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Relative Versus Absolute Standards for Everyday Risk
in Adolescent HIV Prevention Trials: Expanding the
Debate
a
a
Jeremy Snyder , Cari L. Miller & Glenda Gray
a
b
Simon Fraser University
b
University of the Witwatersrand
Version of record first published: 13 Jun 2011.
To cite this article: Jeremy Snyder , Cari L. Miller & Glenda Gray (2011): Relative Versus Absolute Standards for Everyday Risk
in Adolescent HIV Prevention Trials: Expanding the Debate, The American Journal of Bioethics, 11:6, 5-13
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Target Article
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Relative Versus Absolute Standards
for Everyday Risk in Adolescent HIV
Prevention Trials: Expanding
the Debate
Jeremy Snyder, Simon Fraser University
Cari L. Miller, Simon Fraser University
Glenda Gray, University of the Witwatersrand
The concept of minimal risk has been used to regulate and limit participation by adolescents in clinical trials. It can be understood as setting an absolute standard of
what risks are considered minimal or it can be interpreted as relative to the actual risks faced by members of the host community for the trial. While commentators have
almost universally opposed a relative interpretation of the environmental risks faced by potential adolescent trial participants, we argue that the ethical concerns against
the relative standard may not be as convincing as these commentators believe. Our aim is to present the case for a relative standard of environmental risk in order to
open a debate on this subject. We conclude by discussing how a relative standard of environmental risk could be defended in the specific case of an HIV vaccine trial
among adolescents in South Africa.
Keywords: ethics committees, human subjects research, international/global health, institutional review board (IRB), research ethics
One of the tensions that ethical review committees (ERCs)
face when making decisions regarding enrolling children
(persons aged under 18 years) in clinical trials is the need to
balance risks to trial participants against potential benefits
to others if the trial produces generalizable medical knowledge. The concept of minimal risk has been used by ERCs
to ensure that the risks of trial participation to children and
adolescents (persons aged 14–19 years)1 are limited. Within
the concept of minimal risk, there remains debate over the
parameters that constitute minimal risk and a need for contributions toward a more fully elaborated policy regarding
the level at which minimal risk is set so that children and
adolescents are both ethically and legally protected and also
allowed to participate in trials that are beneficial and necessary for public health.
There is enormous need for increased research into a
vaccine for HIV. Increasingly we are reminded of the compelling nature of the HIV pandemic, as every year, millions
die and millions more become infected worldwide (UNAIDS 2008). After 20 years of research and great strides
in HIV treatment, prevention success is now widely accepted as a complex interplay of individual, social, and
environmental level factors that are rooted in gender and
health inequities (Lusti-Narasimhan et al. 2009; Kalichman
et al. 2009; Maman et al. 2009). Until there are fundamental
changes in power structures that fuel inequities and human
rights abuses, our greatest hope for reducing the impact of
HIV is in a preventative vaccine. In Sub-Saharan Africa, despite the enormous antiretroviral (ARV) scale-up programs
occurring over the last few years, many more people become infected every day than are placed on therapy, and in
South Africa alone, HIV prevalence is approaching 6 million (UNAIDS 2010a; UNAIDS 2010b). Not only are young
people, and particularly young women, the fastest growing
HIV-affected group, but adolescents offer the greatest hope
for positive and sustainable change in the future of the epidemic. Adolescents have a fundamental role with respect
to HIV vaccines due to their pre-initiation into behaviours
that increase risk for HIV transmission and the critical biological and socio-epidemiological information they hold
for vaccine development and eventual roll-out (Slack et al.
2007; Jaspan et al. 2006). Despite their importance in HIV
vaccine research, there has to date been no inclusion of HIVuninfected adolescents in HIV vaccine research.
In general, adolescents are a neglected age group with
respect to medical research and particularly in clinical trial
research (Santelli et al. 2003). Unfortunately, their low participation rates have translated into poor survival rates
for other diseases, such as cancers, as compared to both
children and adults, and there is concern that adolescent
The authors thank Stephanie Gatto for her research help in preparing this article.
Address correspondence to Dr. Jeremy Snyder, Simon Fraser University, Health Sciences, 8888 University Drive, Blusson Hall 11300,
Burnaby, British Columbia, V5A 1S6, Canada. E-mail: [email protected]
1. As defined by the Canadian Paediatric Society (2003).
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exclusion from clinical trials relating to HIV vaccines could
delay access to them as a group and also translate into increased morbidity and mortality in the future (Bleyer et al.
