WARNING LETTER

FDA Ref. No.: 24-HFD-45-12-01

Dear Dr. Shah:

This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted at your clinical site between December 5 and December 16, 2022. Investigator Kristin M. Abaonza, representing FDA, reviewed your conduct of a clinical investigation (Protocol (b)(4), “(b)(4)”) of the investigational drug (b)(4), performed for (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 that the rights, safety, and welfare of human subjects have been protected.

At the conclusion of the inspection, Investigator Abaonza presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your January 9, 2023, written response to the Form FDA 483, and your subsequent correspondence dated February 9, 2023.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written responses dated January 9 and February 9, 2023, 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 Title 21 of the Code of Federal Regulations, part 312 [21 CFR 312] governing the conduct of clinical investigations. We wish to emphasize the following:

You failed to ensure that the investigation was conducted according to the investigational plan [21 CFR 312.60].

As a clinical investigator, you are required to ensure that your clinical studies are conducted in accordance with the investigational plan. The investigational plan for Protocol (b)(4), required the clinician-administered assessments related to study-defined efficacy endpoints to be completed by a rater who was blinded to the safety assessments (for example, clinical laboratory evaluations, vital signs, physical examinations, and adverse event assessments). The blinded assessor was responsible for administering protocol required efficacy assessments, including the Montgomery-Asberg Depression Rating Scale (MADRS) assessments, that were required to be completed during all study visits from Visit 2 until Visit 8 or early termination. Protocol (b)(4), also specified that the blinded assessor would not have access to the ClinTrak Electronic Data Capture system and should not have access to subject source data (including laboratory results, electrocardiograms, adverse events, concomitant medications, patient-reported outcomes, and clinician-reported outcomes that are completed by investigators responsible for the assessment of subject safety) that could potentially unblind the assessor to a subject’s treatment assignment. You failed to adhere to this requirement.

Specifically, as a designated blinded rater, you conducted a total of 16 MADRS assessments for all three subjects enrolled at your site (five MADRS assessments for Subject (b)(6), six MADRS assessments for Subject (b)(6), and five MADRS assessments for Subject (b)(6)). However, you were not blinded to certain safety assessments. For example, for Subject (b)(6), you evaluated safety assessments such as vital-sign measurements, including blood pressure, heart rate, and body temperature. Additionally, for Subject (b)(6), you assessed a clinical laboratory report and performed a physical examination.

During the inspection, you acknowledged that you not only reviewed study records, consented subjects, and performed study-related assessments, but you also conducted 16 MADRS assessments for all three subjects. You stated that when you realized that the assessments should be conducted by a rater blinded to the safety assessments, you subsequently filed a protocol deviation and did not conduct any additional MADRS assessments.

Further, in your January 9, 2023, written response to the Form FDA 483, you again acknowledged that you conducted 16 MADRS assessments for all three subjects. You also detailed the corrective and preventive actions your site planned to take, including: (1) clearly identifying protocol requirements that concern blinding, and annotating the source worksheets to clearly identify blinded assessments; (2) consulting with both the sponsor and a third-party quality consulting group to provide clarity in understanding any ambiguities in the protocol, in completing the Delegation of Authority log, or in filing source documents; and (3) clinical investigator and site personnel participation in various clinical research compliance trainings, such as Good Clinical Practice training, for which you provided the training certificates in your February 9, 2023, follow-up written response.

While we acknowledge the actions that your site has taken and plans to take, your response is inadequate because you did not include sufficient details about your corrective action plan. For example, you did not provide sufficient details about the implementation of the proposed practices being instituted at your site to ensure compliance with study protocols, including protocol requirements for blinding procedures, when conducting future clinical investigations. Without this information, we are unable to determine whether your corrective actions appear adequate to help prevent similar violations in the future.

We emphasize that as the clinical investigator, it is your responsibility to ensure that the study is conducted in accordance with the investigational plan and to ensure the integrity of the study data. The primary objective of Protocol (b)(4), was to assess the efficacy of the investigational drug compared to placebo in improving (b)(4) in subjects with (b)(4), as assessed by the change in the MADRS score from Baseline to Week 4 (Day 29). Your administration of at least five of the seven required MADRS assessments for each enrolled subject as an unblinded assessor, as well as your failure to ensure that protocol-required blinding procedures were followed, raises significant concerns about the reliability and integrity of the data collected at your site.

This letter is not intended to be an all-inclusive list of deficiencies with your clinical study of an investigational drug. 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 above deficiencies. 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.

If you have any questions, please call Miah Jung, Pharm.D., M.S., at 240-402-3728. Alternatively, you may e-mail FDA at [email protected].

Your written response and any pertinent documentation should be addressed to:

Miah Jung, Pharm.D., M.S.
Branch Chief
Compliance Enforcement 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 5352
10903 New Hampshire Avenue
Silver Spring, MD 20993

Sincerely yours,
{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
12/12/2023 06:25:07 AM