The Trials of Tenofovir: Mediating the Ethics of Third World
Research
Peter J. Hammer & Tammy Sue
Lundstrom[*]
Abstract
In 2004, Phnom Penh was on the front lines of debates over HIV research.
Press coverage pitted the demands of a tenacious union of
sex workers against
the good intentions of international researchers funded, in part, by the Bill
and Melinda Gates Foundation.
The headlines reveal part of the story:
“Key AIDS Study in Cambodia Now in
Jeopardy.”[1] “Cambodia
Stops Important Tenofovir Prevention
Trial.”[2] “Hun Sen:
Don’t Test Drugs on
Cambodians.”[3]
“Cambodian Leader Throws Novel Prevention Trial into
Limbo.”[4] The drug at issue
was tenofovir, a newer anti-retroviral commonly used to treat HIV infection.
The research question was whether
the drug could be used as an effective
pre-exposure prophylaxis in high risk groups, such as commercial sex workers.
The stakes
are undeniably high. With a vaccine against HIV/AIDS still decades
away,[5] attention must focus on
intermediate strategies to slow the transmission of the disease, including
pre-exposure prophylaxis.[6]
Literally, tens of millions of lives hang in the balance.
While the
imperative for action is strong, so is the demand that medical research be
undertaken in an ethical manner. The ethical
problems raised by human
experiments are complicated. They become even more complicated when the
research subjects are vulnerable
populations in an already resource-poor
developing country. Exploitation is an ever-present risk. Safeguards must be
in place to
prevent the exportation of research to the Third World that would
not meet basic ethical standards. This was not the problem in
Cambodia.
Instead, the Cambodian story illustrates the growing inability of First World
medical ethics to address the demands of
international research. The
unfortunate result was that a well intentioned and well designed research
proposal reached an impasse
that led to its cancellation. How did two groups
that should be allies in the battle against HIV/AIDS—sex workers and
medical
researchers—become pitted against each other as adversaries? It
is important to understand what went wrong in Cambodia so
similar problems can
be avoided in the future.
This article proposes mediation as a framework to
address the social and ethical tensions associated with Third World medical
research.
Section I examines the science behind the tenofovir trials,
explaining the rationale for the study design and the logic for focusing
on high
risk populations. Section II details the social and political trials of
tenofovir, looking at the conflicts culminating
in the study’s
cancellation. Section III explores how the scientific and social concerns might
be better mediated in light
of emerging ethical principles guiding international
research.
I The HIV/AIDS Crisis and the Science Underlying
the Tenofovir Trials
A The HIV Crisis and the Importance of
Prevention
In discussing HIV/AIDS, a sense of urgency is unavoidable. As the World
Health Organization (WHO) declares, “[t]ackling HIV/AIDS
is the
world’s most urgent public health
challenge.”[7] HIV/AIDS is
responsible for more than 20 million deaths in the last quarter
century,[8] with five million new
infections in 2003 alone.[9]
“HIV/AIDS is now the leading cause of death and lost years of productive
life for adults aged 15–59 years
worldwide.”[10] While each
new HIV infection is a tragedy for an individual and a family, the ravages of
the virus go beyond its effects on personal
health. “In many countries,
the cumulative effects of the epidemic will have catastrophic consequences for
long-term economic
growth and seriously damage the prospects for poverty
reduction.”[11] In addition,
HIV infection promotes the spread of other communicable diseases, such as
tuberculosis, to the population as a whole.
This places great stress on public
health systems that are already overwhelmed and underfunded.
One-fifth of
the 34–46 million people living with HIV/AIDS worldwide are in
Asia.[12] In Cambodia, estimates
are that more than 1% of the adult population is infected with the virus that
causes AIDS.[13] These figures
highlight the need for thoughtful, creative and immediate action to diminish the
spread of the virus. Appropriate
interventions can make a difference, as the
WHO reports. “Together, prevention, treatment and long-term care and
support can
reverse the seemingly inexorable progress of the HIV/AIDS epidemic,
offering the worst-affected countries and populations their best
hope of
survival.”[14] Cambodia has
made important progress in implementing a number of HIV prevention measures
among sex workers. “In response
to these programs, condom use between sex
workers and clients rose to more than 90% and the number of men visiting sex
workers was
halved.”[15] It
is estimated that these efforts have reduced HIV prevalence in the general
population from predictions of 10–15% down to
current projections as low
as of 2–3%.[16] HIV prevalence
among female sex workers is much higher, but even these numbers have been
substantially reduced. A 1998 sentinel
surveillance study found an HIV
prevalence rate in sex workers of 42.6%, falling to 28.8% by
2002.[17]
Prevention is
important, but there are serious limitations to traditional “safer
sex” approaches. In many cases, as Sheila
Davey found, “sex workers
are unable to insist on condom use, especially if they are young, victims of
trafficking, or migrants.”[18]
In addition to encouraging condom use, prevention alternatives that empower
women and bypass male involvement must also be developed.
Approaches that can
be controlled by the female partner, such as microbicides, or
“anti-infective gels, creams, impregnated
sponges and similar devices that
women apply before sexual intercourse to prevent HIV
transmission”[19] are
particularly important. According to the WHO:
Epidemiological modeling based on the data from over 70 low-income countries
suggests that even a partially effective microbicide
is likely to have a
significant impact on the epidemic: a product that is only 60% effective in
protecting against HIV could avert
2.5 million new infections over a three-year
period, even if it is used in only 50% of sex acts not protected by condoms, and
assuming
it is used by only 20% of people easily reached by existing health
services.[20]
Unfortunately, the use of microbicides is not without its own problems.
Because waiting time is necessary between insertion and intercourse,
they could
cause irritation with frequent use, which may actually increase the probability
of HIV transmission per sex act. Moreover,
like vaccines, microbial agents are
themselves still in clinical trials.
B Tenofovir as an HIV Prophylaxis
Other preventative strategies can give women greater control over their risk
exposure. Anti-retroviral drugs are known to be effective
in controlling HIV
for persons already infected. Is it possible that antiviral treatment could
reduce the risk of HIV transmission
if taken before exposure to the virus as a
form of prophylaxis? This is where the tenofovir story begins. Tenofovir is a
long acting
anti-retroviral drug of the reverse transcriptase inhibitor class
that can be given once daily, with fewer side effects than many
older agents.
