University of Kentucky MARCS-CMS 600258 — March 26, 2020

WARNING LETTER

• Product: Medical Devices

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• Recipient: Joseph B. Zwischenberger, M.D.; University of Kentucky; 800 Rose Street, Room MA-1A/MN321; Lexington, KY 40536; United States

• Issuing Office: Center for Devices and Radiological Health; United States

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March 26, 2020

WARNING LETTER

Dear Dr. Zwischenberger:

This Warning Letter is to inform you of objectionable conditions observed during the Food and Drug Administration (FDA) inspection conducted at the University of Kentucky (UK) laboratory from November 4, 2019 to November 21, 2019, by an investigator from the FDA’s Office of Bioresearch Monitoring Operations (OBIMO). This inspection was conducted to determine whether activities and procedures related to your participation in nonclinical laboratory studies complied with applicable regulations. The investigator reviewed the study of the Novalung System entitled, “In vivo Evaluation of the Safety and Efficacy of Extracorporeal Circuits for Long-Term Cardiopulmonary Support.”

The Novalung System is a device as that term is defined in section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h), because it is intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or to affect the structure or function of the body. This letter also requests prompt corrective action to address the violations cited and discusses your written response received on December 13, 2019 to the Form FDA 483.

The inspection was conducted under a program designed to ensure that data and information contained in requests for Investigational Device Exemptions, Premarket Approval applications, and Premarket Notification submissions are scientifically valid and accurate. Another objective of the program is to ensure that human subjects are protected from undue hazard or risk during the course of scientific investigations.

Our review of the inspection report prepared by the OBIMO revealed serious violations of Title 21, Code of Federal Regulations (CFR) Part 58 – Good Laboratory Practice for Nonclinical Laboratory Studies, which concerns requirements prescribed under section 520(g) of the Act, 21 U.S.C. § 360j(g), among other provisions. At the close of the inspection, the FDA investigator presented an inspectional observations Form FDA 483 for your review and discussed the observations listed on the form with you. Some of the deviations noted on the Form FDA 483, your written response, and our subsequent review of the inspection report, are discussed below:

1. Failure of the Study Director to fulfill regulatory responsibilities [21 CFR 58.33(a), 58.33(b), 58.33(f), and 58.33(e)].

The study director is responsible for the technical conduct of the study, as well as for the interpretation, analysis, documentation and reporting of results, and represents the single point of study control. The study director’s responsibilities include, among other things: ensuring that the study protocol is followed; ensuring all experimental data are accurately recorded and verified; ensuring that raw data, documentation, protocols, specimens, and final reports are transferred to the archives during or at the close of the study; and ensuring that all applicable good laboratory practice (GLP) regulations are followed.

As the principal point of study control, the study director: did not ensure that all experimental data were accurately recorded and verified; did not ensure that all applicable GLP regulations were followed, e.g., the nonclinical laboratory did not retain all its raw data, documentation, and specimens generated as a result of a nonclinical laboratory study as required by 21 CFR 58.190(a) and did not establish procedures for the handling of test and control articles to ensure, among other things, that proper identification is maintained throughout the distribution process as required by 21 CFR 58.107; did not ensure that raw data, specimens, and records were transferred to the archives for the nonclinical study; and did not ensure that the protocol was adequately followed. Examples of failures include, but are not limited to the following:

a) There were Returned Goods Authorization (RGA) forms for the devices implanted that were either missing, had missing or wrong device serial numbers, or only showed the dates of the initial implant rather than the actual dates of each implant when multiple devices were used; a few examples are illustrated in the below table:

Sheep #/ID	Date of Initial (1st) Device Implant	Date on RGA Form for Initial Device Implant	Date of 2nd Device Implant	Date on RGA Form for 2nd Device Implant	Date of 3rd Device Implant	Date on RGA Form for 3rd Device Implant	Serial Number
Sheep (1) 7087	02/15/2016	Missing RGA form	02/29/2016	Missing RGA form	N/A	N/A	No discrepancy
Sheep (2) 7089	03/07/2016	03/07/2016	03/15/2016	03/07/2016 RGA lists same date as device used during 1st implant	N/A	N/A	No serial numbers recorded on RGA forms
Sheep (3) 6902	03/10/2016	03/10/2016	03/14/2016	03/10/2016 RGA lists same date as device used during 1st implant	03/27/2016	03/10/2016 RGA lists same date as device used during 1st implant	No serial numbers recorded on RGA forms
Sheep (10) 7260	06/20/2016	06/20/2016	07/04/2016	Missing RGA form	N/A	N/A	No discrepancy
Sheep (11) 7273	06/23/2016	06/23/2016	06/23/2016	Missing RGA form	07/08/2016	06/23/2016 RGA lists same date as device used during 1st implant	Wrong serial number recorded

  
b) Sheep study records and other study-related data were stored in various unsecured areas, such as unlocked drawers and unsecured shelves in the sheep lab, or were stored on the study director’s computer, and were not transferred to archives. Specimens were not returned or maintained, and therefore, were not transferred to archives.

c) The protocol schedule, Section 8.0, Table 9-1, lists Sheep 6 through 10 to receive the (b)(4) kits and Sheep 11 through 15 to receive the (b)(4) kits; however, the study data revealed that Sheep 6 through 10 received (b)(4) kits and Sheep 11 through 15 received (b)(4) kits which is contrary to the protocol schedule. This change was made without any amendment to the protocol.

Failure to follow the study protocol compromises the quality and reliability of data generated by the study. In addition, failure to retain and document raw data and specimens prevents review, analysis, and verification of study results. Complete and accurate study data are necessary to allow FDA to fully assess the overall safety and risk of the device prior to the start of clinical trials involving human subjects.

In your written response, you concurred with the observations and indicated that due to the noted observations, among other things: GLP training will be completed with all laboratory staff and periodically thereafter prior to conducting any GLP study in the laboratory; a Standard Operating Procedure (SOP) that addresses the requirements for the receipt, storage, handling, inventory, and distribution of all test and control articles will be prepared and is expected to be completed by February 28, 2020; an SOP documenting the archiving procedure will be completed by February 28, 2020; your Quality Assurance Unit (QAU) will correct errors like those noted above during the draft study report audit before it is finalized, the QAU will also ensure that any study planned changes are addressed through a protocol amendment, and that any study unplanned changes are addressed through a protocol deviation. FDA cannot determine the adequacy of your response at this time since you have not provided all supporting documentation of your corrective and preventative actions. Please provide us documentation of the corrective and preventive actions you have implemented to prevent these types of deviations from recurring in future nonclinical studies, including a copy of all new or revised SOPs documenting the archiving procedure and the requirements for all test and control articles, and documentation of staff training that you have conducted pertaining to your corrective and preventative action plan.

2. Failure of the Quality Assurance Unit (QAU) to fulfill its responsibilities [21 CFR 58.35(a), 58.35(b)(1), 58.35(b)(6), and 58.35(b)(7)]

The QAU is responsible for monitoring each study to assure management that the facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the GLP regulations. These responsibilities include, among other things: maintaining a copy of a master schedule sheet of all nonclinical laboratory studies conducted at the testing facility, reviewing the final study report to assure that the reported results accurately reflect the raw data of the nonclinical laboratory study, and preparing and signing a statement to be included with the final study report which shall specify the dates inspections were made and findings reported to management and to the study director.

Your laboratory failed to follow these regulatory requirements. Examples of these failures include, but are not limited to, the following:

a) The data submitted in table 7-1 of the final report do not accurately reflect the correct sheep from which those data were obtained. Specifically, surgical and euthanasia records show that your laboratory incorrectly reported data in the final report for sheep 8 (Animal # 7182). The reported data are attributable to sheep 8B (Animal # 7215) rather than sheep 8 as evidenced by the surgical and euthanasia dates for those sheep. Your lab only provided data for one (sheep 8B) of the two above mentioned sheep.

b) Laboratory records show that sheep number 15 had episodes of fever which were not documented in the final report.

c) The final study report did not contain a signed statement from the QAU specifying dates inspections were made and findings reported to management and to the study director as required by the GLP regulations, and in the UK’s Sheep Laboratory, Good Laboratory Practices Manual, “Y” (yes) was checked for “Prepare and sign a Quality Assurance Statement to be included in the Final Report which shall specify the dates inspection were made and findings reported to the study director and to management” indicating compliance with the regulations and the laboratory’s procedures even though there was noncompliance.

d) The QAU did not maintain a copy of a master schedule sheet of the nonclinical laboratory studies conducted at the testing facility.

