---

---

---

WARNING LETTER

FDA Ref. No.: 24-HFD-45-10-02

Dear Dr. Greenwald:

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 October 17 and October 27, 2022. Investigator Sherri N. Rohlf, representing FDA, reviewed your conduct of the following clinical investigations:

• Protocol (b)(4), “(b)(4),” of the investigational drug (b)(4), performed for (b)(4)
• 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 Rohlf presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your October 31, 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 written response dated October 31, 2022, 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 ensure that the investigation was conducted according to the investigational plan [21 CFR 312.60].

As a clinical investigator, you are required to ensure that your clinical studies are conducted in accordance with the investigational plan. The investigational plans for Protocols (b)(4) and (b)(4) required you to ensure that subjects met all eligibility criteria before enrollment in the study. For example, certain eligibility criteria for participation in Protocol (b)(4) exclude subjects from participation in Protocol (b)(4), and vice versa. However, you enrolled a subject in Protocols (b)(4) and (b)(4) concurrently, and another subject in Protocols (b)(4) and (b)(4) consecutively. In addition, Protocol (b)(4) also prohibits the use of certain medications. You failed to adhere to these requirements for Protocols (b)(4) and (b)(4). Examples of this failure include, but are not limited to, the following:

a. The investigational plan for Protocol (b)(4) required you to exclude subjects with (b)(4) [for example, (b)(4)]. You failed to adhere to this requirement. Specifically:

Subject (b)(6) was enrolled in Protocol (b)(4) and received study drug from (b)(6); however, this subject was previously enrolled in Protocol (b)(4) as Subject (b)(6) with a documented diagnosis of (b)(4) since (b)(6). Protocol (b)(4) was a clinical investigation evaluating the effects of (b)(4) in subjects with (b)(4).

In your October 31, 2022, written response to the Form FDA 483, you stated that Subject (b)(4) began Protocol (b)(4) in (b)(6) for (b)(4). You stated that this subject was additionally diagnosed with (b)(4) in (b)(6) and was randomized in Protocol (b)(4) in (b)(6). We note that, according to Protocol (b)(4) study records, Subject (b)(6) had (b)(4) diagnosed in (b)(6), not (b)(6). Your response is inadequate because your explanation does not address the fact that a subject with inflammatory arthritis was enrolled in Protocol (b)(4).

Subject (b)(6) was enrolled in Protocol (b)(4) and received study drug from (b)(6), to (b)(6); however, this subject was previously enrolled in Protocol (b)(4) as Subject (b)(6) with a documented diagnosis of (b)(4) since (b)(6). We reiterate that Protocol (b)(4) was a clinical investigation evaluating the effects of (b)(4) in subjects with (b)(4).

In your October 31, 2022, written response, you stated that Subject (b)(6) was randomized to Protocol (b)(4) in (b)(6) with a misdiagnosis of (b)(4). You stated that this subject was “proved to have [(b)(4)] on genetic testing in (b)(6)” and that this (b)(4) diagnosis was not known until (b)(6). However, we note that according to Protocol (b)(4) study records, Subject (b)(6) had (b)(4) diagnosed in (b)(6), not (b)(6). Your response is inadequate because you did not provide documentation supporting the subject’s misdiagnosis of (b)(4).

b. The investigational plan for Protocol (b)(4) required you to exclude subjects who had previously participated in another study of a systemic medication under investigation within the last 12 weeks or at least 5 half-lives before the baseline visit, whichever is longer, or was currently participating in another study of a systemic medication under investigation. You failed to adhere to these requirements. Specifically:

i. Subject (b)(6)’s Protocol (b)(4) baseline visit occurred on (b)(6), and the subject received study drug from (b)(6), to (b)(6). However, this subject was participating in another study of a systemic medication under investigation within 12 weeks before the Protocol (b)(4) baseline visit and throughout the subject’s participation in Protocol (b)(4). Specifically, this subject was enrolled in Protocol (b)(4) from (b)(6) through (b)(6).

ii. Subject (b)(6)’s Protocol (b)(4) baseline visit occurred on (b)(6), and the subject received study drug from (b)(6), to (b)(6). However, this subject participated in another study of a systemic medication under investigation within 12 weeks before the baseline visit. Specifically, this subject was enrolled in Protocol (b)(4), from (b)(6), to (b)(6).

In your October 31, 2022, written response, you stated that Protocols (b)(4) and (b)(4) are observational studies to assess risks in a drug already approved and marketed. You also state that these protocols are not investigational studies of new investigational drugs, so there is no need to wait 12 weeks between the studies. Your statement is factually incorrect, because Protocols (b)(4) and (b)(4) are randomized, controlled (b)(4) interventional studies in which subjects are assigned treatments according to an investigational protocol designed to assess safety outcomes for (b)(4).

c. The investigational plan for Protocol (b)(4) required you to exclude subjects who had used a (b)(4) within 30 days of the baseline visit. Any dose of a (b)(4) was prohibited during the study. You failed to adhere to these requirements. Specifically, Subject (b)(6)’s Protocol (b)(4) baseline visit occurred on (b)(6), and the subject received study drug from (b)(6), to (b)(6). However, this subject used the (b)(4) within 30 days of the Protocol (b)(4) baseline visit and throughout the subject’s participation in the Protocol (b)(4) study, because this subject was also participating in Protocol (b)(4). (b)(4) was dispensed to this subject on (b)(6); (b)(6); (b)(6); and (b)(6). Study records for (b)(6), and (b)(6), document the subject’s 100% compliance with taking (b)(4).

