Shirish M. Gadgeel, 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 August 5 and August 23, 2024. Investigator Dina A. Tallman, 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, Investigator Tallman presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your September 13, 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 September 13, 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 plan for Protocol (b)(4) required you to ensure that subjects met all eligibility criteria before enrollment. Additionally, the investigational plan for Protocol (b)(4) required you to remove from treatment subjects who met certain protocol-defined criteria.

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 you to ensure that subjects met all inclusion criteria before enrollment, including documentation of an (b)(4). Subject (b)(6) was enrolled in Protocol (b)(4) without confirming the subject’s documentation of an (b)(4). Specifically, the subject’s August 24, 2019, (b)(4) report instead documented an (b)(4). Despite not meeting this inclusion criterion, Subject (b)(6) was enrolled and started study drug on August 3, 2021. This subject continued to receive study drug through November 16, 2021, thus receiving up to at least Cycle 6 of study drug.

In your September 13, 2024, written response to the Form FDA 483, you stated that although you had discussions with the medical monitor before enrollment regarding the subject’s eligibility and you were advised that the subject should be eligible, you acknowledge that there is no documentation from the medical monitor or study sponsor regarding this discussion. You also stated that during the FDA inspection, you contacted the current medical monitor, who stated that this subject did not meet this eligibility requirement.

As part your corrective and preventive actions, you stated that upon determination of ineligibility by the study sponsor, the IRB was notified, the sponsor unlocked the electronic data capture (EDC), and the EDC was updated to note that the subject did not meet eligibility requirements. You further stated that the following additional corrective and preventive actions were taken: (1) refresher training for research center staff and hematology/oncology providers on source documentation, research best practices, and protocol compliance and good clinical practice; (2) hiring additional research staff to review study eligibility before the clinical investigator’s review; (3) requesting that all eligibility criteria pertaining specifically to the results of genetic reports, and that may be subject to some degree of medical interpretation, be reviewed, confirmed, and approved by the study sponsor; and (4) revision of “prescreening/screening/eligibility workflow” to ensure that screening and eligibility assessments are timely and systematic.

b. The investigational plan for Protocol (b)(4) required you to remove from treatment any subjects with confirmed disease progression as defined by modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) criteria, or any subjects with disease progression accompanied by worsening of symptoms or deterioration of the subject’s general condition. Subject (b)(6), who was enrolled in Protocol (b)(4), had confirmed disease progression as defined by RECIST 1.1 criteria, according to the subject’s September 16, 2021, and November 9, 2021, tumor measurement reports, thereby meeting the protocol’s requirements for removal from treatment. However, Subject (b)(6) continued to receive intravenous infusions of the investigational drug (b)(4), and was not removed from study treatment for progressive disease until January 3, 2022.

In your September 13, 2024, written response to the Form FDA 483, you stated that the protocol version dated February 5, 2021 (effective at the time of first progression), did not specify whether treatment beyond progression was or was not permissible. As a result, the research center contacted the sponsor to determine if treatment beyond disease progression was permissible, and the sponsor approved continued dosing. You further stated that subsequent protocol amendments included information regarding treatment beyond disease progression, stating that such treatment would be permissible if certain conditions were met.

While we acknowledge your statement that the sponsor approved the continued dosing, based on the information provided, we note that the sponsor did not approve the continued dosing until November 23, 2021. However, Subject (b)(6) had confirmed disease progression beginning on September 16, 2021, and received the investigational drug on October 12, 2021, and November 9, 2021, before any sponsor approval of continued dosing.

Additionally, while your response states that subsequent protocol amendments allowed for treatment beyond disease progression, we note that the protocol version in effect at the time of the subject’s treatment clearly specifies that subjects with confirmed disease progression, as defined by modified RECIST 1.1 criteria, will be removed from treatment. It was not until the protocol version dated March 22, 2023, that an option to continue treatment beyond disease progression is allowed for subjects who have clinical benefits, according to the investigator’s judgment and with sponsor approval.

As part of your written response, you stated that the following corrective and preventive actions were taken, including but not limited to: (1) reporting the treatment beyond progression to the IRB; (2) development of and training of research staff on a Treatment Beyond Progression workflow, which requires staff to determine if treatment beyond progression is permissible according to the protocol; or if treatment beyond progression is not addressed in the protocol, requiring approval from the sponsor and the IRB before it would be permissible; and (3) development of and training of research staff on a RECIST Measurement workflow.

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 ensure that all study-related procedures were followed, including protocol required eligibility requirements and stopping rules for treatment discontinuation, 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.

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.

You failed to obtain legally effective informed consent for Subject (b)(6), who was enrolled in Protocol (b)(4). Specifically, the protocol required subjects to sign a separate special consent for inherited genetic analysis. The IRB approved the separate consent for optional genetic analysis on January 10, 2021. However, for Subject (b)(6), a separate consent was not obtained before collecting blood samples for genetic analysis at two timepoints: Cycle 2, Day 1 (on May 25, 2021) and Cycle 3, Day 1 (on June 15, 2021).

In your September 13, 2024, written response to the Form FDA 483, you stated that due to staff oversight, staff failed to confirm that consent was obtained from the subject before collecting the optional samples at two timepoints. You also stated that if the correct test kit had been used on Cycle 3, Day 1, instead of an unscheduled test kit, there would not have been an option to collect the sample. You further stated that the following corrective and preventive actions were taken: (1) research center staff alerted the sponsor and requested destruction of the blood samples when the oversight was initially discovered in 2022, and the IRB was notified; (2) the laboratory supervisor created a new workflow to prevent recurrence of this issue, which includes a system of mandatory double-checks by the research nurse and research assistant before optional specimen sample collection, and re-review of the informed consent form to ensure that optional samples have been consented to; (3) revision of the study visit document template, to address whether study samples are part of the study protocol and whether the subject has agreed to optional samples; (4) staff retraining on the appropriate lab kit inventory management process, and when to use unscheduled lab kits; and (5) revision of the flowsheet for tracking lab specimen collection for research subjects, for completion by the study coordinator or research nurse to indicate, before specimens are collected, which optional samples the subject has agreed to.

We emphasize that as the clinical investigator, you are responsible for ensuring that informed consent is obtained from subjects, in accordance with 21 CFR part 50. Your failure to obtain informed consent before conducting study-related procedures 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 your site has taken, your response is inadequate because you did not include sufficient details about your corrective action plan. For example, your written response does not provide sufficient details about how you, as a clinical investigator, will ensure adequate oversight of study procedures (for example, adherence to eligibility requirements and informed consent requirements). Without these details, we are unable to determine whether your corrective action plan is adequate 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 studies in accordance with the protocol, and your failure to obtain legally effective informed consent before involving subjects in research, 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 studies of investigational drugs. 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, 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