COVID-19: Master Protocols 
Evaluating Drugs and 
Biological Products for 
Treatment or Prevention 
Guidance for Industry 
 
 
This guidance is intended to remain in effect until March 7, 2024, unless superseded by 
a revised final guidance before that date. For further information, refer to 88 FR 15417, 
March 13, 2023, available at https://www.federalregister.gov/documents/2023/03/13/2023-
05094/guidance-documents-related-to-coronavirus-disease-2019-covid-19.  
   
COVID-19: Master Protocols 
Evaluating Drugs and 
Biological Products for 
Treatment or Prevention 
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) 
Oncology Center of Excellence (OCE) 
 
May 2021 
Clinical/Medical 
   
COVID-19: Master Protocols 
Evaluating Drugs and 
Biological Products for 
Treatment or Prevention 
Guidance for Industry 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
and/or 
 
Office of Communication, Outreach, and Development  
Center for Biologics Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Room 3128 
Silver Spring, MD  20993-0002 
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-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) 
Oncology Center of Excellence (OCE) 
 
May 2021 
Clinical/Medical 
  Contains Nonbinding Recommendations 
Preface 
 
Public Comment 
 
This guidance is being issued to address the Coronavirus Disease 2019 (COVID-19) public 
health emergency. This guidance is being implemented without prior public comment because 
the Food and Drug Administration (FDA or Agency) has determined that prior public 
participation for this guidance is not feasible or appropriate (see section 701(h)(1)(C) of the 
Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 371(h)(1)(C)) and 21 CFR 
10.115(g)(2)). This guidance document is being implemented immediately, but it remains subject 
to comment in accordance with the Agencys good guidance practices. 
 
Comments may be submitted at any time for Agency consideration. Submit written comments to 
the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852. Submit electronic comments to https://www.regulations.gov. 
All comments should be identified with the docket number FDA-2021-D-0409 and complete title 
of the guidance in the request. 
 
Additional Copies 
 
Additional copies are available from the FDA web page titled COVID-19-Related Guidance 
Documents for Industry, FDA Staff, and Other Stakeholders, available at 
https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/covid-19-related-
guidance-documents-industry-fda-staff-and-other-stakeholders and the FDA webpage titled 
Search for FDA Guidance Documents, available at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents. You may also send an e-mail request to COVID19-
productdevelopment@fda.hhs.gov to receive an additional copy of the guidance. Please include 
the Docket number FDA-2021-D-0409 and complete title of the guidance in the request. 
 
Questions 
 
For questions about this document, contact Eithu Lwin at 301-796-0728 or at 
Eithu.Lwin@fda.hhs.gov. 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................2 
III.  DISCUSSION .........................................................................................................4 
A.  Guiding Principles ............................................................................................................. 4 
B.  Trial Design and Conduct Considerations ...................................................................... 4 
C.  Statistical Considerations ................................................................................................. 7 
D.  Administrative and Procedural Recommendations ....................................................... 9 
 
  Contains Nonbinding Recommendations 
COVID-19: Master Protocols Evaluating  
Drugs and Biological Products for Treatment or Prevention 
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 office responsible for this guidance as listed on the 
title page.   
 
 
 
I.  INTRODUCTION 
 
FDA plays a critical role in protecting the United States from threats such as emerging infectious 
diseases, including the Coronavirus Disease 2019 (COVID-19) pandemic. FDA is committed to 
providing timely guidance to support response efforts to this pandemic.   
 
FDA is issuing this guidance to provide recommendations to sponsors of master protocols2 
evaluating drugs3 for the treatment or prevention of COVID-19.  
 
Given this public health emergency, and as discussed in the Notice in the Federal Register of 
March 25, 2020, titled Process for Making Available Guidance Documents Related to 
Coronavirus Disease 2019, available at https://www.govinfo.gov/content/pkg/FR-2020-03-
25/pdf/2020-06222.pdf, this guidance is being implemented without prior public comment 
because FDA has determined that prior public participation for this guidance is not feasible or 
appropriate (see section 701(h)(1)(C) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) 
(21 U.S.C. 371(h)(1)(C)) and 21 CFR 10.115(g)(2)). This guidance document is being 
implemented immediately, but it remains subject to comment in accordance with the Agencys 
good guidance practices. 
 
