Mark J. Savant, M.D - 712306 - 06/26/2025

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WARNING LETTER

FDA Ref. No.: 25-HFD-45-06-02

Dear Dr. Savant:

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 9 and April 17, 2024. Investigator Dustin R. Abaonza, representing FDA, reviewed your conduct of a clinical investigation (Protocol (b)(4), “(b)(4)”) of the investigational drugs (b)(4), performed for the (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 May 8, 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 May 8, 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:

1. 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 you to calculate the volume of the investigational product (IP) administered to enrolled subjects according to the subjects’ body weight. The protocol also required you to ensure that subjects met all eligibility requirements before enrollment. You failed to adhere to these requirements. Examples of these failures include but are not limited to the following:

a. The investigational plan for Protocol (b)(4) required the volume of the (b)(4), for intravenous infusion to be calculated according to the subjects’ body weight in kilograms (kg). You failed to adhere to this requirement. Specifically, Subject (b)(6)’s body weight was documented as 68.9 kg at study entry. However, on January 19, 2022, Subject (b)(6) received a calculated volume of IP according to a body weight of 152 kg instead of 68.9 kg. As a result, the final volume of (b)(4) received by Subject (b)(6) was more than two times the amount of IP that the subject should have received, according to the protocol.

In your May 8, 2024, written response to the Form FDA 483, you stated that Subject (b)(6)’s body weight was incorrectly documented by the clinical research coordinator on the IP prescription provided to the pharmacist as 152 kg rather than 152 lb. You also stated that you signed the prescription electronically, but that you: (1) failed to ensure that the subject’s weight was documented correctly, (2) failed to review the source documents before the treatment visit, and (3) failed to ensure that the study coordinator was adequately trained on the protocol.

b. The investigational plan for Protocol (b)(4) required you to ensure that study subjects met all inclusion criteria before enrollment. The subjects who were randomized to receive (b)(4) were required to meet the additional eligibility criteria found in the investigational agent-specific appendix of the protocol. You failed to adhere to this requirement. Specifically:

i. The investigational plan for Protocol (b)(4), Appendix XV, required you to ensure that subjects of reproductive potential had a negative serum or urine pregnancy test within 48 hours before study entry. Subject (b)(6), a 37-yearold female, was documented as being capable of birthing potential on the subject’s Day 0/Study Entry case report form dated January 19, 2022. However, this case report form indicates that the pregnancy test was not applicable, and no negative serum or urine pregnancy test was documented within 48 hours of study entry. Despite her not meeting this inclusion criterion, Subject (b)(6) was randomized on the study and received the IP on January 19, 2022.

ii. The investigational plan for Protocol (b)(4), Appendix XV, required you to ensure that subjects in phase III of the protocol met the protocol definition of being at “higher” risk of progression to hospitalization or death before enrollment in the study.¹ If subjects did not meet the protocol’s definition of “higher” risk, including subjects who had received at least one dose of a (b)(4), they were considered to be at “lower” risk of progression to hospitalization or death, according to the protocol. However, two subjects did not meet the protocol definition of being at “higher” risk of progression to hospitalization or death. Specifically:

(a) According to study records, Subject (b)(6) did not meet the protocol’s definition for “higher” risk of progression to hospitalization or death. However, on January 17, 2022, this subject was randomized to phase III of the protocol, with the risk of progression indicated as being “high.”

(b) According to study records, Subject (b)(6) was documented to have received two (b)(4), which met the protocol’s definition of “lower” risk for progression to hospitalization or death. However, on January 19, 2022, this subject was randomized to phase III of the protocol, with the risk of progression indicated as being “high.”

In your May 8, 2024, written response to the Form FDA 483, you stated that you did not adequately review the inclusion/exclusion criteria; instead, you relied on the clinical research coordinator to provide you with all the eligibility information, and you made the determination based on the information provided. You further stated that site-created source documents were insufficient; that they lacked inclusion of critical assessments; and that they lacked collection of data required at subject visits, such as the required pregnancy tests at screening/Day 0, and an inclusion/exclusion criteria checklist. You also stated that you failed to ensure that the clinical research coordinator was trained adequately on the protocol.

In addition, in your written response, you detailed the corrective and preventive actions that you and your site have taken or plan to take, including: (1) reporting the protocol deviations to the IRB; (2) requiring investigators to personally write prescriptions and review all source documents to ensure that subjects are given the correct dose of IP; (3) implementing quality checks of all source documents to ensure that the source documents are accurate and complete; (4) including a visit checklist on source documentation for all future studies, to ensure that all required assessments are completed and documented properly; (5) creating a detailed inclusion and exclusion criteria checklist for all future studies, to ensure that eligibility requirements are met; and (6) implementing an onboarding/training plan for all current and new site staff.

