Master Protocols:  Efficient 
Clinical Trial Design 
Strategies to Expedite 
Development of Oncology 
Drugs and Biologics 
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) 
 
March 2022 
Procedural
 
   
Master Protocols:  Efficient 
Clinical Trial Design 
Strategies to Expedite 
Development of Oncology 
Drugs and Biologics 
Guidance for Industry 
 
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Food and Drug Administration 
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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) 
 
March 2022 
Procedural
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  MASTER PROTOCOL DEFINITION AND POTENTIAL OPPORTUNITIES 
AND CHALLENGES ....................................................................................................... 3 
A.  Description and Concept of Master Protocols ............................................................................. 3 
B.  Potential Opportunities and Challenges Posed by Master Protocols ........................................ 3 
IV.  TYPES OF MASTER PROTOCOLS ............................................................................. 4 
A.  Single Investigational Drug or Investigational Drug Combination Across Multiple Cancer 
Populations ..................................................................................................................................... 4 
B.  Investigational Drugs or Investigational Drug Combinations in Single Cancer Type ............ 5 
C.  Other Trial Designs........................................................................................................................ 6 
V.  SPECIFIC DESIGN CONSIDERATIONS IN MASTER PROTOCOLS .................. 6 
A.  Use of a Single Common Control Arm......................................................................................... 6 
B.  Novel Combination of Two or More Investigational Drugs ....................................................... 7 
C.  Studies With Drugs Targeting Multiple Biomarkers ................................................................. 7 
D.  Adding and Stopping Treatment Arms ....................................................................................... 8 
E.  Independent Data Monitoring Committees ................................................................................. 8 
VI.  BIOMARKER DEVELOPMENT CONSIDERATIONS ............................................. 8 
VII.  STATISTICAL CONSIDERATIONS .......................................................................... 10 
A.  Nonrandomized, Activity-Estimating Design ............................................................................ 10 
B.  Randomized Designs .................................................................................................................... 10 
C.  Master Protocols Employing Adaptive/Bayesian Design ......................................................... 10 
D.  Master Protocols With Biomarker-Defined Subgroups ........................................................... 10 
VIII.  SAFETY CONSIDERATIONS ..................................................................................... 11 
A.  Safety Monitoring and Reporting Plans .................................................................................... 11 
B.  Independent Safety Assessment .................................................................................................. 12 
C.  Institutional Review Board/Independent Ethics Committee ................................................... 13 
D.  Informed Consent Document ...................................................................................................... 14 
IX.  ADDITIONAL REGULATORY CONSIDERATIONS ............................................. 15 
X.  CONTENT OF A MASTER PROTOCOL .................................................................. 15 
A.  New IND Submission ................................................................................................................... 15 
B.  Amendments to the Master Protocol .......................................................................................... 16 
i 
   
XI.  COMMUNICATION AND INTERACTIONS WITH FDA....................................... 17 
REFERENCES ............................................................................................................................ 19 
APPENDIX .................................................................................................................................. 20 
 
ii 
  Contains Nonbinding Recommendations 
Master Protocols:  Efficient Clinical Trial Design Strategies to 
Expedite Development of Oncology Drugs and Biologics 
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 
 
This guidance provides recommendations to sponsors of drugs or biologics for the treatment of 
cancer regarding the design and conduct of clinical trials intended to simultaneously evaluate 
more than one investigational drug2 and/or more than one cancer type within the same overall 
trial structure (master protocols) in adult and pediatric cancers. In general, the recommended 
phase 2 dose (RP2D) should have been established for an investigational drug or drugs evaluated 
in a master protocol.  
 
This guidance is intended to serve as advice and a focus for continued discussions among FDA, 
pharmaceutical sponsors, the academic community, and the public.3  
 
This guidance describes aspects of master protocol designs and trial conduct and related 
considerations, such as biomarker codevelopment and statistical analysis considerations, and 
provides recommendations on the information that sponsors should submit to FDA and on how 
sponsors can interact with FDA to facilitate efficient review. 
 
This guidance does not cover first-in-human or early stage clinical trials using expansion cohorts 
to expedite drug development. FDA addresses that topic in the draft guidance for industry 
 
1 This guidance has been prepared by the Office of Oncologic Diseases in the Center for Drug Evaluation and 
Research in cooperation with the Oncology Center of Excellence and the Center for Biologics Evaluation and 
Research at the Food and Drug Administration.  
 
2 For the purpose of this guidance, the term drug refers to human drugs and to biological products that are regulated 
as drugs.  
 
3 In addition to consulting guidances, sponsors are encouraged to contact the review division to discuss specific 
issues that arise during drug development. 
1  Contains Nonbinding Recommendations 
Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of 
Oncology Drugs and Biologics (August 2018).4 
 
There are many aspects of study design, statistical analysis, choice of study endpoints, and 
development of biomarkers that are not addressed in this guidance but are considered in other 
FDA guidances, including the guidances for industry E9 Statistical Principles for Clinical Trials 
(September 1998) and E10 Choice of Control Group and Related Issues in Clinical Trials (May 
2001), which were developed by the International Conference for Harmonisation (ICH) and 
adopted by FDA, as well as the guidance for industry In Vitro Companion Diagnostic Devices 
(August 2014).5 
 
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 
guidances means that something is suggested or recommended, but not required. 
 
 
II.  BACKGROUND 
 
There is increased interest in expediting late-stage drug development (i.e., trials intended to 
provide substantial evidence of effectiveness) through developing trial designs that test multiple 
drugs and/or multiple cancer subpopulations in parallel under a single protocol without a need to 
develop new protocols for every trial. The term master protocol is often used to describe the 
design of such trials, with a variety of terms such as umbrella, basket, or platform describing 
specific designs (Woodcock and LaVange 2017). Examples of trials using master protocols 
include the Lung-MAP trial (NCT02154490; see Figure B in the Appendix),6 the NCI-MATCH 
trial (EAY131, NCT02465060; see Figure C in the Appendix),7 and the Pediatric MATCH trial 
(APEC1621, NCT03155620).8 In contrast to traditional trial designs, where a single drug is 
tested in a single disease population in one clinical trial, master protocols use a single 
 
4 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.  
 
5 See also the guidances for industry Codevelopment of Two or More New Investigational Drugs for Use in 
Combination (June 2013), Adaptive Designs for Clinical Trials of Drugs and Biologics (November 2019), and 
Enrichment Strategies for Clinical Trials to Support Determination of Effectiveness of Human Drugs and Biological 
Products (March 2019). 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/RegulatoryInformation/Guidances/default.htm. 
 
