- Rodo Medical, Inc.
- Issuing Office:
- Center for Devices and Radiological Health
| || |
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
| ||10903 New Hampshire Ave.|
Silver Spring, MD 20993-0002
FEB 20, 2015
VIA UNITED PARCEL SERVICE
Young R. Seo, PhD
Chief Executive Officer
Rodo Medical, Inc.
725 San Aleso Ave., Suite #1
Sunnyvale, CA 94085-1400
Dear Dr. Seo:
This Warning Letter is to inform you of objectionable conditions observed during the Food and Drug Administration (FDA) inspection conducted at Rodo Medical, Inc. from July 29, 2014, to August 1, 2014 by an investigator from the FDA San Francisco District Office. This inspection was conducted to determine whether activities as sponsor of the clinical feasibility study entitled, “(b)(4),” conducted prior to an Investigational Device Exemption (IDE) submission, complied with applicable federal regulations. The Rodo Dental Abutment 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 dated August 21, 2014 to the noted violations.
The inspection was conducted under a program designed to ensure that data and information contained in requests for Investigational Device Exemptions (IDE), Premarket Approval applications, and Premarket Notification submissions (510(k)) 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 district office revealed several violations of Title 21, Code of Federal Regulations (CFR) Part 812 - Investigational Device Exemptions, 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 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 establishment inspection report, are discussed below:
1. Failure to submit an application to the FDA and obtain FDA approval prior to allowing subjects to participate in an investigation. [21 CFR 812.40, 21 CFR 812.42 and 21 CFR 812.20(a)(1)]
A sponsor is required to submit an IDE application to the FDA and obtain approval of the application before allowing subjects to participate in a clinical investigation of a significant risk device. You failed to adhere to the above stated regulations and treated nine subjects without an approved IDE from FDA. An example of your failure includes, but is not limited to, the following:
Your clinical feasibility study entitled, “(b)(4)” was conducted as a non-significant risk (NSR) study at a single clinical site by Clinical Investigator (CI), Dr. Kumar Shah - UCLA School of Dentistry, from August 21, 2011, to March 1, 2013. All nine subjects were enrolled during this time period. According to your study protocol, the objective of the study was to test the feasibility of the Rodo Dental Abutment System (investigational device) to retain restoration and stability on dental implants. Specifically, your firm’s study administered the investigational device to nine subjects without first obtaining FDA approval.
During a pre-submission meeting with FDA on August 12, 2011, prior to enrolling any subjects in your study, FDA informed you that Rodo Medical will need to address the concern of ingress of bacteria into the area between the crown and abutment. FDA recommended a clinical study either through an IDE in the U.S or without IDE outside the U.S. The microbiological evaluation of this abutment design is critical because of the possibility of serious risk to health, safety, or welfare of study subjects, specifically internal contamination which could lead to serious adverse oral sequelae.
Your October 26, 2010, letter to the UCLA Medical Institutional Review Board (IRB) stated your intent to pursue clearance of your device through the 510(k) mechanism. You referenced and provided a copy of the FDA Special Controls document entitled “Guidance for Industry and FDA Staff – Class II Special Controls Guidance Document: Root-form Endosseous Dental Implants and Endosseous Dental Implant Abutments” (2004). Section 12 of this guidance document states the following “If a clinical study is needed to demonstrate substantial equivalence, i.e., conducted prior to obtaining 510(k) clearance of the device, the study must be conducted in accordance with the Investigational Device Exemptions (IDE) regulation, 21 CFR Part 812. FDA believes this device is a significant risk (SR) device as defined in 21 CFR 812.3(m)(4) and, therefore, studies involving these devices do not qualify for the abbreviated IDE requirements of 21 CFR 812.2(b).”
Failure to obtain FDA approval of an IDE prior to subject enrollment and treatment may place study subjects at increased risk of harm and serious illness. FDA approval of an IDE application helps to ensure subject safety and that the risks associated with the device and study procedure are minimized.
Your firm’s response is inadequate. You stated that “there has been no notification by FDA under 21 CFR 812.20(a) that approval of an application is required, and that “the referenced investigation was initiated in good faith.” The evidence collected during your inspection and discussed above demonstrates your knowledge of FDA’s position regarding the risk determination of your device as significant risk and that an IDE is required.
Although you confirm you will conduct any future investigation under an approved IDE, you have not provided FDA with assurance that you understand the process for device risk determination and that proper disclosure to the IRB of previous FDA interaction and recommendations regarding study of your device is required. This is important to provide appropriate protections for subjects in clinical trials.
Please provide us documentation that you have notified the UCLA Medical IRB of the FDA’s risk determination of your investigational device and that future study of this device will require an FDA approved IDE application. We recommend that you review 21 CFR Part 812 governing sponsor responsibilities before starting any new study.
