Ignacio J. Rodriguez, MD

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 18 and September 29, 2020. FDA Investigator Matthew F. Duff reviewed your conduct of a clinical investigation (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 Duff presented and discussed with you Form FDA 483, Inspectional Observations. We acknowledge receipt of your October 20, 2020, 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 October 20, 2020, we conclude that you did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations and the protection of human subjects. We wish to emphasize the following:

As a clinical investigator, you are required to ensure that your clinical studies are conducted in accordance with the investigational plan. The investigational plan for Protocol (b)(4) required you to ensure that subjects met all inclusion and exclusion criteria before enrollment in the study. The protocol also required you to ensure that subjects met randomization criteria before randomization, and to conduct certain study activities throughout the clinical study, such as certain requirements regarding (b)(4). You failed to adhere to these requirements. Examples of this failure include, but are not limited to, the following:

1. The investigational plan for the above-mentioned protocol required you to exclude subjects for conditions including, but not limited to, the following: (b)(4). You failed to adhere to these requirements. Specifically:

a. Subject (b)(6) had a known history and an ongoing diagnosis of (b)(6) at Screening Visit. However, you enrolled and randomized this subject in this study on (b)(6).

b. Subject (b)(6) had an (b)(6) at Screening Visit on (b)(6), and an (b)(6) at Baseline Visit on (b)(6). However, you enrolled and randomized this subject in this study on (b)(6).

c. Subject (b)(6) had a known history and a diagnosis of (b)(6) at Screening Visit. However, you enrolled and randomized this subject in this study on (b)(6).

In your October 20, 2020, written response to the Form FDA 483, you agreed with the observations that these randomized subjects met exclusion criteria. You indicated that it was an oversight/protocol deviation. You also indicated that you will hold a site staff and sub-investigator meeting to re-educate the importance of timely lab results review, and accurate probing and documentation of significant medical history.

We are unable to determine if your written response provides a corrective action plan that, if properly carried out, would prevent this type of violation in the future. Specifically, you did not provide sufficient details about your plan for implementing additional measures and procedures to address the inspection findings regarding the enrollment of ineligible subjects. While you plan to hold a meeting with sub-investigators and study staff to emphasize the importance of reviewing and documenting significant medical history and laboratory results in a timely manner, you did not indicate whether you and your staff will develop plans or procedures to prevent future protocol violations. In addition, your written response does not provide sufficient details about how you personally will ensure adequate oversight of study procedures (for example, adherence to eligibility requirements). Without these details, we are unable to determine whether your corrective action plan is adequate to prevent similar violations in the future.

2. The investigational plan required subjects to meet randomization criteria before randomization, and to call into the interactive response technology (IRT) system at the Baseline (Day 1) Visit.

a. The investigational plan required subjects to have made at least (b)(4) before Baseline Visit to be eligible for randomization. You failed to adhere to this requirement. Examples include, but are not limited to, the following: i. Subject (b)(6) was randomized in the study on (b)(6), and there were no (b)(4) before Baseline Visit. ii. Subject (b)(6) was randomized in the study on (b)(6), and there were (b)(6) within the (b)(4) before Baseline Visit.

b. The investigational plan required subjects to have (b)(4) to be eligible for randomization. You failed to adhere to this requirement. Examples include, but are not limited to, the following: i. Subject (b)(6), (b)(4) indicated (b)(4) on (b)(6). ii. Subject (b)(6), (b)(4) indicated (b)(4) on (b)(6).

c. The investigational plan required subjects who met eligibility criteria and had (b)(4) to be eligible for randomization. Protocol (b)(4):

(b)(4)

You failed to adhere to these requirements. Examples include, but are not limited to, the following:

i. Subject (b)(6), a 69-year-old female, was randomized and administered study drug on (b)(6), but did not obtain the required (b)(6).

ii. Subject (b)(6), a 66-year-old female, was randomized and administered study drug at 10:21 a.m. on (b)(6), but did not obtain the required (b)(4) until later that day, at 2:15 p.m. In addition, this subject refused to have the required (b)(4) but was randomized and administered study drug.

iii. Subject (b)(6) was randomized and administered study drug on (b)(6), but did not obtain the required (b)(4) until (b)(6).

iv. Subject (b)(6), who had a history of (b)(6) at Screening Visit, was randomized and administered study drug on (b)(6), but did not obtain the required (b)(4).

v. Subject (b)(6), a 70-year-old female, refused to obtain the required (b)(4) but was randomized and administered study drug on (b)(6).

vi. Subject (b)(6) was randomized and administered study drug on (b)(6), but did not obtain the required (b)(4) until (b)(6).