1997; Nachman et al. 1993). While other research has outlined several important reasons that complicate adolescent
participation in clinical trials, there is general consensus
that there is an urgent need to increase adolescent participation in HIV prevention trials and that the challenges
to trial participation are not insurmountable (Pomfret et
al. 2010). The large-scale HPV vaccine trial undertaken by
Merck and GSK recently, in which many trial participants
were adolescents, is testimony that adolescent participation
in trials for preventative sexually transmitted disease vaccines, while challenging, can be done (Baylor and Wharton
2009).
While news of the halted 2008 Merck STEP trial and the
companion Phambili trial in South Africa was disappointing on many fronts, there is also concern that the negative
trial results may translate into a more conservative environment for HIV vaccine trial participation that could lead to
stricter rules for enrolling adolescents into trials. Following
the first data safety and monitoring board meeting for the
STEP study, it was determined that the vaccine showed no
efficacy for prevention and the study was halted for futility.
In a subgroup of men who have sex with men with preexisting immunity to adenovirus type 5 and who were uncircumcised, the vaccine may in fact have caused an increase
in susceptibility to HIV acquisition. The STEP trial showed
that increased risk for HIV must be considered in future
HIV vaccine trials; given the requirement that adolescent
trial participants not face more than a minor increase over
minimal risk from participation in trials that hold out no
potential for direct benefit, this result may lead to their late
participation or exclusion from future HIV vaccine efficacy
trials. The potential exclusion of adolescent trial participation is a matter of concern, given the important information
that adolescents hold with respect to HIV vaccine research
(Clements et al. 2004).
The concept of minimal risk has been used to regulate
and limit participation by adolescents in clinical trials. It can
be understood as setting an absolute standard of what risks
are considered minimal or it can be interpreted as relative
to the actual risks faced by members of the host community for the trial. While commentators on this topic have
almost universally opposed a relative interpretation of the
environmental risks faced by potential adolescent trial participants (Nicholson 1986; Freedman et al. 1993; NBAC 2001;
NHRPAC 2002; IOM 2004; Shah et al. 2004; Kopelman 2004;
Shamoo and Resnik 2009; Wendler 2009), we argue that the
ethical concerns against the relative standard may not be
as convincing as these commentators believe. Our aim is
to present the case for a relative standard of environmental risk in order to open a debate on this subject. If, as we
argue, a relative standard of environmental risk can maintain an ethically defensible balance between the interests of
adolescent trial participants and the production of generalizable medical knowledge, then it should be considered for
use by ERCs. We have undertaken this discussion paper to
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contribute toward a dialogue of scholarship regarding the
protection and participation of adolescents in future HIV
vaccine trial research.
In the first section that follows, we examine the concept
of minimal risk and make the case, under certain strict conditions, for a relative interpretation of minimal risk. In the
second section we discuss how a relative standard of environmental risk could be defended in the specific case of an
HIV vaccine trial among adolescents in South Africa.
MINIMAL RISK
The concept of minimal risk of harm has been used to protect adolescents from exploitation and other forms of harm
during participation in clinical trials. If the baseline for measuring minimal risk is set too low—that is, if the baseline
mandates very little risk of harm—then this safeguard may
have the effect of prohibiting the inclusion of adolescents in
clinical trials where their participation is central to the success of the agent under investigation. If so, guidelines that
aim to protect individual children and adolescents from
harm may have the unfortunate side effect of preventing
the creation of generalizable knowledge that could be of
potential importance to a broad range of adolescents.
U.S. federal guidelines describe four categories of permissible research involving children:
1. Research not involving greater than minimal risk (45 CFR
46.404).
2. Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual
subjects (45 CFR 46.405).
3. Research involving greater than minimal risk and no
prospect of direct benefit to individual subjects, but likely
to yield generalizable knowledge about the subject’s disorder or condition. Research in this category is permissible only when the risk represents a minor increase over
minimal risk, understood as risk commensurate with
those inherent in a child’s actual or expected medical,
dental, psychological, social, or educational situations
(45 CFR 46.406).
4. Research not otherwise approvable that presents an opportunity to understand, prevent, or alleviate a serious
problem affecting the health or welfare of children (45
CFR 46.407).
Research that falls under the fourth category of permissible research cannot be approved by ERCs alone and is not
frequently used.
