Lessons from the recently halted microbicide trial in India

[Guest guest]

Lessons from the recently halted microbicide trial in India

Suneeta Krishnan1

Indian Journal of Medical Ethics. July-Sept 2007(3)

In January 2007, two Phase III clinical trials of a candidate

microbicide among women at high risk of HIV in India, South Africa,

Benin, Uganda, and Nigeria were halted. This was done because

analyses of preliminary data by the Independent Data Monitoring

Committee indicated that the product was associated with an increased

risk of acquiring HIV (1,2). The planning, implementation, and

subsequent cessation of these trials illustrate the mechanisms for

protecting participants in microbicide trials in developing

countries. The closure of the trials highlights the complexities of

such decisions and the range of competencies that research teams must

possess.

Microbicides are products that women can use to prevent sexually

transmitted infections, including HIV. They can be produced in the

form of gels, creams, or suppositories. Advocacy related to the

development of microbicides is driven by the hope that these products

will not only increase the number of HIV prevention options that are

available to women, but also address the particular needs of women

who are unable to negotiate the use of condoms with their male

partners.

The microbicide being tested in the aforementioned trials was

Ushercell, a gel containing cellulose sulfate (CS), a product that 11

prior safety and contraceptive trials in India, Africa, and the

United States had indicated was safe for human use (1,3). The CS

trials were launched just a few years after a trial of Nonoxynol-9 (N-

9), a spermicide that was hypothesised to be an effective

microbicide, was stopped. The N-9 trial was halted when researchers

observed an increased risk of HIV and concluded that the gel caused

vaginal lesions that facilitated the acquisition of HIV (4).

Research on N-9 has contributed to a focus on evaluating the safety

of microbicides. Indicators and markers of toxicity that are now

routinely examined include signs and symptoms of genital irritation,

changes in vaginal microflora, and the presence of inflammatory

markers like cytokines. In the case of CS, there was no evidence of

toxicity in the safety trials (3). A full analysis of the CS trial

data, including an examination of other known factors that may

explain the higher rate of seroconversion among CS users such as

frequency of anal sex, condom use, and incidence of other sexually

transmitted infections, will hopefully shed light on these unexpected

results. The results also highlight that further research on

indicators and predictors of harm is critical (5).

The standard of care offered to participants in clinical trials in

developing countries, particularly by developed country sponsors, is

a contentious issue. In the context of HIV prevention trials, this

debate has centred on access to treatment for those who seroconvert

during the trial (6). At a meeting convened by the WHO in July 2003,

vaccine and microbicide researchers, ethicists and others reached a

consensus that providing antiretroviral treatment (ART) to

participants in HIV prevention trials was justified by the principles

of beneficence (maximise benefits to participants), reciprocity

(those who contribute important data to the study by becoming

infected " deserve something in return " ), and justice (all those who

become infected should be treated equally). While few would now

debate whether it is necessary to provide treatment, how it might be

provided and who is responsible for providing treatment remain

contentious.

The CS trial is among the first trials in which research

organisations signed advance agreements with treatment providers

(programmes run by the government and NGOs) and set aside funding for

antiretroviral therapy and other care to participants who acquire HIV

infection during the course of a trial (7). These agreements are at

least in part a result of the considerable efforts of civil society

organisations such as the Global Campaign for Microbicides (GCM) and

the African Microbicides Advocacy Group. Their efforts have gone

beyond ensuring such commitments to monitoring the realisation of

these commitments. The GCM, for example, has independently monitored

the provision of prevention and care services to trial participants

by examining the trial's standard operating procedures and protocols,

visiting sites, and interviewing study staff (5).

Among the safeguards that were established prior to the launch of the

CS trial (and common in most clinical trials) are " stopping rules " -

criteria and a timeline for assessing whether trial data indicate

significant benefit or harm or are unlikely to yield a result

(rendering the study futile). Data are monitored by a data safety

monitoring board (DSMB) called the Independent Data Monitoring

Committee in the CS trial. DSMBs consist of experts in statistics,

medicine, and community issues, and these individuals are not

directly involved in the trial. Formulating stopping rules and

procedures for assessment is critical for both scientific and ethical

reasons. An early stoppage of a trial may result in insufficient data

to reach firm conclusions about the potential harm or benefit of a

product, thereby jeopardising the interests of the participants (8).

