Altruism, Scepticism, and collective decision-making in foreign-born US residents in a tuberculosis

12 Pages·2017·0.62 MB·English

by  Sienna R. Craig

Craigetal.BMCPublicHealth (2018) 18:535
https://doi.org/10.1186/s12889-018-5460-3
RESEARCH ARTICLE Open Access
Altruism, Scepticism, and collective
decision-making in foreign-born U.S.
residents in a tuberculosis vaccine trial
Sienna R. Craig1* , Timothy Lahey2, Apoorva Dixit3 and C. Fordham von Reyn2
Abstract
Background: The current vaccine against tuberculosis, BCG, is effective when givenin most TB-endemic countries
atbirth but has diminished efficacy against pulmonary TB after 15–20 years. As a result, new boostervaccines for
adolescents and adults are being developed to realize theWorld Health Organizationtarget ofglobal elimination of
TB by 2035.MultipleTB candidates thus are in active clinical development.
Methods: One of these, DAR-901,is advancingin human clinical trials. These clinical trials are conducted inBCG
immunized adults with and without HIVinfectionin order to assess safety and efficacy among thepeople most in
need of a new vaccine. A Phase I dose escalation trial of DAR-901 inBCG-immunized adults with or without HIV
infection was conductedbetween 2014 and 2016. This offered an unusual opportunity to qualitativelyexamine why
foreign-born adults living inthe United States–a poorly studied population – decide to participate, or not, in
clinical trials.
Results: We conducted a qualitative study ofindividuals who were recruited to participate inthis Phase Ivaccine
trial,interviewing those who agreed and declined to participate. We found diverse motivations for participation or
refusal; varied understandings of tuberculosis and vaccines; and complex views about how‘informed consent’can
be atodds withcultural understandingsof power, authority, and medical decision-making. These dynamics
included: knowledge (direct or indirect) of tuberculosis, a desire to be altruistic and simultaneous hopes for
personal gain as well as concerns over what remunerationfor participation could mean, theimportance ofpersonal
relationships with care providers in shaping volunteerism, concerns over privacy, and evidence ofhow culture and
history shape medical decision-making.
Conclusions: This US-based trial, aimed ataddressing a crucible global health issue, raises productive questions
about theinterface between altruism and scepticism regarding clinical research participation.
Trial registration: NCT02063555.
Keywords: Volunteerism, Clinical trials, Tuberculosis, Vaccine, Collective decision-making
Background disseminated TB in children, and likely provides
TheWorldHealthOrganizationhastargetedelimination limited protection from TB later in life, but does not
of tuberculosis (TB) in the world by 2035 [1], a goal felt provide sufficient lifelong protection from TB [3].
unreachablewithoutthe introductionofanewandmore Modelling studies indicate that global TB elimination
effective TB vaccine [2]. The current global vaccine by 2035 can only be achieved with the development
against TB, known as BCG, is given at birth in most of a new booster vaccine [4].
TB-endemic countries. BCG lowers the incidence of More than a dozen TB vaccine candidates are now in
activeclinicaldevelopment[5,6].1DAR-901istheleading
TB vaccine candidate aimed at boosting the protective
*Correspondence:[email protected]
1DepartmentofAnthropology,DartmouthCollege,6047SilsbyHall,Hanover, efficacyofBCG[7].APhaseIdoseescalationtrialrecently
NH03755,USA foundthatDAR-901wassafe,tolerableandimmunogenic
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Craigetal.BMCPublicHealth (2018) 18:535 Page2of12
[8]. This study was conducted among HIV-negative and Subjects may see study participation as solidifying the
HIV-infected adults in the United States who received therapeutic bond between them and a clinician [27–29].
BCGatbirthincountrieswhereTBisendemic. In US trials, the patient-physician relationship is a
A Phase 1 vaccine study among foreign-born adults in commonly cited motivating factor for participation, but
the United States presents an unusual research oppor- is rarely acknowledged in the context of global trials
tunity. While the motivations for American citizens to [12, 30]. Ironically,volunteerismcancompetewithfinan-
participate in US-based clinical trials are well researched cial incentives as motivations to participate in clinical tri-
[9–11], as are the motivations for local populations to als [31, 32]. This presents an ethically fraught dynamic,
participate in global clinical trials [12–16], there is a since financial incentives can become coercive [33–35].
relative dearth of literature that addresses study popula- The possibility that subjects can be coerced by financial
tions with unique cross-cultural understanding of both incentivesforstudyparticipationvariesbyage.Vere([36]:
their home country and the US, as sites of clinical p. 142) argues that risk acceptance among young subjects
research and medical intervention. Research trials struc- (i.e.collegestudents)ishigh,andtheycan‘denythatpay-
tured around the recruitment of foreign-born subjects mentisforrisk[and]assertthatitisforinconvenience’to
are uncommon in the United States [17–19]. As aresult, justify participating [37, 38]. This was relevant to our
the motivations for foreign-born individuals to partici- study in that it was being conducted in a college town,
pate in clinical trials – or their decisions not to partici- where many potentially eligible foreign-born, BCG-
pate in such research – are poorly understood. The US- vaccinated individuals would be undergraduate or gradu-
based DAR-901 trial presented an opportunity to learn atestudents.
