To The Editor,
We thank Lawrence Noble and Ivan Hand for raising the very important
issue of ethical standards for placebo controlled trials in developing
countries (1) in reference to our recently published manuscript (2) . We
have given a great deal of thought to this issue.
The key to analyzing the appropriateness of clinical trials is in the
phrase “as a general rule,” used by CIOMS to describe the moral
presumption that study subjects should receive an established effective
intervention, rather than a placebo, if one is available. We agree.
However, we think that there are exceptions.
In the case of newborns with persistent pulmonary hypertension,
nitric oxide is an established intervention in some countries. However,
at the time of our study, it was not available for use in Central and
South America. As of today, the company has made iNO available only to
certain centers – several in Brazil, a handful in Mexico, two in Colombia,
three in Chile and Argentina and none to date in Cuba, Uruguay, Paraguay,
Bolivia, Guatemala, Ecuador, Honduras, Nicaragua, El Salvador, Peru,
Venezuela, or Panama. At the time of our study, it was not available in
Colombia. Part of the reason for the unavailability of nitric oxide is
economic. Nitric oxide costs $500-1000/day. Most countries in Latin
America will not be able to afford this treatment for most patients.
(Sildenafil, by contrast, costs about $30-$40/day, and that includes the
medication, the diluents, the syringes and tubes needed to deliver it.)
There are two key ethical questions in deciding whether a placebo
controlled trial is appropriate, in our view. The first is whether those
patients in the placebo arm are being denied access to a therapy that
would otherwise be available to them. In this study, they clearly were
not. Additionally, one of us has been involved, in an initial multicenter
evaluation of a preparation of IV Sildenafil, with IRB approval in a “more
developed country”. Despite conflicting interests and funding
difficulties, the next phase of this study would have been a large scale
multicenter and placebo-controlled trial in industrialized, developed
nations.
The second issue is more important and more complicated. We believe
that clinical studies of new therapies should only be done in developing
countries (or in any other country, for that matter) if the therapy being
tested is ultimately going to be available for use to benefit the people
in the country in which it is being tested also. Trials should not be
conducted in developing countries to test therapies that will only be
marketed in developed countries. Our study of sildenafil clearly met that
condition. Our goal was to see whether a therapy could be effective that
might actually be made available and might actually be affordable for the
babies of Colombia and the developing world. The best way to test this is
in a randomized placebo-controlled trial.
Such issues have been analyzed in other situations, including trials
of anti-retroviral therapy in developing countries (3-6). As evidenced in
recent reviews, there is widespread disagreement upon the appropriate
standards to be applied. The goal of this study was to try to search, in
a scientific and ethical way, for a “local”, inexpensive and effective
therapy for a condition which does not affect a large segment of the
population but which is associated with high mortality under the local
circumstances. If proven, this inexpensive therapy may become an effective
standard of care for all infants in developing regions, and not just for a
fortunate few.
Sincerely,
Hernando Baquero, Universidad del Norte, Barranquilla, Colombia
Augusto Sola, MANA and Morristown Memorial Hospital, Morristown , New
Jersey
John Lantos, University of Chicago, Chicago, Illinois
Fredy Neira, Universidad del Norte, Barranquilla, Colombia
References:
1) Lawrence Noble, et al. Ethical Concerns of International Studies
.Pediatrics Online, 6 Jun 2006
2) Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral Sildenafil
in Infants With Persistent Pulmonary Hypertension of the Newborn: A Pilot
Randomized Blinded Study. Pediatrics 2006 Apr 1;117(4):1077-83.
3) de The G, Buonaguro F, Charpak N, Franca Junior I, Hutton JL,
Thorstensson R, Valdas E, Zetterstrom R. Ethical issues in research on
control of the HIV/AIDS epidemic: report from a workshop of the world
federation of scientists, Erice, Sicily, Italy, 22-24 August 2003. Acta
Paediatr. 2004 Aug;93(8):1125-8.
4) Kent DM, Mwamburi DM, Bennish ML, Kupelnick B, Ioannidis JP.
Clinical trials in sub-Saharan Africa and established standards of care: a
systematic review of HIV, tuberculosis, and malaria trials. JAMA. 2004 Jul
14;292(2):237-42
5) Killen J, Grady C, Folkers GK, Fauci AS. Ethics of clinical
research in the developing world. Nat Rev Immunol. 2002 Mar;2(3):210-5.
6) Lurie P, Wolfe SM. Unethical trials of interventions to reduce
perinatal transmission of the human immunodeficiency virus in developing
countries. N Engl J Med. 1997 Sep 18;337 (12):853-6.
Conflict of Interest:
None declared
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