The Cambodian Tenofovir Trial Controversy: Lessons to be learnt

Joe Thomas

Solidarity + Volume 1 Issue No. 1. May 2005. Bi-Monthly Newsletter
of the Asia Pacific People's Alliance for Combating HIV/AIDS
(APPACHA)http://health.groups.yahoo.com/group/AIDS_ASIA/files/Solidarity%20%2B/


This article will examine some of the political and ethical issues of clinical
drug trials using the NRTI (nucleotide reverse transcriptase inhibitor) drug,
Tenofovir DF, which was licensed to treat HIV-1 infection by the Department of
Food and Drug Administration (FDA), United States in October 2001 (Clinical
Trials Gov 2005).

Since some scientists believed that Tenofovir also could serve as a pre exposure
prophylaxis for HIV infection, a research project was initiated by the
researchers from the University of California, San
Francisco (UCSF) and the University of New South Wales, Sydney in order to prove
this hypothesis. They selected Cambodia as a potential site for this clinical
experimentation and sex workers in Cambodia as the potential clinical trial
participants.

The Ethics Review Committees (ERC) of the University of California, San
Francisco in the United States of America and the University of New South Wales
in Sydney, Australia, endorsed the trial as it complied with the global
standards of ethics of clinical trails.

However, under intense pressure from the representatives of the sex workers in
Cambodia and the advocates for ethical trials on vulnerable populations, the
Cambodian government withdrew support to these clinical trials, clarifying that
the trial protocol did not adequately address ethical concerns.

Likewise, similar studies planned by other researchers in Thailand and Cameroon
came under intense pressure from the potential trial participants for better
compliance with ethical standards. Community
groups from Thailand staged agitations to protect the interests of
clinical trial participants in Thailand and pressed for modifications to the
protocol of the clinical trial proposed to be conducted there. (Jack, A and
Kazmin, A. 2005)

This clinical trial raises several issues related to the ethics and politics of
international research involving researchers from the resource-rich countries,
initiating and implementing research in resource-scarce settings and in
selecting vulnerable populations as
their potential clinical trial participants. In this context, this
brief commentary examines the following issues of the proposed clinical trial in
Cambodia.

• The nature of informed consent

• The interpretation of the 'risk and benefit' of participating in
the trial
• The options for treatment after the trial, in the event of any long-term
after-effects arising from the trial itself

• The extent to which the researchers were willing to disclose the
risk associated with the study

• The methods adopted by the researchers to assess the risks and
benefits of trial participants expected to participate in clinical trials.

The role of multi-centric ethics review committees and the scope of
community-based ethics review committees also came under the spotlight as part
of this controversy.

This article is based on extensive reviews of literature, interviews
with the activists, sex workers and their representatives in Cambodia, and
summarises some of the lessons to be learnt from the
controversy.

Obligations and responsibilities of the researchers

This controversy provided an opportunity to revisit the issue of
the 'obligations and responsibilities' of the international clinical
researchers. Researchers must not use an approval of an International research
protocol (a research protocol approved by a home country ERC, to conduct a
clinical trial in another country) by an ERC from the researcher's home
institutions as an excuse to minimise their responsibilities towards the
participants of the research.

In some instances, the 'obligations and responsibilities' of the international
clinical researchers are legal obligations. For instance, the legal obligations
and responsibilities of US based
researchers are listed under the Code of Federal Regulations (CFR)
(Title 45. Public Welfare) of the Department of Health and Human Services,
Office for Protection from Research Risks. They are meant to ensure compliance
with regard to research conducted, supported, or otherwise subject to regulation
by the Federal Government outside the United States.

The researchers also have obligations to apply rigorous scientific analysis and
methods in all aspect of the clinical trial. It appears that in the context of
the proposed 'Tenofovir trial' in Cambodia, the researchers' commitment to
scientific rigour was restricted only to the research aspect of the trials.
There was no indication that they were even aware of the need for careful
analysis of the risk and benefit of the trial from a participant's perspective,
or that they owed a greater commitment to the welfare, rights, beliefs and
customs of the communities under study. A far more rigorous and scientific
analysis was essential to understand the risk associated with the participation
of vulnerable populations in clinical trials in Cambodia. A greater measure of
pragmatic efforts was also essential to demonstrate the 'principal of
beneficence' when such research is carried out.

In this case, even as the researcher claimed that Tenofovir had 'minimal
toxicity' (Shafer, 2004), the product information provided by the US Department
of Health and Human Services revealed
quite the contrary: 'Adverse events reported in patients receiving
Tenofovir DF included abdominal pain, anorexia, asthenia, diarrhoea, dizziness,
dyspnea, flatulence, headache, hypophosphatemia, lactic acidosis, nausea,
pancreatitis, renal impairment, rash, and vomiting'.

