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PAPER

The quality of informed consent mapping thelandscape A review of empirical data fromdeveloping and developed countries

Amulya Mandava1 Christine Pace2 Benjamin Campbell3 Ezekiel Emanuel1

Christine Grady1

ABSTRACTObjective Some researchers claim that the quality ofinformed consent of clinical research participants indeveloping countries is worse than in developedcountries To evaluate this assumption we reviewed theavailable data on the quality of consent in both settings

Methods We conducted a comprehensive PubMedsearch examined bibliographies and literature reviewsand consulted with international experts on informed

consent in order to identify studies published from 1966to 2010 that used quantitative methods surveyedparticipants or parents of paediatric participants in actualtrials assessed comprehension andor voluntariness anddid not involve testing particular consent interventionsForty-seven studies met these criteria We compareddata about participant comprehension and voluntariness

The paucity of data and variation in study methodologylimit comparison and preclude statistical aggregation ofthe data

Results and Discussion This review shows that the

assertion that informed consent is worse in developingcountries than in developed countries is a simplification

of a complex picture Despite the limitations ofcomparison the data suggest that (1) comprehension ofstudy information varies among participants in bothdeveloped and developing countries and comprehensionof randomisation and placebo controlled designs ispoorer than comprehension of other aspects of trials inboth settings and (2) participants in developingcountries appear to be less likely than those in developedcountries to say they can refuse participation in orwithdraw from a trial and are more likely to worry aboutthe consequences of refusal or withdrawal

INTRODUCTIONMany prospective research participants in devel-oping countries have little formal education lackfamiliarity with biomedical research and consentprocedures and have limited access to healthcareservices Consequently it is widely believed thatthey have more dif 1047297culty comprehending study information and providing voluntary consent thando their counterparts in developed countries1e11

Such views are echoed in ethics guidelines such asthose of the Council for International Organiza-tions of Medical Sciences (CIOMS)12 in a report by

the National Bioethics Advisory Commission13

and in the popular press For instance a front-page

New York Times article framed the problems withcomprehension in a trial in the Ivory Coast asa matter of an impenetrable wall between scienti1047297ccomplexity and the ability of locals to understanditdone participant was described as ldquostill not grasp[ing]deven after repeated questioningdwhata placebo is or why she might have been given thatinstead of a real medicinerdquo14

But what do we know about the quality of

informed consent in developing country researchDoes available evidence demonstrate that thequality of informed consent from developingcountry participants is worse than the quality of informed consent from participants in developednations

To begin addressing these questions we reviewedand compared available data on the quality of informed consent from research in both developingand developed countries We identify similarities anddifferences between studies of consent in developedand developing countries highlight gaps in theavailable data and make recommendations for

future research on the quality of informed consent

Methods search strategy and selection criteria We conducted a comprehensive PubMed searchusing the Medical Subject Headings (MeSH) termsinformed consent comprehension and decision making incombination with clinical trials or randomized

controlled trials (box 1) In addition we examinedbibliographies15 literature reviews1 6 1 7 and refer-ence lists from relevant papers and consultedwith international experts on informed consent toclinical research

We included studies that met four criteria (1)used quantitative methods to study informed

consent (to allow for comparison of relatively similar data sets) (2) surveyed participants orpaediatric participantsrsquo parents in actual clinicaltrials rather than hypothetical scenarios (as we areconcerned with what participants understand andhow they make decisions in real trials) (3) did nottest informed consent interventions aimed atimproving its quality (to avoid confoundingresults) and (4) assessed at least one of twodomains critical to measuring the quality of informed consent comprehension of study infor-mation and voluntariness of consent While somepublished data on disclosure exist there are little to

no comparable data from non-intervention utilisingtrials that evaluate understanding and

1Department of BioethicsNational Institutes of HealthBethesda Maryland USA2Section of General InternalMedicine Boston UniversitySchool of Medicine BostonMassachusetts USA3Institute for Health Metrics andEvaluation University ofWashington SeattleWashington USA

Correspondence toDr Christine Grady Departmentof Bioethics National Institutesof Health Bethesda MD 20892USA cgradyccnihgov

Received 15 August 2011Revised 1 November 2011Accepted 14 December 2011Published Online First7 February 2012

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comprehension relative to the quality of disclosure A total of 427 studies were identi1047297ed through the PubMed search (1047297gure 1)and 79 from bibliographies literature reviews reference lists andconsultations with experts Of those 506 studies 47 met all fourcriteria 18 studies evaluated the quality of informed consent intrials in developing countries and 32 studies evaluated thequality of informed consent in trials in developed countriesi

(tables 1 and 2) Identi1047297ed studies were reviewed by the authorsand information extracted regarding the type and location of theclinical trial the sample size and the method and timing of assessing informed consent Data about participantsrsquo compre-hension of trial information and voluntariness were extractedincluding understanding of the purpose and nature of theresearch the risks and side effects and randomisation andplacebo controlled design (tables 3e5) as well as perceivedpressure and participant knowledge of the right to refuse toenrol or withdraw from a trial (table 6) Direct comparison ormeta-analysis of study data was not feasible as the relevantstudies did not employ a uniform methodology or study design

