Evelyn Lopez-Brignoni, 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 June 8 and June 23, 2020. Ms. Angelica M. Chica, representing FDA, reviewed your conduct of the following clinical investigations:

Protocol (b)(4)

Protocol (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, Ms. Angelica M. Chica presented and discussed with you Form FDA 483, Inspectional Observations. We acknowledge receipt of your July 7, 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 July 7, 2020, we conclude that you did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations. 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 Protocols (b)(4) and (b)(4) required subjects to take (b)(4) of study medication (b)(4), administered as a (b)(4), to demonstrate the efficacy (b)(4). You failed to adhere to these requirements. Specifically:

a. Protocol (b)(4) study design randomized subjects to receive (b)(4). In total, there were (b)(4). Study medication was provided in (b)(4). To maintain adequate blinding for the study, all subjects received (b)(4) of study medication per dose. Subjects randomized (b)(4). This (b)(4) dosing regimen was reinforced in the informed consent forms, which explicitly stated that each subject was required to take (b)(4). Based on our investigation, four out (b)(4) subjects randomized into Protocol (b)(4) took less than the required (b)(4). As a result, subjects may have taken (1) placebo only rather than the required study drug, or (2) less than the full intended dose of study drug. This raises concerns about the validity and integrity of the data collected at your site.

b. Protocol (b)(4) study design randomized subjects to receive (b)(4), or (b)(4). In total, there were (b)(4) — (b)(4). Study medication was provided in (b)(4), with (b)(4). To maintain adequate blinding for the study, all subjects received (b)(4). Subjects randomized to (b)(4); subjects randomized to (b)(4). This (b)(4) dosing regimen was reinforced in the informed consent forms, which explicitly stated that each subject was required to (b)(4). Based on our investigation, nine out (b)(4) randomized subjects in Protocol (b)(4) received less than the required (b)(4). As a result, some subjects may have taken placebo only rather than the required study drug. This raises concerns about the validity and integrity of the data collected at your site.

As the clinical investigator, it was your responsibility to ensure that the studies were conducted in accordance with the investigational plan, to ensure the integrity of the study data and the safety of subjects. Your failure to ensure that subjects adhered to the dosing regimen (b)(4) for the pediatric clinical studies raises concerns about the validity and integrity of the data collected at your site. In addition, considering that pediatric subjects are a vulnerable population, we are concerned about the severity of the violations and their potential impact on subjects’ rights, safety, and welfare, given that according to the investigational plan, study subjects were inadequately dosed.

In your July 7, 2020, written response to the Form FDA 483, you acknowledged that inadequate dosing occurred. You attributed this to unclear protocol language and inadequate training, which “resulted in several subjects in both studies being dosed (b)(4) when they should have been dosed (b)(4).” In addition, you stated that you thought the “Sponsor/CRO Clinical Research Associate (CRA)” agreed that subjects were to receive (b)(4) instead (b)(4), because the monitoring visits during the studies did not identify any issues with subject dosing.

As a corrective action to the observations listed above, you stated that your site now requires all site staff’s correspondence with the sponsor to be either in writing or via e-mail, including any protocol-related questions. In addition, you have implemented (1) regular training of site staff on standard operating procedures, including one training session on investigational product dosing and compliance; (2) protocol training, including retraining whenever a protocol change or amendment occurs; (3) regular site staff discussions on ongoing studies; and (4) regular quality control oversight of each study.

We acknowledge the corrective actions your site has taken specific to the implementation of site staff training and the documentation of sponsor communication by site staff. However, we request that you also specify the corrective actions that you, as a clinical investigator, have taken to prevent similar violations in the future. We cannot undertake an informed evaluation of your written response until you submit this information.

As discussed above, you failed to conduct the clinical studies in accordance with the investigational plan. Specifically, the majority of subjects randomized into Protocols (b)(4) and (b)(4) did not receive sufficient dosing to support the primary objectives of the studies, which raises 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.

If you have any questions, please call Mark S. Miller, Pharm.D., at 301-796-2798. 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