more aboutvolunteerism inaforeign-bornpopulation. Motivations not to participate in clinical trials are just
Instead of testing a drug or intervention on a ‘treat- as complicated [39]. Subject willingness to participate
ment naïve’ population which might not expect benefit can be dampened by the legacy of unethical clinical
from research outcomes [20], the DAR 901-trial was research, from the Tuskegee syphilis experiments to
conducted in the US on individuals who reflected a glo- more-recent controversies like the Development of
bal ‘target population’ of new TB vaccine development: AntiRetroviral Therapy (DART) trials in several African
those at risk of TB mortality and morbidity, including countries [40, 41]. Mistrust of clinical research too can
people living with HIV. For the HIV-infected subset of be amplified by legacies of colonial medicine ([42]:
potential subjects, the trial was also conducted in a p. 146–174). As research is conducted increasingly by
context of significant pre-existing trust between them private, for-profit and even corporate entities [20], sub-
and physician-scientists.2 And yet, early trial recruitment jects may feel potential community benefit from study
efforts remained difficult, with the rationales for eligible participationhasshifted tocorporate benefitwhich is less
participants’ agreement or refusal to participate initially motivating[43].
opaquetostudy staff. Commonly cited reasons for not volunteering for clin-
To assess foreign-born individuals’ motivations to par- icalstudiesinclude‘lifestyle’conflicts,whichmayinclude
ticipate inaclinical trial, or not,we conducted a qualita- cultural or religious sensibilities that advise against
tive study of those who were both enrolled in and subjecting the body to experimentation or invasive pro-
approached for recruitment into in the Phase I DAR-901 ceduresaswellaslogisticalconflictswithschoolorwork
trial.Ininterviewswith18enrolledanddeclinedindivid- schedules, etc. [21]. Family members, too, may express
uals, we found diverse motivations for participation or concern about their loved ones being ‘experimented on’
refusal; varied understandings of tuberculosis and vac- or similar perceptions of possible harm that outweigh
cines; and complex views about how informed consent thepotentialbenefits[31,44].
can be at odds with cultural understandings of power, The complex mixture of motivations to participate, or
authority, and medical decision-making. This US- not,inclinicalresearchcomestoapointintheinformed
based trial provided an unusual opportunity to ad- consent process [9, 45–47]. Even the simple-seeming
dress an issue that is crucial to the success of global decision to give informed consent to participate in a
health interventions: how altruism and scepticism clinical trial assumes a circumscribed or individualistic
influence medical decision-making regarding clinical understanding of informed consent. This may be com-
research participation. plicated by cultural understandings of power, authority,
Motivations for participation in medical trials include and decision-making as well as the scientific vocabular-
altruism, the desire to contribute to science, and expect- ies, standards, and cultural assumptions behind clinical
ation of personal benefit [12, 20–24]. The predominant studies [48–51]. Nurses can play critical roles in recruit-
motivator can change from early to late stage trials; ment [27, 52]. For instance, subjects are more likely to
altruism can be supplanted in later-phase trials by understand the premise, process, risks, and benefits of a
subject expectation of benefit ([25, 26]: p. 112–128). clinical trial and to ask questions (and therefore exercise
Craigetal.BMCPublicHealth (2018) 18:535 Page3of12
more truly ‘informed’ consent) if a nurse, either with a (1) declined,HIV-negative
physician or instead of a physician, works with the re- (2) enrolled, HIV-negative
search team to explain this concept [17, 25]. This insight (3) enrolled, HIV-infected
is relevant to the DAR-901 trial. As we describe below,
study staff played a crucial role in developing and main- By ‘declined,’ we mean subjects who qualified to
taining rapport and trust – both with those who chose participate in the DAR-901 clinical trial and were
to enrol in the DAR-901 trial and this qualitative study approached by study staff with an intention to recruit,
and those who declined enrolment in either or both but but who declined to participate. We also attempted to
who might also still receive their routine clinical care at interview HIV-infected subjects who declined to partici-
thismedicalinstitution. pate in the trial (a logical fourth cohort), but of the 6
The present study examined which of these complex such individuals we contacted, none agreed to partici-
motivations predominated among foreign-born HIV- pate in the qualitative study either. This is both a limita-
negative and HIV-infected adults asked to participate in tion oftheresearchandanotableresult initself.4
a Phase 1 vaccine clinical trial. Speaking with such To protect confidentiality and facilitate informed
individuals is not equivalent to speaking with potential decision-making,wewere notputincontactwith poten-
subjects in countries where TB is endemic and a new tial study participants unless they expressed an affirma-
vaccine is most likely to be deployed, but our findings tive interest inthe qualitative studyafter being appraised
do point to social dynamics that may occur in such con- of its nature and goals by the DAR-901 study coordin-
texts. Finally, we hope this work informs the relatively ator, with whom they were in contact throughout the
under-studied arena of the lived experiences of foreign- DAR-901 clinical trial process. Interviews with enrolled
born individuals who choose to participate in medical individualswerescheduledconcurrently with studyvisits
researchintheUS. in the DAR-901 trial, to minimize the impact of the
qualitative research on participants’ time. Interviews
Methods took place in private locations without the presence of
PhaseITBvaccinestudysubjectrecruitmentandenrolment DAR-901 study staff. Interviews with individuals who
Information about the clinical trial and participant declined to take part in the study took place off-site, at
recruitment was publicised through a variety of commu- locations of the individual’s choosing at a time that was
nity events, social networks, and physician-scientist out- convenientforthem.
