United Health Products, Inc. - 697777 - 03/24/2025

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Warning Letter

March 24, 2025

Dear Mr. Thom:

This Warning Letter is to inform you of objectionable conditions observed during the Food and Drug Administration (FDA) inspection conducted at United Health Products, Inc. from September 23, 2024, to October 4, 2024, by an investigator from the FDA’s Office of Bioresearch Monitoring Inspectorate (OBMI). This inspection was conducted to determine whether activities and procedures as sponsor in the significant risk clinical study “Efficacy and Safety of HemoStyp as an Adjunct for Management of Secondary Hemostasis in the Operative Setting,” for CelluSTAT Absorbable HemoStat, Premarket Approval (PMA) Application, (b)(4), complied with applicable federal regulations. The CelluSTAT Absorbable Hemostat is a device as that term is defined in section 201(h)(1) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h)(1), 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, dated October 25, 2024, to the noted violations.

The inspection was conducted under the Bioresearch Monitoring (BIMO) Program designed to ensure that data and information contained in requests for Investigational Device Exemptions (IDEs), PMA 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 OBMI revealed serious violations of Title 21, Code of Federal Regulations (CFR) Part 812 - Investigational Device Exemptions and 21 CFR Part 50 - Protection of Human Subjects, which concern requirements prescribed under section 520(g) of the Act, 21 U.S.C. § 360j(g). 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 Form FDA-483, your written response, and our subsequent review of the inspection report are discussed below:

1. Failure to submit an IDE application to FDA and failure to obtain FDA approval prior to beginning an investigation for which FDA’s approval is required [21 CFR 812.20(a)(1) and (2).

Sponsors must submit an IDE application to the FDA if the sponsor intends to use a significant risk device in a clinical investigation. In addition, a sponsor may not begin an investigation for which FDA’s approval of an application is required until FDA has approved the application. You did not submit an IDE application to FDA or obtain FDA approval prior to beginning such an investigation.

You conducted your study, UHP001, without submission and approval of an IDE application to FDA. The Western Copernicus Group (WCG) Institutional Review Board (IRB) determined that the procedures in the research posed a potential significant risk to subjects and requested documentation of the FDA’s non-significant risk (NSR) determination in multiple communications. You provided to the IRB FDA written feedback for (b)(4) and FDA meeting minutes for (b)(4), which had been modified from the FDA official correspondence by removal of references to future IDE submission and by addition of language that purported to indicate FDA agreement that the study was non-significant risk (NSR). In particular, you provided the transmittal email from FDA along with these meeting minutes, which imply that the meeting minutes that you submitted to the IRB were those provided by FDA to you as the official record. The IRB used this documentation, which misrepresented the FDA risk determination for this study, to support their determination of the regulatory status of the study, and to review and approve this study without FDA oversight.

FDA maintains that the study UHP0001 that you have conducted to support (b)(4) as a Class III device is considered a significant risk device clinical investigation for which you should have submitted an IDE application to FDA and obtained FDA approval prior to initiation. Your device is an absorbable hemostat intended to be used as an adjunct to primary hemostasis in surgical procedures to assist in controlling capillary, venous and small arterial hemorrhage when other conventional methods are ineffective or impractical. Absorbable hemostatic agents are intended to be absorbed into the body and are Class III devices per 21 CFR 878.4490. The agency considers such devices to be significant risk devices because they are absorbed internally and present “a potential for serious risk to the health, safety, or welfare of a subject” per 21 CFR 812.3(m). 21 CFR 812.20(a) requires any sponsor who intends to use a significant risk device in an investigation to submit an application to FDA, and to wait to begin the investigation until FDA has approved the application. FDA approval of an IDE application helps to ensure subject safety and that the risks associated with the device and study procedures are minimized.