1 This guidance has been prepared by the Office of New Drugs and the Office of Biostatistics in the Center for Drug 
Evaluation and Research, the Center for Biologics Evaluation and Research, and the Oncology Center of Excellence 
at the Food and Drug Administration. 
 
2 For the purposes of this guidance, master protocol sponsor refers to the person or organization who takes 
responsibility for and initiates the master protocol. In many instances individual investigational drugs chosen for 
evaluation in the master protocol will also be evaluated under a separate investigational new drug application (IND). 
For the purposes of this guidance, a sponsor responsible for the investigation of an individual drug evaluated under 
the separate IND is referred to as the individual investigational drug sponsor. The master protocol sponsor and the 
individual investigational drug sponsor may or may not be the same entity.   
 
3 For the purposes of this guidance, all references to drugs include both human drugs and biological products unless 
otherwise specified. 
 
1  Contains Nonbinding Recommendations 
 
This guidance is intended to remain in effect for the duration of the public health emergency related 
to COVID-19 declared by the Department of Health and Human Services (HHS), including any 
renewals made by the Secretary in accordance with section 319(a)(2) of the Public Health Service 
Act (42 U.S.C. 247d(a)(2)). However, the recommendations and processes described in the guidance 
are expected to assist the Agency more broadly in its efforts to assist sponsors with the design of 
COVID-19 master protocols, including under circumstances outside of the COVID-19 public health 
emergency, and reflect the Agencys current thinking on this issue. Therefore, within 60 days 
following the termination of the public health emergency, FDA intends to revise and replace this 
guidance with any appropriate changes based on comments received on this guidance and the 
Agencys experience with implementation.  
 
The contents of this document do not have the force and effect of law and are not meant to bind 
the public in any way, unless specifically incorporated into a contract. This document is intended 
only to provide clarity to the public regarding existing requirements under the law. FDA 
guidance documents, including this guidance, should be viewed only as recommendations, unless 
specific regulatory or statutory requirements are cited. The use of the word should in Agency 
guidance means that something is suggested or recommended, but not required. 
 
 
II.  BACKGROUND 
 
There is currently an outbreak of respiratory disease caused by a novel coronavirus. The virus 
has been named SARS-CoV-2 and the disease it causes has been named Coronavirus 
Disease 2019 (COVID-19). On January 31, 2020, HHS issued a declaration of a public health 
emergency related to COVID-19, effective January 27, 2020, and mobilized the Operating 
Divisions of HHS.4 In addition, on March 13, 2020, there was a Presidential declaration of a 
national emergency in response to COVID-19.5   
 
This guidance describes FDAs current recommendations to sponsors of master protocols 
evaluating drugs for the treatment or prevention of COVID-19.6 For the purposes of this 
guidance, a master protocol is defined as a protocol designed with multiple substudies, which 
 
4 Secretary of Health and Human Services, Determination that a Public Health Emergency Exists, (originally issued 
Jan. 31, 2020, and subsequently renewed), available at 
https://www.phe.gov/emergency/news/healthactions/phe/Pages/default.aspx. 
 
5 Proclamation on Declaring a National Emergency Concerning the Novel Coronavirus Disease (COVID-19) 
Outbreak (Mar. 13, 2020), available at https://trumpwhitehouse.archives.gov/presidential-actions/proclamation-
declaring-national-emergency-concerning-novel-coronavirus-disease-covid-19-outbreak/. On February 24, 2021, 
there was a Presidential Declaration continuing the national emergency concerning the COVID-19 pandemic beyond 
March 1, 2021. See Continuation of the National Emergency Concerning the Coronavirus Disease 2019 (COVID-
19) Pandemic (February 24, 2021), available at https://www.federalregister.gov/documents/2021/02/26/2021-
04173/continuation-of-the-national-emergency-concerning-the-coronavirus-disease-2019-covid-19-pandemic.   
 
