Inspections, Compliance, Enforcement, and Criminal Investigations

Namsa 3/23/18

 

  

Black HHS-Blue FDA Logo

 

 

 
10903 New Hampshire Avenue
Silver Spring, MD 20993 

 

March 23, 2018
 
VIA UNITED PARCEL SERVICE
 
Jack M. Risdahl, D.V.M., Ph.D.
Director of Preclinical Functional Studies
North American Science Associates
4129 85th Ave N
Minneapolis, MN 55443-1911
 
Dear Dr. Risdahl:
 
This Warning Letter is to inform you of objectionable conditions observed during the Food and Drug Administration (FDA) inspection conducted at North American Science Associates (NAMSA), Inc. from November 1, 2017, to November 17, 2017, by an investigator from the FDA’s Office of Bioresearch Monitoring Operations (OBIMO). The purpose of this inspection was to determine whether your laboratory’s activities and procedures for the (b)(4), Premarket Approval (PMA) Applications (b)(4) and (b)(4), complied with Title 21, Code of Federal Regulations (CFR) Part 58 - Good Laboratory Practice (GLP) for Nonclinical Laboratory Studies, which are requirements prescribed under section 520(g) of the Act, 21 USC 360j(g). The regulation at 21 CFR Part 58 prescribe good laboratory practices for conducting nonclinical laboratory studies that support or are intended to support applications for research or marketing permits for products regulated by FDA [21 CFR 58.1(a)]. 
 
The FDA investigator reviewed the studies entitled:
 
(b)(4)
 
(b)(4) are devices 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 they are 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, dated December 11, 2017 to the noted violations.
 
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. 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. 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 his or her responsibilities [21 CFR 58.33(a), 58.33(b) and 58.33(c)]
 
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 ensuring that the study protocol is followed (21 CFR 58.33(a)) and ensuring all experimental data, which includes observations of unanticipated responses, are accurately recorded and verified (21 CFR 58.33(b)). Additionally, the study director is responsible for assuring unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study are noted when they occur, and corrective action is taken and documented (21 CFR 58.33(c)). 
 
Your study director failed to assure that all experimental data, including observations of unanticipated responses of the test system were accurately recorded and verified, and that unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study were noted when they occurred and corrective action was taken and documented. Your study director also failed to follow the protocol. Examples of failures include, but are not limited to, the following:
 
a.  The study director did not ensure that review and evaluation of clinical pathology data by the attending veterinarian was performed contemporaneous with data collection.
 
I.  For study (b)(4), clinical pathology for thirteen animals was collected and received by the clinical pathology lab between (b)(4) and (b)(4) but was not reviewed by the veterinarian until (b)(4) (60-244 days later). Section 9.4 of the amended final report states that clinical pathology values were used to assess the general health of each animal, but these results were not reviewed during the in-life phase of the study.
 
II.  For study (b)(4) baseline and terminal clinical pathology tests were collected between (b)(4) but were not reviewed and evaluated until the preparation of the final report signed by the attending veterinarian on (b)(4) (55-84 days later).
 
III.  For study (b)(4), baseline and terminal clinical pathology tests were collected between (b)(4) but were not reviewed and evaluated until the preparation of the final report signed by the attending veterinarian on (b)(4) (56-70 days later).
 
Concurrent review of clinical pathology data, while conducting the animal study, is essential to identifying potential health issues and the ability to correlate these findings to the test article. Your firm’s written response states that if a potential health issue had been discovered, that was found to impact the quality and integrity of the study during review of the clinical pathology data, the animal’s data would have been excluded from evaluation or the animal would have been replaced as needed. It also states that this finding has no impact on the results and outcomes of the affected studies. Your firm’s response fails to describe how retrospective review of the data can effectively assess and correlate findings with the animal’s health and the test article after the study has been closed. Your firm’s response also fails to identify any training requirements or documentation, and fails to explain how to prevent this issue from recurring.  
 
b.  The study director failed to ensure that the protocol was followed in regards to kidney sectioning, and blood and urine collection.
 
I.  For study (b)(4), kidneys from five animals were not sectioned per the protocol. The protocol prescribed that (b)(4). Even though a deviation was created, it failed to include two of the five animals, (b)(4).
 
II.  For study (b)(4). However, raw data shows that all terminal blood samples were collected (b)(4).
 
III.  For study (b)(4), the protocol states that (b)(4). However, raw data shows that (b)(4).
 
Failure to follow the protocol impacts the quality and reliability of data contained within the final study report, as well as the overall safety and risk of the device prior to beginning clinical trials involving human subjects. Your firm’s written response states that the final report amendment will include these deviations along with any additional identified nonconformances, the sponsor will be notified, and your firm’s “Laboratory Tests” will be updated. Your firm’s response fails to identify any training requirements or documentation, and fails to explain how to prevent this issue from recurring. 
 
2.    Failure to adequately identify study specimens [21 CFR 58.130(c)]
 
Specimens shall be identified by test system, study, nature, and date of collection. This information shall be located on the specimen container or shall accompany the specimen in a manner that precludes error in the recording and storage of data. Your firm failed to adhere to these regulations by not identifying study samples. Examples of your failure include, but are not limited to, the following:
 
a.  Numerous specimen containers had handwritten notes adhered to their exterior identifying that samples were unaccounted for or missing.
 
b.  Specimens were not identified by study, type, or date of collection for the following studies:
 

NAMSA’s study number
Study closure date
FDA application; Approval
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)

 
Lack of adequate identification of study samples may contribute to errors related to mix-up or mislabeling and may limit the ability to trace specimens back to the study animals. This issue raises questions regarding your firm’s ability to maintain the integrity and reliability of study data.
 
