- Delivery Method:
- VIA UNITED PARCEL SERVICE
- Medical Devices
Recipient NameDensen B. Cao, Ph.D.
- CAO Group, Inc.
4628 W. Skyhawk Drive
West Jordan, UT 84084
- Issuing Office:
- Center for Devices and Radiological Health
10903 New Hampshire Avenue
Silver Spring, MD 20993
October 15, 2018
Dear Dr. Cao:
This Warning Letter is to inform you of objectionable conditions observed during the Food and Drug Administration (FDA) inspection conducted at CAO Group, Inc., from May 1, 2018, to May 7, 2018, by investigators from the FDA’s Office of Bioresearch Monitoring Operations (OBIMO). This inspection was conducted to determine whether activities and procedures as sponsor in the clinical investigation (b)(4), complied with applicable federal regulations. (b)(4) device 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.
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 510(k) 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 812 - Investigational Device Exemptions (IDE) and Part 50 - Protection of Human Subjects, which concerns requirements prescribed under section 520(g) of the Act, 21 U.S.C. § 360j(g). At the close of the inspection, the FDA investigators 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 and our subsequent review of the inspection report are discussed below.
As sponsor, it is your ultimate responsibility to ensure that the clinical investigation was conducted properly and in compliance with FDA regulations, both to protect the rights, safety, and welfare of subjects and to ensure the validity and integrity of the clinical data. However, we have serious concerns with the conduct of your investigation under (b)(4), including, but not limited to, not having Institutional Review Board (IRB) approval, lack of documented informed consent obtained from each subject, and failure to maintain adequate records of each subject’s exposure to the investigational device and outcomes in accordance with the investigational plan. Additionally, given the limited source documents available at your site ((b)(4)), the data provided in the (b)(4) are unverified. Therefore, the validity and reliability of the clinical data submitted to FDA and subject safety and welfare cannot be assured.
We acknowledge that the documented history at FDA for the (b)(4) investigation under Protocol (b)(4) included a communication to you (b)(4), that the proposed study would be considered a non-significant risk investigation. However, the inspectional findings and information submitted as part of the (b)(4) submission indicate that the clinical investigation was initiated prior to this feedback and without IRB approval on November 3, 2017, with last (b)(4) on February 5, 2018. Your failure to obtain IRB approval for this investigation as a nonsignificant risk investigation constitutes conducting an investigation subject to the IDE requirements without an approved IDE and negates applicability of abbreviated requirements under 21 CFR 812.2(b), which allows certain investigations to proceed without prior FDA approval. Thus, this investigation is subject to the full requirements at 21 CFR Part 812.
However, whether a clinical investigation is conducted under the abbreviated requirements at 21 CFR 812.2(b) or is subject to prior FDA approval, compliance with FDA regulations relating to informed consent, IRB oversight, proper monitoring, and pertinent reports and recordkeeping is required, and you failed to adhere to applicable requirements governing the conduct of clinical investigations.
1. Failure to obtain IRB review and approval of the investigation [21 CFR 812.42 and 812.2(b)(1)(ii)]
Before beginning any investigation of a device, the sponsor must present a brief explanation of why the device is not a significant risk device to the reviewing IRB and obtain IRB and FDA approval for the investigation. Your firm failed to adhere to these regulations because it did not obtain IRB and FDA approval before beginning the investigation. Without IRB approval, there is no assurance that subject risks are minimized and reasonable in relation to anticipated benefits, adequate provision for data monitoring is in place, and additional safeguards for subjects are addressed.
The following are examples of this failure found during FDA’s inspection. In the signed affidavit by Robert Larsen, Vice President of Technology & Quality at CAO Group, dated May 7, 2018, Mr. Larsen (b)(4). Further, records obtained during FDA’s inspection note that Mr. Larsen informed John Meadors, D.C., a clinical investigator in the study, on November 1, 2017, that a third-party FDA consultant (b)(4) advised that in order to proceed with the study, CAO Group should confirm with FDA that the study is not a significant risk and obtain IRB approval before conducting any testing. Records also show communications between Mr. Larsen, Dr. Meadors, and Dr. Cao on November 1, 2017, where Mr. Larsen summarized FDA regulations at 21 CFR 812.2(b) and 21 CFR 56.103(a) regarding the requirement for IRB review and approval of the study. However, on November 1, 2017, clinical investigator Dr. Meadors informed Mr. Larsen that (b)(4), (b)(4) subjects were treated. As sponsor, you proceeded to work with the clinical investigator to collect clinical data for the study without addressing this serious noncompliance issue.