6 Under 42 U.S.C.  282(j), including its implementing regulations in 42 CFR part 11, certain applicable clinical 
trials must be registered at www.ClinicalTrials.gov. Within one year of the primary completion date, with certain 
exceptions for submission beyond one year, responsible parties must submit required summary results information 
to www.ClinicalTrials.gov. FDA encourages responsible parties to submit summary results information as soon as 
possible and ahead of required statutory and regulatory deadlines. 
2  Contains Nonbinding Recommendations 
may have different objectives and involve coordinated efforts to evaluate one or more 
investigational drugs in one or more disease subtypes within the overall trial structure.7 Types of 
master protocols include umbrella trials, platform trials, and basket trials.8, 9 This guidance 
primarily focuses on umbrella trials and platform trials, as these are of particular relevance to the 
current landscape of COVID-19 drug development. Umbrella trials evaluate multiple therapies 
simultaneously for a single disease. Platform trials evaluate multiple therapies for a single 
disease in a perpetual manner, with therapies entering or leaving the platform on the basis of a 
decision algorithm.  
 
Well-designed and conducted master protocols can accelerate drug development by maximizing 
the amount of information obtained from the research effort. Compared with conducting separate 
stand-alone trials, conducting an umbrella or platform trial can increase data quality and 
efficiency through shared infrastructure and can reduce overall sample size through sharing of a 
control arm. These efficiencies are of particular importance in the setting of a public health 
emergency such as the current COVID-19 pandemic, where there is a critical need for the 
efficient development of therapies. FDA expects master protocols to continue to play an 
important role in addressing the public health needs created by the current COVID-19 pandemic, 
as well as in future pandemics that might occur.  
 
This guidance primarily focuses on the design, conduct, and statistical considerations of master 
protocols intended to generate or contribute to substantial evidence of effectiveness and adequate 
characterization of safety of drugs for the treatment or prevention of COVID-19. However, the 
principles in the guidance may also apply to master protocols generating proof of concept or 
dose-ranging data for drugs to treat or prevent COVID-19. Additionally, this guidance provides 
administrative and procedural recommendations to sponsors of master protocols for COVID-19 
drugs. This guidance is intended to complement other COVID-19 guidances.10 
 
Sponsors should also review the draft guidance for industry Master Protocols: Efficient Clinical 
Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics.11 While not 
 
7 See also the draft guidance for industry Master Protocols: Efficient Clinical Trial Design Strategies to Expedite 
Development of Oncology Drugs and Biologics (September 2018). When final, this guidance will represent the 
FDAs current thinking on this topic. For the most recent version of a guidance, check the FDA guidance web page 
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
8 Woodcock J, LaVange LM, 2017, Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both, N 
Engl J Med, 377(1):6270.   
 
9 Basket trials study a single targeted therapy in the context of multiple diseases or disease subtypes.   
 
10 See the guidances for industry COVID-19: Developing Drugs and Biological Products for Treatment or 
Prevention (February 2021), Emergency Use Authorization for Vaccines to Prevent COVID-19 (February 2021), 
Development and Licensure of Vaccines to Prevent COVID-19 (June 2020), Investigational COVID-19 
Convalescent Plasma (February 2021), and Statistical Considerations for Clinical Trials During the COVID-19 
Public Health Emergency (June 2020) and the guidance for industry and investigators COVID-19 Public Health 
Emergency: General Considerations for Pre-IND Meeting Requests for COVID-19 Related Drugs and Biological 
Products (May 2020). 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.  
11 When final, this guidance will represent the FDAs current thinking on this topic. 
3  Contains Nonbinding Recommendations 
specific to COVID-19, general principles from the oncology master protocol guidance may also 
inform considerations of master protocols for COVID-19 drugs.   
 
 
III.  DISCUSSION 
 
A.  Guiding Principles 
 
All sponsors developing drugs to treat or prevent COVID-19 should consider the following 
guiding principles when determining whether to conduct a master protocol or a stand-alone trial:  
 
  Both master protocols and stand-alone trials have strengths and limitations including the 
following:  
 
  As noted above, master protocols can accelerate drug development by maximizing the 

amount of information obtained and leveraging infrastructure to increase trial 
efficiency.  
 
