Jenis, Louis G., M.D. 2/14/12
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Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
| ||10903 New Hampshire Avenue|
Silver Spring, MD 20993
February 14, 2012
VIA UNITED PARCEL SERVICE EXPRESS
Louis G. Jenis, M.D.
The Boston Spine Group
299 Washington Street
Newton, MA 02458
Dear Dr. Jenis:
This Warning Letter is to inform you of the objectionable conditions observed during the Food and Drug Administration (FDA) inspection of your clinical site from November 15, to December 7, 2011, by an investigator from the FDA’s New England District Office. This inspection was conducted to determine whether activities and procedures related to your participation in the clinical study entitled, “A multi-Center, Prospective, Randomized Controlled Trial Comparing Cervical Arthroplasty to Anterior Cervical Discectomy and Fusion (ACDF) for the Treatment of Cervical Degenerative Disc Disease (DDD),” involving the Discover Artificial Cervical Disc, Investigational Device Exemption (IDE) G060020, complied with applicable federal regulations. The Discover Artificial Cervical Disc 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 a 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 requests prompt corrective action to address the violations cited and discusses your written response, dated December 21, 2011, to the noted violations on the Form FDA 483.
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 (510(k)) 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 district office revealed serious violations of Title 21, Code of Federal Regulations (21 CFR) Part 812 - Investigational Device Exemptions, which are requirements prescribed under section 520(g) (21 U.S.C. § 360j(g)) of the Act. At the close of the inspection, the FDA investigator presented the 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:
Failure to conduct the investigation according to the signed agreement, the investigational plan, applicable FDA regulations, and any conditions of approval imposed by an Institutional Review Board (IRB) or FDA [21 CFR 812.100 and 812.110(b)].
Clinical investigators are responsible for ensuring that an investigation is conducted according to the signed agreement with the sponsor, the investigational plan, applicable FDA regulations for protecting the rights, safety, and welfare of subjects under the investigator’s care, and any conditions of approval imposed by an IRB or FDA. The “Intended Use” section of the protocol indicates that the device is intended for use on spine arthroplasty of one (1) cervical disc. In addition, the “Exclusion Criteria” of the protocol indicates that subjects are to be excluded if there was any prior surgery at the target level. For reoperation, the protocol section, “Subsequent Secondary Surgical Interventions,” requires a revision to the procedure for any modification or addition of any components to the system and a revision is “a procedure that adjusts or in any way modifies or removes part of the original implant configuration, with or without replacement of a component.” A “reoperation” is “any surgical procedure at the involved level that does not involve removal, modification, or addition of any components to the system” (emphasis added). You have failed to adhere to the above-stated regulations and protocol requirements.
- The study records indicate that (b)(6) was implanted with the control article on the incorrect cervical spine level. Physician notes signed by you on (b)(6), and (b)(6), indicate that the subject has (b)(6). The subject’s operative report and discharge summary show that the procedure was performed on (b)(6), on the (b)(6). The physician note signed by you on (b)(6), shows that the procedure was performed on the incorrect level. In addition, four days after the first surgery, you performed a second procedure on the subject on (b)(6), on the correct disc level, (b)(6)and did not exclude this subject from the study as required by the protocol. Your operative note indicates “removal and reinsertion of (b)(6),” which is a 2-level fusion and it is not authorized by the protocol.
This is a major safety concern because it placed Subject (b)(6) at additional risks of serious harm due to the need for a second surgery only four days after the first. These risks include infection, bleeding, risks associated with anesthesia, and neurological damage including paralysis and death. Two-level fusions can also result in worse clinical outcomes when compared to one-level fusion. The subject has therefore been placed at increased risk of developing long-term complications such as worsening pain and disability as a result of the critical error made by you.
Failure to maintain accurate, complete, and current records of each subject’s case history [21 CFR 812.140(a)(3)].
Clinical investigators are 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). You have failed to adhere to the above-stated regulation in that several inconsistencies or inaccuracies with documentation of dates, and lack of recording adverse events (AEs) and serious adverse events (SAEs) for several subjects were observed. Examples of your failure include, but are not limited to, the following:
- On (b)(6), you signed a note to file that indicates Subject (b)(6) reported pain in the left lower cervical area. However, there is no documentation to show that this event was recorded in the electronic CRF (eCRF).
- For Subject (b)(6), the follow-up visit physician notes, dated (b)(6), and (b)(6), show shoulder discomfort and right trapezial pain, and right shoulder pain, respectively; however, there is no documentation to show that these events were recorded in the eCRF.
- For Subject (b)(6), both the physician note, dated (b)(6), and signed by sub-investigator (b)(4), and the subject’s medical monitor report indicate persistent hand and forearm numbness on the right side. In addition, the medical monitor report indicates that the event is considered device related. However, there is no documentation to show that this SAE was recorded in the eCRF. Furthermore, the physician note, dated (b)(6), signed by (b)(6), indicates that the subject’s arm pain is getting worse. However, there is no documentation to show that this event was recorded in the eCRF.
