Angela D. Ritter, 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 14 and August 17, 2023. Investigators Ann B. Borromeo and Matthew R. Coleman, representing FDA, reviewed your conduct of the following clinical investigations:

Expanded Access Protocol1, “(b)(6),” of the investigational drug (b)(6), which you performed as a sponsor-investigator

Protocol (b)(6), “(b)(6),” of the investigational drug (b)(6), which you conducted as a clinical investigator and performed for (b)(6)

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, Investigators Borromeo and Coleman presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your August 25, 2023, written response to the Form FDA 483, and your subsequent correspondence dated September 21, 2023.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written responses to the Form FDA 483 dated August 25, 2023, and September 21, 2023, 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:

Under 21 CFR 312.305(c), as a sponsor-investigator, you were required to comply with all responsibilities set forth in that section, as well as the responsibilities for sponsors and investigators set forth in subpart D of 21 CFR 312 (see 21 CFR 312.305(c)(3)-(5)).

You failed to adhere to these requirements. Specifically, FDA authorized the individual patient expanded access for emergency use (subject’s initials: (b)(6)) under IND #(b)(4) on May 14, 2020. However, you failed to comply with all the requirements for the expanded access use.

Examples of this failure include, but are not limited to, the following:

a. As a sponsor-investigator, in all cases of expanded access, you are required to maintain an effective IND for the expanded access use (21 CFR 312.305(c)(5)). Under IND #(b)(4), FDA authorized the subcutaneous administration of the investigational drug, (b)(4), weekly for up to two weeks. Subject (b)(6) was administered (b)(4) on May 15, 2020 (Day 0, Baseline), and on (b)(6) (Day 7), as authorized. However, Subject (b)(6) continued to receive the investigational drug, (b)(4), between May 29, 2020, and March 28, 2022, instead of during the authorized two weeks only. This subject was administered an additional 50 doses of the investigational drug that were not authorized under IND #(b)(4) for individual patient expanded access for emergency use. Additionally, you did not submit any information or protocol amendments to FDA regarding the change in the duration of the subject’s exposure to the investigational drug. As a result, you failed to maintain an effective IND for the expanded access use. Your failure to maintain an effective IND for the individual patient expanded access use jeopardized the rights, safety, and welfare of the subject.

We acknowledge that the finding discussed above was not included on the Form FDA 483 you received, and therefore your written response does not directly address this issue.

b. As a sponsor-investigator, you are required to comply with the responsibilities set forth in subpart D of 21 CFR 312. These responsibilities include ensuring that the clinical investigation is conducted in accordance with the general investigational plan and protocol(s) contained in the IND (21 CFR 312.50 and 312.60). The investigational plan for the individual patient expanded access for emergency use required the subcutaneous administration of the investigational drug, (b)(4), weekly for up to two weeks, for a total of two doses given seven days apart (on Day 0 and Day 7). Subject (b)(6) was administered (b)(4) on May 15, 2020 (Day 0, Baseline), and on May 21, 2020 (Day 7). However, Subject (b)(6) continued to receive the investigational drug, (b)(4), between May 29, 2020, and March 28, 2022. As a result, you failed to ensure that the clinical investigation was conducted in accordance with the general investigational plan and protocol contained in the IND. Your failure to conduct the study in accordance with the investigational plan for the single patient expanded access IND jeopardized the rights, safety, and welfare of the subject.

In your August 25, 2023, written response, you acknowledged that the subject received additional treatment with the investigational drug after the first two doses. However, you stated that based on communications with the Contract Research Organization (CRO), (b)(4), you were under the impression that (b)(4) was handling the emergency IND and any communications with FDA. You stated that after the administration of the first two doses of investigational drug, you discussed additional subject dosing with (b)(4), who asked you to send them an amended protocol to allow for additional subject dosing at your discretion, which you did on May 28, 2020. You stated that because you received additional vials of investigational drug from (b)(4), you were under the impression that the protocol amendment was approved. You further stated that (b)(4) did not instruct you to submit the amended protocol to FDA or to the IRB, but rather to (b)(4) itself. You also stated that if you had known that the FDA was not aware of the amended protocol allowing for additional drug dosing, you would not have continued the additional dosing.

