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WARNING LETTER

May 29, 2024

Dear Dr. Rejdak:

This Warning Letter informs you of objectionable conditions observed during a United States Food and Drug Administration (FDA) inspection conducted between May 15 and May 19, 2023. During the inspection, an FDA investigator met with you and your staff to review the conduct and oversight of a clinical study titled:

A Phase III Study to Evaluate the Efficacy, Safety, and Tolerability of Immune Globulin Infusion 10% (Human) with Recombinant Human Hyaluronidase (HYQVIA/HyQvia) and Immune Globulin Infusion (Human), 10% (GAMMAGARD LIQUID/KIOVIG) for the treatment of Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) (Protocol 161403) (hereinafter, the protocol).

FDA conducted this inspection under the Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of clinical research involving investigational products for compliance with applicable requirements, including under 21 CFR Parts 50, 56, and 312.

At the conclusion of the inspection, the FDA investigator presented a Form FDA 483, List of Inspectional Observations (Form FDA 483) for your review and discussed with you and your staff the listed observations. Based upon our review of the Establishment Inspection Report (EIR), the accompanying exhibits and attachments, the Form FDA 483, and your written response, dated June 2, 2023, to the Form FDA 483 (“Response Letter”), we determined that you violated regulations governing the proper conduct of clinical studies involving investigational products in Title 21, Code of Federal Regulations (CFR) Part 312 (available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRsearch.cfm?CFRPart=312).

The violations include, but are not limited to, the following:

1. Failure 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 product [21 CFR 312.62(b)].

In multiple instances, subject ability assessment scores were not entered into (b)(4) tablets at the time of assessment. One of the three assessments used was the Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale. The INCAT score was used as a primary efficacy assessment measure for the protocol. Gaps between assessment end time and data entry ranged from seven minutes to 25 days with no source documentation of 144 assessment values¹ for four subjects over the course of nine visits. Protocol section 18.2 states that data not entered during the study visit should be recorded on paper, and then this documentation will be considered source documentation.

The subject ability assessment scores for these subjects were not entered at the time of assessment, there was no source documentation of the values, and the times and/or dates were later edited to appear as if the values were recorded at the time of assessment.

Your Response Letter states that internet connections were poor due to the COVID-19 pandemic. As a result, raters entered the assessment data into the tablets at a later time, either based on written notes or on their memory. We find this response inadequate for several reasons: (1) it contradicts what was relayed by both sub investigators during the inspection; (2) all affected visits occurred prior to the beginning of the COVID-19 pandemic; and (3) values that were not recorded at the time of the assessment may not be accurate due to the length of time elapsed.

Your Response Letter also states that scores could be entered into tablets in “offline mode” and uploaded once an internet connection was established. We find this explanation inadequate because this modality could not be demonstrated during the inspection. Your contradictory explanations, along with the gaps from assessment time to entry time, raise concerns about the reliability of the data and the integrity of your study conduct.

2. Failure to ensure that the investigation was conducted according to the signed investigator statement, the investigational plan, and applicable regulations; failure to protect the rights, safety, and welfare of subjects under your care [21 CFR 312.60].

Section 18.2 of the protocol states: “If electronic CRFs [case report forms] are provided by the sponsor, only authorized study site personnel will record or change data on the CRFs. If data is not entered on the CRFs during the study visit, the data will be recorded on paper, and this documentation will be considered source documentation.”

Times and/or dates for the aforementioned 144 assessment values were subsequently edited months after the assessment. These values were originally entered into the (b)(4) tablets between November 12, 2019 and February 8, 2020, by blinded raters, but their times and/or dates were later edited by non-study personnel on May 14, July 23, and July 28, 2020 and on July 12, 2022 to match the hand-written assessment times without source documentation of assessment values.

During the inspection, the investigator questioned the revisions found in Audit Trail documents and you verbally stated that you did not know how or why assessment times and dates were edited.

In your Response Letter, you stated that assessment times and dates were manually entered by the eResearch Technology team at the sub investigator’s request for subjects (b)(6) due to connectivity or technical issues. We acknowledge that the Sponsor provided guidance that sites could request updates to the electronic CRF with the caveat that data was documented on paper at the time of assessment, however your site did not have source documentation of assessment scores.

We do not find your response adequate because it contradicts what you stated during the inspection and connectivity issues would not explain why dates and times were subsequently edited. Your response also fails to provide documentation of how and which site staff requested modifications.

3. Failure to retain records required to be maintained for a period of 2 years following the date a marketing application is approved. [21 CFR 312.62(c)]

As a clinical investigator, you are required to maintain records, including case histories, medical records, and doctor’s notes pertaining to the investigation for a period of 2 years following the date a marketing application is approved for the drug indication for which it is being investigated.

(b)(6) recalled having written notes at the time of the two study visits, however she admitted that they may have been discarded. Discarding records prior to the 2-year post-approval period, whether intentional or unintentional, is a failure to retain records.

In your Response Letter, you submitted a photo (allegedly taken February 13, 2020) of an INCAT scale, dated February 7, 2020. You stated that the data was entered into the tablet on March 3, 2020 and (b)(6) destroyed the hand-written page but retained it in an electronic file. This photo file was not presented to the FDA investigator during the inspection but was found on (b)(6) phone following the inspection. You acknowledged that this was improper behavior and stated that it was an isolated event. We find your response inadequate because the photo was not presented during the inspection, and we cannot validate the date the photo was taken.

We emphasize that as the clinical investigator, it is your responsibility to ensure that studies are conducted in accordance with the investigational plan and applicable regulations, to protect the rights, safety, and welfare of subjects, and to ensure the integrity of study data. Your lack of supervision and oversight, failure to maintain adequate and accurate subject case histories, and failure to conduct the clinical study in accordance with the protocol raises significant concerns about the validity and integrity of all the data collected at your site.

This letter notifies you of our observations of violations to the study protocol and provides you an opportunity to address the above deficiencies. You should investigate and determine the causes of any violations and take prompt actions to implement corrections to prevent the recurrence of similar violations in current and future studies for which are you are the study director.

Your recent written response not only conflicts with information you gave during your inspection, it fails to address the observations and to provide any corrective action plans that you have implemented or plan to implement to prevent these types of violations in the future.

If you believe that you have complied with the study protocol and applicable regulations, please include your reasoning and any supporting information for our consideration.

Please submit a written response to FDA within fifteen (15) business days of receipt of this letter. In your response, please provide written documentation of additional actions you have taken or will take to correct any violations and to prevent the recurrence of similar violations in current and future studies for which you are the study director.

Your response should be sent to me at the following address: U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Ave., WO71-G112, Silver Spring, MD 20993-0002. If you have any questions regarding this letter, please contact the Division of Inspections and Surveillance, CBER at 240-402-8979.

We also request that you send a copy of your response to the FDA Office listed below.

Sincerely,
/S/

Melissa J. Mendoza
Director, Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research

cc:

Baxalta US Inc.
300 Shire Way
Lexington, MA 02421

Barbara Wright, Supervisory Investigator
FDA ORA-OBIMO Foreign Cadre
2600 Citiplace Court, Suite 410
Baton Rouge, LA, 70808

__________________

1 Individual numeric assessment values were used to calculate the subject ability assessment scores.