In a landmark study, scientists discovered that tenofovir given shortly after
exposing monkeys to SIV, a simian virus
similar to HIV, could prevent the
monkeys from becoming infected.[21]
This finding supported the theory that tenofovir could be used as a
post-exposure prophylaxis for humans, and possibly as pre-exposure
prophylaxis
in high risk HIV-negative populations in order to prevent infection.
Substantial experience already exists with anti-retrovirals as post-exposure
prophylaxis. In previous studies, the Centers for Disease
Control and
Prevention (CDC) determined that an older drug zidovudine (AZT) could reduce by
79% the risk of health care worker seroconversion
after an occupational exposure
to HIV, such as a needlestick.[22]
Subsequently, the CDC recommended that health care workers sustaining exposures
should receive prophylaxis with anti-retrovirals.
The CDC monitors health care
workers undergoing post-exposure prophylaxis. Although minor side effects such
as nausea and fatigue
are common, serious or lethal side effects are
not.[23] The regimens in the CDC
study included anti-retroviral cocktails of multiple classes of drugs,
[24] increasing the potential for
side effects above that of a single drug such as tenofovir. Moreover, with
regard to potential side
effects, tenofovir’s safety profile is
significantly more favorable than many of its treatment predecessors. Listed
side effects
for tenofovir include “nausea, vomiting, diarrhea, headache,
asthenia, flatulence, and renal
impairment.”[25] In all but a
few cases, side effects of anti-retrovirals are reversible once the drug is
discontinued,[26] so the likelihood
of permanent study drug-related side effects in this setting is remote.
If
anti-retroviral drugs are effective as post-exposure prophylaxis, could their
use be extended to certain high risk groups in a
pre-exposure setting? Tenofovir
is a good candidate for such a test. It has fewer side effects than other
anti-retrovirals and can
be taken in a once-daily dose. Researchers at the
University of California at San Francisco (UCSF) and the University of New South
Wales (UNSW) proposed to offer “960 HIV-uninfected female sex workers . .
. either 300 mg of tenofovir or placebo daily for
1
year”[27] . The researchers
would then assess, by comparing the two groups, whether tenofovir is effective
as prophylaxis. Potential subjects
would be tested upon enrolment to determine
their HIV status. HIV-positive women would be screened out of the study at the
beginning.
Study participants would then be randomly assigned either to the
tenofovir arm of the study and be given a daily dose of the drug
for the
following year, or to the placebo and be given a daily “sugar pill”.
Neither the womennor the researchers would
know who was receiving tenofovir and
who was receiving the placebo. “At the beginning and once a month during
the trial, study
subjects will receive counseling to reduce risky behavior, free
condoms, and free screening and treatment for sexually transmitted
diseases.”[28] The
experiences of patients receiving tenofovir versus those receving placebo would
be compared to asses safety and side effects.
The United States National
Institute of Allergy and Infectious Diseases (NIAID) and the Bill and Melinda
Gates Foundation funded
the study. The research was to be conducted in
collaboration with the Kingdom of Cambodia Ministry of Health.
Studies of
pre-exposure and post-exposure prophylaxis raise different ethical and medical
questions. Risk of actual HIV exposure
is typically higher in the
post-exposure scenario. The course of post-exposure prophylactic treatment is
relatively short, making
side effects less likely. Moreover, alternatives such
as behavioral change are not available in the post-exposure setting. In
contrast,
in the pre-exposure setting, the course of treatment can be much
longer, with the drug potentially being taken for an indefinite
period. This
increases the risk of side effects. Counseling for behavior change may be an
appropriate alternative in the pre-exposure
setting. Similarly, the possibility
that the pre-exposure prophylaxis might actually increase risky behavior must be
seriously considered.
In the end, whether the individual benefits of
pre-exposure prophylaxis outweigh the individual risks depends critically on the
individual’s level of likely HIV exposure. How high is the
individual’s high risk group?
HIV transmission rates affect individual cost benefit analysis. They also have
important implications for study design. HIV transmission
typically occurs
through the exchange of blood and other bodily fluids during sexual intercourse.
Despite the large numbers affected
worldwide, the transmission risk from a
single sexual encounter is low. The CDC estimates that the transmission rate
for receptive
penile-vaginal intercourse is one transmission per 1,000 acts and
the risk for receptive anal intercourse is slightly higher—five
transmissions per 1,000 acts.[29]
This low sexual transmission rate raises challenges for scientific studies of
preventative measures. With low transmission rates,
studies must examine very
large population groups, examine outcomes over a long period, or focus on high
risk groups in order to
determine statistically whether the proposed
intervention is effective. A study design targeting high risk groups, such as
sex workers,
men who have sex with men or injection drug users is likely to be
less costly and to generate statistically significant results in
a shorter time.
These higher risk categories, however, also correspond to vulnerable social
groups. While the economic and statistical desire to
focus on high risk groups
is understandable, testing the preventative efficacy of tenofovir on a group
like Cambodian sex workers
raises important ethical concerns. What medical
treatment will be provided study participants for possible side effects of the
drug
during and after the study? What will happen to the women screened out at
the beginning who learn for the first time that they are
HIV-positive? What
will happen to the women in either the tenofovir or placebo arm who become
HIV-positive during the course of
the study? Could participation in the study
lead participants to engage in more risky behavior, a particularly important
question
for those in the placebo arm? Can one effectively recruit research
subjects and obtain meaningful informed consent in a vulnerable
population, such
as Cambodian sex workers, where cultural, language, and socio-economic factors
differ so dramatically from those
applying to the people conducting the
research?
II The Social and Political Trials of
Tenofovir
The Cambodian Women’s Network for Unity (WNU) was at the center of the
tenofovir dispute. Understanding the history and mission
of the organization
helps place the tenofovir controversy in perspective. WNU describes itself as a
“grassroots representative
collective of Phnom Penh based Sex Workers.
The network seeks to promote the rights of Sex Workers to earn a living in a
safe environment,
free from exploitation and social
stigma.”[30] The organization
was founded in 2000 and is reported to have approximately 5,000 members.
