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  1. Warning Letters

WARNING LETTER

Novo Nordisk Inc. MARCS-CMS 717576 —

Delivery Method:
VIA UNITED PARCEL SERVICE AND VIA E-MAIL
Reference #:
26-HFD-45-03-01
Product:
Drugs
Recipient:
Recipient Name
Mr. David S. Moore
Recipient Title
President
Novo Nordisk Inc.

800 Scudders Mill Road
Plainsboro, NJ 08536
United States

Issuing Office:
Center for Drug Evaluation and Research (CDER)

United States

WARNING LETTER

 

Mr. David S. Moore FDA Ref. No.: 26-HFD-45-03-01
President
Novo Nordisk Inc.
800 Scudders Mill Road
Plainsboro, New Jersey 08536

Dear Mr. Moore:

This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted at your firm, Novo Nordisk Inc. (hereinafter referred to as NNI), between January 13 and February 7, 2025. The investigators representing FDA reviewed your compliance with postmarketing adverse drug experience (PADE) regulations. The inspection revealed serious violations of PADE reporting requirements found in section 505(k) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) [21 U.S.C. 355(k)] and Title 21, Code of Federal Regulations (21 CFR) 314.80. Failure to comply with section 505(k) is a prohibited act under section 301(e) of the FD&C Act [21 U.S.C. 331(e)].

This inspection was conducted as a part of FDA’s Bioresearch Monitoring Program, which includes inspections designed to ensure that accurate, reliable, and timely safety data are submitted to FDA for the monitoring of product safety, and to ensure compliance with PADE regulations.

At the conclusion of the inspection, the investigators presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your written response to the Form FDA 483 dated March 3, 2025, and your subsequent correspondence dated April 11, 2025; May 2, 2025; June 6, 2025; July 11, 2025; September 19, 2025; October 31, 2025; and January 15, 2026.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written response and correspondence dated March 3, 2025; April 11, 2025; May 2, 2025; June 6, 2025; July 11, 2025; September 19, 2025; October 31, 2025; and January 15, 2026, it appears that you did not adhere to the applicable statutory requirements in the FD&C Act and applicable regulations contained in 21 CFR part 314.

We wish to emphasize the following:

Failure to develop written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences (ADEs) to FDA as required by 21 CFR 314.80(b).

As an application holder of products with active ingredients including semaglutide, liraglutide, nedosiran sodium, and estradiol, NNI is required to develop written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences (ADEs) to FDA. You developed written procedures that failed to ensure that you, and your contractor acting on your behalf, complied with all applicable PADE regulations for the surveillance, receipt, evaluation, and reporting of ADEs.

Examples of this failure include but are not limited to the following:

1. You failed to develop written procedures, as required under 21 CFR 314.80(b), that ensured that you, and your contractor acting on your behalf, reported all serious and unexpected ADEs to FDA within 15 calendar days, in accordance with 21 CFR 314.80(c)(1)(i). PADE regulations require the applicant to report each ADE that is both serious and unexpected, whether foreign or domestic, no later than 15 calendar days from the initial receipt of the information by the applicant (21 CFR 314.80(c)(1)(i)). Specifically:

a. Your written procedure Q014048, “Handling of Adverse Events and Other Safety Information” (Ver: 28.0, Effective Date: 03 Oct 2024), allowed ADEs reported to NNI to be rejected or cancelled (and therefore not to be reported to FDA) if the ADE was considered by the reporter to be unrelated to the product. Specifically, Q014048 excludes reports from the definition of “adverse reaction” if “the reporters specifically state that they believe the events to be unrelated or that a causal relationship can be excluded.” This definition is inconsistent with FDA regulations, which define an ADE as “[a]ny adverse event associated with the use of a drug in humans, whether or not considered drug-related.” FDA’s regulations require applicants to develop written procedures for, among other things, the reporting of ADEs regardless of whether the event is considered causally related to the product. An ADE that is determined to be both serious and unexpected must be reported to FDA no later than 15 days from the date of initial receipt. Based on your written procedure, your staff or contractor cancelled or rejected serious and unexpected ADEs that were required to be reported within 15 calendar days because they documented these events as being unrelated to the product. For example, Argus1 Case #1331385 involves a consumer who was disabled after experiencing a stroke, which is a serious and unexpected ADE, while receiving liraglutide. The consumer reported that the stroke was not related to liraglutide; therefore, you rejected this case. As a result, you failed to report serious and unexpected ADEs to FDA within 15 calendar days, as required by PADE regulations.