A key component of the first three categories of permissible research is the concept of minimal risk of harm. But
within the regulatory guidelines and in discussions of these
guidelines by commentators, there is disagreement with regard to how “minimal risk” should be understood (Shah
et al. 2004). Given that these guidelines are used to determine when research involving children is ethical and permissible, this disagreement creates a critical problem for the
conduct of ethics boards. While a range of disagreements
can take place over the concept of minimal risk, a common
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Risk Standards in Adolescent HIV Prevention Trials
point of contention is the baseline for measuring risk. In
order for ERCs to determine when risk is “minimal,” there
must be a baseline established against which to compare
the risks entailed by the research proposal. According to
the federal guidelines, a risk is understood to be minimal if
“the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves
than those ordinarily encountered in daily life or during the
performance of routine physical or psychological examinations or tests” (45 CFR 46.102). What is left unclear in this
statement is which adolescents’ ordinary lives should be
used as a baseline for measuring harm.2
The vague terminology used in 45 CFR 46.102 has led
to debate among members of ERCs over how to interpret
minimal risk (Janofsky and Starfield 1981; Shah et al. 2004).
At least two interpretations of minimal risk are available. An
absolute interpretation of minimal risk sets a single standard
for all children and adolescents, regardless of their lived
environments. Under an absolute interpretation, the federal
guidelines are understood as setting a single standard for
the risk found in the ordinary lives of a certain class or set
of children. This standard class of children would then set
the baseline for risk against which the actual risk found in
proposed clinical trials would be measured. Even if the risks
faced in the daily lives of the potential research subjects are
different from those faced in the daily lives of the members
of the standard class, it is the risks faced by the standard
class that will be used as a basis of comparison.
There are multiple ways in which a single, absolute baseline for measuring risk can be set. A 1977 report by the National Commission for the Protection of Human Subjects
of Biomedical and Behavioral Research (National Commission) states that minimal risk is “the probability and magnitude of physical or psychological harm that is normally
encountered in the daily lives, or in the routine medical or
psychological examination, of healthy children” (xx). Under this interpretation of the guidelines, even if a child faces
higher risk in daily life than a “healthy” child, it is the lived
experiences of the “healthy” child that would determine the
permissibility of enrollment in a research trial. Alternatively,
the South African Medical Research Council (SAMRC) defines “negligible risk” “as equal to the probability and magnitude of physical or psychological harm that is normally
encountered in the daily lives of people in a stable society
or in the routine performance of physical or psychological
examination or test” (SAMRC 2003a, 9.12.4.3.1). While the
baseline risks in the daily life of a “healthy” child and a child
in a “stable” society are importantly different, each sets an
absolute baseline that can be used to measure risk regardless of actual risk faced in the daily lives of the research
population in the proposed trial.
On the relative interpretation of minimal risk, however,
it is the environmental experience of the actual child being
2. This ambiguity is present in other national research guidelines.
The Canadian federal guidelines define minimal risks as “no greater
than those encountered by the subject in those aspects of his or her
everyday life that relate to the research” (Tri-Council 2005, 1.5).
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considered for enrollment in the trial that sets the baseline
for measuring risk. As different children will experience
varying levels of risk in their daily lives, the baseline for
comparing risk will be different for every group of research
subjects. Evidence for one form of this interpretation of minimal risk has been found in the version of 45 CFR 46 entered
into the Federal Register in 1981. This guideline states that
“the risks of harm ordinarily encountered in daily life means
those risks encountered in the daily life of the subjects of the
research” (DHHS 1981). “The daily life of the subjects of the
research” can be interpreted to mean specifically subjects
from the environment that the study would draw on rather
than healthy children or children living in a stable society.
In this interpretation of minimal risk, the determination of
whether a study would create more or less than minimal
risk for potential participants will depend on the health,
social, and environmental risks faced in their daily lives.
Both of these interpretations of minimal risk allow for
some flexibility in response to individual characteristics of a
child or adolescent being considered for enrollment in a human subject trial (though the relative interpretation allows
for much greater flexibility). Specifically, both interpretations can acknowledge the risks associated with child and
adolescent trials will depend on the age of the participant
at the time of enrollment. For example, the risks faced by
a child of toddler age might be less than those faced by an
adolescent given the adolescent’s greater level of activity
and autonomy. Therefore, “research that might be considered to pose greater than minimal risk for a younger child
might be consistent with the risks ordinarily encountered
in the daily lives of an older child and thus might be considered minimal risk for that population” (Fleischman and
Collogan 2008, 452). Flexibility as to how to set the baseline
for minimal risk is present in the regulatory language, then,
but debate remains over how much the actual condition
and characteristics of specific groups of child or adolescent
trial participants should be allowed to influence who may
participate in clinical trials.
