pp. 115-117 in Bioethics in Asia

Editors: Norio Fujiki and Darryl R. J. Macer, Ph.D.
Eubios Ethics Institute

Copyright 2000, Eubios Ethics Institute All commercial rights reserved. This publication may be reproduced for limited educational or academic use, however please enquire with the author.

3.5. Ethical problems and clinical trials. The problem of AZT trials for vertical transmission in developing countries.

Deborah Zion.

Centre for Human Bioethics, Monash University, Australia; University of Tokyo, Japan

"When we gaze at the sky at night" writes the novelist Margaret Atwood "we are looking at fragments of the past." (1) So too when we see the results of clinical trials we look unwittingly at a drama in which the desperation and hopes of the research subjects are only present in the codification of the results. Consequently, it is easy to overlook the suffering of those involved, and to feel little sympathy for them. However, the advent HIV/AIDS has meant that many aspects of medical practice, including the way in which clinical trials are conducted, are being scrutinized with renewed vigour.

It is, unfortunately, easy to see the history of clinical trials in an unfavourable light. The Tuskegee experiment in which poor Black sharecroppers were deliberately left untreated for syphilis has recently become the object of public memory, and its victims have belatedly received an apology. But it is too easy to apply the unethical problems of one trial to others. It is undeniable that the Tuskegee syphilis study was marked by the worst excesses of paternalism and egotism. Subjects were kept in ignorance about their condition, and about the treatment that they were being offered. No consent was sought, and none was given. Trials that are taking place now, especially in the area of HIV medicine, are beset with ethical problems, that need detailed analysis, as informed consent has been given by the trial subjects, although the manner in which this consent was obtained is ethically questionable.

The Public Citizen's Health Research Group has recently brought to light ethically dubious trials of the drug AZT, that are currently taking place in developing countries. The objective of these trials is to establish the minimum dose necessary to prevent transmission of the virus to the unborn child. Therefore the women are randomized into high dose, low dose and placebo arms of the trial. These women gave their informed consent to enter the trial.

The trouble with using such a standard trial formula in this case is that AZT has been proved effective in blocking approximately two thirds of transmissions of HIV to the fetus. Thus, the Public Citizen's Health Research Group has state that these trials violate the Helsinki declaration in that g(i)n any medical study, every patient - including those of a control group, if any- should be assured of the best proven diagnostic and therapeutic method.h (2)

The rejoinder to such criticism- that no treatment at all is available for women in many of the countries in which the trials are being run and therefore any treatment is better than none- has disturbing implications. Namely, that it is ethically acceptable to exploit the suffering of vulnerable populations, even though the means to alleviate it are known, because if no trial at all were offered the women in question would have contracted HIV anyway. Furthermore, it is often argued that women on such trials gave were competent to give their consent, and that therefore the trial is ethically legitimate.

Peter Lurie et al raise a common objection to such a claim. Namely that the lack of options is in itself coercive to potential subjects. Therefore, if subjects cannot obtain HIV prophylaxis elsewhere, this in itself acts as a coercive influence, and therefore invalidates their ability to autonomously consent (3). Given that many investigators rely heavily on informed consent in order to smooth out ethical snarls in research, this claim merits close examination.

Autonomy as competence, or autonomy as freedom?

In general, investigators rely upon an ideal of informed consent that equates autonomy and competence, rather than with freedom. Therefore, if a patient is mentally competent to consent, his or her consent is considered to be autonomous. Andrew Moore and Martin Wilkenson rely on this view when they discuss the issue of payment for research participants, gdesperate need-unfreedom-does not, in itself, undermine consent. Our argument depends on the doctrine of informed consent. If the sole alternative to death is some lifesaving treatment, then one is unfree to turn it down, but this does not rule out autonomous choice of the treatment.h (4)

Thus Moore and Wilkenson's view of informed consent relies upon equating autonomy with rationality and competence. But such a view-while no doubt a godsend to trial investigators- raises many problems. The first of these is that a view of autonomy based upon competence rather than upon freedom leaves investigators the chance to ignore the problems inherent in unequal power relations and the possibility of exploitation that may result from them. The way out given to investigators by informed consent, that anyway the subject consented to be exploited makes a mockery of the very mechanisms that informed consent is supposed to protect- namely, the well being and dignity of the subject. But using such a definition also ignores the way in which choice can be structured by those with vested interests, so that they ultimately do not have to take responsibility for the misery that they have caused on the basis that the subject, in full knowledge of the trial procedure, gave his or her consent.

In other situations, however, we expect people who use others as a means to an end to take responsibility for what they have done. The philosopher, Bernard Williams' famous story of Jim and the Indians illustrates how being placed in such a position in no way removes responsibility from those who are manipulating the situation.. Jim, a tourist, finds himself in a small South American country that has been taken over by a military government. Twenty Indians have been rounded up and are awaiting execution. Here is the story: Jim is told that he has a choice. He can either kill one of the Indians himself, and the rest will be released, or watch all of them being shot (5). Now Jim has a so-called choice, but it seems meaningless to say that he has an autonomous choice, even though he is mentally competent (6). Instead the responsibility for the crime that Jim finds himself part of rests with those army officers giving Jim this so-called choice.