In your October 20, 2020, written response to the Form FDA 483, you agreed with these observations. For Subject (b)(6), you indicated that the “(b)(4) did not reveal any safety findings,” and for Subject (b)(6), you indicated that the “(b)(4) did not reveal any safety findings.” However, you did not submit the actual (b)(4) for these subjects to corroborate these statements.

You indicated that you created a Clinical Quality Management Plan on July 6, 2017, and added it to your site’s standard operating procedures. You stated that the Clinical Quality Management Plan includes a checklist for all study visits to be reviewed by the sub-investigator/clinical investigator and clinical coordinator before and during study visits to ensure that all visit activities are completed accurately. You also indicated that the Clinical Quality Management Plan will be used for all future studies at your site in order to minimize/eliminate oversights and errors. In addition, you stated that you will hold a site staff and sub-investigator meeting to re-educate the importance of reviewing randomization criteria before randomization in the IRT system. If they are properly carried out, your corrective actions appear adequate to prevent the recurrence of similar violations in the future.

3. The investigational plan required the completion of certain study activities involving (b)(4), including (b)(4) at Screening Visit. The investigational plan also required that all study activities (including (b)(4)) at (b)(4) be performed (b)(4), unless otherwise noted. The investigational plan further specified that confirmation of (b)(4) eligibility of the subject must be received from the Central Reader before administration of Week (b)(4) study drug. You failed to adhere to these requirements. Specifically:

a. Subject (b)(6) did not obtain Week (b)(4) but was administered Week (b)(4) study drug on (b)(6).

b. Subject (b)(6) did not obtain Week (b)(4) but was administered Week (b)(4) study drug on (b)(6).

c. Subject (b)(6) did not obtain Week (b)(4) until (b)(6), and (b)(6). These dates were at least three days after the subject received Week (b)(4) study drug on (b)(6).

d. Subject (b)(6) did not obtain Week (b)(4) until (b)(6), almost two months after receiving Week (b)(4) study drug on (b)(6).

e. Subject (b)(6) did not obtain Week (b)(4) until (b)(6), almost two months after receiving Week (b)(4) study drug on (b)(6). f. Subject (b)(6) obtained Week (b)(4) and had Week (b)(4) study drug administered on (b)(6), but confirmation from the Central Reader was not received until (b)(6).

In your October 20, 2020, written response to the Form FDA 483, you agreed with these observations and stated that they occurred due to your lack of oversight and your high workload.2

You indicated that you created a Clinical Quality Management Plan on July 6, 2017, and added it to your site’s standard operating procedures. You stated that the Clinical Quality Management Plan includes a checklist for all study visits to be reviewed by the sub-investigator/ clinical investigator and clinical coordinator to ensure that all study visit prerequisites are completed before the subject’s visit. You also indicated that you will continue to adhere to the Clinical Quality Management Plan for all future studies at your site in order to minimize/eliminate oversights and errors. In addition, you stated that you will hold a site staff and sub-investigator meeting to re-educate the importance of reviewing continuing eligibility criteria before study drug administration. If they are properly carried out, your corrective actions appear adequate to prevent the recurrence of similar violations in the future.

We emphasize that eligibility criteria for each clinical investigation, as well as any procedures required by the protocol, are designed both to minimize foreseeable harm to enrolled and randomized subjects, and to optimize the interpretability of collected data. Therefore, enrollment and randomization of subjects who do not meet eligibility and randomization criteria, and failure to perform procedures required by the protocol, jeopardize subject safety and welfare and raise concerns about the validity and integrity of the data collected at your site.

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. Within 15 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 FDA regulations, please include your reasoning and any supporting information for our consideration.

If you have any questions, please call Mark S. Miller, Pharm.D., at 301-796-2798. Alternatively, you may e-mail FDA at CDER-OSI-Advisory@fda.hhs.gov. Your written response and any pertinent documentation should be addressed to:

Mark S. Miller, Pharm.D., BCPS, RAC CAPT, USPHS 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