reach to eligible patients, particularly in the case of the After establishing basic rapport with potential inter-
HIV-infected cohort. This generated an initial group of viewees, discussing the goal of this qualitative study, and
individuals who approached the study coordinator with giving them time to ask questions, we elicited oral
the intent to possibly participate. The study coordinator consent to the interview and the audio recording of that
would then meet individually for an hour with prospect- interview. The interview script revolved around open-
ive participants to explain the trial and review informed ended prompts focused on subjects’ understandings of
consentmaterialsthatdescribedrisksandbenefitsofthe tuberculosis as well as ‘clinical research’ in general and
study. This also included a detailed discussion about the DAR-901 trial specifically, including follow up ques-
what participation in the trial would involve: namely, ten tions about the feasibility of a 3-dose vaccine series. We
clinical visits over ten months and six blood draws per asked participants to describe in their own words the
patient, with those who enrolled in the study offered process of being recruited to the trial, their motivations
$600asremuneration fortimeandtravel.Afteraninitial to volunteer or not, and the nature of that decision-
screening process to determine eligibility and the in- making process. Interviews allowed for reflections on
depth consentprocess,78subjectsagreedtobescreened the differences in health care and medical systems be-
for the trial and 59 individuals were found to be eligible tween participants’ home countries and the US. In
andwere enrolled inthetrial. speaking with study staff, we aimed to gather their per-
spectives on designing and executing this study. The
Qualitativestudyofpotentialsubjectmotivationsfor semi-structured interviews each took about one hour
participation and were all conducted in English. Interviewees were
To explore potential research subject motivations to givena$50giftcardascompensationfortheirtime.5
volunteer – or not – in a Phase I TB vaccine trial, we As a way of gaining further contextual understanding
conducted 18 in-depth, semi-structured ethnographic of the trial, including processes of recruitment, we also
interviews with enrolled and declined study subjects interviewed five study investigators, including the PIs
among three foreign-born cohorts participating in the and a studycoordinator. Study staff expressed interestin
DAR-901 study.3 We categorized participants into three this qualitative study because they had been on the
groups: frontlines of subject recruitment and management of
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enrolled subjects, both of which were intensive. For of tuberculosis in general and of the DAR-901 vaccinein
example, for the 59 subjects enrolled in the trial, the particular.
studycoordinatorplaced1416phonecallsandfacilitated
nearly 600patient visitsover10months. Enrolledsubjects
Upon completion of interviews, we generated tran- Study subject motivations to participate in the DAR-901
scripts and, along with additional observational field Phase 1 study centred around a generalized sense of
notes and debriefs between researchers, coded these for altruism, often expressed as a desire to ‘help others,’
qualitative themes. We have summarized the results coupled with a sense that this trial was ‘special.’ Trust in
from each cohort based on the open and focused coding study staff, a desire to combat TB-related stigma, and fi-
oftheinterview transcripts. nancial incentives were also motivating factors. Enrolled
subjects were motivated to participate in the DAR-901
Results trial because of the significance of DAR-901 itself, and
Table 1 summarizes basic demographics of individuals the vaccine’s potential positive impact on global health.
who participatedinthis qualitativestudy. All enrolled participants stressed that they felt they had
a specific contribution to make to this trial, given its
Tovolunteerornottovolunteer? locationandinclusioncriteria.OneHIV-negativesubject
Participants came from diverse geographic, cultural, and said there was ‘no reason not to participate. This [is]
socioeconomic backgrounds. Education levels varied going to help people.’ One subject experienced an
significantly, ranging from those with advanced degrees adverse skin reaction to the vaccine, but said she had no
to those who had received little (less than 3 years) to no ill will towards the trial investigators because her ‘data
formal primary education in their home country. The point’ was ‘only going to help the study…I already had
annualtuberculosis incidence rates in countries of origin onescar [from BCG],andsoIhaveanother one.’
varied from very low (Canada 5/100,000; Australia 6/ Anotherparticipant inthe HIV-negative cohort said,‘If
100,000) to very high (DR Congo 325/100,000; Nigeria they were recruiting just any student, I wouldn’t have
(322/100,000) [53]. Study participants included highly been as compelled to do it just because I would have
educated people often employed at the parent academic been, like, I’m sure lots of people are doing it. But there
institution or hospital, or students in the process of aren’t that many international students here.’ A third
completing undergraduate or professional degrees; or HIV-negative enrolled subject said her father offered to
people from regions of the world characterized by pay her not to do the study, presumably for fear of
political-economic instability who have come to northern potential risks, but ‘I felt through doing this study, I was
New England as refugees or economic migrants. The contributing to something significant…If you have that
majority of individuals in the HIV-infected cohort had opportunity, you should take it, as long as it is not going
lived through significant experiences of uncertainty and to inversely impact your health and well-being…This is
trauma, in the context of structural inequality and/or eventually going to help people and keep them healthy.’
overtpoliticalviolence. Others echoed this sense that any risks of participation
In the DAR-901 trial, nearly every encounter between in the study were outweighed by the potential to
participants and study staff was cross-cultural in that all contribute to ‘overcoming a huge disease burden’ as
study staff were US citizens who self-identified as white/ another enrolled HIV-negative participant put it. One
Caucasian whereas most foreign-born study subjects in HIV-infected individual said,‘The danger is minimal, the
all cohorts identified as non-white. In the context of our benefit is tremendous. People everywhere have been
qualitative study, the first and second authors were kindtome, so…’.
