Randy J. Epstein, M.D./Chicago Cornea Consultants, Ltd.

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 September 19 and October 26, 2022. Investigators Colleen E. Burke and Lisa Hayka, representing FDA, reviewed your conduct of the following clinical investigations:

Protocol PXL-330, “Safety and Effectiveness of the PXL-Platinum 330 System for Corneal Cross-Linking in Eyes with Corneal Ectasia,” of an investigational combination product consisting of the investigational drugs riboflavin 0.25% transepithelial solution and riboflavin 0.1% hypotonic solution in combination with ultraviolet-A (UVA) light, which you performed as a sponsor-investigator1

Protocol (b)(4), “(b)(4),” of an investigational combination product consisting of the investigational drug (b)(4), which you conducted as a clinical investigator and performed for (b)(4) as the sponsor

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 Burke and Hayka presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your November 5, 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 November 5, 2022, 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 part 312] governing the conduct of clinical investigations and the protection of human subjects. We wish to emphasize the following:

1. You failed to submit an Investigational New Drug application (IND) for the conduct of a clinical investigation with investigational new drugs that is subject to 21 CFR 312.2(a) [21 CFR 312.20(a), 312.20(b), and 312.40(a)].

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. You initiated and conducted a clinical investigation of an investigational drug subject to section 505 of the FD&C Act [21 U.S.C. 355] without submitting and having in effect an IND.2 Specifically, you initiated and conducted a clinical investigation of a combination product consisting of the investigational drugs riboflavin 0.25% transepithelial solution and riboflavin 0.1% hypotonic solution in combination with UVA light, conducted under Protocol PXL-330, without submitting and having in effect an IND. No FDA records indicate that you submitted an IND before initiating and conducting this clinical investigation, in which thirty-two human subjects were enrolled.

In your November 5, 2022, written response to the Form FDA 483, you acknowledged the observation and stated that you have come to understand that just because the Institutional Review Board (IRB) approved the study as written does not mean that you did not require an IND. You further stated that, since the inspection, you and your research staff have done a thorough review of 21 CFR part 312 regulations to better understand your responsibilities as a research site. You also stated that you will consult with the local FDA office for guidance, should you ever conduct another investigator initiated trial.

We acknowledge your recognition that IRB review and approval do not fulfill the requirement to submit, and to have in effect, an IND before initiating a clinical investigation. We also acknowledge your statement that you will consult with the FDA for guidance on future investigator-initiated clinical investigations. However, your response is inadequate because your corrective action plan did not include sufficient information to address how you, as a sponsor-investigator, will determine when an IND is required for clinical investigations of products regulated by FDA, in accordance with 21 CFR part 312.

We also acknowledge your statement and your note to file that you and your research staff have reviewed the 21 CFR part 312 regulations. However, your written response did not provide details about any completed or proposed training on compliance with the FD&C Act and FDA regulations governing the conduct of clinical investigations, including the IND regulations at 21 CFR part 312, that 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-investigator, you are responsible for compliance with IND requirements, including 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 the clinical investigation you conducted under Protocol PXL-330 raises significant concerns about the safety and welfare of enrolled subjects, and raises concerns about the validity and integrity of data collected at your site during the conduct of the clinical investigation.

As the sponsor-investigator of the clinical investigation you conducted under Protocol PXL-330, you were required to maintain adequate records showing the receipt, shipment, or other disposition of the investigational drug. These records were required to include, as appropriate, the name of the investigator to whom the drug is shipped, and the date, quantity, and batch or code mark of each shipment.

You failed to adhere to this requirement. Specifically, for Protocol PXL-330, you failed to maintain adequate records showing the receipt, shipment, and other disposition of the investigational drugs riboflavin 0.25% transepithelial solution and riboflavin 0.1% hypotonic solution.

In your November 5, 2022, written response, you acknowledged the observation and stated that the coordinator treated the investigational drug riboflavin as a procedural medication used in clinic practice, rather than as an investigational product used in research. You acknowledged the need for adequate recordkeeping, even in an investigator-initiated trial. You also stated that you and your research staff have done a thorough review of 21 CFR part 312 regulations, and that you have revised your site’s standard operating procedure (SOP) on study investigational product (IP) storage protocol to ensure that all information is appropriately documented in the future. These revisions appear to include requiring documentation of the dates of receipt/dispensation, quantity received and dispensed, and lot number and expiration date of IP, if applicable.

We acknowledge your statement and your note to file that you and your research staff have reviewed the FDA 21 CFR part 312 regulations and revised your SOP. However, we request that you also specify the corrective actions that you, as a sponsor-investigator, have taken to prevent similar violations in the future. For example, you did not provide sufficient details about how you plan to implement your revised SOP to ensure that you will maintain adequate drug disposition records in future clinical investigations. Without this information, we are unable to determine whether your corrective actions appear adequate to help prevent similar violations in the future.

We emphasize that as a sponsor-investigator, you are responsible for maintaining adequate records showing the receipt, shipment, or other disposition of the investigational drug. Your failure to maintain adequate drug disposition records raises concerns about the validity and integrity of the data collected at your study site.

This letter is not intended to be an all-inclusive list of deficiencies with your clinical study of an investigational product. 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 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 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., Branch Chief, Compliance Enforcement Branch, 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