6 See information on this trial at https://www.clinicaltrials.gov/. 
 
7 See information on this trial at the National Cancer Institute web page at https://www.cancer.gov/about-
cancer/treatment/clinical-trials/search/v?id=NCT02465060&r=1 as well as https://www.clinicaltrials.gov/. 
 
8 See information on this trial at https://www.clinicaltrials.gov/. 
 
2  Contains Nonbinding Recommendations 
infrastructure, trial design, and protocol to simultaneously evaluate multiple drugs and/or disease 
populations in multiple substudies, allowing for efficient and accelerated drug development.  
 
Because of the complexity of these trials, which evaluate multiple drugs and/or disease 
populations, and their intent to support regulatory approval, it is important that such trials be well 
designed and well conducted to help ensure human subject safety and to generate data that meets 
regulatory standards for demonstrating each investigational drugs safety and effectiveness.9 
 
 
III.  MASTER PROTOCOL DEFINITION AND POTENTIAL OPPORTUNITIES 
AND CHALLENGES 
 
A.  Description and Concept of Master Protocols 
 
For the purpose of this guidance, a master protocol is defined as a protocol designed with 
multiple substudies, which 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. In general, FDA recommends that the sponsor establish the RP2D for the 
investigational drug or drugs before evaluation using a master protocol. However, individual 
drug substudies under the master protocol might incorporate an initial dose-finding phase, for 
example, in pediatric subjects when sufficient adult data are available to inform a starting dose 
and the investigational drug provides the prospect of direct clinical benefit to pediatric subjects 
(21 CFR 50.52).  
 
A master protocol may be used to conduct the trial or trials for exploratory purposes or to 
support a marketing application and can be structured to evaluate, in parallel, different drugs 
compared with their respective controls or to a single common control. The sponsor can design 
the master protocol with a fixed or an adaptive design10 with the intent to modify the protocol to 
incorporate or terminate individual substudies within the master protocol. For examples of types 
of master protocols, see section IV., Types of Master Protocols.  
 
B.  Potential Opportunities and Challenges Posed by Master Protocols 
 
The potential advantage of a master protocol is flexibility and efficiency in drug development, 
consistent with FDAs goal of helping to make safe and effective drugs and drug combination 
treatments available to the public. A master protocol provides an opportunity to incorporate 
efficient approaches, such as a shared control arm and/or the use of centralized data capture 
systems to enhance efficiency. However, a master protocol can also create challenges in the 
 
9 Under 42 U.S.C.  282(j), including its implementing regulations in 42 CFR part 11, certain applicable clinical 
trials must be registered at https://www.clinicaltrials.gov/. Within 1 year of the primary completion date, with 
certain exceptions for submission beyond 1 year, responsible parties must submit required summary results 
information to https://www.clinicaltrials.gov/. FDA encourages responsible parties to submit summary results 
information as soon as possible and ahead of required statutory and regulatory deadlines. 
 
10 See the guidance for industry Adaptive Designs for Clinical Trials of Drugs and Biologics. 
 
3  Contains Nonbinding Recommendations 
conduct and analysis of the trial that, if not properly addressed, can increase risk to human 
subjects or delay the development of the drug.11 
 
Examples of potential challenges include the following: 
 
(1) Difficulty attributing adverse events to one or more investigational drugs can occur when 
multiple drugs are administered within each investigational treatment arm and the trial 
lacks a single internal control for those drugs. 
 
(2) With multiple drugs being studied across multiple protocols and investigational new drug 
applications (INDs), assessing the safety profile of any given investigational drug is 
difficult.  
 
(3) The presence of multiple study groups allows potential overinterpretation of findings, 
resulting in delays in drug development. For example, an apparent difference in efficacy 
in a biomarker-defined subpopulation could be identified based on multiple ad hoc 
between-arm comparisons that prove to be false.  
 
 
IV.  TYPES OF MASTER PROTOCOLS 
 
This section provides examples of types of master protocols and considerations related to their 
designs. FDA encourages sponsors to discuss with the review division plans to develop drugs 
under a master protocol early in the development program to obtain feedback on the design of 
such a protocol before the submission of the protocol to an IND.  
 
A.  Single Investigational Drug or Investigational Drug Combination Across 
Multiple Cancer Populations 
 
A master protocol designed to test a single investigational drug or drug combination in different 
populations defined by different cancers, disease stages for a specific cancer, histologies, number 
of prior therapies, genetic or other biomarkers, or demographic characteristics is commonly 
referred to as a basket trial (shown in Figure 1). A basket trial evaluating an investigational drug 
combination may include a dose-finding or safety lead-in component to identify safe doses of the 
combination before proceeding with an activity-estimating component. 
 
Figure 1: Schematic Representation of a Master Protocol With Basket Trial Design 
 
 
Single investigational drug or drug 
combina tion (T1)* 
 
 
 
D1*  D2  D3  D4  D5 
 
 
11 See also the ICH guidance for industry E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) 
(March 2018). 
4  Contains Nonbinding Recommendations 
 
* T = investigational drug; D = protocol-defined subpopulation in multiple disease subtypes; D5 = dashed lines 
indicate potential amendments to include additional subpopulations. 
 
 
The substudies within basket trials are usually designed as single-arm, activity-estimating trials 
with overall response rate as the primary endpoint. A strong response signal seen in a substudy 
may allow for expansion of the substudy to generate data that could potentially support a 
marketing application. Each substudy should include specific objectives, the scientific rationale 
for inclusion of each population, and a detailed statistical analysis plan (SAP) that includes 
sample size justification and stopping rules for futility or efficacy. For specific aspects related to 
design and analysis related to a master protocol for a basket trial, see section V., Specific Design 
Considerations in Master Protocols, and section VII., Statistical Considerations.  
 
An example of a master protocol with basket trial design is the phase 2 trial evaluating 
vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations (see Figure A in the 
Appendix) (Hyman et al. 2015). 
 
B.  Investigational Drugs or Investigational Drug Combinations in Single 
Cancer Type 
 
A master protocol that is designed to evaluate multiple investigational drugs administered as 
single drugs or as drug combinations in a single disease population is commonly referred to as an 
umbrella trial (shown in Figure 2). Substudies within umbrella trials can include dose-finding or 
safety lead-in components to identify safe doses of an investigational drug combination before 
proceeding with an activity-estimating component. As previously stated, sponsors should ensure 
the RP2D for each investigational drug has been established before evaluation in a master 
protocol.  
 
