WARNING LETTER
Angela M. Stupi, M.D. MARCS-CMS 665471 —
- Delivery Method:
- VIA UNITED PARCEL SERVICE
- Product:
- Drugs
- Recipient:
- Angela M. Stupi, M.D.
144 Emeryville Drive, Suite 220
Cranberry Township, PA 16066
United States
- Issuing Office:
- Center for Drug Evaluation and Research | CDER
United States
WARNING LETTER
FDA Ref. No.: 23-HFD-45-08-01
Dear Dr. Stupi:
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 September 1 and September 29, 2022. Investigator Cynthia L.. Rakestraw, representing FDA, reviewed your conduct of the following clinical investigations, performed for (b)(4):
- Protocol (b)(4), “(b)(4),” of the investigational drug (b)(4)
- Protocol (b)(4), “(b)(4),” of 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 Rakestraw presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your October 4, 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 October 4, 2022, written response, 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:
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 determine whether subjects met inclusion or exclusion criteria before enrollment in the studies. In addition, Protocol (b)(4) required that you administer the study drug in specific body locations as specified in the protocol. You failed to adhere to these requirements. Specifically:
1. The investigational plan for Protocol (b)(4) required subjects to have a stimulated whole salivary flow rate at screening of >0.1 mL/min to be eligible for inclusion in the study. You failed to adhere to this requirement.
Specifically, Subject (b)(6) was enrolled and randomized into Protocol (b)(4) without having a stimulated whole salivary flow rate at screening of >0.1 mL/min. At Subject (b)(6)’s screening visit on (b)(6), as well as at the baseline visit on (b)(6), this subject was not able to produce or excrete saliva. As a result, no stimulated whole salivary flow rate for Subject (b)(6) was determined at screening or at baseline. However, Subject (b)(6) was randomized on (b)(6), and received multiple doses of study drug over six study visits from (b)(6).
In your October 4, 2022, written response, you stated that while you provided paraffin for subjects to chew to help them produce saliva, and the stimulated whole salivary flow rate assessment was attempted at screening for this subject, the test could not be completed. You stated that you should have communicated with the sponsor to seek an extension of Subject (b)(6)’s screening period, to allow for additional attempts to assess this subject’s stimulated whole salivary flow rate at another visit. You further stated that the sponsor’s monitoring team reviewed this observation but did not generate a query report.
You stated that saliva production is quite problematic in this study population. As a result, the sponsor subsequently amended the protocol to remove this inclusion criterion. You also stated that on October 18, 2019, you were asked to generate a note to file (NTF) stating that the screening [visit] lab results, physical exam, and detailed conversation with you disclosed a score of (b)(4) [for Subject (b)(6)], which meets inclusion criteria.
Although we acknowledge the difficulties of obtaining saliva production in the study’s subject population, Subject (b)(6) was enrolled under Protocol (b)(4) Amendment 2, under which a key inclusion criterion of a stimulated whole salivary flow rate of >0.1 mL/min was not met. In addition, a secondary efficacy objective of Protocol (b)(4) was to evaluate the effect of (b)(4) on salivary gland function by comparing to placebo the change from baseline in salivary flow rate (unstimulated and stimulated) at 24 weeks. Your failure to exclude subjects who were unable to produce a stimulated whole salivary rate of >0.1 mL/min at screening, as required by the protocol, raises concerns about the integrity of the data collected at your site and jeopardizes the rights, safety, and welfare of subjects.
Further, your response is inadequate because our review of Protocol (b)(4) showed that contrary to your written response, the criterion of stimulated whole salivary flow rate >0.1 mL/min was not removed from the protocol’s eligibility criteria. In fact, all versions of the protocol required a stimulated whole salivary flow rate >0.1 mL/min. Additionally, regarding the site-generated NTF, your response is inadequate because you did not provide a copy of the referenced NTF or any documentation to support Subject (b)(6)’s eligibility.