However, failure to stop a trial when harm is being caused is clearly

an ethical violation.

Identifying stopping rules is a complex exercise, which requires

weighing available scientific knowledge with ethical concerns. The

ability to implement these rules is equally complex. The stoppage of

the CS trial highlighted the importance of having a communication

plan (9). These plans should include identifying and consistently

interacting with various groups that are likely to be affected by the

results of a trial, such as participating communities, media,

advocacy groups, reporters, donors, and research partners; training

researchers to interact with the media; and putting in place

mechanisms for sharing information. A key lesson of the CS trial is

that " communications capabilities [need to be] embedded in research "

in order to ensure dissemination of accurate information (9).

The lessons we may draw for conducting clinical trials in India

include the importance of the active involvement of civil society

organisations to safeguard participants' rights, the need for careful

balancing of ethical and scientific considerations when establishing

DSMBs and trial stoppage rules, and attention to communication and

dissemination of research. The engagement between the CS trial

investigators and civil society organisations illustrates the

opportunities and responsibilities that networks of individuals and

organisations interested in bioethics in India can take on, as an

increasing numbers of clinical trials are initiated in India.

Expanding institutional ethics committees and DSMBs, and increasing

the availability of training in research ethics all will be critical

to ensure adequate protection of participants in Indian trials.

Greater interaction between health advocates, researchers, media

persons, and others is also needed to ensure effective communication

of the risks and benefits of such research.

References:

1. Press release. Phase III trials of cellulose sulfate microbicide

for HIV prevention closed. Arlington, VA. 2007 Jan 31. [cited 2007

May 10]. Available from:

http://www.conrad.org/press/phasehttp://www.conrad.org/pressroom.htmII

Itrials.htm

2. Gawrylewski A. Failure of HIV microbicide raises concerns. The

Scientist [serial on the Internet]. 2007 Feb 21 [cited 2007 May 10].

Available from: http://www.the-scientist.com/news/display/52861/

3. Doncel G. Update on current microbicide trials: update on the

CONRAD cellulose sulfate trial, preclinical evaluation of cellulose

sulfate. Presentation at the Fourteenth Conference on Retroviruses

and Opportunistic Infections; 2007 Feb 25-28; Los Angeles. [cited

2007 May 12]. Available from:

http://www.retroconference.org/2007/data/files/webpage_for_CROI.htm

4. Van Damme L, Ramjee G, Alary M, Vyulsteke B, Chandeying V, Rees H,

et al. Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1

transmission in female sex workers: a randomised controlled trial.

Lancet 2002; 360: 971-7.

5. No author listed. Background information for advocates on

cellulose sulfate trials. 2007 Feb 5. [cited 2007 May 12]. Available

from: http://www.global-campaign.org/CS-background.htm

6. Heise L, Wood S. Rethinking the ethical roadmap for clinical

testing of microbicides. Washington, DC: Global Campaign for

Microbicides; 2005. [cited 2007 May 12]. Available from:

http://www.global-campaign.org/researchethics.htm

7. No author listed. A joint statement issued by AMAG, GCM and AVAC -

a civil society response. 2007 Jan 31. [cited 2007 May 12]. Available

from: http://www.global-

campaign.org/clientfiles/civil_soc_press_release%209.doc

8. Cannistra SA. The ethics of early stopping rules: who is

protecting whom? J Clin Oncol 2004; 22: 1542-5. [cited 2007 May 14].

Available from http://jco.ascopubs.org/cgi/content/full/22/9/1542

9. ET, Shears KH. Embedding communication in microbicides

research: Lessons from the cellulose sulfate trial closures.

Presentation at the Alliance for Microbicide Development's annual

meeting; 2007 March 20-21; Washington, DC. [cited 2007 May 12].

Available from: http://www.microbicide.org/meetings/meeting10.shtml

________________

1Visiting faculty, Centre for Public Policy, Indian Institute of

Management, Bangalore; assistant adjunct professor, University of

California, San Francisco, USA. Addressfor correspondence: Women's

Global Health Imperative, 50 Beale Street, 12th floor, San Francisco,

CA 94105, USA e-mail: suneeta.krishnan@...

http://www.issuesinmedicalethics.org/153cm121.html