During the inspection, you stated that you opened deviation DV0166369 in April 2024 after discovering that not all reportable serious and unexpected ADEs were submitted to FDA because the ADEs were cancelled or rejected by your staff or contractor and were documented as being “incidental” or “incidental and unrelated.” You identified your written procedures, including Q014048 (both the current and prior versions), as a root cause for this deviation, because both the current and prior versions allowed ADEs reported to NNI to be rejected or cancelled based on the reporter’s assessment of a lack of causality of the event to the product. The root-cause analysis noted that while the exclusion of certain ADEs from reporting as described in the written procedures was consistent with foreign regulatory authority regulations, it was not consistent with U.S. regulations. Although you closed deviation DV0166369 in December 2024, you did not ensure that your corrective and preventive actions were effectively implemented to resolve the existing issues and to prevent recurrence of the noncompliance. Specifically, while you ensured that prior versions of Q014048 were no longer in use, you did not update the definition of “adverse reactions” to remove references to relatedness and causality in the current version of Q014048. Additionally, you closed deviation DV0166369 without confirming the completion of your corrective action to submit all reportable serious and unexpected ADEs to FDA. Although you stated in your written response that you submitted these ADEs to FDA after the investigators discussed them with you during this inspection, you did not provide the case numbers and dates submitted to FDA for all cases with serious and unexpected ADEs that were identified as part of deviation DV0166369. As a result, FDA cannot verify that all serious and unexpected ADEs identified in this deviation were submitted to FDA. Furthermore, you did not provide sufficient information regarding how you will implement the corrective and preventive actions identified in this deviation to ensure that all serious and unexpected ADEs are reported to FDA.

In your written response dated March 3, 2025, and in subsequent correspondence, you described corrective actions including but not limited to: (1) revising procedures and other documents to remove certain terminology that created ambiguity and led to serious and unexpected ADEs not being reported to FDA; (2) updating definitions and documentation of the term “spontaneous cases”; and (3) performing a retrospective review of cases to ensure that all valid cases were submitted to FDA. Further, you stated that all cases that were identified as 15-day Alert reports as part of deviation DV0166369 had been submitted to FDA as of February 6, 2025.

While we acknowledge the corrective and preventive actions you have taken or plan to take, your written response and subsequent correspondence are inadequate because you did not provide sufficient details for the Agency to determine whether your actions effectively resolved the existing issues and will prevent similar violations in the future. Specifically, you did not provide sufficient details about how your updated procedures, guidance, and training materials will ensure future compliance with reporting serious and unexpected ADEs to FDA in a timely manner.

b. Your written procedure Q014048, “Handling of Adverse Events and Other Safety Information” (Ver: 28.0, Effective Date: 03 Oct 2024), states that the minimum criteria for Individual Case Safety Reports (ICSRs) to qualify for submission in an expedited manner are: (1) one or more identifiable reporters; (2) a single identifiable patient; (3) a suspected NNI product; and (4) a suspected adverse reaction. However, your written procedure did not ensure that you, and the call-center contractors acting on your behalf, correctly received, reviewed, and processed ADE information, which resulted in the failure to submit serious and unexpected ADEs that were required to be reported to FDA within 15 calendar days.

Specifically, you and your contractors inappropriately invalidated 15-day Alert reports because of a lack of patient identifiers; however, during the inspection, FDA identified valid patient identifiers in source documents for these reports. These reports were not submitted to FDA until they were discussed with you during the inspection. For example, Argus Case #1342548 includes a consumer reporting a death for a male patient who received semaglutide; however, you invalidated the case because you failed to capture the patient identifier. During the inspection, FDA found the patient identifier in the source documents for this case. As a result of this erroneous invalidation, you failed to report serious and unexpected ADEs to FDA within 15 calendar days, as required.

We note that you identified this issue when (b)(4) served as your call-center contractor between May 12 and October 12, 2023. You later terminated your contract with (b)(4) ⁽ᵇ⁾ ⁽⁴⁾ and switched your call-center contractor to (b)(4), starting on October 13, 2023. You also opened deviation DV0155511 in December 2023 in response to issues observed with (b)(4). Although you switched your call-center contractor to (b)(4) and completed corrective and preventive actions as part of deviation DV0155511, you continued to invalidate cases of ADEs for lack of a patient identifier, despite the patient identifiers’ being available in accordance with written procedure Q014048 and the cases’ otherwise qualifying as reportable. Therefore, you did not ensure that your corrective and preventive actions (for example, review and creation of training resources and content for vendors) were effectively implemented to resolve the existing issues and to prevent recurrence of the noncompliance.