This was conveyed to you in the Form FDA-483, and your response dated October 25, 2024 is inadequate. Your written response includes a discussion of the interactions with FDA regarding this study and describes your misunderstanding of those interactions and of NSR/significant risk studies. It indicates that the meeting minutes for (b)(4) that you had provided to the IRB were your modifications to the minutes received from FDA and that you had informally emailed them to FDA. However, there is no record of your submission of these revised meeting minutes to FDA either by email or with a Meeting Minutes Disagreement amendment, the procedure outlined in FDA’s transmittal email for handling changes to meeting minutes. Importantly, there is also no agreement by FDA on these meeting minutes that you had revised. Your response also does not speak to the modifications that were made to the official FDA correspondence for (b)(4), where you inserted the word “NSR” in describing the name of the study and removed references to a (b)(4). FDA is greatly concerned about your misrepresentation of the FDA’s stance regarding the risk determination of the study to the IRB, which resulted in you inappropriately conducting this study without submitting and obtaining approval of an IDE application from FDA prior to initiation.

2. Failure to ensure proper monitoring of the investigation [21 CFR 812.40].

Sponsors are responsible for ensuring that a clinical investigation is properly monitored. However, you failed to properly monitor your clinical investigation. Examples include, but are not limited to, the following:

a. Although you had described in the study protocol, UHP001, sections 10 and 14.9, that details regarding monitoring would be provided in the study specific Monitoring Plan and clinical site monitoring would be documented in a Clinical Monitoring Plan (CMP), respectively, you did not have an effective and implemented CMP during study conduct.

b. You did not maintain adequate documentation regarding those monitoring activities that did occur:

i. You failed to maintain adequate site initiation visit (SIV) documentation for the two clinical investigation sites. There were several discrepancies in documentation of SIV Monitoring Visit Reports, investigator site’s personnel training logs (SIV Training Logs), and Site Visit Logs. For example, the SIV Monitoring Visit Report for site 01 documented the visit was held on-site on December 17, 2018, with the clinical investigator and research coordinator. However, the SIV Training Log for site 01 documented the clinical investigator received SIV training on December 10, 2018, and the research coordinator received SIV training on March 19, 2019. The Site Visit Log for site 01 documented a single SIV date as December 19, 2018.

ii. You failed to maintain adequate interim monitoring documentation for the two clinical investigation sites. For example, the Site Visit Log for site 01 documented the interim monitoring visit was held on-site on July 9, 2019, but there was no interim monitoring report for this visit. In addition, the site visit log for site 02 documented the interim monitoring visit was held on-site on September 10, 2019, but there was no interim monitoring report for this visit.

Proper monitoring helps ensure that the safety, rights, and well-being of the subjects are protected, and that the data are complete and accurate. Monitoring should be an on-going program performed with the frequency necessary to ensure that the investigation is conducted according to the investigational plan, FDA regulations, and any conditions of approval required by the FDA or the reviewing IRB. Inadequate monitoring can lead to reporting of inaccurate data, missing data, enrollment of subjects that do not meet eligibility criteria, and poor adverse event reporting, among other concerns. In addition, without adequate monitoring there is no assurance that your study conduct is compliant and that any instances of noncompliance are resolved properly.

This was conveyed to you in the Form FDA-483, and your written response dated October 25, 2024 is inadequate. Your response includes a retrospectively-created CMP, new Standard Operating Procedures (SOPs) for clinical monitoring, clinical site selection, and site initiation, and revised Site Visit Logs for both clinical investigation sites. Your response indicates that the retrospectively-created CMP reflects the monitoring practices that were followed during the study conduct and indicates that the updated Site Visit Log added visits that occurred for SIV training for both clinical investigation sites, but were not present on the initial Site Visit Log. You did not provide SIV Monitoring Visit Reports for the additional SIV training conducted for both clinical investigation sites that were added to the Site Visit Logs. You also did not provide the interim monitoring reports for both clinical investigation sites that document the activities that occurred during the interim monitoring visits, nor did you provide the follow-up communication to the investigator/study personnel that discusses visit findings, outstanding action items, and requests for additional information. These items are needed to assess the adequacy of the monitoring conducted for this study.

3. Failure to secure clinical investigator’s compliance with the signed agreement, the investigational plan, applicable FDA regulations, and any other conditions of approval imposed by the reviewing IRB or FDA, or if compliance could not be obtained, failure to discontinue shipments of the device to the investigator and terminate the investigator’s participation in the investigation [21 CFR 812.46(a)].

