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Recruitment and Engagement in Preventive Clinical Trials: Interdependencies and Mediation

Ollivier-Yaniv, Caroline PhD

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JAIDS Journal of Acquired Immune Deficiency Syndromes: October 1, 2018 - Volume 79 - Issue - p S3-S7
doi: 10.1097/QAI.0000000000001812
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Abstract

This collective work takes a standpoint based in the human and social sciences to examine a decisive time in any research related to HIV-AIDS, ie, when healthy, seronegative individuals agree and decide to take part in preventive clinical trials.

The problems encountered in the recruitment of volunteers [Université Paris-Est Créteil, Vaccine Research Institute, Céditec (E.A 3119)] (these can be connected with the difficulties involved in recruiting HIV researchers), to use the same words as the investigators, depend on factors that have undergone transformation over several decades: the normalization of the epidemic after a period of exceptionalism, the change in focus of social communities to other causes, the changes in the disease from a therapeutic point of view (new drug treatments and preventive drugs), the absence of compensation for participation in trials, the absence of any direct health benefits for the participants, and the fear of volunteers or their relatives of the idea of transforming their healthy body into a postexperimental body.1 Thus, research on the prevention of HIV seems to be dependent on the consent of a limited number of people and groups because their reasons for taking part in such experiments, which are just as much personal as they are for the sake of science, are necessarily very particular. Despite everything, as several chapters of this work show, the trials are continuing and volunteers are being recruited; however, this may take time and is performed using recruitment methods and selection criteria that are redefined on an ongoing basis.

To understand what makes it possible and legitimate to recruit healthy individuals for preventive HIV trials, including for the people who seek to determine how we can continue to recruit, 2 related factors must be taken into consideration: the social characteristics of the volunteer both as the object and subject of research as defined in the recruitment procedures, and how recruitment is perceived by these volunteers, given their social status, skills (in understanding the objectives of a trial and how it works), interactions, and expectations of the experience on both personal and physical levels.2

IDENTIFYING THE INTERDEPENDENCIES AND MEDIATIONS INVOLVED

What is the purpose of these 2 issues? Why is it relevant and important to see recruitment as a collection of interconnected dependencies and mediation produces or not a mutual understanding between a volunteer and an investigator?

First of all, it emphasizes that the recruitment of subjects for preventive research is a manifestation of “delegated or personal biopolitic,”3 as well as an experience of subjectivation. Anyone who becomes a trial participant because he meets the inclusion criteria and has gone through experiences that compelled him to take the formal step to register his “informed consent” has an attitude of control over his body and is not a person who can be coerced or punished into consent, but “necessarily has self-awareness, which assumes that the subject is able to express motivations or reasons which one can accept […], to have a reasonable discussion of the things which will be done to his body, and to control impulses related to these topics which are likely to be quite powerful (life, death, sexuality)” (Ref. 3 p. 55). The volunteer's trajectory through the recruitment process is also a process of self-discovery and an experience that defines the subject: his engagement “shapes the action which he takes, the burden which he accepts, and the social role which he agrees to play”4 and constitutes, in this regard, a “technique of the self.”5

It should also be noted in this regard that the recruitment of healthy individuals for clinical trials, especially for the prevention of a disease as complex (medically and socially) as HIV, is fundamentally distinct from a domination relation, which sometimes imbued the therapeutic relationship before the development of greater, although still relative, medical equality and autonomy of patients,6 and although the roles and skills of researchers, investigators, and volunteers are still generally asymmetrical. If we take the proposition seriously that recruitment is an interdependent process based on a form of reciprocity, it cannot be seen solely in terms of persuasion or of the individual's acceptability. It is fruitful to conceive of it in terms of self-interest in the sense that self-interest, as it is defined in the sociology of sciences, “is based on a certain interpretation of the role which the participants are required and desire to play and with which they identify.”7

At last, it means that recruitment cannot be limited solely to a misunderstanding or an error on the part of volunteers, which would signify a gap between common sense or a scientific lack of capacity and the advancements. It should be primarily seen as comprising a series of mediations and advancements misunderstanding, ie, heterogeneous and diverging interpretations of the description or characteristics of the clinical trial.

Although there is no “therapeutic disagreement”8 in this case since treatment is not being offered, it should be noted that the use of the appropriate language to describe and define a preventive clinical trial is socially determined, and that the polysemy or the connotations of certain terms9 may result in different ways of understanding information even when the description of the clinical trial has been written with great care and ethical concern and uses nontechnical language. This can be the case even when the individual or entity concerned receives extensive documentation. Rather than declaring failure, seeing the recruitment process as a series of disagreements can help to gain more time because it encourages researchers to pay closer attention to the available information and how it is transmitted, as well as to the mediation, to be organized with the volunteers.

