- Delivery Method:
- VIA UNITED PARCEL SERVICE
- Medical Devices
Recipient NamePhilip R. Kennedy, MD, PhD
- Kennedy, Philip R.
3400 McClure Bridge Road, Suite D402
Duluth, GA 30096
- Issuing Office:
- Center for Devices and Radiological Health
10903 New Hampshire Avenue
Silver Spring, MD 20993
February 27, 2020
Dear Dr. Kennedy:
This Warning Letter is to inform you of objectionable conditions observed during the Food and Drug Administration (FDA) inspection conducted at your clinical site from October 2, 2019, to October 16, 2019, by investigators from the FDA’s Office of Bioresearch Monitoring Operations (OBIMO). This inspection was conducted to determine whether activities and procedures as sponsor-investigator in the significant risk clinical study “(b)(4)”, Investigational Device Exemption (IDE) (b)(4), complied with applicable federal regulations. The (b)(4) product 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 October 17, 2019 to the noted violations.
The inspection was conducted under a program designed to ensure that data and information contained in requests for IDEs, Premarket Approval 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 the OBIMO revealed several 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, 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 inspection report, are discussed below:
1. Failure to ensure proper monitoring and Institutional Review Board (IRB) review and approval [21 CFR 812.40].
Sponsors are responsible for ensuring proper monitoring of the investigation. However, there is no documentation indicating that monitoring was done. 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.
In addition, sponsors are responsible for ensuring that IRB review and approval are obtained. There is no documentation indicating that any continuing review by an IRB was conducted from 2002 and the end of the 2019 FDA inspection. However, the records show that the study remained open to enrollment and you continued to collect study data without IRB approval, in particular, study data were collected for (b)(4) from June 1, 2009 through January 1, 2016. Your failure to ensure that IRB review and approval was obtained at least annually delays or prevents the IRB from considering any changes in the research or research-related events and determining whether the human subject protection measures are adequate or need to be changed.
Your written response states “there is a lack of IRB continuing review records after 2002 because no other patients have been enrolled since (b)(4) was enrolled in 2003/4 and the study began in 2004.” Your written response further states that there was no study to monitor after 2010, though you resumed collecting study data in 2013. Your written response is inadequate in that you failed to provide any documentation to show proper monitoring and that IRB continuing review and approval was obtained. Also, your response does not include any information on how you plan to ensure that these issues won’t recur in this study or future studies.
2. Failure to submit complete and accurate progress reports [21 CFR 812.150(b)(5)].
At regular intervals, and at least yearly, a sponsor shall submit progress reports to all reviewing IRBs. In the case of a significant risk device, such as yours, a sponsor shall also submit progress reports to the FDA. You have failed to adhere to the above-stated regulation.
Specifically, review of the study documentation found that no correspondence occurred with an IRB from February 13, 2009 to the end of the 2019 FDA inspection. Within this timeframe, data for subject ER were collected and recorded. In addition, though there were documents labeled as “Annual Report to the Food and Drug Administration” for 2010-2012, 2014, and 2019 at your site, FDA records show no progress reports for the years 2010, 2011, 2012, 2014, 2015, 2016, 2017, and 2018 were actually submitted to FDA.
These reports are important for ensuring the safety and welfare of study subjects. Information gathered from these reports can be useful to FDA as they provide vital information on the potential effects of a significant risk device. Failure to submit accurate and complete progress reports to the FDA limits the Agency's ability to oversee the clinical study and properly evaluate the safety and effectiveness of the device.
In your written response, you stated that there are letters from the IRB. However, the IRB correspondences collected during the FDA inspection were very limited and did not include the 2009 to 2019 timeframe. Nor did you provide any such letters with your written response. Similarly, no documentation of any kind (e.g., E-mail, FedEx, UPS, or USPS) was provided to indicate the submission of the progress reports to FDA. Regarding the electronics replacement, you stated that notifying the FDA was overlooked but you will do so in the future. We determined your response to be inadequate. Please assess the root cause and provide a corrective and preventive action plan to avoid these violations in the future.
3. Failure to maintain accurate, complete, and current records of shipment, receipt, use, or disposition of a device and failure to maintain the records during the investigation and for a period of 2 years after the date on which the investigation is terminated or completed [21 CFR 812.140(a)(2)(i) and (iii), 21 CFR 812.140(b)(2), and 21 CFR 812.140(d)].
As a sponsor-investigator, you are responsible for maintaining, accurate, complete, and current records of shipment, receipt, use, or disposition of an investigational device that relate to the type and quantity of the device, dates of shipment and receipt, and batch number or code mark, and why and how many units of the device have been returned to the sponsor, repaired, or otherwise disposed of. In addition, as a sponsor-investigator, you are responsible for maintaining study records during the investigation and for 2 years after the latter of the following two dates: the date the investigation is terminated or completed, or the date that the records are no longer required to support a future marketing application or submission. You have failed to adhere to the above-stated regulations. Examples of your failures include the following:
- FDA review of records at your site found that there was no documented device accountability information. Subject records did not include documentation of the type, quantity, batch number, or code mark of the implanted device. This includes information relating to the device that was retrieved from subject ER, as well as for the implanted electronics replacement. Device accountability records are necessary to ensure that the use of investigational devices is consistent with the conduct of clinical research, limited to the investigational use, and traceable to individual subject exposure. This helps prevent the misuse of investigational devices by untrained persons on subjects for which the device is not indicated.
- Review of the study documentation revealed that source records (e.g., informed consent documents, data record books, hospital records, and/or medical records) for subjects (b)(4), which were previously reviewed during the last inspection dated May 5, 2009 to May 29, 2009, were no longer in the subjects’ records for review during the October 2019 inspection. Subject source records are important to ensure that subjects are adequately consented, are receiving the necessary study procedures and are needed to monitor the subjects’ outcomes from their participation in research.
In your written response, you did not provide any corrective and preventive action plans to avoid these violations in the future.
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-investigator 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 sponsor or clinical investigator. 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 to:
Attention: Veronica Calvin, MA
Food and Drug Administration
Center for Devices and Radiological Health
10903 New Hampshire Avenue
Building 66, Room G116
Silver Spring, Maryland 20993-0002
A copy of this letter has been sent to FDA’s OBIMO East via email at ORABIMOE.Correspondence@fda.hhs.gov. Please send a copy of your response to that office.
The Division of Clinical Science 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: https://www.fda.gov/training-and-continuing-education/cdrh-learn.
If you have any questions, please contact Irfan Khan at (301) 796-5659 or Irfan.Khan@fda.hhs.gov.
Soma Kalb, PhD
DCEA1: Division of Clinical Science and Quality
Office of Clinical Evidence & Analysis
Office of Product Evaluation and Quality
Center for Devices and Radiological Health