To the Editor: I thank Mr Coffey and Dr Ross1Coffey M.J. Ross L.F. Ethics of placebos in clinical asthma trials.J Allergy Clin Immunol. 2006; 117: 470Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar for their commentary on my article. They clearly enunciate a point of view which Emanuel and Miller2Emanuel E.J. Miller F.G. The ethics of placebo-controlled trials: a middle ground.N Engl J Med. 2001; 345: 915-919Crossref PubMed Scopus (285) Google Scholar have referred to as “active-control orthodoxy,” that is, the idea that placebo-controlled trials (PCTs) should never be performed for conditions for which there is “standard therapy.”2Emanuel E.J. Miller F.G. The ethics of placebo-controlled trials: a middle ground.N Engl J Med. 2001; 345: 915-919Crossref PubMed Scopus (285) Google Scholar My article is a brief refutation of this view. I agree with Coffey and Ross1Coffey M.J. Ross L.F. Ethics of placebos in clinical asthma trials.J Allergy Clin Immunol. 2006; 117: 470Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar that scientific validity is not a sufficient condition for ethical clinical research, although it is a necessary condition. The first part of my article addressed why many investigators, the Food and Drug Administration, and I believe that there remain “compelling and scientifically sound methodological reason[s]” to use PCTs, despite the existence of “standard therapy.”3Onder R.F. The ethics of placebo-controlled trials: the case of asthma.J Allergy Clin Immunol. 2005; 115: 1228-1234Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar An important point raised by Coffey and Ross1Coffey M.J. Ross L.F. Ethics of placebos in clinical asthma trials.J Allergy Clin Immunol. 2006; 117: 470Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar is their contention that asthma patients “were actually harmed” by enrollment in PCTs because subjects randomized to a placebo arm were more likely to withdraw for “worsening of asthma.”4Coffey M.J. Wilfond B. Ross L.F. Ethical assessment of clinical asthma trials including children subjects.Pediatrics. 2004; 133: 87-94Crossref Scopus (26) Google Scholar This is, of course, expected if the active treatments in the PCTs are efficacious. What do Coffey and Ross1Coffey M.J. Ross L.F. Ethics of placebos in clinical asthma trials.J Allergy Clin Immunol. 2006; 117: 470Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar mean when they say patients were harmed? In another article, they state that “the harm of an asthma exacerbation may be short-lived and easily reversed (minor harm) or it may lead to hospitalization or even death (major harm).”4Coffey M.J. Wilfond B. Ross L.F. Ethical assessment of clinical asthma trials including children subjects.Pediatrics. 2004; 133: 87-94Crossref Scopus (26) Google Scholar It would be a serious concern if patients in PCTs were suffering such “major harm” by being randomized to placebo. When one looks at the authors' data regarding reported hospitalizations, however, one finds that the rate of hospitalization for patients enrolled in placebo arms of PCTs (5 of 4398; 0.1%) was almost identical to that of patients enrolled in active-treatment arms (9 of 8867; 0.1%).4Coffey M.J. Wilfond B. Ross L.F. Ethical assessment of clinical asthma trials including children subjects.Pediatrics. 2004; 133: 87-94Crossref Scopus (26) Google Scholar Of 1180 children who received placebos in asthma trials, there were no reported hospitalizations.4Coffey M.J. Wilfond B. Ross L.F. Ethical assessment of clinical asthma trials including children subjects.Pediatrics. 2004; 133: 87-94Crossref Scopus (26) Google Scholar Finally, of all patients enrolled in PCTs, there was a 0.1% rate of hospitalization, whereas there was a 0.9% rate of hospitalization in patients enrolled in active-control and add-on trials.4Coffey M.J. Wilfond B. Ross L.F. Ethical assessment of clinical asthma trials including children subjects.Pediatrics. 2004; 133: 87-94Crossref Scopus (26) Google Scholar This may indicate that patients were monitored more closely, or sicker patients excluded, in PCTs. I believe that these data support my conclusion that properly designed, reviewed, approved, and monitored PCTs of asthma may safely and ethically be conducted.3Onder R.F. The ethics of placebo-controlled trials: the case of asthma.J Allergy Clin Immunol. 2005; 115: 1228-1234Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar The issues of “exacerbations” and “equipoise” both concern the question whether research subjects may be allowed to sacrifice anything to promote the purpose of the research. If the answer to this question is no, then the entire biomedical research enterprise is on dubious moral grounds. If a subject may not ethically bear the risk of being randomized for a short time to placebo, how does one ask the same subject to consent to phlebotomies, lung biopsies, bronchoprovocation challenges, or exposure to unknown risks of new immune modifying agents? If the current Declaration of Helsinki stands for barring researchers and subjects from participating in well designed, carefully monitored PCTs, then the World Medical Association should revisit this document.
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