In yet another instance of research aberration, the principal investigators of
the Cambodian trial turned out to be non-clinical epidemiologists, in violation
of regulations that stipulate that only experienced and qualified clinicians are
competent to undertake research in complex anti-retroviral (ARV) regimes.


The researchers claimed that the rationale behind their selection of
Cambodia as a clinical trial site had to do with 'altruistic intentions', in
response to the high prevalence of HIV disease in the country. However, the real
motivations for the selection of Cambodia may well be less altruistic than
opportunistic, since there
is clearly a higher statistical probability of proving the research
hypothesis in a higher rather than lower HIV prevalence setting.


Informed consent is an ongoing dialogue

Informed consent has increasingly been interpreted as 'an ongoing
process of dialogue' between the researcher and the research participants (CFR
45). Compliance with 'informed consent' is also a
legal requirement (45 CFR 46.116) for US based researchers. The
documentation of informed consent must comply with 45 CFR 46.117.

According to the 'Code of Federal Regulations' of the United States
of America, informed consent is a process, not just a form. Information must be
presented to enable persons to voluntarily
decide whether to participate as a research subject. It is a
fundamental mechanism to ensure 'respect for persons' through
the provision of thoughtful consent for a voluntary act. The
procedures to be used in obtaining informed consent should be
designed to educate the subject population, in terms that they can
understand. Therefore, informed consent language and its
documentation (especially explanation of the study's purpose,
duration, experimental procedures, alternatives, risks, and
benefits) must be written in 'lay language', (i.e. understandable
to the people being asked to participate). The written presentation
of information is used to document the basis for consent and for the
subjects' future reference. The consent document should be revised
when deficiencies are noted or when additional information will
improve the consent process' (CFR 45).


It was evident from the field observations, that the principal
researchers of the proposed trial in Cambodia had demonstrated a
blasι attitude towards facilitating the process of 'informed
consent' among the potential trial participants. For instance, none
of the 'informants' interviewed for this article had ever even seen
a copy of the informed consent form.

The limitations of the mechanisms for the review of ethics of
clinical trials

This controversy brought to attention the need to strengthen local
ERC systems and the question of the effectiveness of transnational
ethics review mechanisms.


One of the key issues overlooked by the researchers of the proposed
Cambodian clinical trial was the need to consolidate local ethics
review systems, including the creation of the community-based ethics
review committees, as part of their extended responsibility. While
researchers may argue that such responsibilities go beyond the
immediate scope of their proposed research, the fact remains that
resources have to be allocated for the strengthening of local ethics
review systems as part of any complex clinical research project.

The research protocol for the Tenofovir trial had previously been
approved by ethics review committees of two prominent Universities,
comprising experts on ethics issues. Nevertheless and ironically
enough — serious lapses in ethical compliance were detected by a
group of impoverished sex workers in Cambodia. Despite their obvious
lack of training in analysing the ethical complexities of clinical
trials, they raised core questions of ethics of clinical trials and
the responsibilities of the researchers.

Thus, this controversy also exposed certain inherent limitations of
the international ethics review procedures, seen as characteristically high on
rhetoric but notoriously low in commitment to enforcing the ethical principles
that they preached.

The Tenofovir trial controversy is a warning note for the community
groups that the approval of a trial by an ERC associated with high-
profile institutions is not essentially a guarantee for an ethically
sound research. In addition, this is a reminder to the ERCs
approving such trials of the need to be more vigilant in their
responsibilities.

Methods of assessing risk and benefits of clinical trials

When the principal investigator of a research study claims that the
trial involves 'little risk' for the participants, he/she is not
only expected to be candid and precise about the nature and extent
of the risk, but also owes the participants an explanation as to how
this risk (including possible long-term repercussions) was
calculated.

Apropos the Tenofovir trial, Cambodian sex workers and their
representatives had themselves identified several categories of
risks (AIDS_ASIA E-Forum 2005). Furthermore, the methods and tools
used for assessing the risk and benefit also need to be disclosed as
part of the description or validation of the research methods.
However, based on the available documentation, the researchers did
not demonstrate the use of rigorous scientific methods of assessing
risk and benefits of clinical trials as applied to their proposed
trial.

Negotiating for minimum standards of 'Duty of Care'

Researchers are bound by the principle of 'duty of care', which
ensures that their decisions and actions do not harm the short and
long-term well-being of people and resources. According to UNAIDS
Guidance for HIV Vaccine Trials (2000), care and treatment for
HIV/AIDS and its associated complications are mandatory for
participants in HIV preventive vaccine trials, as is the 'minimum'
requirement of adhering to the highest standards of health care
achievable in the host country.