In addition, you stated that you received an FDA email communication on July 27, 2020, stating that “by now treatment should have been completed” and providing instructions for closing out the IND. You stated that you informed the CRO that FDA was not aware of the patient’s continuing treatment, and the CRO replied that it would handle it. You also stated that you did not respond to the FDA email because you believed you only needed to respond if you wished to close out the IND.

We acknowledge your statement that you relied too much on the CRO, which you believed was managing the IND for the investigational drug supplier. We also acknowledge your statements that in the future you will communicate directly with FDA for guidance; that you will submit protocol changes to the FDA; and that you will personally respond to all communications from FDA, regardless of whether you believe another entity is responding on your behalf.

However, your written response is inadequate because you did not provide information about any completed or proposed corrective actions that would prevent similar violations in the future. For example, you did not provide sufficient details about any policies and procedures that you would institute, as a sponsor-investigator, both to ensure that a clinical investigation is conducted according to the authorized protocol and to ensure that future studies will be conducted in compliance with applicable FDA regulations. You also did not provide details on any planned or completed trainings on compliance with FDA regulations governing the conduct of clinical investigations, including the IND regulations at 21 CFR part 312, which would help to ensure your ability to maintain an effective IND for expanded access use. Without this information, we are unable to determine whether you will be able to prevent similar violations in the future.

We emphasize that as a sponsor-investigator, it was your responsibility to ensure that this study was conducted in accordance with the investigational plan and in compliance with FDA regulations, to protect the rights, safety, and welfare of study subjects. Your failure to conduct the clinical study in accordance with the protocol under IND #(b)(4) for individual patient expanded access for emergency use jeopardized the rights, safety, and welfare of the subject.

c. As a sponsor-investigator, you are required to ensure that IRB review of the expanded access use is obtained in a manner consistent with the requirements of 21 CFR part 56 (21 CFR 312.305(c)(4)). You are also required to comply with the responsibilities set forth in subpart D of 21 CFR part 312, which includes ensuring that an IRB that complies with the requirements set forth in 21 CFR part 56 will be responsible for the initial and continuing review and approval of a proposed clinical investigation (see 21 CFR 312.66). Further, for expanded access use authorized under emergency procedures, the emergency use must be reported to the IRB within five working days of treatment initiation, and any subsequent use of the investigational drug requires prior IRB review and approval (see 21 CFR 56.104(c)). You failed to ensure that an IRB that complies with 21 CFR part 56 conducted prospective IRB review and approval for the subsequent use of the investigational drug following the authorized emergency access use. You also failed to ensure that an IRB that complies with 21 CFR part 56 continued to review and approve your continued conduct of the clinical investigation.

Specifically, FDA authorized the individual patient expanded access for emergency use (Subject (b)(6)) under IND #(b)(4) on May 14, 2020. Subject (b)(6) was administered the investigational drug on May 15 and May 21, 2020, as authorized by emergency IND #(b)(4). However, after the initial two doses of investigational drug that were authorized and administered on an emergency basis, you continued to administer investigational drug to Subject (b)(6) between May 29, 2020, and March 28, 2022, without obtaining prospective IRB review and approval for the subsequent use of the investigational drug. Further, during the 95 weeks when Subject (b)(6) received 50 additional doses of investigational drug after the initial, authorized two doses, you did not seek continuing IRB review and approval for the continued use of the investigational drug, and you had no further communication with the IRB. IND #(b)(4) was active until April 27, 2023, when you submitted a request to withdraw the IND for completed treatment.

In your August 25, 2023, written response, you acknowledged the observation and stated that you had understood that the CRO would be handling the IRB submissions. You also stated that you believed “subsequent use” meant use in a new subject, rather than subsequent treatment in the same subject. You further stated that at the time, it did not occur to you that you would need to submit to the IRB for continuing review if the treatment lasted longer than one year, because there was no expiration date on the IRB acknowledgement letter. Lastly, you stated that at the time, your only regulatory specialist was very sick.

