Antonio E. Blanco, M.D./Vista Health Research, LLC

FDA Ref. No: 23-HFD-45-09-02 Dear Dr. Blanco:

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 January 11 and January 30, 2023. Investigator Richard A. Lyght, representing FDA, reviewed your conduct of the following clinical investigations:

Protocol (b)(4), “(b)(4),” of the investigational drug (b)(4), performed for (b)(4)

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 Lyght presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your February 17, 2023, written response to the Form FDA 483.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written response dated February 17, 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 and the protection of human subjects. We wish to emphasize the following:

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 you to ensure that subjects met certain inclusion criteria before enrollment into the study. In addition, Protocol (b)(4) required you to perform certain safety procedures at specific time points, as specified in the protocol. You failed to adhere to these requirements. Specifically:

1. The following subjects were randomized without documentation of a surgical diagnosis (for example, laparoscopy or laparotomy) of (b)(4) established by visualization or histology within 10 years before the subject’s entry into the Washout Period or the Screening Visit, and received multiple doses of investigational drug:

Subject ID Washout Period or Screening Visit Randomization

(b)(6) (b)(6) (b)(6)

In your February 17, 2023, written response, you acknowledged that subject records were incomplete at the time of the inspection but indicated that you believed all subjects met inclusion criteria. You further stated that you retroactively located the surgical reports for three subjects, Subjects (b)(6), and provided copies of their records. In addition, you stated that you were in the process of obtaining surgical reports for the remaining five subjects and would include these reports in a follow-up communication. You also stated that as part of your corrective and preventive actions, the following will be completed: • Review of current procedures and practices to identify any gaps in the process • Revision of procedures to ensure that all required elements are included with study documentation, and that the information is organized to facilitate retrieval • Quality reviews of study intake records to ensure that all inclusion criteria are met and documented • Implementation of quarterly quality review of subject records to verify compliance with the established procedures • Safe archiving of data through the established data retention period

We acknowledge the actions your site plans to take and your efforts to locate and send the missing supportive records. However, your written response is inadequate because the three surgical reports that you provided document medical encounters and surgical procedures that took place or were performed for each of these subjects more than 10 years before the subject’s entry into Washout or Screening. As such, the documentation provided does not support the eligibility of Subjects (b)(6) and (b)(6) for Protocol (b)(4). In addition, 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 procedures and practices being instituted at your site to ensure compliance with the protocol, particularly to ensure subjects’ eligibility before enrollment. Also, you did not provide details on any planned or completed trainings related to the responsible conduct of clinical trials or compliance with FDA regulations. Without this information, we are unable to determine if your corrective action plan is adequate to prevent similar violations in the future.

2. Protocol (b)(4) required subjects to have the following e-Diary documentation during the last 35 days before Study Day 1 to be eligible for inclusion into the study:

(b)(4) AND either

(b)(4), OR

(b)(4)

You failed to adhere to this requirement. Specifically, Subject (b)(6) was randomized on (b)(6), with 12 days of (b)(4), and 0 days of (b)(4). As such, this subject did not have the required e-Diary documentation of at least 2 or 4 days of (b)(4) and an average (b)(4) score of at least (b)(4), respectively.

In your written response, you acknowledged that Subject (b)(6) did not have e-Diary entries for (b)(4) to support eligibility. You indicated that as part of your corrective and preventive action plan, you will update your periodic review process to verify that subject e-Diary entries include the information required by the protocol.

While we acknowledge the actions your site plans to take, your response is inadequate because you did not provide sufficient details about the proposed updates to the periodic review process or how you intend to implement these updates to ensure compliance with the protocol, including verification of subject e-Diary entries. Without this information, we are unable to determine if your corrective action plan is adequate to prevent similar violations in the future.

3. Protocol (b)(4) required subjects to have (b)(4) safety imaging procedures performed during the Screening Period ((b)(4)) and at Month 6 ((b)(4)), Month 12 ((b)(4)), Month 18 ((b)(4)), and Month 24 ((b)(4)) study visits. (b)(4) were to be performed at the Premature Discontinuation visit, depending on when the subject was discontinued from the study and whether certain criteria were met. The protocol required (b)(4) scans to be conducted during the study to assess study-specific safety stopping criteria for bone mineral density. Additionally, the protocol required subjects to be withdrawn from the study if the subject develops clinically significant gynecological findings or conditions on the (b)(4) (confirmed by repeat (b)(4) and/or saline infusion sonography and/or office hysteroscopy) that, in the opinion of the Investigator or Sponsor, would preclude the subject from continuing in the Treatment Period for safety reasons.

You failed to adhere to these requirements. Specifically, protocol-required safety imaging procedures were not conducted for the following subjects:

a. For Subject (b)(6), (b)(4) was not performed at Treatment Period Month 12 ((b)(6)) and Month 18 ((b)(6)) study visits. b. For Subject (b)(6), (b)(4) was not performed at Treatment Period Month 6 ((b)(6)) and Month 12 ((b)(6)) study visits. In addition, (b)(4) was not performed at Treatment Period Month 12 ((b)(6)). c. For Subject (b)(4), (b)(4) was not performed at Treatment Period Month 6 ((b)(6)) and Month 12 ((b)(6)) study visits.

In your February 17, 2023, written response to this violation, you acknowledged that the protocol-required study imaging procedures were in place to help ensure subject safety. You stated that many of the issues occurred during the COVID-19 pandemic. However, we note that the missed (b)(4) and (b)(4) safety imaging procedures referenced above for Subjects (b)(6) occurred before the start of the COVID-19 public health emergency. You also stated that you documented in subject records your attempts to encourage compliance with the study requirements, but that your attempts were unsuccessful. In addition, you stated that as part of your corrective and preventive actions, the following will be completed:

Establish procedures regarding independent quarterly compliance checks of all subject records to verify protocol compliance, and document the results

Escalate noncompliance to the Director of Clinical Operations and the Study Sponsor for resolution and/or further guidance regarding how to proceed with noncompliant study subjects after three contact attempts

While we acknowledge the actions your site plans to take, your response is inadequate because you failed to provide sufficient details about your corrective action plan. For example, you did not provide sufficient details about the process for the proposed quarterly compliance checks, or details about the procedures that you will implement to aid in performing the compliance checks. Without this information, we are unable to determine if your corrective action plan is adequate to prevent similar violations in the future.

We emphasize that failure to conduct the clinical investigation in accordance with the protocol raises significant concerns about your protection of the study subjects enrolled at your site, and raises concerns about the validity and integrity of the data collected at your site. Specifically, the enrollment of subjects who do not meet eligibility criteria, and the failure to perform protocol-required safety imaging procedures, jeopardize subject safety and welfare and raise concerns about the reliability of the data at your site. As the clinical investigator, you are responsible for ensuring compliance with the protocol-required eligibility criteria and with protocol-required safety procedures.

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 adequately address this matter 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 CDER-OSI-Communications@fda.hhs.gov. 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