanced
Vulnerable patients – general
conceptbetweenprotectionofdignityofpatientsunable
aspects to give consentand the goal of our communityand the
researcher–tohelpagroupofotherillpeople[27],[28],
The word ‘vulnerable’ has its origins in the Latin verb [29].
‘vulnerare’, ‘to wound’. It refers to a person’s state of
beingliabletosuccumb,astomanipulation,persuasion
Vulnerable patients – minors
ortemptation.ICHGCPGuidelineE6[1]definesvulner-
ablesubjectsasindividualswhosewillingnesstovolun-
Children have not attained the legal age for consent to
teer in a clinical trial may be unduly influenced by the
treatmentorproceduresinvolvedintheresearchunder
expectation,whetherjustifiedornot,ofbenefitsassoci-
theapplicablelawofthejurisdictioninwhichtheresearch
atedwithparticipation,orofaretaliatoryresponsefrom
willbeconducted.Theyareboth,vulnerablesubjectsin
seniormembersofahierarchyincaseofrefusaltoparti-
need of protectionfrom research risksand a neglected
cipate.Examplesaremembersofagroupwithahierarch-
classthatneedsbetteraccesstothebenefitsofresearch.
ical structure, such as medical, pharmacy, dental, and
Basedon the EUDirective [30], Germandruglaw regu-
nursing students, subordinate hospital and laboratory
latesin§40(4)and§41(2)clinicaltrialsonchildren.
personnel, employees of the pharmaceutical industry,
In respect of a clinical trial on minors, the medicinal
membersofthearmedforces,andpersonskeptindeten-
productmustbeintendedtodiagnoseorpreventdiseases
tion.Othervulnerablesubjectsincludepatientswithin-
inminorsandtheuseofthemedicinalproductmustbe
curablediseases,personsinnursinghomes,unemployed
indicatedinaccordancewithmedicalknowledgeforthe
orimpoverishedpeople,andpatientsinemergencysitu-
purpose of diagnosing or preventing diseases in the
ations, ethnic minority groups, homeless persons,
minor.Themedicinalproductisindicatedifitsadminis-
nomads,refugees,minors,andthoseincapableofgiving
tration to minors is medically indicated. Clinical trials
consent[1].
performedonadultscannotbeexpectedtoproducesat-
Themoreprotectiontrialparticipantsneedandespecially
isfactory test results according to medical knowledge,
patients whose decisional competence seems to be
the consentis granted by the legalrepresentative after
questionable, the more difficult it is for others to take
being informed. It must correspond to the minor’s pre-
decisionsontheirbehalfaboutwhetherornottheyshould
sumedwillwheresuchawillcanbeascertained.Before
participate in the clinical trial. Many people enrolled in
thestartoftheclinicaltrial,theminorshallbeinformed
clinicaltrialscanbeconsideredvulnerable,andsuchtri-
by an investigator who is experienced in dealing with
alsoftenraiseconcernsbecauseofthediminishedability
minors about the trial, the risks and benefits as far as
ofvulnerablepatientstoconsiderandprotecttheirown
possible.Ithastobetakenintoaccounttheminor’sage
interests. Which patients are vulnerable and what are
andmentalmaturity.Shouldtheminordeclareorexpress
the criteria for a patient to be unable to give consent?
inanyotherwaythathe/shedoesnotwishtotakepart
Does it only belong to legal capacity? Beauchamp [25]
intheclinicaltrial,thismustberespected.
notestolegalcompetence,thatlegalcapacityasacat-
Thedeterminationofthelevelsofriskandtheassociated
egorydistinctfrompsychologicalcapacity.Somepatients,
potentialbenefitsarethebasisforethicalapprovability.
suchasprecociousminors,mayhavepsychologicalabil-
In the following examples, levels of risk are considered
ity,butnolegalcapacity.Somepatientsmayhavelegal
tobeinbalancewiththebenefitforatrialwiththepedi-
capacity without psychological capacity. To say that
atricpopulation[31].
someone is legally competent is to say that no-one is
justifiedintheauthorizinginterventionsintheperson’s • Minimalrisk,whichcouldbedefinedasprobabilityof
affairsorinactingonhis/herbehalf[25].Claimedishere, harm or discomfort not greater than that ordinarily
thatlegalcapacitycanexistintheabsenceofdecisional
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Kuthningetal.:Aspectsofvulnerablepatientsandinformedconsent...