Figure 2:  Schematic Representation of a Master Protocol With Umbrella Trial Design 
 
 
 
  Control 
 
Single 
  tumor type  T1* 
  or 
  histological 
T2 
sub-type 
 
(D1)* 
 
  T3 
 
 
TX 
 
 
* T = investigational drug or investigational drug combination; D = protocol defined subpopulation in single disease 
subtypes; TX = dashed lines indicate potential amendments to include future treatment arms. 
5  Contains Nonbinding Recommendations 
 
Umbrella trials can employ randomized controlled designs to compare the activity of the 
investigational drug or drugs with a common control arm. The drug chosen as the control arm for 
the randomized substudy or substudies should be the standard of care (SOC) for the target 
population, and this may change over time if newer drugs replace the SOC. For specific aspects 
related to design and analysis related to a master protocol for an umbrella trial, see section V., 
Specific Design Considerations in Master Protocols, and section VII., Statistical Considerations.  
 
An example of a master protocol with umbrella trial design is the original version of the LUNG-
MAP trial, a multidrug, multi-substudy, biomarker-driven trial in human subjects with 
advanced/metastatic squamous cell carcinoma of the lung where docetaxel was the common 
control arm in four of the five substudies (Herbst et al. 2015). Eligible subjects were assigned to 
substudies based on their biomarkers or to a nonmatch therapy substudy for subjects not eligible 
for the biomarker-specific substudies. Within the substudies, subjects were randomized to a 
biomarker-driven target or to SOC therapy (see Figure B in the Appendix).   
 
C.  Other Trial Designs 
 
Master protocol designs may also incorporate design features common to both basket and 
umbrella trials and may evaluate multiple investigational drugs and/or drug combination 
regimens across multiple tumor types.  
 
An example of a master protocol with a complex trial design is the NCI-MATCH trial, which 
aims to establish whether human subjects with one or more tumor mutations, amplifications, or 
translocations in a genetic pathway of interest identified in solid tumors or hematologic 
malignancies derive clinical benefit if treated with drugs targeting that specific pathway in a 
single-arm design (see Figure C in the Appendix) (Abrams et al. 2014).  
 
 
V.  SPECIFIC DESIGN CONSIDERATIONS IN MASTER PROTOCOLS 
 
A.  Use of a Single Common Control Arm 
 
For oncology clinical trials, FDA recommends that a sponsor use a common control arm to 
improve efficiency in master protocols where multiple drugs are evaluated simultaneously in a 
single disease (e.g., umbrella trials). FDA recommends that the control arm be the current SOC 
so that the trial results will be interpretable in the context of U.S. medical practice. Changes in 
SOC for the target population can occur during the conduct of the trial because of a new drug 
approval or new scientific evidence, making it no longer ethical to randomize human subjects to 
the previous SOC. In that case, the sponsor should suspend subject enrollment until the protocol 
and the protocol informed consent document are modified to include the new SOC as control. 
The SAP should be modified as soon as possible and before any analysis of the data.  
 
In general, comparative analyses should be conducted only between a test drug and the common 
control and not between experimental treatment arms (for statistical considerations in the use of 
common control, see section VII., Statistical Considerations). Where an IND sponsor has right of 
6  Contains Nonbinding Recommendations 
reference to data in more than one experimental arm, a comparison between such experimental 
arms might also be proposed prospectively. 
 
B.  Novel Combination of Two or More Investigational Drugs 
 
In master protocols with substudies intended to evaluate concomitant administration of two or 
more investigational drugs, the sponsor should provide strong scientific rationale for the use of 
the drug combination regimen. FDA recommends that the sponsor ensures the RP2D has been 
identified for each individual drug in all cases where each drug may have antitumor activity. 
 
The master protocol should summarize available safety, pharmacology, and preliminary efficacy 
data for each investigational drug; the biological rationale for use of the drugs in combination 
rather than use of an individual drug; and evidence, if any, of synergy when used in combination. 
In some instances, the master protocol may include a dose-finding component for novel 
combinations where the RP2D of the combination regimen has not been established. Safety data 
from a minimum of six subjects treated at the proposed dosage for the drug combination regimen 
should be available before proceeding with the efficacy evaluation. The sponsor should submit 
results of the dose-finding phase to the IND for the master protocol before proceeding with the 
efficacy phase. If such an approach is considered in a pediatric population, the sponsor should 
ensure, for a particular tumor type and/or relevant mutations, that the full relevant age range of 
pediatric subjects (generally speaking 0 to 17 years of age) is addressed and the investigational 
drug provides the prospect of direct clinical benefit to pediatric subjects. For additional 
requirements that pertain to clinical investigations in pediatric subjects, see 21 CFR 50 subpart 
D. Specific age eligibility should depend on the prevalence of the particular tumor type in 
children. 
 
For clinical development programs designed to evaluate combinations of two or more 
investigational drugs, it is important that the general investigational plan describe the approach to 
demonstrating the contribution of each investigational drug to the observed treatment effect to 
support a benefit-risk assessment.12 
 
C.  Studies With Drugs Targeting Multiple Biomarkers 
 
FDA recommends early discussion with the review division of biomarker development plans 
when the sponsor plans to use one or more biomarkers to inform human subject selection for 
trials. The sponsor should provide the rationale for conducting the substudy in a biomarker-
defined population, such as a tumor biomarker likely to predict a therapeutic response to the 
investigational drug based on the drugs purported mechanism of action (drug target) or a 
biomarker that enriches the study for subjects with one or more prognostic factors. For master 
protocols with drugs targeting multiple biomarkers, it is important that subject selection tests be 
analytically validated with well-defined criteria for marker positivity before initiation of the trial.   
 
 
12 See the guidances for industry Codevelopment of Two or More New Investigational Drugs for Use in Combination 
and Enrichment Strategies for Clinical Trials to Support Determination of Effectiveness of Human Drugs and 
Biological Products.  
 
7  Contains Nonbinding Recommendations 
In master protocols containing substudies with drugs that target multiple biomarkers, the 
protocol should contain a prespecified plan for allocation of subjects who are potentially eligible 
for more than one substudy. Human subject allocation and sample size assumptions for each 
randomized substudy should take into consideration the potential prognostic implications of 
specific biomarkers.  
 
For additional information, see section VI., Biomarker Development Considerations, and section 
VII., Statistical Considerations. 
 
