Richard W. Foltin, Ph.D.

This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted between February 28 and March 17, 2023. Investigator Omadevi Somai, representing FDA, reviewed your role as the sponsor of the following clinical investigations of the investigational drug (b)(4):

• Protocol #(b)(4), (b)(4) • Protocol #(b)(4), (b)(4) • Protocol #(b)(4), (b)(4) • Protocol #(b)(4), (b)(4) • Protocol #(b)(4), (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 Somai presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your March 23, 2023, written response to the Form FDA 483.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your March 23, 2023, 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:

FDA regulations require a sponsor to submit, and to have in effect, an IND before initiating a clinical investigation of a drug that is subject to 21 CFR 312.2(a) [see 21 CFR 312.20 and 312.40(a)] in human subjects, unless the clinical investigation qualifies for an IND exemption under 21 CFR 312.2. You failed to comply with these requirements. Specifically, you initiated and conducted the following clinical investigations of investigational drugs subject to section 505 of the FD&C Act [21 U.S.C. 355] without submitting and having in effect an IND1:

• The clinical investigation of the investigational drug (b)(4) ((b)(4)) conducted under Protocol #(b)(4) • The clinical investigation of the investigational drug (b)(4) ((b)(4)) conducted under Protocol #(b)(4)

FDA records indicate that you failed to submit an IND before conducting Protocols #(b)(4) and #(b)(4), in which human subjects were enrolled and were administered study drugs before submission of an IND. Specifically, you initiated Protocols #(b)(4) and #(b)(4) and started enrollment of human subjects approximately 11.5 months and 10.5 months, respectively, before submission of an IND on June 8, 2022. Four human subjects were enrolled in Protocol #(b)(4) between June 24, 2021, and June 3, 2022, and two were administered study drug between July 9, 2021, and June 2, 2022. Six human subjects were enrolled in Protocol #(b)(4) between July 22, 2021, and May 18, 2022, and five were administered study drug between August 4, 2021, and April 10, 2022.

In your March 23, 2023, written response to the Form FDA 483, you stated that you failed to tell the clinical investigator for Protocols #(b)(4) and #(b)(4) to submit new studies to FDA before initiating any subject-related procedures. You also stated that after you discovered this error, both studies were submitted to FDA for inclusion under IND #(b)(4).

As part of your corrective action plan, you stated that after you discovered the error, you increased your study oversight. You also stated that you are now informed by email (a) when each new study participant is enrolled in any of your ongoing studies, and (b) if any ongoing study participant is dropped from a study. You further stated that you held a training session to review all the procedures that must be accomplished before starting a new study and before enrolling study participants.

We acknowledge your submission of Protocols #(b)(4) and #(b)(4) to IND #(b)(4) in June 2022. Although Protocols #(b)(4) and #(b)(4) were submitted to this existing IND in accordance with 21 CFR 312.30(a), we note that this submission occurred after subject-related procedures had been initiated for these clinical studies. Additionally, your response is inadequate because your corrective action plan did not include sufficient details to address how you, as the sponsor, will prevent similar violations in the future. For example, your response does not include sufficient details about the procedures being instituted at your site or about the training session provided to ensure compliance with the FD&C Act and FDA regulations governing the conduct of clinical investigations, including the IND regulations at 21 CFR part 312, which would help to ensure that you will be able to determine when an IND is required. Without this information, we are unable to determine whether you will comply with IND regulations in the future.

As a sponsor, you are responsible for compliance with IND requirements, which includes submitting and having in effect an IND before initiating a clinical investigation, and it is your responsibility to be aware of and to follow all applicable FDA regulations. Your failure to submit, and to have in effect, an IND before initiating Protocols #(b)(4) and #(b)(4) raises significant concerns about the safety and welfare of enrolled subjects. It also raises concerns about the validity and integrity of the data collected during the conduct of these clinical investigations.

This letter is not intended to be an all-inclusive list of deficiencies with your clinical studies 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 deficiencies described 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.

If you have any questions, you may email FDA at CDER-OSI-Communications@fda.hhs.gov.

Your written response and any pertinent documentation should be addressed to:

Brittany L. Garr-Colón, MPH 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