RESULTSStudy characteristicsEighteen studies conducted in 11 different developing countriesexamined the consent of participants in clinical research onvaccines nutritional supplements HIV treatments immune

correlates in children diarrhoeal disease in children anti-malarial drugs and genetics (table 1) Sample sizes ranged from33 to 700 research participants Seven studies intervieweda parent of a participating child1 8 2 1 2 2 2 4 2 6 2 9 3 3 and of thoseseven three interviewed only the mothers22 24 33 Thirteenstudies19e21 23 26 e33 35 used structured or semi-structuredinterviews while 1047297ve used questionnaires1 8 2 2 2 4 2 5 3 4 In ninestudies participants were interviewed close to the time of consent18 23 24 26 28 29 33e35 and in eight others interviews wereconducted 1e14 months or longer after the participant gaveconsent19e22 25 27 30 31 In one study the timing was notspeci1047297ed32

Thirty-one studies conducted in eight developed countries

examined the consent of participants involved in oncologycardiology gynaecology HIV analgesicsanaesthesia neurologicalantidepressant antipsychotic emergency management arthritispaediatric asthma paediatric febrile convulsion diabetes malariaand genetics research (table 2) Sample sizes ranged from 21 to570 research participants Six studies surveyed the parents of children in paediatric trials4 0 4 2 4 5 4 8 5 4 5 7 Sixteen studies usedstructured interviews19 38 39 42 45 47 48 50 54 57 58 60e64 nine usedmailed surveys37 41 43 46 49 51e53 59 and six used questionnaires18

36 40 44 55 56 In eight studies questions were asked close in time towhen consent was given in each case within 48 h of consent 18

39 40 42 48 55 60 64 the remaining 23 studies surveyed participantsweeks to months after consent19 36 e38 41 43e47 49e54 56 e59 61e63

Comprehension and recall of trial informationParticipant understanding of research purpose risksside effectsand design varied substantially across informed consent studiesfrom both developing and developed countries Across studiescomprehension of trial purpose or nature appeared to be betterthan comprehension of trial design and randomisation

Trial purpose and nature

Available data show no substantial difference between partici-pants in developing countries and those in developed countrieswith respect to their understanding of trial purpose de1047297ned asthe goal of a given clinical trial (table 3) In the developedcountry studies that measured it understanding of trial purposeranged from 10 of US males who understood the purpose of avariety of trials they were participating in62 to 100 of Canadian participants who understood the purpose of a neuro-oncology trial45 Understanding of trial purpose in developingcountry studies also varied ranging from 26 of Malian parentswho understood the purpose of a malaria trial for their chil-dren26 to 90 of mothers with children in a paediatric in1047298uenzatrial in The Gambia33 Similarly reported understanding of trialnature assessed by participantsrsquo understanding that they wereparticipating in research and of the investigational and experi-mental nature of research interventions varied from 31 of participants in a US phase 1 oncology trial50 to almost 100 of participants in both a Swedish and a Finnish trial 51 59 and from47 of women in a Bangladeshi nutritional trial for ironsupplements32 to 100 of women in an HIV trial in CocirctedrsquoIvoire30

Risksside effectsThe percentage of participants who could recognise or nametrial side effects and risks also ranged widely among the studiesreviewed (table 4) Reported understanding of side effects varieddepending on how the questions were frameddmore partici-

pants were able to recognise side effects from a list than wereable to name or explain them in response to open-ended ques-tions For example 86 of participants in a US analgesic trialrecognised at least one side effect from a list but only 48 wereable to name at least one without the help of a list58 In a USrheumatoid arthritis trial 30 responded that they knew thetrial drugs were not completely safe but were not asked torecognise or name the speci1047297c risks of the drugs44

In consent studies of developing country trials 79 of participants in a South African vaccine trial knew the risksinvolved22 and 97 of Thai participants recognised possible sideeffects of an experimental HIV vaccine35 yet only 7 of Malianparents recognised that the investigational vaccine being givento their child might have side effects26

Randomisation and placebo trial designUnderstanding of randomisation also varied among participantsin both developing and developed country trials but across allstudies understanding of randomisation was low compared tounderstanding of other aspects of a trial (table 5) In developedcountry studies understanding of randomisation appeared to vary according to how close to actual consent it was measured Forexample 68 of parents understood randomisation when askedwithin 48 h of consent in US paediatric oncology trials 48 and asmany as 79 understood randomisation in an HIV vaccine trialwhen assessed immediately after disclosure55 Yet fewer than half of the participants were reported to comprehend randomisation

in six developed country studies in which understanding wasassessed months or years after consent44 46 47 51 53 63

