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WARNING LETTER

Dear Mr. Abunadi:

This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted between June 27 and July 8, 2022. Investigator Theressa B. Smith, representing FDA, reviewed the role of Samm Solutions, Inc., d.b.a. BTS Research, as the testing facility of the following nonclinical laboratory studies:

• Protocol (b)(4): "(b)(4) of the investigational drug (b)(4), performed for (b)(4) (formerly performed for (b)(4))
• Protocol (b)(4): “(b)(4),” of investigational drug (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 the quality and integrity of study data, in accordance with Title 21 of the Code of Federal Regulations (CFR), part 58 [21 CFR 58] – Good Laboratory Practice (GLP) regulations.

At the conclusion of the inspection, Investigator Smith presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your two written responses to the Form FDA 483, dated July 29, 2022, and November 23, 2022.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written responses, 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 21 CFR 58 governing the conduct of nonclinical laboratory studies. We wish to emphasize the following:

1. The study director failed to assure that all experimental data were accurately recorded and verified, and failed to assure 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(b) and (c)].

The study director of each nonclinical laboratory study has overall responsibility 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 shall ensure that all experimental data, including observations of unanticipated responses of the test system, are accurately recorded and verified; and shall ensure that unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study are noted when they occur, and that corrective action is taken and documented. The study directors at your testing facility for Protocols (b)(4) and (b)(4) failed to adhere to these requirements.

Specifically, the study directors for both nonclinical laboratory studies failed to accurately record and verify analytical results for clinical pathology. They also failed to note unforeseen circumstances that may have affected the quality and integrity of the study. Examples include but are not limited to the following:

a. Protocol (b)(4) required clinical pathology investigations on the day of necropsy (Day 28 of the study) for animals designated as Main, including evaluation of clinical chemistry parameters (for example, serum phosphorus and alkaline phosphatase) and coagulation parameters (activated partial thromboplastin time (PTT), prothrombin time (PT), and fibrinogen). However, the following clinical pathology investigations were not evaluated on the day of necropsy for the following Main animals:

i. Serum phosphorus was not evaluated for Group 1 (Animals 1001 through 1010 and Animals 1501 through 1510) on Day 28, April 12, 2021.

ii. Serum phosphorus and alkaline phosphatase were not evaluated for Group 2 (Animals 2001 through 2010 and Animals 2501 through 2510) on Day 28, April 13, 2021.

In your written responses to the Form FDA 483, you stated that phosphorous and alkaline phosphatase were not evaluated because of the unavailability of the reagents needed and your having only expired reagents on hand. However, there is no documentation that the study director noted these unforeseen circumstances when they occurred. Subsequently, on June 15 and 16, 2021, serum phosphorus and alkaline phosphatase for the animals in Groups 1 and 2 were analyzed.

However, although these animals were subsequently analyzed, the serum phosphorus analysis results of the samples in the final report for most Group 1 animals do not match the analysis results listed on the laboratory worksheet. In your written responses, you state that it was not possible to obtain phosphorus data for these animals. Additionally, in your written responses, you state that alkaline phosphatase results were not available for Animals 1003 and 1505; however, the June 15, 2021, laboratory results report alkaline phosphatase results for these animals.

iii. Activated partial thromboplastin time (PTT), prothrombin time (PT), and fibrinogen for Group 3 (Animals 3504 through 3510) were not evaluated on Day 28, April 20, 2021. These coagulation parameters were flagged with error codes (Early Reaction Error, Measurement Error), and no results were reported in the final report.

In your written responses, you stated that the coagulation analyzer was not functioning properly and was not providing results. You further stated that the technician did not report the lack of results to the study director because he planned to rerun the samples. You also stated that, on June 21 and June 23, 2021, repeat testing occurred for Animals 3504 through 3510, but results were not available because the operator did not have enough sample to test. Additionally, some samples from Group 1 (Animals 1001 through 1015 and Animals 1501 through 1515) and Group 4 (Animals 4011 through 4015 and Animals 4511 through 4515) were reanalyzed on June 21 and June 23, 2021. There is no documentation that the study director noted the unforeseen circumstances (that is, the problems with the coagulation analyzer, the insufficient quantity of samples for analysis, and the repeat analysis of samples) when they occurred.

b. Protocol (b)(4) required clinical pathology investigations on the day of necropsy (Day 183 of the study), including clinical chemistry parameters (for example, gamma glutamyl transferase (GGT)). However, GGT was not evaluated for study animals on Day 183, March 14, 2021. GGT parameters were out of range, and all animals were attributed with a minimal GGT value of <4.0 U/L, without being retested.

