---

---

---

WARNING LETTER

FDA Reference Number: 22-HFD-45-06-01

Dear Dr. Goodman:

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 November 29 and December 13, 2021. Investigator Kristin M. Abaonza, representing FDA, reviewed your conduct as the sponsor-investigator of a clinical investigation (Protocol (b)(4) the investigational drug (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 Abaonza presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your December 29, 2021, written response to the Form FDA 483, and your subsequent correspondence dated February 10, February 25, March 14, and May 4, 2022.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written response to the Form FDA 483, Inspectional Observations, 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:

1. You failed to submit an Investigational New Drug application (IND) for the conduct of clinical investigations with an investigational new drug 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 investigational new drug application (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 before submitting and having in effect an IND¹. Specifically, you initiated and conducted the clinical investigation of the investigational drug (b)(4), conducted under Protocol (b)(4), before having in effect an IND.

Notably, the IND went into effect on (b)(4), 30 days after FDA received the IND. You enrolled and treated four human subjects² with the investigational drug from September 17 to October 1, 2019, before the (b)(4), IND effective date. You were required to have an IND in effect under 21 CFR 312.40 before enrolling and treating subjects with (b)(4).

In your December 29, 2021, written response, you acknowledged that your enrollment and treatment of four subjects before the IND was in effect did not meet regulatory requirements. You stated that you erroneously thought the Institutional Review Board (IRB) approval also meant that the IND was approved, because you thought the IRB would not approve a study without IND approval. In addition, you stated that the four subjects who received the investigational drugs (b)(4) before the IND was in effect, were screened for enrollment after you received the initial IRB approval letter on August 27, 2019. We note that you did not submit the IND to FDA until (b)(4), after the initial IRB approval on August 27, 2019. Neither the IRB approval itself nor your screening of subjects after receiving IRB approval met your obligation to have an IND in effect before beginning enrollment and treatment of subjects.

In your December 29, 2021, written response, you stated that you were implementing the following corrective actions:

1. A new “Study Start-Up Checklist” that will require confirmation of IND approval by FDA before study initiation

2. New “IND Submissions and Approval Logs” that will document IND submission dates, IND approval dates, and receipt of IND approval

3. Review of FDA regulations and guidance documents

4. Creation of study site standard operating procedures (SOPs) to guide all study-related activities and responsibilities

5. Site staff-documented training on FDA regulations, good clinical practice (GCP), and the new study site SOPs

6. Hiring of a new study coordinator and Contract Research Organization (CRO).

We acknowledge your recognition that IRB review and approval does 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 implement corrective and preventive actions to ensure that regulatory requirements are met in future clinical investigations. However, your response is inadequate because your corrective action plan does not provide sufficient information about 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 312(a). Without this information, we are unable to determine whether your corrective action plan is adequate to prevent similar violations in the future.

As a sponsor-investigator, you are responsible for compliance with IND requirements, 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 a clinical investigation of an investigational drug raises significant concerns regarding 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.

2. You failed to obtain informed consent and assent of children in accordance with the provisions of 21 CFR part 50 [21 CFR 312.60, 21 CFR 50.20, 21 CFR 50.27, and 21 CFR 50.55].

As a clinical investigator, it is your responsibility to obtain informed consent in accordance with 21 CFR part 50 and to comply with additional specific responsibilities in 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 document approved by the IRB, signed and dated by the subject or the subject’s legally authorized representative at the time of consent (21 CFR 50.27).

In addition, FDA’s regulations at 21 CFR 50.55(a) require the IRB to determine that adequate provisions are made for obtaining the assent of children. 21 CFR 50.55(g) requires an IRB to determine whether and how assent must be documented. For Protocol (b)(4), the IRB required documented assent for minors between the ages of 10 and 17 before their enrollment in the study.

You failed to adhere to these requirements. Specifically:

a. You failed to obtain legally effective written consent from subjects before their enrollment in Protocol (b)(4). Specifically, you did not obtain the legally effective informed consent of Subjects (b)(4) and (b)(4), who were enrolled into Protocol (b)(4).

In your December 29, 2021, written response, you acknowledged that you enrolled two subjects without proper consent because of an administrative and training error. You stated that these subjects were given a verbal explanation of study details that was precise and correct. In addition, you stated that you were implementing the following corrective actions:

1. IRB notification

2. A new “Study Visit Checklist,” with confirmation of signed consent and date

3. A new “Informed Consent Checklist” and “Informed Consent Source Documentation”

4. Review of and training on relevant FDA GCP regulations and guidance documents

5. Creation of SOPs to guide study-related activities and responsibilities

6. Hiring of a new study coordinator and CRO

b. Protocol (b)(4) states that when a subject deemed legally incompetent, such as a minor child, is able to give assent to decisions about participation in research, the investigator must obtain that assent in writing. You failed to obtain written assent of subjects between the ages of 10 and 17 before their enrollment in the study, as required by the IRB. Specifically, the following minors were enrolled without IRB-approved written assent:

i. Subject (b)(6) (11 years old) was enrolled on (b)(6).
ii. Subject (b)(6) (16 years old) was enrolled on (b)(6).
iii. Subject (b)(6) (15 years old) was enrolled on (b)(6).
iv. Subject (b)(6) (17 years old) was enrolled on (b)(6).
v. Subject (b)(6) (17 years old) was enrolled on (b)(6).
vi. Subject (b)(6) (16 years old) was enrolled on (b)(6).

In your December 29, 2021, written response, you stated that you erroneously enrolled minors without assent because of an administrative and training error. You assured FDA that although written assent documentation was not obtained, verbal assent was obtained before any study procedures were conducted. In addition, you noted that you are implementing the following corrective actions:

1. IRB notification

2. A new “Study Visit Checklist,” with confirmation of signed assent and date if subjects are minors

3. A new “Informed Consent Checklist” and “Informed Consent Source Documentation”

4. Review of and training on relevant FDA GCP regulations and guidance documents

5. Creation of SOPs to guide study-related activities and responsibilities

6. Hiring of a new study coordinator and CRO

We acknowledge the corrective and preventive actions that you state you are implementing and your assurance that verbal consents and assents were obtained. However, despite your statements, we remain concerned that you did not obtain written consent from subjects and written assent from minor subjects, as required, before enrolling subjects and administering investigational product. We are particularly concerned about the severity of the violations and their potential impact on subjects’ rights, considering that pediatric subjects are a vulnerable population.

As a clinical investigator, you are 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 and obtaining written assent of minors before their enrollment, when required by the IRB.

Your failure to obtain informed consent in accordance with 21 CFR part 50 and IRB-approved written assent before involving subjects in research jeopardized the safety and welfare of subjects by denying them an 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 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 [email protected]. 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

Sincerely yours,
{See appended electronic signature page}
David C. Burrow, Pharm.D., J.D.
Director
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
U.S. Food and Drug Administration

--------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.
--------------------------------------------------------------------------------------------
/s/
------------------------------------------------------------
DAVID C BURROW
07/14/2022 08:00:08 AM

____________________

1 Protocol (b)(4) did not qualify for any of the exemptions listed at 21 CFR 312.2 from the application of 21 CFR 312.

2 Subjects (b)(6), (b)(6), (b)(6)  and (b)(6).