Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drug and Biological Products

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

34957138fnl09-06-22.docx
Submitting Documents
Using Real-World Data
and Real-World Evidence
to FDA for Drug and
Biological Products
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Oncology Center of Excellence (OCE)
September 2022
Procedural

Submitting Documents
Using Real-World Data
and Real-World Evidence
to FDA for Drug and
Biological Products
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., 4 th 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
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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)
September 2022
Procedural

Contains Nonbinding Recommendations
TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	EXAMPLES OF SUBMISSIONS USING RWD/RWE THAT FDA INTENDS TO
TRACK .......................................................................................................................................... 3
IV. 	IDENTIFYING RWD/RWE AS PART OF A REGULATORY SUBMISSION ........ 3
A. 	Purposes of Using RWD/RWE ..................................................................................................... 3
B. 	Study Designs Using RWD to Generate RWE ............................................................................ 4
C. 	RWD Sources Used to Generate RWE ........................................................................................ 4
APPENDIX: SAMPLE PRESENTATION OF INFORMATION TO BE INCLUDED
WITH SUBMISSIONS CONTAINING RWD/RWE ................................................................ 6

Contains Nonbinding Recommendations
1
Submitting Documents Using Real-World Data and Real-
World Evidence to FDA for Drug and Biological Products
Guidance for Industry1
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the
title page.
I. 	INTRODUCTION
To facilitate FDA’s internal tracking of submissions to the Agency that include real-world data
(RWD) and real-world evidence (RWE), this guidance encourages sponsors and applicants to
identify in their submission cover letters certain uses of RWD/RWE. This guidance does not
address FDA’s substantive review of the RWD/RWE submitted as part of the Agency’s standard
review process.
This guidance applies to submissions for investigational new drug applications (INDs), new drug
applications (NDAs), and biologics license applications (BLAs) that contain RWD/RWE
intended to support a regulatory decision regarding product safety and/or effectiveness.
For the purposes of this guidance, FDA defines RWD and RWE as follows:
• 	RWD are data relating to patient health status and/or the delivery of health care that are
routinely collected from a variety of sources. Examples include:
− 	Electronic health record (EHR) data
− 	Medical claims data
− 	Product or disease registry data
− 	Data obtained from digital health technologies
− 	Data gathered from other sources that can inform on health status, such as
questionnaires
1 This guidance has been prepared by the Office of Medical Policy in the Center for Drug Evaluation and Research
in cooperation with the Center for Biologics Evaluation and Research and the Oncology Center of Excellence at the
Food and Drug Administration.

Contains Nonbinding Recommendations
2
• 	RWE is the clinical evidence about the usage and potential benefits or risks of a medical
product derived from analysis of RWD. RWE can be generated from RWD using many
different study designs, including but not limited to, interventional studies2 (clinical
trials) or non-interventional3 (observational) studies.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.
II. 	BACKGROUND
The availability of RWD and evolving analytic techniques to generate RWE have created interest
within the research and medical communities in the use of RWD/RWE to enhance clinical
research and support regulatory decision-making.
The 21st Century Cures Act (Cures Act),4 signed into law on December 13, 2016, is intended to
accelerate medical product development and bring innovations faster and more efficiently to the
patients who need them. Among other provisions, the Cures Act added section 505F to the
Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355g). Pursuant to this section,
FDA created a framework for a program (RWE Program) to evaluate the potential use of RWE
in regulatory decision-making.5
By enhancing FDA’s understanding of the scope and use of RWD and RWE submitted to
support regulatory decisions, internally tracking these submissions as described in this guidance
can inform FDA’s RWE program under section 505F of the FD&C Act.6
2 For the purposes of this guidance, an interventional study or clinical trial is a study in which participants, either
healthy volunteers or volunteers with the disease being studied, are assigned to one or more interventions, according
to a study protocol, to evaluate the effects of those interventions on subsequent health-related biomedical or
behavioral outcomes.
3 For the purposes of this guidance, a non-interventional or observational study is a type of study in which patients
received the marketed drug of interest during routine medical practice and are not assigned to an intervention
according to a protocol.
4 Public Law 114-255.
5 See the Framework for FDA’s Real-World Evidence Program, available at
https://www.fda.gov/media/120060/download. The framework and RWE Program also cover biological products
licensed under the Public Health Service Act.
6 Information about FDA’s RWE Program can be found in the Framework for FDA’s Real-World Evidence Program,
available at https://www.fda.gov/media/120060/download.