PREVENTIVE HIV RESEARCH: BIOLOGICAL AND SOCIAL DISCONTINUITY COMPLEXITY

The history and function of clinical trials for the prevention of HIV in the global process of research aiming to end the epidemic, a topic that is also examined in the interview with Jean-Danièle Lelièvre, is typically complex in both biomedical and social terms.

In a competitive international context both in strictly scientific terms as well as in terms of funding for research and development {generally stable for the past decade [Resource Tracking for HIV Prévention R&D Working Group, 2016, p. 3–4. http://www.hivresource-tracking.org/wp-content/uploads/2016/12/Resource_Tracking_Report_2015.pdf (viewed in May 2017)]}, current research on HIV-AIDS can be divided into 2 main groups: therapeutic strategies and prevention strategies, which are also interrelated. Therapeutic strategies typically have a before and an after, beginning with the invention and spread of triple therapies as of 1996. The disease thus became chronic, but with heavy treatment. In regions of the world where these treatments became accessible (mainly in the “Northern” countries), the association between AIDS and death transformed and was taken up as the motto of organizations such as Act Up. From being incurable, AIDS became relatively controllable. As medicine developed around the epidemic, it also became less politicized. The development of treatments was also accompanied by a decline in the use of condoms10 and an increase in the number of new infections, particularly among homosexuals.11 As a result, prevention became the topic of new scientific and technological developments, indicating a true “biomedicalization” of prevention and even of sexuality since 2008.12 The construction of the paradigm of combined prevention for risk groups “at risk” is therefore based on the recommendation simultaneously to use condoms, undergo regular screening tests (for HIV, other sexually transmitted diseases, and hepatitis C), and receive preventive antiretroviral treatment, whether on a constant basis or occasionally whenever a risk is anticipated (pre-exposure prophylaxis or PrEP).

The development of preventive research therefore continues to be an important part of efforts to eradicate the disease on a worldwide scale. These efforts are supported by national and international medical institutions, the scientific community, particularly through the International Aids Society [http://www.iasociety.org/Default.aspx?pageld=349 (May 2017)], philanthropic foundations, and the pharmaceutical industry.

These strategies are currently being developed throughout the world along various lines (these were presented at the biennial international conference HIVR4P—HIV Research for Prevention) such as circumcision, microbicides, PrEP, drugs used for prevention, and vaccine development. The latter focus, which began as soon as the epidemic became a subject of study in the 1980s, has been regarded with increasing skepticism due to results that are deemed to be insufficient. In 2009, the publication of the results of the RV144 trial, or the “Thai trial,” which was the result of an international collaboration involving over 16,000 paid volunteers and scientists from Thailand and the United States, renewed interest in vaccine research in the field of HIV worldwide.13,14

France is currently ranked number 4 in the world in terms of research funding and development for the prevention of HIV [with 8 million dollars invested in 2015, behind the United States (850), Canada (27), and the United Kingdom (21), and ahead of Japan (5). Cf. HIV Prévention Research & Development Investments (2000–2015), Resource Tracking for HIV Prévention R&D Working Group, 2016, p. 13. http://www.hivresourcetracking.org/wp-content/uploads/2016/12/Resource_Tracking_Report_2015.pdf (viewed in May 2017)]. The ANRS is the public institution that is organizing and funding this research. It is an international player in the research on a preventive HIV vaccine, particularly through the creation in 2012 of the Vaccine Research Institute (VRI) and its engagement in the European consortium EHVA (European HIV Vaccine Alliance), of which it is the coordinator.

This preventive research is conducted in standard clinical trials. The trials are complex because they involve healthy individuals who agree to lend themselves, in the literal sense of the word, to a medically and ethically controlled experiment by providing their “informed consent,” which is also a “physical consent.”1 The agreement of these healthy people is therefore a requirement for the execution of HIV prevention strategies in terms of both feasibility and legitimacy. In other words, the impossibility of recruiting volunteers would indicate an absence of confidence or hope in individuals and society that the disease can be eradicated.

These historical and contemporaneous observations led to the recruitment of volunteers for the preventive trials that are the topic of the present work, which mainly deals with recruitment for vaccine trials (in France and the United States) and PreP (in France).

