American Journal of Epidemiology Advance Access originally published online on April 9, 2007
American Journal of Epidemiology 2007 165(10):1219; doi:10.1093/aje/kwm081
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LETTERS TO THE EDITOR |
RE: "BIAS IN CLINICAL INTERVENTION RESEARCH"
Department of Public Health, University of Helsinki, FIN-00014, Finland
(e-mail: harri.hemila{at}helsinki.fi)
In her Journal review discussing the potential biases of controlled trials, Gluud stated that "[t]he purpose of blinding is to prevent bias associated with patients' and investigators' expectations. If interventions are compared with no intervention, an identical placebo may be used. The compared interventions must be identical in taste, smell, appearance, and mode of administration. Any difference may destroy the blinding" (1, p. 496).
The last sentence of this quotation was based on three references, two of them focusing on vitamin C and common cold trials (2, 3). However, the Karlowski et al. trial (2) and the Chalmers review (3) were both shown to be erroneous a decade ago (4–6). For example, Karlowski et al. did not mention that 42 percent of the recorded common cold episodes were missing from their subgroup analysis that was the basis for their proposal that "the effects [of vitamin C] demonstrated might be explained equally well by a break in the double blind" (2, p. 1038). In the concurrent review, Karlowski et al.'s subgroup analysis led to a proposal that, in general, "the effects of ascorbic acid [vitamin C] on [common cold] symptoms are the result of the power of suggestion" (3, p. 535).
The lack of validity of Karlowski et al.'s (2) placebo explanation is important for methodological and biologic reasons. First, the Karlowski et al. trial has been extensively used as an example of "placebo effect in action"; for example, it was the only original study cited in the CONSORT statement (7) and the Cochrane Handbook (8). Second, Karlowski et al.'s trial and Chalmers's review (3) are the most frequent citations in medical textbooks when stating that vitamin C is ineffective against the common cold (6), whereas placebo-controlled trials have shown quite consistently that it is effective, even though the practical significance is unsettled (9).
Furthermore, Gluud (1) did not refer to a recent, large meta-analysis of trials directly comparing a placebo group with a no-treatment group, which found no difference between the groups when the outcome was binary; only in studies on pain was there a difference between the placebo and no-treatment groups (10).
Although it is reasonable to use placebo control when feasible, particularly in trials with subjective outcomes, there is no evidence of large and universal placebo effects, and there are examples of placebo-effect speculations being misused to reject findings inconsistent with authors' preconceptions (2–6).
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ACKNOWLEDGMENTS |
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Conflict of interest: none declared.
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References |
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 TOP References |
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- Gluud LL. Bias in clinical intervention research. Am J Epidemiol (2006) 163:493–501.
[Abstract/Free Full Text] - Karlowski TR, Chalmers TC, Frenkel LD, et al. Ascorbic acid for the common cold. A prophylactic and therapeutic trial. JAMA (1975) 231:1038–42.
[Abstract/Free Full Text] - Chalmers TC. Effects of ascorbic acid on the common cold. An evaluation of the evidence. Am J Med (1975) 58:532–6.[CrossRef][Web of Science][Medline]
- Hemilä H. Vitamin C, the placebo effect, and the common cold: a case study of how preconceptions influence the analysis of results. J Clin Epidemiol (1996) 49:1079–84. discussion 1085, 1087.[CrossRef][Web of Science][Medline]
- Hemilä H, Herman ZS. Vitamin C and the common cold: a retrospective analysis of Chalmers' review. J Am Coll Nutr (1995) 14:116–23.[Abstract]
- Hemilä H. Do vitamins C and E affect respiratory infections? Doctoral thesis. In: University of Helsinki, Helsinki, Finland (2006) 21–5. 36–8. (http://ethesis.helsinki.fi/julkaisut/laa/kansa/vk/hemila/).
[Abstract/Free Full Text] - Begg C, Cho M, Eastwood S, et al. Improving the quality of reporting of randomized controlled trials: the CONSORT statement. JAMA (1996) 276:637–9.
[Abstract/Free Full Text] - Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions 4.2.5 (updated May 2005). Sections 6.4 and 6.6. (http://www.cochrane.org/resources/handbook/hbook.htm). (Accessed July25, 2006).[CrossRef][Web of Science][Medline]
- Douglas RM, Hemilä H, D'Souza R, et al. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev (2004 Oct) 18(4):CD000980.
- Hrobjartsson A, Gøtzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med (2001) 344:1594–602.
[Abstract/Free Full Text]
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  M. Marmor, I. Belitskaya-Levy, and A. A. Arslan RE: LETTER TO THE EDITOR ON "BIAS IN CLINICAL INTERVENTION RESEARCH" Am. J. Epidemiol., February 15, 2008; 167(4): 500 - 501. [Full Text] [PDF]
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H. Hemila THE AUTHOR REPLIES Am. J. Epidemiol., February 15, 2008; 167(4): 501 - 502. [Full Text] [PDF]
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L. L. Gluud THE AUTHOR REPLIES Am. J. Epidemiol., May 15, 2007; 165(10): 1219 - 1220. [Full Text] [PDF]
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