Box 1 MeSH terms strategy

(informed consent[mh] AND (Comprehension[mh] OR decision-making[mh])AND (randomized controlled trials as topic[mh] OR clinical trial astopic[mh])AND (Humans[Mesh] AND English[lang]))

i

Ellis18

and Marshall19

each studied informed consent in both a developed anda developing country

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Five developing country studies measured understanding of randomisation (table 5) four of those 1047297ve measured it within1 week of consent18 20 26 28 29 Comprehension of randomisationranged from as high as 90 of parents whose children wereenrolled in a malaria vaccine trial in Mali18 to as low as 19 of parents whose children were enrolled in a malaria treatment trialin Uganda29

Between 64 and 88 of participants understood the study design in six developed country trials41 44 46 53 63 64 yet only 39of the participants in a set of Canadian trials recalled their ownchance of receiving placebo and 29 of them ldquothought that thedoctor [had known] what kind of medication they weretakingrdquo46 Knowledge of placebo was measured in three devel-oping country studies 10 of mothers enrolling children in

a Gambian trial understood the placebo control design33 13 of Ghanaian trial participants knew that not all trial capsules werethe same23 and 49 of South African participants knew they had a 50 chance of receiving placebo27

Although measured infrequently individualsrsquo understandingof research design diverges from their understanding of how itspeci1047297cally applies to them In one Thai HIV treatment trial31 correctly responded that half the participants would get theinvestigational drug yet 48 said they had a 5050 chance of receiving it28 In a Ugandan malaria trial 19 of parents knewthat not all children would receive the same treatment eventhough 84 recalled being told about treatment assignment29

Similarly in a US rheumatoid arthritis trial 87 of participants

said that some people in the trial would get placebo but only 50 thought they personally could receive placebo44

VoluntarinessData on voluntariness is organised into two categories (1)participantsrsquo perceptions of pressure (not reported in a table)and (2) participantsrsquo knowledge of the right to refuse orwithdraw from participation (table 6)

PressureQuestions assessing perceptions of pressure differed acrossinformed consent studiesdsome focused on whether or notparticipants knew or felt that participation was voluntary whileothers asked more speci1047297c questions about the source andamount of pressure felt by participants

Most (90e99) participants in a US hypertension triala Canadian neuro-oncology trial and UK paediatric trials

reported no pressure to participate19 38 40 or reported thatparticipation was voluntary52 At the same time 31 of USoncology and cardiology trial participants said that they felt thatthey had little other choice than to participate 54 25 of parentsin a Netherlands paediatric oncology trial indicated that they felt obliged to participate53 and 18 of Danish participants in anacute myocardial infarction trial reported feeling lsquounder pres-surersquo although 70 said the decision was lsquofully theirsrsquo41

Five developing country informed consent studies measuredgeneral perceptions of pressure and voluntariness Most mothers(95) in a Ghanaian paediatric trial21 and most participants(99) in a South African in1047298uenza vaccine trial27 said partici-pation was voluntary Similarly most parents in an Indian

paediatric trial (98) reported that they joined the study freely without any pressure or compulsion24 In contrast in another

Figure 1 PRISMA 2009 flow diagram(adapted from Moher D Liberati ATetziaff J et al The PRISMA GroupPreferred reporting items for systemicreviews and meta analyses thePRISMA statement PLoS Med 20096e1000097 For more information visithttpwwwprisma-statementorg)This figure is produced in colour in the

online journald

please visit the websiteto view the colour figure

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South African trial 84 of the evaluation group and 93 of thesensitisation group reported feeling that participation wascompulsory34

In consent studies that distinguished sources of pressure moretrial participants reported feeling pressure from their disease orcircumstances than from other people Although 29 of USphase I and phase II oncology trial participants said that theirphysician did not actively want them to make their own deci-sion61 only 14 in a Swedish gynaecology trial59 7 in anotherUS oncology trial62 and 6 in a set of varied US trials reportedfeeling pressure from a clinician39 In the same oncology study inwhich 7 reported pressure from a clinician and 9 from theirfamilies a full 75 reported pressure due to their progressive

cancer39 In another US paediatric oncology trial 70 of theparents cited high levels of distress and lsquofeeling overwhelmedrsquo

during the consent process45 Few participants in developedcountry trials reported pressure from anticipated consequencesof withdrawing 98 of UK anaesthesia trials participants52

86 of Canadian neuro-oncology trial participants38 and 85 of Danish cardiology trial participants41 knew that refusal toparticipate would not compromise their care

In developing country studies reported pressure from otherswas also generally low ranging from 6 of participantsreporting pressure from spouses family or the research team ina Ugandan paediatric malaria treatment trial29 to 26 reportingpressure from village elders in a Malian paediatric vaccine trial26