Caucasian US citizens, while the third was a foreign- Motivationsforparticipationalsoinvolvedconceptions
born individual who recently became naturalized as a of perceived direct and indirect benefit. Not all individ-
US citizen. uals we interviewed had direct experience with TB, but
Our interviews revealed multiple dynamics of volun- some did, either by having tested positive for TB expos-
teerism and drivers of medical decision-making in rela- ure themselves, through relatives who had suffered from
tion to clinical research; and a variety of understandings the disease, or in recognition of high mortality and
Table1Gender,Age,andCountryofOriginofInterviewees
Cohort Gender AverageAge CountryofOrigin
Declined,HIV-negative F:2M:4 23.7 SouthKorea[2],Ghana[2],China,Pakistan
Enrolled,HIV-negative F:3M:3 32 India[3],China,Lebanon,Nigeria
Enrolled,HIV-infected F:3M:3 47.8 Liberia[2],Cuba,Canada,DRCongo,Australia
Craigetal.BMCPublicHealth (2018) 18:535 Page5of12
morbidity from TB in their home communities. These A stated sense of altruism and a sense that this trial
individuals cited experience withTB as a motivation for wasboth‘special’and‘important’didnotnecessarilycor-
participation in the DAR-901 trial. As one HIV-infected relatewithawillingnesstotellothersabouttheirpartici-
individual described, ‘When I was in Liberia and Ivory pation. In fact, the majority of interviewees said they
Coast, people died of TB. My daughter had TB…Three discussed their enrolment in this study with either no-
years ago,TB came to her.’ In some cases, enrolled sub- bodyoronlyafewpeople.Notallstudyparticipantstold
jects were motivated to participate because of perceived their spouse or parents that they participated. Others
reduced risk of TB that exposure to the DAR-901 vac- actively kept their enrolment from loved ones. As one
cine could offer – even though the trial was placebo- HIV-negative participant said,‘It would justbe too much
controlled, blinded and experimental. One HIV-negative explain and they’d be worried or tell me not to do it
subject, who had tested positive for TB exposure but because it’s not good for me.’ In another case, a HIV-
decided not to take the recommended prophylactic anti- infected enrolled individual said she would not share in-
biotic regimen, thought that his participation ‘may just formation about her participation with others, although
help keep me healthy. You never know.’Another in the shehadenrolledinthetrial.
HIV-infected cohort cited the growing number of new
immigrants to the US (although he was also an immi- Friends[possibly others wholiveintheregionand
grant) and the possibility for increased TB exposure. ‘I had beenapproached about participatinginthistrial]
know it won’t hurt me and it might offer some protec- calledmetoaskifIwasgoing toparticipate.Isaid
tion astheworld continues tochange.’ no, Iamnot participating….InAfrica,wekeepsecrets.
Only individuals in the HIV-infected cohort cited a We don’twantanyonebut Godorthedata people for
desire to reduce TB-related stigma as a motivation for this study toknowoursecrets.
volunteerism. While discussion of HIV serostatus was
not universal – and actively avoided by some subjects – This individual went on to describe the logics of
all but one HIV-infected study subject mentioned TB- ‘sending sickness’ [54] and how this pervaded her
related stigma as a reason to participate in the DAR-901 decision-making processes. Sharing information could
vaccine trial. One individual spoke about seeing how renderher vulnerable.Interestingly, thisindividualexpli-
people with TB were treated in his country of origin: citly stated that her main interlocutor in the decision
‘People who were ‘shunned, ostracized…or treated like about participation was God. ‘God owns me, owns my
human garbage’ due to their TB status. Another individ- life,’she said – a comment that not only dovetailed with
ualdescribed howhernephewdiedofTB andherfamily a stated Christian ethic of ‘helping others’ as motivation
was affected by the stigma. She explained that despite for participation but also toward much more wide-
the knowledge that TB is curable, ‘there can be whole ranging aspects of her lived experience: her survival
areas of the hospital that are under quarantine but also through civil war, rape, HIV infection, and immigration
deeply marked by stigma related to TB. People assume totheUS.
that if you have TB, you also have HIV.’ Even though Study subjects did not always receive support for par-
her nephew was HIV-negative,‘nobody would come visit ticipation fromlovedonesiftheydiddecidetotellthem.
himinthehospital.’ Theseindividuals sawthepossibility Only one interviewee mentioned his decision to enrol to
of an effective TB vaccine as a way to put an end to everyone in his family. ‘My mom was the only one who
stigma as well as improve health in their countries of was a bit concerned because, obviously, there is risk
origin. associated with everything. Her not being a biologist, I
Enrolled interviewees described trust of study staff explained it [the idea of a booster vaccine] to her but
who also served as clinicians where they receive care as there was still a sceptical side to her.’ One HIV-negative
a motivation to participate. As one person put it, ‘I’m participant, a healthcare provider himself whose parents
close to them. [Without a personal connection] I don’t are both physicians in his country of birth, said that
think I would have considered it.’ Some enrolled study when he mentioned the possibility of his participation,
subjects expressed sympathy for the challenges of study they tried to dissuade him. ‘They were just fearful that
recruitment as a factor motivating participation. ‘From there would be some side effects,’ he explained. In the
doing clinical research myself…I know it’s sometimes end, he decided to enrol in the study but declined to tell
really hard to recruit subjects and so that can really slow his parents, actively denying participation when they
your progress.’ Those in the HIV-infected cohort were asked.Inthesetwocasesandothers,adesiretobealtru-
directly motivated to participate by the trust they had in isticled todeception within a social circle.
their providers. As one individual put it,‘I hope it works. Moneywasamotivatorforsomeparticipants,sincethey
I hope it makes it so I don’t get TB. I hope Dr. X makes would earn approximately $600 for participation in the
more vaccines. Heshouldmake oneforHIV.’ DAR-901 trial. Remuneration was especially appealing to
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younger subjects, such as undergraduate students, and medicaltrialson minoritiesthatwill give someone pause
those who were working low-paying jobs or on govern- before joining something like this.’ The subjects empha-
ment assistance. Conversely, payment was a dis-incentive sized how important trust was in even attracting them
tootherswhointerpretedtheremunerationrateasreflect- to get more information about the trial. Without the
ive of risk. Some felt that remuneration was suspiciously personal connections that many subjects had to DAR-
high. ‘The more [the trial] pay[s], the more [the trial is] 901 researchers, they would not have even considered
hidingsomething,’saidoneenrolledindividual.Othersfelt participatinginthefirstplace.
the trial was not paying enough given the amount of time One individual who declined to participate did so be-
thatthetrialdemanded.Oneenrolledindividualsaid,‘Ido cause her family forbade her out of concern for vaccine
researchalso…soIunderstandtheneedtorecruitpeople risk. ‘[I declined] because my husband won’t allow it be-
andIdounderstandthere’snotenoughmoneytobeflash- cause he thinks it was dangerous.’ When asked if she
ing around to get people, but … if you are going to try to would have volunteered if her husband had not inter-
entice people and ask them to do a series of tests…the vened, she enthusiastically said she would ‘because it
moneyincentivecouldhavebeenhigher.’ helps make the vaccine better, and TB has a lot of
impact on the health of developing countries like China.
