Warning letters.

The following are recent FDA warning letters to clinical investigators, IRBs, sponsor/monitors, CROs and testing labs issued in August 2007. Each letter is $7 plus retrieval. Please order by RECORDRETRIEVE Number (e.g., 12338W, 12399W, etc.). Copies of responses to the letter, along with any 483s and EIRs, are available from RECORD-RETRIEVE: (703) 779-8777, or SERVICE@FDAINFO.COM

Pamela Grady, Ph.D., St. Paul, MN, Aug. 30 (Rockville, MD)

An investigation was conducted May 9 through May 16, 2007 for clinical investigator Pamela Grady, Ph.D., of Boston Scientific Cardiovascular, which revealed several violations, including a "failure to immediately conduct an evaluation of any unanticipated adverse device effects (UADE) and a failure to prepare and submit complete, accurate, and timely effects to FDA and to all reviewing IRBs within 10 working days."

Specifically, at least five deaths occurred in the study and at the time of the inspection two of these deaths had not been evaluated to determine if there was a relationship between the deaths and the investigational device or to determine if they would be considered to be UADEs, FDA wrote Aug. 30.

Also two UADEs occurred in which subjects contracted blood stream infections, found to be a result of non-sterile, contaminated batch used during the procedure. However, the sponsor did not notify all IRBs of the risk. The sponsor instead submitted a "Notice of IDE Change" to FDA, which described changes to manufacturing and quality sampling processes.

The sponsor responded to these violations by stating "it will provide a refresher training course on adverse event reporting requirements." However, in FDA's opinion this was inadequate because it did not address the basic issue of ensuring timely follow-up with study sites when initial adverse event information is incomplete.

The response also said that the submission process was discussed with the FDA reviewer and that it was "mutually agreed that future UADEs will be reported to FDA only if they lead to further interventions or clinical events, or if there was a significant increase in the occurrence rate." The letter said that this response did not address the original issue of UADEs not being reported to FDA.

The letter continued by stating that the sponsor "failed to provide clinical investigators with information they needed to conduct the investigation properly and ensure that nay reviewing IRB and FDA are informed of significant new information in a timely manner."

The firm in its response said it had discussed this issue with the reviewer and agreed that it will include a summary of all safety data from the study in future IDE reports and the adverse event summaries will be provided annually. However, FDA said the sponsor failed to present written documentation and an adequate time frame for when this information will be provided.

The letter finally stated that the firm failed to submit complete and accurate progress reports at least annually to all reviewing IRBs and to FDA. Specifically, in the sponsor's January 2007 progress report to FDA, it states that only one death occurred in the study. However, in the sponsor response, two deaths were listed these deaths were not reported to FDA.

William Tobler, M.D., Cincinnati, OH, Sept. 4 (Rockville, MD)

The warning letter for the inspection completed May 8 through May 22, 2007 at Mayfield Clinic & Spine Institute stated several objectionable conditions in the procedures used in the participation of a clinical study completed by investigator William Tobler, MD.

According to the Sept. 4 letter, the sponsor failed to ensure the investigation was conducted in accordance with the signed agreement with the sponsor, the investigational plan and applicable FDA regulations.

For example, there was no documentation for study subjects enrolled to indicate that they were evaluated for their eligibility for the study. None of the Eligibility CRFss were signed by the investigator.

All of the CRFs that were signed in space marked "Investigator's Signature" were signed by the study coordinator and not by the investigator. The letter stated that "there was no documentation that the investigator reviewed or verified any of the information reported to the study sponsor or on the CRFs."

Also, the letter noted, that follow-up visit evaluations were not performed for several subjects; the investigator allowed IRB approval to expire three times during the study; the study contained 14 reports of adverse events that were reported after the study closed; and the study protocol requires that all adverse events be reported on the appropriate CRF and this was not completed correctly.

The inspection also revealed that the firm failed to maintain accurate and complete records for each subject's case history and exposure to the device. Specifically, the study subjects' records contained numerous inaccuracies and inconsistencies. In another instance, the investigator failed to ensure that the current, IRB-approved version of the informed consent was correctly documented.

FDA concluded that the sponsor response to these violations was not sufficient. The sponsor stated that it will provide training to study coordinators on the definition of serious adverse events and to ensure proper documentation and reporting procedures. However, the letter stated, "responsibility for accurate and complete implementation of the study should lie with the investigator, rather than study coordinators."

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