HealthPartners Neuroscience Center Research and Innovation(26-HFD-45-05-02)

Issuing Office:

Center for Drug Evaluation and Research (CDER)

United States

WARNING LETTER

FDA Ref. No.: 26-HFD-45-05-02

Dear Dr. Hanson:

This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted at HealthPartners Neuroscience Center Research and Innovation (HPNC) between March 17 and 21, 2025. The investigators representing FDA reviewed the role of HPNC as the testing facility for the following nonclinical laboratory studies of the investigational drug (b)(4), performed for sponsor-investigator (b)(4) (formerly performed for (b)(4)).

• Protocol (b)(4): “(b)(4)”

• Protocol (b)(4): “(b)(4)”

This inspection was conducted as a part of FDA’s Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of research and to help ensure the quality and integrity of study data, in accordance with Title 21 of the Code of Federal Regulations, part 58 (21 CFR 58), Good Laboratory Practice (GLP) for Nonclinical Laboratory Studies.

At the conclusion of the inspection, the FDA investigators presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your April 11, 2025, written response to the Form FDA 483, and your subsequent correspondence dated June 13, 2025.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written responses dated April 11 and June 13, 2025, it appears that you did not adhere to the applicable statutory requirements in the Federal Food, Drug, and Cosmetic Act (FD&C Act) and applicable regulations contained in 21 CFR 58 governing the conduct of nonclinical laboratory studies. We wish to emphasize the following:

1. Failure of the testing facility management to assure that tests for mixtures of articles with carriers were conducted by appropriate analytical methods to determine the uniformity of the mixture and the concentration of the test or control article in the mixture, as applicable [21 CFR 58.31(d) and 21 CFR 58.113(a)(1)].

The testing facility management for each nonclinical laboratory study must ensure that test and control articles or mixtures have been appropriately tested for identity, strength, purity, stability, and uniformity, as applicable. For each test or control article that is mixed with a carrier, tests by appropriate analytical methods must be conducted to determine the uniformity of the mixture and to determine, periodically, the concentration of the test or control article in the mixture. The testing facility management failed to adhere to these requirements.

Specifically, the protocol and final study report for Study (b)(4) stated that the test article, (b)(4), was dissolved in sterile water to a final dose concentration of 1%, 10%, or 20% (b)(4) (0.5 mg, 5 mg, and 10 mg, respectively), and for Study (b)(4), to a final dose concentration of 1%, 10%, or 20% (b)(4) (2 mg, 20 mg, and 40 mg, respectively). However, after reconstituting the test article with sterile water to the desired final dose concentration, the testing facility failed to test, by appropriate analytical methods, the resulting mixtures to determine their uniformity and concentration before dosing all animals in studies (b)(4) and (b)(4).

In your April 11, 2025, written response to the Form FDA 483, and in your subsequent correspondence dated June 13, 2025, you acknowledged that the characteristics of the test article were not analyzed. As corrective and preventive actions, you stated that the following actions were taken: (1) you created a new SOP titled “Receipt, Identification, Storage, Handling, Mixing, and Method of Sampling Chemicals,” which includes procedures for test article characterization; (2) you provided the certificate of analysis for the (b)(4) lot used in study (b)(4); (3) you performed mass spectrometry testing on April 19, 2025, on stored frozen dosing aliquots representative of formulated test articles administered to animals in both studies; and (4) you amended the final study reports for both studies to include the results of this subsequent testing, noting that the selected test article samples were within the concentration specified in the protocol.

While we acknowledge the corrective and preventive actions that your testing facility has taken, your response is inadequate because you did not include sufficient details about your corrective action plan. For example, while you provided the results of the testing performed on the stored aliquots that were representative of the test articles administered to animals, this testing occurred after animal dosing and the studies had been completed. We also note that while you provided the testing results for the concentration of these samples, you did not provide the testing results regarding the uniformity of the samples. 

