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WARNING LETTER

Ref.: 21-HFD-45-10-01

Dear Dr. Zadra:

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 May 3 and May 7, 2021. Investigator Craig A. Garmendia, representing FDA, reviewed your conduct of a clinical investigation [Protocol (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 Garmendia presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your May 27, 2021, 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 27, 2021, 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:

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 ensure that subjects met all inclusion criteria before enrollment in the study. The protocol also required certain laboratory tests, such as (b)(4), to be performed at specific time points. You failed to adhere to these requirements. Examples of this failure include, but are not limited to, the following:

a. The investigational plan for the above-mentioned protocol required subjects to meet inclusion criteria before enrollment.

The investigational plan required that at the Screening/Baseline visit, subjects have (b)(4). The investigational plan further required that subjects with (b)(4). You failed to adhere to this requirement because you enrolled a subject (Subject (b)(4)) in this study who did not meet the inclusion criteria, and that subject received study drug from (b)(4), to (b)(4). Specifically, Subject (b)(4).

In your May 27, 2021, written response to the Form FDA 483, you acknowledged that this enrolled subject did not meet inclusion criteria. You indicated that the study coordinator made an error in converting the (b)(4) values of (b)(4). Of note, the (b)(4) value on the subject’s laboratory report is (b)(4) and is marked as low with a reference range of (b)(4) to (b)(4). As the clinical investigator, you are ultimately responsible for ensuring compliance with the subject eligibility criteria stated in the protocol.

b. The investigational plan required that from Weeks (b)(4) be performed (b)(4) before the (b)(4) study drug doses. You failed to adhere to these requirements. Specifically:

i. For Subject (b)(4) was not performed at Weeks (b)(4). However, this subject received study drug for 9 months.

ii. For Subject (b)(4) was not performed at Weeks (b)(4). At Week (b)(4) was performed before the (b)(4), instead of before the (b)(4), of the (b)(4) study drug doses. However, this subject received study drug for almost 3 months.

iii. For Subject (b)(4) was not performed at Weeks (b)(4). However, this subject received study drug for 7 months.

c. The investigational plan required that during the maintenance phase, (b)(4) be performed (b)(4). The investigational plan also required that during the maintenance phase, (b)(4) be collected (b)(4). You failed to adhere to these requirements. Specifically, for Subject (b)(4), laboratory tests were not performed at (b)(4) during the maintenance phase.

For items b. and c. above, in your May 27, 2021, written response to the Form FDA 483, you acknowledged that you did not ensure compliance with the protocol lab procedure requirements. You indicated that the study coordinator was responsible for ensuring that all required labs were performed. However, as the clinical investigator, you had oversight of the study and you were ultimately responsible for ensuring compliance with the lab procedure requirements stated in the protocol.

In your May 27, 2021, written response to the violations listed above, you stated that a corrective action you took was to review the subjects’ medical records and confirm that the above subjects experienced no adverse events as a result of not meeting eligibility criteria and not having all required safety-related labs performed.

In addition, you stated that a preventive action you took was the development of a new SOP, “Protocol Compliance,” that requires the use of a per-study visit checklist that is to include study-specific inclusion and exclusion criteria and visit-specific procedure requirements, including any required labs to be collected, processed, and reported. You also indicated that staff are required to receive training for this SOP and to notify you promptly of any noncompliance. However, the SOP does not include any provisions requiring you to personally ensure protocol compliance or to adhere to the regulatory requirements you are responsible for as a clinical investigator.

We acknowledge the actions your site has taken, including the development of a new SOP and site staff training. However, we request that you specify the corrective actions that you, as a clinical investigator, have taken to prevent similar violations in the future. We note that your statement that you are not currently involved in research as a Principal or Sub-Investigator does not demonstrate how you will prevent future violations should you participate as a clinical investigator in a future clinical study. Therefore, we cannot undertake an informed evaluation of your written response’s effectiveness in preventing the recurrence of similar violations until you submit additional information.

We emphasize that enrollment of subjects who do not meet eligibility criteria and failure to perform safety-related labs, tests, and procedures as required by the protocol, jeopardize subject safety and welfare.

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 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 FDA 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 or e-mail her 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 (Acting)
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 5219
10903 New Hampshire Avenue
Silver Spring, MD 20993
U.S.A.

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
10/14/2021 09:57:23 AM