2. Failure to properly monitor an investigation under the abbreviated requirements for a non-significant risk (NSR) study. [21 CFR 812.2(b)(1)(iv)]
The abbreviated requirements under 21 CFR 812.2(b)(1)(iv) specify that the sponsor must comply with the requirements of 21 CFR 812.46 with respect to monitoring an investigation. Under 21 CFR 812.46, a sponsor who discovers that an investigator is not complying with the signed agreement must either promptly secure compliance or discontinue shipments of the device to the investigator and terminate the investigator’s participation in the investigation.
You failed to conduct proper monitoring by not ensuring that the clinical investigator (CI) complied with the signed agreement specifically with regard to the UCLA Medical IRB approvals of study protocols and informed consent documents. The Clinical Study Agreement between Rodo Medical and the Clinical Investigator, Dr. Kumar Shah, states the following in Section 3.1; the “Principal Investigator and/or Institution shall provide the Sponsor with evidence of all such approvals.”
There is no documentation that the Clinical investigator provided you with evidence of the IRB’s approval of the protocol or of two of the three informed consent documents used in the Rodo study. In your response you state that “in the future you will maintain documentation for all approved protocols and will ensure that monitors verify that the CI is in compliance.” This response is inadequate because you have not provided any corrective or preventive actions, e.g., standard operating procedures (SOPs) and training documents delineating how you plan to prevent this from recurring in future studies.
3. Failure to maintain records under the abbreviated requirements concerning adverse device effects (whether anticipated or unanticipated) and complaints. [21 CFR 812.2(b)(1)(v)]
The abbreviated requirements under 21 CFR 812.2(b)(1)(v) specify that the sponsor must maintain the records required under 812.140(b)(5), which include records concerning adverse device effects (whether anticipated or unanticipated) and complaints. You did not maintain adequate documentation of adverse device effects. For example, the (b)(4) clinical site reported a complaint of an unexpected crown fracture in one study subject (R09) who received your investigational device. The CI notified you of this event on November 20, 2012 and later in a summary report of the feasibility study that this event was an unexpected complication with the abutment system. In your final report to the UCLA IRB you stated “there were no study device failures and adverse events with any of the enrolled patients.”
Maintenance of records concerning adverse device effects is important because the records create an awareness of hazards and risks to study subjects. For example, a crown fracture can allow ingress of oral fluids including bacteria. Crown fracture could also compromise the endosseous implant structure and be associated with pain, discomfort and an inability to eat effectively.
In your response you state that porcelain fractures occur during crown restorations in dental implant and conventional crown and bridge laboratory techniques, and are not related to the Rodo device but rather the laboratory crown fabrication process. You also state that in the future, the study protocol will include crown fracture as an anticipated event and all adverse events will be documented appropriately. This response is inadequate because you have not provided any corrective or preventive actions, e.g., SOPs for adverse event reporting and documentation.
In your response, please provide copies of the policies and procedures that you have developed to ensure reporting of adverse device effects (anticipated and unanticipated) are in place for future studies.
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.
In addition to the violations described above, the FDA investigator also discussed with you the importance of adequate study monitoring by qualified study monitors. There is no documentation that study monitoring was conducted to ensure data integrity and human subject protections. You told the FDA investigator that the CI and IRB were responsible for monitoring the feasibility study. However, a monitoring plan was not put in place to ensure that the CI followed the investigational plan, and multiple protocol deviations occurred during the course of the study.
Inadequate monitoring can put subjects at risk because monitoring helps to identify problems or deviations that occur during a study. These include: potential defects with the device and its performance; adverse events that may affect subject safety; and protocol deviations that may affect subject safety and data integrity. Also, inadequate monitoring weakens your ability as a sponsor to effectively oversee your clinical study and prevents you from determining if additional clinical training is needed.
Within 15 working days of receiving this letter, please provide documentation of the additionalactions 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. In your corrective action plan please 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 to:
Attention: Adam Donat
Food and Drug Administration
Center for Devices and Radiological Health
Office of Compliance
Division of Bioresearch Monitoring
10903 New Hampshire Avenue
Building 66, Room 3450
Silver Spring, Maryland 20993-0002.
A copy of this letter has been sent to FDA’s San Diego District office. Please send a copy of your response to that office (1431 Harbor Bay Pkwy Alameda, CA 94502-7070).
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/ucm162015.htm
If you have any questions, please contact Karen Ulisney directly at 301-796-5513 or by email at email@example.com.
Jan B. Welch, MHS, MT (ASCP) SBB
Office of Compliance
Center for Devices and