Declinedsubjects If this booster works, this will do good to not only the
In interviews with individuals who declined participation US but many countries in the world. But my husband is
in the DAR-901 trial, they said they were simply not in- verystubborn.’
terested enough in the study to volunteer or that the ‘in-
convenience’ and time commitment required of the trial Tuberculosis,vaccines,andDAR-901
was prohibitive. However, time was not the only factor Understandings of tuberculosis varied widely among
discouraging study participation. Most individuals who those we interviewed. Highly educated individuals –
declined participation said they were averse to the idea, both those who enrolled and those who declined – dis-
as one person put it, of ‘adding anything unnecessary to cussed disease aetiology and pathology in technical bio-
one’s body.’ This was true even for people who had a medical terms. Interviewees with undergraduate degree
medical and/or clinical research background. Some or lower education could provide a general description
people who declined participation said they no longer ofthedisease,withoneexception.Amongsubjectswith-
seeTB as a deadly disease or they might not have direct out a medical background, a basic understanding of the
exposure to TB disease. Interestingly, those who voiced disease was often tied to exposure to social media and
this reason did not give it as their own rationale for de- other public health campaigns in their countries of ori-
clining participation; rather they cited it as a rationale gin. As one declined individual described,‘We grew up
advanced by individuals who influenced their decision. learning about the Seven Killer Diseases, which are the
Interviewees who declined to participate also cited scep- diseases you get vaccinated for as a child. And TB is one
ticism about clinical research in general. Many noted of them.’ As another declined subject described, ‘TB is
concerns that the trial’s remuneration structure signalled commonly referred to in movies and shows, so everyone
ahiddenrisk inthe vaccineitself. has a general idea that the disease affected the lungs and
Some speculated about how TB was transmitted, in- results in coughing up blood.’ In some instances, this
cluding discussing the possibility that risk of TB expos- basic familiarity with TB and with the BCG vaccine
ure could somehow be heightened by their participation translatedintoeasierconversations withthose ina social
in the trial; two individuals expressed a lack of trust in or medical decision-making circle about the idea of a
study staff. However, this was not a dominant sentiment. ‘booster vaccine.’ Others found it more difficult to de-
Indeed, one interviewee whose work schedule eventually scribe the potential benefits of this new vaccine, and
precluded study enrolment said that trust for the knowledge of TB was more limited to a discussion of its
clinician-scientists made him still feel ‘committed’ to the symptoms (e.g. ‘coughing blood’) and associated social
trial,eventhoughhe could notparticipatedirectly. stigmas(e.g.asa signof ‘beingHIVpositive’).
None of the interviewees who declined participation In response to general questions about the purpose of
expressed an overt sense of fear as their reason for de- the DAR-901 trial recruitment criteria, all enrolled and
clining participation, but several speculated that others declined individuals articulated understanding that the
might have declined participation because of fear about trial required testing this new vaccine on people who
the vaccine or its associated risks. Some individuals had received BCG vaccines in their countries of origin.
voiced general suspicion about clinical research, even if Among the HIV-infected cohort, understanding of the
this was not directed at this trial. ‘In general, people trial’s goals and the science behind the administration of
have a lot respect for physicians, but sometimes that re- a vaccine booster varied widely. However, the founda-
spect is abused…Even in the US, there have been many tional understanding that this was a vaccine which was
Craigetal.BMCPublicHealth (2018) 18:535 Page7of12
being developed to help prevent TB was clear to all par- animal trials) and deemed safe. Many expressed a gen-
ticipants, as was the understanding that a new vaccine eral confidence in ‘the government’ and ‘agencies that
would ‘boost’ or enhance the immunity provided by the approveclinicalresearch,’eventhoughmostinterviewees
‘old vaccine’ [BCG]. All but one subject articulated an (except those involved in clinical research themselves)
understanding that DAR-901 was similar to BCG, but could notnamewhich federal agency would need togive
‘hopefully better.’ The majority of interviewees were sur- its approval for a new vaccine to be put into widespread
prised to learn that BCG did not provide lifelong protec- clinicaluse.
tion; prior to their participation in the DAR-901 trial, Such comments also often led to discussions of the
many had assumed that no further vaccine would be contrast between the US health system compared to the
needed. ‘I feel it was very interesting… that the TB system they knew in their country of origin. As one
vaccine [BCG], after a certain amount of years, was no participant expressed, war and political instability in her
longer effective. But we never knew. Our knowledge central African country has meant that ‘there is no real
[was]thatit[BCG]is[fora]lifetime, andweneverreally health care.’ This individual went on to describe how
worried.’ ‘you haveto sometimes pawn your belongings, like aTV,
Individuals expressed a range of opinions about vac- to pay for the care that you need to receive in the health
cines ingeneral. Manyintervieweesvoicedabelief inthe care system.’ She continued, ‘If you have a surgery for
role that vaccines play in disease prevention. Fears about yourappendix,youhavetobringyourownbloodserum.