D.  Adding and Stopping Treatment Arms 
 
Master protocols evaluating multiple investigational drugs can add, expand, or discontinue 
treatment arms based on findings from prespecified interim analyses or external new data.13  
 
Before initiating the trial, the sponsor should ensure that the master protocol and its associated 
SAP describe conditions that would result in adaptations such as the reestimation of the sample 
size based on the results of an interim analysis or discontinuation of an experimental arm based 
on futility rules. 
 
E.  Independent Data Monitoring Committees 
 
If results from one or more substudies are anticipated to form the basis of a marketing 
application, the master protocol should describe and provide the charter for an independent 
radiologic review committee to perform blinded tumor-based assessments, as appropriate. In 
addition, the protocol should describe and provide a charter for an independent data monitoring 
committee (IDMC) or other appropriate independent entity to monitor efficacy and safety 
results.14 The IDMC charter should authorize the committee to conduct prespecified and ad hoc 
assessments of efficacy and futility and recommend protocol modifications or other actions, 
including sample size adjustment and discontinuation or modification of a substudy based on 
futility or overwhelming evidence of efficacy.  
 
Pediatric expertise should be provided on IDMCs that will review pediatric studies; an ethicist 
should be considered for all studies, pediatric and adult.  For additional responsibilities related to 
safety monitoring, see section VIII. B., Independent Safety Assessment. 
 
 
VI.  BIOMARKER DEVELOPMENT CONSIDERATIONS 
 
Master protocols evaluating biomarker-defined populations should explain why use of the 
biomarker is appropriate and employ in vitro diagnostic (IVD) tests, either as single biomarker 
tests or as a platform assessing multiple biomarkers, that are analytically validated. Use of IVDs 
 
13 See the guidance for industry Adaptive Designs for Clinical Trials of Drugs and Biologics. 
 
14 See the guidance for clinical trial sponsors Establishment and Operation of Clinical Trial Data Monitoring 
Committees (March 2006). 
 
8  Contains Nonbinding Recommendations 
with inadequate analytical performance characteristics (e.g., precision, accuracy) may produce 
unreliable results with respect to performance of the drug. Protocols with IVD tests that are not 
analytically validated can be placed on clinical hold for deficiencies in design to meet the stated 
objectives (21CFR 312.42(b)(2)(ii)).15   
 
Sponsors should establish procedures for sample acquisition, handling, and the testing and 
analysis plans as early as possible in the biomarker development program. Sponsors should 
discuss with the review division whether to submit the IVDs analytical validation data for FDA 
to determine whether the clinical results will be interpretable. Further, when the trial uses an 
investigational IVD, sponsors and institutional review boards (IRBs) should assess what 
investigational device requirements16 apply using the definitions in 21 CFR 812.3 and the criteria 
found in 21 CFR 812.2 that address the level of risk that the device presents to trial subjects (i.e., 
significant risk, nonsignificant risk) and address exempted device investigations.17,18 Clinical 
investigations of devices that pose a significant risk generally require both FDA and IRB 
approval before initiation.19 FDA approval can be obtained through submitting an investigational 
device exemption (IDE) application to FDA ( 812.20).20 Sponsors can contact the appropriate 
center at FDA (the Center for Devices and Radiological Health (CDRH) or the Center for 
Biologics Evaluation and Research (CBER)) for the device, or sponsors can submit all 
information about the oncology codevelopment program, including IVD information in the IND 
submitted to the Center for Drug Evaluation and Research (CDER) or CBER, to seek trial risk 
determination.21 
 
Sponsors interested in pursuing the development of a specific biomarker test for marketing as a 
device should consult the appropriate center at FDA (CDRH or CBER) responsible for review of 
the IVD. 
 
 
15 See the draft guidance for industry and FDA staff, Principles for Codevelopment of an In Vitro Companion 
Diagnostic Device with a Therapeutic Product (July 2016). When final, this guidance will represent FDAs current 
thinking on this topic. 
 
16 21 CFR part 812. 
 
17 See the guidance for sponsors, clinical investigators, IRBs, and FDA staff FDA Decisions for Investigational 
Device Exemption Clinical Investigations (August 2014) and the guidance for IRBs, clinical investigators, and 
sponsors IRB Responsibilities for Reviewing the Qualifications of Investigators, Adequacy of Research Sites, and the 
Determination of Whether an IND/IDE is Needed (August 2013). 
 
18 See the draft guidance for industry, FDA staff, sponsors, and IRBs Investigational IVDs Used in Clinical 
Investigations of Therapeutic Products (December 2017). When final, this guidance will represent FDAs current 
thinking on this topic.  
 
19 21 CFR 56.103 and 812.20. 
 
20 See the guidance for sponsors, clinical investigators, IRBs, and FDA staff, FDA Decisions for Investigational 
Device Exemption Clinical Investigations. Additional information is available at https://www.fda.gov/medical-
devices/investigational-device-exemption-ide/ide-approval-process. 
 
21 See the guidance for industry Investigational In Vitro Diagnostics in Oncology Trials: Streamlined Submission 
Process for Study Risk Determination (October 2019). 
9  Contains Nonbinding Recommendations 
 
VII.  STATISTICAL CONSIDERATIONS 
 
A.  Nonrandomized, Activity-Estimating Design 
 
In nonrandomized protocols, where the primary endpoint is overall response rate, the planned 
sample size should be sufficient to rule out a clinically unimportant response rate based on the 
lower bound of the 95 percent confidence interval around the observed response rate. The 
analysis plan should describe the futility analyses to be conducted. FDA recommends designs, 
such as the Simon two-stage design, that limit exposure to an ineffective drug (Simon 1989). 
However, other statistical approaches may be acceptable and, if proposed, should be described in 
detail in the SAP. If a sponsor anticipates that the results would form the basis of an efficacy 
claim in a marketing application, the clinical protocol and SAP should ensure that collected data 
are of adequate quality for this purpose. If preliminary results from a substudy or substudies 
suggest a major advance over available therapy, the sponsor should meet with the review 
division to discuss modifications to the protocol (e.g., to propose interim analyses for efficacy or 
consider early termination of the trial) or to modify the development program (e.g., discuss 
potential for breakthrough therapy designation). 
 
B.  Randomized Designs 
 
If a sponsor incorporates randomization into an umbrella trial design, FDA recommends use of a 
common control arm when possible. The general comments about generation of an appropriate 
SAP and information about futility analysis in the previous section (VII. A., Nonrandomized, 
Activity-Estimating Design) also apply to randomized trials. Before initiating the proposed 
substudy, the sponsor should meet with the division to discuss the SAP with regard to how the 
strength of evidence will be assessed and how potential sources of bias will be controlled.  
 