encounteredindailylifeorduringtheperformanceof • The minor has received information according to its
routinephysicalorpsychologicalexaminationsortests. capacityofunderstanding,fromstaffwithexperience
• Minorincreaseoverminimalrisk,withbenefittoindi- withminors,regardingthetrial,therisksandthebe-
vidualorbenefittothegroup,andwiththebenefitto nefits.
risk balance being at least as favorable as that of • Theexplicitwishofaminorwhoiscapableofforming
availablealternativeapproaches. an opinion and assessing this information to refuse
• Greater than minor increase over minimal risk with participationortobewithdrawnfromtheclinicaltrial
benefit for the individual that is especially favorable atanytimeisconsideredbytheinvestigatororwhere
inrelationtoavailablealternativeapproachesforthe appropriatetheprincipalinvestigator.
individual’scondition.
Withregardtobenefitforthegroup,itisalsoemphasized Parents – representatives
in the European Convention on Human Rights and Bio-
medicine which states in its article 17.2 “Exceptionally
Theinformedconsentprocessforthepediatricpopulation
and under the protective conditions prescribed by law,
is different from a trial with adults. The Clinical Trials
wheretheresearchhasnotthepotentialtoproducere-
Directive 2001/20/EC Article 4 requires the informed
sults of direct benefit to the health of the person con-
consentofthelegalrepresentative,itmustrepresentthe
cerned,suchresearchmaybeauthorized[…]”if:
minor’spresumedwillandmayberevokedatanytime,
1. “The research has the aim of contributing, through withoutdetrimenttotheminor.Article4(a)oftheClinical
significantimprovementinthescientificunderstand- Trials Directive 2001/20/EC requires that the specific
ingoftheindividual’scondition,diseaseordisorder, andwritteninformedconsentofparent/legalrepresen-
totheultimateattainmentofresultscapableofcon- tativemustbesoughtpriortoenrollingachildinatrial.
ferring benefit to the person concerned or to other Consent in line with the Clinical Trials Directive should
personsinthesameagecategoryorafflictedwiththe beobtainedfromtheparent(s)/legalrepresentative(s)at
samediseaseordisorderorhavingthesamecondi- thesametimeasassentissoughtfromthechild.Infor-
tion”; mation should be given by an experienced investigator,
2. “Theresearchentailsonlyminimalriskandminimal orhisadequatelytraineddelegate,toeachparent,orthe
burdenfortheindividualconcerned;andanyconsid- legalrepresentative(s),onthepurposeofthetrialandits
erationofadditionalpotentialbenefitsoftheresearch nature,the potentialbenefits and risks.They also have
shallnotbeusedtojustifyanincreasedlevelofrisk toknowthenamesoftheinvestigators(s)whoarerespon-
orburden”. sibleforconductingthetrialwithbackgroundprofessional
information (such as education, work experience) and
WithimplementationoftheDirective2001/20/ECclinical
getdirectcontactdetails(telephoneande-mail)forfur-
research in minors is now extended from direct benefit
ther information regarding the trial. The parent/legal
fortheindividualtobenefitforthegroupofaffectedpa-
representative(s)shouldbegivensufficienttimeandne-
tientsintheEuropeanUnion.Parentshaveanimportant
cessaryinformationtoconsiderthebenefitsandrisksof
roleiftheirchildrenshallbeincludedinaclinicaltrial:It
involving the child in the clinical trial. The role of the
isachallengeforaninvestigatortoillustratethebenefit
physicianchangesfromsolelybeingthetreatingdoctor
forthesingleorgroupofpatients.Toexplaintothemthat
to an investigator, who in addition conducts the clinical
theirseverelyillchildcouldpossiblyreceiveplaceboina
trial often per contract with a sponsor. However, the in-
placebocontrolledtrial,andtoexplainthecomplexityof
vestigator should not take part in the decision making,
aplacebocontrolledtrialdoesnotmakeiteasier.Parents
butshouldensurethattheinformationhasbeenunder-
have to be fully involved in the process and to feel that
stood and that there has been enough time allowed to
theyaresufficientlyinformed.