2. Failure to ensure that each investigator participating in an investigation of the device obtains and documents informed consent from each subject under the investigator’s care as required by 21 CFR Part 50 (21 CFR 812.43(c)(4) and 812.2(b)(1)(iii))
A sponsor is responsible for ensuring that the participating investigator properly documents and obtains informed consent from each subject. You failed to adhere to this regulation when you failed to provide study records during the inspection to confirm that informed consent was obtained for any of the subjects participating in the study (as shown in the (b)(4) data which includes (b)(4) subjects). As sponsor, you are also required to obtain an agreement from each investigator that they will conduct the investigation according to the investigational plan, FDA regulations, and conditions of approval as required by the reviewing IRB or FDA. The reported use of an inadequate informed consent document that was not specific to the study or approved by an IRB is an example of your firm’s failure to satisfy this regulation.
This failure brings into question whether these subjects were afforded the opportunity to provide adequate, knowledgeable, informed consent. A valid informed consent process ensures that research subjects have a clear understanding of risks of participation in a research protocol, have sufficient opportunity to consider whether to participate in the study, and make an informed decision if they decide to participate.
3. Failure to monitor an investigation (21 CFR 812.46 and 21 CFR 812.2(b)(1)(iv)).
A sponsor is responsible for monitoring their investigations, which includes securing compliance to the investigational plan and applicable regulations by all participating investigators. A sponsor who discovers that an investigator is not complying with either the signed agreement, investigational plan, or other regulations set out by FDA or the reviewing IRB, shall promptly secure compliance or terminate the investigator’s participation in the investigation. Your firm failed to adhere to these regulations when it did not monitor the study.
Specifically, Mr. Larsen stated in his signed affidavit that CAO Group (b)(4). 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 condition of approval required by FDA or the reviewing IRB. Monitoring is needed to review records, source documents and study procedures for the presence and appropriate documentation of adverse events and protocol deviations for effective management of important risks to subjects and data quality. Consequently, your failure to monitor the study compromises the quality and reliability of the data submitted to support (b)(4). We note that there were several protocol violations during the study that undermine the quality and scientific integrity of the study. For example, per Protocol (b)(4), the investigation was a randomized, blinded comparison of an active and control group. However, the inspectional records indicate that the clinical investigator Dr. Meadors informed you on February 2, 2018, (b)(4).
4. Failure to maintain accurate, complete, and current records regarding the investigation (21 CFR 812.140(b) and 21 CFR 812.2(b)(1)(v) and (vi)).
A sponsor is responsible for maintaining complete, accurate, and current records. These records include records concerning the device(s) and records of correspondence between other sponsors, monitors, investigators, IRBs, or FDA. Sponsors are further required to maintain the signed investigator agreements, and records of adverse events, in addition to any other records required by FDA. These records shall be maintained in one location and available for FDA inspection for a period of 2 years. The two-year period begins on the latter date of either the date on which the investigation is terminated or completed, or the date that the records are no longer required for purposes of supporting the application. Your firm failed to adhere to these regulations when it could not produce any records except for the (b)(4) records. Further, Mr. Larsen (b)(4).
Complete and accurate records allow FDA to verify certain data or validate the clinical investigation through onsite inspections. As such, adequate maintenance of study records is essential to ensuring that the clinical investigation was conducted in accordance with the signed agreement, investigational plan, and applicable FDA regulations. This includes records confirming that the informed consent process was done appropriately; that any adverse events and safety concerns have been accurately recorded and evaluated; and records of all observations and data pertinent to the investigation such as device accountability.
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 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 “(b)(4)” and be sent to:
Attention: Veronica J. Calvin
Branch Chief, BCB I
Food and Drug Administration
Center for Devices and Radiological Health
Office of Compliance
Division of Bioresearch Monitoring
10903 New Hampshire Avenue
Building 66, Room 3508
Silver Spring, Maryland 20993-0002
A copy of this letter has been sent to FDA’s OBIMO – West email at ORABIMOW.Correspondence@fda.hhs.gov. Please send a copy of your response to that office.
The Division of Bioresearch Monitoring 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 Janette.Collins-Mitchell@fda.hhs.gov.
Owen Faris, Ph.D.
Division of Bioresearch Monitoring
Office of Compliance
Center for Devices and Radiological Health