THE RECRUITMENT OF HEALTHY VOLUNTEERS: A LARGELY UNKNOWN PROCESS UNDERGOING TRANSFORMATION

The work in the social sciences on recruitment for clinical trials is generally rather fragmented compared with the importance of the research conducted in the trials. The majority of the available work concerns the situation in the United States and private pharmaceutical research, which notably compensates the participants.15–17 The spread in France and Europe of the notion of “the commercialization of science”15 or the concept of a population “ready to be recruited”17 was irrelevant due to the particular nature of the context from a social, political, legal, and cultural point of view as well as the ethics of researchers.

In addition, some works have studied the recruitment phase in some specific therapeutic trials, eg, regarding HIV in the countries of the South18 and in cancer trials in France.19 The rare works that concern recruitment for preventive HIV trials are usually part of public health or epidemiological research. This topic is detailed in the chapter by Mathilde Couderc in this book.

The rare number of works in the social sciences on the phase preceding a trial, in contrast with the large amount of research conducted on the execution of trials, is partially due to the difficulty involved in making this phase observable because the epistemological and methodological expectations of research require that it covers a whole range of identifiable practices, both in space and time. Making recruitment as an object therefore depends on the existence of participants, practices, discourses, premises that can be found and accessed by researchers, and the agreement of the investigators responsible for the trial.

This agreement refers to the specific context and varying views of researchers in the social sciences regarding the recruitment process, as indicated in several chapters in this book. Such researchers were involved in the recruitment process as well as the trial itself as observers or active investigators. This is emphasized clearly in the chapter written by Alain Giami and Françoise Linard on a specific project conducted by the social sciences department of the ANRS related to VAC trials in the 1990s. During this project in 1992, the “Volunteers for a Vaccine” network was set up to meet 2 needs: to create a group of people willing to take part in vaccine trials and to ensure that medical, behavioral, and psychological criteria were taken into consideration. This network, which was designed to comply with the ethical principles of biomedical research, is a process for the selection of volunteers based on a protocol developed jointly by researchers in social sciences and psychology in particular. This protocol relies on an analysis of the application letters of volunteers (analyzed in the article by Olivier Fillieule) based on research conducted entirely a posteriori, followed by more in-depth individual interviews.

The growing awareness among investigators of the difficulties of the recruitment of healthy volunteers led to the integration of a more diverse range of contributors in the recruitment procedures, ie, communications experts to inform and enroll volunteers, and researchers in the social sciences to analyze (rather than develop) and sometimes to evaluate the enrollment process in situ and the motivations of volunteers.

Thus, the organization of one of the last rounds of recruitment conducted by the VRI (for the ANRS-VRI01 trial in 2014, requiring close to 100 volunteers younger than 45 years) involved a diverse range of contributors, some of whom had nothing to do with the biomedical world or were not involved in any particular way in HIV. Experts in institutional communications and fundraising produced information on the trial jointly with the investigators, which was distributed in the public domain (through a website, a Facebook page, posters, and an insert in the free daily press).20 In the Ipergay trial, a media communications strategy was also implemented for the purpose of drawing attention to the trial involving gay, seronegative men, who described themselves as engaging in risky practices but without rejecting prevention.

The recent European scientific literature contains other experiences of collaboration between investigators and professional staff in the fields of IT, communications, and recruitment for the purpose of recruiting healthy volunteers in trials related to HIV,21 analyzed by researchers in the social sciences. This phenomenon, which may be considered indicative of a new division of work of recruitment, would benefit from comparison with the notion of the “science of recruitment,”16 which was developed to account for the standardization of the methods and tools used to recruit target groups such as underrepresented populations in the case of the biomedical trials in the United States in the 1990s. As Frédéric Le Marcis emphasizes in the Postface [as well as a work specifically dedicated to “experiences and viewpoints in research,” which also appeared in the same collection in 2010 (Chabrol and Girard22)] of the present work (and Ref. 22), it also encourages relative work by the researchers in social sciences to reconcile access to original data (practices, discourse, participants, etc.) and the distance required to be objective and analytical.

A DIACHRONIC AND MULTIDISCIPLINARY PERSPECTIVE

The research collected in this book primarily provides a diachronic view of recruitment for preventive HIV trials, going back to the very first trials conducted in France.

We decided to start by presenting the works dealing with the most recent recruitment, ie, the ANRS-VRI01 trial and the Ipergay pre-exposure prophylaxis trial, because they are highly indicative of the present concerns involved in the recruitment of healthy individuals, although the 2 populations concerned in these 2 trials were completely different, particularly regarding sexual behavior during the trial (minimal risk-taking for ANRS-VRI01 compared with risk practices in Ipergay). These 2 trials are indicative of a standardization of recruitment as a result of the integration of auxiliary experts in media communications and the use of ordinary language to convey biomedical information regarding the principles and risks of the trial. These media campaigns therefore provide a means to observe some discrepancies or contradictions between the constructed figures of the volunteers in the media campaigns and the representations held by the target populations of volunteers (see the chapter by Mathieu Trachmann and Gabriel Girard), as well as the different ways in which biomedical categories and behavioral recommendations for the duration of the trial are understood. This topic is described in the chapter by Mathilde Couderc.

