Notice2026-04253
M14 General Principles on Planning, Designing, Analyzing, and Reporting of Non-Interventional Studies That Utilize Real-World Data for Safety Assessment of Medicines; International Council for Harmonisation; Guidance for Industry; Availability
Primary source
Metadata and text below are from the Federal Register, a public-domain U.S. government work. Always verify the official published version before relying on it for any legal matter.
Published
March 4, 2026
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA or Agency) is announcing the availability of a final guidance for industry entitled "General Principles on Planning, Designing, Analyzing, and Reporting of Non- interventional Studies That Utilize Real-World Data for Safety Assessment of Medicines." The guidance was prepared under the auspices of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The guidance outlines general principles on planning, designing, analyzing, and reporting non-interventional studies that utilize real-world data for safety assessment of medicines (i.e., drugs, vaccines, and other biological products). The recommendations in this guidance, while focused on safety, are applicable to non-interventional studies assessing effectiveness and are aligned and complementary with the FDA's other guidances on the generation real world evidence. The guidance includes recommendations and high-level best practices for the conduct of these studies, including articulating the research question, selecting appropriate data sources, defining key variables, addressing potential biases and confounding, conducting analyses, reporting, and submission. The guidance is intended to streamline the development and regulatory assessment of postmarketing non-interventional safety studies that include real-world data. The guidance replaces the draft guidance "M14 General Principles on Plan, Design, and Analysis of Pharmacoepidemiological Studies that Utilize Real-World Data for Safety Assessment of Medicines" issued in July 2024. FDA is also announcing the withdrawal of the guidance entitled "Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data Sets," published May 2013.
Full Text
<html>
<head>
<title>Federal Register, Volume 91 Issue 42 (Wednesday, March 4, 2026)</title>
</head>
<body><pre>
[Federal Register Volume 91, Number 42 (Wednesday, March 4, 2026)]
[Notices]
[Pages 10615-10617]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2026-04253]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2024-D-2754]
M14 General Principles on Planning, Designing, Analyzing, and
Reporting of Non-Interventional Studies That Utilize Real-World Data
for Safety Assessment of Medicines; International Council for
Harmonisation; Guidance for Industry; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of availability.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing
the availability of a final guidance for industry entitled ``General
Principles on Planning, Designing, Analyzing, and Reporting of Non-
interventional Studies That Utilize Real-World Data for Safety
Assessment of Medicines.'' The guidance was prepared under the auspices
of the International Council for Harmonisation of Technical
Requirements for Pharmaceuticals for Human Use (ICH). The guidance
outlines general principles on planning, designing, analyzing, and
reporting non-interventional studies that utilize real-world data for
safety assessment of medicines (i.e., drugs, vaccines, and other
biological products). The recommendations in this guidance, while
focused on safety, are applicable to non-interventional studies
assessing effectiveness and are aligned and complementary with the
FDA's other guidances on the generation real world evidence. The
guidance includes recommendations and high-level best practices for the
conduct of these studies, including articulating the research question,
selecting appropriate data sources, defining key variables, addressing
potential biases and confounding, conducting analyses, reporting, and
submission. The guidance is intended to streamline the development and
regulatory assessment of postmarketing non-interventional safety
studies that include real-world data. The guidance replaces the draft
guidance ``M14 General Principles on Plan, Design, and Analysis of
Pharmacoepidemiological Studies that Utilize Real-World Data for Safety
Assessment of Medicines'' issued in July 2024. FDA is also announcing
the withdrawal of the guidance entitled ``Best Practices for Conducting
and Reporting Pharmacoepidemiologic Safety Studies Using Electronic
Healthcare Data Sets,'' published May 2013.
DATES: The announcement of the guidance is published in the Federal
Register on March 4, 2026.
ADDRESSES: You may submit either electronic or written comments on
Agency guidances at any time as follows:
Electronic Submissions
Submit electronic comments in the following way:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
<bullet> Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
<bullet> For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2024-D-2754 for ``M14 General Principles on Plan, Design and
Analysis of Non-interventional Studies That Utilize Real-World Data for
Safety Assessment of Medicines.'' Received comments will be placed in
the docket and, except for those submitted as ``Confidential
Submissions,'' publicly viewable at <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through
Friday, 240-402-7500.
