"Daniel C. Tarquinio, D.O./Center for Rare Neurological Diseases

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 October 18 and November 5, 2021. Investigator Sereen G. Morgan-Murray, representing FDA, reviewed your conduct of the following clinical investigations of the investigational drug (b)(4), performed for (b)(4):

Protocol (b)(4)

Protocol (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 Morgan-Murray presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge our receipt of your November 24, 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 November 24, 2021, written response to the Form FDA 483, 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. Following the completion of Protocol (b)(4), subjects were given the option to enroll in Protocol (b)(4), an open-label extension study. The investigational plans for both studies required you to ensure that subjects met all inclusion and exclusion criteria before enrollment in the studies. Specifically, the investigational plan for Protocol (b)(4) required you to exclude (b)(4). In addition, the investigational plan for Protocol (b)(4) required you to exclude subjects who were (b)(4).

You failed to adhere to these requirements. Specifically, you enrolled subjects in (b)(4) and subsequently in an open-label extension study, Protocol (b)(4); however, each of these subjects had previously been enrolled and was actively participating in another clinical study, Protocol (b)(4), involving another study drug ((b)(4)). Examples of this failure include, but are not limited to, the following:

1. Subject (b)(6) was enrolled into Protocol (b)(4) on (b)(6), and was subsequently enrolled in Protocol (b)(4) on (b)(6). However, this subject was already enrolled and participating in Protocol (b)(4) from (b)(6), through (b)(6).

2. Subject (b)(6) was enrolled into Protocol (b)(4) on (b)(6), and was subsequently enrolled in Protocol (b)(4) on (b)(6). However, this subject was already enrolled and participating in Protocol (b)(4) from (b)(6), through (b)(6).

3. Subject (b)(6) was enrolled into Protocol (b)(4) on (b)(6). However, this subject was already enrolled and participating in Protocol (b)(4) from (b)(6), through (b)(6).

4. Subject (b)(6) was enrolled into Protocol (b)(4) on (b)(6), and was subsequently enrolled in Protocol (b)(4) on (b)(6). However, this subject was enrolled in Protocol (b)(4) on (b)(6), the same day on which the subject was enrolled in Protocol (b)(4); and the subject remained in Protocol (b)(4) through (b)(6).

In your November 24, 2021, written response to the Form FDA 483, you acknowledged this observation. You explained that this subject population has rare and ultra-rare diseases, and therefore the issue of dual enrollment in clinical trials is often discussed. You explained that, before enrolling any subjects in Protocol (b)(4), you had sought clarification on exclusion criteria from the sponsor’s medical monitor, specifically with respect to (b)(4) in Protocol (b)(4). You noted that the medical monitor had commented that he did not think it satisfied the exclusion criteria because (b)(4) was only used for (b)(4) emergencies. You also noted that you understood the exclusion criterion for Protocol (b)(4) to be “(b)(4)” with Protocol (b)(4). However, as you noted, these verbal communications were not documented. You also indicated that the sponsor’s new medical monitor for Protocols (b)(4) and (b)(4) “(b)(4).” As such, you stated that you allowed subjects to decide which study they wanted to continue in, and then disenrolled them from the other study; this matter was discussed with the sponsor and the Institutional Review Board.

You indicated that you performed a root-cause analysis and developed corrective and preventive action plans, which include formalizing standard operating procedures (SOPs). Examples of your corrective actions include strict adherence to the protocol (to include a comparison of eligibility criteria when rolling over subjects from one study into another study); a written clarification memo from the sponsor or a protocol amendment in cases of ambiguity; the establishment of documentation practices for meetings, telephone calls, and other discussions; eligibility verification and co-enrollment checks; and an audit of enrollment logs once per quarter. Examples of your new or revised SOPs include Root Cause Analysis and Corrective and Preventive Actions; Protocol Implementation and Compliance; Communication Practices; Subject Screening, Eligibility, and Enrollment; Quality Management; and templates for telephone logs, study contact forms, and audit forms. In addition, you detailed a strategy for auditing study records, with the first (b)(4) audit of study binders beginning in December 2021, and the first (b)(4) audit of telephone logs, study contact forms, and enrollment logs beginning in January 2022. You specified that the results of these audits will be submitted to FDA.

You stated that you confirmed that no other subjects (other than those cited on the Form FDA 483) were co-enrolled in any of your studies since the opening of your site in 2017; thus, this issue was unique to subjects participating in Protocols (b)(4) and (b)(4).

Your written response is inadequate because your corrective action plan is not sufficient to prevent similar violations in the future. Specifically, we note that only the current research coordinator has been trained on the new and revised SOPs. Several of the SOPs specify that they are applicable to all clinical research personnel at your site, including you as the clinical investigator; however, there are no details that you and other study staff have been or will be trained on them. In addition, you did not provide details regarding when and how the current research coordinator was trained on these SOPs. Without these details, we are unable to determine whether your corrective actions appear adequate to help prevent similar violations in the future.

Enrollment of subjects who do not meet eligibility criteria jeopardizes subject safety and welfare and raise concerns about the validity and integrity of the data collected at your study site. FDA is particularly concerned that you enrolled four subjects into a clinical study, and subsequently into an extension study, without ensuring their eligibility for either study.

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.

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 5219 10903 New Hampshire Avenue Silver Spring, MD 20993