  Potential limitations of master protocols include their complexity, which necessitates 

a high degree of up-front planning and coordination.  
 
  In contrast, a stand-alone trial may be easier to design and conduct; however, 

typically, fewer scientific questions can be addressed.  
 
  Given the different types of data that need to be generated during drug development (e.g., 
proof of concept, dose-ranging, substantial evidence of effectiveness, safety data) a 
development program may include both master protocols and stand-alone trials.  
 
  For all trials in the development program, a sponsor should clearly identify objectives 

to allow for the selection of an appropriate trial design.  
 
  Sponsors should provide justification for the to-be-evaluated dose(s). This 

justification may require measurement of biological activity in applicable 
investigational products (e.g., neutralizing antibody titers in convalescent plasma). 
 
  In general, master protocols are not intended for first-in-human investigation.  

 
  Sponsors considering master protocols for the development of COVID-19 drugs should 
engage FDA early in their planning to determine the appropriateness of such approaches. 
 
B.  Trial Design and Conduct Considerations 
 
Master protocol sponsors evaluating drugs to treat or prevent COVID-19 should consider the 
following: 
 
4  Contains Nonbinding Recommendations 
  A master protocol should include an appropriate randomized comparator arm. In the 
COVID-19 setting, a high potential exists for confounding when comparisons are made 
to participants12 who were not concurrently randomized because of changes over time 
such as changes in the standard of care including background treatments and supportive 
care, circulating SARS-CoV-2, availability of health care resources, or the distribution of 
enrollment across trial sites and regions.  
 
  Master protocol sponsors should seek concurrence from the Agency before implementing 
a change where a drug evaluated under the master protocol is incorporated into the trial 
as either background therapy or as part of the control arm. It is possible that a drug may 
be incorporated into the control arm but not as background therapy for all arms in 
situations where it would be inappropriate to add therapies together (e.g., similar 
mechanism of action).  
 
  For master protocols evaluating multiple drugs, some participants may not be eligible to 
receive a particular drug for safety reasons (e.g., diminished renal or liver function). In 
these situations, protocols should be designed to prevent participants from being 
randomized to drugs they are not eligible to receive. 
 
  Master protocol sponsors should make every effort to incorporate blinding into their 
trials. Sponsors should consider the following:  
 
  In a placebo-controlled trial where investigational drugs have multiple routes of 

administration or variable dosing schedules, blinding could be achieved through 
either of the following:   
 
  A multiple-dummy design (e.g., for a master protocol with three investigational 
arms a participant will receive three placebos or one investigational drug and two 
placebos, leading to complete blinding)  
 
or  
 
  A distinct, blinded placebo control for each drug (e.g., for a master protocol with 
three investigational arms a participant will receive one substance, either the 
investigational drug randomized to or its matching placebo). In this case, the 
sponsor could randomize the participants to an intervention-specific subprotocol 
(among those they are eligible for) and then randomize them to either that 
investigational drug or its matched placebo. Statistical comparisons between an 
investigational drug and placebo can include participants who were eligible to be 
randomized to the drug but were randomized to placebo groups for other 
interventions. 
 
  In trials where blinding is impractical, FDA strongly recommends an objective 

endpoint (e.g., all-cause mortality). 
 
12 For the purposes of this guidance, participant refers to a person enrolled in a COVID-19 prevention or treatment 
trial. 
5  Contains Nonbinding Recommendations 
 
  In cases where drugs are intended to affect different aspects of the disease (e.g., 
anticoagulants, antivirals), there may be multiple intervention-specific endpoints. Master 
protocol sponsors should discuss endpoint selection with the Agency, given the potential 
for additional complexities in trial design, conduct, and analysis.  
 
