Introduction & Position Statement
The ethics of placebo-controlled trials have been the subject of controversies over time and have divided the scientific, regulatory and the ethicist communities. Some argue for the use placebo only when there is no proven intervention for the condition under study, while others think it should not even be used when there is an effective therapy available (1). Notwithstanding arguments to the contrary, I think it is ethically justifiable to use placebo-control trials under certain circumstances even when there is an effective treatment/intervention available.
Supporting Arguments
The complexity of the debate over the use of Placebo-Control Trials (PCT) in clinicals trials encompasses 3 domains: scientific, regulatory and ethical that have a common denominator that is the protection of human subjects and their well-being: They are intertwined and the separation here is made for distinctive ethical categorization.
The sciences
Clinical trial’s main goal is to determine the effectiveness and safety of a new drug/intervention being tested. Through the scientific method of randomized design, such as PCT, subjects are divided into a treatment group and a placebo group, in order to determine if the new treatment/intervention is more effective and safer than placebo or no intervention (2). A new drug /intervention may be tested against an existing one, which has already proven to be effective and safe. To compare existing drugs/intervention to a new one, the Active Control Trial (ACT) designs in which all patients receive an active drug new or existing can be used (3). As Temple R. et al. explained, the goal of these study is also to demonstrate that the new treatment is “no more than a little worse than” the existing treatment. Defined as non-inferiority studies or equivalence studies, they are meant to demonstrate if the new intervention may have other specific advantages such as a more favorable toxicity profile, a more convenient dosing regimen, a more desirable formulation or route of administration (4).
Even if they show equivalency in effectiveness, they lack “assay sensitivity”, which is the ability of a trial to distinguish an effective treatment from a less effective or ineffective one. Thus, making it difficult draw conclusions due to the lack of internal validity. In such case without a placebo group the finding can be misleading or uninterpretable. Hence, the only way that a drug should be approved is by being superior to placebo or no treatment (3). PCT can be carried out even in the case of medical conditions with proven effective interventions, because of the methodologic limitations of trials using active treatment control (3). In fact, when the lack of difference is not found due to the presence of a placebo condition, the medications might be equally effective or ineffective because of errors in measurement or in selection. Regardless of the intervention, patients may show improvement in their condition as a result of spontaneous remissions or symptomatic fluctuations characteristic of their illnesses (3, 5).
Methodologically, PCTs may be justified when they are necessary to prove that a new treatment has efficacy in a disease with a high placebo response rate; in a condition that waxes and wanes in severity, or has spontaneous remissions, or has an uncertain and unpredictable course; or when therapies exist that are only minimally effective or have serious adverse effects; or in the absence of any effective therapy. The use of placebos may also be justified to assure that physicians and patients are blinded to treatment assignment so as to minimize bias in assessment of study end points. Scientifically it is generally accepted that PCT is the best scientific methods to prove the effectiveness of a therapy. because it is using good scientific methods to prevent exposing trial participants to unjustified high risk with no hope of providing useful information (3, 6).
Placebo controls are acceptable when certain methodologic and ethical criteria are both fulfilled. When there is a scientific methodologic justification for the use of placebo, the trial must then fulfill ethical considerations regarding risk (6).
The Ethics
Article 33 of The Declaration of Helsinki in its current version, despite calling for extreme caution to avoid abuse, stipulates: the benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best proven intervention(s), except in the following circumstances: 1) Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 2) Where for compelling and scientifically sound methodological reasons the use of any intervention less effective than the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy or safety of an intervention and 3) the patients who receive any intervention less effective than the best proven one, placebo, or no intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention (7). Thus, recognizing the use of placebo, even in the presence of an effective treatment, when there are scientifically sound methodological reasons or when patients receiving placebo are not exposed to any additional risk of serious or irreversible harm (3, 6, 7).
The Regulatory
Current regulations provide guidance for clinical research involving human subjects. FDA regulation on human subjects’ protection (21 CFR 50) and Institutional Review Boards (IRBs) (21CFR 56) in conjunction with DHHS 45 CFR 46 111 and 45 CFR 46 116 safeguard the right, safety and wellbeing of potential subjects involved in clinical trial (8,9). The FDA puts an emphasis on IRBs, when reviewing research protocol for approval, to focus on risk-benefit assessment and minimizing harm to subjects. Randomly assigned participants to placebo arm should be prevented form the risk and harm that may lead to dying; suffering from irreversible morbidity or disability in cases of treatments for headache, gastrointestinal upset, acne, impotence and hair loss (2).
IRB must implement scrupulous standards set by the regulators to ensure that harm to subjects is minimized (3). Miller FG et al. added that IRBs should approve research with children only when the research qualifies for one of three risk-benefit categories: 1) minimal risk; 2) greater than minimal risk, but presenting the prospect of direct benefit; and 3) greater than minimal risk without the prospect of direct benefit but likely to produce generalizable knowledge about the subjects’ disorder or condition. (10)
In cases of no treatment and treatment whose safety and efficacy have not been established, subjects in placebo arm are receiving essentially the same thing they would have received outside of the research context i.e., no effective treatment (6,11,12). This poses minimal risks to participants, especially when it is implemented in a short period of time. The informed consent makes the use of PCT despite the existence of effective therapy ethically permissible. A PCT may proceed legitimately if participants are fully informing about the risks and potential benefits of the trial, including the risks of being deprived of standard therapy, (11).
