Since the beginning of the modern era of clinical trials, double-blinded, placebo-controlled randomized controlled trials (RCTs) have represented the gold standard paradigm for the evaluation of the safety and efficacy of drugs. RCTs are powerful tools to reduce prominent sources of bias in clinical trials by randomly assigning participants to distinct groups; these groups each receive different treatments, which are compared with a measured response.
Blinding and Placebos in Clinical Trials
The simple model of an RCT involves an experimental group, given the novel treatment being evaluated, and a control group. There are a variety of ways in which the experiment–control relationship can be structured: comparing the new drug with a placebo (an inert substance with no pharmacologic activity), comparing it with the current standard of care, or comparing the new drug plus the current standard of care with the standard of care alone, among others.
Many RCTs are blinded, a practice in which information that may influence the participants and clinical researchers is withheld until after the completion of the trial. Blinding trials eliminate a range of sources of experimental bias, including the placebo effect, the observer effect and confirmation bias.
Many trials require that study participants, caregivers, and researchers assessing clinical outcomes not know which intervention was given to each patient until after the outcome assessment or beyond. As effective as blinded, placebo-controlled RCTs are in reducing experimental bias, they are not intrinsically ethical, and the decision to pursue this trial design must be made under deep consideration of factors including the disease indication, the acuteness of the medical need, relevant disease progression timelines, toxicity profiles and the effectiveness of existing treatments. By definition, blinded, placebo-controlled RCTs are only justified in situations where there is clinical equipoise — legitimate uncertainty within the medical and research communities about the relative benefits of treatments. For many clinical trials exploring cancer treatments, this criterion is not met, and ethical treatment of trial participants requires conducting the trials using other models.
To help sponsor pharma and biopharma companies, contract research organizations (CROs), clinical logistics organizations (CLOs) and academic researchers to make the best ethical decisions in the design of clinical trials for development programs for small molecule or biologic drugs to treat hematological malignancies and oncological diseases, the U.S. Food and Drug Administration (FDA) issued a new guidance titled “Placebos and Blinding in Randomized Controlled Cancer Clinical Trials for Drug and Biological Products: Guidance for Industry” in August 2019.1 As is typical for the FDA’s guidance documents, the recommendations are nonbinding and are not legally enforceable, but rather depict that agency’s current thinking about the topic and represent its assessment of overall best practices for these trials.
Ethical Issues with Placebos
In the guidance document, the FDA describe situations in which blinding and placebo controls are either impossible to effectively maintain in cancer clinical trials or inappropriate to the goal of providing ethically informed treatment to clinical trials participants.
Foremost among these considerations is the inappropriateness of using placebo controls for hematologic malignancies or oncological diseases, for which there is a standard effective therapy. As there is no ethnical rationalization for treating cancer patients with placebos and hence depriving the control group of the available effective treatment, active control trials must be conducted. Depending upon the nature of the experimental treatment, this could be an open-label trial comparing the experimental treatment with a standard therapy, or an add-on trial in which both groups receive the standard of care, with the experimental group also receiving the new therapy and the control group adding a placebo.
Ethical Issues with Blinding
Another source of ethical complications in cancer clinical trials involves the toxicity of the treatments and the potential for disease progression over the course of the trial. Because of the considerable toxicity profiles associated with many anticancer agents, true blinding may not be possible, because investigators may be able to infer the treatment a given patient received based on the adverse effects observed. Beyond this pragmatic concern, blinding in such cases may interfere with the ability to treat the patients appropriately. Patients may experience adverse effects from the investigational treatment that require therapeutic management, and those management decisions need to be definitively informed by specific knowledge of the treatment received by each patient, which requires unblinding, at least concerning the investigators and clinical evaluators.
Similarly, in cases where patients experience progression of the disease, maintaining blinding could prevent patients from receiving the appropriate subsequent therapy at the most appropriate time, preventing the patient from promptly receiving an approved therapy (if available) or enrolling in another clinical trial. Maintaining blinding of a clinical trial beyond the point of disease progression would prevent clinicians from making truly informed decisions about further treatment, to the clear disadvantage of the enrolled patients, and so blinding, if applied at all, should terminate at an appropriate time.
The FDA’s Recommendations
In light of the above, the FDA makes a few clear recommendations for the use of placebos and blinding in clinical trials of cancer treatments. First, the agency suggests that, owing to the ethical issues discussed above, placebo-controlled clinical trial designs for cancer treatments are only appropriate in selected circumstances — when the current standard of care is surveillance only or when the trial implements an add-on design.
Second, the FDA does not require or recommend patient-level blinding at the time of disease recurrence or progression, and explicitly recommends unblinding of the patient and investigator when disease recurrence or progression (objectively measured) occurs, unless there is no available alternative treatment. The agency further recommends patient- and investigator-level unblinding when a patient experiences an adverse effect likely related to the toxicity profile of the investigational treatment.
Finally, the FDA strongly suggests that sponsors provide a detailed plan in the relevant protocol for how blinding is to be maintained and the circumstances and timeline for unblinding, as well as to provide detailed justification for any decisions or elements of the trial design that are not in line with the agency’s recommendations.
1. Placebos and Blinding in Randomized Controlled Cancer Clinical Trials for Drug and Biological Products: Guidance for Industry. U.S. Food and Drug Administration. Aug. 2019. Web.