In your March 3, 2025, written response and in subsequent correspondence, you stated proposed corrective actions, including but not limited to: (1) conducting retrospective reviews of cases to ensure that all valid cases were submitted to FDA; (2) drafting work instructions related to ICSR quality checks and verification, including source data verification; (3) planning a phased approach to transition safety case intake from the contracted call-center agents to dedicated insourced patient safety agents, who are health care professionals; (4) performing an assessment of the vendor management program; and (5) creating a Vendor Management team, a Vendor Quality team, and a Training team dedicated to your U.S. Patient Safety team, to ensure adequate vendor training and oversight.

While we acknowledge the corrective and preventive actions you have taken or plan to take, your written response is inadequate because you did not provide information about whether your proposed actions will prevent similar violations in the future. For example, you did not provide specific information about how you will ensure that vendors acting on your behalf correctly receive, review, and process ADE information, including how you will maintain oversight related to delegated functions. Specifically, you did not provide sufficient details about how your Vendor Management, Quality, and Training teams will operate, what their activities will be, or how these teams will ensure that contractors acting on your behalf will accurately and completely capture ADEs, perform quality check activities, and comply with all applicable PADE requirements. In addition, you did not describe how the “insourced” call center will operate, nor did you provide adequate information to ensure that your insourced call center will comply with PADE requirements in the future.

c. Your written procedure Q040018, “Handling Individual Safety Cases in the Global Safety Database” (Ver 43.0, Effective Date: 17 May 2024), states that most serious adverse reactions should enter medical review by calendar day 9 following the awareness date, and they should complete medical review by calendar day 10 following the awareness date. However, your written procedure failed to ensure that cases completed “medical review” within the timelines specified in your written procedure. Rather, cases remained in “medical review” status longer than specified in your written procedure, resulting in your failure to submit 15-day Alert reports to FDA within the required time frame. During the inspection, FDA identified and made you aware of serious and unexpected ADEs that were not submitted to FDA because they remained in “medical review” status beyond the timeline specified in your written procedures. For example, in Argus Case #1334278, you received information on December 9, 2024, from a consumer who reported suicidal ideation while taking semaglutide. This case entered “medical review” status on December 16, 2024; however, medical review was not performed until February 3, 2025, after being identified during FDA’s inspection, and the case was submitted to FDA on February 5, 2025. As a result, you failed to report serious and unexpected ADEs to FDA within 15 calendar days, as required by PADE regulations.

In your March 3, 2025, written response and your April 11, 2025, correspondence, you stated that your corrective actions included but were not limited to a requirement for daily review of patient safety cases across each workflow state. However, your written response is inadequate because you did not provide any information about whether your proposed actions will prevent similar violations in the future. For example, you did not provide sufficient details regarding the root cause of this violation, including why these cases remained in “medical review” status beyond the time frames specified in your written procedure. You also have not provided an assessment of whether, and to what extent, this issue implicates the timely reporting of other cases in your product portfolio.

2. You failed to develop written procedures that ensured all ADEs that are the subject of 15-day Alert reports were promptly investigated in accordance with 21 CFR 314.80(c)(1)(ii). PADE regulations require that the applicant must promptly investigate all ADEs that are the subject of postmarketing 15-day Alert reports (21 CFR 314.80(c)(1)(ii)).

Your written procedure Q0360683, “Case Management Workflow at Novo Nordisk Inc. Patient Safety” (Ver: 7.0, Approved Date: 04 Nov 2024), stated that you did not require follow-up on reported ADEs if consent was not obtained from the reporter and if the reporter was a non-health care professional. Based on this written procedure, you, and your contractor acting on your behalf, failed to promptly investigate ADEs that were subject to 15-day Alert reporting because you did not follow up with reporters to request additional information unless you explicitly obtained consent from the reporter. PADE regulations do not require the obtaining of consent to acquire additional information. As a result, you failed to investigate serious and unexpected ADEs as required by PADE regulations.

For example, Argus Case #1171264 includes a non-health care professional reporting the death of a patient receiving semaglutide; however, you failed to promptly investigate because consent was not obtained from the reporter and the reporter was a non-health care professional, as stated in your written procedure. This case was closed without your reporting it to FDA.

Procedure Q0360683 also required that NNI perform two follow-up attempts for serious cases in which a death is reported, to obtain relevant safety information for reporting to FDA. However, you failed to promptly investigate Argus Case #1079792, in which a physician reported to your company representative that a patient taking semaglutide was depressed and committed suicide. You failed to document any attempt to obtain additional information from the reporter, including patient identifiers. As of the date of issuance of this letter, this case has not been submitted to FDA.