<bullet> Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on
[[Page 10616]]
<a href="https://www.regulations.gov">https://www.regulations.gov</a>. Submit both copies to the Dockets
Management Staff. If you do not wish your name and contact information
to be made publicly available, you can provide this information on the
cover sheet and not in the body of your comments and you must identify
this information as ``confidential.'' Any information marked as
``confidential'' will not be disclosed except in accordance with 21 CFR
10.20 and other applicable disclosure law. For more information about
FDA's posting of comments to public dockets, see 80 FR 56469, September
18, 2015, or access the information at: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852, 240-402-7500.
You may submit comments on any guidance at any time (see 21 CFR
10.115(g)(5)).
Submit written requests for single copies of this guidance to the
Division of Drug Information, Center for Drug Evaluation and Research,
Food and Drug Administration, 10001 New Hampshire Ave., Hillandale
Building, 4th Floor, Silver Spring, MD 20993-0002. Send one self-
addressed adhesive label to assist that office in processing your
requests. See the SUPPLEMENTARY INFORMATION section for electronic
access to the guidance document.
FOR FURTHER INFORMATION CONTACT:
Regarding the guidance: David Moeny, Center for Drug Evaluation and
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg.
22, Rm. 2474, Silver Spring, MD 20993-0002, <a href="/cdn-cgi/l/email-protection#3f7b5e49565b1172505a51467f595b5e1157574c11585049"><span class="__cf_email__" data-cfemail="226643544b460c6f4d474c5b624446430c4a4a510c454d54">[email protected]</span></a>; or
Phillip Kurs, Center for Biologics Evaluation and Research, Food and
Drug Administration, 240-402-7911.
Regarding the ICH: Brooke Dal Santo, Center for Drug Evaluation and
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg.
51, Rm. 6304, Silver Spring, MD 20993-0002, 301-348-1967,
<a href="/cdn-cgi/l/email-protection#c486b6ababafa1ea80a5a897a5aab0ab84a2a0a5eaacacb7eaa3abb2"><span class="__cf_email__" data-cfemail="1052627f7f7b753e54717c43717e647f507674713e7878633e777f66">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of a guidance for industry
entitled ``M14 General Principles on Planning, Designing, Analyzing,
and Reporting of Non-interventional Studies That Utilize Real-World
Data for Safety Assessment of Medicines.'' The guidance was prepared
under the auspices of ICH. ICH seeks to achieve greater regulatory
harmonization worldwide to ensure that safe, effective, high-quality
medicines are developed, registered, and maintained in the most
resource-efficient manner.
By harmonizing the regulatory requirements in regions around the
world, ICH guidelines enhance global drug development, improve
manufacturing standards, and increase the availability of medications.
For example, ICH guidelines have substantially reduced duplicative
clinical studies, prevented unnecessary animal studies, standardized
the reporting of important safety information, and standardized
marketing application submissions.
The six Founding Members of the ICH are FDA; the Pharmaceutical
Research and Manufacturers of America; the European Commission; the
European Federation of Pharmaceutical Industries Associations; the
Japanese Ministry of Health, Labour, and Welfare; and the Japanese
Pharmaceutical Manufacturers Association. The Standing Members of the
ICH Association include Health Canada and Swissmedic. ICH membership
continues to expand to include other regulatory authorities and
industry associations from around the world (refer to <a href="https://www.ich.org/">https://www.ich.org/</a>).
ICH works by engaging global regulatory and industry experts in a
detailed, science-based, and consensus-driven process that results in
the development of ICH guidelines. The regulators around the world are
committed to consistently adopting these consensus-based guidelines,
realizing the benefits for patients and for industry.
As a Founding Regulatory Member of ICH, FDA plays a major role in
the development of each of the ICH guidelines, which FDA then adopts
and issues as guidance for industry. FDA's guidance documents do not
establish legally enforceable responsibilities. Instead, they describe
the Agency's current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory requirements
are cited.