Notions of individual and group empowerment
are central organizational themes.
While the specter of HIV is ever present in the lives of Cambodian sex workers,
there are dangers
far more immediate, such as daily threats of violence and
abuse from clients, the police and brothel owners.
Groups like WNU are on
the front lines of efforts to improve condom use and introduce safer sexual
practices. As WNU reports, demanding
safer sexual practices begins with
building the individual self esteem of its members:
The network has made significant achievements since its inception in
2000—sex workers have improved their attitudes to healthcare
and
approaches to HIV/AIDS prevention; improved their client negotiation skills;
gained the courage to speak out about their problems;
engaged in information
sharing from workshops on HIV/AIDS and sex worker rights with their friends and
peers. Together they have
achieved solidarity and the collective strength that
comes from one voice. They have an understanding of the value of their lives,
and the importance of HIV/AIDS
prevention.[31]
Preventative measures such as the promotion of condom use have been very
effective in bringing down rates of HIV infection in Cambodia.
[32] The participation of groups like
WNU is central to the success of these efforts.
Exploitation is a daily fact
of life for marginal groups in Cambodia. Trust is difficult to earn and
skepticism is a necessary trait
for survival. When rumors first started
circulating about proposed medical research targeting Cambodian sex workers, the
sex workers
naturally turned to WNU. WNU adopted a proactive role. They
pursued a negotiating position that sought to protect the rights and
dignity of
the sex workers as potential research subjects. WNU’s specific concerns
are outlined in a background statement
issued in conjunction with a March 29,
2004 press conference.[33] These
concerns reflect a sophisticated understanding of international ethical
standards governing medical research in developing
countries.
The WNU
Statement raises three substantive concerns and two procedural objections. The
substantive concerns will be addressed first.
WNU was concerned about (1) the
availability of medical treatment for side effects, both during and after the
study period; (2)
the access to tenofovir as a prophylaxis for sex workers in
the future if the study proved the drug’s efficacy in preventing
HIV
infection; and (3) the danger that the study may encourage higher risk
practices, particularly for those in the placebo control
group. While not
specifically raised in the Statement, a natural concern also existed for the
women who would be screened out of
the study after learning that they are HIV
positive and the women who become HIV positive during the course of the trials.
As of
2004, access to anti-retroviral treatments in Cambodia for those infected
with HIV was minimal to
non-existent.[34]
Most media
attention focused on WNU’s demand for continuing medical coverage for
potential adverse side effects. In the press,
this was often portrayed as a
demand for lifetime insurance, suggesting either the unreasonableness or the
naïveté of
the sex workers. This is not correct. The WNU demand for
long term medical guarantees was limited to study-related side effects.
The Network wants insurance against possible side effects of Tenofovir for 30
years or more and not just health care for the duration
of the trial. When the
researchers are finished and leave Cambodia who will take responsibility for sex
workers and their families
who may be suffering longer term side
effects?”[35]
The WNU demand resonates with ethical standards designed to govern
international clinical research. CIOMS Guideline 19 addressing
the “Right
of injured subjects to treatment and compensation,” provides as
follows:
Investigators should ensure that research subjects who suffer injury as a result
of their participation are entitled to free medical
treatment for such injury
and to such financial or other assistance as would compensate them equitably for
any resultant impairment,
disability or handicap. In the case of death as a
result of their participation, their dependants are entitled to compensation.
Subjects must not be asked to waive the right to
compensation.[36]
The ethical norm is clear: Researchers should be responsible for
study-related side effects.
WNU’s demands for insurance reveal a deeper psychological concern and
underscore a basic breakdown in communication with study
researchers. A demand
for insurance is reflective of underlying conditions of uncertainty. There are
ways to address uncertainty
other than through the provision of insurance, such
as providing credible information regarding the risks of future side effects.
The WNU Statement reflects an incomplete understanding of the actual risk of
side effects. It correctly notes that tenofovir as
pre-exposure prophylaxis has
only been tested in animals and that the drug has not been tested on
HIV-negative humans.[37] Similarly,
the Statement correctly notes the known side effects of the drug, ranging from
“diarrhea, nausea, [and] weakness
to major liver and kidney failure and
‘brittle bone’
disease.”[38] Not
acknowledged, however, is the fact that there is substantial clinical experience
with tenofovir in HIV-positive persons and
with post-exposure prophylaxis. The
likelihood and severity of tenofovir’s side effects are known with some
degree of certainty.
Recognizing this, the researchers likely felt that the chance of long term
side effects was remote and, therefore, that insurance
was not necessary. The
question, however, is how could this sentiment be credibly conveyed to the women
of WNU? In business, sellers
with superior information will often extend
warranties (a form of insurance) to convey their assurances of product safety
and reliability.
In the presence of asymmetric information, sellers who are
unwilling to warrant their goods are rightly met with skepticism. From
this
perspective, the WNU demand for insurance for future side effects actually
functioned as a test of the researchers’ veracity.
WNU asked “If
the researchers are so sure that this drug is safe for HIV-women to take, in the
short and long term, why don’t
they commit to insurance for us and our
families? If we get sick or can’t work it can be the difference between
life and death
for our
families.”[3]
This
reasoning is sound from an economic perspective, but it is also a classic form
of Cambodian logic—reasoning in the form
of a question. If one focuses
only on the question or the demand, one misses the basis of what is often a
persuasive argument.[40] Dismissing
the demand for insurance without providing credible alternative mechanisms to
convey the actual likelihood of future
risks simply added to WNU skepticism and
distrust.
WNU’s second substantive demand was for access to tenofovir after the
study, if the drug proved to be effective at preventing
HIV infection.
If our members agree to take the risk, which may one day benefit people in
richer countries and the drug company, then we deserve
adequate protection to
our future lives and families. The high cost of this drug means that even if it
is successful in preventing
HIV/AIDS, Cambodian sex workers will most likely
never be able to afford it.[41]
Again, this demand resonates with emerging international standards and
expectations. CIOMS Guidelines 10 and 21 seek to ensure that
the benefits of
the research are made reasonably available to the populations supporting
the research efforts. CIOMS Guideline 10 addresses “Research in
populations and communities
with limited resources”.
