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Post-publication Peer Reviews to:
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![[Read P3R]](/icons/misc/sectionDOWN.gif){kind=icon}
Ethical Concerns of International Studies
A reality out of sight
Sildenafil for PPHN
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Lawrence Noble, Attending Neonatologist Albert Einstein College of Medicine, Ivan Hand
Send letter to journal:
noble{at}aecom.yu.edu Lawrence Noble, et al.
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Dear Sirs: We read with interest the recent article on oral sildenafil and persistent pulmonary hypertension of the newborn1. We believe it to be an important pilot study in the use of this drug for newborn infants. Of concern, however, is the ethical issue of randomizing this drug with placebo when alternative therapies, such as nitric oxide and prostacyclin, are available. The Council for International Organizations of Medical Sciences (CIOMS) recent guidelines states that, as a general rule, research subjects in the control group should receive an established effective intervention2. Although the institutional review board at the host hospital reviewed the research protocol in this study, CIOMS guidelines state that institutional review committees of the host country, as well as the country of the sponsor should review studies and withhold approval of research proposals that fail to meet their scientific or ethical standards2. It is highly unlikely that an institutional review board in a more developed country would have approved this study. The higher than normal mortality rate of the control group raises the possibility that the medical team discerned which infants had received placebo and decided that further treatment was futile. Care must be taken to ensure that all patients are protected, no matter where the study takes place. 1. Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn: A Pilot Randomized Blinded Study. Pediatrics 2006; 117: 1077-1083 2. World Health Organization. International ethical guidelines for biomedical research involving human subjects. Geneva: Council for International Organizations of Medical Sciences, 2002 Conflict of Interest:None declared |
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Hernando M Baquero, Attending Neonatologist Universidad del Norte, Barranquilla, Colombia, Augusto Sola, Jhon Lantos, Fredy Neira
Send letter to journal:
hbaquero{at}uninorte.edu.co Hernando M Baquero, et al.
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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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Javeed Travadi, Neonatologist John Hunter Children's Hospital, Newcastle, Australia, Himanshu Popat
Send letter to journal:
javeed.travadi{at}hnehealth.nsw.gov.au Javeed Travadi, et al.
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Dear Sir, We read with great interest the article on use of oral Sildenafil in infants with persistent pulmonary hypertension (PPHN) published in April 2006 issue of Pediatrics [1]. We commend the efforts of Hernando et al to systematically evaluate use of oral Sildenafil in infants with severe PPHN and would like to make the following comments. The authors state that the subjects were evaluated with an echocardiogram and the pulmonary pressures were estimated and right to left shunt was demonstrated at the start of study but there is no mention of the pulmonary pressures in the two groups. We would suggest that left ventricular output and stroke volume are the better parameters to predict severity as compared to pulmonary pressures. [2] Although there is a mention of no difference in need for inotropic support and the requirement of volume boluses between two groups, it would be interesting to know if the degree of support required in the two groups was different. We would also like to draw attention to the disparate etiologies of PPHN in the study arms. Meconium aspiration accounted for 4/7 cases in treatment group and 2/6 cases in placebo group while respiratory distress syndrome accounted for 3/7 cases in treatment group and 4/6 cases in placebo group. The outcome of PPHN is dependent on the underlying etiology and meconium aspiration related PPHN has the better outcomes compared to other etiologies of PPHN [3]. The greater number of neonates with meconium aspiration in the treatment arm may have influenced the results. Certainly off-label use of Sildenafil outside a randomised clinical trial should be discouraged till we establish its effectiveness and safety in neonates as rightly pointed out by Hernando et al. References: 1. Hernando Baquero, Amed Soliz, Freddy Neira, Maria E. Venegas, and Augusto Sola. Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn: A Pilot Randomized Blinded Study. Pediatrics 2006; 117: 1077-1083. 2. Skinner JR, Hunter S, Hey EN. Haemodynamic Features at presentation in persistent pulmonary hypertension of the newborn and outcome. Archives of Disease in Childhood 1996;74:F26-32. 3. Walsh MC, Stork EK. Persistent Pulmonary Hypertension of the Newborn. Clin Perinatol.2001;28:609-627. Conflict of Interest:None declared |
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