Reported pressure came from various sources for example fromvillage elders (26) the research team (12) and a spouse (7)

in the aforementioned Malian study26 and from a close friend(15) a family member (7) or their doctor (2) in an HIVtreatment trial in Thailand28 Similarly in a Ugandan paediatrictrial 15 of parents reported feeling pressure from othersincluding spouses (6) family or friends (6) or the researchteam (6) but 58 reported pressure because of their child rsquosillness29 However in one Gambian trial 9 of mothers offeredspontaneously and 36 agreed when directly questioned that itwould have been hard to refuse participationdsome reportedfeeling group pressure after watching other mothers agree toparticipate33

Participants in developing countries reported pressure fromfear of the consequences of withdrawing Although in one South

African trial 88 said their usual care would not be affected if they refused27 87 of participants in a Bangladeshi trial feltthat the trial offered such advantages that they couldnrsquotrefuse32 Similarly 32 of the evaluation study group and 23of the sensitisation group in a South African perinatal HIVtransmission trial thought that care would be compromised if they did not participate34 and 44 of parents in a paediatricmalaria vaccine trial in Mali said they would lose healthcareaccess if they withdrew26

Knew they could refuse or withdrawThe clearest differences between respondents in developed anddeveloping country informed consent studies were related to

knowledge of the right to refuse to participate in research orto withdraw (table 6) In 15 of 18 developed country studies that

Table 1 Developing country consent studies

Authors Country Sample Type of clinical research Method of evaluation

Ellis et al 201018 Mali 89 M and F Malaria vaccine phase 1 trial Questionnaire administered after ICdocument reviewed but before consent700 Parents

Vallely et al 201020 Tanzania 99 F Placebo controlled trial of HIVvaginal microbicide

Interviews at 4 24 and 52 weeks

Sarkar et al 200921 India 368 Parents Birth cohort study of diarrhoeal disease Structured interviews 3e7 monthspost-trial

Oduro et al 2008

22

Ghana 270 Mothers Paediatric trials evaluating immunecorrelates of protection against malaria Questionnaire administered at endof study

Hill et al 200823 Ghana 60 F Vitamin A supplementation trial Semi-structured interviews after consent

Minnies et al 200824 South Africa 192 Mothers Paediatric caseecontrol trial of immunecorrelates against severe childhood TB

Self-administered questionnaire with staffhelp if necessary within 1 h of consent

Kaewpoonsri et al 200625 Thailand 84 M and F Malaria drug trials Interview at third follow-up visit

Marshall et al 200619 Nigeria 307 M and F Genetic studies of hypertension Interviews administered at variabletimes usually long after consent

Krosin et al 200626 Mali 163 P are nts Pae diatric mala ria vacc ine prevention tria l Que stionnaire within 48 h a fte r c onsen t

Moodley et al 200527 South Africa 334 M and F Influenza vaccine trial Interviews 4e12 months post-trial

Pace et al 200528 Thailand 141 M and F HIV study of IL-2 effectiveness Interviewers administered surveyimmediately after consent

Pace et al 200529 Uganda 347 Parents Paediatric malaria treatment study Interviews immediately after consent

Ekouevi et al 200430 Cote drsquoIvoire 55 F HIV mother-to-child transmissionprevention trial

Interviews a median of 136 daysafter consent

Joubert et al 200331 South Africa 92 F Trial of vitamin A for prevention ofmother-to-child HIV transmission

Interviews a median of 14 monthsafter consent

Lynoe et al 200132 Bangladesh 105 F Nutritional trial of iron supplementsfor pregnant women

Interviews after consent

Leach et al 199933 The Gambia 137 Mothers Paediatric trial of Haemophilus influenzae type B conjugate vaccine

Interviews within a week of consent

Karim et al 199834 South Africa Evaluation studygroup 56 F

Perinatal HIV transmission trial Questionnaires administered beforeand after counselling and consent

Sensitisation controlgroup 56 F

Pitisuttithum et al 199735 Thailand 33 M and F HIV vaccine trial with drug users Questionnaire before signing consent

To evaluate the informed consent obtained for the HIV testing that preceded induction into the perinatal transmission trial researchers administered both pre- and post-counsellingquestionnaires to an evaluation study group (nfrac1456) A sensitisation control group (nfrac1456) received only post-counselling questionnaires so as to measure the sensitising effect of thepre-counselling questionnaire given to the evaluation study groupF female IC informed consent M male

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measured this more than 75 of trial participants knew they could withdraw or refuse18 19 36 37 40 43 44 49 52e54 60e62 64 and in10 of these studies 90 or more said they could withdraw fromresearch18 19 36 37 40 43 44 49 53 60 In one US paediatric oncology trial 90 of the majority race English speaking parents 78 of the minority race English speaking parents and 60 of the

minority race non-English speaking parents knew they hada right to withdraw their children from the trial48

In contrast in 1047297ve of 15 developing country studies thatmeasured it less than half of respondents knew they couldwithdraw from research22 26 30e32 As few as 10 of mothers inMali knew they could withdraw their child from a malariavaccine trial at any time26 and 27 of participants in an HIVtrial in Cocircte drsquoIvoire knew they could withdraw at any time30