In your October 31, 2022, written response, you stated that Subject (b)(6) began Protocol (b)(4), a study of (b)(4), in (b)(6) for (b)(4). You stated that this subject was instructed to stop (b)(4) and was enrolled in Protocol (b)(4). You stated that, unbeknownst to your site, the subject did not stop (b)(4). You stated that, in November 2021, the subject disclosed to the site that she decided not to stop (b)(4) and had lied to the site. We note that you documented in your signed memo-to-file that after your site became aware that the subject had not stopped (b)(4) as instructed, you continued the subject’s concurrent participation in Protocol (b)(4) and Protocol (b)(4) for at least 6 months. We also note that this subject’s participation in Protocol (b)(4) was ongoing at the time of FDA’s inspection in October 2022.

d. The investigational plan for Protocol (b)(4) required you to prohibit the use of (b)(4) other than the (b)(4) inhibitor investigational product. However, Subject (b)(6) was concurrently enrolled in Protocol (b)(4) (as Subject (b)(6)) and received Protocol (b)(4) study drug, (b)(4), a (b)(4), for almost 9 months (from (b)(6), to (b)(6)) while enrolled in Protocol (b)(4).

In your October 31, 2022, written response, you stated that Subject (b)(6)’s concurrent participation in Protocols (b)(4) and (b)(4) originally occurred because of this subject’s decision to take both studies’ drugs ((b)(4) and (b)(4)) and not inform your site. You stated that in November 2021, this subject disclosed to the site that she decided not to stop (b)(4) and had lied to the site. We note that you documented in your signed memo-to-file that after your site became aware that the subject had not stopped (b)(4) as instructed, you continued the subject’s concurrent participation in Protocol (b)(4) and Protocol  (b)(4) for at least 6 months. Specifically, we note that your site dispensed Protocol (b)(4) study drug, (b)(4), to this subject on (b)(6), and (b)(6), after this subject began participation in Protocol (b)(4). We also note that this subject’s participation in Protocol (b)(4) was ongoing at the time of FDA’s inspection in October 2022.

e. The investigational plan for Protocol (b)(4) required subjects whose (b)(4) is inadequately controlled by a (b)(4) to not receive the specific (b)(4) to which the subject had an inadequate response or intolerance before the study. Before participation in the study, Subject (b)(6) had discontinued the (b)(4) because of inadequate response. Yet Subject (b)(6) was started on the same (b)(4), on (b)(6) (Study Visit 5), and continued on (b)(4) in Protocol (b)(4) for at least 22 months.

In your October 31, 2022, written response, you stated that Subject (b)(6) had an inadequate response to (b)(4) that was recorded correctly in the subject’s past medical history. You also stated that this was a violation missed by the site.

Your written response is inadequate because, although you stated that you will contact the sponsor and the IRB, you did not provide assurances of corrective actions or a corrective action plan to prevent similar violations from occurring if you participate as a clinical investigator in a future clinical investigation. Without this information, we are unable to determine whether you will comply with FDA regulations in the future.

We emphasize that your failure to conduct the clinical investigation in accordance with the protocol, and specifically, your failures (1) to exclude subjects who did not meet eligibility criteria and (2) to ensure that subjects did not take protocol-prohibited medications, raise significant concerns about your protection of the study subjects enrolled at your site and about the validity and integrity of the data collected at your site. As the clinical investigator, you are responsible for ensuring compliance with the protocol-required eligibility criteria and with prohibited medication requirements.

2. You failed to maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation [21 CFR 312.62(b)].

As a clinical investigator, you are required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. For Protocol (b)(4), you failed to maintain adequate and accurate case histories that document subjects’ diagnoses and concomitant medications. Examples of this failure include, but are not limited to, the following:

a. Subject (b)(6) received (b)(4) treatment when enrolled in Protocol (b)(4) as Subject (b)(6). In addition, Subject (b)(6)’s study records, when enrolled in Protocol (b)(4) as Subject (b)(6), document a diagnosis of (b)(4) since (b)(6). However, Subject (b)(6)’s Protocol (b)(4) subject records did not document (b)(4) treatment or a diagnosis of (b)(4).

b. Subject (b)(6)’s study records, when enrolled in Protocol (b)(4) as Subject (b)(6), document a diagnosis of (b)(4) since (b)(6). However, Subject (b)(6)’s Protocol (b)(4) subject records did not document a diagnosis of (b)(4).

We acknowledge your statements in your October 31, 2022, written response that you corrected the study records for Protocols (b)(4) and (b)(4). However, your written response is inadequate because it does not provide supporting documentation of these corrections. We also acknowledge your statement with respect to Subject (b)(6) enrolled on Protocol (b)(4) receiving (b)(4), that the site did not know initially that this individual was participating in both studies, Protocols (b)(4) and (b)(4). However, we note that even after you became aware that this individual was participating in both studies concurrently, you failed to document (b)(4) as a concomitant medication. In addition, your written response did not provide assurances of corrective actions or a corrective action plan to prevent similar violations from occurring if you participate as a clinical investigator in a future clinical investigation. Without this information, we are unable to determine whether you will comply with FDA regulations in the future.

We emphasize that as a clinical investigator, you are responsible for maintaining adequate and accurate case histories. Your failure to maintain adequate and accurate case histories, including your failure to document exclusionary diagnoses and prohibited medications, compromises the validity and integrity of the data generated 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.

This letter notifies you of our findings and provides you with an opportunity to address the deficiencies specified 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 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, or e-mail her 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

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
10/20/2023 10:54:23 AM