For example, there is disagreement as to whether unhealthy children may be disproportionately represented in
a trial, including cases where there are no unhealthy children enrolled in trials at all. Unhealthy children might be
sought out for clinical trial participation if tests of the efficacy of an intervention for a specific medical condition require exposure to children with that condition. For example,
a trial of a treatment for childhood leukemia might require
participation by children with leukemia rather than healthy
children. In these cases, the concern is that the burdens and
risks associated with trial participation fall disproportionately on unhealthy children while the benefits of the trial,
given that it may produce generalizable knowledge, can potentially be shared by healthy and unhealthy children alike
(Ross 2003). That is, it would seem to be unfair to use the
fact that unhealthy children are ill as grounds for subjecting
them to risks that healthy children are not asked to face.
Kopelman (2004b) responds to this concern by noting
that justice is often interpreted as requiring that we treat
like cases alike. If all children create a single class of agents,
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then it may be unjust to subject unhealthy children to a
greater portion of the burdens and risks of trial participation than healthy children would face. She argues, however,
that children and adolescents with different levels of health
are “different in a relevant way; namely, their asthma, diabetes, cancer, physical disability, or other disorder sometimes justifies such studies to benefit those with similar disorders” (2004b, 752). That is, exposing a group of children
to disproportionately greater risks may be morally defensible if the research trial has the potential to benefit children with similar medical conditions. In these cases, differences in the health of groups of children and adolescents are
morally relevant differences and using the unhealthiness of
some children as grounds for treating them differently than
healthy children would not violate the requirements of justice.
Kopelman does not take this argument for differential
treatment of healthy and unhealthy children to justify a
relative standard of risk. That is, we can allow unhealthy
children disproportionate exposure to the risks associated
with trial participation without maintaining that the standard for what constitutes a minimal risk should be relative to the daily lives of unhealthy children. In order to
ensure that disproportionately high levels of trial participation by unhealthy children do not result in a relative
standard of risk, Kopelman proposes an upper limit for risk
to unhealthy child trial participants. According to this limit,
the risk should “a) represent no more than a minimal risk
for children with conditions who are enrolled in studies
and b) be no more than a minor increase over minimal risk
for healthy children were they enrolled” (2004b, 756). These
guidelines serve to ensure that the standard for minimal
risk applied to healthy and unhealthy children remains absolute rather than relative. Even if unhealthy children are
allowed to face a disproportionate amount of the risk associated with trial participation, the standard of what risks
are greater than minimal will remain the same for healthy
and unhealthy children alike.
This resistance to adopting a relative standard of risk
continues when other individual risk factors in children’s
everyday lives are considered. Different children will face
different levels of risk in their everyday lives due to their
environment, including risks from violence, low income, endemic disease, political instability, and other sources. Commentators are largely clear that the baseline for measuring
risk should not be relative to these wider environmental
factors. Instead, an absolute standard of an “average” child
in a “stable” society should be used (NBAC 2001; NHRPAC
2002; IOM 2004; Shamoo and Resnik 2009). While the everyday risks faced by a child in a more dangerous environment
might be greater than those faced by an “average” child, it
is the risks faced in the lives of this idealized class of children that are widely accepted and used as a baseline for
measuring risk.
The rationale for this restriction is varied and often unclear. In many cases, a relative standard is said, with little argument, to be exploitative of disadvantaged children
(Shah et al. 2004) or is said to allow researchers to take
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advantage of these children (Wendler 2009). A more developed charge maintains that allowing for a relative standard
of risk in clinical trials would be unjust as it would shift
new risks onto already disadvantaged populations (Nicholson 1986). Kopelman cautions against the wider application of a relative standard as it “would violate justice requirements that burdens and benefits must be distributed
equitably, especially since studies generally benefit everyone” (2004a, 363). A relative standard would potentially
allow researchers to venue shop for disadvantaged populations of adolescents who face heightened levels of risk
in their everyday lives (Freedman et al. 1993). Clinical trials could then be shifted to these groups, adding to their
already high levels of risk. In fact, studies with potential
therapeutic benefits for research subjects have tended to be
conducted among relatively privileged populations while
studies without the potential for therapeutic benefits have
historically been conducted among socioeconomically disadvantaged groups (Barber 1973). Any benefits from these
trials, however, would be distributed to adolescents everywhere or limited to more privileged adolescents with the
greatest financial means to take advantage of these newly
available clinical findings.
