William C. Domb, DMD
- William C. Domb, DMD
190 N. Mountain
Upland, CA 91786
- Issuing Office:
- Center for Devices and Radiological Health
| || |
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
| ||10903 New Hampshire Avenue|
Silver Spring, MD 20993
VIA UNITED PARCEL SERVICE
March 24, 2015
William C. Domb, DMD
190 N. Mountain
Upland, CA 91786
Dear Dr. Domb:
This Warning Letter is to inform you of objectionable conditions observed during the Food and Drug Administration (FDA) inspection of your clinical site from September 18, 2014 to October 16, 2014, by investigators from the FDA Los Angeles District Office. This inspection was conducted to determine whether activities and procedures related to your participation as the sponsor-investigator of the significant risk clinical study entitled, “Expectations for IRB Research Associates and Oxygen/Ozone Simplified and Suggested Research Treatment Protocols A Historical Review of Current Trends of Dental Colleagues,” complied with applicable federal regulations. Ozone generators 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 October 28, 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 serious violations of Title 21, Code of Federal Regulations (CFR) Part 812 - Investigational Device Exemptions and Part 50 - Protection of Human Subjects, which concerns requirements prescribed under section 520(g) of the Act. 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 to submit an IDE application to the FDA and obtain approval of the IDE from FDA and an Institutional Review Board prior to allowing subjects to participate in the investigation of a significant risk device. [21 CFR 812.20(a)(1), 21 CFR 812.42, and 21 CFR 812.110(a)]
A sponsor must submit an IDE application to the FDA and obtain FDA approval of the application in addition to Institutional Review Board (IRB) approval before allowing subjects to participate in a significant risk clinical investigation of a device. You failed to adhere to these regulations by initiating sixteen clinical sites and treating three subjects without an approved IDE from FDA.
FDA has determined that an approved IDE from FDA is required to study ozone generators because these devices are significant risk devices under 21 CFR 812.3(m) in that they present a serious risk to the health and safety of subjects. These risks include but are not limited to damage to pulmonary tissue leading to respiratory compromise, damage to intraoral soft tissue and mucosa and significant eye irritation or more serious ocular injury if there is significant ozone gas leakage. Accordingly, your failure to obtain FDA approval of an IDE prior to subject enrollment placed study subjects at increased risk of harm associated with the investigational device and any study related procedures.
2. Failure to prepare an adequate investigational plan. [21 CFR 812.25(b-e) and 21 CFR 812.40]
It is your responsibility as a sponsor, to ensure that the investigational plan contains all of the elements required in 21 CFR 812.25. However, you failed to comply with these requirements in that your investigational plan does not include the following;
- A written protocol describing the methodology to be used and an analysis of the protocol demonstrating that the investigation is scientifically sound. Specifically, your investigational plan does not include the study endpoints, statistical hypotheses, or a statistical analysis plan.
- A description and analysis of all increased risks to which subjects will be exposed by the investigation and the manner in which these risks will be minimized. Specifically, your investigational plan does not include a risk analysis or a plan to minimize risk to subjects.
- A description of each important component, ingredient, property, and principle of operation of the device and of each anticipated change in the device during the course of the investigation. Specifically, your investigational plan does not include a description of the model of ozone generator that is to be investigated and parameters for maximum amount of ozone that can be administered.
- The sponsor's written procedures for monitoring the investigation. Specifically, your investigational plan does not include provisions on the procedures sponsors will use to monitor data safety.
In your response, you state that your Institutional Review Board (IRB) will ensure that future protocols contain adequate information about the device. However, it is your responsibility as the study sponsor and not the IRB’s, to ensure that the investigational plan is adequate. Your response is inadequate because it does not describe how you will ensure that the investigational plan is adequate for future studies. Please describe the measures that you intend to take for future studies to prepare an adequate investigational plan. These measures may include revised standard operating procedures or staff training. Your response should include documentation of any actions you have taken.
3. Failure to select investigators qualified by education and experience and failure to obtain signed agreements from participating investigators. [ 21 CFR 812.43(a) and 812.43(c)]
As a sponsor, it is your responsibility to select investigators qualified by education and experience and obtain a signed agreement from each participating clinical investigator. You failed to comply with these requirements. Examples of your failure include, but are not limited to, the following:
- You failed to ensure that all investigators were qualified to participate in the study. Specifically, you permitted a podiatrist, whose experience and training is in treating conditions related to the foot, ankle, and related structures of the leg, to participate as an investigator in your study, which is limited to dental and oral applications of the investigational device. Furthermore, you did not have criteria for determining if investigators were qualified to participate in your study.
- You also failed to obtain investigator agreements, financial disclosure information, and curricula vitae from all sixteen clinical investigators in your study.