As a part of your corrective and preventive action plan, you stated in your written response that you plan to implement the following:
- Monthly research meetings to include review of eligibility
- Site-generated eligibility checklist
- Eligibility checklist review by two study coordinators (SCs) followed by yourself to ensure consistency and completeness of this checklist
2. The investigational plan for Protocol (b)(4) required that to be eligible for inclusion in the study, subjects must have a diagnosis of moderate to severe (b)(4) with prior documented radiologic evidence (X-ray or radiologist’s report) fulfilling the Modified New York criteria. The Modified New York criteria radiologic evidence required sacroiliitis grade ≥2 bilaterally or grade 3-4 unilaterally. You failed to adhere to these requirements.
Specifically, two subjects (Subjects (b)(6) and (b)(6)) were enrolled and randomized into the study without a diagnosis of moderate to severe (b)(4) with prior documented radiologic evidence fulfilling such criteria. Specifically:
a. Subject (b)(6) was screened on (b)(6), and enrolled on (b)(6), without prior documented radiological evidence to fulfill the Modified New York criteria, as required by the protocol’s inclusion criterion. Specifically, the subject’s documented radiologic evidence prior to screening, consisting of an (b)(6), X-ray report, showed unremarkable sacroiliac (SI) joints, with no documentation of sacroiliitis grade ≥2 bilaterally or grade 3-4 unilaterally. However, Subject (b)(6) was randomized and received multiple doses of the study drug from (b)(6), to (b)(6). The subject continued participation in the study until the sponsor closed the study in November 2019.
In your October 4, 2022, written response, you stated that you had been following the patient before enrollment into the study, and that despite the X-ray’s showing unremarkable SI joints, this subject continued to have signs and symptoms (for example, lower back pain) related to the SI joints, more suggestive of (b)(4).
b. Subject (b)(6) was screened on (b)(6), and enrolled on April 10, 2019, without prior documented radiological evidence to fulfill the Modified New York criteria, as required by the protocol’s inclusion criterion. Specifically, although your clinical notes dated December 27, 2018, indicate that the subject’s “SI joints appeared normal bilaterally except for slight sclerosis,” there was no documentation of prior radiologic evidence of sacroiliitis grade ≥2 bilaterally or grade 3-4 unilaterally. However, Subject (b)(6) was randomized and received multiple doses of study drug from (b)(6). The subject continued participation in the study until the sponsor closed the study in November 2019.
In your October 4, 2022, written response, you stated that you had been following the patient before enrollment into the study. You stated that the subject’s low back pain started four years before enrollment, that it was multifactorial, and that (b)(4) may have contributed to her condition. You also stated that the subject had a positive HLA-B27, and that you discussed that the subject may have suggested (b)(4). In addition, you stated that you personally reviewed the subject’s previous X-rays and observed fusion at L4-5, which was “suspicious” for (b)(4).
In addition, with respect to both subjects, you stated that these protocol queries or deviations were not brought to your attention during the regular monitoring visits by the contract research organization (CRO), and that on September 17, 2019, you were asked to assess the radiologic grade of sacroiliitis based on the Modified New York criteria.
Further, for both Subjects (b)(6) and (b)(6), you stated that from a clinical standpoint, both subjects were expected to meet the inclusion criterion, and that you should have ordered additional computed tomography (CT) or magnetic resonance imaging (MRI) studies to assess whether these subjects met the Modified New York criteria and to confirm your diagnostic suspicion of (b)(4) before enrollment.
While we acknowledge your clinical assessment that Subjects (b)(6) and (b)(6) appeared to have met the clinical criteria for (b)(4), your response is inadequate because you did not obtain or subsequently provide radiologic evidence (X-ray or radiologist’s report) to show that these subjects met the radiological criterion of the Modified New York criteria for (b)(4), as required by the protocol. Your failure to exclude subjects who did not have radiologic evidence of (b)(4), as required by the protocol, raises concerns about the integrity of the data collected at your study site, and jeopardizes the rights, safety, and welfare of subjects.
As a part of your corrective and preventive action plan, you indicated that you plan to take the following steps:
- Prescreen subjects before their enrollment into clinical trial(s)
- Ensure that all x-rays and laboratory assessments are performed before screening and enrollment
- Review the protocol’s eligibility criteria (performed by you and two other study staff)
- Include additional MRI or CT assessments as part of your documentation to confirm subject’s eligibility criteria
3. Protocol (b)(4) required you to administer the study drug in specific body locations (that is, left/right thigh, left/right upper arm, abdomen). You failed to adhere to these requirements.