cometoadecision.Theinvestigatormustmakesurethat
According to Regulation (EC) No 1901/2006, the term
childrenknowwhatwillhappentothemduringthestudy,
pediatricpopulationreferstothepartofthepopulation
therisksandbenefitsandthattheymaywithdrawtheir
agedbetweenbirthand18years.Ageofassentcan/is
assentatanytime.Obtainingassentgiveschildrenarole
to be determined by Ethics Committees and has to be
inshareddecisionmakingandremindsusthatchildren
consistentwithlocallegalrequirements,whichdifferwith
shouldbetreatedwithdignityandrespect.Assentofthe
an extreme variance in all countries and regions world-
minorsthemselvesisrequiredwhentheyareabletoun-
wideduetodifferentregulations,culturesandreligions.
derstand the nature, importance and consequences of
AccordingtotheEUDirective2001/20ECinadditionto
theclinicaltrial.Thereisnopossibilitytoconcludefrom
any other relevant restriction, a clinical trial on minors
earlierexpressionoftheirpresumedwillingnesstotake
maybeundertakenonlyif[30]:
partinaclinicaltrial.Thisimpositionindeedisjustifiable
• Theinformedconsentoftheparentsorlegalrepresen- onlywiththeguaranteeofaveryhighprotection.Depend-
tativehasbeenobtainedandconsentmustrepresent ingontheiragetheyshouldprovideasignatureandthe
theminor'spresumedwillandmayberevokedatany participationmustcorrespondtotheassumedwillofthe
time,withoutdetrimenttotheminor. littlesubject.
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Somestudiesaboutcognitivedevelopmentanddecision Illiteracy
makinginjuvenilesshowthat,accordingtothemeasures
used, children above age fourteen are, in general, as Purelyilliteratepersonscannotreadorwriteinanycapa-
capableasadultstomakedecisions[32].whilechildren city,forallpracticalpurposes.Incontrast,functionallyil-
belowageelevenlackmanycapacitieswhichareneces- literatepersonscanreadandpossiblywritesimplesen-
sarytomakedecisions[33].Somechildreninthemiddle tenceswithalimitedvocabulary,butcannotreadorwrite
group(ageseleventofourteen)havethecapacitytomake well enough to deal with the everyday requirements of
decisions,whileothershavenot[32].Howeveritisworth life in their own society. In many parts of the world, pa-
notingthatchildrenwillhavelessbackgroundknowledge tientsandtheirrelativeslackeducationand/ortheydo
aboutmedicinethanadultsandthusmayrequireconsid- notreadandwritewellenoughtounderstandhealthin-
erablymoreinstructiontoachieveadequateunderstand- formation,includingtypicalinformedconsentinformation
ing. In addition they may lack a general context of life thatwouldbeprovidedtothembytheinvestigator,when
experiencesbywhichtojudgetherisksandbenefitsof decidingtobeenrolledintoastudyornot.TheGerman
the proposed treatment. The EU Directive 2001/20 EC Alphabund[34]definesfunctionalilliteracy:“existswhen
states, that every effort should be made to understand thewrittenskillsofadultsarelowerthanthosewhichare
and respect differences of opinions between the child theminimumandconsideredamatterofcoursetocope
and his/her parents or legal representative. Objections with day-to-day requirements in society. [...] If a person
raised by a child at any time during a trial should be cannotreadoneorseveralitemsofinformationdirectly
considered:Hereemergesadilemmafortheinvestigator containedinasimpletextsothatthesenseisunderstood
andthe parents/legalrepresentative/s)onhow to deal and/orthepersonisatasimilarskillslevelwhenwriting.”
withthissituation.Therearevaryingviewsbelongingto UNESCO talksabout functionalilliteracy when full com-
thistopicandresearchisneededtoaddressthepaucity mandofreading,writingandmath’sskillsislacking[34].