In addition, while we acknowledge that you created an SOP that includes test article characterization, your written response does not include details about how you will implement these procedures to ensure that testing to determine the concentration and uniformity of test articles is performed in accordance with FDA regulations. For example, your response does not provide sufficient details regarding any completed or planned training of study personnel on this new SOP, or any training on FDA regulations governing the conduct of nonclinical laboratory studies. Without this information, we are unable to determine whether your testing facility will be able to prevent similar violations in the future.

Your testing facility management failed to ensure that tests by an appropriate analytical method were conducted to determine the uniformity and concentration of the mixtures of articles with carriers at the beginning and throughout the study period, to verify the protocol-specified dose concentrations. Because of this failure, FDA is concerned about the uniformity of the mixtures and about the concentration of the test articles in the mixtures used in the nonclinical laboratory studies conducted at your testing facility.

2. Failure of the Quality Assurance unit (QAU) to review the final study report to assure that the reported results accurately reflect the raw data of the nonclinical laboratory study [21 CFR 58.35(b)(6)].

The QAU must review the final study report to ensure that the reported results accurately reflect the raw data of the nonclinical laboratory study. The QAU at your testing facility did not adhere to these requirements. Specifically, for Protocol (b)(4), the following observations were not accurately documented in the final study report:

a. The deaths of two male rats (Rats #41 and #42 in the 10% (b)(4) dosing group) during the conduct of the study were not reflected in the final study report.

b. A Day 13 clinical observation of abnormal nose was observed in Female Rat #53 in the 10% (b)(4) dosing group, and a Day 13 clinical observation of abnormal porphyrin was observed in Female Rat #51 in the 1% (b)(4) dosing group. However, the final study report inaccurately documents that abnormal nose was observed on Day 13 in the 1% (b)(4) dosing group, and that abnormal porphyrin was observed on Day 13 in the 10% (b)(4) dosing group.

c. Female Rat #84 in the 20% (b)(4) dosing group died on Day 3 of dosing. However, the final study report inaccurately documents that Rat #84 died on Day 1 of dosing.

In your April 11, 2025, written response to the Form FDA 483, you acknowledged the observation and stated that you amended the final study reports to make the necessary corrections. You stated that to address the root cause of the violation, you developed a new SOP titled “QAU Review of Final Report” and a checklist to be used in the QAU review of final study reports.

While we acknowledge the corrective and preventive actions that your testing facility has taken, your response is inadequate because you did not include sufficient details about your corrective action plan, including how procedures will be implemented at your site to ensure compliance with FDA regulations. For example, your corrective action plan does not include QAU training on the new SOP or the new checklist, or QAU training on FDA regulations governing the conduct of nonclinical laboratory studies, including the QAU’s role and responsibilities. Additionally, your corrective action plan does not include a description of any planned audits to check for compliance with new QAU procedures. Without these details, we are unable to determine whether your corrective actions are adequate to prevent similar violations in the future.

Because your testing facility’s QAU failed to ensure that the reported results in the final study report accurately reflect the raw data of the nonclinical laboratory studies, FDA has concerns about the integrity of the data generated and reported from the nonclinical studies conducted at your testing facility.

3. Failure of the testing facility management to assure the availability of equipment as scheduled and that the equipment used in the generation, measurement, or assessment of data shall be of appropriate design and adequate capacity to function according to the study protocol [21 CFR 58.31(e) and 21 CFR 58.61].

Testing facility management must ensure that equipment is available as scheduled. Additionally, equipment used in the generation, measurement, or assessment of data in a nonclinical laboratory study must be of appropriate design and adequate capacity to function according to the study protocol. The testing facility management failed to adhere to these requirements.

Specifically, during the conduct of nonclinical laboratory studies (b)(4) and (b)(4), the testing facility management failed to ensure that equipment of appropriate design and adequate capacity was available to analyze the blood of rat and rabbit species for the protocol-required hematology and serum chemistry laboratory parameters. As a result, the testing facility failed to generate the following Day 15 data:

• Hematology test results for male and female rats for Protocol (b)(4)

• Serum chemistry test results for male rats for Protocol (b)(4)

• Hematology test results for male and female rabbits for Protocol (b)(4)

Additionally, the testing facility management did not cross-validate the equipment used to analyze blood samples, to demonstrate their ability to accurately analyze rat blood in Protocol (b)(4) or rabbit blood in Protocol (b)(4).