Before undertaking research in populations or communities with limited
resources, the sponsor and the investigator must make every
effort to ensure
that: (1) the research is responsive to the health needs and the priorities of
the population or community in which
it is to be carried out; and (2) any
intervention or product developed, or knowledge generated, will be made
reasonably available for the benefit of that population
or
community.[42]
Similarly, CIOMS Guideline 21 “Ethical obligations of external sponsors
to provide health care services” states that “external
sponsors are
ethically obligated to ensure the availability of . . . services that are
necessary as part of the commitment of a sponsor
to make a beneficial
intervention or product development as a result of the research reasonably
available to the population or community
concerned.”[43] The
tenofovir researchers did little to respond to WNU’s
demand.
WNU’s third substantive concern dealt with was the effects the
trials might have on inducing high risk behavior. WNU warned
that women
involved in the trial would not know if they are taking the drug or a placebo
and may mistakenly think that condom use
is not necessary. Alternatively, they
might take greater risks with clients in order to increase their income.
We believe that even if the experiment participants are given counseling or
condoms many young women will still believe that they
are safe from HIV
infection as long as they are involved in the experiment. Condom use is our
most effective and cheapest protection
from HIV/AIDS and we are worried women
will stop using them because they think they are protected by the
drug.[44]
The possibility that a prophylaxis could undermine safe sexual practices is a
serious concern and one under express examination in
the tenofovir studies of
gay men planned in San Francisco and
Atlanta.[45] The problem of adverse
behavior change amongst sex workers in Cambodia is even more complicated and the
potential dangers more real.
The women have direct economic incentives to take
risks because payment is often higher for unsafe services, such as intercourse
without a condom. Moreover, WNU members are subject to the demands of pimps,
brothel owners and clients in an environment where
they have limited means of
self protection. The type of education, counseling and oversight provided to
both the tenofovir and the
placebo arms of the study are critical aspects of
ethical study design.[46]
Even
more significant than WNU’s substantive concerns may be the procedural
objections raised by the organization. WNU demanded
(1) the right to
information and (2) that the researchers enter into a series of discussions with
them as a legitimate stakeholder
in the process. “WNU believes that all
sex workers who participate in the trial have the right to ask questions and be
fully
informed about the risks and to demand better medical and financial
protection.”[47] “WNU
plans to continue outreach activities to its members on this issue and have
further meetings, workshops and press conferences
to negotiate protection for
its members’ health and human
rights.”[48]
Information
is critical to any notion of informed consent. Traditional research ethics
envision a dyadic relationship between the
researcher and the research subject.
The research subject is typically viewed as an isolated, autonomous decision
maker. This model
is inadequate when addressing the ethical demands of research
subjects who are vulnerable groups in developing countries. Study
design should
incorporate a broader community education component and aspire to a level of
transparency that will facilitate the
development of trust. In this process,
space must be made at the table for other important stakeholders. In addition
to informed
consent, the ability to credibly convey information, such as the
likelihood and severity of side effects, could have addressed substantive
concerns like the need for long term insurance.
Unfortunately, healthy
communication was lacking in Cambodia. The situation deteriorated even further
as study implementation began.
On June 15, 2004, the WNU held a press
conference objecting to practices researchers were allegedly using to recruit
sex workers
into the study. “A number of sex workers have reported that
when they were approached by recruiters, they refused to provide
the name of the
drug and would say only that it is good for the sex workers and has no side
effects.”[49] “Some sex
workers have been told that the drug will prevent HIV and not being clear and
honest that the drug is experimental
and its effectiveness for HIV prevention
and long-term side effects is not
known.”[50] It is impossible
to verify these claims using outside sources. There is no doubt that given
cultural, linguistic and socio-economic
barriers, obtaining legitimate
“informed consent” in this setting presents a difficult challenge.
It is interesting
to observe, however, how closely WNU’s objections echo
previous complaints by the US Food and Drug Administration against Giliad
Sciences, Inc., the manufacturer of tenofovir. The FDA has warned that Giliad
was making misleading and exaggerated claims regarding
the efficacy of tenofovir
and failing to properly warn patients about side effects in treating
HIV/AIDS.[51] Illustrating
WNU’s sophistication, as well as how much smaller the Internet can make
the world, the FDA warnings were known
by WNU and a copy of the Warning Letter
was posted on their website. At a minimum, statements made during trial
recruitment and
their similarity to misstatements by the drug’s
manufacturer in the United States added to the growing atmosphere of
distrust.
Ethical issues regarding the Cambodian tenofovir trials gained
international attention at the July 2004 International AIDS Conference
in
Bangkok when ACT-UP Paris sprayed fake blood on Giliad posters and complained
about the inadequacy of counseling and safe sex
education being built into the
trials.[52] To the surprise of all,
Prime Minister Hun Sen called an end to the tenofovir trials on August 4,
2004.[53] “Cambodia is not a
trash bin country,” the Prime Minister declared, stating that
“[t]hey should not conduct experiments
with Cambodians. They should do it
with animals.”[54] Towards
the end of the year, the focus shifted from Cambodia to Cameroon, where an
identical study of tenofovir was underway. Similar
ethical questions were
raised, leading to a postponement of the African
trials.[55] Those trials have been
resumed and there is increasing pressure in Cambodia to restart the cancelled
tenofovir study.[56] On March 4,
2005, WNU sent a letter to Prime Minister Hun Sen opposing efforts to restart
the trials.[57] The letter
continued to complain that researchers have not “provided information and
documents related to the trial,”
and asked, regardless of the fate of the
tenofovir study, for the creation of “a community committee to supervise
the ethics
of any clinical trials” that might be conducted in the
future.[58] Whether it is the
trials of tenofovir or some other drug in some other country, the dilemmas of
conducting medical research in developing
countries are here to stay.
III Mediating the Ethics of Third World
Research
A dangerous misconception is that a study that meets the ethical strictures
of the first world will necessarily satisfy the ethical
needs of the third
world. The reality is much more complex. A study protocol obtaining
Institutional Review Board (IRB) approval
in the U.S. or Australia cannot simply
be exported to a country like Cambodia. Substantial differences in economic
resources and
prevailing medical standards between rich and poor countries
create many obvious challenges. Less appreciated, however, is the fact
that
first world IRBs play a very specialized ethical function that is necessarily
predicated upon a network of other social institutions
capable of addressing
ancillary social needs. This permits a complex division of labor, whereby
certain social and medical concerns
can be removed from the purview of
“research ethics”. Comparable institutional networks do not exist
in most developing
countries. Consequently, the ancillary considerations that
can be ignored in developed countries cannot be ignored in developing
countries.
