Medical Device Daily Washington Editor

FDA's inspection regime has naturally evolved over time, and the recipient of a recent warning letter gave Medical Device Daily some perspective on how things have changed over the years. Gail Bryne, who owns Brymill Corp. (San Diego, California) with her husband, received a Feb. 18 warning letter and told MDD that FDA's inspections in the 1960s, when they first opened the business, were "rudimentary" compared to the inspections conducted today.

Regarding the Feb. 18 warning letter, Bryne said, "We received a letter from FDA stating that our updated procedures and proposed corrective actions adequately address the items listed in the warning letter." She estimated that the previous inspection took place three to five years ago, and remarked that the company had just obtained clearance for a new product, hence the likelihood that this was a pre-approval inspection.

Brymill, which makes liquid-nitrogen cryosurgical devices, was cited for five deviations from the quality systems regulations (QSR), including for a lack of "raw data used to support the verification of the software used in" the firm's Tracker, a device designed to track skin temperature during cryosurgical procedures.

The firm's complaint-handling procedures were cited as failing to require that service reports be reviewed. FDA listed as an example one service report that did not specify the nature of the complaint, stating that the company could not document any effort to determine the reason for the return of the device.

Third-party manufacturing issues cropped up, as has been the case with many warning letters since early 2008, and Brymill was cited for lack of documentation of any audits of a third party and for lack of certificates of conformance for purchased components. FDA also cited Brymill for lack of employee training for complaint handling.

Canadian firm cited for MDR lapse

As commonplace as third-party manufacturing citations are in warning letters for the past year and a half, citations for problems with medical device reporting (MDR) procedures also are commonly found in warning letters, and a May 12 warning letter to Pyng Medical (Richmond, British Columbia) is no exception. Each of the three citations in the warning letter are directly or indirectly connected to MDR procedures in connection with the Fast1, a device designed for insertion across the sternum for rapid delivery of drugs and other therapeutic agents in trauma settings.

FDA said that Pyng had not reported as an MDR that surgeons were unable to insert the Fast1 into a patient after three attempts in January 2007. FDA stated that the company's January 2009 response "does not adequately address the MDR issues" and that "despite your claim of having submitted a report FDA has not received" an MDR on this incident as of this March 27.

The firm apparently did not report an April 2007 incident in which the "portal tip of the insertion tubing" of the Fast1 "disconnected during attempted removal." The company's response to this citation, FDA asserts, "demonstrates a lack of understanding" of MDR requirements "and a misunderstanding of the definition of 'having caused or contributed'" to a reportable event. The agency also stated that it never received any of five MDRs Pyng claimed to have filed.

The warning letter also alleges that Pyng's MDR procedures lacked "a standardized review process or procedure for determining when an event meets the criteria" for an MDR. In a separate citation, FDA also states that complaint files did not give evidence of a complete investigation into each of the previously referenced events. The warning letters states that Pyng "needs to make a reasonable effort to find out and document what happened to the patient as a result of the reported failure" in addition to determining why the device failed.

At press time, Pyng had not responded to calls for comment.

Doc plays sponsor, snares warning

Those who engineer clinical trials for small and large device firms can attest to the amount of work involved, and warning letters to physicians who act as both clinical investigators (CIs) and sponsors hint that doctors often find out the hard way that the workload is bigger than anticipated.

This may have been the case in the May 20 warning letter to Richard Ringel, MD, a physician at Johns Hopkins Medicine (Baltimore), who drew three citations as a sponsor and only one as a CI. Ringel was cited as the primary investigator for having failed to ensure that a data safety monitoring board met at the required frequency. Ringel's proposed fixes were redacted from the letter, but FDA noted that it wanted to see "copies of corrective actions you have implemented or plan to implement to ensure" that protocols will be followed.

In his capacity as a sponsor, Ringel was cited for failure to ensure that a data coordinating center "monitored each of the investigative sites as stated per protocol." FDA writes in the warning that Ringel's response did not spell out "ongoing oversight of the clinical study," adding that the monitoring schedule "should not be a one-time event."

FDA also charged the pediatric cardiologist with failing to obtain financial disclosure data from 11 other CIs involved in the study and for failing "to obtain signed investigator agreements for all" participating CIs (the agency redacted the number of CIs for whom Ringel lacked signed investigator agreements). Ringel evidently provided FDA with a copy of the agreements and disclosure forms, but the agency called for "copies of corrective actions" to ensure that the problem would not recur.

Attempts to contact Ringel for comment were unsuccessful.