We acknowledge that the finding described above was not included on the Form FDA 483 you received, and that the observation on the Form FDA 483 was limited to the unreported hematology laboratory results for Day 15 female rats in the final study report for Protocol (b)(4). Therefore, your written responses to the Form FDA 483 do not directly address the extent of this finding as discussed in this letter.

In your April 11, 2025, written response to the Form FDA 483, regarding the unreported hematology results, you stated that you amended the final study reports to make the necessary corrections. The amended final study reports gave details of the equipment that your testing facility used for hematology laboratory parameters testing in the study animals, and they explained that the hematology results obtained using the equipment were below or above the range of the machine, and therefore no results were displayed on the equipment.

While we acknowledge the corrective actions that your testing facility has taken regarding the unreported hematology results, your response is inadequate because we are unable to determine whether your testing facility will be able to ensure the availability of equipment of appropriate design and adequate capacity to evaluate protocol-required laboratory parameters in the animal species included in future nonclinical studies conducted at your testing facility. Because the testing facility management failed to ensure that appropriate equipment was available to conduct protocol-required laboratory assessments, FDA has concerns about the integrity of the data generated and reported from the nonclinical studies conducted at your testing facility.

4. Failure of the testing facility to establish standard operating procedures in writing, setting forth nonclinical laboratory study methods that management is satisfied are adequate to insure the quality and integrity of the data generated in the course of the studies [21 CFR 58.81(a) and 58.81(b)].

A testing facility must establish and follow written SOPs for nonclinical laboratory studies, to ensure the quality and integrity of the data generated in the studies. Your testing facility did not adhere to these requirements. For example, your testing facility failed to establish SOPs for:

a. Receipt, identification, storage, handling, mixing, and method of sampling of the test and control articles

b. Test system observations

c. Laboratory tests

d. Handling of animals found to be moribund or dead during a study

e. Collection and identification of specimens

In your April 11, 2025, written response to the Form FDA 483, and in your subsequent correspondence dated June 13, 2025, you acknowledged the observation and stated that you created an SOP titled “SOP Creation, Review, and Approval.” Additionally, you created SOPs for the five procedures that were identified as lacking, along with additional SOPs that were not previously established. You also revised existing SOPs to include versioning and dates. We acknowledge your corrective and preventive actions. However, we emphasize that as a testing facility conducting nonclinical laboratory studies under 21 CFR 58, it is your responsibility to establish SOPs before conducting nonclinical laboratory studies. You are also responsible for following your written SOPs to ensure consistency in study conduct and to ensure the quality and integrity of data generated during your studies.

As evidenced by FDA’s inspection findings, the deficiencies found in the oversight and conduct of the testing facility management and QAU at your testing facility demonstrate a failure to comply with FDA’s GLP regulations governing the conduct of nonclinical laboratory studies. As a result, FDA is concerned about the validity and integrity of the nonclinical data generated by your testing facility.

We emphasize that as a testing facility conducting nonclinical laboratory studies under 21 CFR 58, you are responsible for ensuring that nonclinical laboratory studies submitted to FDA are conducted and reported in accordance with FDA regulations to ensure the quality and integrity of study data. Your failure to conduct and report nonclinical studies in accordance with FDA regulations raises concerns about the validity and integrity of the data collected at your site.

This letter is not intended to be an all-inclusive list of deficiencies with the nonclinical laboratory studies of investigational drugs conducted at your testing facility. 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 any ongoing or future studies comply with FDA regulations.

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 without further notice to you. If you believe that you have complied with the FD&C Act and relevant regulations, please include your reasoning and any supporting information for our consideration.

Your written response, and any questions or concerns about this letter or the inspection, should be sent via email to the FDA at CDER-OSI-Communications@fda.hhs.gov.

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
Food and Drug Administration

--------------------------------------------------------------------------------------------
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.
--------------------------------------------------------------------------------------------
/s/
------------------------------------------------------------
DAVID C BURROW
05/19/2026 12:58:47 PM