However in some developing country trials a higher percentageof participants knew they could withdraw or refuse for example

Table 2 Developed country consent studies

Authors Country Sample Type of clinical research Method of evaluation

Ellis et al 201018 USA 171 M and F Malaria vaccine phase I trial Questionnaire administered after ICdocument reviewed but before consent

Ravina et al 201036 USA 149 M and F Phase II Parkinsonrsquos trial Self-administered questionnaire atfinal clinical trial visit

Bergenmar et al 200837 Sweden 282 M and F Phase II and phase IIIoncology trials

Mail surveys sent within 3 dayse2weeks of consent

Knifed et al 200838 Canada 21 M and F Neuro-oncology trial Interviews within 1 month of IC

Agrawal et al 200639 USA 163 M and F Phase I oncology trials Interview immediately after consent

Franck et al 200740 UK 109 Parents 25 Different paediatric studies Questionnaire taken immediatelyafter and 3 months after consent

Marshall et al 200619 USA 348 M and F Genetic studies of hypertension Interviews long and variably after consent

Gammelgaard et al 200441

Denmark 103 M and F Acute myocardial infarction trials Mail survey sent to participants in thestudy 3 weeks after IC

Kodish et al 200442 USA 137 Parents Paediatric leukaemia trial Parent pairs interviewed within 48 hof consent

Lynoe et al 200443 Sweden 44 M and F Chronic haemodialysis trials Mail survey about 1 week afterdisclosure of information

Criscione et al 200344 USA 30 M and F Rheumatoid arthritis trial Questionnaire 1e4 weeks after consent

Kupst et al 200345 USA 20 Parents Paediatric oncology trials Interviews 1 month after IC

Pope et al 200346 Canada 190 M and F Cardiology ophthalmology andrheumatology trials

Mail survey 2e5 months after consent

Schats et al 200347 The Netherlands 37 M and F Subarachnoid haemorrhage

emergency management trials

Interviews 7e31 months after IC

(median of 20 months)

Simon et al 200348 USA Majority English speakers60 parents

Paediatric oncology trials Parents interviewed 48 h after consent

Minority English Speakers27 parents

Minority non-Englishspeakers 21 parents

Joffe et al 200149 USA 207 M and F Oncology trials phase I II and III Mail survey 1e2 weeks after consent

Daugherty et al 200050 USA 144 M and F Phase I oncology trials Interviews within 1 week of firstadministration of investigational treatment

Hietanen et al 200051 Finland 261 F Oncology trial of tamoxifen Mail survey 5e17 months after consent

Montgomery et al 199852

UK 158 M and F 3 In-house and 3 multi-centreanaesthesia trials

Mail survey up to 24 months afterconsent

Van Stuijvenberg et al 199853

The Netherlands 181 Parents Paediatric trial of ibuprofen forfebrile convulsions

Mail survey up to 2e3 years afterconsent

ACHRE 199654

USA 570 M and F Oncology and cardiology trials Brief interviews followed by in-depthinterviews

Harrison et al 199555 USA 71 M and F HIV vaccine trial Self-administered questionnaire afterdisclosure and before consent

Harth et al 199556 Australia 62 Parents Paediatric trial of oral asthma drug Self-administered questionnaire6e9 months after entered trial

Estey et al 199457 Canada 29 M and F Not specified Interviews 1e6 weeks after consent

Miller et al 199458 USA 168 M and F Trial of analgesic drugs Interviews 30e90 days after entered trial

Lynoe et al 199159 Sweden 43 F Gynaecology trial of antiphlogisticdrugs for fallopian tube inflammation

Mail survey 18 months after study

Benson et al 198560 USA Depression study24 M and F

Antidepressant trial andantipsychotic trial

Interviews immediately following IC

Schizophrenia study24 M

Penman et al 198461 USA 144 M and F Oncology trials phase II and III Interviews 1e3 weeks after consent

Riecken et al 198262 USA 112 M 50 Different trials Interviews within 10 weeks of consent

Howard et al 198163 USA 64 M and F Cardiology trial of b-blockers (BHAT)for acute myocardial infarction

Interviews 2 weekse15 months afterconsent

Bergler et al 198064 USA 39 M Hypertension trial of hydrochloro-thiazide versus propranolol

Interviews and quizzes just afterconsent repeated 3 months later

The trial involved 156 participants but only 112 indicated that they were aware that they were participating in a trial and therefore only 112 were asked questions about voluntarinessACHRE Advisory Committee on Human Radiation Experiments F female IC informed consent M male

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50 of parents in a paediatric diarrhoeal trial21 knew they couldleave the trial at any time gt90 of adults and parents of chil-dren in a Malian malaria vaccine trial18 knew they could with-draw from the trial and 88 of Thai vaccine participants knewthey could lsquorefuse to participate at any timersquo35 One study of a South African HIV trial17 reported that 93 of the womenknew they had the right to quit but 98 said they believed thehospital would not allow them to quit34

