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 
 
34957138fnl09-06-22.docx    
Submitting Documents 
Using Real-World Data 
and Real-World Evidence 
to FDA for Drug and 
Biological Products 
Guidance for Industry 
 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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 https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs  
 
and/or 
 
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Center for Biologics Evaluation and Research 
 Food and Drug Administration 
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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 
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 FDAs 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 FDAs substantive review of the RWD/RWE submitted as part of the Agencys 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.  
1  Contains Nonbinding Recommendations 
 
  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, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys 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 FDAs 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 FDAs 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 FDAs 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 FDAs RWE Program can be found in the Framework for FDAs Real-World Evidence Program,  
available at https://www.fda.gov/media/120060/download. 
 
2  Contains Nonbinding Recommendations 
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 FDAs 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. 
3  Contains Nonbinding Recommendations 
 
  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 FDAs current thinking on this topic. 
 
11 Ibid. 
4  Contains Nonbinding Recommendations 
  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 FDAs 
current thinking on this topic. 
5  Contains Nonbinding Recommendations 
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: 
_____________________________________________________ 
 
6