Randomized clinical trials (RCTs)
constitute a world-wide acknowledged standard of proof to decide about the
efficacy of a drug. Their implementation involves many different ethical
dilemmas (e.g., in what conditions it is fair to allocate treatments at random?),
but most of these are well known, and several agreed guidelines exist to sort
them out whenever they appear. Or at least they do in countries where serious
institutional review boards (IRBs) are in operation to monitor the trials. But
RCTs are also an industrial procedure that the pharmaceuticals should use very
often to make their business grow. And since there are many countries in which
the absence of serious IRBs is positively correlated with a lower cost of RCTs,
there is a strong incentive for the industry to conduct their trials there.
There is a single methodological yardstick, RCTs,  that guarantee the cogency
of the results of the test, making it acceptable for Western regulatory
agencies. But there is often a double ethical standard to conduct the trials,
since the subjects of the experiment will be treated very differently depending
on its geographical location. This is the topic of Ruth Macklin’s path-breaking
essay. Her goal is to debunk the various ethical arguments provided to justify
the existence of such double-standards and argue for a unified system of
ethical guidelines to conduct medical research in our world.

The subject under discussion is
mapped in chapter 1. Macklin defines there what she takes to be a developing
country in this context: namely, a country in which there are fewer
opportunities for the majority of the population to access the successful
products of research. This implies that clinical trials provide a unique
occasion for them to gain access to new drugs, even in the testing stage. However,
this also puts these people in a position of inferiority regarding the
pharmaceutical companies when it comes to negotiate the details of the trial.
The case in point that brought international attention to the problem was a
1997 study of maternal-to-child HIV transmission conducted in a developing
country: the contrasting drug was a placebo instead of the best available
treatment, as it should have been according to the developed world bioethical
standards. Macklin introduces here the Declaration of Helsinki, issued by the
World Medical Organization in various amended versions, which she will
critically use — together with other similar texts — as a framework for
carrying out the discussion in the rest of the book. Her aim is to improve
these ethical research guidelines in a way that is ”usefully prescriptive
without being hopelessly aspirational” (p. 30).

Chapter 2 discusses the problem of
the standard of care, which mainly appears in the following circumstances: on
the one hand, what sort of drug (if any) should be provided to the control
groups in countries where no alternative treatment is available for the study subjects;
on the other hand, what level of medical attention should be provided to them
beyond the actual goals of the study? Macklin surveys the debate on what the
standard should be, and presents an ample review of the guidelines provided by
various organizations. She undermines here the various arguments for a double
standard (e.g., ”something is better than nothing”) on considerations both of
principle and practical significance, which are expanded in the following
chapters.

In Chapter 3, Macklin addresses the
issue of distributive justice by contextualizing the idea to the area of
scientific research. She argues in favor of a moral imperative to provide
post-trial benefits to research subjects, drawing from various arguments
ranging from equity as maximization to compensatory justice. In this light she
reviews many guidelines again, criticizing those that leave room for the
opposite conclusion. Yet even if her point is granted, there is the open
question of what sort of benefits should be provided. A similar conclusion is
reached in the following chapter through an analysis of exploitation. Macklin
proposes a definition (p. 101) in which the key point is the lack of adequate
compensation to research subjects due to their lack of, so to speak, bargaining
power. This definition is extensively contrasted with the guidelines, but now
Macklin obtains more concrete conclusions as to the practical implications of
the analysis. The entitlement to post-trial benefits is now defended as the
proper measure to prevent exploitation. And these benefits appear to be mostly
an easier access to the resulting drugs. But Macklin also focuses on the
circumstances in which consent may be exploitative — the list of particular
circumstances in which exploitation in international research is likely to
happen is particularly illuminating in this respect (pp. 118-122).

Chapter 5 then analyses the
possible safeguards to guarantee that consent is properly granted and the
subjects’ rights are duly protected during the trial. After some illustrations
showing the need for such safeguards, Macklin argues for a universalistic
conception of consent grounded in individual autonomy against group, or gender,
biased definitions, defended on a cultural relativistic basis. In a similar
spirit, Macklin defends the convenience of extending the competencies of IRBs
beyond their actual boundaries, so that they can survey privately sponsored
trials abroad when no reasonable alternative is provided.

Chapter 6 focuses on how to make
drugs affordable. Its moral implications are already clear at this stage: it
would make less defensible the use of placebo in clinical trials conducted in
underdeveloped countries and would substantiate the idea of post-trial
benefits. Four complementary strategies are discussed: differential pricing in
essential drugs; prior agreements to make the drug under trial available in the
countries where it is conducted; joint initiatives of international agencies
and private-public partnerships to produce affordable drugs; and the manufacture
of generic copies of patented drugs for poor countries. Macklin presents
different examples of each strategy, emphasizing their more positive prospects.

Chapter 7 returns to matters of
principle and restates the case already made using the human rights vocabulary,
acknowledging its role as a global standard for international organizations. Chapter
8, the final chapter, discusses how to develop research guidelines in
accordance with all these considerations, using a quite realistic approach.

Macklin’s effort deserves all
praise since she takes into account most of the many possible approaches to her
subject, and builds a unified and coherent case. Though Macklin navigates at
ease in the endless details of the various declarations and proposals discussed,
it is not difficult to get lost: the analysis is necessarily brief to keep the
essay’s extension within reasonable limits, so many arguments are just outlined
and the reader is referred to an ample bibliography to complete them. In this
respect, a general references section (instead of one at the end of each
chapter) would have been helpful. Yet, the thorough index appended somehow
compensates for this and makes the book really accessible. All in all, it is a
great survey of a terribly complex issue and it will greatly improve its
discussion from now on.

As to the cogency of Macklin’s
proposal of a unified standard for medical research, it is difficult not to be
sympathetic, and the arguments she provides may well ground a wide consensus.
Yet, this is a book in which bioethical discussion often yields policy
recommendations, and in this respect I sometimes miss a more concrete
discussion of how these would work under different circumstances. Since case
studies are for Macklin a good enough ground to build her arguments for or
against different policies, I would have liked a case-based analysis of the
efficacy of her own proposals, i.e., one in which agents are not motivated by
ethical considerations alone but also by their particular interests in the many
scenarios in which these proposals should be implemented. Obviously, this is
too much to ask of a book which is mostly intended as an essay in applied
ethics. Yet, when this field is expanded to encompass all the circumstances
that she (wisely) takes into account, the arguments necessarily becomes
something more than ethics and a more interdisciplinary discussion would do
much to strengthen her conclusions, making them more credible. That being said
this is a pioneering work, and it is fair to say that it makes the very
discussion of ethical clinical testing in developing countries possible.

© 2006 David Teira

David Teira, Ph.D. UNED (Madrid)

Categories: Ethics