As part of monitoring responsibilities, a sponsor is responsible for securing the investigator’s compliance with the investigational plan to ensure adherence with the study protocol and other regulatory requirements. You failed to obtain and secure the clinical investigator’s compliance with the investigational plan and applicable FDA regulations. Examples include, but are not limited to, the following:

a. Forty (40) subjects had baseline laboratory results indicating thrombocytopenia or no baseline platelet laboratory results. As a result, these subjects met exclusion criterion # 9, which lists subjects with a coagulation disorder, thrombocytopenia, liver disease and anti-thrombin therapy as not eligible for study. You did not ensure that investigators properly enrolled subjects according to the investigational plan.

b. According to your Protocol Deviation Log, there were three (3) subjects whose informed consent forms were not signed by the subject, which violates inclusion criterion # 4, as well as 21 CFR 812.100, which requires that investigators obtain informed consent in accordance with 21 CFR Part 50. You did not ensure that investigators obtained informed consent according to the investigational plan and applicable FDA regulations.

Securing clinical investigator compliance is a critical component of monitoring and is critical for ensuring the safety and welfare of study subjects. Failure to secure compliance impacts the reliability and quality of the data resulting from the study and in turn adversely impacts FDA’s ability to assess the overall safety and effectiveness of the device. As you failed to conduct proper monitoring, you did not identify that enrollment criteria were violated or that informed consent was not properly obtained, and also did not take steps to secure compliance with these requirements. Having failed to secure the investigator’s compliance, you also did not discontinue shipments of the device to the investigator and terminate the investigator’s participation in the investigation.

This was conveyed to you in the Form FDA-483, and your written response dated October 25, 2024 is inadequate. While your response acknowledged the issue of enrolling subjects that did not meet the eligibility criteria related to thrombocytopenia and provided a comprehensive corrective action and preventative action plan, you have not addressed the issue of failing to obtain informed consent. Specifically, you did not provide any root cause analysis regarding the informed consent protocol deviations. You also did not identify any corrective or preventative actions taken to ensure that informed consent is properly obtained by investigators such that human subjects are adequately protected.

4. Failure to immediately conduct an evaluation of any unanticipated adverse device effects and failure to report results of such an evaluation to FDA and to all reviewing IRB’s and participating investigators within 10 working days [21 CFR 812.46(b)(1) and 21 CFR 812.150(b)(1)].

As a sponsor, you are responsible for conducting an evaluation of any adverse device effects that are reported as serious and unanticipated to ensure adverse events are adequately recorded and reported, and that appropriate follow-up occurs. You failed to conduct these evaluations. Examples include, but are not limited to, the following:

a. You failed to evaluate the unanticipated adverse device effect (UADE) for subject 02-0074 that occurred on April 30, 2019. Information for this UADE was recorded in an Adverse Event (AE) Form; however, there is no documentation to show that the UADE was evaluated as required by 21 CFR 812.46(b)(1) and study protocol, UHP001, section, 9.8.2.

b. You failed to evaluate the UADE for subject 02-0074 that occurred on May 12, 2019. Information for this UADE was recorded in an AE Form; however, there is no documentation to show that the UADE was evaluated as required by 21 CFR 812.46(b)(1) and study protocol, UHP001, section, 9.8.2.

Proper evaluation of UADEs, as required by 812.46(b)(1), is a critical step in ensuring the safety and welfare of study subjects. Appropriate review and evaluation of UADEs and their resolution allows for any necessary changes to be made to the investigational plan to protect study participants. Furthermore, the regulations under 812.150(b)(1) require that a sponsor who conducts an evaluation of an unanticipated adverse device effect under 812.46(b) report the results of such evaluation to FDA. Proper evaluation and timely reporting to FDA of the result of any evaluation of a UADE is important for FDA’s assessment of the overall safety profile of the device.

