Mehran Michael Bahrami, M.D.

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 April 8 and April 19, 2024. Investigators Chantae D. Mitchell and Ana P. Barido, 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).

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, Investigators Mitchell and Barido presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your April 30, 2024, 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 April 30, 2024, 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 investigations are conducted in accordance with the investigational plan. The investigational plans for Protocols (b)(4) and (b)(4) required you to ensure that subjects met all eligibility criteria before enrollment in the studies. In addition, the investigational plan for Protocol (b)(4) required you to conduct certain study visits and procedures in-person, which included certain safety laboratory assessments at specific study visits. You failed to adhere to these requirements.

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

a. The investigational plan for Protocol (b)(4) required subjects to meet all inclusion criteria to be eligible for study participation, including, but not limited to, (1) (b)(4) symptom onset less than or equal to 7 days before randomization, and (2) (b)(4) infection first confirmed by PCR, nucleic acid testing, or direct antigen testing, with samples collected less than or equal to 4 days before randomization. You failed to adhere to this requirement.

Specifically, Subject (b)(6) was documented as having symptoms of possible (b)(4) on January 26, 2021, approximately 15 days before the subject was randomized on February 10, 2021. This is more than the protocol-required time frame for (b)(4) symptom onset of within 7 days before randomization. In addition, the subject’s samples confirming (b)(4) infection were collected on January 27, 2021, approximately 14 days before randomization. This is more than the protocol-required time frame for sample collection of within 4 days before randomization.

In your April 30, 2024, written response, you stated that subjects who did not meet the inclusion criteria were excluded from the study. However, study records demonstrate that Subject (b)(6) was enrolled and administered study drug between February 10 and 14, 2021.

b. The investigational plan for Protocol (b)(4) required you to exclude subjects from the study if they had one or more conditions associated with a high risk for severe (b)(4), including, but not limited to, smoking (current and former). You failed to adhere to this requirement.

Specifically, Subjects (b)(6) and (b)(6) were documented as being current smokers and as having a history of smoking. However, Subjects (b)(6) and (b)(6) were enrolled and randomized on December 3, 2022, and December 19, 2022, respectively.

In your April 30, 2024, written response, you stated that risk factors for smoking were re-evaluated, and that subjects were excluded from the study who did not meet inclusion criteria. However, study records demonstrate that Subjects (b)(6) and (b)(6) were enrolled and administered study drug between December 3 and 7, 2022, and between December 19 and 23, 2022, respectively.

c. The investigational plan for Protocol (b)(4) required study visits for Day 1 through Day 20 to be conducted in-person. The protocol defined an in-person visit as a visit conducted at a medical facility or elsewhere by a health care provider (where permitted). Additionally, study procedures including vital signs, physical examination, and safety laboratory assessments were to be conducted during specific protocol-required in-person study visits, in accordance with the schedule of study procedures. You failed to adhere to these requirements.

Specifically, Subjects (b)(6), and (b)(6) had virtual visits for Day 3 (May 19, 2023), Day 5 (May 21, 2023), Day 10 (May 26, 2023), and Day 15 (May 31, 2023), instead of in-person visits, as required by the protocol. As a result, in-person study procedures including vital signs, physical examination, and safety laboratory assessments were not performed in accordance with the schedule of study procedures.

In your April 30, 2024, written response, you stated that the four subjects who were administered investigational product had all in-person visits except three subjects who had virtual visits, who were excluded from the study. However, study records demonstrate that these four subjects were enrolled and administered study drug between May 17 and May 21, 2023.

We emphasize that as the clinical investigator, it is your responsibility to ensure that studies are conducted in accordance with the investigational plan. Your failure to ensure that subjects met the protocol-required eligibility criteria before enrollment in the study, and your failure to perform study visits and safety laboratory assessments in accordance with the protocol, raise significant concerns about your protection of the study subjects enrolled at your site, and raise concerns about the validity and integrity of the data collected at your site.

2. You failed to retain records required to be maintained under 21 CFR 312 for a period of two years following the date a marketing application is approved for the drug for the indication for which the drug is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until two years after the investigation is discontinued [21 CFR 312.62(c)].

As a clinical investigator, you are required to retain adequate and accurate case histories that record all observations and other data pertinent to the investigation for each individual administered the investigational drug or employed as a control in the investigation. You are required to retain these records for a period of two years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or the application is not approved for such indication, until two years after the investigation is discontinued and FDA is notified. You failed to adhere to these requirements.

Specifically, for Protocols (b)(4) and (b)(4), you failed to retain electronic case report forms for all randomized subjects. You were required to retain case histories, including electronic case report forms, until two years after the investigation was discontinued and FDA was notified, which was on May 2, 2024; however, these records were not available for review during the inspection conducted at your clinical site.

In your April 30, 2024, written response, you stated that you were hired as an employee for the site as a Principal Investigator and that all the studies were appropriately and professionally completed until Protocol (b)(4), when the site owner no longer observed employee’s work, discussed performance with you, and was not present at the site for extended periods. Further, you stated that the case report form was requested from the site owner, but she did not reply to your requests, and you terminated your contract with the site. However, as the clinical investigator, it is your responsibility to retain the study records for both protocols because it has not yet been two years since either investigation was discontinued. Your failure to retain study records as required by FDA regulations raises concerns about the validity and integrity of the data collected at your site.

While we acknowledge the information provided in your written response, your written response is inadequate because you did not provide information about any completed or proposed corrective actions, or about how you, as the clinical investigator, would prevent similar violations in the future. For example, you did not provide sufficient details about any policies and procedures you would institute at your site to ensure compliance with study protocols when conducting future clinical investigations. Additionally, you did not provide details concerning any planned or completed training on the responsible conduct of clinical trials or compliance with FDA regulations. Without this information, we are unable to determine whether your corrective actions appear adequate to prevent similar violations in future clinical investigations.

We emphasize that as the clinical investigator, it is your responsibility to ensure that studies are conducted properly and in compliance with FDA regulations, both to protect the rights, safety, and welfare of subjects and to ensure the integrity of study data. Your failure to conduct the clinical study in accordance with the protocol and your failure to retain study records raise significant concerns about your protection of the study subjects enrolled at your site, and raise 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 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 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.

If you have any questions, you may email FDA at CDER-OSI-Communications@fda.hhs.gov.

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

Brittany L. Garr-Colón, MPHBranch ChiefCompliance Enforcement BranchDivision of Enforcement and Postmarketing SafetyOffice of Scientific InvestigationsOffice of ComplianceCenter for Drug Evaluation and ResearchU.S. Food and Drug AdministrationBuilding 51, Room 535210903 New Hampshire AvenueSilver Spring, MD 20993