The Willowbrook School studies serve as an illustration
of how the use of a relative standard of risk creates the potential for exploitation and injustice. Residents of this statesupported institution, the majority of whom were mentally
handicapped, were deliberately infected with hepatitis in
order to study the natural course of the infection with the
goal of developing a vaccine (Ramsey 1970). Researchers in
the study reasoned that hepatitis was endemic in the Willowbrook School, and therefore the infected children were
already at very high risk of contracting the disease. Based
on the already elevated level of risk faced by these children,
the researchers argued, deliberate infection did not significantly increase their already extremely high level of risk of
contracting the disease (Krugman 1986).
Part of what is morally problematic about the Willowbrook Studies is that the children in the study were singled
out as a population that would easily serve the interests both
of the researchers and of the general population who would
benefit from any research results. The heightened risk faced
by the children in the Willowbrook School was seen as creating an opportunity for research, but the research was not
designed nor intended to be of special use in reducing the
risks faced by similarly situated children. An absolute standard of risk would eliminate this form of abuse, as it would
prevent “singling out people or groups with higher daily
risks in order to ‘excuse’ higher research risks as minimal”
(Kopelman 2000, 754). The risks faced by the children at the
Willowbrook School were relevant to research on hepatitis
A only in the sense that they created a population on which
research, which would benefit all children, could easily be
performed. For this reason, the heightened risk faced by
these students did not mark them as a distinct class of children in a manner where differential treatment and exposure
to higher levels of risk of harm through trial participation
would be justified.
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But does a relative standard for risk, applied to the
greater environmental risks faced by some groups of children and adolescents, necessarily entail injustice and exploitation? We believe that the answer to this question is
not clear, and is certainly not as obvious as is often implied
by the general consensus against the wider use of a relative
standard. Specifically, we assert that the rationale for the use
of a relative standard in the context of unhealthy children
and adolescents may be applicable to groups facing greater
environmental risks. If we apply a broader concept of health
beyond disease outcomes and consider health as inextricably linked to social justice through individual, social, and
environmental inequities that fuel health outcomes, then we
could consider the lived environment as having great influence over adolescent health outcomes. Those who charge
that the wider use of a relative standard of minimal risk
would be unjust emphasize that justice requires treating
like cases alike. However, the different levels of environmental risk faced by children may account for a morally
relevant difference between groups insofar as these environmental risks form vulnerabilities that require research
on adolescents and children to significantly improve health
outcomes. If a relative standard of minimal risk can be applied in a manner that specifically benefits similarly situated children and adolescents facing elevated levels of risk
in their daily lives, then there is a strong case that a relative
standard of risk applied to environmental risk can serve the
aims of justice.
Following a proposal by David Wendler (2004), we
would like to argue that a relative standard of risk for environmental risk (or what Wendler calls the subjective risk
standard) in studies that do not have the potential to provide therapeutic benefit may be ethically defensible when
and only when: (1) the scientific question is relevant to the
needs of the host community; (2) the study meets standards
of scientific necessity; and (3) the host community receives
sufficient indirect benefit. These requirements aim to ensure
that the choice to locate the trial in a community could be
justified by the unique health and environmental circumstances of that community and the scientific necessity of the
population’s participation in the trial and not for the convenience of the researchers. The second provision is intended
specifically to prevent the selection of high-risk communities based on the ease with which a trial may be conducted in that location or decreased costs arising from that
location—that is, to prevent new opportunities for venue
shopping on the part of researchers.3 For a benefit to be of
foreseeable use to a community under the third condition,
the researchers proposing the trial must have a clear plan,
with access to adequate, established, and sustainable funding, to apply any knowledge gained from the trial to the
health needs of children and adolescents in the trial community, including trial participants.
3. Though, conceivably, a researcher could use considerations of
cost to choose among two or more communities in which the research meets standards of scientific necessity and all other relevant
ethical standards.
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When these conditions have been met, a relative standard of risk can appropriately be used for determining
whether a fourth condition is met: (4) Clinical equipoise
is established such that research participants will not be
left prospectively worse off than they would have been
had the trial not occurred. While these children will face
greater risks through trial participation, the intervention
must not be known to create risks worse than those to which
they would otherwise have been subjected (Wendler 2004).4
Wendler argues that protections of this kind can serve to
protect children from being exploited in clinical trials. When
protections restrict the use of a relative standard for minimal risk to ensure that the benefits of the trial are directed at
the host community, the trial can serve to mitigate some of
the vulnerabilities faced by the members of that community.