Obtaining signed investigator agreements and ensuring that all participating investigators are adequately qualified helps to confirm that they are able to safely perform study procedures and understand the study’s requirements. These agreements also help to prevent participating investigators from using the products outside of the clinical investigation avoiding any harm to others from uncontrolled or unsupervised uses of the investigational device.
In your response, you state that you will have selection criteria for investigators in future studies and your IRB will ensure that investigators sign investigator’s agreements. Your response is inadequate because it places sponsor responsibilities with the IRB, and lacks sufficient detail to ensure that you will select qualified investigators. Sponsor responsibilities include ensuring monitoring, obtaining investigator agreements along with financial disclosure information from each investigator, as well as ensuring investigators are reporting adverse effects and complying with the study protocol (see 21 CFR part 812 subpart C).
Please provide a more detailed explanation of the actions you plan to take as a sponsor to select qualified investigators and obtain signed investigator’s agreements, along with a timeline of implementation. Your response should provide documentation of these actions, such as revised standard operating procedures and list of staff trained, as well as dates trained.
4. Failure to ensure that informed consent was obtained in accordance with 21 CFR Part 50. [21 CFR 812.100, 21 CFR 50.20, 21 CFR 50.25]
A clinical investigator is responsible for obtaining and documenting informed consent from a subject using an IRB approved consent form prior to involving the subject in the clinical investigation. In seeking informed consent, basic elements, and additional elements when appropriate, must be provided to each subject as described in 21 CFR 50.25. The basic elements that must be included in your informed consent are:
- A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental.
- A description of any reasonably foreseeable risks or discomforts to the subject.
- A description of any benefits to the subject or to others which may reasonably be expected from the research.
- A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject.
- A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that the Food and Drug Administration may inspect the records.
- For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained.
- An explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject.
- A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.
You failed to comply with FDA regulations relating to informed consent because your informed consent documents did not adequately address all eight of the basic elements of informed consent, described above, as required by 21 CFR 50.25(a). These documents were used as part of the consenting process for the three subjects enrolled at your clinical site.
The elements omitted from the informed consent document include important information such as the risks and benefits of participating in the study, the extent of the subject’s confidentiality, the subject’s financial burden, important contact information, and statements that the subject is participating voluntarily. Study subjects are required to have this information prior to study enrollment. By failing to properly obtain the subjects' informed consent with the use of a complete informed consent document you failed to provide your subjects with sufficient opportunity to consider whether or not to participate in the study and thus, did not adequately protect the rights and safety of those human subjects.
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 decided to participate.
In your response, you state that you will ensure that your IRB only approves informed consent documents containing the required elements. Your response is inadequate in that it fails to recognize that it is your responsibility as a clinical investigator to ensure that informed consent was obtained in accordance with 21 CFR Part 50.
Please provide an explanation of the actions that you, as a clinical investigator, plan to take to ensure that informed consent will be obtained and documented in accordance with 21 CFR Part 50 in future studies and a timeline of implementation. Your response should provide documentation of these actions, such as revised standard operating procedures and records of staff training, as well as dates trained.
5. Failure to ensure proper monitoring of the investigation. [21 CFR 812.40 and 812.43]
As a sponsor, you are responsible for ensuring proper monitoring of the investigation. You failed to comply with this requirement. Specifically, there is no documentation indicating that you performed any monitoring since the initiation of your study.
Proper monitoring helps ensure that the safety, rights, and well-being of the subjects are protected and that the data is 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 FDA or the reviewing IRB. Monitoring is needed in order to review records, source documents and study procedures for the presence and appropriate documentation of adverse events and protocol deviations.
In your response, you state that your IRB will select monitors to ensure clinical investigator compliance. Your response is inadequate since it fails to recognize that it is your responsibility as a sponsor to ensure proper monitoring of the investigation and does not provide the corrective and preventive actions that you intend to take as a sponsor.
Please provide a list of the actions that you, as a sponsor, plan to take to ensure proper monitoring offuture studies and a timeline of implementation. Your response should provide documentation of these actions, such as revised standard operating procedures and records of staff training, as well as dates trained.
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 sponsor and clinical investigator to ensure compliance with the Act and applicable regulations.
Within 15 working days of receiving this letter, please provide documentation of the additional 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 # EC140537/E001” and be sent to:
Attention: Adam Donat, MS
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 Los Angeles District Office, 19701 Fairchild Rd, Irvine, CA 92612. 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/ucm162015.htm
If you have any questions, please contact Adam Donat, MS, at (301) 796-5316 or Adam.Donat@fda.hhs.gov.
Jan B. Welch, MHS, MT (ASCP) SBB
Office of Compliance
Center for Devices and