Amy Lightner, MD

CBER-25-682593

March 25, 2025Dear Dr. Lightner:

This Warning Letter informs you of objectionable conditions observed during a Food and Drug Administration (FDA) inspection conducted at your clinical study site between April 3, 2023, and April 26, 2023. The FDA Investigators met with you during the inspection to review your conduct and oversight as a sponsor-investigator of the following clinical investigations:

(b)(4)

FDA conducted this inspection under the Bioresearch Monitoring (BIMO) Program, which includes inspections designed to review the conduct of research involving investigational products (IPs) and to help ensure that the rights, safety, and welfare of human subjects have been protected. At the conclusion of the inspection, a Form FDA 483, Inspectional Observations, was issued and discussed with you.

Based on our review of the Establishment Inspection Report (EIR), documents accompanying that report, the Form FDA 483, and your written response dated May 10, 2023, to the Form FDA 483 (response letter), you violated applicable requirements governing the conduct of clinical studies involving investigational drugs and biological products, including regulations published in Title 21 of the Code of Federal Regulations, part 312 (21 CFR part 312) (available at https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-312?toc=1) that are issued under the authority of section 505(i) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(i)) and section 351(a)(3) of the Public Health Service Act (PHS Act) (42 U.S.C. 262(a)(3)). The applicable provisions of the CFR are cited for each violation listed below. The violations include but are not limited to the following:

The protocols for studies (b)(4) provide for exclusion of subjects based on specific criteria, including tests for (b)(4) panels. These protocols also specified procedures for recording and reporting Adverse Events (AEs).

A. As a Sponsor-Investigator you failed to adhere to requirements specified in protocols (b)(4) for determining if subjects met specified eligibility criteria to be enrolled in the relevant clinical investigation. For example:

The following subjects were dosed with the IP prior to collecting samples and obtaining the results of eligibility screening tests that are required by the protocol prior to enrolling subjects in the studies listed and to adequately evaluate subjects for exclusion from the study:

IND/Protocol/Subject:ExclusionCriterionTestSpecimenCollectionDateDateResultedDate Dosed

(b)(4), (b)(6)(b)(4), (b)(6)(b)(4), (b)(6)(b)(4), (b)(6)(b)(4), (b)(6)(b)(4), (b)(6)

Your response letter explains that some subjects (in studies (b)(4)) were from out of town and that the study team did not have adequate time to complete the protocol-specified laboratory and imaging assessments prior to dosing certain subjects with the IP. This explanation does not justify your failure to evaluate subjects’ eligibility in accordance with the protocol. While your proposal to prevent recurrence of this violation for subjects from out of town by asking them to arrive 2-3 days prior to dosing may help address the issue going forward, your response letter does not specify your reasons for not conducting the required laboratory and imaging assessments for subjects who were not from out of town. In addition, your proposed checklist is generally an adequate corrective action to ensure all subjects meet the eligibility criteria except you have proposed that it will be completed in the preoperative area just prior to the subject entering the operating room. Due to the amount of source records necessary to complete the proposed checklist, we recommend that it be completed at least 24 hours prior to administration of the IP to enhance subject safety by helping to ensure that only eligible subjects receive the IP.

B. The Protocols for studies (b)(4) state that information on all AEs should be recorded immediately in the source document, and in the appropriate adverse event section of the case report form (CRF) or in a separate adverse event worksheet, and that all clearly related signs, symptoms, abnormal diagnostic, laboratory procedure or results should be recorded in the source document. The protocols further state that the sponsor-investigator will report to the Cleveland Clinic IRB any serious AEs (SAEs). However, for the subjects (b)(4), for example, you failed to record and report SAEs to the IRB as required by the protocol(s).

SubjectDescription of Event notrecorded or reportedProtocol #

(b)(6)Subject was hospitalized for acute kidney injury and for abdominal pain, nausea, and vomiting on (b)(6) and for abdominal pain, nausea and vomiting on (b)(6).(b)(4)

(b)(6)Subject was admitted for worsening symptoms including fever, chills and abdominal pain, in addition to concerns for progressive (b)(4) on (b)(6)(b)(4)

In your response letter, you acknowledged that SAEs should have been recorded and documented as such for subject (b)(6).1 You stated that for subject (b)(6), the hospitalization was at an outside hospital. However, that is incorrect because subject (b)(6) was hospitalized at (b)(6) from (b)(6) and you did not provide an explanation for why it was not documented as an SAE. Please address this in your response to this letter. We reviewed your Corrective Action and Preventative Action (CAPA) plan included in your response letter, and the actions you have proposed on pages 5-6 and the attached Standard Operating Procedure (SOP) are acceptable if successfully implemented.

C. Protocol (b)(4) and the Data and Safety Monitoring Board (DSMB) charter required all safety/adverse event data to be sent to the DSMB. We reviewed the DSMB meeting minutes, and they include no reference to AEs. In addition, there was no documentation provided to FDA during the inspection that AEs from the adverse event review forms for subjects in (b)(4), (b)(6), were sent to the DSMB.