of empiricaldataconcerningthe informedconsentpro- In many parts of the world, patients and their relatives
cessinpediatricclinicalresearch.Researchontheinter- lack education and/or they do not read and write well
actionbetweeninvestigators,childrenandstressedpar- enoughtounderstandhealthinformation,includingtyp-
entswhohavetodecideontrialparticipationoftheirill icalinformedconsentinformationthatwouldbeprovided
childcouldalsobeveryvaluableinordertosupportthem tothembytheinvestigator,whendecidingtobeenrolled
ifneeded. intoastudyornot.Illiteracyisacriticalproblemthataf-
fects all corners of our earth; it has no boundaries and
exists among every race and ethnicity, age group, and
Children’s assent
economicclass[35].Thissilentepidemicofpeopleun-
abletoreadthreatensover796millionadultsworldwide
Assentreferstotheminor’sagreementtoparticipatein
[35]. Although attending school until the age of 16 is
the clinical trial, after being provided with information
mandatory in Germany, around 7,5 million of over 80
appropriatetoitsageandcognitiveabilities.Thetermof
million people in Germany are still functional illiterates
assentisnotexplicitlyincludedintheClinicalTrialsDir-
[36], [37]. They may have gone to school for years, but
ective2001/20/EC,whichonlyrequiresthattheminor’s
they read and write so poorly that it’s hard for them to
willshouldbeconsidered.Assentshouldbeunderstood
leadanormallife.IlliteracywaslongignoredinGermany
inthecontextofArticle4(c)oftheClinicalTrialsDirective
or dismissed as a problem in poorer, less developed
as the expression of the minor’s will to participate in a
countries.Indeed,mostoftheworld’s800millionilliter-
clinical trial. The capacity of a child to make voluntary
ates live in developing countries. But particularly since
informeddecisions,i.e.toassent,evolveswithage,ma-
thePISAstudiescarriedoutbytheOrganizationforEco-
turity and previous experience of life and illness. While
nomic Cooperation and Development (OECD) showed
assent may not be possible in all age groups (e.g.
thatpupilsherelagfarbehindtheirpeersinotherhighly
neonates)orinallresearchconditions(e.g.researchin
developed countries, educators and the public have
emergencysituations),theinformationprocessprovided
realized that many schoolchildren find it tough to write
to the child and the child’s response should be docu-
correct German [38]. Extremely low literacy rates are
mented in the source data. If the minor is in a position
concentratedinthreeregions,SouthandWestAsia,Sub-
tocomprehendthenature,significanceandimplications
SaharanAfrica,andtheArabstates,whereone-thirdof
oftheclinicaltrialandtoformarationalintentioninthe
themenandhalfofthewomenareilliterate.Africa,asa
light of these facts, then his/her assent should also be
wholecontinent,haslessthana60%literacyrate.Over
required.Anopportunityforacounselingsessionshould
two-thirdsofthenon-literateadultspopulatethefollowing
beoffered,notonlytothelegalrepresentativebutalso
countries: India, China, Bangladesh, Pakistan, Nigeria,
to the minor. The clinical trial may only be conducted if
Ethiopia,Indonesia,andEgypt.Staggeringnumbersshow
itsubjectsthepersonconcernedtoaslittleburdenand
that India alone has over 440 million illiterate citizens
other foreseeable risks as possible. Both the degree of
[35].
burdenandtheriskthresholdmustbedefinedspecifically
If a subject is unable to read or if a legally acceptable
in the trial protocol and monitored constantlyby the in-
representative is unable to read, an impartial witness
vestigator[33].
should be present during the entire informed consent
GMSGermanMedicalScience2013,Vol.11, ISSN1612-3174 8/12
Kuthningetal.:Aspectsofvulnerablepatientsandinformedconsent...
discussionbeforeenrolmentintoaclinicaltrial[1].After studyprotocoltotherelevantlegalandethicalauthority.
thewritteninformedconsentformandanyotherwritten All records were labeled and stored. ADOC, or similar
information to be provided to subjects is read and ex- standardized procedures designed with the same prin-
plainedtothesubject/legalrepresentative,andafterthe ciples, enables valid informed consent to be obtained
subject/legalrepresentativehasorallyconsentedtothe fromilliteratepopulationsforparticipationinclinicalre-
subject’sparticipationinthetrialand,ifcapableofdoing search, and should be available as an alternative to
so,hassignedandpersonallydatedtheinformedconsent writtenandsignedconsentwhereneeded[41].
