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Guidance Snapshot

Master Protocols for Drug and 

Biological Product Development

Draft Guidance

What Is Recommended In 

This Guidance?

This guidance provides 

recommendations on the design 

and analysis of trials conducted 

under a master protocol. It focuses on randomized 

umbrella and platform trials (see definitions below) 

intended to contribute to evidence of safety and 

effectiveness of drugs. The document also provides 

guidance on the submission of master protocol 

documents for FDA review.

Why Is This Guidance 

Important?

Compared with traditional standalone trials under separate 

protocols, trials conducted under 

master protocols can share control arms, protocol 

elements, infrastructure, and oversight, thereby 

maximizing the amount of information obtained 

from a research effort. This document provides 

guidance to support well-designed, wellconducted trials using master protocols to 

accelerate drug development, particularly 

in certain settings, such as where subject 

recruitment is challenging. 

What Is A Master Protocol?

A protocol designed with multiple substudies:

• These substudies may have different 

objectives

• These substudies are coordinated within an 

overall study structure to evaluate: 

° One or more medical products 

° One or more diseases or conditions

Guidance Snapshots are a communication tool and are not a substitute for the guidance document. 

To learn more about master protocols, read the draft guidance. To see additional Guidance 

Snapshots, check out the pilot program.
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Examples of trial types 

that could utilize 

a master protocol

Umbrella trial

Evaluates multiple medical 

products at the same time for 

a single disease or condition

Platform trial

Evaluates multiple medical 

products for a disease or 

condition and medical products 

can enter or leave the platform 

in an ongoing manner

Basket trial

Evaluates a medical product 

for multiple diseases, conditions, 

or disease subtypes

Trial Design Considerations

Randomization

• Removes systematic imbalances between treatment arms to ensure 

reliable inference.

• Consider a randomization scheme that allocates more subjects to the 

control arm than each individual drug arm (can increase power for 

each drug versus control comparison for a given sample size).

• Randomization ratios can change when products enter or exit a platform trial. Comparisons should account for time periods of different 

randomization ratios.

Control Group

Platform trials in which products enter and exit should generally only 

use concurrent control subjects who meet drug-specific eligibility 

criteria for primary comparisons.

Blinding to Treatment Assignment

Critical to avoid bias, but complex strategies may be needed as the 

number of drugs, routes of administration, and dosing schedules 

increases.

Multiplicity

FDA generally does not recommend controlling for multiplicity across 

comparisons of different drugs to the control, but multiplicity control 

across different analyses (e.g., of different endpoints) for a given drug 

remains important.

Comparison Between Drugs

Not required, but may be useful and if conducted, should be 

prespecified in the statistical analysis plan. Sponsors should consider 

entering into data-sharing agreements to allow for leveraging of 

information across drugs.

Independent, External Data Monitoring Committee (DMC)

Recommended to oversee data access plans, analyses, and 

communication of results while maintaining trial integrity and preventing 

inadvertent dissemination of information when multiple drugs are being 

studied.

Guidance Snapshots are a communication tool and are not a substitute for the guidance document. 

To learn more about master protocols, read the draft guidance. To see additional Guidance 

Snapshots, check out the pilot program.
www.fda.gov 3

Background About the Guidance

In May 2021, FDA published the guidance for industry COVID-19: Master Protocols Evaluating Drugs and 

Biological Products for Treatment or Prevention, which focused on master protocols evaluating drugs for the 

treatment or prevention of COVID-19. That guidance was intended to remain in effect only for the duration of 

the public health emergency related to Coronavirus Disease 2019 declared by the Secretary of Health and 

Human Services under section 319 of the Public Health Service Act, which has now expired. FDA is issuing 

this draft guidance because many of the recommendations set forth in the 2021 guidance are applicable 

outside the context of the section 319 public health emergency and are applicable to other therapeutic 

areas, not just COVID-19.

Drug Development Timeline

*When to Apply the Guidance Recommendations

BASIC 

RESEARCH

PROTOTYPE 

DESIGN OR 

DISCOVERY

PRECLINICAL 

DEVELOPMENT

CLINICAL 

DEVELOPMENT*

PHASE 1* PHASE 2* PHASE 3*

FDA 

FILING & 

APPROVAL

POSTMARKET OR 

POSTAPPROVAL 

STUDIES

Recommendations From the Guidance Apply to Clinical Development

The regulatory considerations for a master protocol have increased complexity compared to those for a protocol for a 

stand-alone trial given the involvement of additional stakeholders, the potential for frequent changes, and the quantity of 

documentation. Because of these complexities, each master protocol should be submitted as a new IND to FDA, and a master 

protocol sponsor should request a pre-IND meeting to discuss the protocol and submission details.

Guidance Recap Podcast

Hear highlights from FDA staff

Speaker: Gregory Levin, PhD, Associate Director for Statistical Science and Policy in the Center for 

Drug Evaluation and Research’s Office of Biostati

Click here to listen

Click here to 

read transcript

Continue the Conversation

Share your thoughts on the 

draft guidance

Click here to provide 

official comments to 

the FDA Docket

Guidance Snapshots are a communication tool and are not a substitute for the guidance document. 

To learn more about master protocols, read the draft guidance. To see additional Guidance 

Snapshots, check out the pilot program.

(docket opens on 12/22/2023)