Americo F. Padilla, 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 February 1 and February 16, 2024. Investigator Richard A. Lyght, representing FDA, reviewed your conduct of the following clinical investigations:

Protocol (b)(4) (also referred to as Protocol (b)(4)), “(b)(4),” of the investigational drug (b)(4)), performed for (b)(4) (formerly performed for (b)(4))

Protocol (b)(4), “(b)(4)),” of the investigational drug (b)(4), performed for (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 Lyght presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your February 28, 2024, written response to the Form FDA 483, and your subsequent correspondence datedMarch 4, 2024.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written responses dated February 28, 2024, and March 4, 2024, 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:

As a clinical investigator, you are required to obtain informed consent, and to comply with additional specific obligations, in accordance with 21 CFR part 50. FDA's regulations at 21 CFR 50.20 state that, except as provided in 21 CFR 50.23 and 21 CFR 50.24, no investigator may involve a human being as a subject in research covered by the regulations unless the investigator has obtained the legally effective informed consent of the subject or the subject’s legally authorized representative. Except as provided in 21 CFR 56.109(c), informed consent shall be documented by the use of a written consent form approved by the Institutional Review Board (IRB) and signed and dated by the subject or the subject’s legally authorized representative at the time of consent (21 CFR 50.27).

Additionally, for children in clinical investigations that involve greater than minimal risk with the prospect of direct benefit to individual subjects, FDA’s regulations at 21 CFR 50.52(c) require adequate provisions to be made for soliciting the assent of children and the permission of their parents or guardians as set forth in 21 CFR 50.55. Permission by a parent or guardian must be documented in accordance with and to the extent required by 21 CFR 50.27 (21 CFR 50.55(f)).

You failed to adhere to these requirements. Protocol (b)(4) was a clinical trial involving children and adolescents, ages ≥6 to <18 years. The IRB determined that Protocol (b)(4) was a research study that meets the criteria found in the risk category described in 21 CFR 50.52. As a result, you were required to obtain the permission of a parent or guardian, which must be documented in accordance with and to the extent required by 21 CFR 50.27.

You failed to obtain legally effective written consent from two subjects before their enrollment in Protocol (b)(4), because you did not obtain permission from the subjects’ parent or guardian before the subjects’ enrollment in the study. Specifically:

1. Subject (b)(6) was enrolled in Protocol (b)(4) on October 10, 2022; completed a 28-day Screening Phase; and was randomized on November 9, 2022. Before enrollment, on (b)(6), the subject’s sibling signed the informed consent as the subject’s parent or guardian; however, the subject’s sibling is not the subject’s parent or guardian. Parental permission was not obtained from the subject’s parent until (b)(6), approximately 10 months after Subject (b)(6) was enrolled in the study.

2. Subject (b)(6) was enrolled in Protocol (b)(4) on November 16, 2022; completed a 28-day Screening Phase; and was randomized on December 15, 2022. Before enrollment, on (b)(6), the subject’s uncle signed the informed consent as the subject’s parent or guardian; however, the subject’s uncle is not the subject’s parent or guardian. Parental permission was not obtained from the subject’s parent until (b)(6), approximately 9 months after Subject (b)(4) was enrolled in the study.

In your February 28, 2024, written response, you explained that the root cause for this observation was errors and deficiencies in the documentation process of legal guardians’ representatives regarding participation in the study. You indicated that as a corrective action, the subject and their parent returned to the site to consent, confirming parental agreement for study participation. You also indicated that as a preventive action, you will ensure that proper documentation for consent of minors is captured in accordance with 21 CFR 50.27, and that you would work with your quality assurance department to implement a process for obtaining documentation, such as a court-issued legal guardianship document. You also noted that permission from parents or guardians will be documented in a separate form that will be completed before any study procedures are done.

We acknowledge your statement that you will implement corrective and preventive actions to ensure compliance with 21 CFR 50.27. However, despite your statements, we remain concerned that you did not obtain written consent from the parent or legally authorized representative of two subjects before enrolling the subjects and administering investigational product. We are particularly concerned about the severity of the violations and their potential effect on subjects’ rights, since pediatric subjects are considered a vulnerable population.

Furthermore, we are unable to undertake an informed evaluation of the adequacy of your response because you did not provide sufficient details regarding the procedures implemented at your site as part of your corrective action plan to prevent similar violations in the future. For example, your written response does not provide sufficient details about how you will ensure proper documentation for the consent of minors, or about your plan to implement a process of obtaining documentation in coordination with your quality assurance department. Your explanation, when taken into consideration with the violations described above, suggests systemic failures in your conduct of clinical investigations. Without these details, we are unable to determine whether your corrective actions appear adequate to help prevent similar violations in the future.

We emphasize that as the clinical investigator, you are ultimately responsible for compliance with all applicable FDA regulations governing the conduct of clinical investigations and the protection of human subjects, including obtaining legally effective informed consent from subjects before their enrollment.

Your failure to obtain informed consent in accordance with 21 CFR part 50 before involving pediatric subjects in research jeopardizes the safety and welfare of subjects and raises concerns about whether subjects had an adequate opportunity to fully assess the risks and benefits of their participation in the clinical investigation.

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.

This letter notifies you of our findings and provides you with an opportunity to address the deficiencies noted 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.

Should you have any questions or concerns regarding this letter or the inspection, please email FDA at CDER-OSI-Communications@fda.hhs.gov. Your written response and any pertinent documentation should be addressed to:

Brittany L. Garr-Colón, MPHBranch ChiefCompliance Enforcement BranchDivision of Enforcement and Postmarketing SafetyOffice of Scientific InvestigationsOffice of ComplianceCenter for Drug Evaluation and ResearchU.S. Food and Drug AdministrationBuilding 51, Room 535210903 New Hampshire AvenueSilver Spring, MD 20993