In the absence of a placebo group, a finding of no difference in an active-control study therefore can mean that both agents are effective, that neither agent was effective in that study, or that the study was simply unable to tell effective from ineffective agents. In other words, to draw the conclusion that the test article was effective, one has to know with assurance that the active-control would have shown superior results to a placebo, had a placebo group been included in the study.
For certain drug classes, such as analgesics, antidepressants or antianxiety drugs, failure to show superiority to placebo in a given study is common. This is also often seen with antihypertensives, anti-angina drugs, anti-heart failure treatments, antihistamines, and drugs for asthma prophylaxis. In these situations, active-control trials showing no difference between the new drug and control are of little value as primary evidence of effectiveness and the active-control design the study design most often proposed as an alternative to use of a placebo is not credible.
In many situations, deciding whether an active-control design is likely to be a useful basis for providing data for marketing approval is a matter of judgment influenced by available evidence. If, for example, examination of prior studies of a proposed active-control reveals that the test article can very regularly almost always be distinguished from placebo in a particular setting subject population, dose, and other defined parameters , an active-control design may be reasonable if it reproduces the setting in which the active-control has been regularly effective.
It is often possible to design a successful placebo-controlled trial that does not cause investigator discomfort nor raise ethical issues. Treatment periods can be kept short; early "escape" mechanisms can be built into the study so that subjects will not undergo prolonged placebo-treatment if they are not doing well.
In some cases randomized placebo-controlled therapy withdrawal studies have been used to minimize exposure to placebo or unsuccessful therapy; in such studies apparent responders to a treatment in an open study are randomly assigned to continued treatment or to placebo. Subjects who fail e. Many researchers think that treatment earlier in the disease process may help prevent or delay dementia. Food and Drug Administration toll-free druginfo fda. NIA scientists and other experts review this content to ensure it is accurate and up to date.
Registries and Matching Services for Clinical Trials. Clinical Trials Placebos in Clinical Trials. Even if the demands of science argue in favor of such a protocol, the canons of ethics forbid it. The Nuremberg Code, the Declaration of Helsinki, and the Belmont Report have all provided the framework for the current Office for Protection from Research Risk OPRR guidebook that informs institutional review boards in their assessments of human subjects protocols.
At times, however, federal regulations may conflict with the ethical guidelines provided by the OPRR. Although ethical guidelines do not rule out placebo-controlled studies, they emphasize the well-being of participants and the need for scrutiny by an institutional review board.
These guidelines call on institutional review boards to perform a careful risk-benefit analysis when considering whether to allow a placebo-controlled trial. A possible reason for the persistence of placebo controls in many drug trials is that research that is privately sponsored must answer to the Food and Drug Administration to get approval for new drugs. Placebo-controlled clinical trials still seem to be required for the Food and Drug Administration to approve the use of a new drug.
The Food and Drug Administration addresses the ethical concerns of using placebo controls by suggesting that such trials may be short, should provide for withdrawal if a participant's condition worsens, and should frequently monitor the progression of the disease. Yet, the Food and Drug Administration has historically withheld its approval of some drugs when placebo controls were not used.
Second, trials that are intended to show no significant differences between two therapies—that is, that two drugs are therapeutically equivalent—could reduce the emphasis on strict scientific conduct. Third, equivalence trials assume that the active control was effective specifically in the study in which it was used and, thus, would have been superior to a placebo had one been used.
We will address each of these concerns separately. If a new drug is being compared with an existing therapy that is known to be effective, the sponsor will either have to settle for showing equivalency or, in addition, a more favorable profile of side effects.
Two medications with similar effects may show significant differences when compared with a placebo but not when compared with each other. Although sponsors may balk at the prospect of lengthy trials with a large number of participants, the equivalence-versus-superiority argument is a marketing concern and does not ethically justify exposing participants to an avoidable risk.
The second issue is an ethical rather than a statistical one. Equivalence trials are intended to show the comparability of new and existing therapies, and anything that obscures differences favorable or unfavorable between the two would help support this claim.
Some have argued that this provides an incentive for investigators to be lax in screening potential participants for inclusion, assessing outcomes, and monitoring compliance. This behavior jeopardizes scientific integrity. The third concern, about active controls, is that showing equivalence to an active control assumes that the control drug would be superior to a placebo had one been used in that particular trial.
Approved drugs, by definition, have shown efficacy as part of the Food and Drug Administration approval process. If an approved drug with a historical profile is used as the control for an investigation involving a disease with objective measures of progression or remission, then it is unnecessary to make assumptions regarding the drug's efficacy in the current trial.
We propose that definable conditions exist that should be addressed before placebo-controlled trials are permitted to proceed. The assessment of these clinical conditions is grounded in the ethical requirements outlined in the Belmont Report 12 and reflects the current guidance of the OPRR guidelines.
For the approval of placebo controls in phase 2, 3, and 4 trials, the following questions should be considered:. Do participants have a disease or condition for which treatment is available, normally prescribed, and of known efficacy?
Will lack of treatment likely result in progression of the disease or condition or the infliction of pain or suffering during the trial? If the disease process is irreversible, how great is the burden of this progression, and how likely is existing treatment to resolve or reduce this burden?
Is there substantial evidence that the experimental treatment is of therapeutic benefit? The answers to these questions should serve to guide institutional review boards in determining whether a placebo-control group is justified. Complete ethical accountability requires that sponsors, institutions, and investigators accept responsibility for subjects who suffer harm because they were given a placebo rather than an available standard therapy.
A signed consent form should not shield investigators from claims of malpractice if standard therapy for a condition was intentionally withheld and the subject suffered irreversible harm. We are indebted to Robert J Levine for his review and guidance with this manuscript and gratefully acknowledge his contribution. Competing interests: None declared. National Center for Biotechnology Information , U. Journal List West J Med v. West J Med.
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