Records in the Electronic Medical Record (EMR) show that the condition of participant (b)(6) deteriorated after the IP administration, and the (b)(4) may have been used to treat worsening of symptoms and healing of (b)(4) that was reported by the participant. According to the protocol, the surgical procedure was required to be sent to the DSMB as an SAE for evaluation and attribution. Therefore, your response explanation that the (b)(4) was performed for logistical, not medical, reasons is not adequate for not sending this to the DSMB for review.

Your response letter states that the DSMB met per its charter but that meeting minutes were not thorough enough to reflect its discussion of adverse events. You indicate that you “have outlined new meeting minutes to provide structure and ensure each meeting includes discussion and a decision by the DSMB.” In addition, your response letter states that you intend to follow the CAPA outlined on pages 5-6 to address training, communication, study review meetings, and process changes to address documentation lapses. However, your response letter did not include a copy of your proposed new format for meeting minutes or include proposed revisions to the DSMB charter. Therefore, we are unable to determine the adequacy of your proposed corrective actions at this time.

2. You failed to ensure proper monitoring of the investigation(s) and to ensure that the investigation(s) were conducted in accordance with the general investigational plan and protocols contained in the IND. 21 CFR § 312.50. For example, an independent medical monitor was to review all AEs for all subjects according to the protocols for studies (b)(4). Per the protocols “[a]ll safety/adverse event data will be sent to the Independent Medical Monitor for review. All safety/adverse events within 7 days of a [subject] being treated will be sent to the Independent Medical Monitor.” However, there was no documentation that AEs were sent to the medical monitor(s) for participants in studies (b)(4) as required by the protocols.

You stated in your response letter that you continuously communicated with the medical monitor, but you failed to provide any records of these communications. You proposed a plan to keep a paper and electronic record of all future communications with the medical monitor and to request a trained study monitor to conduct (b)(4) review of the studies/subjects. If successfully implemented, these proposed corrective and preventative actions are acceptable.

3. You failed to retain records and reports as required for 2 years after a marketing application is approved for the drug; or, if an application is not approved for the drug, until 2 years after shipment and delivery of the drug for investigational use is discontinued and FDA has been so notified 21 CFR § 312.57(c).

For example, at the time of the inspection in April 2023, no marketing application for the drug being studied under IND (b)(4) had been approved and shipment and delivery of the drug under that IND had not been discontinued. However, not all complete and contemporaneous source records and reports were available for study (b)(4) under IND (b)(4) during the inspection.

Your response letter acknowledges that you failed to retain study records and reports for study (b)(4) for the 2-year time period required by 21 CFR § 312.57(c). You state that this occurred because the company supplying the investigational product for this study, (b)(4), closed its Electronic Data Capture (EDC) system. According to your response, (b)(4) still has the ability to access the EDC and can share this access with FDA. Please note that FDA investigators reviewed the files provided by (b)(4) during the inspection; however, the files provided by (b)(4) lacked source data on AEs. Your response letter states that you plan to have an academic EDC for future trials when working with industry partners. However, your explanation for not maintaining records and reports for the study (b)(4) and your CAPA plan provided in the response letter do not adequately address your lack of oversight of the storage, maintenance, and retention of the records for study (b)(4). The CAPA plan is inadequate because it does not describe how you plan to maintain appropriate controls and secure access to EDC systems and source records to ensure that that complete records and reports are maintained for the required regulatory duration.

We emphasize that as a sponsor-investigator, it is your responsibility to ensure that your clinical investigations are conducted in compliance with the FD&C Act, PHS Act, and applicable FDA regulations, both to protect the rights, safety, and welfare of subjects, and to ensure the integrity of study data. This includes ensuring proper monitoring of your clinical investigations; ensuring that the investigations are conducted in accordance with the general investigational plan and protocols; protecting the rights, safety, and welfare of subjects under your care; and preparing and maintaining adequate study records (see, e.g., 21 CFR 312.50, 312.57, 312.60, 312.62). Your failures to ensure that enrolled subjects met protocol-specified eligibility criteria and that adverse events were documented and reported as required by the protocol and applicable FDA regulations risked jeopardizing the rights, safety, and welfare of enrolled subjects. Additionally, your lack of supervision and oversight, and failure to conduct the clinical studies in accordance with the respective protocols raises significant concerns about the validity and integrity of all the data collected at your site in the course of your investigations.

This letter is not intended to be an all-inclusive list of deficiencies with your clinical investigations. It is your responsibility to fully comply with the law. You should address any deficiencies and ensure that any ongoing or future studies comply with the FD&C Act, PHS Act, and applicable FDA regulations.

This letter notifies you of our concerns and provides you an opportunity to address them. Failure to adequately address these matters may lead to regulatory action. Failure to respond to this letter and to take appropriate corrective action could result in FDA taking regulatory action without further notice to you.

Your response should be sent via email to CBERBIMONotification@fda.hhs.gov and cc OIIBIMODivision1Correspondence@fda.hhs.gov. If you have any questions regarding this letter, please contact the Division of Inspections and Surveillance, CBER at 240-402-8979.