DISCUSSIONThis is the 1047297rst comparison of quantitative studies of the quality of informed consent from individuals participating in clinicaltrials in both developed and developing countries Our reviewshows that the assertion that research informed consent isworse in developing countries than in developed countries is anoversimpli1047297cation of a complex picture of the quality of consentThe quality of informed consent depends on the type andamount of information disclosed adequate comprehension of trial information and a voluntary decision to enrol The existingdata which use comprehension and voluntary decision-makingas measures of the quality of consent do not support a cate-gorical difference between the quality of consent from individ-

uals in developed countries and the quality of consent fromindividuals in developing countries

A paucity of data especially from participants from devel-oping countries as well as variations in trial type study methodology sample size measures used and timing of datacollection relative to obtaining consent limits comparisonand statistical aggregation Nonetheless these data suggestcertain important trends and point to the need for furtherresearch

Our review highlights the following (1) comprehension of study information varies among trial participants in both

developed and developing countries and comprehension of randomisation and placebo controlled designs is generally lowerthan comprehension of other aspects of a trial (2) researchparticipants report different sources of pressure to enrol andthose in developing countries are less likely than those indeveloped countries to say they can refuse or withdraw fromparticipation and more likely to worry about the consequencesof refusal or withdrawal

Data show a range of understanding of trial information inboth developed and developing country trials Individuals acrossstudies tended to know that they were involved in research andoften responded correctly to questions about the nature andpurpose of the research yet participants everywhere had more

dif 1047297

culty understanding information about trial designrandomisation and placebo controls Not only are these methods

Table 3 Understanding of research nature and purpose

Developed country studies Developing country studies

Author Country Understood purpose Author Country Understood purpose

Knifed et al 200838 Canada 100 Leach et al 199933 The Gambia 90

Ravina et al 201036 USA 926 Pace et al 200528 Thailand 88

Franck et al 200740 UK 85 Minnies et al 200824 South Africa 806

Howard et al 198163 USA 80 Pace et al 200529 Uganda 80

Miller et al 199458 USA 73 Kaewpoonsri et al 200625 Thailand 50

Van Stuijvenberget al 199853

The Netherlands 53 Sarkar et al 200921 India 43

Marshall et al 200619 USA 41 Marshall et al 200619 Nigeria 39

Benson et al 198560 USA 37 each in depressionand schizophrenia studies

Krosin et al 200626 Mali 26

Daugherty et al 200050 USA 31 Joubert et al 200331 South Africa 28 but 40 knew the substancebeing tested was vitamin A

Harth et al 199556 Australia 13

Riecken et al 198262 USA 10

Developed country studies Developing country studies

Author Country Understood nature Author Country Understood nature

Knifed et al 200838 Canada 100 Ekouevi et al 200430 Cote drsquoIvoire 95e100

Criscione et al 200344 USA 100 Moodley et al 200527 South Africa 95

Hietanen et al 200051 Finland 100 Minnies et al 200824 South Africa 854 knew was research 367

knew there were no immediate benefits

Lynoe et al 199159 Sweden 98 Vallely et al 201020 Tanzania 77 knew gel may not prevent HIV

Howard et al 198163 USA 92 Hill et al 200823 Ghana 75 knew was research but 93 thoughttrial capsules were a lsquomedicine or vitaminrsquo

Ravina et al 201036 USA 89 understood drugswere experimentaly

Lynoe et al 200132 Bangladesh 47

Ellis 201018 USA 85 Krosin et al 200626 26

Penman et al 198461 USA 78

Gammelgaard et al 200441 Denmark 72

Riecken et al 198262 USA 72

Bergenmar et al 200837 Sweden w70

Kupst et al 200345 USA 55

Schats et al 200347 T he Netherlands 38

Joffe et al 200149 USA 30

Arranged from highest to lowest y Yet only 57 knew that participation in the study was not part of usual Parkinsonrsquos disease treatmentACHRE Advisory Committee on Human Radiation Experiments

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and concepts unfamiliar to many people but such methods may be contrary to their expectations or hope for therapeutic bene1047297tmaking them more dif 1047297cult to comprehend Notably some

studies reveal discrepancies between participantsrsquo understandingof what will happen in a trial and how this information willaffect them directly Knowledge of facts and appreciation of

Table 5 Understanding of study design and randomisation

Developed country studies Developing country studies

Author Country Understood study design Author Country Understood study design

Van Stuijvenberg

et al 199853The Netherlands 88 placebo design Moodley et al 200527 South Africa 49 knew they had a 50 chance

of receiving placebo 19understood placebo

Criscione et al 200344 USA 87 placebo design Hill et al 200823 Ghana 13 understood lsquonot all trial capsuleswere the samersquo

Howard et al 198163 USA 86 double blind design Leach et al 199933 The Gambia 10 placebo designy

