Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics Guidance for Industry: Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

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
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, rm. 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)
March 2022
Procedural

i
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

ii
XI. 	COMMUNICATION AND INTERACTIONS WITH FDA....................................... 17
REFERENCES............................................................................................................................ 19
APPENDIX .................................................................................................................................. 20

Contains Nonbinding Recommendations
1
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.

Contains Nonbinding Recommendations
2
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 FDA’s 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/.

Contains Nonbinding Recommendations
3
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 drug’s 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 FDA’s 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.

Contains Nonbinding Recommendations
4
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
11 See also the ICH guidance for industry E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1)
(March 2018).
Single investigational drug or drug
combination (T1)*
D2	D1* 	D3 	D4 	D5

Contains Nonbinding Recommendations
5
* 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
* 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.
Single
tumor type
or
histological
sub-type
(D1)*
T1*
T2
T3
Control
TX

Contains Nonbinding Recommendations
6
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

Contains Nonbinding Recommendations
7
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 drug’s 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.

Contains Nonbinding Recommendations
8
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).

Contains Nonbinding Recommendations
9
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 IVD’s 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 FDA’s 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 FDA’s 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).

Contains Nonbinding Recommendations
10
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.

Contains Nonbinding Recommendations
11
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).

Contains Nonbinding Recommendations
12
These reporting obligations are described, along with recommendations to help sponsors comply
with expedited safety reporting requirements, in the draft guidance for industry Sponsor
Responsibilities—Safety 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 Responsibilities—Safety
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 FDA’s 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 Responsibilities—Safety Reporting Requirements and Safety
Assessment for IND and Bioavailability/Bioequivalence Studies.

Contains Nonbinding Recommendations
13
(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 Responsibilities—Safety 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 IRB’s 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 FDA’s current
thinking on this topic.
33 21 CFR 56.109(f).

Contains Nonbinding Recommendations
14
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.

Contains Nonbinding Recommendations
15
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).

Contains Nonbinding Recommendations
16
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.

Contains Nonbinding Recommendations
17
(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 FDA’s 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).”).

Contains Nonbinding Recommendations
18
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).

Contains Nonbinding Recommendations
19
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 Institute’s Precision
Medicine Initiatives for the New National Clinical Trials Network, Am Soc Clin Oncol Educ
Book, 34:71–76.
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):1514–1524.
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):726–736.
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): 44–53.
Simon R, 1989, Optimal Two-Stage Designs for Phase II Clinical Trials, Control Clin Trials,
10(1):1–10.
Woodcock, J and LM LaVange, 2017, Master Protocols to Study Multiple Therapies, Multiple
Diseases, or Both, N Engl J Med, 377(1):62–70.

Contains Nonbinding Recommendations
20
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):726–736.
*
*

Contains Nonbinding Recommendations
21
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):1514–1524.

Contains Nonbinding Recommendations
22
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 Institute’s Precision Medicine Initiatives for
the New National Clinical Trials Network, Am Soc Clin Oncol Educ Book, 34:71–76.
*

Contains Nonbinding Recommendations
23
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.

Contains Nonbinding Recommendations
24
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
Identifier
Location
of Study
Objectives
of the
Study
Study
Design
and type
of control
Test products,
Dosage regimen,
Route of
Administration
No. of
subjects or
diagnosis of
patients
Healthy
subjects or
diagnosis of
patients
Duration of
Treatment
Study
status;
type of
report
Master
CANCER123
CA123-S1
CA123-S2
CA123-S3
CA123-S4
* eCTD = electronic common technical document.