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WARNING LETTER 24-HFD-45-11-02

November 27, 2024

Dear Dr. Phan:

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 April 1 and April 5, 2024.  Investigators Ann B. Borromeo and Cheryl A. Grandinetti, representing FDA, reviewed your conduct of a clinical investigation (Protocol (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, Investigators Borromeo and Grandinetti presented and discussed with you the Form FDA 483, Inspectional Observations.  We acknowledge receipt of your April 26, 2024, written response to the Form FDA 483, and your subsequent correspondence dated June 3, 2024.  

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written responses dated April 26 and June 3, 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.  

We wish to emphasize the following:

You failed to ensure that the investigation was conducted according to the investi-gational 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 plan for Protocol (b)(4) required the administration and evaluation of clinical outcome assessments (COAs) testing (b)(4) for (b)(4) subjects with (b)(4).  These clinical outcome tests of (b)(4) included the clinician-reported (b)(4).

To correctly administer and score the (b)(4) required by the protocol, the starting and stopping instructions for (b)(4) must be followed to ensure that subjects are administered (b)(4) items that closely approximate their ability levels.  According to the (b)(4) Manual, to be scored correctly, all (b)(4) must be administered and entered according to the appropriate (b)(4). 

You failed to adhere to these requirements.  Examples of this failure include but are not limited to the following:  

Site assessors inconsistently and incorrectly applied the (b)(4) and routinely tested subjects on assessment items beyond established (b)(4) testing requirements.  Specifically, at least 11 of the 29 subjects whose records were reviewed during the inspection had additional items administered beyond what was needed to establish the (b)(4) for the (b)(4) assessments at Baseline.   However, it is impossible to retrospectively account for all instances of noncompliance for the 42 enrolled subjects at your site, because of the inadequate and inconsistent documentation of the assessments. 

According to Protocol (b)(4), you were required to administer and score the (b)(4) assessments.  However, at your clinical site, the procedures for establishing the (b)(4) for the (b)(4) assessments were not followed and were established inconsistently.  The inconsistent and incorrect process of establishing the (b)(4) for the (b)(4) assessments may have yielded differential opportunities for subjects to demonstrate their level of (b)(4) skills, thus limiting the interpretability of the scores between different subjects in the study and between different time points for the same subject.  As a result, your failure to follow the instructions for establishing a (b)(4) for required assessments raises significant concerns about the interpretability of the study data. 

We acknowledge that this finding was not included on the Form FDA 483 you received, and therefore your written responses do not address this violation.  However, this finding was discussed with you during the inspection.

You indicated during the inspection that one of the site assessors who performed several of these assessments was no longer employed at your clinical site.  However, none of the site assessors appear to have undergone any retraining.  Furthermore, no corrective or preventive actions to address this finding appear to have been taken or planned.

We emphasize that as the clinical investigator, it was your responsibility to ensure that this
study was conducted in accordance with the investigational plan, to ensure the integrity of the study data.  One of the primary efficacy endpoints for Protocol (b)(4) was the (b)(4) as measured by the (b)(4) assessments.  Your failure to correctly administer and score the protocol-required (b)(4) assessments for this (b)(4) study raises significant 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.

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, MPH
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
11/27/2024 09:01:01 AM