We acknowledge your statements that you have now hired an additional regulatory specialist; that you understand that the amended protocol should have been submitted to the IRB; and that you have learned to question the IRB if an IRB approval expiration date is not provided for a new study that you have submitted for IRB review and approval. However, your response is inadequate because you did not provide information about any completed or proposed corrective actions that would prevent similar violations in the future. For example, you did not provide sufficient details about a corrective action plan to ensure compliance with applicable FDA regulations, including any policies or procedures that you would institute to ensure initial and continuing review and approval by an IRB that complies with 21 CFR part 56. You also did not provide details about any completed or proposed trainings to ensure compliance with initial and continuing review and approval by an IRB that complies with 21 CFR part 56. Without this information, we are unable to determine whether you will be able to prevent similar violations in the future.

IRB review serves an important role in the protection of the rights and welfare of human research subjects. The purpose of IRB review is to ensure, both in advance and by periodic review, that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in the research. Your failure to ensure prospective IRB review and approval for the subsequent use of the investigational drug, and continuing IRB review and approval of the clinical investigation under IND #(b)(4), impeded the IRB’s ability to determine the adequacy of your application to conduct the clinical investigation, which raises significant concerns about the extent to which the subject’s rights and welfare were protected.

d. As a sponsor-investigator, in all cases of expanded access, you are responsible for submitting annual reports to FDA, as required by 21 CFR 312.33 (21 CFR 312.305(c)(5)). Under the authorized emergency IND expanded access use, you were required to submit annual reports of the progress of the clinical investigation within 60 days of the anniversary date on which the IND went into effect. IND #(b)(4) went into effect on May 14, 2020. On May 9, 2022, FDA sent you a Pre-Termination Letter, stating that it had not received the annual report that was due on May 14, 2021, and informing you of FDA’s intent to terminate your IND. You did not submit any annual reports for this IND, which you withdrew for completed treatment on April 27, 2023.

In your September 21, 2023, written response, you acknowledged the observation and stated that you were under the impression that the CRO, (b)(4), was handling all correspondence with FDA on your behalf. You further stated that if you ever participate in another emergency IND, you have now learned to communicate directly with FDA, and not to assume that another entity is communicating on your behalf.

We acknowledge your statement that you assumed the CRO [(b)(4)] was handling all correspondence with the FDA on your behalf. We also acknowledge your statement that you will communicate directly with FDA in the future. However, your written response is inadequate because you were directly informed by the FDA in the Emergency IND Acknowledgment Letter dated May 18, 2020, that as a sponsor-investigator, you were responsible for submitting annual progress reports within 60 days of the anniversary date on which the IND became active. Further, your written response is inadequate because you did not provide information about any completed or proposed corrective actions that would prevent similar violations in the future. For example, you did not provide details about a corrective action plan that you would institute, as a sponsor-investigator, to ensure compliance with applicable FDA regulations, including any policies or procedures to ensure that annual reports of the progress of the clinical investigation are submitted to FDA. You also did not provide details on any completed or proposed trainings on compliance with FDA regulations governing the submission of annual reports for expanded access use. Without this information, we are unable to determine whether you will be able to prevent similar violations in the future.

We wish to emphasize that, as the sponsor-investigator for the individual patient expanded access for emergency use, you were ultimately responsible for the oversight and conduct of the expanded access use for this patient. Additionally, as the sponsor-investigator, you had oversight of the study, and you were ultimately responsible for compliance with all applicable FDA regulations governing the conduct of clinical investigations and the protection of human subjects. These responsibilities included maintaining an effective IND, adhering to the investigational plan, ensuring continuing IRB review and approval of the proposed clinical investigation, and submitting annual reports. Your failure to adhere to the requirements for all expanded access uses, raises significant concerns about the adequacy of your protection of the study subject.

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-mentioned 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 that 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 email 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