These protections can serve to ensure that the differences in
environmental risks faced in the everyday lives of children
serve as morally relevant differences, justifying differential
treatment. While the relative standard for environmental
risk creates the prospect of placing additional burdens on
already vulnerable trial participants, these restrictions ensure that additional risks over existing vulnerabilities are
minimal. For those individuals choosing to participate in
research under these standards, they are given an opportunity to help generate research that will be of direct use to
their community. Under these protections, the elevated risks
faced by some children can justify targeted research into the
health needs of their community, rather than serving simply
as an expedient for the researcher.
This proposal provides a response to one of the frequent
charges used against the relative standard, that it will serve
simply to exploit already heavily disadvantaged children
and adolescents. As David Wendler puts it, critics charge
that the relative standard “would allow researchers to expose some people to greater risks simply because they already face greater risks in their daily lives” (2005, 38). This is
a legitimate worry and would condemn wider use of the relative standard if it necessarily entailed this form of exploitation. However, the protections that we build into our proposed application of the relative standard (and that could be
built into other formulations of this standard) help to ensure
that this standard will serve the interests of child and adolescent research participants rather than allow them to be
merely used as expedients to research. Wendler’s claim that
the relative standard targets disadvantaged children “simply because” they are disadvantaged underlines the form of
wrongdoing that has led many commentators to condemn
wider use of the relative standard. However, by ensuring
that research will serve and is justified by the needs of the
host community, our application of the relative standard
ensures that children coping with risk for adverse health
outcomes relevant to their lived environment are targeted
for research participation because of their situationally relevant need for clinical intervention and research into health
outcomes specific to their lived environments. At the same
4. Adapted from proposed relative standard for multinational research in adults (Wendler, Emanuel, and Lie 2004).
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time, these children will not be selected simply out of an interest in expediently conducting research in an ethically lax
manner. Returning to the case of the Willowbrook School
study, then, that research would have violated these protections in three instances. First, it would fail the scientific
necessity requirement as there was no scientific case presented for conducting this research on an institutionalized
and mentally handicapped adolescent population. Second,
it is not clear that there was any provision for making any
vaccine resulting from the trial available to the Willowbrook
school community. Third, as the participants in the Willowbrook study were intentionally infected with hepatitis, the
requirement of clinical equipoise was clearly violated.
We should not allow the injustices faced by vulnerable
communities to serve as another impediment to developing new interventions that can improve the welfare of these
communities. A relative standard of minimal risk, in specific (and probably rare) conditions, can serve to mitigate
the effects of injustice rather than merely allow researchers
to take advantage of injustice. In the case of HIV, while
this pandemic has devastated specific populations globally
and greatly reduced the life expectancy of some, HIV endemicity, while compelling, is rare globally. The combination of the serious impact of HIV on individuals living in
HIV-endemic settings and the fact that this condition is currently rare underscores the appeal of a relative standard.
While critics of the wider use of a relative standard are
right to note that less vulnerable communities may benefit
from the generalizable results of studies in more vulnerable
host communities (Kopelman 2004b), the focus of and justification for these studies can still be directed at the needs
of the host communities. Just as unhealthy children may
justifiably face a disproportionate share of the burden of research participation out of an interest in advancing research
targeting their health needs, we would like to argue that
children facing elevated environmental risks may not necessarily be exploited by participation in trials aimed specifically at positively reducing the environmental risk for poor
health outcomes within the trial population. In this way,
the needs of adolescents rendered vulnerable to poor health
outcomes only by circumstance can be served even while
generalizable knowledge, with its consequential benefits, is
produced.
CASE: HIV VACCINE TRIALS
To see how these guidelines might be put into effect, consider the case of an HIV vaccine trial in adolescents in
South Africa. The South African Medical Research Council (SAMRC) maintains that “as children are at risk of HIV
infection, children stand to benefit from the development
of HIV preventive vaccines. Therefore, children should be
included in clinical trials in order to verify safety, immunogenicity and efficacy from their standpoint” (SAMRC 2003b,
35). Never before has there been a disease of the global magnitude of HIV where adolescents are situated in the central
position with respect to prevention, given the age at which
behaviors are initiated and risk patterns established. Unlike
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for any other disease, adolescents’ biological, social, and environmental information is central to the development and
eventual roll-out of an effective HIV vaccine (Jaspan et al.