C.  Master Protocols Employing Adaptive/Bayesian Design 
 
In master protocols that incorporate adaptive designs, the SAP should provide all information 
described in the guidances for industry Adaptive Designs for Clinical Trials of Drugs and 
Biologics and Enrichment Strategies for Clinical Trials to Support Determination of 
Effectiveness of Human Drugs and Biological Products. The SAP should also describe plans for 
futility analyses.22 Master protocols can use a Bayesian statistical method or other methods for 
planning or modifying the sample size, dropping an arm, and other adaptive strategies. The SAP 
should include details on implementation of Bayesian or other methods.  
 
D.  Master Protocols With Biomarker-Defined Subgroups 
 
In master protocols with basket or complex design, where human subject assignment to a 
treatment arm is based on the presence of a specific biomarker of interest, the protocol should 
clearly specify how subjects with more than one biomarker of interest will be assigned to 
 
22 See also the ICH guidance for industry E9 Statistical Principles for Clinical Trials and the guidance for clinical 
trial sponsors Establishment and Operation of Clinical Trial Data Monitoring Committees. 
 
10  Contains Nonbinding Recommendations 
substudies. There are two approaches to making such assignments that FDA recommends from a 
clinical trial design perspective, but other approaches may also be appropriate. One approach is 
to prioritize biomarkers or treatments. For example, in the BATTLE-1 trial, investigators ranked 
the biomarker groups based on their predictive values and assigned human subjects with multiple 
biomarkers to the group for one of their biomarkers that has the highest predictive value (Kim et 
al. 2011). The other approach is based on a prespecified randomization ratio. For example, the 
Lung-MAP trial uses a reversed ratio of prevalence rates. Using reverse prevalence ratios, 
subjects in the trial with tumors that have biomarkers with low prevalence have a greater 
likelihood to be assigned to a substudy for the lower prevalence population.23 Consideration 
should be given to the clinical relevance, if any, of low-prevalence passenger mutations that 
coexist with driver mutations, for which adjustment to randomization may not be needed. 
Sponsors should provide justification for the selected approach and should state in the 
justification whether the proposed approach of assigning subjects with more than one biomarker 
of interest to a particular substudy would impact the prevalence of the biomarkers in each 
subpopulation and whether any statistical methods to address this potential issue/bias are needed. 
 
 
VIII.  SAFETY CONSIDERATIONS 
 
A.  Safety Monitoring and Reporting Plans 
 
The sponsor of the master protocol IND is required to ensure proper monitoring of the 
investigations and to ensure that the investigations are conducted in accordance with the general 
investigational plan and protocols contained in the IND (21 CFR 312.50).24 Similarly, the 
sponsor of the investigational product IND for a drug that will be administered under a master 
protocol IND is responsible for monitoring the safety of its drug and evaluating all accumulating 
safety data, including data from trials not conducted by the sponsor of the investigational product 
IND (21 CFR 312.32(b)). The sponsor of the master protocol IND should establish a systematic 
approach that ensures rapid communication of serious safety issues to all participating clinical 
investigators and FDA under IND safety reporting regulations.25 Additionally the master protocol 
IND sponsor should ensure rapid communication of serious safety issues to the sponsors of all 
products used in the master protocol, according to the established safety reporting plan. In 
addition, the approach should describe the process for rapid implementation of protocol 
amendments to address serious safety issues.26  
 
Safety monitoring and reporting obligations of the sponsor of the master protocol IND and 
sponsors of each IND covered by the master protocol remain unchanged in master protocol trials. 
 
23 See the guidance for industry Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease 
(October 2018). 
 
24 See the guidance for industry Oversight of Clinical Investigations  A Risk-Based Approach to Monitoring 
(August 2013). 
 
25 21 CFR 312.32. 
 
26 21 CFR 312.30(b)(1) and 312.30(b)(2)(ii). 
 
11  Contains Nonbinding Recommendations 
These reporting obligations are described, along with recommendations to help sponsors comply 
with expedited safety reporting requirements, in the draft guidance for industry Sponsor 
ResponsibilitiesSafety Reporting Requirements and Safety Assessment for IND and 
Bioavailability/Bioequivalence Studies (June 2021).27  
 
For master protocols in oncology, FDA may expect a sponsor to conduct aggregate analyses of 
all SAEs at intervals based on the volume of safety data collected or based on the number of 
subjects accrued into the master protocol in order to fulfill its review obligations under 
312.32(b). A sponsor would then be required to submit events that qualify for reporting under 
312.32(c) and as described in the draft guidance for industry Sponsor ResponsibilitiesSafety 
Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence  
Studies. The frequency of the cumulative aggregate safety analyses should be discussed with the 
 
Agency at a pre-IND meeting, taking into account specific program needs.
 
Given the complexity of and the generally rapid accrual to these trials, resulting in increased 
risks to subjects should there be a failure to promptly identify suspected and unexpected serious 
adverse reactions, sponsors should select medical monitors who have training and experience in 
cancer research and in the conduct of clinical trials so that safety information can be promptly 
assessed.   
 
B.  Independent Safety Assessment  
 
For all master protocols, the sponsor should institute an IDMC or other appropriate independent 
entity structured to assess safety in addition to efficacy (section V. E., Independent Data 
Monitoring Committee). The sponsor should describe in the IND the constitution of this 
committee and the definition of its responsibilities. The committee should complete the real-time 
review of all serious adverse events as defined in FDA regulations and periodically assess the 
totality of safety information in the development program.28 The IDMC or other appropriate 
independent entity should have responsibility for conducting prespecified and ad hoc 
assessments of safety to recommend protocol modifications or other actions including, but not 
limited to, the following:   
 
(1) Discontinuing or modifying a substudy based on safety information obtained from the 
protocol or from information external to the trial 
 
(2) Changing the eligibility criteria if the risks of the intervention appear to be higher in a 
particular subgroup 
 
(3) Altering the drug dosage and/or schedule if the adverse events observed appear likely to 
be mitigated by such changes 
 
 
27 When final, this guidance will represent the FDAs current thinking on this topic. 
 
28  See the guidance for clinical trial sponsors Establishment and Operation of Clinical Trial Data Monitoring 
Committees and the draft guidance for industry Sponsor ResponsibilitiesSafety Reporting Requirements and Safety 
Assessment for IND and Bioavailability/Bioequivalence Studies. 
12  Contains Nonbinding Recommendations 
(4) Instituting screening procedures that could identify those subjects at increased risk of a 
particular adverse event 
 
(5) Identifying information needed to inform current and future trial subjects of newly 
identified risks via changes in the informed consent document and, if appropriate, 
recommending reconsent of current subjects to continue trial participation 
 
For more information regarding entities that review aggregate data for IND safety reporting, see 
section VI of the guidance for industry Sponsor ResponsibilitiesSafety Reporting Requirements 
and Safety Assessment for IND and Bioavailability/Bioequivalence Studies. 
 