vaccines did not come up as a reason to decline partici- Outside of the hospital setting, many people just try to
pation in the DAR-901 trial, but underlying medical un- treat themselves, relying on home remedies or trad-
derstandings behind such decisions varied. For example, itional medicines.’
as one declined subject said,‘Vaccines are not as danger- Many subjects mentioned schools and churches as
ous as drugs because they’re helping. You prevent some- ideal sites for administration, and felt that this should be
thing. But drugs are poison to help you get rid of some something offered through public health care. In con-
condition.’ This individual indicated thatthey were more trast, some noted dynamics of distrust, either saying that
inclined to participate in a vaccine trial than they would they would not trust the quality of the vaccine if it came
have been to participate in a drug trial. Another individ- from the state instead of an international nongovern-
ual in the HIV-infected cohort viewed vaccines posi- mental organization. A declined HIV-negative subject
tively: ‘I used to run to a vaccine camp when it came [to noted,‘In China…now, the hospital has become a much
our village],’she said, referring specifically to early child- more economically independent unit. You have to man-
hood vaccination efforts in her country of origin. ‘I used age and make [money]. Each hospital…has to make
to try to get everyone to come. People would carry money and one way is through their pharmacies.’
babies, and I used to think that everyone should come Although most participants felt that general awareness
todothe vaccinestobehealthy.’ ofTBwashigh intheircountriesoforigin, theyalso said
And yet, this same individual later said that her reac- that many probably were still under the impression that
tion was not necessarily the norm in her community, they were protected from TB if they received BCG,
citing dynamics of fear and mistrust of biomedical unlesstheywere HIV-infected.
authority. She used the 2014 Ebola outbreak in West
Africa, and a possible Ebola vaccine, as a cautionary tale. Discussion:Researchandlivedexperience,consentand
When discussing the possibility of administering DAR- culture
901 in her country of origin, she said,‘Before you give, As our qualitatively coded data revealed, altruism, scepti-
you have to explain very well. Most people will beafraid. cism, personal commitments, self-interest and monetary
People thought vaccines brought Ebola.’ In a similar incentives all contribute to the decision-making of poten-
vein, another interviewee acknowledged the association tialresearchstudysubjects.Wefoundthiswastrueinthe
of militarized medicine with histories of colonial vio- foreign-born BCG immunized patients in both the HIV-
lence. He emphasized the ‘public relations’ work that negative and HIV-infected cohorts we interviewed, and
would need to be done in ‘some countries’ to ‘combat thatthespecificsoftheclinicalresearchquestionmodified
the idea of “What are these white faces doing to us?”… thesedynamics.Wefoundtherewasaninterplaybetween
You would need good education and marketing cam- narratives of sacrifice and those of giving back, between
paigns. You would have to say, “This vaccine is going to altruism and scepticism, as well as tensions between
save lives.” Because anti-vaccine sentiment is something individual and collective sensibilities about volunteering
thatisrealonthe social andpolitical sideofthings.’ for medical research. These dynamics were inflected by
In contrast, most interviewees reasoned that for DAR- cultural sensibilities on the one hand, such as through
901 to be tested on people like them in the US, it must ethno-physiological conceptions of risk [55], and experi-
have been rigorously tested before (some specifying encesofstructuralinequalityontheother,suchasthelack
Craigetal.BMCPublicHealth (2018) 18:535 Page8of12
ofaccessto healthcareina country oforiginor the lived less ‘developed’ countries. These topics came up in all
impactswar.WeheedFarmer’scall([56]:p.47–48)notto but two interviews. Beyond comparisons of clinical trials
conflate cultural difference with structural violence, which study vaccine versus drugs advanced by a corpor-
including when it comes to making sense of people’s ation, interviewees spoke about how financial incentives,
decisions about whether or not to volunteer for clinical either to individuals or institutions in under-resourced
research. settings, could influence research. Some interviewees de-
While many individuals were willing to participate in scribed a sense of imbalance in how clinical research
medical research, they were less willing to talk about seemed to be conducted in their countries of origin.
their participation in clinical research with others. Altru- They expressed desires for these efforts to be more
istic expressions were coupled with a desire for privacy, ‘ethical’ormore‘mutuallybeneficial’tothe communities
concerns about what friends and family would think, or inwhichtheresearchisconducted.Onedeclinedsubject
responses to others’ fears about participation. This find- said,
ing reflects the ways that individual and social drivers
can both compel and hinder volunteerism and compli- In mostcases,when thefundingdriesuporthe
cates narratives that would equate such actions with a projectwindsup,that[is] it.TheEuropeansandthe
sense of recognized or visible social action. Altruism, Americansjust walkout andarefine.Essentially,
while common, was also complicated by the ways some you’veutilized [our] bodies,you’vegainedknowledge,
individuals tied participation in the trial to possibilities personal,professional,andacademic advancement.
for direct personal benefit, either in the form of possible And,inreturn,[you’ve]hiredafewpeople andbuilt a
protection from TB or financial gain. Volunteerism in few buildings,but [you] haven’treally given[us]
this context was also shaped by many enrolled partici- anything.
pants’ perceptions of the US health care system as well
as respect and trust for the physician-scientists involved Another interviewee pointed out that even if a subject
in this trial, including trusted intermediaries who used population is truly informed and fully consenting, their
social and clinical networks to make initial introductions agency could still be limited or threatened if was not
betweenpotentialparticipantsandstudystaff. protected by the judiciary in country in which research
Despite a detailed informed consent form and discus- is being done. ‘If your patient population is well-
sion between study subjects and study staff, there was educated, they know their rights. And ifyou haveagood
significant variation among those we interviewed about law enforcement system, then they can actually exercise
what a vaccine is and what it can and can’t do. These their rights, as opposed to the patient population not
findings raise interesting questions about how informed knowing their rights and not necessarily understanding
consent can be influenced by cultural difference, educa- the risks,’ One enrolled subject described. ‘They don’t
tion, socioeconomic position, and other aspects of lived have the privilege to go sue someone. In which case, I
experience,asothers havealso discussed [48,57–62]. can see [medical researchers] going in with good inten-
Several interviewees questioned whether some popula- tions but I can still the patient population getting
tions would ever be able to give fully informed consent, exploited.’