The lack of proper documentation for your QAU and its inspection activities does not allow for appropriate assurance that the facilities, equipment, personnel, methods, practices, records, and controls are in accord with FDA GLP regulations. A reliable QAU is integral to the successful completion of any GLP study. Without appropriate QAU oversight, there is no assurance that what is reported in the final study report is accurate as evidenced during the inspection. Failure to properly perform QAU functions calls into question the validity of the entire study.

In your written response letter, you concurred that the QAU failed to review the final study report to assure that it was accurate and indicated that your laboratory plans to establish a formal QAU with qualified QA staff, and that going forward, the final report and data audit for all GLP studies will be completed in accordance with 21 CFR 58.35(b)(6). In addition, you indicated that UK has agreed to establish a GLP Oversight Committee no later than February 10, 2020 consisting of four members who will be responsible for advising and providing GLP assistance to any UK research laboratory intending to conduct a GLP study. You also indicated that due to the noted observations, and the possibility of other report errors, you plan to prepare and complete an amended final report by May 31, 2020, which will be fully audited by (b)(4) and will include a signed GLP quality assurance statement specifying dates of inspections and findings reported to management and to the study director. We recommend that you also conduct a systemic audit of your nonclinical lab procedures to ensure that you have adequately captured and resolved your laboratory’s deviations. FDA cannot determine the adequacy of your response at this time since you have not provided all supporting documentation of your corrective and preventative actions. Please provide us documentation of the corrective and preventive actions you have implemented to correct the deviations and to prevent these types of deviations from recurring in future nonclinical studies, including a copy of the amended final report after it has been completed that includes a signed GLP quality assurance statement specifying dates of inspections and findings reported to management and to the study director, and documentation of staff training that you have conducted pertaining to your corrective and preventative action plan.

The violations described above are not intended to be an all-inclusive list of problems that may exist with your nonclinical study. It is your responsibility as a test facility to ensure compliance with the Act and applicable regulations.

Within 15 working days of receiving this letter, please provide documentation of the additional corrective and preventative actions that you have taken or will take to correct these violations and to prevent the recurrence of similar violations in current or future studies for which you are the testing facility. Any submitted corrective action plan must include projected completion dates for each action to be accomplished as well as a plan for monitoring the effectiveness of your corrective actions. Failure to respond to this letter and take appropriate corrective action could result in the FDA taking regulatory action without further notice to you. In addition, FDA could initiate disqualification proceedings against you in accordance with 21 CFR 58.202.

Your response should reference “CTS # EC200010/E001” and be sent to:

Attention: Sheena A. Green, M.S.
Assistant Director, Clinical Evidence Quality Team 2
Food and Drug Administration
Center for Devices and Radiological Health
Office of Clinical Evidence & Analysis
DCEA1: Division of Clinical Science & Quality
10903 New Hampshire Avenue
Building 66, Room G202
Silver Spring, Maryland 20993-0002

A copy of this letter has been sent to FDA’s OBIMO – East via e-mail at ORABIMOE.Correspondence@fda.hhs.gov. Please send a copy of your response to that office.

If you have any questions about the content of this letter, please contact Martin Hamilton at 301-796-5666 or Martin. Hamilton@fda.hhs.gov.

Sincerely yours,
/S/

Soma Kalb, PhD
Director
DCEA1: Division of Clinical Science and Quality
Office of Clinical Evidence & Analysis
Office of Product Evaluation and Quality
Center for Devices and Radiological Health