  Collection of safety data is important for novel drugs as well as repurposed drugs being 
evaluated for COVID-19, as the safety profile of repurposed drugs may differ in a new 
population. However, under certain circumstances and with the Agencys concurrence, a 
selective approach to safety data collection for drugs with a well-characterized safety 
profile and low toxicity may be appropriate.13 The following should be considered when 
determining if selective safety data collection is appropriate:   
 
  The type of master protocol and drugs expected to be evaluated may impact the 

approach to safety data collection. For example, in a master protocol with a shared 
control arm and selective safety data collection, if collection of additional safety data 
(which are not being collected under the master protocol) is needed for a new drug in 
a subprotocol, the comparisons of that outcome could only utilize the subset of 
participants in the control group for whom the appropriate safety data were collected.  
 
  Master protocol sponsors should provide justification to support a selective safety 

data approach, taking into account the safety profile of the drugs expected to be 
evaluated as well as the role of the master protocol in adequately characterizing safety 
within the overall clinical development program. 
 
  Master protocol sponsors are reminded that selective safety data collection does not 

alter safety reporting requirements.14  
 
  In trials with a selective approach to safety collection, where the data collected differs 

between treatment arms, sponsors should address the impact of such differences in 
their risk-based monitoring plans.15 This is because of the increased potential for data 
collection errors when the data collected differs between treatment arms. 
 
  Sponsors must provide adequate oversight to ensure protection of the rights, safety, and 
welfare of subjects enrolled in clinical trials and to ensure the integrity of the data 
 
13 See the guidances for industry COVID-19: Developing Drugs and Biological Products for Treatment or 
Prevention (February 2021) and Determining the Extent of Safety Data Collection Needed in Late-Stage Premarket 
and Postapproval Clinical Investigations (February 2016). 
 
14 See 21 CFR 312.32 and 21 CFR 312.64(b). See also the guidance for industry and investigators Safety Reporting 
Requirements for INDs and BA/BE Studies (December 2012) and the draft guidance for industry Safety Assessment 
for IND Safety Reporting (December 2015). When final, this guidance will represent the FDAs current thinking on 
this topic. 
15 See the guidance for industry Oversight of Clinical Investigations  A Risk-Based Approach to Monitoring 
(August 2013).  
 
6  Contains Nonbinding Recommendations 
submitted to FDA.16 The added complexity of master protocols may increase the 
potential for protocol deviations impacting the safety and welfare of subjects and the data 
integrity of these trials. Accordingly, sponsors should take measures (e.g., training at a 
site level) to help reduce the likelihood of clinically significant protocol deviations from 
occurring when designing, implementing, and monitoring their trials.17 
 
  Before involving any subjects in a clinical investigation under a master protocol, the 
investigator must obtain the legally effective informed consent of the subject or the 
subjects legally authorized representative.18  
 
  FDA recommends the use of a central institutional review board to review the master 
protocol.19  
 
  The master protocol sponsor should appoint an independent, external data monitoring 
committee or other appropriate independent entity structured to assess safety and 
efficacy.20  
 
C.  Statistical Considerations 
 
Master protocol sponsors evaluating drugs to treat or prevent COVID-19 should consider the 
following: 
 
  Some master protocols can incorporate proposals for complex adaptive21 or Bayesian 
designs. Given the added complexity of these designs and that simulations are often 
required for a comprehensive evaluation of the operating characteristics, FDA strongly 
encourages master protocol sponsors to discuss these plans early with the Agency. 
 
  Master protocol sponsors should base statistical analyses for a given investigational drug 
on comparisons against only those control arm participants who were concurrently 
randomized. Sponsors considering alternative approaches should seek concurrence from 
the Agency.  
 
 
16 In general, 21 CFR part 312, subpart D (Responsibilities of Sponsors and Investigators). 
 
17 See the guidance for industry Determining the Extent of Safety Data Collection Needed in Late-Stage Premarket 
and Postapproval Clinical Investigations (February 2016). 
 
18 See 21 CFR 50.20. Per FDA regulations at 21 CFR 50.55, if a child is to be enrolled in a clinical investigation, the 
parent(s) or guardian must provide permission, with the assent of the child when appropriate. 
 