form, the witness should sign and personally date the Therearemanyaspectsofclinicaltrialsthatthoseliving
consentform. By signingthe consentform, the witness indevelopingcountriesdonotunderstand.Workdonein
atteststhattheinformationintheconsentformandany Kilifi, Kenya, suggests that misunderstandings have
other written information was accurately explained to, contributed to concerns and rumors, which potentially
and apparently understood by, the subject/legal repre- undermineethicalaspectsofresearchandlocaltrustin
sentative,andthatinformedconsentwasfreelygivenby theinstitution[42].Toaddressthechallengeofinformed
the subject/legal representative [1]. The consent form consent for this population, the World Medical Associ-
should document the method used for communication ation, the South African Medical Association, the Steve
with the prospective subject and the specific means by Biko Centre for Bioethics in Johannesburg and some
whichtheprospectivesubjectcommunicatedagreement pharmaceuticalcompaniespartneredwithBooksofHope,
toparticipateinthestudy.Avideotaperecordingofthe aliteracyempowermentprogramthatseekstoempower
consentinterviewisrecommended[39]. illiteratepopulations.In2005a‘SpeakingBook’hasbeen
Sufficient time should be allowed for questions to be launchedforilliteratepeopletoexplainthefundamentals
asked and answered, both by the subject, and by the related to participating in a clinical trial. The Speaking
personobtainingconsenttoensurethesubjectcompre- Book is a book that uses cartoons in addition to text,
hendstheconsentinformation.Theresponsibilityofen- whichisspokenwhenthecorrespondingbuttonispushed
suringthatapotentialsubjectunderstandstheresearch for that page. It uses visual messages accompanied by
andtherisksandbenefitsinvolvedfallsupontheinvesti- soundandtherecordedtextservesasascript.Contrary
gatorandnotuponthepotentialsubject. toradioandtelevision,theSpeakingBookdoesnotde-
Itiscriticaltotheconsentprocessthattheinvestigator pendonaccesstoelectricityorproximity.In2008approx-
notonlyfieldsquestionsbutalsoasksquestions.Asking imately4,500booksweredistributedinSouthAfricaand
questionscanfurtherthediscussion,elicitquestionsfrom SpeakingBooksarecalledaWorldChangingIdea[35].
the potential subject, prompt the potential subject to Oneistitled:Whatitmeanstobepartofaclinicaltrial
thinkmorecarefullyaboutthestudy,andhelptheinves- [35].
tigatordecidewhetherthepersonhasadequatelyunder-
stoodthestudy.Usefulquestionswillbeopen-endedand
Discussion
non-directive.Ratherthanaskingforyesornoanswers,
theyaskforexplanationbecausethesequestionsoften
canbeansweredinavarietyofways,anddonotalready The main function of consent, as articulated in all
contain the correct answer. Open-ended questions are guidelinesforclinicalresearch,istofacilitateanindividu-
often introduced with “what”, “where”, “how often”, al’s freedom of choice, respect autonomy, and thus to
“when”,and“pleasedescribe”[40]. ensure welfare of the participants in clinical trials. To
Examplesofopen-endedquestionsare: enrollapatientintoaclinicaltrialwithouthavingobtained
“Just so that I'm sure you understand what is expected writtenandsignedconsentistobeconsideredasaseri-
of you, would you please explain to me what you think ousissueintheconductofaclinicaltrial.However,there
we'reaskingyoutodo?” aresomecircumstanceswhereitisverydifficulttoobtain
“Describeinyourownwordsthepurposeofthestudy.” properlyinformedconsent.Consideringinformingminors
“Whatmorewouldyouliketoknow?” whenparentsdifferintheiropinionornoparentsorlegal
“What is the possible benefit to you of participating in representativesareavailable,whichwouldbethemost
thisstudy?Whatarethepossiblerisks?” unethicalthingtodo:Totrytoanswerarelevantquestion
“Canyoudescribewhatthealternativestoparticipation without consent? To never conduct the trial so that no
inthisstudyare?”[40] oneknowstherightwaytosolveaspecificproblem,with
A method of informed consent for illiterate populations theaddedpossibilitythatchildrenwillcontinuetoreceive
hasbeendescribedintheLancet[41]whereaudiovisual suboptimalcare?Thisissueneedstogetattentionfrom
documentationoforalconsent(videoandaudiotapere- lawyers and Ethics Committees. The question if shared
cording and photography (ADOC) has been developed decisionmakingreallyaddsprotectiontotheminorcould
which consists of written and oral steps. To document notbeansweredandfurtherresearchonthatissuecan
theconsentprocessandpreventfalsification,oralsteps berecommended.