Specifically, Subjects (b)(6), and (b)(6) received multiple study drug injections in their forearms instead of in their thighs, upper arms, or abdomens as required by the protocol, during the following study visits:
|
Subject # |
Week (Wk)/Visit |
Date |
Injection site |
|
(b)(6) |
Wk 0/Baseline/Visit 101 |
(b)(6) |
Left forearm |
|
(b)(6) |
Wk 0/Baseline/Visit 101 |
(b)(6) |
Left forearm |
|
Wk 4/Visit 102 |
(b)(6) |
Left forearm |
|
|
Wk 8/Visit 103 |
(b)(6) |
Left forearm |
|
|
Wk 12/Visit 104 |
(b)(6) |
Left forearm |
|
|
Wk 16/Visit 105 |
(b)(6) |
Left forearm |
|
|
Wk 20/Visit 106 |
(b)(6) |
Left forearm |
|
|
(b)(6) |
Wk 0/Baseline |
(b)(6) |
Right forearm |
|
Wk 12/Visit 104 |
(b)(6) |
Left forearm |
|
|
Wk 16/Visit 105 |
(b)(6) |
Left forearm |
In your October 4, 2022, written response, you stated that the sponsor’s monitor visited your site “for 18 months” and that the monitor did not bring this observation to your attention during the clinical trial or in any of the monitoring reports. You stated that this observation was first brought to your attention by the monitor in September 2019.
Your written response is inadequate because as a clinical investigator, you were required to ensure the study was conducted according to the investigational plan, including the administration of study drug into protocol-specified body sites (that is, left or right upper arm, left or right thigh, or abdomen). Although the monitor did not bring this observation to your attention during the conduct of the clinical trial, as the clinical investigator, you are ultimately responsible for ensuring compliance with the investigational plan. Your failure to ensure that the study drug was administered to subjects in specific body locations as required by the protocol, raises concerns about the integrity of the data collected at your study site, and jeopardizes the rights, safety, and welfare of subjects.
As a part of your corrective and preventive action plan, you noted that you plan to take the following steps:
- Review of protocol requirements concurrently and on the day of a study visit
- Administration of study drug by two study coordinators
- Documentation of study drug injection sites
- Verification that protocol-required study assessments are accurate, after the first subject is enrolled into the study and a monitoring visit has occurred
In your October 4, 2022, written response, you also state that you did not attend the sponsor investigator’s meeting because your site was chosen after this meeting occurred. You emphasized that you are committed to taking all actions necessary to ensure that the specific items listed in the FDA-483 are addressed, and you included a plan of action for the future. You stated that Protocol (b)(4) was a “very time-consuming (b)(4) trial” and that you plan not to conduct “any feasibility or assessment of any (b)(4) trials” in the future.
While we acknowledge the actions that your site plans to take, your response is inadequate because you did not include sufficient details about your corrective action plan. For example, you did not provide sufficient details about the policies and procedures being
instituted at your site to ensure compliance with the protocol, and particularly to ensure subjects’ eligibility before enrollment and to ensure your adherence to the investigational plan. In addition, you did not provide details concerning any planned or completed trainings for you and your staff related to the responsible conduct of clinical trials or compliance with FDA regulations. Without this information, we are unable to determine if your corrective action plan is adequate to prevent similar violations in the future.
We emphasize that as the clinical investigator, it was ultimately your responsibility to ensure that this study was conducted properly and in compliance with FDA regulations, both to protect the rights, safety, and welfare of study subjects and to ensure the integrity of study data. Your failure to ensure that subjects met eligibility criteria before enrollment in the study, and your failure to perform study procedures (including administration of study drug) as required by the protocol, raise significant concerns about the safety of subjects enrolled in this study and the reliability of data 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 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 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
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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.
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/s/
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DAVID C BURROW
08/08/2023 06:35:27 AM