Placebos and Blinding in 
Randomized Controlled 
Cancer Clinical Trials for 
Drug and Biological 
Products 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
August 2019 
Clinical/Medical 
   
Placebos and Blinding in 
Randomized Controlled 
Cancer Clinical Trials for 
Drug and Biological 
Products 
Guidance for Industry 
 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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guidances 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
August 2019 
Clinical/Medical 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  CONSIDERATIONS FOR USING PLACEBOS AND BLINDING............................ 2 
  Contains Nonbinding Recommendations 
Placebos and Blinding in Randomized Controlled Cancer Clinical 
Trials for Drug and Biological Products 
Guidance for Industry1 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the 
title page. 
 
 
 
I.  INTRODUCTION 
 
This guidance provides recommendations to industry about the use of placebos and blinding in 
randomized controlled clinical trials in development programs for drug or biological products2 to 
treat hematologic malignancies and oncologic diseases. This guidance does not address the 
statistical analyses that can be considered when data are unblinded in these trials. 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
 
 
II.  BACKGROUND 
 
Placebos, defined as inert substances with no pharmacologic activity, are commonly used in 
double-blind, randomized controlled clinical trials. Blinding investigators and patients in these 
trials to the treatment patients are receiving decreases the likelihood of biased observations of the 
effectiveness outcomes, may decrease differential patient drop out, and allows for unbiased 
observation of outcome measures, which are particularly important when the assessment includes 
subjective endpoints. For example, a placebo-controlled study design may be useful or preferred 
in maintenance therapy, in add-on trial designs, in trials of adjuvant therapies (for which standard 
                                                 
1 This guidance has been prepared by the Office of Hematology and Oncology Products in the Center for Drug 
Evaluation and Research (CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) at 
the Food and Drug Administration. 
 
2 For the purposes of this guidance, all references to drugs or drug products include both human drugs and 
biological products and drug-led and biologic-led combination products regulated by CDER and CBER, unless 
otherwise specified.  This guidance does not apply to medical devices or device-led combination products regulated 
by the Center for Devices and Radiological Health. 
  1  Contains Nonbinding Recommendations 
of care is surveillance), and for indications where no treatment is available (best supportive care 
can be added to both arms to ensure all available care is provided to patients). However, in 
development programs for malignant hematologic and oncologic disease, the use of a placebo in 
double-blind, randomized controlled clinical trials may present practical and ethical concerns. 
 
In many cases, because of the toxicity profile of the active treatment, patients and investigators 
may infer which treatment patients are receiving, so using a placebo control may not blind the 
treatment. For patients with hematologic malignancies and oncologic diseases that have standard 
effective therapy available, using a placebo (not an active treatment) generally would not be 
considered ethical, so an active control trial should be conducted. One such active control 
superiority trial design option is to conduct an open-label trial with a physicians choice of one of 
a few standard therapies as the comparator. In open-label comparative trials for which 
investigator bias may be of concern, a blinded central independent review of scans may mitigate 
bias regarding endpoint assessment.3 Another option has been to compare the investigational 
drug product with the placebo, with each added to the standard of care (an add-on trial). 
 
Continued blinding of patients and investigators at the time of disease progression or occurrence 
of serious adverse events is usually not acceptable. In a blinded immunotherapy trial, for 
example, a patient who develops suspected drug-related serious adverse events on the control 
arm may receive unnecessary treatments (e.g., immunosuppressive drug products including a 
high dose of glucocorticoids, cyclophosphamide, interleukin-6 antagonist, or infliximab) for 
management of adverse events incorrectly attributed to the investigational drug product. 
 
Maintaining the blind after disease progression could also affect the selection and timing of a 
patients subsequent therapy, potentially preventing a patient who had been on a placebo arm 
from receiving an approved therapy or delaying or preventing the patients entry into other 
clinical trials (for those trials of similar drug products that may have specific exclusion criteria 
based on prior treatment with an active drug or class of drugs). Unblinding in those cases would 
therefore allow informed decision-making about additional treatment options (see below). 
 
 
III.  CONSIDERATIONS FOR USING PLACEBOS AND BLINDING 
 
Given that using a placebo in randomized controlled clinical trials of therapies to treat 
hematologic malignancy and oncologic disease for which there is known effective therapy is 
ethically unacceptable, sponsors should consider using a placebo-controlled design only in 
selected circumstances (e.g., when surveillance is standard of care) or with certain trial design 
features (e.g., when the trial uses an add-on design). When considering a placebo control, 
sponsors should take the following into account: 
 
  Sponsors should provide the rationale for the trial design. Justification is particularly 
important in the setting of a sham surgical procedure, when invasive methods are 
required to administer a placebo (e.g., intrathecal administration, intratumoral 
                                                 
3 See the guidance for industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (December 
2018).  We update guidances periodically.  To make sure you have the most recent version of a guidance, check the 
FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
  2  Contains Nonbinding Recommendations 
administration, repeated intravenous administration via an indwelling catheter), when 
primary adverse event prophylaxis is required (e.g., antihistamine, acetaminophen, and/or 
corticosteroids to prevent infusion reaction), when there is an available therapy, or when 
a placebo is given as monotherapy and not combined with an active drug or drugs.4 
 
  FDA does not require patient-level maintenance of blinding at the time of disease 
recurrence or progression. Unless there are no available appropriate treatment 
alternatives, FDA recommends unblinding only the patient and the investigator at the 
time of documented disease recurrence or progression by an objective measurement or 
measurements to ensure optimal patient management. If sponsors intend to maintain 
patient-level blinding when disease recurs or progresses and there are existing available 
treatments, the informed consent document should acknowledge the risks of this 
approach, and the protocol should include justification for the potential added risk. 
 
 
  As stated in the guidance for industry and investigators Safety Reporting Requirements 
for INDs and BA/BE Studies (December 2012), FDA recommends unblinding the patient 
and the investigator when the patient has an adverse event suspected to be related to the 
investigational drug product and for which management of the adverse event with one or 
more drug products with substantial toxicity or invasive procedures is being considered. 
In such cases of unblinding, the patient can be removed from treatment based on benefit-
risk analysis, but the patient data should not be removed from the trial. If sponsors intend 
to maintain patient-level blinding when a suspected drug-related serious adverse event 
occurs, the informed consent document should acknowledge the risks of this approach, 
and the protocol should include justification for the potential added risk. 
 
 
  Sponsors should provide a detailed description in the protocol and in the statistical 
analysis plan of the proposal for blinding (including whether the physiological effects or 
adverse events associated with the investigational drug product would lead to some 
degree of unblinding) and planned unblinding (unblinding driven by potential need for 
medicines with substantial toxicity or invasive procedures for managing adverse events). 
                                                 
4 See the ICH guidance for industry E10 Choice of Control Group and Related Issues in Clinical Trials (May 2001) 
and https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-
involving-human-subjects/. 
  3