C.  Institutional Review Board/Independent Ethics Committee  
 
A clinical trial being conducted under a master protocol IND must not be initiated until an IRB 
or independent ethics committee has reviewed and approved the protocol, and the trial remains 
subject to continuing review by an IRB.29 After initiation, modifications to the master protocol 
must be approved by the IRB or independent ethics committee before implementation, with the 
exception of protocol amendments that are necessary to eliminate apparent immediate hazards to 
trial participants, which can generally be immediately implemented but are required to be 
reported to the IRB afterward.30 
 
Sponsors are required to keep each participating investigator informed of new observations 
discovered by or reported to the sponsor on the drug, particularly with respect to adverse effects 
and safe use.31 Investigators are required under  312.66 to report all unanticipated problems 
involving risk to human subjects or others to the IRB. FDA considers a serious and unexpected 
adverse event that meets the criteria for sponsor reporting to FDA and all investigators in an IND 
safety report under  312.32 to be an unanticipated problem[ ] involving risk to human subjects 
or others that therefore must be reported to the IRB by the investigator. The investigator must 
convey this information to the IRB during the time of the IRBs continuing review, or sooner, if 
the information is an unanticipated problem involving risk to human subjects or others.32 This 
information can include a description of the detailed plan for timely, periodic communication of 
trial progress, cumulative safety information, and other reports from the IDMC. This information 
is necessary to allow the IRB to evaluate, for example, the risks to human subjects of the 
ongoing investigation and the adequacy of the informed consent document.33  
 
 
29 21 CFR 56.103(a); 21 CFR 312.66. 
 
30 21 CFR 56.108(a)(4), 56.104(c), and 21 CFR 312.66. 
 
31 21 CFR 312.55(b). 
 
32 See 21 CFR 312.66 and the draft guidance for industry Investigator Responsibilities  Safety Reporting for 
Investigational Drugs and Devices (September 2021).When final, this guidance will represent the FDAs current 
thinking on this topic. 
 
33 21 CFR 56.109(f). 
 
13  Contains Nonbinding Recommendations 
To facilitate IRB review of master protocols, FDA recommends the use of a central IRB.34 The 
central IRB should have adequate resources and appropriate expertise to review master protocols 
in a timely and thorough manner. In its discretion, an IRB can invite individuals with 
competence in special areas (i.e., consultants) to help review complex issues that require 
expertise beyond or in addition to that available on the IRB.35  
 
For research conducted under a master protocol, safety data may rapidly accumulate. IRBs 
should consider convening additional meetings (i.e., ad hoc meetings of an existing IRB) to 
review the safety data that the investigator has provided to the IRB for any unanticipated 
problem involving risk to human subjects or others. The purpose of such meetings would be to 
expeditiously review the unanticipated problems and, if needed, any proposed trial 
modifications. Alternatively, a separate, duly constituted specialty IRB can be established and 
specifically charged with meeting on short notice to review new information and modifications 
to trials with master protocols. Such an IRB would need to satisfy the same requirements of any 
IRB (i.e., 21 CFR part 56); however, it could be designed to facilitate a quorum by keeping 
membership to a minimum (i.e., 21 CFR 56.107 requires that each IRB have at least five 
members) and being composed of experienced members who are capable of meeting and 
reviewing trial-related materials on short notice. Ad hoc meetings of an existing IRB or the 
establishment of a separate specialty IRB designed to facilitate the review of trials with master 
protocols are acceptable approaches that, if appropriately constituted and operated, can satisfy 
the regulatory requirement for IRB oversight.  
 
Irrespective of the type of IRB that is used, if the master protocol includes plans to enroll 
pediatric subjects in the trial, FDA recommends the IRB include (either as a member or an 
invited nonvoting expert) an individual or individuals who have expertise in the management of 
pediatric oncology patients.36 IRBs reviewing protocols involving pediatric subjects also should 
include an individual or individuals with experience with the regulatory requirements for the 
inclusion of pediatric subjects in clinical trials, including the requirements for parental 
permission and assent.37  
 
D.  Informed Consent Document 
 
In addition to submitting informed consent documents to the IRB for review, the sponsor may 
need to submit the original and all updated informed consent documents to the IND to allow 
FDA to assess that human subjects have the information to make informed decisions about 
participation in the trial (21 CFR 50.20). Depending upon the design of the trial, a sponsor may 
consider the use of informed consent documents specific to each substudy. 
 
 
34 See 21 CFR 56.114 and the guidance for industry Using a Centralized IRB Review Process in Multicenter Clinical 
Trials (March 2006). 
 
35 21 CFR 56.107(f). These individuals may not vote with the IRB.  
 
36 21 CFR 56.107. 
 
37 21 CFR 56.107 and 21 CFR 50 subpart D. 
 
14  Contains Nonbinding Recommendations 
In addition to new safety information, updates to the informed consent document to reflect 
protocol modifications may be required.38 Protocol amendments submitted under 21 CFR 312.30 
should be accompanied by the revised informed consent documents unless immediate 
modifications are intended to eliminate an apparent immediate hazard to subjects, in which case 
the sponsor should submit the revised informed consent document as soon as possible.  
 
 
IX.  ADDITIONAL REGULATORY CONSIDERATIONS 
 
Because of the complexity of master protocols and the need to avoid miscommunication that 
could compromise subject safety, sponsors should submit each master protocol as part of a new 
IND to FDA. For INDs that contain master protocols, sponsors should consider the following:  
 
  The master protocol should be the only trial that is conducted under the IND.   
 
  The sponsor should submit the master protocol to the review division in CDER or CBER 
responsible for reviewing the primary indication or indications. If more than one 
indication is being investigated, the sponsor should submit the IND to the most 
appropriate clinical review division within the Office of Oncologic Diseases in CDER, or 
within CBER, taking into account the population to be studied. 
 