In your written responses, you explained that the technician documented in the raw data that GGT control was ignored due to abundant past evidence of very minimal (practically undetectable) amounts of GGT in Sprague Dawley rats; and that, for this reason, he proceeded with the rest of the measurements, disregarding the GGT. You also noted that at the time the study was conducted, the study director was not required to document the review date of study data.

In your written responses to the Form FDA 483, you stated that report amendments have been or will be issued for Protocols (b)(4) and (b)(4), and that these amendments will include a revised review and protocol deviations. You also stated that the following SOPs have been revised: (1) SOP A12.04, “Review and Verification of Data,” and (2) SOP G45.04, “Calibration, Use, and Maintenance of the RX Imola Clinical Chemistry Analyzer,” to detail any special circumstances related to the exclusion of any parameter.

We acknowledge the corrective and preventive actions that your testing facility has taken and plans to take; however, your response is inadequate because you did not provide complete raw data that support reanalysis of clinical pathology investigations and the results included in the amended reports. We cannot undertake an informed evaluation of your written response because you did not provide complete raw data.

The study director of each nonclinical laboratory study has overall responsibility for the technical conduct of the study, as well as the interpretation, analysis, documentation, and reporting of results, and represents the single point of study control. Because the study directors at your testing facility failed to ensure that experimental data were accurately recorded and verified; that unforeseen circumstances were documented when they occurred; and that corrective action was taken and documented, FDA has concerns about the quality and integrity of the data generated from the nonclinical laboratory studies conducted at your testing facility.

2. The study director failed to authorize all deviations in the study from standard operating procedures and ensure the deviations were documented in the raw data [21 CFR 58.81 (a)]; The final study report did not include a description of all circumstances that may have affected the quality and integrity of the data [21 CFR 58.185 (a)(9)].

The study director must authorize all deviations from standard operating procedures in a study and document all study deviations in the raw data. Additionally, the study director must include in the final study report a description of all circumstances that may have affected the quality and integrity of the data. Similarly, as required by SOP A14.0, “Nonclinical Study Report Generation and Approval,” final study reports shall also include amendments and deviations forms issued during the study that include a description of all circumstances that may have affected the quality or integrity of the data. The study directors at your testing facility did not adhere to these requirements. Specifically:

a. As required by SOP A14.0 the following deviation forms were required to be included in the final study report for Protocol (b)(4); however, these were not included in the final study report:

1. Deviation form, “SOP Deviation 1,” describing the following deviations from SOP B01.03 (Defining, Manually Reporting, and Correcting Raw Data) and SOP F07.01 (Dose Formation Analysis Range):

(a) Eye examination for Animal 3502 was not documented at the time of the actual eye examination.

(b) The batch number of the vehicle was incorrectly documented as the lot number on formulation sheets.

(c) Mean concentration for the formulation analysis samples for Groups 2, 3, and 4 were all outside of the acceptable theoretical difference range.

2. Deviation form, “SOP Deviation 2,” describing a deviation from SOP B01.03: Temperatures were not recorded for the refrigerator used to store test article in December 2018.

b. Deviation from SOP A03 (“Archival Procedures”), which requires submission of the Archive Submission Form (submission worksheet) to record physical data and documentation pertaining to the assigned GLP study submitted to the archive, was not authorized by the study director and was not documented in the raw data. The study was also not recorded on the electronic archive log. These deviations were not included in the final study report.

c. Deviation of the protocol requirement to retain target tissues at necropsy on Day 183, for histology processing and histopathological evaluation of tissues from certain Main animals. For example, histology worksheets and individual gross and microscopic reports document repeated findings in which tissues were missing upon processing for Main animals, including Animals 4008, 4014, and 4501. These deviations were not included in the final study report.

In your written responses, you acknowledge that the SOP deviations and the missing tissues deviation should have been included in the final study report. You stated that SOP A14.04 was revised to reflect the requirement to file all deviations in the final study report; that training on SOP revisions was conducted; and that the SOP and missing tissue deviations have been or will be included in an amended final report.