19 See 21 CFR 56.114. Note that 56.114 does not reflect a legal requirement. 
 
20 Master protocol sponsors should review the guidance for industry COVID-19: Developing Drugs and Biological 
Products for Treatment or Prevention (see section III. A. 2.) and the guidance for clinical trial sponsors 
Establishment and Operation of Clinical Trial Data Monitoring Committees (March 2006) for additional 
information. 
 
21 See the guidance for industry Adaptive Designs for Clinical Trials of Drugs and Biologics (November 2019). 
7  Contains Nonbinding Recommendations 
  If some participants are eligible for only some treatment arms in the trial, master protocol 
sponsors should base statistical analyses for a given treatment arm on comparisons 
against only those control arm participants  who were eligible for that treatment arm. 
 
  If the overall randomization ratio to an investigational drug and its comparator changes 
during the trial, comparisons between the investigational drug and comparator group 
should account for time periods of different randomization ratios, such as by stratifying 
by the time period. The randomization ratio may change, for instance, if new 
investigational drugs are entered over time into trials with certain randomization 
schemes. For example, one randomization scheme could change the randomization ratio 
from 1:1:1 (control:Drug A:Drug B) to 2:1:1:1 (control:Drug A:Drug B:Drug C) when 
the third drug, Drug C, enters the trial. 
 
  In umbrella or platform trials in the COVID-19 setting, sponsors do not need to perform 
multiplicity adjustments for the multiple comparisons of different investigational drugs to 
the comparator group to ensure control of the overall familywise type I error rate. 
However, sponsors should be aware of the possibility of multiple correlated erroneous 
findings, and it is critical to incorporate additional considerations (e.g., the clinical 
meaningfulness of the estimated effect; the quality of trial design and conduct; 
information from relevant external studies; results for other drugs studied under the 
master protocol, if available and relevant) beyond the p-value from a single comparison 
into the evaluation of the persuasiveness of evidence supporting the effectiveness of a 
drug. 
 
  To reduce the risk of a poorly or highly performing control arm leading to multiple 
correlated erroneous findings in an umbrella or platform trial of multiple investigational 
drugs, sponsors can consider use of a randomization ratio other than equal allocation to 
have a greater proportion of participants in the control arm. Greater than proportionate 
randomization to the control arm may also increase overall power for a fixed total sample 
size. 
 
  In some scenarios, dissemination of results for one investigational drug can lead to 
inadvertent dissemination of information about other drugs under ongoing evaluation in 
the trial, potentially affecting trial conduct and integrity. For example, in an event-driven 
trial, the fact that one drug has reached the target number of events for the final analysis 
could imply that other drugs still in the trial have had fewer events. Knowledge of 
accumulating data can affect the course and conduct of a trial, and the behavior of its 
sponsor, investigators, and participants, in ways that are difficult to predict and 
impossible to adjust for. Therefore, it is paramount that the analysis and communication 
of results for one investigational drug not lead to inadvertent dissemination of 
information for other drugs.  
 
  FDA does not require comparisons between investigational drugs in an umbrella or 
platform trial, but the comparisons may be useful for comparative effectiveness research 
and informing treatment guidelines. Master protocol sponsors planning on conducting 
these comparisons should prespecify them in the statistical analysis plan. 
8  Contains Nonbinding Recommendations 
 
D.  Administrative and Procedural Recommendations 
 
Master protocol sponsors evaluating drugs to treat or prevent COVID-19 should consider the 
following: 
 
  A sponsor considering the submission of a master protocol should request a pre-
investigational new drug application (pre-IND) meeting to discuss the protocol and 
submission details. The cover letter for these meeting requests should clearly state 
REQUEST FOR MEETING-MASTER PROTOCOL (Meeting Type). 
 
  The master protocol IND should include only the master protocol  and the master 
protocol should be conducted under that IND only. 
 
  Regarding cross-references between INDs, sponsors should consider the following:  
 
  The master protocol should not be incorporated into other INDs via cross-reference.  

 
  INDs for individual investigational drugs22 being evaluated in a master protocol can 

cross-reference limited elements of the master protocol IND (e.g., clinical data).  
 