In the Federal Register of July 5, 2024 (89 FR 55613), FDA
published a notice announcing the availability of a draft guidance
entitled ``M14 General Principles on Plan, Design, and Analysis of
Pharmacoepidemiological Studies That Utilize Real-World Data for Safety
Assessment of Medicines.'' The notice gave interested persons an
opportunity to submit comments by September 3, 2024.
After consideration of the comments received and revisions to the
guideline, the final draft of the guideline was submitted to the ICH
Assembly and endorsed by the regulatory agencies in September 2025.
This guidance finalizes the draft guidance issued on July 5, 2024,
and includes comprehensive and focused recommendations for conducting
non-interventional studies that utilize real-world data for safety
assessment of medicines. Revisions to the guidance as a result of
public comment include a comprehensive revision on the sections for
Initial Design and Feasibility and the Conceptual Framework; enhanced
discussion of the use of quantitative bias analysis for study design,
feasibility, and interpretation; an enhanced discussion on protocol
development including characteristics and types of data sources; and
additional depth and reference to supporting resources.
In the Federal Register issue of May 14, 2013 (78 FR 28228), FDA
announced the availability of a guidance for industry entitled ``Best
Practices for Conducting and Reporting Pharmacoepidemiologic Safety
Studies Using Electronic Healthcare Data'' that provided
recommendations on the design, conduct, and reporting of such studies.
This guidance incorporates the general principles of the May 14, 2013
guidance and is updated to reflect the FDA's current thinking on best
practices for conduct and reporting of non-interventional safety
studies for medicines. Accordingly, upon publication of this guidance
FDA intends to withdraw the May 14, 2013 guidance.
This guidance is being issued consistent with FDA's good guidance
practices regulation (21 CFR 10.115). The guidance represents the
current thinking of FDA on ``M14 General Principles on Planning,
Designing, Analyzing, and Reporting of Non-interventional Studies That
Utilize Real-World Data for Safety Assessment of Medicines.'' 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.
II. Paperwork Reduction Act of 1995
While this guidance contains no collection of information, it does
refer to previously approved FDA collections of information. The
previously approved collections of information are subject to review by
the Office of Management and
[[Page 10617]]
Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3521). The collections of information supporting investigational new
drug regulations in 21 CFR part 312 have been approved under OMB
control number 0910-0014. The collections of information supporting FDA
approval of new drugs in 21 CFR part 314 have been approved under OMB
control number 0910-0001. The collections of information supporting
general licensing provisions of biological products in 21 CFR part 601
have been approved under OMB control number 0910-0338. The collections
of information supporting adverse experience reporting in 21 CFR part
310.305, 329.100, 314.80, 314.81, and 314.98, have been approved under
OMB control number 0910-0230. The collections of information supporting
MedWatch safety and adverse event reporting have been approved under
OMB control number 0910-0291. The collections of information supporting
biological products postmarket adverse experience reporting in 21 CFR
part 600 have been approved under OMB control number 0910-0308. The
collections of information supporting medical device reporting in 21
CFR part 803 have been approved under OMB control number 0910-0437.
III. Electronic Access
Persons with access to the internet may obtain the guidance at
<a href="https://www.regulations.gov">https://www.regulations.gov</a>, <a href="https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs">https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs</a>, or <a href="https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances">https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances</a>, or <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents">https://www.fda.gov/regulatory-information/search-fda-guidance-documents</a>.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2026-04253 Filed 3-3-26; 8:45 am]
BILLING CODE 4164-01-P
</pre><script data-cfasync="false" src="/cdn-cgi/scripts/5c5dd728/cloudflare-static/email-decode.min.js"></script></body>
</html>Indexed from Federal Register on March 4, 2026.
This is legal information, not legal advice. Laws vary by jurisdiction and change frequently. Always verify current law with official sources and consult a licensed attorney in your jurisdiction for advice on your specific situation.