You also stated in your written responses that during the time when the archival storage was being relocated, the form (submission worksheet) was not used to log the archiving, but the archiving process was followed. You included an e-mail from the study coordinator to the QAU to note the submission of the final report and raw data for archiving.

While we acknowledge your corrective and preventive actions that your testing facility has taken and 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 a list documenting which raw data or documents were submitted to the archive for Protocol (b)(4). In addition, you did not provide the signed amended final study report for Protocol (b)(4) referenced in your November 23, 2022, response. Without these details, we are unable to determine whether your corrective actions appear adequate to help prevent similar violations in the future. Without this information, we cannot undertake an informed evaluation of your written response, and it is not clear whether your corrective and preventive actions will adequately ensure that ongoing and future studies will be conducted in compliance with applicable FDA regulations.

Failure to include a description of all circumstances that may affect the quality and integrity of the data in the final study report, including SOP and protocol deviations, raises concerns about the quality and integrity of the study records and data generated from the nonclinical laboratory studies conducted at your testing facility. The records and final study report of an investigation are crucial to the reconstruction of events leading to the collection and reporting of the data and must reflect the procedure and condition of the study. The information in these essential documents forms the basis for establishing scientific interpretations and conclusions and must therefore reflect all circumstances affecting the quality and integrity of the data.

3. The quality assurance unit (QAU) failed to assure that the reported results in the final study report accurately reflect the raw data of the nonclinical laboratory study [21 CFR 58.35 (b)(6)].

The QAU must review the final study report to ensure that the reported results accurately reflect the raw data of the nonclinical laboratory study. The QAU at your testing facility did not adhere to these requirements.

Specifically, the following observations/data were not accurately documented in the final study reports for Protocols (b)(4) and (b)(4):

a. Protocol (b)(4) (Final Report: (b)(4)):

i. Clinical observations of increased activity on Day 42 (April 30, 2021) for Animal 4515 was not reflected in the final study report. We note that the Form FDA 483 inaccurately identified this animal as Animal 4514.

ii. Additional dosing of Group 2 animals (Animals 2001 through 2010 and Animals 2501 through 2510) on Day 1 (March 17, 2021) was not reflected appropriately in Appendix 1 (Individual Animal Estimated Dose Levels) of the final study report.

b. Protocol (b)(4) (Final Report: (b)(4)):

i. The date of study director reassignment, July 8, 2020, was inaccurately recorded in the final study report as July 8, 2018.

ii. Dates for the administration of the test article and vehicle for the animals in this study are inaccurate in several sections of the final report. For example:

  (1) Group 1 animals were dosed on June 12, 2018; however, the date recorded for this respective time point in the final report was June 11, 2018.
  (2) Group 4 animals were dosed on June 15, 2018; however, the date recorded for this respective time point in the final report was June 14, 2018.

iii. Unscheduled clinical observations that occurred between October 9 and 10, 2018, regarding masses/lumps/bumps found in animals, including Animals 4018, 4020, 4021, 4024, and 4027, were not reported in the final study report.

iv. There are discrepancies in the record for the dates and circumstances of the deaths of Animal 1006 (sacrificed date: June 20, 2018; actually found dead on June 25, 2018), Animal 3009 (sacrificed date: June 25, 2018; actually found dead on June 23, 2018), and Animal 1511 (sacrificed date: July 7, 2018; actually found dead on July 26, 2018), as recorded in the final report in Text Table 9: Found Dead and Early Sacrifice Animals, and as recorded on the Necropsy Tissue Collection Form and in the Pristima data (Date of Death).

v. The Death Status Report maintained in the Pristima software for Animal 4529 reflects an unscheduled death on December 17, 2018; however, the death of this animal is not reported in the final study report.

In your written responses to the Form FDA 483, regarding the observations related to Protocol (b)(4) (Final Report: (b)(4)), you acknowledged that the QA auditor failed to ensure that certain raw data were accurately reflected in the final study report. You stated that the QA auditor inadvertently missed the inclusion of certain raw data and is no longer working for the company. You stated that the final report has been or will be amended to include the raw data.

