Inspections, Compliance, Enforcement, and Criminal Investigations
Traina, Steve M., M.D. 27-Jul-07
Department of Health and Human Services
Public Health Service
9200 Corporate Boulevard
JUL 25 2007
VIA FEDERAL EXPRESS
Steven M. Traina, M.D.
Orthopedic Associates, Inc.
4700 East Hale Parkway, Suite 550
Denver, Colorado 80220
Dear Dr. Traina:
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 February 27 to March 15, 2007, by an investigator from the FDA Denver District Office. The purpose of this inspection was to determine whether activities and procedures related to your participation in the clinical study of the [redacted] PMA [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.
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 serious violations of Title 21, Code of Federal Regulations (21 C.F.R.), Part 812 - Investigational Device Exemptions, Part 50 - Protection of Human Subjects, and Section 520(g) (21 U.S.C. 360j(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 and Ms. Shirley M. Narango, RN, your clinical research coordinator. The deviations noted on the FDA 483 and our subsequent review of the inspection report are discussed below:
Failure to ensure that an investigation is conducted according to the signed agreement, investigational plan, and applicable FDA regulations 121 CFR 812.100 and 21 CFR 812.110(b)].
You failed to adhere to the above-stated regulations, specifically with respect to the inclusion and exclusion criteria for the study. Examples of this failure include but are not limited to the following:
• Subject [redacted] had a [redacted] in 1990 on his ipsilateral leg. The protocol states that subjects with [redacted] are excluded from the study.
• In the Admittance of Patient section of the protocol, investigators are instructed to complete the Screening Evaluation to determine a subject's eligibility for the study. A review of subject files revealed screening forms were not completed for subjects: [redacted] and [redacted]
• The Follow-up Procedures (Data Collection) section of the protocol states that functional and radiographic evaluations are to be completed postoperatively. The protocol specifies the timetable for these visits as the following: [redacted]
• Follow-up examinations were missed or were performed outside the window for the following subjects: [redacted] and [redacted]
• Radiographic images (x-rays) were not taken for the following subjects within the window for protocol-required examination visits: [redacted] week and [redacted] year examination visits [redacted] year examination visit, and [redacted] week and [redacted] year examination visits.
• The Follow-up Procedures (Data Collection) section of the protocol states "[redacted] Radiographs for subject [redacted] and [redacted] were taken during the period in which IRB approval for the study had expired, and should have been retaken during re-visits, as requested by the study sponsor. As an investigator, you are responsible for following the requirements of the study protocol and the sponsor.
• Subject [redacted] was randomized into the study on April 10, 2002, and was assigned to receive the [redacted]. However, during the surgery, the subject received the [redacted].
Failure to maintain accurate, complete, and current records [21 CFR 812.140(a)(2)(i) and 812.140(a)(3)(ii) and (d)].
Pursuant to the above stated regulations, as a clinical investigator, you are responsible for maintaining accurate, complete, and current records of all study-related matters, including receipt and use of a device, which relates to the type and quantity, dates of receipt, and batch number or code mark of the device (21 CFR 812.140(a)(2)(i). You are required to maintain all records for a period of two years after the latter of the following: the date on which the investigation is terminated or completed, or the date that the records were no longer required for purposes of supporting a premarket approval application or a notice of completion of a product development protocol (21 CFR 812.140(a)(3)(ii) and (d). You failed to adhere to the above-stated regulations. Examples of this failure include but are not limited to the following:
• Product labels were missing from the [redacted] case report forms for [redacted] for subject [redacted] and [redacted] respectively.
• All or part of the device information (catalog and lot numbers) and dates of receipt and usage were either missing or incorrect for at least nine subjects (subjects [redacted]) and the usage dates recorded on the log were incorrect for subjects [redacted] and [redacted]
• A majority of source documents were not retained at your clinical site. Therefore, discrepancies between the office visit notes and case report forms could not be resolved for the following subjects: [redacted], and [redacted]
Failure to submit progress reports on the investigation at the required intervals, but in no event less often than yearly, to the reviewing IRB [21 CFR 812.150(a)(2) and 812.150(a)(3)].
Federal regulation requires that an investigator submit progress reports on the investigation to the sponsor and the reviewing IRB at regular intervals, but in no event less often than yearly. In addition, the investigator agreement that you signed states that progress reports are to be submitted to the sponsor and IRB at yearly intervals.
Furthermore, each IRB approval letter sent to you clearly stated when the renewal was due and that it was your responsibility to submit the renewal request to the IRB. You failed to submit annual progress reports to the IRB, as well as timely renewal requests, which resulted in gaps in IRB approval. Several subjects were found to have been enrolled during the study expiration period. Examples include:
• IRB approval expired on February 20, 2003, and was not renewed until April 16, 2003. Subject [redacted] was enrolled on March 24, 2003, and Subject [redacted] was enrolled on March 26, 2003, during the period in which IRB approval was expired.
• IRB approval expired on February 2004, and was not renewed until April 21, 2004. Subject [redacted] was enrolled on April 7, 2004, and Subject [redacted] was enrolled on April 20, 2004, during the period in which IRB approval was expired.
• IRB approval expired on March 16, 2006, and was not renewed until August 16, 2006.
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.
Within fifteen (15) working days of receiving this letter, please provide written documentation of the actions you have taken or will take to correct these violations and prevent the recurrence of similar violations in current or future studies for which you are the clinical investigator. In addition, please provide a complete list of all clinical trials in which you have participated for the last five years, including the name of the study and test article, the name of the sponsor, the number of Patients enrolled, and the current status of the study. Failure to respond to this letter and take appropriate corrective action could result in the FDA taking regulatory action without further notice to you. In addition, FDA could initiate disqualification proceedings against you in accordance with 21 C.F.R. 812.119.
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/. Any submitted corrective action plan must include projected completion dates for each action to be accomplished. Please send your response to: Attention: Linda Godfrey, 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 the FDA Denver District Office, Bldg 20, Denver Federal Center, PO Box 25087, 6th Avenue & Kipling Street, Denver, CO 80225. Please send a copy of your response to that office.
If you have any questions, please contact Linda Godfrey at (240) 276-0125 or by email at Linda.Godfrey@fda.hhs.gov.
Timothy A. Ulatowski
Office of Compliance
Center for Devices and