Correspondence to: Robert J. Temple, M.D., Center for Drug Evaluation and Research, 5600 Fishers Lane, HFD-40, Rockville, MD 20857 (e-mail: temple{at}cder.fda.gov).
In this issue of the Journal, Chvetzoff and Tannock (1) review the responses of patients on placebo or best supportive care in 47 randomized trials in a variety of tumors to assess placebo effects in oncology. In considering the implications of this work, it is unfortunate that the name for the effect of drug-taking itself, the placebo effect (i.e., an effect unrelated to what the drug does), is the same as the name of dummy drug, the placebo, used to blind (mask) the study treatments. This nomenclature has led to confusion between the "placebo effect" and the "effect in the placebo group." Effects of the latter type include, as the authors recognize, not only placebo effects but also changes resulting from the natural course of the disease (which are very important in most symptomatic conditions), regression to the mean, and a variety of nonspecific influences, some of them potentially biased. Some of these effects represent real improvement of the patient, but others do not. A true placebo effect is, by definition, real improvement; in contrast, other effects in the placebo group that are not placebo effects, such as an apparently improved status resulting from a patients hopes or desire not to disappoint the physician or from a more favorable interpretation by an investigator of a physical sign or patient report, are not real improvements.
Clinical studies of drug treatments are randomized and double-blinded so that patient groups are similar at baseline (i.e., they have the same likelihood of spontaneous change) and are also as similar as possible during the trial with respect to all influences on outcome except study treatment. Randomization achieves comparability at baseline, but it is blinding that ensures similarity of other influences, such as a true placebo effect, patient and investigator hopes and expectations, the effects of other therapy, or the likelihood of dropout. There is no reason to believe that the most important reason for non-treatment-related changes in the placebo group is the placebo effect.
Whether true placebo effects are frequent or important is difficult to know, because relatively few studies are designed to assess these effects and because the natural history of many conditions is not established. The substantial improvements in placebo treatment patients in depression trials (2) and other settings (3), for example, have led to suggestions that medical use of placebos might be of value (4). It is possible, however, that all or most of the observed improvements in placebo groups may simply represent the natural course of patients entering these trials.
Recently, by examining all available trials of a variety of treatments (pain, obesity, asthma, hypertension, smoking, and other conditions) that had both a placebo group and a group given no therapy at allthe only real way to assess placebo effectHrobjartsson and Gotzsche (5) concluded that such trials, with the possible exception of short-term pain studies, provided little evidence of placebo effects. Even the small evidence of benefit they saw could reflect not a placebo effect but the inevitably unblinded nature of the comparison of placebo and no treatment at all, with the no-treatment group possibly reporting worse results because of the certainty that they were not given active drug. Although this work has stimulated objections, e.g., to the wide variety of studies used in the meta-analysis (6) and to the authors failure to appreciate the effect of factors other than drug-taking, such as the doctorpatient relationship (7,8), so that both the placebo and no-treatment groups could have had a "placebo response," few controlled studies convincingly show an effect of drug taking itself (as opposed to an effect of the whole therapeutic environment, which could have an effect, although this too is hard to study).
Fortunately, the analysis of Chvetzoff and Tannock is not affected by arguments about placebo effects. It is useful precisely because, by examining effects in placebo groups, it assesses the magnitude of all the possible causes of improvement in an untreated group, not just placebo effects. (Indeed, the title of their review might better have been "Effects in Placebo Groups in Oncology.") Their analysis is therefore potentially useful in considering trials that do not have a concurrent control group, a kind of trial quite common in oncology, generally called a phase II trial. As a general matter, the U.S. Food and Drug Administration has been extremely skeptical about accepting as evidence of drug effect in single-arm trials anything other than tumor responses. Is it possible that there are other endpoints that might also be persuasive in single-arm studies because they rarely, if ever, improve in groups given no active treatment?
In considering this question, two points deserve attention. First, the effect seen in a blinded placebo group should be considered a low estimate of the non-drug-related changes that might be seen in an unblinded group of patients given a putative effective treatment that was in fact ineffective. Second, it is critical to distinguish group effects (that is, change from baseline of the whole group) from individual responses. If a treated group were to have, overall, no change in a symptom like pain but had some patients with improvement and some with deterioration, it might be plausible to consider the improvements real (albeit not common) and to consider the deterioration or lack of effect in the remaining patients the expected outcome in nonresponders with malignant disease.