Ethical third world research must therefore address a range of social and
political issues not typically associated with
the “ethics” of first
world medical research. Furthermore, when addressing this broader range of
social concerns, the
very process of ethical review must itself take on more the
characteristics of well functioning political processes, namely transparency,
accountability and legitimacy.
What exactly does this mean? Research in the
first world takes place against a backdrop of robust civic institutions and
elaborate
social systems dedicated to providing citizens comprehensive
therapeutic care. This permits research ethics to perform a highly
specialized
institutional function and to do so in a realm that can legitimately ignore a
range of difficult ancillary social and
political questions. For example,
whether a placebo design research protocol is ethical depends upon its
incorporation of the prevailing
standard of care. In the first world,
determining the standard of care is largely a positive undertaking: what is the
best alternative
treatment a research subject would receive if they were not
part of the study? The constraints determining the best alternative
treatment
in the developed world are largely matters of technology, not economics. When
research is exported from the first to the
third world, however, and when the
prevailing standard of care is lower due to economic rather than medical
constraints, defining
the acceptable standard of care for research unavoidably
takes on normative dimensions. Research ethics in this environment confronts
issues that become increasingly social and political in
nature.[59]
Once this is
acknowledged, many mainstays of traditional medical ethics are called into
question. Is it possible to address disparities
in medical resources between
first and third world standards of care in a responsible way without creating
“undue inducements”?
Similarly, it is well established in the
developed world that researchers have no ethical obligation to treat
non-study-caused medical
problems, but merely refer such persons to existing
clinical resources. This standard is defensible where medical services are
generally
available, but is far more contestable when no alternative treatment
exists because of a lack of medical and financial resources.
Even those who
might continue to defend the absence of an affirmative duty to provide care as
“ethical”, must feel uncomfortable
about such a position in an
HIV/AIDS prophylaxis study where those who become HIV positive during the course
of research have no
realistic access to care and anti-retrovirals. On the other
hand, any effort to provide medical care for non-study-related problems
would
face the first world criticism that such care would be an unethical inducement,
undermining the validity of participant informed
consent. There are no easy
answers, but these tensions highlight the shortcomings and inadequacies of
existing ethical standards.
The trials of tenofovir are illustrative in this
regard. The standard first world ethical position is articulated as
follows:
Mary Fanning, associate director for clinical research at the National Institute
of Allergy and Infectious Diseases, says offering
volunteers 30 to 40 years of
care, as the protest group demands, wouldn’t pass an ethics test because
it is an “undue
inducement.” Incentives “so enormous”
could entice volunteers to enroll in a study regardless of the risks, she
says,
tainting the informed consent process.[60]
The inadequacy of this reasoning is suggested by ethics blogger Stuart Rennie
with a boxing analogy:
In this corner, the sex workers union demanding 30 to 40 years of medical care
for sex workers in the study who acquire HIV. In
that corner, Mary Fanning,
associate director of clinical research at NIAID, countering that offering such
compensation would be
tantamount to undue inducement, would invalidate voluntary
informed consent, and hence would be, um, unethical. In this corner,
ACT‑UP Paris claiming that the $3 offered to prospective participants
already constitutes unethical inducement, and calling
for the immediate
termination of Viread [tenofovir] trials worldwide until participants were
assured of effective HIV prevention
education and resources, and received access
to adequate treatment and care in the event of HIV infection. In that corner,
Ward
Cates of Family Health International (the North Carolina‑based
non‑profit health organization overseeing the Cambodia
and Cameroon
trials) arguing that the human rights of study participants were respected,
because the care being offered to them was
well above the standard of care in
Cambodia. Any reasonable sex worker, it seems, would be better off joining the
trial than plying
her trade outside it (but isn’t that, um, undue
inducement?).[61]
The WNU demands were not radical or irrational. The Union’s demands
reflected recognized standards of international medical
ethics as articulated in
the CIOMS Guidelines. As such, the impasse in Cambodia was not simply a failure
of a team of first world
researchers to take seriously the concerns of a union
of sex workers. The trials of tenofovir illustrate the basic inability of
existing research infrastructures to address a much broader range of
contemporary ethical demands.
Under emerging international standards,
researchers who choose to work in developing countries are called upon to take
on new social
responsibilities. For example, CIOMS Guidelines 10 and 21 require
that future benefits derived from the research be made “reasonably
available” to study
participates.[62] Consistent with
these standards, WNU sought assurances that if tenofovir were proven effective
as an HIV/AIDS prophylaxis, sex workers
in Cambodia would be assured future
access to the drug. While perhaps originally grounded in ethical concerns,
assuring future access
also raises political and economic concerns. In this new
environment, the lines between ethical, social and political responsibilities
start to become blurred. Not surprisingly, therefore, asking even basic
questions about how such ethical commitments are to be operationalized
suggests
how ill equipped traditional IRBs are to address these issues. These are
social, as well as ethical concerns. Properly
addressing these questions will
require new processes that will increasingly take on characteristics that look
more civic than ethical
in nature.
The commentary to CIOMS Guideline 10,
which deals with how the benefits of research are to be made reasonably
available to the study community, is revealing in this regard.
When an investigational intervention has important potential for health care in
the host country, the negotiation that the sponsor should undertake to
determine the practical implications of “responsiveness,” as well as
the “reasonable
availability,” should include representatives of
stakeholders in the host country; these include the national government, the
health ministry, local health authorities, and concerned scientific and ethics
groups,
as well as representatives of the communities for which subjects are
drawn and non-governmental organizations such as health advocacy
groups.[63]
The lesson is clear. New institutional processes are necessary to work in
conjunction with traditional ethical review boards to implement
these
responsibilities. These processes must be undertaken in a manner that openly
acknowledges and accommodates their social and
political dimensions.