 
X.  CONTENT OF A MASTER PROTOCOL 
 
A.  New IND Submission 
 
INDs containing master protocols are subject to all the requirements under 21 CFR 312. To 
ensure that all required aspects are complete, a master protocol must contain the required 
elements for clinical protocols described in 21 CFR 312.23(a)(6)(iii) and should contain all the 
information described in sections V, VI, VII, and VIII of this guidance. Specifically, the protocol 
and IND submission must address the following elements:  
 
(1) Core elements as required per 21 CFR 312.20-23 
 
(2) Submission in electronic (electronic common technical document (eCTD)) format39  
 
The protocol and IND submission should also address the following elements:  
 
(3) Appropriate letters of authorization to the other INDs for each investigational drug also 
being studied under the IND for the master protocol indicating the location of chemistry, 
 
38 21 CFR 50.25(a). 
 
39 See the guidance for industry Providing Regulatory Submissions in Electronic Format  Certain Human 
Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications  
Guidance (February 2020). 
  
15  Contains Nonbinding Recommendations 
manufacturing, and controls; nonclinical pharmacology and toxicology; clinical 
pharmacology; and clinical information in the IND referenced in support of the master 
protocol IND 
 
(4) Suggested IND title as PROTOCOL NAME: List of investigational drugs (e.g., 
LUNG-MAP: Drug X, Drug Y, Drug Z)   
 
(5) Submission of each substudy within the same IND under a separate folder in Section 
5.3.5. of the eCTD (as shown in Figure D in the Appendix) to facilitate review 
 
(6) Inclusion of a list of all the substudies in Section 5.2 of the eCTD, in addition to the 
master protocol title (as shown in Figure E in the Appendix) 
 
The master protocol should also include the following:  
 
(1) A detailed description of the trial design as text and as a visual depiction 
 
(2) Procedures for sample acquisition, handling, and testing of biomarkers, as well as 
information pertaining to any IVDs employed in the trial, as appropriate 
 
(3) Prominent identification of all substudies 
 
(4) Description of all groups responsible for monitoring subject safety (e.g., IRB, IDMC) 
 
(5) Description of the plan for submission of interim safety and efficacy results 
 
(6) The proposed informed consent document 
 
B.  Amendments to the Master Protocol 
 
Protocol amendments that substantively affect the safety or scope of the master protocol should 
contain the following:40 
 
(1) An updated informed consent document 
 
(2) A clean and tracked changes version of the amended master protocol document 
 
(3) A list of the proposed changes in tabular format with the rationale for each proposed 
change and the following supportive information, if available: 
 
(a)  Summary of available safety and efficacy data 
 
 
40 See 21 CFR 312.30(d) and 312.31(b) for content and format requirements for protocol amendments and 
information amendments. 
 
16  Contains Nonbinding Recommendations 
(b)  New nonclinical toxicology or pharmacology data and clinical data as appropriate 
to support the protocol modification 
 
In general, to facilitate communications and expedite the drug development program, FDA 
recommends that a sponsor submit a substudy for disease-specific development to a new master 
protocol IND reviewed by the appropriate disease-specific team, particularly when that team is 
located in another review division. In such instances, the sponsor should cross-reference to the 
original master protocol IND information on common elements (e.g., description of groups 
responsible for monitoring patient safety) rather than resubmit the information with the substudy. 
 
 
XI.  COMMUNICATION AND INTERACTIONS WITH FDA 
 
Sponsors should consult guidances for industry for best communication practices41 and 
meetings42 with FDA to ensure open lines of dialogue before and during the drug development 
process. With regard to master protocols, sponsors should consider the following:  
 
  FDA encourages the sponsor of the master protocol to request a pre-IND meeting. This 
can allow the sponsor and FDA to reach key agreements on the design and conduct of the 
protocol. 
 
  The cover letter for all meeting requests should clearly state REQUEST FOR 
MEETING-MASTER PROTOCOL (Meeting Type). 
 
  The sponsor should notify the regulatory project manager via secure email or a phone call 48 
hours before submitting any protocol amendment that substantively affects the safety or 
scope of the protocol. 
 
  The cover letter for such protocol amendments should be clearly marked as Protocol 
Amendment-MASTER PROTOCOL. 
 
  If the amendment contains changes intended to eliminate an apparent immediate hazard to 
subjects (e.g., closure of a substudy for unacceptable toxicity, modification of eligibility or 
monitoring to mitigate the risks), the sponsor should implement immediately the revised 
protocol.43 The sponsor must ensure that FDA is subsequently notified by protocol 
 
41 See the guidance for industry and review staff Best Practices for Communication Between IND Sponsors and 
FDA During Drug Development (December 2017). 
 
42 See the draft guidances for industry Formal Meetings Between the FDA and Sponsors or Applicants of BsUFA 
Products (June 2018) and Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products 
(December 2017). When final, these guidances will represent the FDAs current thinking on these topics.  
 
43 See 21 CFR 312.30(b)(2)(ii) (allowing protocol changes intended for this purpose to be implemented 
immediately provided FDA is subsequently notified by protocol amendment and the reviewing IRB is notified in 
accordance with 56.104(c).). 
 
17  Contains Nonbinding Recommendations 
amendment and the reviewing IRB is notified in accordance with 21 CFR 56.104(c).44 For 
other substantive changes that affect safety, scope, or the scientific quality of the study, the 
cover letter should contain a statement that the revised protocol will not be initiated until 30 
days after submission to the IND to allow FDA to assess the risks of the proposed change and 
until the change has been approved by the IRB.45  
 
44 See 21 CFR 56.104(c) (permitting IRB exemption for emergency use of a test article). 
 
45 See 21 CFR 312.30(b)(2)(i)(b) (permitting a protocol change to be made once the sponsor has submitted the 
change to FDA and the change has been approved by the IRB). 
18  Contains Nonbinding Recommendations 
REFERENCES 
 
Abrams J, B Conley, M Mooney, J Zwiebel, A Chen, JJ Welch, N Takebe, S Malik, L McShane, 
E Korn, M Williams, L Staudt, and J Doroshow, 2014, National Cancer Institutes Precision 
Medicine Initiatives for the New National Clinical Trials Network, Am Soc Clin Oncol Educ 
Book, 34:7176. 
 
