AIDS Trial: What lessons to be learned from Cambodian trial fiasco

[Guest guest]

[Moderators Comment: In the context of the Genetic Engineering Approval

Committee (GEAC) of the Union Environment and Forests Ministry on Wednesday

approved phase-I of the clinical trial of a new preventive recombinant AIDS

vaccine, Modified Vaccina Ankara (MVA) or TBC-M4, it may be of interst to find

out what Lessons to be

learnt from the Cambodian Tenofovir trial controversy]

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The Cambodian Tenofovir Trial Controversy: Lessons to be learnt

Joe

Solidarity +. Volume 1 Issue No. 1. May 2005. Bi-Monthly Newsletter of the Asia

Pacific People's Alliance for Combating HIV/AIDS (APPACHA)

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 receivingTenofovir 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

thereis 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 blasé 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 ational 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 approvalof 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.

AIDS_ASIA/message/278

(Accessed on 17 March 2005)

Jack, 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, 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: EthicalIssues in AIDS

Vaccines. Science Magazine January 9, 1998, Volume 279, Number 5348.American

Association for the Advancement of Science.

______________________________

Views are of the author:

Dr. Joe 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

AIDS_ASIA/files/Solidarity%20%