Until
more formal institutions are developed, it is natural to think of mediation as a
framework to address these questions. It is
also clear, however, that mediation
will face a number of difficult challenges. Mediation is a process-oriented
solution. This
stands in sharp contrast to the substantively proscriptive
nature of traditional ethical review. Identifying legitimate mediation
partners, who can speak for the study subjects, and defining the rights and
entitlements of the disparate stakeholders will be problematic.
Beyond
providing informed consent and agreeing to comply with the study protocol,
research subjects are not traditionally viewed
as “stakeholders” in
the research process. Mediation will be more complicated, contentious and
participatory than traditional
ethical research review and approval. This can
be difficult and unpredictable. Those who think that time and money will be
saved
by exporting research to the third world need to think again, at least if
they are committed to conducting research in a responsible
manner.
If
mediation is to be successful, there are a number of prerequisites. To begin
with, the relevant stakeholders must be identified
and engaged. Participants in
the process have to approach the exercise in good faith. Norms of healthy
communication, mutual respect
and full disclosure of information need to be
encouraged. True understanding will require a willingness of participants to
sympathetically
engage the concerns of other stakeholders. Furthermore,
mediating the more expressly social dimensions of third world research will
require processes that serve more political and not scientific functions. To be
effective, these mechanisms need to be modeled in
accordance with the standards
of well functioning civic institutions. Is the system open? Is the system
accountable? Is the system
legitimate?
Judged by these standards, the
failings of the Cambodian tenofovir trials become evident. The challenges were
to prevent the exploitation
of a vulnerable social group, to make adequate
assurances for the medical treatment of study-related side effects, and to
ensure
future access to any treatment proven efficacious in the study.
Addressing these concerns called for an effective mediation exercise.
The CIOMS
speaks of the need to include a wide range of stakeholders in these
deliberations, including groups like
WNU.[64] This is particularly true
when the research subjects are vulnerable groups who are likely to be
disenfranchised from existing political
processes.[65] Even in developed
countries with strong traditions of representative democracy, there is little
reason to have faith that government
ministries can effectively represent the
interests of socially marginal groups like sex workers, gay men and IV drug
users.
It is impossible to appreciate fully from second hand press reports
why the impasse between the researchers and the WNU could not
be resolved. We
can only offer some educated guesses. The researchers appeared to treat their
mandate as a fait accompli and to
view their previous IRB approval as a basis
for not having to reexamine the ethical and social concerns raised by WNU. This
mind
set is probably representative of most medical researchers. IRB review in
developed countries is a rigorous process. In the minds
of the researchers, all
of the important ethical questions had already been resolved. From this
perspective, WNU was viewed as a
potential public relations problem that had to
be managed, but not as a group that had to be seriously engaged. This posture,
however,
fails to appreciate that there are important social and political
dimensions to third world medical research that must be negotiated
and resolved
in the country where the research is to take place, not in the country of
funding sponsorship. From this standpoint,
the impasse leading to the
cancellation of the study was nearly unavoidable. No mediation can be
successful when one of the central
stakeholders fails to acknowledge that there
is anything that requires discussion and resolution.
Reflective of this
denial was the failure of researchers to be forthcoming with information. The
limited access to information is
troubling even from the perspective of
traditional informed consent. Informed consent presupposes the disclosure of
appropriate
information. Whether one is dealing with WNU as a group, or its
individual members, prospective study participants have the right
to ask
fundamental questions about the study and to be given access to relevant
information. This was not done in Cambodia. We
believe it is fair for research
subjects to ask for and be provided copies of the study protocol. We also
believe that it is fair
to ask for and receive copies of minutes of IRB meetings
or summaries of IRB discussions that purportedly addressed and resolved
“ethical” issues relating to the study. This level of transparency
will make the first world IRB process more accountable
as a civic institution,
as well as provide the information needed to facilitate truly informed consent.
Information and transparency
are also essential for building the cooperation and
trust necessary for successful mediation.
Groups like WNU cannot and should
not be ignored. As the WHO recognizes in its “3 by 5” initiative,
if progress is to
be made in the war against AIDS, more, not less involvement of
civil organizations will be required.
[66] Civil organizations need to be able
to advocate for vulnerable populations from which they draw their members, even
if such advocacy
challenges traditional ethical constructs and regulatory
processes. WNU is not the first civic organization to challenge traditional
research regimes. In the United States, organizations like ACT UP were
responsible for accelerating the pace of change in AIDS
research.[67] Researchers should
view WNU’s participation as a stimulus that could help redefine
considerations for ethical third world
research, rather than as an impediment to
study recruitment. In the future, this strategy would necessitate involving
civil organizations
like WNU at the early planning stages of the research. In
accordance with CIOMS Guidelines, these groups should be engaged in discussions
as to what type of care should be provided during the study and on what care is
necessary on an ongoing basis to address study-related
side effects. The end
result would be to create allies rather than adversaries.
The goals of HIV
researchers, sex workers and health care providers are the same. There is a
collective need to take pragmatic steps
to curtail the spread of the virus and
to provide effective, compassionate medical care to those already infected with
the disease.
What happened to the tenofovir trials in Cambodia is regrettable.
At the same time, the conflict helps focus much-needed attention
on the
political and social demands of third world research, demands that traditional
research ethics and IRBs are ill equipped to
address. It is not possible to
know whether a mediation framework could have overcome the problems that led to
the cancellation
of the Cambodian research. The cancellation of the Cambodian
study, however, suggests that future researchers must more effectively
engage
groups like WNU if important HIV/AIDS research is to succeed.
[*] Peter Hammer, J.D., Ph.D., is a Professor
of Law at Wayne State University Law School. Tammy Lundstrom, J.D., M.D., is
Vice President,
Chief Quality and Safety Officer, Detroit Medical Center, and
Assistant Professor, Department of Medicine, Division of Infectious
Diseases,
Wayne State University. Professor Hammer has spent more than a decade working
on Cambodian law and development matters.
Doctor Lundstrom has spent a good
part of her career treating poor and medically underserved HIV/AIDS patients in
the Detroit community.
[1] Marilyn Chase
& Gautam Naik, Key AIDS Study in Cambodia Now in Jeopardy, WALL ST.
J., Aug. 12, 2004, at B1.
