Tyrone L. McCall, M.D./Cornea Associates of Texas

This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted between September 12 and 19, 2022. Investigator Joanne M. Schlossin, representing FDA, reviewed the role of Cornea Associates of Texas (“Cornea Associates”) as the sponsor, and your role as the authorized representative of the sponsor and a clinical investigator for the following clinical investigations:

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 Schlossin presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your September 27, 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 written response dated September 27, 2022, it appears that Cornea Associates, as the sponsor, 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.

As the sponsor, Cornea Associates failed to comply with these requirements. Cornea Associates initiated and conducted a clinical investigation 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. Specifically, Cornea Associates initiated and conducted a clinical investigation of a combination product consisting of the investigational drugs (b)(4), conducted under Protocol (b)(4), without submitting and having in effect an IND. FDA has no records indicating that Cornea Associates submitted an IND before initiating and conducting this clinical investigation, in which 69 human subjects were enrolled.

In your September 27, 2022, written response to the Form FDA 483 on behalf of Cornea Associates, you stated that Cornea Associates misunderstood the IND exemption criteria requirements under 21 CFR 312.2(b)(1)(i), specifically with respect to an investigation not intended to be reported to FDA as a well-controlled study in support of a new indication for use nor intended to be used to support any other significant change in the labeling for the drug. You further explained that this error was discovered upon further review with an Institutional Review Board (IRB) and that study enrollment was immediately stopped. You also stated that after Cornea Associates identified the deficiency, it immediately corrected the deficiency by submitting an IND to FDA on December 6, 2019.

While we acknowledge that Cornea Associates immediately stopped enrollment upon discovering that a sponsor had to submit, and to have in effect, an IND before conducting Protocol (b)(4), we reiterate that the combination product consisting of investigational drugs (b)(4) is not a lawfully marketed product in the United States and therefore did not qualify for an IND exemption under 21 CFR 312.2. Therefore, Cornea Associates was required to submit and have in effect an IND before initiating and conducting Protocol (b)(4).

Additionally, we note that the sponsor, Cornea Associates, not the IRB, is responsible for compliance with IND regulations, including the requirements at 21 CFR 312.2, and that the sponsor is responsible for being aware of and following all applicable FDA regulations.

In your written response, you further stated that Cornea Associates created a Corrective and Preventable [Preventive] Action Plan to prevent the recurrence of this violation in the future. You noted that this plan includes a pre-IND meeting with FDA for any prospective IND study, before submitting the study for IRB approval, to ensure a full understanding and agreement of the requirements before conducting a new clinical investigation.

This written response is inadequate because it did not provide sufficient details about how Cornea Associates will determine when an IND is required for clinical investigations of products regulated by FDA, and how it would comply with IND regulations in accordance with 21 CFR part 312. Also, while you stated your intent to have a pre-IND meeting with FDA for any prospective IND study before submitting the study for IRB approval, you did not provide details on how you would determine whether an IND is required and how you would ensure that this meeting with FDA occurred. Finally, your written response did not provide details on any completed or proposed training of Cornea Associates or other study staff on compliance with FDA laws and regulations governing the conduct of clinical investigations, including the IND regulations at 21 CFR part 312, that would help to ensure that Cornea Associates will be able to determine when an IND is required. Without these details, we are unable to determine whether Cornea Associates will comply with IND regulations in the future.

Cornea Associates’ failure to submit, and to have in effect, an IND before initiating its clinical investigation with investigational drugs raises significant concerns regarding the safety and welfare of enrolled subjects, and raises concerns about the validity and integrity of data collected during the conduct of the clinical investigation. This letter is not intended to be an all-inclusive list of deficiencies with your clinical study of an investigational drug. As the sponsor, Cornea Associates is responsible for ensuring adherence to each requirement of the law and relevant FDA regulations. Cornea Associates 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