either because of sustained challenges of language and Subjects in our study recognized that, in cases where
culture or because of broader differences in worldview people feel that clinical research is their only option for
and distinct social dynamics that shape the consent clinical care, true informed consent is impossible. One
process. One declined individual cited the sense that study staff member shared that the head of an institu-
‘Asian societies have a collectivist mentality and this tional review board in a country in which he had
desire to benefit the greater good would take precedent conducted research once questioned him about ‘why
over individual harm.’ However, this same individual Americans wasted time splitting hairs’ over the details of
(from South Korea) went on to say that ‘with ethics review. As long as a trial was providing care for
modernization, Korea now has idea of western ethics so patients, this official argued, what did ethics review
there is now a similar definition of informed consent for matter?
both countries.’ Collective decision-making practices Study staff involved in this trial and in the previous
clearly influenced many potential study subjects, either SRL-172 trial in Tanzania noted that while FDA regula-
by discouraging participation or influencing disclosure tions are very stringent in the US, WHO regulations are
ofadecision toparticipate. less consistently enforced in Tanzania. They observed
Interviewees were aware of the potential blurred that the subject pool in Tanzania was more vulnerable
boundaries between clinical researchand clinical care, as than those in the US because they recognized that
they relate to the political-economy of medical research, clinical research was connected to a source of primary
research ethics, and the ‘outsourcing’ of clinical trials to care. One staff member noted,‘While most subjects in
Craigetal.BMCPublicHealth (2018) 18:535 Page9of12
Americaarelookingtoputgravyontheirpotatoes,most contributingmeaningfully toavalid andbeneficialscien-
subjects in Tanzania are looking for the potatoes tific endeavour, run by people who were both qualified
themselves.’ On this topic, one declined subject said, and cared about the participants and about improving
‘Some people [are] waiting to die, so why not get free health outcomes generally, and reducing TB mortality,
treatment?’ Such comments not only speak to this re- morbidity, and stigma specifically. For those who
search versus care dynamic, but also point to differences declined enrolment, generalized scepticism about the
between avaccine trial of this type and a drug trial, even motivations of physician-scientists, the ethical challenges
if such distinctions may at times be lost on study sub- of clinical research, and perceptions of personal risk
jects. We summarize our coded findings in terms of the were articulated alongside more mundane concerns
keymotivationsandconcernsofenroleesinthetubercu- about timing and effort required to participate. Financial
losis vaccine trialinTable2. incentives were a motivating factor for some and a locus
of scepticism for others. Personal relationships between
Conclusion study staff and research subjects were crucial to recruit-
Using in-depth semi-structured interviews of declined mentandsuccessfulcompletion ofthetrial.
and enrolled study subjects in the DAR-901 trial, we Insights from this study can help inform outreach and
identified major themes influencing foreign-born recruitment, informed consent, and education efforts in
individuals’ decisions about whether or not to enrol in a ongoing and future clinical trials involving foreign-born
phase I TB vaccine clinical trial which took place in the individuals. This study provides useful cross-cultural
United States. Individuals who chose to enrol in the feedback at a critical moment in TB vaccine develop-
DAR-901 trial linked a generalized sense of altruism ment. Our findings highlight the perceived value and
with a very specific understanding of what this vaccine need for a TB vaccine; they also identify opportunities
could accomplish. Study enrolees believed they were for education about the limits of BCG. We also found
Table2Keymotivationsandconcernsofenroleesinthetuberculosisvaccinetrial
Codedtheme Dynamic Response
Knowledge(direct/indirect)oftuberculosis Manysubjectsweremotivatedtoparticipate Educatepotentialsubjectsaboutpublic
duetoawarenessofthetuberculosis healthproblemaddressedbystudy&how
epidemicandtheroleoftuberculosis interventionaimstohelppeople
vaccinesindiseaseprevention
Altruism Subjectsparticipatedinstudytoaid Mentionpotentialforstudyparticipationto
developmentoftuberculosisvaccine helpat-riskcommunities
Personalrelationships Studysubjectswithconnectionstoclinicians Non-coerciveinvitationtoparticipatein
involvedinstudyortrustedintermediaries studybyknownclinicianswherepossible
whorecommendparticipationwere
motivatedtoparticipate
Personalgain Somesubjectsexpecttobenefitclinically Transparencyaboutpotentialstudybenefits,
fromparticipation ifany.Itisimportantforsubjectsto
understandthattheirdecisiontoparticipate
instudy(ornot)shouldhavenoimpacton
qualityofclinicalcare
Privacy Manysubjectslimitedreleaseofinformation Protectsubjectprivacyinaccordancewith
aboutstudyparticipation&itsindications theirpreferences
Collectivedecision-making Theopinionsofrespectedpeers,including Duringconsentconversation,askpotential
familymembers,influencedmany subjectsiftheywouldlikestudystaffto
approachedindividualstoparticipateornot discussstudywithrespectedpeersaswell
(unlessprivacyofdecisionalready
mentioned)
Remuneration Financialincentivestoparticipateinthe Selectanon-coerciveincentiveto
studywereviewedpositivelybysome participateincollaborationwith
subjects&withsuspicionbyothers representationfromcommunitiesfrom
whichrecruitingsubjects
Convenience Timerequiredofsubjectsintrialcan Beparsimoniouswithsubjecttime
dis-incentiviseparticipation investments;alignfinancialincentivesto
them
Riskaversion Somesubjectsdeclinedoutoffearthe Educatesubjectsaboutrisks/benefitsof
vaccinecouldharmthem studyintervention&measurestakento
observe&mitigatethemduringconductof
trial
Craigetal.BMCPublicHealth (2018) 18:535 Page10of12
that TB stigma, collective decision-making, and tailored Availabilityofdataandmaterials
health communications were highly influential to potential Thedatasetsgeneratedand/oranalysedduringthecurrentstudyarenot
publiclyavailableduetoissuesofparticipantprivacy,butareavailablefrom
TB vaccine trial subjects. Results from these qualitative in-
thecorrespondingauthoronreasonablerequest.