It is clear that a view of autonomy that is based solely on competence is inadequate when dealing with the complexities of international trials, where investigators from wealthy nations decide upon the range of choices that will be offered to their impoverished subjects. Autonomy as competence is just one part of a more encompassing and significant view of autonomy that is based upon freedom. The philosopher Joseph Raz has suggested that " the autonomous person has the capacity to control and create his own life... that capacity involves.. the availability of adequate options." (7)

Does freedom equal choice?

What then of the argument that as no other treatment is available to these women, the offering an AZT trial actually increases their freedom? This argument can be quickly demolished on two grounds. The first is that while the trial may improve the chances for these women in the same way that entering a lottery may improve the chances for an impoverished person, it does not increase their degree of freedom. Moore and Wilkenson, despite their belief in a competence based view of autonomy, do state that "(i)f the sole alternative to death is some lifesaving treatment, then one is unfree to turn it down." (8) Thus if there is no treatment alternative, then the presence of a trial may indeed be coercive rather than freedom producing.

The second reason why entering such a trial may improve a subject's chances without improving her freedom is based upon the connection between freedom and respect for persons. One of the benchmarks of a society in which freedom is cherished are institutions that protect the dignity of its citizens. Thus taking advantage of another's suffering is a way in which the freedom of others is exploited. The philosopher Allen Wood remarks that gproper respect for others is violated when we treat their vulnerabilities as opportunities to advance our own interests or projects. It is degrading to have your weaknesses taken advantage of, and dishonourable to use the weakness of others for your own ends.h (9)

Freedom, autonomy and trials in developing countries.

Are we to conclude from this analysis that it is never possible to run a clinical trial in a developing country? It is certainly the case that the kinds of options that are available to subjects in Western democracies make it easier to equate freedom with autonomy. But this does not mean that it is impossible to create such conditions in developing nations that have poor healthcare. The problem is that it is very expensive to do so without the infrastructure that comes with a national healthcare system that is properly funded. Let us return to the AZT vertical transmission trial and see how both freedom and autonomy could have been enhanced.

If trial organizers had promised all the women entering the trial the most effective dose of AZT to block transmission, and then had asked if any women, out of altruism, would like to be randomized into low or high treatment arms - and leaving out the placebo arm, without putting any pressure on them to do so, we would see the kind of trial in which freedom, autonomy, and the chance for survival were maximized. Of course, all women who gave birth to children infected with HIV who had entered the trial should also be offered the best treatment available for themselves and their children.

It is easy to imagine trial investigators and drug company economists shaking their heads at the cost of such a trial. But the question remains: who are clinical trials for? Who should bear responsibility for trial subjects? Drug companies have much to gain in the short term from a successful trial. Unfortunately ethical practice is often expensive. Nevertheless, drug companies, like ethics committees and trial organizers need to ensure that research subjects are protected from exploitation.

Finally, I would like to draw to your attention a trial that took place in Thailand to test dose levels of AZT. However, here the principle researcher refused to allow a placebo arm, using instead a high and low dose group and comparing results. While the trial is still somewhat ethically vexed. it is a great improvement on the trials I have already described. All the women on this trial received some treatment.

Coda

Since I wrote this paper, on 23 October, 1997, researchers stopped the placebo arm of the trial taking place in Uganda.

References

1. Margaret Attwood, Cat's Eye , Virago Press, London, 1990, pp.331-2

2. World Medical Association Declaration of Helsinki: recommendations guiding physicians in biomedical research involving human subjects. Adopted by the 18th World Medical Assembly, Helsinki, 1964 and revised by the 29th World Medical Assembly Tokyo, 1975, the 35th World Medical Assembly, Venice, 1983, and the 41st World Medical Assembly, Hong Kong, 1989. Quoted in letter to Donna Shalala from Public Citizen, April 22, 1997 p.2.

3. Ibid, p.3.

4. Andrew Moore and Martin Wilkenson, "Inducement in Research," Bioethics, Vol.11, no.4, October 1997, forthcoming, p.7.

5. Bernard Williams, "A critique of utilitarianism, " in J.J.C. Smart and Bernard Williams Utilitarianism. For and Against Cambridge University Press, Cambridge, 1973, pp.77-151 p.98.

6. I am indebted to Ms. Lynn Gillam for this insight.

7. Joseph Raz The Morality of Freedom, Clarendon Press, Oxford, 1986, p.408.

8. Moore and Wilkenson, op.cit.p.7.

9. Allen Wood, "Exploitation" Social Philosophy and Policy, 1995, p.147.


Please send comments to Email < asianbioethics@yahoo.co.nz >.

To contents page
To Japanese version
To Eubios book list
To Eubios Ethics Institute home page