were documented by audio recording, video recording, Consideringifasignatureofachildreallyisnecessary,
and photography (triple media recording [TMR]). The Germandruglawasksforinformedconsentiftheminor
documents describing the study, the planned consent iscapableofunderstandingthenature,significanceand
procedure and consent form were submitted with the implicationsoftheclinicalinvestigation.Thesignatureof
GMSGermanMedicalScience2013,Vol.11, ISSN1612-3174 9/12
Kuthningetal.:Aspectsofvulnerablepatientsandinformedconsent...
theminorcanbeoneinterpretationofthelaw.Incaseit • Backgroundandhistoryofinformedconsent
only should protect the investigator from a possible ac- • Aspectsofclinicalresearchwithvulnerablepatients,
cuse then it does not add protection of the minor and minors,illiterates
doesnotreflectthattheinvestigatorinformedtheminor • LocallawsandICH-GCPGuidelines
inanappropriateway. • Studentscouldbeencouragedtoplacethemselvesin
Thecompleteinformedconsentprocesscombinedwith thepositionofapatiente.g.achildoranunconscious
enhancededucationandcounsellingmaterialscanlead patient→roleplayswithfeedbackontheirperform-
to good comprehension of informed consent issues. ancefromtheircounterpart
Strategiestoimprovecommunicationwithpatientsinclud- • Communicationtechniquesandhands-ontrainingwith
ingtheuseofvideotapes,groupdiscussions,simulations modelinformedconsentForm,psychologicalconver-
or animated cartoon illustrations like for instance the sationtechniques,e.g.onhowtoexplainexactlywhich
Speaking Book [35] could be taught. Video clips about elementsoftreatmentandcareareresearchandare
patients’ rights could be arranged in different waiting thereforeoptional
areasoftheinstitutions.Theexposuretothesematerials • AlternativestoleafletsuchastheSpeakingBook
could make it simpler for them to recognize when they
In2011theEuropeanCommissionlaunchedahigh-level
arebeinginvitedtobepartofaresearchtrial[43].These
expertgrouponliteracy[48],[49].Wewouldliketoen-
products probably can overcome illiteracy and because
couragetheorganizationandsupportofsuchacampaign
theycantransmitaveryclearmessagewiththeinclusion
inordertoachieveimprovementofliteracyrates.
ofcartoonsinthecommunication.Forpatientswhoare
illiterateandthosewhoinformthattheirverbalagreement
canberegardedasconsentasignatureonaninformed Notes
consent form might be not applicable. The investigator
could document the patient’s verbal consent into the
Competing interests
patientfilesimilartotheprocesswhenaminorgivesas-
sent.
The authors declare that they have no competing in-
The increasing width of information, not only related to
terests.
medically related interventions, but also to items such
asdataprotection,letstheinformedconsentformsoften
Acknowledgements
increasetoavoluminousleaflet[44].Theconditionsfor
vulnerablepatientsinformedconsentare manifold and
WewouldliketoexpressourspecialthankstoGabriele
therequirementscouldbetailoredtotheirneeds.Ethics
Niedeggenforhercriticalandconstructivereview.
Committees, investigators lawyers and sponsors could
cooperateandthinkaboutareformofthedocumentin
Authorship
limitingthelengthofconsentformandstructurethere-
quiredinformationinaquestion&answerstyle.Aquote
Theauthorsassurethattheworkcompletedistheirown
fromaUScasemayillustratethispoint:“Aphysicianviol-
andthatnoothersourcesorassistancesforthosestated
ates his duty to his patient ... if he withholds any facts
have been used. The co-author has read and approved
which are necessary to form the basis of an intelligent
thefinalmanuscript.
consentbythepatient...[but]...thepatient’sinterestin
information does not extend to a lengthy polysyllabic
discourseonallpossiblecomplications.Amini-courseon References
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