This was conveyed to you in the Form FDA-483, and your written response dated October 25, 2024 is inadequate. Your response includes a description that the clinical site did not report these AEs to the sponsor as UADEs, and that they therefore were not handled as UADEs. In addition, you provided an updated SOP (CLN-06 Adverse Event Monitoring) to include UADE reporting requirements. However, these documents do not describe how an AE designated as a UADE by an investigator on the AE paper form is reported to the sponsor. It appears that the designation of an AE as a UADE is not captured in the electronic case report form (eCRF) and therefore these two AEs were not reported to the sponsor as UADEs, despite being identified by the investigator as such. As a result, these two AEs were not properly evaluated to determine whether they met the definition of a UADE, as required by the study protocol, UHP001, sections 9.1 and 9.8. Neither the updated SOP nor the protocol provide adequate detail to prevent a recurrence of this scenario in future studies. In addition, you did not provide source documentation for subject 02-0074 that was obtained according to Section 9.4 of the study protocol, UHP001, to assess the causal relationship between the AE and the investigational device. This documentation is needed to ensure that you have adequately conducted an evaluation of reported AEs as expected in the UHP001 study protocol. Although in this case, these two AEs were ultimately determined not to be UADEs through your postinspection activities, timely investigation of UADEs identified by study investigators while the study is ongoing is required by 21 CFR 812.46(b)(1) and a critical element of good clinical practices and does not appear to be assured by your corrective actions.

Finally, section 7.6.1 of your updated SOP provides UADE reporting requirements and suggests that the requirement only applies to IDE studies. The evaluation requirement under 812.46 and reporting requirement under 812.150(b)(1) for UADEs also apply to non-significant risk studies subject to abbreviated requirements per 812.2(b), not just studies being conducted under an IDE. The regulatory requirements should be clarified and corrected in the SOP.

5. Failure to maintain accurate, complete, and current device shipment and disposition records [21 CFR 812.140(b)(2)].

As a sponsor, you are responsible for maintaining accurate, complete, and current records relating to an investigation. Specifically, records of shipment must include the name and address of the consignee, type and quantity of device, date of shipment, and batch number or code mark, and records of disposition must describe the batch number or code marks of any devices returned to the sponsor, repaired, or disposed of in other ways by the investigator or another person, and the reasons for and method of disposal. You failed to maintain the necessary records. Examples include, but are not limited to, the following:

a. You failed to maintain records of investigational devices received by a sponsor employee, investigational devices returned to the sponsor, or unused investigational devices disposed of for the (b)(4) investigational device units packaged.

b. You failed to maintain accurate device accountability records for both clinical investigation sites. For example, your Master Device Accountability Log documented that there were 230 subjects who received the investigational device in site # 01 and 4 subjects who received the investigational device in site # 02, with zero returned devices. However, there were only a total of 118 subjects randomized to receive the investigational device and the other subjects were assigned to the control group. In addition, the UHP001 Inventory Log for Site # 02 indicated that only 1 device was used, but the Master Device Accountability Log documented that there were 4 devices used.

Proper records of device shipment and disposition are necessary for control of devices and to confirm that the investigational device is used only by qualified investigators on subjects appropriately enrolled in the study. If the devices were used by unqualified individuals on patients not enrolled in the study, there would be an increased risk of harm to both the user and patient.

This was conveyed to you in the Form FDA-483, and your written response dated October 25, 2024 is inadequate. Your response provided a SOP for investigational device management and a corrected Master Accountability Log. However, you did not provide source documentation of study subjects’ randomization assignment to verify the changes made to the Master Accountability Log and to demonstrate that device usage was appropriate.

The violations described above are not intended to be an all-inclusive list of problems that may exist with your clinical study. It is your responsibility as a study sponsor 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 study sponsor. 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.

Your response should reference “CTS# (b)(4)” and be sent via email to: Irfan.Khan@fda.hhs.gov.

A copy of this letter has been sent to FDA’s OII BIMO Division 1 via email OIIBIMODivision1Correspondence@fda.hhs.gov. Please send a copy of your response to that office.

The Division of Clinical Policy and Quality has developed introductory training modules in FDA-regulated device clinical research practices, which are available on the FDA website. The modules are for persons involved in FDA-regulated device clinical research activities. These modules are located at the following website address: http://www.fda.gov/Training/CDRHLearn/.

If you have any questions, please contact Alejandra Cambonchi by phone at (301) 796-0552 or email at Alejandra.Cambonchi@fda.hhs.gov.

Sincerely yours,
/S/

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