We emphasize that as the clinical investigator, it is your responsibility to ensure that studies are conducted in accordance with the investigational plan, 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 resulted in an overdose of the investigational product to a subject, as well as the enrollment of subjects who did not meet all eligibility requirements. This conduct 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.

2. You failed to obtain informed consent in accordance with the provisions of 21 CFR part 50 [21 CFR 312.60 and 21 CFR 50.20].

As a clinical investigator, you are required to obtain informed consent in accordance with 21 CFR part 50. FDA’s regulations at 21 CFR 50.20 state that, except as provided in 21 CFR 50.23 and 21 CFR 50.24, no investigator may involve a human being as a subject in research covered by the regulations unless the investigator has obtained the legally effective informed consent of the subject or the subject’s legally authorized representative.

Protocol (b)(4), the “Phase III Main Informed Consent Form,” which was approved by the IRB on August 11, 2021, stated that subjects would receive information about specific study drugs being tested in a separate consent form. This separate consent form, “Informed Consent Form Addendum for Study Drugs,” which was also approved by the IRB on August 11, 2021, was used to inform potential subjects about all the study drugs they might receive in the study, including the associated risks of the study drugs.

You failed to obtain legally effective informed consent for two subjects before their enrollment in Protocol (b)(4). Specifically, Subjects (b)(6) and (b)(6) signed the “Phase III Main Informed Consent Form” on January 17, 2022; however, neither subject signed the “Informed Consent Form Addendum for Study Drugs.”

In your May 8, 2024, written response to the Form FDA 483, you stated that you failed to read the full IRB approval letter and were therefore unaware of the requirement to obtain informed consent from subjects using the additional “Informed Consent Form Addendum for Study Drugs.” You also detailed the corrective and preventive actions that you and your site have taken or plan to take, including: (1) submitting the deviation to the IRB; (2) contacting the subjects to come onsite to obtain the missed consent; (3) updating site informed consent standard operating procedures (SOPs) to include the use of a study-specific informed consent checklist and process document, as well as providing staff training on the updated SOPs; and (4) hiring a quality-control professional to manage IRB approval notifications and implementation.

We emphasize that as the clinical investigator, you are responsible for ensuring that legally effective informed consent is obtained from subjects before their enrollment. Your failure to obtain informed consent in accordance with 21 CFR part 50 before involving subjects in research jeopardizes the safety and welfare of subjects by denying them an opportunity to fully assess the risks and benefits of their participation in the clinical investigation.

While we acknowledge the corrective and preventive actions that you and your site have taken and plan to take, your response is inadequate because you have not provided sufficient details about your corrective action plan. For example, you did not provide sufficient details about the policies, procedures, and training plan being implemented at your site to prevent similar violations in the future.

We emphasize that as the clinical investigator, you are ultimately responsible for compliance with all applicable FDA regulations governing the conduct of clinical investigations and the protection of human subjects, 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, your failure to obtain the legally effective informed consent before involving subjects in research, and your lack of oversight and supervision of the clinical study, raise significant concerns about your protection of 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 that 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-Communications@fda.hhs.gov. Your written response and any pertinent documentation should be addressed to:

Brittany L. Garr-Colón, MPH
Branch Chief
Compliance Enforcement Branch
Division of Enforcement and Post-marketing 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
06/26/2025 06:42:31 AM

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1 The protocol considered the following subjects at “higher” risk of progression to hospitalization or death as long as the subject did NOT receive any doses of a (b)(4): (1) ≥ 65 years of age; (2) ≥ 55 years of age and satisfying at least one of the following: history of cardiovascular disease (for example, myocardial infarction, stroke, heart failure), hypertension with at least one medication recommended or prescribed, or chronic obstructive pulmonary disease (COPD) or other chronic respiratory disease requiring daily prescribed therapy; (3) ≥ 18 years of age and satisfying at least one of the following: body mass index ≥ 35 kg/m2, chronic kidney disease requiring hemodialysis or peritoneal dialysis, Type 1 or Type 2 diabetes, or exogenous or endogenous immunosuppression (that is, HIV infection or receiving corticosteroids equivalent to prednisone ≥ 20 mg daily for at least 14 consecutive days, within 30 days before study entry); or (4) treatment with biologics, immunomodulators, or chemotherapy within 90 days before study entry.