Your firm’s written response states that the Standard Operating Procedure (SOP) entitled Collecting Specimens for Histopathology was updated to require additional labeling information, training was conducted, and that specimens were relabeled in accordance with the revised SOP. However, your firm’s response fails to describe how the specimens were traceable and identifiable by type and date of collection, and thus relabeled.
 
3.    Failure to provide for orderly storage and expedient retrieval of all raw data, documentation, protocols, specimens, and interim and final reports, and to have an archive index [21 CFR 58.190(b) and 58.190(e)]
 
There shall be archives for orderly storage and expedient retrieval of all raw data, documentation, protocols, specimens, and interim and final reports. Conditions of storage shall minimize deterioration of the documents or specimens in accordance with the requirements for the time period of their retention and the nature of the documents or specimens. Also, material retained or referred to in the archives shall be indexed to permit expedient retrieval.
 
Your firm failed to properly archive specimens generated in the following studies: 

NAMSA’s study number
Study closure date
FDA application; Approval
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)

 
During the inspection, FDA’s investigator observed that specimens were stored outside of your firm’s archives, in a tissue and supply closet. In addition, digital media consisting of 18 images of test and control articles from study (b)(4) were archived in the study file for study (b)(4). Studies (b)(4) and (b)(4) have different corporate sponsors. Also, your firm does not have an index of materials retained in the on-site archives, thus preventing expedient retrieval of such materials.  
 
Incorrect archiving of study materials affects the integrity and reliability of study data as it prevents accurate retrieval of such data for review, analysis, and verification. Also, failure to have an index prevents data from being readily available, located expeditiously, analyzed, and reconciled when necessary. 
 
Your firm’s written response states that updates to the Data Handling, Storage, and Retrieval SOP clarify the archival process and requirements, and include a description of appropriate storage locations. Your response also states that an inventory of the archives was created, the SOP was updated to include the requirement for maintaining an archive inventory, and that all archive records were indexed. However, your firm’s response fails to identify training requirements that would assist in preventing this issue from recurring.
 
4.    Failure to adequately identify reagents and solutions used in the laboratory areas [21 CFR 58.83]
 
All reagents and solutions in the laboratory areas shall be labeled to indicate identity, titer or concentration, storage requirements, and expiration date. Deteriorated or outdated reagents and solutions shall not be used. Your firm failed to adhere to these regulations by having reagents and solutions in the laboratory area which lacked concentration, storage requirements, and expiration date. Additionally, this is also a requirement found in your firm’s SOP, Labeling and Storage of Reagents and Solutions.
 
Lack of adequate labeling poses a risk of using the wrong reagent or solution. This raises concerns regarding the reliability and accuracy of the test results. Your firm’s written response states that your firm’s assessment concluded that no reagents or solutions were used past the expiration date, and that there was no impact to the study testing. However, your firm’s response fails to explain how an adequate assessment was conducted to determine the impact on study data, when there were multiple reagents and solutions with no expiration date.
 
The violations described above are not intended to be an all-inclusive list of problems that may exist with your GLP studies. It is your responsibility as a nonclinical laboratory to ensure compliance with the Act and applicable regulations.  
 
We have received and reviewed your response dated December 11, 2017. We have noted your Corrective and Preventive Action (CAPA) plan has been initiated. However, your response appears incomplete. Please provide copies of new and updated SOPs, worksheets, and checklists. New training and refresher training plans with corresponding training verification or timeline for completion, monitoring plan for study directors, and notifications submitted to the sponsors should be provided, along with plan to address labeling of reagents and solutions.
 
Within 15 working days of receiving this letter, you must provide written documentation of the specific corrective actions that you have taken or will take to address all of the violations noted above and to prevent recurrence of similar violations in current or future nonclinical laboratory studies conducted by your facility. Any submitted corrective action plan must include projected completion dates for each action to be accomplished.     Failure to respond to this letter and take appropriate corrective action could result in FDA taking regulatory action without further notice to you, including disqualification proceedings in accordance with 21 CFR 58.202.
 
Your response should reference “CTS # EC170689/E001” and be sent to: 
 
Attention: Sheena Green, MS
Branch Chief, BCB II
Food and Drug Administration
Center for Devices and Radiological Health
Office of Compliance
Division of Bioresearch Monitoring
10903 New Hampshire Avenue
Building 66, Room 3520
Silver Spring, Maryland 20993-0002.
                       
A copy of this letter has been sent to FDA’s OBIMO – West via email at ORABIMOW.Correspondence@fda.hhs.gov. Please send a copy of your response to OBIMO-West at the same email above.
 
We are also interested in having a conference call with you to further discuss the concerns and provide guidance for future non-clinical studies involving FDA regulated devices that you will conduct. Please contact Krista Flores by phone at (301)796-5484 or by email at Krista.Flores@fda.hhs.gov with possible dates and times or with questions regarding the content of this letter.
 
 
Sincerely yours,
/S/ 
William H. Maisel, M.D., MPH
Acting Director
Office of Compliance
Center for Devices and Radiological Health
 

 

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