2006).
If we were to apply Wendler’s criteria for allowing a relative standard of risk to the case of an HIV trial among adolescents in South Africa, the following four criteria would
form the basis for discussion.
1. The Relevance of the Scientific Question to the Host
Community
There is without a doubt adequate evidence regarding the
sweeping impact that HIV/AIDS is having in South Africa
where some 5.5 million are living with HIV, millions have
died, and thousands of children have been left orphaned by
the deaths of one or more parents (Shisana et al. 2009).
Young women (≤24 years) are the fastest growing HIVinfected population, and women now account for 60% of all
HIV infections (Abdool Karim et al. 2009). The multigenerational effects of apartheid, including cultural repression,
lack of meaningful employment and educational opportunities, entrenched poverty, and unprecedented levels of
physical and sexual violence, are likely intersecting with
gendered power relations and fueling the HIV epidemic,
particularly among women (Mantell et al. 2009). Evidence
suggests that HIV has reduced life expectancy by up to half
(CIA 2010) and has had enormous impacts on the economic
viability of the black South African population already rendered vulnerable from years of apartheid and governmentsanctioned poverty. In South Africa, HIV prevalence overall is approximately 11% (UNAIDS 2008), but in some
areas such as Soweto, HIV prevalence is likely much higher
(Shisana et al. 2009). National surveys indicate that 4% of
men and 15.5% of women between the ages of 15 and 24
years are HIV infected, yet only 11% and 19%, respectively,
of this group are aware of their HIV-positive status (Pettifor
et al. 2005). There are few South African adolescents who
have not been personally affected by HIV through the morbidity and mortality of loved ones, and while HIV knowledge is high, sexual risk taking also remains high (Pettifor
et al. 2005). Unlike for Canada and the United States, where
overall HIV prevalence is less than 1% and largely confined
to vulnerable populations such as sex workers, intravenous
drug users (IDUs), and men who have sex with men (MSM)
(UNAIDS 2008), South Africa’s endemic is now a generalized heterosexual epidemic where the risks for transmission
to young people coming into sexual maturity are highly
relevant.
2. The Scientific Necessity of the Study
Previous research has described the necessity for adolescent participation in HIV vaccine trials on a number of levels, from the biological to the socio-epidemiological. Adolescents form an important target group for HIV vaccine
delivery as studies show that the mean age of sexual activity initiation is 16 and 15 years, respectively, for boys
June, Volume 11, Number 6, 2011
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Risk Standards in Adolescent HIV Prevention Trials
and girls (Health Systems Development Unit 1998). Therefore, vaccinating presexual adolescents offers important
and arguably the greatest hope for curbing the HIV pandemic. In addition to their preventative role for an effective vaccine, there are many questions to be answered at
the trial phase, including adolescent consent issues such as
who has the decision-making power over vaccine participation. Importantly, there has been no exploration of how this
decision may affect adolescents in the longer term, including relationships and sexual decision making. These sociobehavioral questions cannot be answered by adult populations because evidence shows that adolescents have vastly
different decision-making processes then adults (Swartz
et al. 2005). The analyses of population demographic data,
including who is willing to participate and who is not,
how shared parent and adolescent consent is actualized,
and what the most appropriate target group is for an HIV
vaccine, will play an important role in an eventual HIV vaccine roll-out campaign so that the population is efficiently
and effectively covered. Finally, adolescents hold biological
information that may be important for dosing and vaccine
efficacy, given their stage of development that differs from
adults. The importance of engaging the community to begin answering these questions through trial participation is
underscored.
3. Sufficient Benefit for the Host Community
There is no question regarding the importance of a successful HIV vaccine on a global scale, and few would argue that
South Africa, with the highest number of HIV infections
in the world, is a compelling location for a primary site
to launch an HIV vaccine roll-out campaign. In addition,
South Africa, compared to other African countries, has considerable economic stability and infrastructure to support
the research, manufacturing, licensure, and distribution of
a vaccine. Were an HIV vaccine trial to proceed, as argued
earlier, there would need to be a written guarantee, within
vaccine trial guidelines, that if a successful HIV vaccine
were to be found, the primary point to begin its distribution
would necessarily need to be the trial community and not
either more or less economically robust settings. In order
for this guarantee to be adequate, funding for distribution
of the vaccine in the trial host community would need to be
secured prior to the start of the vaccine trial.
