Robert J. Hayashi, M.D./Washington University School of Medicine, Department of Pediatrics

Ref.: 23-HFD-45-03-02 Dear Dr. Hayashi:

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 June 23, 2022, and July 8, 2022. Investigator Carmen Y. Fisher, representing FDA, reviewed your conduct of the following clinical investigations:

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

Protocol (b)(4), “(b)(4), of investigational drug (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 Fisher presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your July 28, 2022, written response to the Form FDA 483.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your July 28, 2022, written response, 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) requires that you omit certain (b)(4) treatments for subjects randomized into the (b)(4). In addition, the investigational plan for Protocol (b)(4) requires you to ensure that subjects meet certain treatment eligibility criteria before each treatment cycle. You failed to adhere to these requirements. Specifically:

1. The investigational plan for Protocol (b)(4) requires that you omit administration of Day 1 (b)(4) during the final 2 cycles of maintenance therapy for subjects randomized into the (b)(4). Subject (b)(6) was a pediatric subject (5 years old) randomized to the (b)(4); however, this subject was administered 12 mg of (b)(4) on Day 1 of the subject’s final two cycles of maintenance therapy (Cycles 5 and 6), on (b)(6), respectively. As a result, this subject underwent invasive procedures associated with (b)(4) administration, including lumbar punctures for the collection of cerebrospinal fluid and the use of general and local anesthesia. Subjects administered (b)(4) are exposed to an increased risk of neurotoxicity (for example, seizures and encephalopathies) associated with (b)(4), and an increased risk of infection associated with lumbar punctures.

In your July 28, 2022, written response to the Form FDA 483, you acknowledged the observation, stating that you take full responsibility for this deviation. You stated that once the error was brought to your attention on February 8, 2022, you notified the subject’s mother, the study chair, and the National Cancer Institute, Pediatric Central IRB (Pediatric CIRB). You stated that the subject experienced no adverse events resulting from the additional doses of (b)(4) and lumbar punctures. You also created and began implementing a Corrective and Preventive Action Plan (CAPA).

You also stated that you assembled a team, the Clinical Trials Command Center (CTCC), which includes members of the clinical trials task force, the Quality and Safety Committee, and divisional leadership, to field prompt notifications of challenges to your clinical operations as they relate to clinical trial conduct on a weekly basis, and to formulate strategies and actions to eliminate difficulties to prevent errors and optimize patient safety. You described protocol-specific actions that the CTCC has implemented and will monitor. For example, updates to the electronic medical record (EMR) ordering system were made to remove (b)(4) from Day 1 of Cycles 5 and 6 for (b)(4), in anticipation that the end of therapy will be in proximity to these cycles, and therefore subjects will not receive (b)(4).

Furthermore, you stated that you contacted the Children’s Oncology Group (COG) Quality Assurance Office and the study chairs, and that you shared suggestions for a protocol amendment that could raise awareness of this issue, to minimize any recurrence of this event at your center and other centers. You also stated that education was provided to the study staff caring for patients on Protocol (b)(4), reinforcing the need to calculate the end of therapy and when the last administration of (b)(4) is planned. Additionally, you stated that procedural standard operating procedures (SOPs) were created for (b)(6) ordering, to minimize errors in (b)(6) administration, and that training on these SOPs was provided.

2. The investigational plan for Protocol (b)(4) requires an (b)(4) before the initiation of any cycle of 3-day interval of (b)(4) ((b)(4)) administration. If this treatment eligibility criterion is not met, the 3-day course of (b)(4) ((b)(4)) is not initiated. Subject (b)(6) had a calculated (b)(4) on (b)(6); however, this subject received a 3-day course of (b)(4) ((b)(4)) on Days 1 to 3 of Cycle 3 ((b)(6)). Thus, you failed to ensure that the only enrolled subject in Protocol (b)(4), Subject (b)(6), met the required treatment eligibility criterion before the administration of (b)(4).

In your July 28, 2022, written response to the Form FDA 483, you acknowledge the observation, stating that you take full responsibility for this deviation. You explained that a provider examining the subject had mistakenly understood the protocol to require an (b)(4) for the initiation of a cycle, and this provider had authorized the study drug to be dispensed.

As described above, you stated that you created and began implementing a CAPA. Corrective actions included notifying the subject’s family and the study chair. You also stated that the subject was monitored for toxicity, and that there were no identifiable significant adverse events associated with this error.

Additionally, you stated that preventative actions include: (1) the initiation of a “double check” system, in which a nurse and a provider check the drug and dose before dispensing an oral investigational (b)(6) agent; (2) the creation of procedural SOPs for (b)(6) ordering, to minimize errors in (b)(6), with training on these SOPs; (3) education for providers and nurse coordinators on the calculation of (b)(4); and (4) good clinical practice training.

We acknowledge the corrective and preventive actions that your site has taken and plans to take. However, given the significance of the protocol deviations involving pediatric subjects, we request documentation following up on some of the trainings you listed in your CAPA. For example, you stated in your CAPA that you were going to provide mandatory training by August 15, 2022, to all study personnel who participate in the management of clinical trials subject to an IND. We request that you submit documentation that this training occurred, and that you explain how this training will ensure that ongoing and future clinical investigations will be conducted in compliance with applicable FDA regulations. We cannot undertake an informed evaluation of your written response until you submit this information.

We emphasize that as the clinical investigator, it is your responsibility to ensure that studies are conducted in accordance with the investigational plan, 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 the unnecessary administration of intrathecal methotrexate and the performance of invasive procedures, such as lumbar punctures and the sedation of a pediatric subject; and the initiation of study treatment cycles for a subject, despite that subject’s not meeting the treatment eligibility criterion. This conduct raises significant concerns about your protection of the study subjects enrolled at your site, and also raises 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 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