With respect to observations regarding Protocol (b)(4) (Final Report: (b)(4)), you acknowledged the observations and stated that as a corrective action, the report has been or will be amended to include accurate or missing data. You also stated that the method for reviewing data will be changed to a more comprehensive review that includes a sampling technique for a number of animals and their end points from start to finish of the study, rather than modulated review of forms. Last, you indicated that the QAU inspection SOP C06 will be revised to include guidance on the sampling inspection for raw data by following selected animals from start to end of study, including all end points. While we acknowledge the actions your site plans to take, your response is inadequate because you did not include sufficient details about your corrective action plan, including the procedures being instituted at your site to ensure compliance, such as the revised SOP C06.

Because the QAU of your testing facility failed to ensure that the reported results in the final study report accurately reflect the raw data of the nonclinical laboratory studies, FDA has concerns about the integrity of the data generated and reported from the nonclinical studies conducted at your testing facility.

4. The study director failed to assure that all raw data, documentation, protocols, specimens, and final reports are transferred to the archives during or at the close of the study [21 CFR 58.33(f)].

The study director must ensure that all raw data, documentation, protocols, specimens, and final reports are transferred to the archives during or at the close of the study.

The study directors at your testing facility for both Protocols (b)(4) and (b)(4) failed to adhere to this requirement. Specifically:

a. For Protocol (b)(4), the study director failed to ensure that all study records were transferred to the archives at the close of the study. For example, the following documents were reported as having been submitted to the archive on September 10, 2021, but were not maintained in the testing facility’s archives at the close of the study:

(1) Signed protocol amendments
(2) Signed protocol deviations
(3) Final report
(4) Animal Care and Use Protocol
(5) Freezer logs for the equipment used to store the test article

b. For Protocol (b)(4), the study director failed to ensure that all study records were transferred to the archives at the close of the study. For example, the following three study memos were not submitted to the archives:

(1) A June 6, 2018, memo regarding deviations related to randomization and replacement of animals due to corneal dystrophy
(2) A June 12, 2018, memo regarding renumbering of animals in Groups 2 and 3 and replacement of animals
(3) An undated memo regarding inconsistencies in the measurements of tumor masses in clinical observations

We acknowledge that the finding discussed above regarding the June 12, 2018, and undated memos were not included on the Form FDA 483 you received, and that your written responses therefore do not address these specific issues.

In your written responses to the Form FDA 483, you acknowledged that the study directors for Protocol (b)(4) and Protocol (b)(4) failed to ensure that all data were forwarded to the archives. We note that the failure to archive data is a repeat finding from FDA’s June 2019 inspection of your testing facility. With respect to Protocol (b)(4), you stated that the study director functioned remotely for most of his role and relied on a study coordinator, who is no longer with the firm. With respect to Protocol (b)(4), you stated that because the archival storage was being relocated, the appropriate forms were not used to log for archiving.

As a corrective action, you stated that the study director has been retrained on procedures to ensure the proper archiving of study records. You also stated in your written response that a planned corrective action is to have the QAU monitor the archiving process for all future studies. While we acknowledge the actions your site has taken and 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 how the study director will comply with archiving requirements to prevent the recurrence of such findings in future studies. Also, you did not provide the training record on proper archiving for the study director. Without this information, we cannot undertake an informed evaluation of your written response, and it is not clear whether your corrective and preventive actions will adequately ensure that ongoing and future studies will be conducted in compliance with applicable FDA regulations.

Failure to ensure that all raw data, documentation, protocols, specimens, and final reports are transferred to the archives during or at the close of the study raises concerns about the integrity of study records and data.

As evidenced by FDA’s inspection findings, the deficiencies found in the oversight and conduct of the study directors and the QAU at your testing facility demonstrate a failure to comply with FDA’s GLP regulations governing the conduct of nonclinical studies. As a result, FDA is concerned about the validity of the nonclinical data generated by your testing facility.

We emphasize that as a testing facility conducting nonclinical laboratory studies under part 58, you are responsible for ensuring that those nonclinical laboratory studies are conducted in accordance with FDA regulations to ensure the quality and integrity of the study data. Your failure to conduct the nonclinical studies in accordance with the study protocol, SOPs, and FDA regulations raises 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 the nonclinical laboratory studies of investigational drugs conducted at your testing facility. 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 that you have complied with the FD&C Act and relevant FDA 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
10/20/2023 10:52:35 AM