In your written response dated March 3, 2025, you attributed the failure to promptly investigate serious and unexpected ADEs to a procedural gap that required unnecessary consent from the reporter. In your written response and in subsequent correspondence, you described corrective actions including but not limited to: (1) revising local and global SOPs and trainings to remove the requirement to obtain consent from reporters for follow-up; (2) removing fields requiring reporters’ consent from local IT platforms; (3) sending a communication to all vendors and revising safety data exchange agreement (SDEA) templates to clarify that consent is not a predicate requirement to collecting information from a reporter; and (4) conducting a retrospective review of cases to assess that appropriately timed and documented follow-up attempts with reporters were conducted. However, your written response is inadequate because you did not provide information about how your proposed or completed corrective actions would prevent similar violations in the future. For example, you did not provide sufficient details about your quality-control activities, including how you will maintain oversight of vendors with whom you contract to fulfill any of your ADE responsibilities.

Additionally, your written response did not specifically address how you will conduct appropriate follow-up, as required by 21 CFR 314.80(c)(1)(ii), for 15-day Alert reports that were not submitted at the time of the inspection.

In your March 3, 2025, written response, and in subsequent correspondence, you described corrective actions including but not limited to your engagement with a consultant to perform reviews of your pharmacovigilance processes and associated interfaces, as well as your deviation system and your corrective and preventive action system, to ensure that all cases have been reported to FDA and all deviations have been handled adequately. You also stated that your consultant is engaged in a retrospective review of all closed pharmacovigilance-related deviations dating back to June 2017, and that you have created a deviation review board. We acknowledge that your retrospective review of deviations is complete and that you have received the final report. For each major deviation that may affect compliance with PADE regulations and that has a Quality Assurance approval date after 01 Jan 2021, including those listed on the Deviations Handling request provided to the investigators during the inspection, you should submit a description of the deviation, date of identification, current status, the root-cause analysis, an assessment of the impact, the status of all corrective and preventive actions, and the timeline and results for effectiveness checks.

While we acknowledge the corrective and preventive actions your firm has taken since our inspection, your response is inadequate because you did not provide sufficient details to determine whether your actions will effectively prevent similar violations in the future. Your explanations, when taken into consideration with the violations described above and your failure to adequately address your noncompliance, suggest systemic failures with your surveillance, receipt, evaluation, and reporting of ADEs to FDA. In addition, your failure to identify and assess the root cause(s) of deficiencies discussed in this letter raises concerns about your firm’s ability to monitor the safety of your products, including through oversight of vendors with whom you contract to fulfill any of your ADE responsibilities. While this inspection focused on NNI’s compliance with PADE regulations for a sample of NNI’s products, including semaglutide, liraglutide, nedosiran sodium, and estradiol, based on the nature of the inspection’s findings and your written response and correspondence, we have serious concerns about the scope and impact of these violations on your entire product portfolio.

FDA relies on the complete, accurate, and timely submission of ADEs to monitor a product’s safety profile and uphold FDA’s mission to protect and promote public health. Reporting ADEs to FDA within the required time frames is necessary for the ongoing monitoring of drug safety profiles. Failure to report and investigate ADEs may limit the safety information that FDA may need when monitoring potential safety signals.

We emphasize that as an application holder, it is your responsibility to ensure that you comply with all applicable PADE requirements, including when you contract with a vendor to fulfill any of your ADE responsibilities. Your failure to develop procedures that ensure the submission of 15-day Alert reports and the prompt investigation of ADEs that were the subject of 15-day Alert reports raises significant concerns about your ability to accurately and completely report product safety information to the FDA in accordance with PADE requirements.

This letter is not intended to be an all-inclusive list of deficiencies that exist at NNI. It is your responsibility to ensure adherence to each requirement of the law and relevant FDA regulations. You should address any deficiencies and establish procedures to ensure that you comply with FDA regulations.

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b) and allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

This letter notifies you of our findings and provides you with an opportunity to address the deficiencies noted above. Within 15 business days of your receipt of this letter, you should notify this office in writing of the actions you have taken to prevent similar violations in the future. Failure to address this matter adequately may lead to regulatory action. If you believe you have complied with the FD&C Act and relevant regulations, please include your reasoning and any supporting information for our consideration.

Should you have any questions or concerns regarding this letter or the inspection, please email FDA at CDER-OSI-ADE@fda.hhs.gov. Your written response and any pertinent documentation should be addressed to:

Dipti Kalra R.Ph., M.S., MBA Branch Chief
Postmarketing Safety Branch
Division of Enforcement and Postmarketing Safety Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
U.S. Food and Drug Administration Building 51, Room 5343
10903 New Hampshire Avenue Silver Spring, MD 20993-0002

Sincerely,

{See appended electronic signature page}

David C. Burrow, Pharm.D., J.D. Director
Office of Scientific Investigations Office of Compliance
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
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This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.
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/s/
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DAVID C BURROW
03/05/2026 08:24:50 AM

______________________

  1. 1Argus is NNI’s drug safety database.
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