Herbst RS, DR Gandara, FR Hirsch, MW Redman, M LeBlanc, PC Mack, LH Schwartz, E 
Vokes, SS Ramalingam, JD Bradley, D Sparks, Y Zhou, C Miwa, VA Miller, R Yelensky, Y Li, 
JD Allen, EV Sigal, D Wholley, CC Sigman, GM Blumenthal, S Malik, GJ Kelloff, JS Abrams, 
CD Blanke, and VA Papadimitrakopoulou, 2015, Lung Master Protocol (Lung-MAP)A 
Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung 
Cancer: SWOG S1400, Clin Cancer Res, 21(7):15141524. 
 
Hyman DM, I Puzanov, V Subbiah, JE Faris, I Chau, J-Y Blay, J Wolf, NS Raje, EL Diamond, 
A Hollebecque, R Gervais, ME Elez-Fernandez, A Italiano, R-D Hofheinz, M Hildago, E Chan, 
M Schuler, SF Lasserre, M Makrutzki, F Sirzen, ML Veronese, J Tabernero, and J Baselga, 
2015, Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations, N Engl J 
Med, 373(8):726736. 
 
Kim ES, RS Herbst, II Wistuba, JJ Lee, GR Blumenschein Jr., A Tsao, DJ Stewart, ME Hicks, J 
Erasmus Jr., S Gupta, CM Alden, S Liu, X Tang, FR Khuri, HT Tran, BE Johnson, JV Heymach, 
L Mao, F Fossella, MS Kies, V Papadimitrakopoulou, SE Davis, SM Lippman, and WK Hong, 
2011, The BATTLE Trial: Personalizing Therapy for Lung Cancer, Cancer Discov, 1(1): 4453. 
 
Simon R, 1989, Optimal Two-Stage Designs for Phase II Clinical Trials, Control Clin Trials, 
10(1):110. 
 
Woodcock, J and LM LaVange, 2017, Master Protocols to Study Multiple Therapies, Multiple 
Diseases, or Both, N Engl J Med, 377(1):6270.
19  Contains Nonbinding Recommendations 
APPENDIX 
 
Example of a Master Protocol With a Basket Trial Design 
 
An example of a master protocol with basket design is the phase 2 trial evaluating vemurafenib 
in multiple nonmelanoma cancers with BRAF V600 mutations, as shown in Figure A.  
 
Figure A:  Vemurafenib in Nonmelanoma Cancers Harboring BRAF V600 Mutations1 
* 
* 
 
*NSCLC = Non-small cell lung cancer; ECD = Erdheim-Chester disease; LCH = Langerhans cell histiocytosis. 
 
1 Hyman DM, I Puzanov, V Subbiah, JE Faris, I Chau, J-Y Blay, J Wolf, NS Raje, EL Diamond, A Hollebecque, R 
Gervais, ME Elez-Fernandez, A Italiano, R-D Hofheinz, M Hildago, E Chan, M Schuler, SF Lasserre, M Makrutzki, 
F Sirzen, ML Veronese, J Tabernero, and J Baselga, 2015, Vemurafenib in Multiple Nonmelanoma Cancers with 
BRAF V600 Mutations, N Engl J Med, 373(8):726736. 
 
20  Contains Nonbinding Recommendations 
Example of a Master Protocol With an Umbrella Trial Design 
 
An example of a master protocol with an umbrella design is the original version of the LUNG-
MAP trial, a multidrug, multi-substudy, biomarker-driven trial in patients with 
advanced/metastatic squamous cell carcinoma of the lung, as shown in Figure B. 
 
Figure B:  LUNG-MAP Trial in Patients With Squamous Cell Carcinoma of the Lung2 
 
 
*Archival formalin-fixed, paraffin-embedded tumor, fresh core needle biopsy if needed. NGS = next generation 
DNA sequencing; OS = overall survival; PFS = progression free survival; TT = targeted therapy; CT = 
chemotherapy (docetaxel or gemcitabine); TKI = tyrosine kinase inhibitor (erlotinib). 
 
 
2 Herbst RS, DR Gandara, FR Hirsch, MW Redman, M LeBlanc, PC Mack, LH Schwartz, E Vokes, SS 
Ramalingam, JD Bradley, D Sparks, Y Zhou, C Miwa, VA Miller, R Yelensky, Y Li, JD Allen, EV Sigal, D 
Wholley, CC Sigman, GM Blumenthal, S Malik, GJ Kelloff, JS Abrams, CD Blanke, and VA Papadimitrakopoulou, 
2015, Lung Master Protocol (Lung-MAP)A Biomarker-Driven Protocol for Accelerating Development of 
Therapies for Squamous Cell Lung Cancer: SWOG S1400, Clin Cancer Res, 21(7):15141524. 
21  Contains Nonbinding Recommendations 
Example of a Master Protocol With a Complex Trial Design 
 
An example of a master protocol with a complex trial design is the NCI-MATCH trial, as shown 
in Figure C.  
 
Figure C:  National Cancer Institute Match Trial Scheme3 
* 
*RECIST = response evaluation criteria in solid tumors; SD = stable disease. 
 
 
3 Adapted from Abrams J, B Conley, M Mooney, J Zwiebel, A Chen, JJ Welch, N Takebe, S Malik, L McShane, E 
Korn, M Williams, L Staudt, and J Doroshow, 2014, National Cancer Institutes Precision Medicine Initiatives for 
the New National Clinical Trials Network, Am Soc Clin Oncol Educ Book, 34:7176. 
22  Contains Nonbinding Recommendations 
Examples of How to Use eCTD for a Master Protocol 
 
Figure D (below) gives an example of how a sponsor can submit each substudy within the same 
investigational new drug application under a separate folder in section 5.3.5. of the electronic 
common technical document (eCTD). 
 
Figure D:  Schematic Figure of eCTD with an IND with Master Protocol CANCER 123 
and Substudies S-1, S-2, S-3, and S-4* 
 
 
* eCTD = electronic common technical document; IND = investigational new drug application. 
 
23  Contains Nonbinding Recommendations 
Figure E (below) gives an example of how a sponsor can include a list of all the substudies in 
section 5.2 of the eCTD, in addition to the master protocol title. 
 
Figure E:  Module 5.2 of eCTD Tabular Listing of All Clinical Studies and Substudies* 
 
Study  Location  Objectives  Study  Test products,  No. of  Healthy  Duration of  Study 
Identifier  of Study  of the  Design  Dosage regimen,  subjects or  subjects or  Treatment  status; 
Study  and type  Route of  diagnosis of  diagnosis of  type of 
of control  Administration  patients   patients  report 
Master 
               
CANCER123 
CA123-S1                 
CA123-S2                 
CA123-S3                 
CA123-S4                 
* eCTD = electronic common technical document.  
24