terviewsreiteratetheneedandvalueofdevelopingrelation-
ships with trusted community leaders (including clinician- Authors’contributions
scientists) as part of the research effort. These data also SRCconductedinterviewswiththeenrolled,HIV-infectedpopulationandwas
theprimarycontributortodataanalysisandarticlewriting.TLcontributedto
raiseproductivequestionsaboutthepossibilitiesandlimits
theconceptanddesignofthestudyandwasamajorcontributorinwriting
of non-coercive incentives for participation in clinical re- themanuscript.ADconductedinterviewswiththedeclined,HIV-negative
search, and suggest the enduring importance of continued population,enrolled,HIV-negativepopulation,andstudystaff.ADandCFR
contributedwritingthearticle,boththroughtheengagementofstudydata
conversation about the process of conducting ethical,
withwiderliteratureandeditingthemanuscriptthroughtosubmissionstage.
culturally-sensitive,andrelationship-influencedscience. Allauthorsreadandapprovedofthesubmittedmanuscript.
Ethicsapprovalandconsenttoparticipate
Endnotes TheDartmouthCommitteefortheProtectionofHumanSubjects,whichis
1Aeras is a non-profit foundation charged with thenameforDartmouth’sInstitutionalReviewBoard/EthicsCommittee,
approvedthisstudy(CPHS#28941).Intheethicsreviewprocess,wereceived
advancingthedevelopment ofTBvaccines.
permissionforawaiverofwrittenconsent,andinsteadtheresearchers
2DAR-901, is an inactivated polyantigenic whole cell obtainedverbalconsentfromalloftheparticipants.Wedocumentedthis
mycobacterial vaccine. An earlier form of DAR-901, verbalconsentonapassword-protectedinformationsheetandde-identified
transcriptoftheinterview.Thestudyalsoprovidedallparticipantswithan
called SRL 172, was used in a seven-year Phase III in
informationsheetdetailingthepurposeofthestudyandhowtheir
Tanzania sponsored by the U.S. National Institutes of informationwouldbesharedandused.
Health and involving adults with HIV infection who
received BCG at birth. In that trial, receipt of SRL 172 Competinginterests
Theauthorsdeclarethattheyhavenocompetinginterests.
was associated with significantly lower risk of
microbiologically-proven tuberculosis. This trial remains
Publisher’s Note
the only trial in which a new tuberculosis vaccine has
SpringerNatureremainsneutralwithregardtojurisdictionalclaimsin
shown efficacy in humans. Dartmouth and the global TB publishedmapsandinstitutionalaffiliations.
vaccine research foundation Aeras collaborated to de-
Authordetails
velop an improved and scalable method for manufactur-
1DepartmentofAnthropology,DartmouthCollege,6047SilsbyHall,Hanover,
ingthe vaccine,now designatedDAR-901. NH03755,USA.2GeiselSchoolofMedicine,DartmouthCollege,Hanover,
3Dartmouth College Committee for the Protection of USA.3DartmouthCollege,Hanover,USA.
Human Subjects (CPHS) approved this study (CPHS
Received:8August2017Accepted:12April2018
#28941).
4We hadseveralinformal phone conversationswithde-
clined HIV-infected individuals, who initially expressed References
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Acknowledgements
vaccinetrialswithdiagnostic andprognostic biomarkers.ExpertRev
Theauthorsthankallparticipantsinthisqualitativestudy,aswellasthe
Vaccines[Internet].2017[cited2017Jul19];(just-accepted).Available
studystaff,particularlyBrendaHaynes,aswellasDavidLeibandL’uaie
from:http://www.tandfonline.com/doi/abs/10.1080/14760584.2017.
Kailanifortheirsupportandencouragementforthiswork.
1341316
7. vonReynCF,MteiL,ArbeitRD,WaddellR,ColeB,MackenzieT,etal.
Funding PreventionoftuberculosisinBacilleCalmette–Guérin-primed,HIV-infected
TheparenttrialwasfundedbyAeras.Thisinterviewanalysisofpotential adultsboostedwithaninactivatedwhole-cellmycobacterialvaccine.AIDS.
subjectmotivationtoparticipateinaphaseITBvaccinetrialwasfundedby 2010;24(5):675–85.
SYNERGY,TheDartmouthClinicalandTranslationalScienceInstitute,a 8. vonReynCF,LaheyT,ArbeitRD,LandryB,KailaniL,AdamsLV,etal.Safety
programoftheNationalInstitutesofHealth(NIH)ClinicalandTranslational andimmunogenicityofaninactivatedwholecelltuberculosisvaccine
ScienceAward(CTSA)program,“PhaseItrialofDAR-901inforeign-bornHIV boosterinadultsprimedwithBCG:arandomized,controlledtrialof
positivesubjects:safetyandvolunteerism.” DAR-901.PLoSOne.2017;12(5):e0175215.