The process of negotiating for a comprehensive care package should
be agreed upon through a host/community/sponsor dialogue, which
reaches a consensus prior to the initiation of a trial (UNAIDS
2000). Researchers need to acknowledge the right of the trial
participants to negotiate for 'minimum standards' of care (which, in
turn, will be fixed after a systematic assessment of the risk and
benefits) both during and after the trial. However, it appears that
the potential Cambodian trial participants, efforts for
negotiating for a higher standard of 'duty of care' was ridiculed by
the researchers.

Health Equity: The criteria for prioritising clinical trial research
questions

Adequacy of research must also be justified on principles of justice
and equity. In a country like Cambodia, where vast health inequities
exist, researchers who carry out projects that may not produce
immediate benefits for the 'researched' community, have an
additional obligation to maximise the benefits and
reduce the risk associated with these trials, while assisting in the
development or facilitation of a strategic clinical research agenda.
Considering the high HIV disease burden prevalent in Cambodia, it is
imperative that an HIV clinical research must contribute towards
health equity benefits that are immediate.

Conclusion

In 1997, UNAIDS convened an 'expert group' to identify ethical
issues in AIDS vaccine trials (UNAIDS 1997). This group recognised
that 'thoughtful people of goodwill' can disagree on
ethical interpretations of the guidelines and that most of the
current guidelines will be applicable in their present form to the
ethical questions of AIDS vaccine research (Bloom 1998). Further
guidelines were proposed by UNAIDS in 2000 with specific emphasis
on the 'duty of care' (UNAIDS 2000).

By way of a response to the present controversy, a process of
further consultation, albeit less transparent and less participatory
in nature, has been initiated with the aim of developing a further
consensus on these issues. It is appropriate and timely that the
UNAIDS responded to the call to mediate to break the impasse.

However, at the same time, mediators should take care not to convey
the impression that they are trying to 'clean up the mess' created
by inconsiderate researchers. Considering the gravity of the ethical
dilemmas posed by the Tenofovir trial controversy, the mediatory
efforts undertaken by UNAIDS must be guided by the
deliberations of its own ethics review committees. It follows that
more concerted efforts are crucial both to create awareness of and
adherence to national standards as also to revise them at regular
intervals, based on prevailing local and international standards.

The case of the Tenofovir trials has also forced us to ask the
critical question of whether ethical guidelines should remain mere
guidelines or be made mandatory as legal obligations as well.

In conclusion, this controversy has sounded a clarion call for
heightened community vigilance with regard to the ethical aspects of
clinical trials, since it has become apparent that the mere approval
of a trial by an ERC is not in itself a sufficient promise of a
sensitive and ethically reliable study.

References

AIDS_ASIA E-Forum. (2005) Unethical Tenofovir trial: Cambodian sex
workers' Concern. Message 278.
http://health.groups.yahoo.com/group/AIDS_ASIA/message/278
(Accessed on 17 March 2005)

Jack, Andrew and Amy Kazmin (2005) Thai Aids campaigners question
new clinical trials. Financial Times. 12 March 2005 (Accessed on 12
March 2005) http://news.ft.com/cms/s/0bcd9024-929b-11d9- bca5-
00000e2511c8.html

Shafer, Kimberly Page (2004) Use of ARV in prevention of HIV
infection in high-risk populations. Women & HIV Research Directions,
International AIDS Conference, Bangkok, Thailand 2004.

UNAIDS (1997). Ethical Considerations in Clinical Trials of
Preventive HIV Vaccines. Proceedings of meeting held from 23 24
September 1997 (UNAIDS, Geneva, Switzerland, 1997).

UNAIDS (2000) Vaccine Research, UNAIDS Guidance Document. UNAIDS,
Geneva, Switzerland, 2000.

Code of Federal Regulations. Title 45. Public Welfare. Department Of
Health And Human Services, National Institutes of Health, Office For
Protection From Research Risks. Part 46. Protection Of Human
Subjects. Revised, November 13, 2001, Effective December 13, 2001.

www.ClinicalTrials.gov. Daily Tenofovir DF to Prevent HIV Infection
among Sex Workers in Cambodia.
http://www.clinicaltrials.gov/ct/show/NCT00078182 (Accessed on 12
March 2005)

http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.114 th
(Accessed on 9 March 2005)

Bloom, Barry R. (1998) The Highest Attainable Standard: Ethical
Issues in AIDS Vaccines. Science Magazine January 9, 1998, Volume
279, Number 5348.American Association for the Advancement of Science.
______________________________

Dr. Joe Thomas is associated with APPACHA
(joe_thomas123@...)

Solidarity + Volume 1 Issue No. 1. May 2005
Bi-Monthly Newsletter of the Asia Pacific People's Alliance for
Combating HIV/AIDS

http://health.groups.yahoo.com/group/AIDS_ASIA/files/Solidarity%20%