# 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 The guidance replaces the draft guidance “M14 General Principles on Plan, Design, and Analysis of Pharmacoepidemiological Studies that Utilize Real-World Data for Safety Assessment of Medicines”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:
• *Federal eRulemaking Portal:**https://www.regulations.gov.* Follow the instructions for submitting comments. Comments submitted electronically, including attachments, to *https://www.regulations.gov* 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 *https://www.regulations.gov.*
• 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:
• *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.
• 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 *https://www.regulations.gov* or at the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-402-7500.
• 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 *https://www.regulations.gov.* 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: *https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.*
*Docket:* For access to the docket to read background documents or the electronic and written/paper comments received, go to *https://www.regulations.gov* 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, *[email protected];* 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, *[email protected].*
**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 *https://www.ich.org/* ).
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 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 *https://www.regulations.gov, https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs,* or *https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances,* or *https://www.fda.gov/regulatory-information/search-fda-guidance-documents.*
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.