A Medical Device Daily

Arrow International (Reading, Pennsylvania), a maker of various catheters for cardiac and other uses, has been in the news quite a bit of late, partly because of a merger engineered this past summer. However, the issuance of a fourth warning letter to Arrow in the past 30 months may end up giving its partner in business a bad case of corporate indigestion. In any case, the letter warned the firm that FDA will issue no more warning letters if the firm fails to get its operations under control, hinting at stronger action.

Arrow’s board gave former CEO Carl Anderson his walking papers this past summer (Medical Device Daily, June 1, 2007), but the tumult did not begin there. The board had announced in May that it was looking at strategic options for the firm, a move that did not sit well with the representative of one of the larger investors in the company.

Board member Richard Niner, who represented the Robert McNeil Trust, resigned in protest of the move, saying that he “forcefully opposed” a sale because the company was “in the midst of a turnaround and value-building program.” All the same, the company merged recently with Teleflex Medical (Research Triangle Park, North Carolina), which paid $45.50 a share (Medical Device Daily, July 24, 2007) in a deal valued at about $2 billion.

The Oct. 10 warning letter said that Arrow had received three warning letters in the summer of 2005, one each for facilities in Mount Holly, New Jersey, Reading, Pennsylvania, and San Antonio. According to FDA, Carl Anderson, a former CEO for Arrow, had “participated in a regulatory review meeting” with the agency’s New Jersey District Office in November 2006 to go over violations found in the September 2006 inspection of the Mount Holly plant. The current warning letter addresses operations in plants in Everett, Massachusetts and Asheboro, North Carolina disclosed in inspections that each spanned more than three weeks between January and February 2007.

FDA warned the company “if we continue to observe similar problems at the same or other Arrow International facilities, you will not receive any further warnings from our office prior to us taking regulatory action against your firm.”

In the first citation, FDA said that personnel at the Asheboro plant did not confirm the replacement of a valve in a sterilizer corrected for a thermal excursion. Temperatures in the sterilizer were said to have exceeded 48.1 degrees Celsius “for ten minutes on Aug. 14, 2006,” and that personnel did not check to establish whether the replacement of a relay switch had addressed the problem. A subsequent sterilization cycle was also terminated due to high temperatures, a problem that was addressed by the replacement of a stem valve.

The warning letter detailed 15 other violations of good manufacturing practices (GMPs), and the agency said that problems with quality management, corrective and preventive action (CAPA), complaint handling and training “were previously brought to your attention in two warning letters” issued in June and August 2005. FDA added that Arrow’s “corporate-wide ‘Project Excellence’ program has had more than two years” to put a CAPA plan into place, seemingly to little or no avail. FDA also said that Arrow’s proposed corporate quality system “failed to adequately correct these systemic quality problems.” The warning letter was signed by both Thomas Gardine, the director of FDA’s Philadelphia office and Tim Ulatowski, the director of compliance at the Center for Devices and Radiological Health.

At press time, Arrow and Teleflex had not returned calls to Medical Device Daily for comment.

FDA offers Q&A for IVD guidance

Makers of diagnostics often find that they are exempt from clinical study regulations found in 21 CFR 812, but the existing guidance is dated December 1999. Much has changed since then, and FDA is working on a new guidance for in vitro diagnostics studies (IVDs). FDA has published a “Q&A” related to a new guidance to give industry a heads up on the expectations for diagnostics studies.

The agency said that any IVDs designed prior to the 1976 Medical Device Amendments are grandfathered in, as are any IVDs based on a predicate. As for the “substantial risk” qualification, the guidance will focus on whether “misdiagnoses and/or error in treatment ... would be considered a significant risk if the potential harm could be life-threatening or could result in permanent impairment.” Any false positives that could result in unnecessary confirmatory testing, treatment or “psychological trauma” — instances in which the misdiagnosis is of a life-threatening disease or condition — would also qualify as high-risk IVDs.

A new diagnostic would be exempt from study requirements if the results can be confirmed by a “medically established means of diagnosis (e.g., another cleared or approved IVD or culture)” and so long as the test results for the investigated IVD do not influence the course of treatment during the course of the study. Failing a back-up diagnostic procedure, the sponsor has to obtain an IDE. The diagnostic can be used outside the study protocol if the patient has “a serious disease or condition” for which there is no “generally accepted alternative,” and when “there is no time to use existing procedures to get FDA approval for the emergency use.”

In a non-emergency situation, the IVD under investigation can be used for diagnosing a single patient or small group of patients under a compassionate use basis, but this would require a change to any study protocol that did not encompass this application. This would also require FDA’s stamp of approval.