- For Subject (b)(6), the operative report, dated (b)(6), shows that the subject experienced migration of the study device; however, this is not documented as an AE or SAE.
- For Subject (b)(6), the operative report dated (b)(6), and the cardiac consult dated (b)(6), show that the subject developed cardiac slowing and then a prolonged period of total electrical asystole lasting approximately a minute. An AE was completed for cardiac arrest and was sent to the sponsor on March 11, 2010, which is outside the one business day reporting requirement per the protocol. In addition, this AE is recorded in the eCRF and medical monitor report with an onset date of (b)(6), instead of March 9, 2010, as seen on the operative report.
- For Subject (b)(6), the re-operation SAE report to the sponsor shows an incorrect subject number. In addition, the re-operation is recorded in the eCRF but there is no documentation to show that the initial operation performed on the incorrect cervical spine level is recorded in the eCRF.
Inconsistency and inaccurate records of AEs and SAEs are major subject safety and data quality concerns. Discrepancies in reporting AEs may call into question the integrity and reliability of the data you obtained during the course of the study and increase the risk of harm to the participating subjects.
Failure to ensure that an investigation is conducted in accordance with the signed agreement, investigational plan, applicable FDA regulations, and any conditions of approval imposed by an IRB or FDA and failure to submit progress reports on the investigation to the sponsor and reviewing IRB at regular intervals [21 CFR 812.100, 812.110(b), and 21 CFR 812.150(a)(3)].
Clinical investigators are responsible for conducting an investigation in accordance with the signed agreement with the sponsor, the investigational plan, 21 CFR Part 812, and other applicable FDA regulations, and any conditions of approval imposed by an IRB or FDA. Clinical investigators are also responsible for preparing and submitting progress reports on an investigation to the sponsor, the monitor, and the reviewing IRB at regular intervals, but in no event less often than yearly. You have failed to adhere to the above-stated requirement. On two different occasions, IRB approval lapsed 43 days and 22 days due to your staff submitting progress reports late. Examples of your failure include, but are not limited to, the following:
- On August 21, 2007, your study coordinator sent a letter that indicates the IRB closed the study on August 6, 2007, due to a lack of continuing review and non‑receipt of your progress report. On August 30, 2007, the IRB acknowledged receipt of the information and granted a temporary extension to follow-up with subjects currently enrolled. As a result of your site’s late submittal of the progress report, the IRB conducted continuing review and approval of the study on September 18, 2007 (43 days later than expiration).
- The IRB approval for the study expired on June 14, 2011. Again, your staff submitted the progress report late, on July 1, 2011, which resulted in the IRB reviewing and approving the study on July 6, 2011 (22 days later than expiration).
Failure to adhere to these requirements may increase the risk of harm to the participating subjects.
Your written response is inadequate. In your response, you stated that “the logistical procedure to schedule surgery within the Boston Spine Group has been modified to prevent this error from recurring in the future”; however, you have failed to provide a copy of the procedure and documentation to show that you and your staff were trained on it.
In addition, you provided a copy of your site’s AE and SAE training slides and documentation of the study coordinator training on the following standard operating procedures (SOPs):
- Routine Adverse Event Reporting,
- Serious Adverse Event Reporting, and
- Handling IRB Correspondences.
However, you have failed to provide copies of the above SOPs. Please provide copies of the SOPs as well as documentation of the date implemented, dates of training on all revised or newly created procedures, a list of staff trained including you and the sub-investigators, and dates of training. Also, we recommend that all of your measures be re-evaluated in three to six months to ensure no further action is necessary.
In addition, sub-investigators (b)(4) performed study procedures on subjects 010, 013, and 016. However, there is no documentation to show that (b)(4) received (b)(4) training prior to performing study procedures. Please note that clinical investigators and/or sub-investigators performing study procedures without adequate training is a major safety concern as there are many unique attributes to each device that require device-specific training.
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 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 clinical investigator. In addition, please provide a complete list of all FDA regulated device clinical research in which you have participated for the last five years, including the names of the studies and test articles, the names of the sponsors, the number of subjects enrolled, and the current status of the studies. 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 CFR 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 plans must include projected completion dates for each action to be accomplished and a plan for monitoring the effectiveness of your corrective actions.
Your response should reference “CTS # G060020/E004” and be sent to:
Attention: Linda D. Godfrey
Food and Drug Administration
Center for Devices and Radiological Health
Office of Compliance
Division of Bioresearch Monitoring
10903 New Hampshire Avenue
Building 66, Room 3462
Silver Spring, Maryland 20993-0002
A copy of this letter has been sent to FDA’s NWE-DO, One Montvale Avenue, Stoneham, MA 02180. Please send a copy of your response to that office.
For further information concerning the Bioresearch Monitoring program, please visit our Internet homepage. Valuable links to related information are included at this site. http://www.fda.gov/cdrh/comp/bimo.html
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 Ms. Linda Godfrey by telephone at (301) 796-5490 or via email at Linda.Godfrey@fda.hhs.gov
Steven D. Silverman
Office of Compliance
Center for Devices and
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