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Madigan Army Medical Center Tacoma, WA
Correspondence to: COL Edward R. Carter, MD, FCCP, Division of Pediatric Pulmonology, Children’s Hospital and Regional Medical Center, 4800 Sand Point Way, Mail Stop 3D-4, Seattle, WA 98105
To the Editor:
The article by Bisgaard et al1 in the December 2001 issue of CHEST provides some useful information concerning the cost effectiveness of inhaled corticosteroids in very young children with persistent asthma. However, I have concerns with the ethics of subjecting young children with persistent asthma to a placebo controller therapy. This study was an offshoot of a multicenter trial, published in 1999, that prospectively evaluated the efficacy of two different doses of fluticasone compared to placebo in young children with asthma.2 A pharmaceutical company sponsored the study, and one of the authors of the December 2001 paper was an employee of that company. In the initial prospective study, from which the cost-effectiveness data were obtained, 237 children, 1 to 3 years old, were randomized to receive fluticasone, 100 µg/d or 200 µg/d, or placebo for 12 weeks. Based on the inclusion criteria (having asthma symptoms or requiring albuterol on at least 7 days of the 14-day run-in period), these children had moderate persistent asthma. Patients could remain in the study if they had one exacerbation requiring prednisone but were withdrawn if they had two exacerbations. Cromolyn was the only controller medication that was allowed other than study drug, and it was unlikely that many patients were taking cromolyn. Thus, most of the 81 very young children randomized to the placebo group did not receive any controller therapy for 3 months. Is this ethical? It is well established that patients of all ages with moderate persistent asthma benefit from controller therapy. The study would have provided just as much useful information if it had dropped the placebo arm and simply evaluated the two doses of fluticasone. The study then would have required fewer patients and would have avoided the ethical issue of using a placebo.
The Declaration of Helsinki addresses the issue of using placebos in clinical trials as follows: "The benefits, risks, burdens, and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of a placebo, or no treatment, in studies where no proven prophylactic, diagnostic, or therapeutic method exists."3 I do not believe that the study by Bisgaard et al met these criteria for use of a placebo. It is one thing to ask adults to take a placebo, but the toddlers in this study were too young to understand that they were participating in a study. It is not surprising that fluticasone was found to be more efficacious and cost-effective than placebo, but it is also evident that the children in the placebo group had more symptoms and perhaps more suffering. Is this an appropriate use of a placebo?
References
Copenhagen University Hospital Copenhagen, Denmark
Correspondence to: Hans Bisgaard, MD, Professor of Pediatrics, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark; e-mail: Bisgaard{at}copsac.dk
To the Editor:
We acknowledge the comments of Dr. Carter concerning medical ethics and the use of placebo in our study,1 2 3 evaluating the safety, efficacy, and cost-effectiveness of inhaled fluticasone propionate in very young children, 1 to 3 years old, with persistent asthma-like symptoms.
The statement by Dr. Carter that "it is well established that patients of all ages with moderate persistent asthma benefit from controller therapy" is fundamentally not true, as in the infant age group, efficacy data are sparse and the objective demonstration of unequivocal efficacy remains a challenge. There is little or no consensus on a precise definition of asthma in children in the 1- to 3-year age group or indeed on grading of disease severity. Clearly, evidence from studies in adult and older children cannot be extrapolated to infants. Asthma-like symptoms may reflect different underlying pathology in different age groups, and infants probably represent a different and certainly more heterogeneous pathology.4 5
Since our first publication in 1990, demonstrating the effect of inhaled corticosteroids in a group of young toddlers,6 and up until the planning in 1996 of our study in question,1 there have been only a few small studies in this age group and even some contradictory reports.7 8 Therefore, we find our demonstration of a dose-related response to inhaled fluticasone propionate over placebo, published in 1999, to be important and necessary evidence on the efficacy of this treatment.
Furthermore, our study has provided the first insight into the heterogeneity of response to inhaled corticosteroid in this age group. In post hoc analyses, we demonstrated characteristics of the group of children responding to treatment.2 Such a distinction between "responders" and "nonresponders" addressed the important question of who should be treated, helping clinicians to target the treatment. Analysis of responders to treatment is a major challenge for future improvement of pharmacotherapy and requires placebo-controlled trials.
Sodium cromoglycate (SCG) has been a recommended controller therapy in national and international asthma management guidelines for this age group, although the evidence of its efficacy is ambiguous.9 SCG was permitted throughout the study. All children (including those treated with placebo) received oral or inhaled salbutamol on an "as-required" basis throughout. Furthermore, through participation in a controlled clinical trial, all of our patients, including those receiving placebo, received potentially better and closer monitoring than in normal clinical practice.
It is worth noting that the study protocol (and hence the inclusion of the placebo arm) was approved by the Ethics Committee (Institutional Review Board) of each of the 33 participating centers, thereby endorsing the appropriateness of the ethics of the study design. Informed consent for participation was obtained from each child’s parent(s), who were free to withdraw the child from the study at any time.
In view of the above, the use of placebo with free access to SCG and bronchodilator therapy in our study is not considered inappropriate. We believe that the use of a placebo treatment arm can provide better understanding of the disease in these young children and of the clinical benefits of inhaled corticosteroids. Hence, we do not believe that any of the current or past principles enunciated in the Helsinki Declaration have been contravened in this study.
References
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