Inspections, Compliance, Enforcement, and Criminal Investigations
Katzen, Barry M.D. 30-Jan-08
Department of Health and Human Services
Public Health Service
9200 Corporate Boulevard
VIA FEDERAL EXPRESS
JAN 30 2008
Barry T. Katzen, M.D.
Baptist Cardiac and Vascular Institute
8900 N. Kendall Drive
Miami, FL 33176-2118
Dear Dr. Barry Katzen:
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 15 to October 17, 2007, by an investigator from the FDA Florida District Office. The purpose of this inspection was to determine whether activities and procedures related to your participation in the clinical study titled [redacted], complied with applicable federal regulations. [redacted] 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). 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 (IDE), Premarket Approval (PMA) 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 repeated serious violations of Title 21, Code of Federal Regulations (21 C.F.R.) Part 812 -- Investigational Device Exemptions. 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 and our subsequent review of the inspection report are discussed below:
Failure to conduct the investigation according to the signed agreement, the investigational plan, and applicable FDA regulations. [21 CFR 812.100 and 21 CFR 812.110(b)] Failure to obtain, in a non-emergency situation, prior approval by the sponsor of changes in or deviations from the investigational plan and failure to obtain such approval from FDA and the reviewing IRB, where the changes or deviations could have affected the rights, safety, or welfare of human subjects. [21 CFR 812.150(a)(4)]
It is the responsibility of the investigator to conduct the investigation in accordance with the signed investigator agreement, investigational plan, and applicable FDA regulations. For the [redacted] study, follow-up examinations and diagnostic tests were not performed in accordance with the investigational plan.
In addition, an investigator is responsible for notifying the sponsor and the reviewing IRB of any deviations from the investigational plan to protect the life or physical well-being of a subject in an emergency. Such notice shall be given as soon as possible, but no later than 5 working days after the emergency occurred. Except in such an emergency, prior approval by the sponsor is required for changes in or deviations from a plan. If these changes or deviations may affect the scientific soundness of the plan or rights, safety, or welfare of hum an subjects, FDA, and IRB approval is required in accordance with 812.35(a).
You failed to perform follow-up examinations and diagnostic tests according to the investigational plan. [redacted]. You failed to obtain these diagnostic procedures for [redacted] subjects enrolled and you failed to secure prior sponsor and IRB approval for these deviations. Examples of these failures include, but are not limited to, the following:
A) [redacted] were not performed for subjects [redacted]. In addition, you failed to secure prior sponsor and IRB approval for these deviations.
B) [redacted] were not performed [redacted]. In addition, you failed to secure prior sponsor and IRB approval for these deviations:
1) Subject [redacted];
2) Subject [redacted];
3) Subject [redacted] performed during the [redacted]; however, there was no documentation of a [redacted] being performed; and
4) Subject [redacted]
Please provide copies of policies, procedures, and training with expected completion dates that are being developed and implemented to ensure that this investigation and any other investigations in which you participate will be conducted in accordance with the signed investigator agreement, investigational plan, and applicable FDA regulations. In addition, please provide copies of policies, procedures, and training with expected completion dates that are being developed and implemented to ensure sponsor and IRB approval of deviations are obtained prior to treating subjects in non-emergency situations.
Failure to maintain accurate, complete, and current records of each subject's case history and exposure to the device. [21 CFR 812.140(a)(3)]
An investigator is responsible for maintaining accurate, complete, and current records of each subject's case history and exposure to the device, which encompasses the case report forms (CRFs) and supporting data. In addition, 21 CFR 812.140(a)(3)(ii) mandates that case histories shall contain all relevant observations, including records concerning adverse device effects (whether anticipated or unanticipated). In addition, the Investigator Agreement that you signed indicates under [redacted] that you "agree to maintain and retain accurate, complete, and current records" including "records (case record forms) of each subject's case history . . ." You failed to maintain accurate, complete, and current records of [redacted] subject's case histories. Examples of these failures include, but are not limited to, the following:
Discrepancies were noted between diagnostic test reports, progress reports, and CRFs. Examples of these discrepancies include, but are not limited to the following:
A) Subject [redacted] progress note dated [redacted] dated [redacted], identified the [redacted. In the CRP dated [redacted]
B) Subject [redacted] identifies the [redacted] performed on [redacted], however, the investigator's signature is dated [redacted], which is over [redacted] prior to the [redacted]. In addition, the [redacted] dated [redacted], noted the maximum [redacted], which was changed on [redacted]. However, the [redacted] dated [redacted].
C) Subject [redacted] noted the date of [redacted] as [redacted], which was changed from [redacted]. The subject had a [redacted] on [redacted] instructions are dated [redacted].
D) Subject [redacted] date was changed from [redacted]. However, the subject's progress notes end [redacted], and the [redacted] instructions are dated [redacted]. In addition, the [redacted], and the [redacted] notes two different [redacted].
Please provide copies of policies, procedures, and training with expected completion dates that are being developed and implemented to ensure case histories for this investigation and any other investigations in which you participate will be complete, current, and accurate. Please include a plan to evaluate and correct the case histories for the current investigation.
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 clinical investigator to ensure compliance with the Act and applicable regulations.
You were previously inspected by the FDA from April 8 through April 16, 2003. As a result of that inspection you were issued an Untitled Letter on October 16, 2003. During the recent FDA inspection similar deviations were noted, including failure to conduct the investigation in accordance with the investigational plan, failure to obtain sponsor and IRB approval of protocol deviations, failure to document adverse device effects, and inaccurate case histories. It appears the corrective actions you developed and implemented after the last FDA inspection are ineffective. Please submit an updated corrective action plan to correct and prevent the noted deficiencies.
The regulations in 21 CFR Part 812 describe sponsor responsibilities as well as those of investigators. IRB responsibilities are spelled out in 21 CFR Part 56, Institutional Review Boards. These three sets of responsibilities overlap to ensure appropriate conduct of clinical studies and the protection of the rights and welfare of participating subjects. Therefore, though the sponsor involved in your study may have been remiss in fulfilling their responsibilities, you are still held responsible for knowing and following the regulations pertinent to your activities as a clinical investigator in FDA-regulated studies.
We request written documentation within fifteen (15) working days of receiving this letter of the actions you have taken or will take to ensure that the violations noted during this study will not be repeated in any future studies for which you are the clinical investigator. You will find information to assist you in understanding your responsibilities and planning your corrective actions in the FDA Information Sheets Guidance for Institutional Review Boards and Clinical Investigators, which can be found at http://www.fda.gov/oc/ohrt/irbs/. Your response should be sent to: Attention: Doreen Kezer, Food and Drug Administration, Center for Devices and Radiological Health, Office of Compliance, Division of Bioresearch Monitoring, 9200 Corporate Boulevard, HFZ-310, Rockville, Maryland 20850.
A copy of this letter has been sent to Florida District Office at 555 Winderley Place, Suite 200, Maitland, FL 3275. Please send a copy of your response to that office.
If you have any questions, please contact Doreen Kezer, (240) 276-0125, e-mail Doreen.firstname.lastname@example.org.
Timothy A. Ulatowski
Office of Compliance
Center for Devices and