[2] John S.
James, Cambodia Stops Important Tenofovir Prevention Trial, AIDS
TREATMENT NEWS, July 23, 2004, at 4.
[3]
Corinne Purtill & Yun Samean, Hun Sen: Don’t Test Drugs on
Cambodians, CAMBODIA DAILY, Aug. 4, 2004, at
1.
[4] Jon Cohen, Cambodian Leader
Throws Novel Prevention Trial into Limbo, 305 SCIENCE 1092 (2004).
[5] The World Health Organization
(WHO) notes that although “more than 30 candidate HIV vaccines” are
in the pipeline, none
is expected to be available for use in the immediate
future. WORLD HEALTH ORG. [WHO], THE WORLD HEALTH REPORT 2004: CHANGING
HISTORY,
at xvi (2004) [hereinafter WHO, WORLD HEALTH REPORT], available
at http://www.who.int/whr/2004/en/report04_en.pdf.
[6] For a discussion of the
importance of intermediate preventative measure, see Project Inform,
The World’s Most Important AIDS Research?, PROJECT INFORM PERSP.,
Nov. 2004, http://www.thebody.com/pinf/nov04/research.html.
[7] WHO, WORLD HEALTH REPORT,
supra note 5, at xi.
[8] Id.
[9] Id.
[10] Id.
[11] Id. at 9.
[12] Id. at xv.
[13] Id. at 3.
[14] Id. at xv.
[15] Id. at 13.
[16] Id. at 12. See
also Jon Cohen, Thailand & Cambodia: Two Hard Hit Countries Offer
Rare Success Stories, 301 SCIENCE 1658 (2003).
[17] Cohen, supra note 16,
at 1659.
[18] Sheila Davey, Sex and
Drugs Fuel Simmering AIDS Crisis in Asia and Pacific, 79 BULL. WORLD HEALTH
ORG. 1000 (2001).
[19] WHO, WORLD HEALTH REPORT,
supra note 5, at 77.
[20] Id.
[21] Roberta J. Black, Animal
Studies of Prophylaxis, AM. J. MED., May 19, 1997, at 39. See also
Che-Chung Tsai et al., Effectiveness of Postinoculaiton
(R)-9-(2-Phosphonylmethoxypropyl) Adenine Treatment for Prevention of Persistent
Simian Immunodeficiency
Virus Infection Depends Critically on Timing of
Initiation and Duration of Treatment, 72 J. VIROLOGY 4265 (1998).
[22] Denise Cardo et al., A
Case-Control Study of HIV Seroconversion in Health Care Workers After
Percutaneous Exposure, 337 NEW ENG. J. MED. 1485 (1997).
[23] Ctrs. for Disease Control
& Prevention, U.S. Dep’t of Health & Human Servs.,
Anti-retroviral Postexposure Prophylaxis After Sexual, Injection-Drug Use, or
Other Nonoccupaitonal Exposure to HIV in the United
States: Recommendations from
the U.S. Department of Health and Human Services, 54 MORBIDITY &
MORTALITY WKLY. REP. 1, 4 (2005) [hereinafter CDC, Postexposure Prophylaxis
Report].
[24] Id.
[25] Id. at 10.
[26] Id. at 4.
[27] Khabir Ahmad, Trial of
Anti-retroviral for HIV Prevention on Hold, 4 LANCET INFECTIOUS DISEASES
597, 597 (2004).
[28] AIDS Prevention: Study
Will Test Anti-retroviral Drug Tenofovir to Prevent HIV Infection, DRUG WK.,
Oct. 10, 2003, at 9.
[29] CDC, Postexposure
Prophylaxis Report, supra note 23, at 7.
[30] This background information
is taken from the organization’s website. Women’s Network for Unity
Home Page, http://www.womynsagenda.org/Program/SWs/SWNU.html
(last visited Oct.
7, 2005).
[31] Id.
[32] For a discussion of
Cambodia’s success in improving safe sex practices and reducing HIV
transmission amongst sex workers, see supra notes 15-17 and accompanying
text.
[33] Women’s Network for
Unity, Background to WNU Press Conference on Tenofovir Trials in Cambodia on
March 29, 2004, http://www.womynsagenda.org/Program/SWs/WNU/wnu29mar04.pdf
[hereinafter WNU Background Statement].
[34] Hopefully, HIV therapies
will be more widely available in the future. See WHO, “3 BY 5"
PROGRESS REPORT 19 (2004), available at
http://www.who.int/3by5/ProgressReportfinal.pdf (discussing efforts to increase
availability of avtiretroviral treatments in Cambodia).
[35] WNU Background Statement,
supra note 33.
[36] See COUNCIL FOR
INT’L ORGS. OF MED. SCIS., INTERNATIONAL ETHICAL GUIDELINES FOR BIOMEDICAL
RESEARCH INVOLVING HUMAN SUBJECTS, Guideline
19 (2002) [hereinafter CIOMS,
GUIDELINES], available at
http://www.cioms.ch/frame_guidelines_nov_2002.htm. See also World Med.
Ass’n [WMA], World Medical Association Declaration of Helsinki, Ethical
Principles for Medical Research Involving Human Subjects, princ. 29 (2004)
[hereinafter WMA, Declaration of Helsinki], available at
http://www.wma.net/e/policy/pdf/17c.pdf.
[37] WNU Background Statement, supra
note 33.
[38] Id.
39 Id. (quoting Kao Tha, President of Women’s Network
for Unity).
[40] A similar example of
Cambodian logic can be found in the Press Release accompanying WNU’s June
15, 2004 Press Conference: “If
they are so sure this drug is safe, why
don’t they send their own sisters and daughters to test it? They have a
lot more money
than sex workers and have protection if the drug makes them sick.
Also, if it was their sisters or daughters, they would be a lot
more honest
about the risks and side effects.” Press Release, Women’s Network
for Unity, Women’s Network for Unity
Protests Drug Trial Recruitment
Tactics (June 21, 2004),
http://www.womynsagenda.org/Program/SWs/WNU/wnu21june04.pdf [hereinafter
June
21st Press Release].
[41] WNU Background Statement,
supra note 33.