Harrison et al 199555 USA 79

Pope et al 200346 Canada 76 placebo design

Bergler et al 198064 USA 64 (at start) 28 (3 months later)

Developed country studies Developing country studies

Author Country Understood randomisation Author Country Understood randomisation

Ravina et al 201036 USA 90 yet only 67 understood therewas a 1 in 3 chance of receiving placebo

Ellis et al 201018 Mali 80 of adults

90 of parents

Simon et al 200348 USA 68 of majority English speakers Krosin et al 200626 Mali 68

26 of minority English speakers

14 of minority non-English speakers

Bergenmar et al 200837 Sweden 85 Pace et al 200528 Thailand 31

Gammelgaard et al 200441 Denmark 79 Moodley et al 200527 South A fr ica 21

Criscione et al 200344 USA 50 Pace et al 200529 Uganda 19

Van Stuijvenberget al 199853

The Netherlands 50

Kodish et al 200442 USA 50

Howard et al 198163 USA 43

Pope et al 200346 Canada 39

Benson et al 198560 USA 33 of depression study 16of schizophrenia study

Hietanen et al 200051 Finland 23

Schats et al 200347 The Netherlands 22

Arranged from highest to lowest

yWhen broken down into those who had received a written information sheet at least a week before consent 15 of those who had received the sheet understood that there was a placebogroup versus 4 of those who had not received prior written information

Table 4 Understanding of risks and side effects

Developed country studies Developing country studies

Author Country Understood risks or side effects Author Country Understood risks or side effects

Daugherty et al 200050 USA 100 named gt1 side effect Pace et al 200528 Thailand 98 recognised side effects

Harrison et al 199555 USA 89 recognised side effects Pitisuttithum et al 199735 Thailand 97 recognised side effects

Knifed et al 200838 Canada 71 knew at least one g eneral risky Minnies et al 200824 South Africa 792 knew risks

Benson et al 198560 USA Depression study 62 knew risks Leach et al 199933 The Gambia 53 named $1 side effect

Schizophrenia study 42 knew risks

Howard et al 198163 USA 61 could name 1 side effect Oduro et al 200822 Ghana 20 knew direct ris ks

Miller et al 199458 USA 48 named and 86 recognised gt1 risk Pac e et al 200529 Uganda 18 named 1 or more side effects

Ravina et al 201036 USA 47 knew which d rugs had highest risks93 knew PD could get better worse ornot change

Krosin et al 200626 Mali 7 said there wer e sid e effectsz

Estey et al 199457 Canada 41 named gt1 risk Kaewpoonsri et al 200625 Thailand 66 recalled being told of risks

Van Stuijvenberget al 199853

The Netherlands 40 knew side effects

Joffe et al 200149 USA 37 knew research risks

Penman et al 198461 USA 31 named gt3 of 11 risks

Criscione et al 200344 USA 30 knew there were risksx

Bergler et al 198064 USA 28 (at sta rt) 3 (3 months la ter)

Bergenmar et al 200837 Sweden 18 kne w res earch ris ks

Schats et al 200347 The Netherlands 6 knew side effects

Arranged from highest to lowesty29 did not recall ANY risks of the trial drug the rest of the participants could name general risks and at most participants could name up to four specific risks or side effectszThe question was complex and multi-choice The correct answer was the only one that included a mention of side effects However it also included information about the potential benefits ofthe medicine (eg that it could prevent malaria and correct other health problems)xBut were not asked to name or identify themPD Parkinsonrsquos disease

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those facts are different aspects of understanding both of whichare important to informed consent65 This discrepancy is a chal-lenge for informed consent everywhere and although fewstudies attempted to measure it the present data do not suggesta difference in appreciation between developed and developingcountry participants

Second the data on refusal and withdrawal indicate a trou-bling trend Finding it dif 1047297cult to refuse participation in orwithdraw from a trial feeling pressure to join or stay enrolled ina trial or worrying about the consequences of withdrawing allrelate to the voluntariness of an enrolment decision Studieswhich used these measures of voluntariness show that a disqui-eting number of participants and more in developing country trials than developed country trials do not know or do not

believe that they can refuse to participate or can withdraw fromresearch Few studies probed these responses further to explainwhy participants felt they could not refuse or withdraw Possibleexplanations include deference to authority cultural norms ora founded or unfounded fear of not being able to access neededcare

Lastly while investigations of the impact of pressure onvoluntariness were limited overall few research participantsreport feeling pressured to participate in research and those thatdid often felt pressure from their circumstancesesuch as wors-ening illness or fear that care would be withdrawndmore thanfrom other people Participants in developing countries weremore likely to report pressure from fear of the consequences of

withdrawing including decreased access to healthcare Theseissues merit further study