This increasing professionalism and standardization of recruitment mechanisms are concomitant with growing difficulties in recruiting volunteers, as well as the need to make recruitment campaigns for HIV prevention trials stand out in the public domain.

Appeals to support HIV research through media events intended to raise donations of money but not to encourage the participation of volunteers have become commonplace. At the same time, they need to compete with other pathologies that have been turned into social causes (eg, genetic diseases) or politicized public problems (cancer). These observations indicate the importance of communication in the strategic and persuasive sense of the term and in the actions of the government and scientific community regarding health and prevention.23 This phenomenon of standardization is still relative, especially when compared with the context of the United States. This is examined in the chapter in English by Marci Cottingham, Jill Fischer et al, who emphasize the major difference of contextual to the compensation of participants.

Other chapters (Alain Giami and Françoise Linart, Olivier Fillieule, Christine Durier, et al) make up a second subset of the work: they provide a diachronic view of the motivations of healthy volunteers, which justifies their participation to a clinical trial concerning the prevention of HIV, particularly vaccine trials. It underscores the continuity of certain reasons for engagement connected with stable socioprofessional and demographic characteristics despite the transformation in the social and medical context of the disease. Whatever the disciplines and the methodologies involved, we see that altruism (sometimes linked to a personal involvement with the disease) and a sense of general interest are sustainable, as does a relationship of trust and sometimes even submission regarding medical research and the hopes that it seems to ensure.

The persistence of the questions of volunteers regarding “false seropositivity,” or in other words, the probability of seropositivity induced by participation to the trial in certain people, is remarkable. This question, which is the subject of the chapter written by Mathilde Couderc based on a comprehensive socioanthropological study, also seems to be salient in the professional American volunteers, whose perception of the risks has been studied by Marci Cottingham, Jill Fischer et al. The follow-up of the COHVAC cohort, which evaluates the psychological and social impact of participation to vaccine trials and the results of which are presented in the article by Christine Durier et al, provides additional and consistent information: it effectively shows that even the individuals for whom participation in a vaccine trials seems a posteriori to be an eminently positive experience, the only regrets mentioned, even if they are rare, are connected with induced seropositivity. This observation, which seems to be a factor preventing engagement in preventive HIV clinical trials, has been clearly identified in the American literature (VISR, Working Group of the Global HIV Vaccine Enterprise, 2014).24 It can also be seen as a key “misunderstanding,” which can be put at the heart of information campaigns as well as the mediation processes that comprise a process for the recruitment of healthy volunteers.

It should also be noted that the use of multiple disciplines in this book is an indication of the diversity of the researchers who have developed analyses on recruitment for HIV clinical trials. Some of them, but not all, have dedicated the majority of their research to this disease. This book therefore helps, along with others, to highlight this topic so that it can act as a point from which to observe the mediation between medicine, science, and society, the changes in forms of engagement, and the transformations in biopolitics which, given the transformation of knowledge about living things and the subjective ways in which subjects experience their bodies, is giving way to “biosociality.”25

Finally, this book, as any collective publication, is the product of many encounters and would not have been possible without the involvement and trust of the individuals and groups concerned. The first people we should mention are those who took part in the clinical trials. We thank them for agreeing to take part, not only in the biomedical research but also in the social sciences and epidemiology surveys.

The analysis of the recruitment process of a clinical trial also relies on the possibility to understand the process objectively and to construct objects of study. Regardless of the methodology used (interviews, questionnaires, corpora, etc.), their design partly depends on the agreement of the sponsors of the trial. The biomedical teams of the ANRS and the VRI and most of the authors in the present collection had carried out or still are carrying out this long multidisciplinary work during the preparation of the studies, as well as on the occasion of a social sciences meeting organized by the VRI at the University Paris-Est Créteil in June 2015.

This work would not have been possible without the trust of the authors, some of whom agreed to publish entirely new research in the collection. Its development and distribution, both in terms of the scientific content and the publishing of the book, would not have been possible without the support of the “Research in Public Health and Human and Social Sciences” department of the ANRS.

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Keywords:

recruitment; preventive clinical trials; healthy volunteers; engagement in clinical trials

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