The influence of regulators in the US and internationally, in asserting that placebo controls are an indispensable part of a rigorous randomized controlled design, is undeniable. Despite the fact that they may accept a multitude of other trial designs for drugs approval, PCT is the gold standard (11, 13). Regulators stance on placebo controls that make them ethically permissible, when an effective treatment exist, is based on three premises: 1) the existence of an informed consent; 2) the physicians’ participation without exposing patients to risks of permanent disability or death; and 3) the assay sensitivity, that ascertains the validity of a comparison between a new drug/intervention and a standard therapy or existing drug (11). For conditions in which forgoing therapy imposes no important risk, however, the participation of patients in PCTs seems appropriate and ethical, as long as patients are fully informed (4). Regulatory guidance requires, through Informed consent, that patients should be given the opportunity to voluntarily enroll or continue to stay in the study. They should be explained the consequences of remaining untreated and availability of active treatment elsewhere. The investigator and informed consent documents must fully disclose to potential participants the fact that the trial involves use of a placebo control (4, 6, 11). The investigator should inform participants in a timely manner if information becomes available that may be relevant to the subject’s willingness to continue participation in the trial. Additionally, it is imperative for them to know whether they have received a placebo or intervention to make an informed decision about whether to withdraw from the trial; they should be aware of the risks of remaining unblinded in the trial for a long period (14). Additionally, subject selection must minimize the likelihood of serious adverse consequences, and subjects must be capable of providing informed, voluntary consent, or have consent provided by a suitable surrogate.
Counter Position and Supporting Argument(s)
As mentioned above, Article 33 of The Declaration of Helsinki in its current version also states: The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best proven intervention(s) (7). This stipulation validates the ACT design and seems to reject the use of placebos in case an established treatment exists, because the clinician perspective is to only use a new drug that is proven superior or at least non-inferior than the existing one (3,13) Additionally, this constitutes the basis of clinical equipoise requiring that, if patients are to be randomly assigned to one of two interventions in a clinical trial, there must be genuine doubt about which is better, this reflects the traditional view that physicians must never knowingly compromise the care of their patients, even for the sake of future patients. Since it is unethical in clinical practice to administer an inferior treatment (or a placebo) to a patient instead of the best proven therapy, withholding a proven effective treatment in clinical research should be considered unethical in the absence of clinical equipoise (2,3,10,13,15).
Rebuttal
The doctrine of clinical equipoise is fundamentally flawed and is based on premise that clinical research and clinical practice ought to be grounded on the same moral principles. As noted by Miller “the presumption that randomized clinical trials must be compatible with the ethics of the physician-patient relationship assumes erroneously that the randomized clinical trial is a form of therapy”. It must be recognized that clinical research and clinical care are fundamentally different practices governed by different moral principles. Whereas in clinical practice, the principles of beneficence and non-maleficence are always patient-centered; in clinical research, beneficence concerns the promotion of the social good of improving health by means of generalizable knowledge, while non-maleficence limits the risks to which participants can be exposed for the sake of this goal (16 pg. 266). Since this concern is mostly raised by physicians/investigators, the separation of clinical research and clinical medicine should be clearly defined. Miller and Brody made that distinction when they said “Clinical medicine aims at providing optimal medical care for individual patients. … Clinical research is dedicated primarily to promoting the medical good of future patients by means of scientific knowledge derived from experimentation with current research participants—a frankly utilitarian purpose” (17, pg 21).
Conclusion
There are reasons that justify study designs that use placebo, provided that:
- Scientifically the PCT is recognized as being the best trial design to ascertain the effectiveness and the safety of a new drug. PCT can be carried out even in the case of medical conditions for which there are interventions known to be effective, because of the methodologic limitations of trials in which active treatment is used as the control. 2) Ethically the Declaration of Helsinki recognizes the necessity of using placebo, even in the presence of effective treatment when patients receiving placebo are not exposed to any additional risk of serious or irreversible harm. 3) Regulatorily, there are guidance documents issued to provide protection and ways to assess the risk-benefit ratio to minimize harm to subjects, safeguarding them from suffering irreversible side effects, severe discomfort as well as death. They are executed through IRBs review of proposals and documented inform consent. Above all, PCT is the required design of excellence by regulators over the world for new drugs approval.
As shown above, placebo-controlled Trials, even in the case of medical conditions for which there are drugs/interventions known to be effective, are scientifically feasible, ethically justifiable, and may be necessary or desirable to meet regulatory standards for drug approval. Thus, despite the emergence of novel designs in clinical trials, and as long as scientific, ethical and regulatory conditions are met, PCT will continue to be used for years to come.
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