Recommendations for future researchThese data reveal that there is much to be done to improve thequality of informed consent in both developed and developingcountries and that additional research would facilitate de1047297nitiveconclusions about the quality of informed consent around theworld Currently available evidence regarding the effectivenessof strategies to improve consent is limited66 e68 Variation inmethodology trial types and populations across studiesreviewed raised challenges about how to accurately understandand measure the quality of informed consent Design andimplementation of improvement measures depends on carefulattention to and rigorous delineation of what the quality of consent entails

Studies of the quality of informed consent would be greatly

enhanced by a core set of validated questions that measure thecomprehension and voluntariness of participants at the time of decision-making and by comparison of participants from similarmedically de1047297ned groups participating in similar types of research Studying the quality of consent in multi-nationaltrials such as was done in one multi-site hypertension study wereviewed19 would allow for useful comparisons betweendeveloped and developing countries Additionally more detailedand comprehensive studies of voluntariness are neededincluding investigation of sources of pressure to participate andfears about withdrawal or refusal Future studies should includedetailed investigation of associations between cultural normsand attitudes and socio-demographic characteristics such as

education literacy and socioeconomic status to better under-stand the impact of these factors on informed consent in both

Table 6 Voluntariness knew could withdraw or refuse

Developed country studies Developing country studies

Author Country Knew could withdraw Author Country Knew could withdraw

Joffe et al 200149 USA 90 99 knew could refuse Ellis et al 201018 Mali 96 of adults

93 of parents

Ellis et al 201018 USA 98 Karim et al 199834 South Africa 93 of evaluation study group88 of sensitisation control groupy

Ravina et al 201036 USA 98 felt lsquofree to refuse

to participatersquo

Pitisuttithum et al 199735 Thailand 88 knew could refuse

Marshall et al 200619 USA 97 Moodley et al 200527 South Africa 87

Criscione et al 200344 USA 96 Pace et al 200528 Thailand 71

Benson et al 198560 USA Depression study 95 75knew could refuseSchizophrenia study 8375 knew could refuse

Marshall et al 200619 Nigeria 67

Minnies et al 200824 South Africa 65

Bergenmar et al 200837 Sweden 93 100 knew could refuse Pace et al 200529 Uganda 65 41 knew could refuse

Franck et al 200740 UK 91 Kaewpoonsri et al 200625 Thailand 531

Van Stuijvenberget al 199853

The Netherlands 91 Lynoe et al 200132 Bangladesh 48 65 knew could refuse

Lynoe et al 200443 Sweden 90 Sarkar et al 200921 India 50

Simon et al 200348 USA 90 of majority English speakers Ekouevi et al 200430 Cote drsquoIvoire 27

78 of minority English speakers Joubert et al 200331 South Africa 24 (but 92 said care wouldno longer be good if they quit)

60 of minority non-English speakers Oduro et al 2008

22

Ghana 21Montgomeryet al 199852

UK 83 Krosin et al 200626 Mali 10

Penman et al 198461 USA 80

Riecken et al 198262 USA 80 95 knew could refuse

ACHRE 199654 USA 78

Bergler et al 198064 USA 77 (at start) 61 (3 months la ter)

Harth et al 199556 Australia 45 (but 32 said would not be allowed)

Schats et al 200347 The Netherlands 25 59 knew could refusez

Arranged from highest to lowest yHowever 98 of the evaluation study group and 100 of the sensitisation control group said hospital would not allow themzKnew participation was not obligatoryACHRE Advisory Committee on Human Radiation Experiments

J Med Ethics 201238356e365 doi101136medethics-2011-100178 363

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developed and developing countries Innovative strategies andrigorous studies are sorely needed to facilitate improvement ininformed consent to better satisfy one of the fundamentalrequirements of ethical research

Contributors AM CP and BC were responsible for acquisition of data analysis andinterpretation of data drafting of the manuscript and critical revisions of themanuscript EE was responsible for the original conception and design of the studyand critical revisions of the manuscript CG was responsible for conception design andimplementation of the study acquisition of data analysis and interpretation of datacritical revisions of the manuscript supervision and final approval

Funding This research was supported by the Department of Bioethics of the NIHClinical Center

Competing interests None

Provenance and peer review Not commissioned externally peer reviewed

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48 Simon C Zyzanski SJ Eder M et al Groups potentially at risk for making poorlyinformed decisions about entry into clinical trials for childhood cancer J Clin Oncol 2003212173e8

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Research ethics

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68 Benitez O Devaux D Dausset J Audiovisual documentation of oral consent a newmethod of informed consent for illiterate populations Lancet 20023591406e7

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FROM THE BMJ EVIDENCE CENTRE

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W H E N Y O U P U RC H AS E

J Med Ethics 201238356e365 doi101136medethics-2011-100178 365

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developing and developed countrieslandscape A review of empirical data fromThe quality of informed consent mapping the

and Christine GradyAmulya Mandava Christine Pace Benjamin Campbell Ezekiel Emanuel

doi 101136medethics-2011-100178

20122012 38 356-365 originally published online February 7J Med Ethics

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