It is therefore critical to note that there were, in fact, individual apparent "responders" to placebo treatment for most of the symptomatic measures examined by Chvetzoff and Tannock, including pain, appetite, and even weight gain and performance status. Indeed, weight gain in individual patients, a seemingly more objective measure than symptomatic improvement, occurred at similar rates in the drug and placebo groups in most of the studies reported, as did change in performance status (although only two trials reported individual performance status results). On the other hand, group changes in weight and performance status in placebo groups were not seen in any study. Group improvements in these measures were also not seen in the treated groups. Individual responses on quality-of-life scores were not reported in the 10 trials reviewed by Chvetzoff and Tannock, but mean values did not improve in any placebo group (or any treated group, for that matter).
Given the observations of Chvetzoff and Tannock, it would be difficult to argue that a modest rate of symptomatic improvement in uncontrolled (and thus unblinded) studies provides evidence that a treatment is of clinical benefit. As noted above, one might expect that non-drug-related responses would be even more common in such an unblinded single-arm study than in a study using a blinded control group (although responses did not seem greater in the unblinded best supportive care groups considered by Chvetzoff and Tannock). Chvetzoff and Tannock found that objective tumor responses were unusual in the 10 trials that reported these responses, with only two trials reporting objective tumor responses above 2%: a lung cancer trial (9) that reported a 6% tumor response rate and a renal cell carcinoma trial (10) that reported a 7% tumor response rate (better than the response to the active treatment). It thus appears that tumor response rates of more than 10% are unlikely to be seen in an untreated group and can therefore generally be considered evidence of a drug effect, especially if responses are assessed by blinded observers.
Although individual placebo-treated patients in the studies reviewed by Chvetzoff and Tannock showed improvements in pain, appetite, weight, and performance status, overall improvement in an entire placebo group was very unusual and was seen only for pain and, in one study, appetite. It therefore seems at least possible that a good-sized group improvement in a measure such as appetite, weight, performance status, or even quality of life might be interpreted as a drug effect. This possibility, however, should probably not lead to attempts to document clinical effects on such outcomes in single-arm trials. In the studies considered by Chvetzoff and Tannock, even subjects given active drugs only rarely showed group improvement in weight gain, performance status (none of eight trials), or quality of life (none of 10 trials). Such a finding in an uncontrolled setting thus would probably be treated skeptically. Moreover, the failure to see group improvements suggests that seeking to show one would usually be futile. An effective drug would seem to be much more likely than a placebo to show a group advantage, even though the treated group as a whole was declining or stable, with drug-treated patients showing a decreased rate of decline compared with placebo-treated patients.
It thus seems reasonably clear that, except for assessment of response rate, single-arm trials are a suboptimal way to assess benefits of treatment. Individual patient improvements are unpersuasive because Chvetzoff and Tannock show that such improvements can be seen in the absence of effective treatment, and group improvements are improbable.
REFERENCES
1 Chvetzoff G, Tannock IF. Placebo effects in oncology. J Natl Cancer Inst
2003;95:1929.
2 Walsh TB, Seidman SN, Sysko R, Gould M. Placebo response in studies of major depression. JAMA
2002;287:18407.
3 de Oliveira GG. The placebo effect: a brief review. Am J Ther 1995;2:21724.[Medline]
4 Ernst E, Herxheimer A. The power of placebo. BMJ
1996;313:156970.
5 Hrobjartsson A, Gotzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med
2001;344:1594602.
6 Spiegel D, Kraemer H, Carlson RW. Is the placebo powerless? [letter] N Engl J Med
2001;345:1276.
7 Miller FG. Is the placebo powerless? [letter] N Engl J Med 2001;345:1277.
8 Einarson TE, Hemels M, Stolk P. Is the placebo powerless? [letter] N Engl J Med 2001;345:1277.
9 Selawry O, Krant M, Scotto J, Kazam E, Schneiderman M, Olson K, et al. Methotrexate compared with placebo in lung cancer. Cancer 1977;40:48.[Medline]
10 Gleave ME, Elhilali M, Fradet Y, Davis I, Venner P, Saad F, et al. Interferon gamma-1b compared with placebo in metastatic renal-cell carcinoma. Canadian Urologic Oncology Group. N Engl J Med
1998;338:126571.
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |