Real-World Data:  Assessing 
Registries to Support 
Regulatory Decision-Making 
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) 
 
December 2023 
Real World Data/Real World Evidence (RWD/RWE) 
54619456fnl12-19-23.docx   
Real-World Data:  Assessing 
Registries to Support 
Regulatory Decision-Making 
for Drug and Biological 
Products
 
Guidance for Industry 
 
 
 
Additional copies are available from: 
 
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Center for Drug 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) 
 
December 2023 
Real World Data/Real World Evidence (RWD/RWE) 
  Contains Nonbinding Recommendations 
 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DISCUSSION .................................................................................................................... 4 
A.  Using Registry Data to Support Regulatory Decisions ............................................................... 4 
B.  Relevance of Registry Data ........................................................................................................... 5 
C.   Reliability of Registry Data ........................................................................................................... 7 
D.  Considerations When Linking a Registry to Another Registry or Another Data System .... 10 
E.  Considerations for Regulatory Review ...................................................................................... 12 
 
    
 
 
 
  Contains Nonbinding Recommendations 
Real-World Data:  Assessing Registries to Support Regulatory 
Decision-Making 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   
 
The 21st Century Cures Act (Cures Act),2 signed into law on December 13, 2016, was intended 
to accelerate medical product development and bring innovations and advances 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).  In response to the requirements 
in section 505F, FDA created a framework for a Real-World Evidence (RWE) Program to 
evaluate the potential use of RWE to help support the approval of a new indication for a drug3 
already approved under section 505(c) of the FD&C Act or to help support or satisfy 
postapproval study requirements.4  In the context of this program, this guidance provides 
considerations for sponsors proposing to design a new registry or use an existing registry to 
support regulatory decision-making about a drugs effectiveness or safety.  This guidance does 
not provide recommendations on choice of study design or statistical methods used to analyze 
data from registries.  
 
FDA is issuing this guidance as part of its RWE Program and to satisfy, in part, the mandate 
under section 505F of the FD&C Act to issue guidance on the use of RWE in regulatory 
decision-making.5  FDA defines real-world data (RWD) and RWE as follows: 
 
1 This guidance has been prepared by 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. 
 
2 Public Law 114-255. 
 
3 For the purposes of this guidance, all references to drugs include both human drugs and biological products. 
 
4 See the Framework for FDAs Real-World Evidence Program, available at 
https://www.fda.gov/media/120060/download.  In addition to drug and biological products approved under section 
505(c) of the FD&C Act, this framework is also intended for application to biological products licensed under the 
Public Health Service Act. 
 
5 See section 505F(e) of the FD&C Act.  
 
  1  Contains Nonbinding Recommendations 
 
  RWD are data relating to patient health status and/or the delivery of health care routinely 
collected from a variety of sources. 
 
  RWE is the clinical evidence about the usage and the potential benefits or risks of a 
medical product derived from analysis of RWD. 
 
Topics covered in this guidance include: 
 
  Considerations regarding a registrys fitness-for-use in regulatory decision-making, 
focusing on attributes of a registry that support the collection of relevant and reliable data 
 
  Considerations when linking a registry to another data source for supplemental 
information, such as data from medical claims, electronic health records (EHRs),6 digital 
health technologies,7 or other registries  
 
  Considerations for supporting FDA review of submissions that include registry data 
 
Whether registry data are fit-for-use in regulatory decision-making depends, in part, on attributes 
that support the collection of relevant and reliable data (described in this guidance).   
 
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 
 
For the purposes of this guidance, a registry is defined as an organized system that collects 
clinical and other data in a standardized format for a population defined by a particular disease, 
condition, or drug exposure.  Establishing registries involves enrolling a predefined population 
and collecting prespecified health-related data for each patient in that population (patient-level 
data).  Data about this population can be entered directly into the registry (e.g., clinician- or 
patient-reported) and can also include data from other sources that characterize registry 
 
6 For additional discussion, 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.  We update 
guidances periodically.  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. 
 
7 For additional discussion on the use of digital health technologies in clinical investigations, see the draft guidance 
for industry Digital Health Technologies for Remote Data Acquisition in Clinical Investigations (December 2021).  
When final, this guidance will represent FDAs current thinking on this topic. 
 
  2  Contains Nonbinding Recommendations 
participants.  Such external data sources can include, but are not limited to, data from medical 
claims, laboratory or vital statistics databases, EHRs, or medical device outputs.   
 
Registries range in complexity regarding the extent and detail of the data captured and how the 
data are curated.  For example, registries used for quality assurance purposes related to the 
delivery of care for a particular health care institution or health care system tend to collect 
limited data related to the provision of care.  Registries designed to address specific research 
questions tend to systematically collect longitudinal data in a defined population, on factors 
characterizing patients clinical status, treatments received, and subsequent clinical events.  The 
data collected and the standard operating procedures for data collection and management are 
relevant when considering how registry data can be used.  
 
Registries have the potential to support sponsors drug development programs, and registry data 
can be used to inform the design and support the conduct of either interventional studies (clinical 
trials) or non-interventional (observational) studies.  Examples of such uses include, but are not 
limited to:  
 
  Characterizing the natural history of a disease8 
 
  Providing information that can help determine sample size, selection criteria, and study 
endpoints when planning an interventional study 
 
  Selecting suitable study participantsbased on factors such as demographic 
characteristics, disease duration or severity, and past history or response to prior 
therapyto include in an interventional study (e.g., randomized trial)  
 
  Identifying biomarkers or clinical characteristics that are associated with clinical 
outcomes of relevance to support the planning of interventional and non-interventional 
studies 
 
  Supporting inferences about safety and effectiveness when: 
 
  Ascertaining clinical outcomes or other clinical data in an interventional study 
 
  Including registry data as an external control for an interventional trial9   
 
 
8 Disease registries are common platforms to acquire the data for natural history studies intended to understand 
aspects of the disease such as prognostic variables and outcomes.  Natural history studies are likely to include 
patients receiving the current standard of care and/or emergent care, which may alter some manifestations of the 
disease.   
 
9 For additional discussion on the use of external controls, see the draft guidance for industry Considerations for the 
Design and Conduct of Externally Controlled Trials for Drug and Biological Products (February 2023).  When 
final, this guidance will represent FDAs current thinking on this topic. 
 
  3  Contains Nonbinding Recommendations 
  Evaluating a drug received during routine medical practice (e.g., to evaluate clinical 
outcomes in populations underrepresented in clinical trials)  
 
 
III.  DISCUSSION  
 
A.  Using Registry Data to Support Regulatory Decisions 
 
Registry data can have varying degrees of suitability within a regulatory context, depending on 
several factors, including regulatory intent (e.g., to evaluate a specific safety risk, to provide 
information on long-term efficacy outcomes, or to serve as an external control for an 
interventional study to inform effectiveness); the patient population enrolled; the data collected; 
and how registry datasets were created, maintained, curated, and linked to other datasets.  
Registry data collected initially for one purpose (e.g., to obtain comprehensive clinical 
information on patients with a particular disease) may or may not be fit-for-use for another 
purpose (e.g., to examine a drug-outcome association in a subset of these patients).  Sponsors 
proposing to use registry data to support regulatory decision-making by FDA are responsible for 
ensuring that attributes of the registry support the collection of relevant and reliable data, 
including in situations where the data are from a registry not managed or designed by the 
sponsor.    
 
An existing registry can be used for purposes other than those originally intended, and reuse of a 
registrys infrastructure to support multiple interventional and non-interventional studies can 
generate efficiencies, such as when the number of eligible patients is limited.  Sponsors 
proposing to use data from an existing registry should ensure that the informed consent provided 
by patients participating in the registry allows for the sponsors proposed use of the registry data 
or that patients are re-consented for the proposed use.  
 
A registry that is designed prospectively to collect data to answer a specific research question 
can have advantages over an existing registry that is repurposed to answer the same question, 
because developers of a registry intended to answer a specific research question can design the 
registry to collect drug/environmental exposures, outcomes, and covariates tailored to the 
research question of interest.  
 
Sponsors should consider both the strength and limitations of using registries as a source of data 
to generate evidence for regulatory decision-making.  Registries may have advantages over other 
RWD sources, given that registries collect structured and predefined data elements and can offer 
longitudinal, curated data about a defined population of patients and their corresponding disease 
course, complications, and medical care.  In addition, registries can systematically collect data 
that medical claims datasets or EHR datasets may lack (e.g., patient-reported outcomes, 
treatment adherence, measures of disease severity). 
 
Registries can have limitations for use in a regulatory context.  For example, existing registries 
may focus on one disease, with limited information on comorbid conditions, even after linkage to 
other data sources.  In addition, the enrolled patients may not be representative of the target 
population of interest due to challenges related to patient recruitment and retention.  For 
  4  Contains Nonbinding Recommendations 
example, patients with more severe disease may be more likely to be enrolled in a registry 
compared to patients with milder disease or vice versa, depending on the requirements for 
registry participation; or enrolled patients might have different self-care practices, 
socioeconomic backgrounds, or levels of supportive care compared with the entire population of 
interest.  These issues, if not addressed, can potentially introduce bias into analyses that make 
use of registry data.   
 
As with other sources of RWD, registries are generally better suited as a data source for 
regulatory purposes when sponsors aim to capture objective data on clinical events such as death 
or hospitalization.  Subjective data, such as pain scores, can be collected in a registry, but 
additional challenges are involved to standardize such measurements.10  In addition, for both 
objective and subjective data, sponsors should consider whether registry participants knowledge 
of treatment received could introduce bias into the study findings.   
 
Before using registry data in a study intended to support regulatory decision-making by FDA, 
sponsors should consider whether the data are fit-for-use by assessing the datas relevance and 
reliability.  For the purposes of this guidance, the term relevance includes the availability of data 
for key study variables (exposures, outcomes, covariates) and sufficient numbers of 
representative patients for the study, and the term reliability includes accuracy, completeness, 
and traceability.11 
 
Sponsors should consult with the appropriate FDA review division regarding the appropriateness 
of using a specific registry as an RWD source for studies that are intended to provide evidence in 
support of a regulatory decision by FDA.  Sponsors should also submit the protocols and 
statistical analysis plans to the Agency before conducting the study. 
 
B.  Relevance of Registry Data 
 
When considering whether to use an existing registry for regulatory purposes, a sponsors overall 
assessment of the relevance of the registry data should ensure that the registry is adequate for 
evaluating the scientific objectives.  As a part of this assessment, sponsors should evaluate the 
data elements captured by the registry.  
 
The specific data elements that should be captured by a registry depend on the sponsors 
intended use or uses of the registry.  For example, the minimum set of data elements in a registry 
may need to be more comprehensive if the sponsor intends to use the registry data for an external 
control arm in an externally controlled trial, compared to if the sponsor intends to use the registry 
 
10 For additional discussion on how FDA reviews and evaluates patient-reported outcome instruments used to 
support claims in approved medical product labeling, see the guidance for industry Patient-Reported Outcome 
Measures:  Use in Medical Product Development to Support Labeling Claims (December 2009).  This guidance will 
be replaced by a series of guidances on patient-focused drug development (PFDD) when the PFDD guidances are 
finalized.  For additional information, see https://www.fda.gov/drugs/development-approval-process-drugs/fda-
patient-focused-drug-development-guidance-series-enhancing-incorporation-patients-voice-medical. 
 
11 Traceability is the method (e.g., audit trail) that allows for knowledge of data provenance (i.e., the origin of a 
piece of data and how it got into the registry). 
 
  5  Contains Nonbinding Recommendations 
to identify participants for an interventional study.  Sponsors should confirm that the registry 
supports data consistency by capturing data elements uniformly, using the same formats and 
definitions, for a defined patient population and a specific time period.  The registry should 
document any data elements that are no longer being collected, new data elements that have 
begun to be collected, and any changes in formats or definitions over time.  
  
The assessment of the datas relevance is context dependent.  When assessing the relevance of a 
registry for a specific regulatory purpose, sponsors should consider the methods used to identify 
and retain registry patients and the effect those methods have on the representativeness of the 
population in the registry.  In particular, the inclusion and exclusion criteria used to enter patients 
into a registry may result in the patient population in a registry differing from the target 
population for the sponsors drug development program.    
 
A registry should have a plan to reduce missing assessments and to minimize loss to follow-up of 
registry participants. For example, a registry should have plans for outreach to patients who do 
not maintain contact with the registry or have difficulty doing so (e.g., text messages, phone 
calls, emails, offers of transportation assistance). Sponsors should consider factors that may 
influence which patients remain enrolled in the registry and how they may differ from those who 
do not remain (e.g., because of factors such as adverse events experienced, disease progression, 
or location of care).  Sponsors should consider the extent and reasons for missing assessments 
and for loss to follow-up to understand the potential impact of missing data on study findings.  
 
Registries generally include data elements that capture information about patient characteristics, 
treatments received, and health outcomes for patients enrolled in the registry.  Such information 
typically includes a unique patient identifier; the date of patient consent to participate in the 
registry; and baseline characteristics of the patient at that time, such as demographic factors, 
comorbidities, medical history, and other information.  
 
Sponsors should ensure that a registry includes data elements necessary for the intended use of 
the registry.  Sponsors should confer with the appropriate FDA review division about the 
adequacy of registry data to support a regulatory decision, including the completeness and timing 
of data collection.  The following are non-exhaustive examples of potential data that can be 
included in a registry: 
 
  Demographic and clinical information: 
 
  Patient demographic factors, including date of birth, sex, sexual orientation, gender, 
race, and ethnicity, as well as measurements such as height and weight 
 
  Substance use, such as alcohol, recreational drugs, and tobacco 
 
  Primary diagnosis of interest, including date of diagnosis, diagnostic test name and 
result, diagnostic code, and genetic or other testing, if available; specific approach to 
capture grade, severity, and/or burden of disease and important milestones in disease 
progression 
 
  6  Contains Nonbinding Recommendations 
  Patient comorbidities, including current status (e.g., complications, disease 
manifestations) of those diseases, dates of assessments, and therapies for individual 
comorbid conditions  
 
  Additional relevant information regarding characteristics thought to modify disease 
severity or progression 
 
  Information on treatment of the disease of interest and comorbid conditions:  
 
  Drug chemical name and product name, formulation and dosage, start and end dates, 
and reason for discontinuation (as applicable) for each treatment 
 
  Type and date of procedures and periprocedural complications (as applicable) 
 
  Other health-related information: 
 
  Specific clinical events of interest (e.g., heart attack, stroke, hospitalization, death) 
and date of occurrence  
 
  Other clinical outcomes (e.g., disease progression or relapse, disability, functional 
status, quality of life) and date of occurrence or assessment12 
 
  Pregnancy-related outcomes13 
 
C.   Reliability of Registry Data 
 
When considering using data from an existing registry or establishing a registry de novo, 
sponsors should ensure that there are processes and procedures to govern registry operation, 
education and training of registry staff, resource planning, and practices that help ensure the 
quality of the registry data.  Sponsors submitting data to FDA from registries held by another 
organization should work closely with that organization to ensure that processes and procedures 
are in place to support the reliability of the registry data.  In addition, sponsors should have 
access to metadata associated with registry data intended to support regulatory decision-
making.14  
 
 
12 See footnote 11.  
 
13 For further discussion of the design of pregnancy safety studies, including recommended data elements, see the 
draft guidance for industry Postapproval Pregnancy Safety Studies (May 2019).  For further discussion of clinical 
lactation studies, see the draft guidance for industry Clinical Lactation Studies:  Considerations for Study Design 
(May 2019).  When final, these guidances will represent FDAs current thinking on these topics.   
 
14 For additional discussion of metadata, see the draft guidance for industry Electronic Systems, Electronic Records, 
and Electronic Signatures in Clinical Investigations:  Questions and Answers (March 2023).  When final, this 
guidance will represent FDAs current thinking on this topic. 
 
  7  Contains Nonbinding Recommendations 
Governance attributes that help ensure that the registry can achieve its objectives include, but are 
not limited to:  
 
  An established data dictionary, which is available for those who intend to use the registry 
data to perform analyses.  The data dictionary should generally include: 
 
  Data elements and corresponding definitions 
 
  Ranges, units, allowable values, and format for the data elements as well as 
corresponding data standards and terminologies used 
 
  Information regarding the origin of the data for each data element 
 
  Defined processes and procedures for the registry, such as: 
 
  Collection, organization, maintenance, and storage of data, including processes to 
help ensure that data within a registry can be verified by source data (as applicable) 
for that registry   
 
  Documentation of (1) queries to ensure registry data are logically, consistently, and 
completely entered, including dates, times, and results of queries, and (2) steps taken 
to resolve issues identified, such as invalid, missing, or inconsistent data, including 
any changes made to the registry data 
 
  Prespecified rules for entering, modifying, searching, and retrieving registry data, 
including for situations in which registry data are combined with data from another 
source 
 
  Validation of the electronic systems used to collect registry data15   
 
  Conformance with 21 CFR part 11, as applicable, including maintenance of access 
controls and audit trails to demonstrate the provenance of the registry data and to support 
traceability of the data16 
 
Sponsors also should ensure that a registry adheres to applicable jurisdictional human subject 
protections requirements, including protecting the privacy of patient health information, when 
designing a registry or considering use of data from an existing registry.  FDA also recommends 
 
15 Validation of electronic systems means a process of establishing and documenting that the specified requirements 
of an electronic system can be consistently fulfilled from design until decommissioning of the system or 
transitioning to a new system.  This topic is also discussed in the draft guidance for industry Electronic Systems, 
Electronic Records, and Electronic Signatures in Clinical Investigations:  Questions and Answers.  
 
16 For additional discussion on the use of electronic records and electronic systems under part 11, see the draft 
guidance for industry Electronic Systems, Electronic Records, and Electronic Signatures in Clinical Investigations:  
Questions and Answers.    
 
  8  Contains Nonbinding Recommendations 
that an institutional review board or independent ethics committee be consulted when developing 
a registry to review data collection and other procedures associated with the registry.  
 
Factors that FDA considers when assessing the reliability of registry data include whether the 
data were collected in accordance with the prespecified protocol.  FDA also considers whether 
the registry personnel and processes in place during data collection and analysis are adequate to 
minimize errors and maintain integrity of the study data.  Sponsors should address whether the 
registry has privacy and security controls in place to ensure that the confidentiality and security 
of data are preserved.17   
 
Sponsors should use common data elements to promote standardized, consistent, and universal 
data collection.  Such an approach can facilitate comparing or linking registry data to data from 
other sources.  Standardized terminology and the associated data standards used by the registry 
should facilitate conformance with FDAs requirements for submitting study data in applicable 
drug submissions.18     
 
Additional policies and procedures should be in place that enable FDA to assess the quality of 
the data (e.g., to address issues such as errors in coding or interpretation of source documents, 
data entry, cleaning, transfer, and linkage). 
 
Registries in the form of an electronic database should have safeguards in place, including data 
management strategies, to support data reliability.  Data management strategies should include 
processes and procedures to: 
 
  Implement and maintain version control by documenting the date, time, and originator19  
of data entered in the registry; performing preventative and/or corrective actions to 
address changes to the data (including flagging erroneous data without deleting the 
erroneous data, while inserting the corrected data for subsequent use); and describing 
 
reasons for any changes to data without obscuring previous entries 
 
  Ensure that data transferred from another data format or system are not altered in the 
migration process 
 
 
17 For recommendations on controls to ensure confidence in the reliability, quality, and integrity of electronic source 
data in FDA-regulated clinical investigations, see the guidance for industry Electronic Source Data in Clinical 
Investigations (September 2013). 
 
18 See FDAs Study Data Standards Resources web page, available at 
https://www.fda.gov/forindustry/datastandards/studydatastandards/default.htm.  For additional discussion of 
considerations for the use of data standards currently supported by FDA in applicable drug submissions containing 
study data derived from RWD sources, see the draft guidance for industry Data Standards for Drug and Biological 
Product Submissions Containing Real-World Data (October 2021).  When final, this guidance will represent FDAs 
current thinking on this topic. 
 
19 Source data originators include persons, systems, devices, and instruments.  For additional information, see the 
guidance for industry Electronic Source Data in Clinical Investigations.  
 
  9  Contains Nonbinding Recommendations 
  Seek to integrate data in the registry that were previously collected using data formats or 
technology (e.g., operating systems, hardware, software) that are now outdated 
 
  Account for changes in clinical information collected over time (e.g., to align data 
elements with evolving diagnostic criteria or treatment guidelines)  
 
  Explain the auditing rules and methods used and the mitigation strategies used to reduce 
errors  
 
  Describe the types of errors that were identified based on audit findings and any 
corrective actions taken. 
 
Indicators of data consistency, accuracy, and completeness should be assessed periodically, with 
the frequency dependent on the purposes of the registry data (e.g., for the sole purpose of 
facilitating recruitment in a randomized controlled trial versus using the registry data in an 
interventional or non-interventional study analysis).  Routine descriptive statistical analyses 
should be performed to detect the extent of any missing data, inconsistent data, outliers, and 
losses to follow-up.  
  
D.  Considerations When Linking a Registry to Another Registry or Another 
Data System 
 
When a registry does not capture all the necessary information to answer the question of interest 
in an interventional or non-interventional study, sponsors may consider obtaining supplemental 
information from another source.  For example, sponsors may consider linking the data on a 
patient in the registry to the same patient in another data system or systems, such as another 
registry, an EHR, a medical claims database, or a digital health technology. This linkage may 
occur by populating the registry with data from another data system or by combining external 
data with registry data at the time of the analysis. 
 
If a registry is to be populated with data from another data system, sponsors should consider the 
potential impact of the additional data on overall integrity of the registry data.  Sponsors should 
use strategies to account for missing data, correct for redundant data, resolve any inconsistencies 
in the data, and address other potential problems, such as the ability to protect patient privacy 
while transferring data securely.  Sponsors should have a plan for addressing the adequacy and 
accuracy of patient-level linkages (i.e., that the same patient is being matched).  Sponsors also 
should consider any jurisdictional requirements (e.g., country-specific laws) when seeking to link 
patient-level data to another registry or data system.   
 
Sponsors should also consider whether the data sources to be linked are interoperable and 
support appropriate informatics strategies (e.g., data element mapping) to ensure appropriate data 
integration.  Sponsors should ensure that (1) sufficient testing is conducted to demonstrate 
interoperability of the linked data systems, (2) the automated electronic transmission of data 
elements to the registry functions in a consistent and repeatable fashion, and (3) the data are 
accurately, consistently, and completely transmitted.  Predefined rules to check for logical 
  10  Contains Nonbinding Recommendations 
consistency and value ranges should be used to confirm that data within a registry were retrieved 
accurately from a linked data source and that the operational definitions for the linked variables 
are aligned.  
 
Documentation of the process sponsors used to validate the transfer of data from an external data 
source to the registry should be available for FDA to review during sponsor inspections.  
Sponsors should also ensure that software updates to the registry database or additional data 
sources do not affect the integrity, interoperability, and security of data transmitted to the 
registry.20  For example, issues such as the correct temporal alignment of linked data and registry 
data should be considered.  
 
The appropriateness of using additional data sources also depends on how the sponsor intends to 
use the linked data and the ability to obtain similar data for all patients.  For example, for each 
potential data source, the sponsor should consider whether: 
 
  The linkage is appropriate for the proposed research question (e.g., the additional data 
source provides relevant clinical detail and/or long-term follow-up information) 
  
  The linkage of records between the two (or more) databases can be performed accurately  
 
  The linkage may compromise the representativeness and relevance of the patient 
population, if only a subset of the overall registry population is represented in the linked 
dataset 
 
  The variables of interest in the registry and additional data sources have consistent 
definitions and reliable ascertainment approaches  
 
  The data linked from external sources have been captured with sufficient accuracy, 
consistency, and completeness to meet study objectives 
 
  The source data are available for any data sources used to supplement registry data 
 
  The procedures and access controls in place protect the privacy of patient data  
 
  Informed consent(s) provided by patients contributing data to each data source would 
allow for the linkage  
 
After a sponsor decides to use an additional data source or sources to supplement the registry, the 
sponsor should develop and describe the approach used to link such data to the registry.  FDA 
does not endorse a particular approach to linkage.  The sponsor should also describe how data 
integrity will be evaluated after the linkage, including plans to assess any inaccuracies introduced 
by the linkage (e.g., overcounts of a particular data measure, duplication of patients or variables), 
 
20 For additional discussion on the use of electronic records and electronic systems under part 11, see the draft 
guidance for industry Electronic Systems, Electronic Records, and Electronic Signatures in Clinical Investigations:  
Questions and Answers.  
  11  Contains Nonbinding Recommendations 
steps taken to address issues identified, and approaches taken to address issues that cannot be 
fully rectified.  When sponsors intend to submit registry data to FDA that include data from 
sources owned by another organization, sponsors should work closely with the other 
organization to ensure that appropriate methods for data entry, coding, cleaning, and 
transformation are in place for each linked data source.   
 
E.  Considerations for Regulatory Review  
 
Sponsors interested in using a specific registry as a data source for a study intended to support a 
regulatory decision by FDA should meet with the relevant FDA review division before 
conducting the study.21  Sponsors should confer with FDA regarding (1) the ability to accurately 
define and evaluate the target population based on the planned inclusion and exclusion criteria; 
(2) which data elements will come from the registry (versus other data sources) and their 
adequacy, as well as the frequency and timing of data collection; (3) the planned approach for 
linking the registry to another registry or other data system, when linking is anticipated; (4) the 
planned methods to ascertain and validate outcomes, including diagnostic requirements and the 
level of validation or adjudication of outcomes; and (5) the planned methods to validate the 
diagnosis of the disease being studied.   
 
Sponsors should submit protocols and statistical analysis plans for FDA review and comment 
before conducting an interventional or a non-interventional study when including data from 
registries. 22  All essential elements of the design, analysis, and conduct of a study using registry 
data should be predefined, and for each study element (e.g., eligibility criteria, exposures, 
outcomes, covariates), the protocol should describe how that element will be ascertained from 
the selected data source or sources. 
 
Sponsors seeking to use registry data to support a drugs effectiveness and/or safety in a 
marketing application should ensure that patient-level data are provided to FDA in accordance 
with applicable legal and regulatory requirements.23, 24  If the registry data are owned and 
controlled by third parties, sponsors should ensure that relevant patient-level data can be 
provided to FDA and that metadata and source records necessary to verify the RWD are made 
available for inspection, as applicable.25   
 
21 For example, sponsors can request a Type C meeting for non-interventional studies.  See the draft guidance for 
industry regarding formal meetings with FDA, Formal Meetings Between the FDA and Sponsors or Applicants of 
PDUFA Products (September 2023).  When final, this guidance will represent FDAs current thinking on this topic. 
 
22 For additional discussion, see the guidance for industry Considerations for the Use of Real-World Data and Real-
World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (August 2023).   
 
23 See, e.g., 21 U.S.C. 355, 42 U.S.C. 262, and 21 CFR 314.50 and 601.2. 
 
24 Ibid. 
 
25 See 21 CFR 312.58. 
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