[42] CIOMS, GUIDELINES,
supra note 36, Guideline 10 (emphasis added). See also WMA,
Declaration of Helsinki, supra note 36, princ. 30 (“At the
conclusion of the study, every patient entered into the study should be assured
of access to the
best proven prophylactic, diagnostic and therapeutic methods
identified by the study.”); Christine Grady, The Challenge of Assuring
Continued Post-Trial Access to Beneficial Treatment, 5 YALE J. HEALTH
POL’Y L. & ETHICS 425 (2005).
[43] CIOMS, GUIDELINES,
supra note 36, Guideline 21 (emphasis added).
[44] WNU Background Statement,
supra note 33.
[45] Sabin Russell, Antiviral
Drug Used to Treat AIDS to be Tested as Vaccine, S.F. CHRON., Dec. 1, 2004,
at A9. In studies performed in the Untied States and Brazil among homosexual
men, the availability of
post-exposure prophylaxis did not appear to increase
sexual risk-taking behaviors. See CDC, Postexposure Prophylaxis
Report, supra note 23, at 4.
[46] A substantive concern not
raised by WNU but deserving consideration is the possible promulgation of
tenofovir resistance in those
sex workers receiving the drug who go on to become
HIV-positive. Resistance to most anti-retrovirals occurs rapidly if used as
single
drugs therapy in treating known positive patients. If widespread
tenofovir resistance developed it would undermine the drug’s
use both as a
prophylaxis and as a therapeutic treatment. It is true that utilizing a single
drug therapy for prophylaxis would
leave other classes of HIV drugs available
for treatment of study participants who developed tenofovir-resistant HIV
infection.
This assumes, however, that these women would be lucky enough to
have access to therapeutic treatment in the first place.
[47] WNU Background Statement,
supra note 33.
[48] Id.
[49] June 21st Press Release,
supra note 40.
[50] Id.
[51] Warning Letter from Thomas
W. Abrams, Dir., Div. of Drug Mktg., Adver. & Commc’ns, U.S.
Dep’t of Health & Human
Servs., to John C. Martin, President &
Chief Executive Officer, Gilead Scis., Inc. (July 29, 2003), available at
http://www.womynsagenda.org/Program/SWs/WNU/fda29july03.pdf.
[52] James, supra note 2,
at 4.
[53] Purtill & Samean,
supra note 3, at 1.
[54] Id.
[55] U.N. Integrated Reg’l
Info. Networks, Cameroon: Clinical Trials of Anti-HIV Drug on Sex Workers in
Question, INTEGRATED REGIONAL INFO. NETWORKS, Jan. 27, 2005; see also
U.N. Integrated Reg’l Info. Networks, Cameroon: Government Suspends
Trial of AIDS Drug, INTEGRATED REGIONAL INFO. NETWORKS, Feb. 4, 2005.
[56] Allen Myers, Cambodia:
Sex Workers Fight Proposed Drug Trial, GREEN LEFT WKLY., Mar. 23, 2005,
http://www.greenleft.org.au/back/2005/620/620p18.htm (“The Cambodian
government is under
pressure to allow a controversial trial of the
anti‑HIV drug tenofovir.”).
[57] See Letter from Kao
Tha et al., Secretariat of Women’s Network for Unity, to Samdech Hun Sen,
Prime Minister, Cambodia (Mar. 4,
2005), available at
http://archives.healthdev.net/sex‑work/msg00556.html.
[58] Id.
[59] The commentary on Guideline
11: Choice of Controls in Clinical Trials of the INTERNATIONAL ETHICAL
GUIDELINES FOR BIOMEDICAL RESEARCH
INVOLVING HUMAN SUBJECTS provides a window
into these contentious issues. See CIOMS, GUIDELINES, supra note
36, Guideline 11 cmt.
[60] Chase & Naik, supra note 1,
at B1. As should be clear from the earlier discussion, WNU was not demanding
30–40 years of free medical care, but
simply assurances of long term
post-study treatment of study induced side
effects.
[61] Posting of Stuart Rennie to
The Gilead Saga, American Journal of Bioethics Editors Blog,
http://blog.bioethics.net/2005/02/gilead‑saga.html
(Feb. 18,
2005).
[62] CIOMS, GUIDELINES,
supra note 36, Guidelines 10, 21.
[63] Id. Guideline 10 cmt.
(emphasis added).
[64] Id.
[65] It was not enough for the researchers
to work collaboratively with the Cambodian Ministry of Health. Cambodia is at
best a fledgling
democracy, whose government institutions face daily struggles
with corruption. See, e.g., Rotten at the Core: Graft is Slowing
Cambodia’s Return to Better Health, ECONOMIST, Feb. 17, 2005; World
Bank Warns Corruption Could Threaten Cambodian Economy, THAI PRESS REPS.,
Feb. 16, 2005 (“World Bank President James Wolfensohn says the three
greatest obstacles to Cambodia's growth
are ‘corruption, corruption,
corruption.’”). As is true in many developing countries, the
healthiest and most
proactive forms of civic society are often found in the
non-governmental organization (NGO) community.
[66] WHO, WORLD HEALTH REPORT,
supra note 5, at 26. The “3 by 5” initiative is a
multidisciplinary partnership, the goal of which is to provide needed HIV
treatment to 3 million HIV-infected individuals in the developing world by the
end of 2005. Id. at xii. The program acknowledges that
“[p]olitical commitment and national ownership of programmes are
essential.” Id. at xiii. The program emphasizes the role that
“associations of people living with HIV/AIDS and their advocates,
faith-based
organizations, and other groups such as trade unions” play in
HIV/AIDS treatment and prevention strategies in developing countries,
and
welcomes their participation. Id. at 43.
[67] The WORLD HEALTH REPORT
states that “[g]roups such as the AIDS Coalition to Unleash Power (ACT
UP), formed in the USA in 1987,
combined a successful advocacy strategy with the
building of a formidable scientific knowledge base, which enabled members to
become
informed participants in medical research and the policy-making process.
During the 1980s and 1990s, these groups won increased
funding for antiviral
drug research, increased AIDS services budgets at federal, state and local
levels, an accelerated testing process
for drugs, and expanded access to
experimental drugs for people not accepted into clinical trials.”
Id. at 46.
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