Contains Nonbinding Recommendations
3
III. 	EXAMPLES OF SUBMISSIONS USING RWD/RWE THAT FDA INTENDS TO
TRACK
This guidance focuses on submissions to FDA that rely on RWD/RWE to support a regulatory
decision regarding product effectiveness and/or safety. Relevant submission types may include
initial IND applications, meeting requests, study protocols, and final study reports submitted to
INDs, BLAs, or NDAs. Representative examples of study designs that may be included in
regulatory submissions are:
• 	Randomized clinical trials that use RWD to capture clinical outcomes related to safety or
effectiveness
• 	Single-arm trials that use RWD in an external control arm
• 	Observational studies, such as observational cohort and case-control studies, that generate
RWE intended to help support an efficacy supplement
• 	Clinical trials or observational studies that use RWD or RWE to fulfill a postmarketing
requirement (PMR) or postmarketing commitment (PMC)7
This guidance recommends that sponsors and applicants not identify submissions that contain
RWD/RWE if those data are not intended to support product labeling. For example, submissions
using RWD only to generate hypotheses or to plan a clinical trial (e.g., to identify potential trial
participants), studies incorporating RWD only in exploratory modeling or simulations, studies
using RWD only to validate an endpoint, or studies using RWD only in the qualification process
for Drug Development Tools8 should not be identified in submissions to FDA for the purposes of
this guidance.
IV. 	IDENTIFYING RWD/RWE AS PART OF A REGULATORY SUBMISSION
We recommend that sponsors include the following specific information in the cover letter of a
submission containing RWD/RWE in support of product labeling.9
A. 	Purposes of Using RWD/RWE
List the proposed purpose or purposes for which RWD/RWE will be used, such as:
7 For additional information about postmarketing study requirements and commitments, see the guidance for
industry Postmarketing Studies and Clinical Trials — Implementation of Section 505(o)(3) of the Federal Food,
Drug, and Cosmetic Act (April 2011). We update guidances periodically. For the most recent version of a
guidance, check the FDA guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
8 Information about FDA’s Drug Development Tool (DDT) qualification program is available at
https://www.fda.gov/drugs/development-approval-process-drugs/drug-development-tool-ddt-qualification-programs.
9 Applicants may use any format to provide the requested information. A sample table containing the requested
information is provided in the appendix.

Contains Nonbinding Recommendations
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• 	Support safety and/or effectiveness for a product not previously approved by FDA
• 	Support labeling changes for an FDA-approved product, including but not limited to:
− 	Adding or modifying an indication
− 	Changing the dose, dose regimen, or route of administration
− 	Expanding the labeled indication of the product to a new population
− 	Adding comparative effectiveness information
− 	Adding or modifying safety information
− 	Proposing other labeling changes
• 	Help to support or satisfy a PMR/PMC
B. 	Study Designs Using RWD to Generate RWE
Identify the clinical study design or designs that involve RWD as part of a submission to support
a regulatory decision, including but not limited to:
• 	Randomized controlled trials that utilize RWD to collect trial endpoints, including the use
of RWD to supplement control arm data
• 	Single-arm trials analyzed with an external (e.g., historical) control arm that relies on
RWD
• 	Observational studies
C. 	RWD Sources Used to Generate RWE
Indicate the type of RWD sources used to generate RWE, including:
• 	Electronic health record data10
• 	Medical claims data11
10 See the draft guidance for industry Real-World Data: Assessing Electronic Health Records and Medical Claims
Data to Support Regulatory Decision-Making for Drug and Biological Products (September 2021). When final, this
guidance will represent FDA’s current thinking on this topic.
11 Ibid.

Contains Nonbinding Recommendations
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• 	Product, disease, or other registry data12
• 	Data collected from digital health technologies in non-research settings
• 	Other data sources (e.g., questionnaires) that can inform on health status (to be specified)
12 See the draft guidance for industry Real-World Data: Assessing Registries to Support Regulatory Decision-
Making for Drug and Biological Products (November 2021). When final, this guidance will represent FDA’s
current thinking on this topic.

Contains Nonbinding Recommendations
6
APPENDIX: SAMPLE PRESENTATION OF INFORMATION TO BE INCLUDED
WITH SUBMISSIONS CONTAINING RWD/RWE
The table below represents an example of how sponsors and applicants can identify a submission
containing real-world data (RWD)/real-world evidence (RWE) as part of their cover letter
accompanying such submissions to FDA.
General Information
Generic/proprietary name of product: _____________________________________________
Disease/medical condition: ____________________________________________________
Purposes of Using RWD/RWE as Part of the Submission (select all that apply)
 To support safety and/or effectiveness for a product not previously approved by FDA
 To support labeling changes for an approved product, including:
 Add or modify an indication
 Change dose, dose regimen, or route of administration
 Expand the labeled indication of the product to a new population
 Add comparative effectiveness information
 Add or modify safety information
 Other labeling change – specify: ____________________________________________
 To support or satisfy a postmarketing requirement (PMR)/postmarketing commitment
(PMC)
Study Designs Using RWD to Generate RWE (select all that apply)
 Randomized controlled trial with pragmatic elements and those using RWD to supplement
a control arm
 Single-arm trial that uses RWD in an external control arm
 Non-interventional (observational) study
 Other study design – specify: _________________________________________________
RWD Sources Used to Generate RWE (select all that apply)
 Electronic health records data
 Medical claims data
 Product, disease, or other registry data
 Data from digital health technologies in non-research settings
 Other data sources (e.g., questionnaires) that can inform on health status – specify:
_____________________________________________________