4. Clinical Equipoise and Minimal Risk of Prospective
Harm
One of the inherent tensions in regards to an HIV vaccine
trial is with regard to harm of participants. Following the
most recent failed HIV vaccine trial, the Merck STEP trial,
there remain questions about whether the vaccine itself increased risk for HIV acquisition among trial participants. To
date the research has been inconclusive on this point; however, other HIV vaccine trials have also discussed whether
participation in the trial itself leads participants into engaging in higher risk behaviors due to a potential false sense of
June, Volume 11, Number 6, 2011
security (Chesney, Chambers, and Kahn 1997). While these
concerns are important and must be included in a thorough discussion of adolescent inclusion in HIV vaccine trials, we must also keep in mind that to date, no HIV trial
vaccine has been shown to be directly responsible for infecting an individual. Unlike cases such as the Willowbrook
School studies, there are few concerns that adolescents in
this case would acquire HIV from the actual vaccine under
trial. Nonetheless, there remains concern over increased risk
for sexual transmission (or in exceptional circumstances in
the context of South Africa, injection drug use transmission)
of HIV as a result of trial participation.
The exceptional circumstance regarding the relative risk
of HIV for South African adolescents, combined with their
centralized importance for uncovering an effective vaccine,
may be reason to explore other options aside from the exclusion of adolescents from early phases of clinical trials in
order to mitigate the increased risk to the individual adolescent. For example, adolescent participants of HIV vaccine trials could be offered gold standard behavioral risk reduction counseling, access to male circumcision, provision
of condoms, and treatment of sexually transmitted infections, as well as postexposure prophylaxis. If this standard
were applied, adolescents would necessarily be assured per
guideline HIV prevention measures (UNAIDS/WHO 2007).
While this is to be expected, to date, adolescents in endemic
communities have not had widespread access to HIV prevention measures despite international guidelines, due to
resource constraint, lack of political will, and ideological
tensions. While the additional protections offered by these
steps have to date been small, it could be calculated into
the evaluation of the risks created by trial participation. In
addition, the concept of hope has been discussed as central to adolescent engagement in risk-reducing behaviors
(Harrison et al. 2010; Campbell and MacPhail 2002). Their
participation in an HIV vaccine trial not only may provide
hope for the future for these personally affected adolescents,
but also may provide hope for their friends, families, and
communities.
We believe that these factors surrounding proposed HIV
vaccine trials in adolescents within South Africa lead to a
plausible ethical case for the use of a standard of minimal
risk that is relevant to the risk environment of these adolescents. The use of a relative standard of risk should not
be limited only to the specific context of HIV vaccine trials
among adolescents in South Africa, but would likely be applicable in other communities with levels of environmental
risk greater than those in “stable” societies. As we have argued, the use of a relative standard will only be appropriate
under specific conditions that aim to ensure that a relative
standard is justified by the interests of the host community
for the trial and not researchers or other communities.
If the use of a relative standard of risk still proves unpalatable for some, we believe that the protections discussed
in this paper, coupled with the importance of increasing
adolescent participation in HIV vaccine trials, could justify
approval of such a trial under 45 CFR 46.407, where research
that is otherwise not approvable will be allowed in light of
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the opportunity to better understand, prevent, or alleviate
a serious threat to the health of children. The high level of
risk for HIV faced by adolescents who would be enrolled
in these trials, coupled with the protections outlined earlier, creates a plausible case that the differential treatment
of adolescents facing elevated risks of HIV infection would
not be unjust. Under either subsection of 45 CFR 46, as we
have argued, allowing trial participation by children most
affected by HIV may not be unethical.
This paper does not claim to address all potential objections to our case for a relative standard of environmental
risk. Rather, our aim is to challenge the conventional wisdom that a relative standard of risk is clearly exploitative of
disadvantaged communities generally, and adolescents in
South Africa particularly. We hope that through this paper,
constructive debate on the concept of minimal risk in child
and adolescent trials will be possible. Fleischman, A., and L. Collogan. 2008. Research with children.
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Health Systems Development Unit. 1998. Adolescent sexuality and
reproductive health in the Northern Province. Johannesburg, South
Africa: Department of Community Health, University of the Witwatersrand.
Institute of Medicine. 2004. Ethical conduct of clinical research involving children. Washington, DC: National Academy Press.
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