  The master protocol IND can reference information in the INDs for the individual 

investigational drugs to be evaluated in the master protocol IND to support the safety 
of those individual investigational drugs, such as nonclinical study findings, drug 
product quality specifications, and clinical data.  
 
  To reference information in another sponsors IND, a letter from that sponsor 

authorizing such reference must be provided.23 
 
  A new investigational drug24 proposed for evaluation in the master protocol should be 
submitted as a protocol amendment to the master protocol IND. All drugs to be evaluated 
in a master protocol are expected to have undergone previous clinical testing in humans 
and, therefore, to have a separate IND file. In rare cases where there may not be a 
separate IND for the drug (e.g., a drug developed solely outside of the United States), 
master protocol sponsors should consult FDA.   
 
  FDA recommends the following procedures regarding protocol amendments: 
 
 
22 In many instances individual investigational drugs chosen for evaluation in the master protocol will also be 
evaluated under a separate IND. The master protocol sponsor and the individual investigational drug sponsor may or 
may not be the same entity. See also footnote 2.   
 
23 21 CFR 312.23(b). 
 
24 For purposes of this guidance, those not-previously-developed drugs are referred to as new investigational drugs. 
9  Contains Nonbinding Recommendations 
  The master protocol sponsor should clearly mark the cover letter for protocol 

amendments with Protocol Amendment-MASTER PROTOCOL. 
 
  Master protocol sponsors should submit protocol amendments that substantively 

affect the safety, quality, or scope of the master protocol at least 30 days before 
initiation of the changes. For example, to add a new individual investigational drug to 
the master protocol, the master protocol IND sponsor should submit the protocol 
amendment at least 30 days before initiation of that arm of the protocol.  
 
  A sponsor should notify the regulatory project manager at least 48 hours before 

submitting any protocol amendment that could substantively affect the safety, quality, 
or scope of the master protocol. 
 
  FDA recommends that master protocol sponsors review figure D of the appendix in the 
draft guidance for industry Master Protocols: Efficient Clinical Trial Design Strategies to 
Expedite Development of Oncology Drugs and Biologics25 for an example of the 
organization of an electronic common technical document submission for a master 
protocol.  
 
  FDA recommends that the master protocol sponsor ensure the dissemination of 
information and advice from FDA to the individual investigational drug sponsor(s).  
 
  The master protocol sponsor should establish a systematic approach  that ensures the 
rapid communication of serious safety issues to clinical investigators and FDA under 
IND safety reporting regulations.26 This should include a process for rapid 
implementation of protocol amendments to address serious safety issues.27 
 
  With regard to safety reporting, sponsors should be aware:  
 
  All clinical investigators are required to submit safety reports to the master protocol 

sponsor.28  
 
  Master protocol sponsors are required to submit safety reports to FDA and all 

participating investigators when the sponsor determines that a serious adverse event is 
unexpected and there is a reasonable possibility that the drug caused the serious 
 
25 When final, this guidance will represent the FDAs current thinking on this topic. 
 
26 See 21 CFR 312.32. 
 
27 See 21 CFR 312.30(b)(1) and 312.30(b)(2)(ii). 
 
28 21 CFR 312.64(b)). 
10  Contains Nonbinding Recommendations 
adverse event (i.e., there is evidence to suggest a causal relationship between the drug 
and the adverse event).29 
 
  FDA requests that the master protocol sponsor forward the initial safety report to the 

relevant individual investigational drug sponsor who is required to promptly review 
the information.30  
 
  The individual investigational drug sponsor should review the report, add any 
relevant context or additional information, and submit a modified report to their 
active IND(s) for the investigational drug, if required,31 as a follow-up safety 
report32 that references the initial safety report submitted by the master protocol 
sponsor. 
 
29 21 CFR 312.32(c)(1). Sponsors are also required under 21 CFR 312.55(b) to keep each participating investigator 
informed of any new observations discovered or reported to the sponsor on the drug, particularly with respect to 
adverse events and safe use.  
 
30 21 CFR 312.32(b). 
 
31 21 CFR 312.32(c)(1). 
 
32 21 CFR 312.32(d). 
11