WASHINGTON WRAP-UP

FDA's shortest-serving commissioner was apparently driven from office last year by his failure to rid himself of $50,000 worth of stock in Teleflex Medical. The firm is a Limerick, PA–based manufacturer of medical devices, surgical instruments, and disposable medical products marketed under the Deknatel, Hudson RCI, KMedic, Pilling, Rusch, and Weck brands. Now Lester M. Crawford faces a criminal investigation by a federal grand jury—the first FDA chief to do so in the agency's 100-year history, celebrated this summer.

There is a very wide world of difference between a criminal investigation and an indictment, and an even wider difference between an indictment and a conviction. Nevertheless, Crawford's plight is already seen as the price of mixing FDA science with politics.

Even if the grand jury exonerates him, Crawford's standing among his forebears has been dealt a blow. The news was revealed by Crawford's lawyer in a politically volatile civil court case against FDA in New York. The civil case was an effort by the Center for Reproductive Rights to depose Crawford about his role in delaying over-the-counter marketing of the Plan B emergency contraceptive. However, Crawford's attorney told the court that Crawford would plead the Fifth Amendment because of the grand jury investigation.

The attorney, Barbara van Gelder of Wiley Rein & Fielding, told a court-conducted teleconference that she had advised Crawford to refuse to answer questions about the Plan B issue. It, too, had been referred to the U.S. Attorney's Office in Washington, DC, she said. Therefore, it could also become a criminal matter before the grand jury, in addition to Crawford's financial disclosures while at FDA and statements to Congress concerning the Teleflex stocks.

Details of ongoing federal investigations are rarely discussed or even acknowledged by the investigators. But the U.S. Attorney's financial disclosure investigation mentioned by van Gelder is presumably related to Crawford's sudden departure last September after barely two months as permanent commissioner. When he left, it was speculated that he improperly held stock in FDA-regulated companies while at the agency.

In April, it was reported that Crawford had sold the Teleflex stock just before his resignation. In 2004, an agency ethics official had flagged Teleflex among those stock holdings Crawford should sell. Crawford's abrupt resignation led to a probe by the HHS Inspector General, which at press time was ongoing. Van Gelder told the Wall Street Journal that Crawford “fully disclosed everything and [he is] prepared to defend that.”

It may not come as a surprise to many that Crawford might think his family stock holdings in regulated companies are not a big deal. This is especially true in light of the aggressively industry-friendly Bush administration. Crawford has usually shown a relaxed attitude toward the no-man's-land that previous commissioners thought existed between FDA and the firms it regulates.

While still new at the helm as acting commissioner, Crawford told an AdvaMed annual meeting in March 2004 that his door was always open to device manufacturers. He bragged that he was the only commissioner who'd ever had his home phone listed in the phone book, saying, “So give me a call!” He had returned to the agency from a position at the food industry–funded Center for Food and Nutrition Policy at Georgetown University.

Crawford is an affable, ready-to-please veterinarian with a Southern gentlemanly charm and a distinguished résumé. No matter how his present predicaments turn out, historians will likely see him as a victim of the political cauldron that is Washington—a cauldron that increasingly affects the supposedly scientific decision-making processes at FDA.

Guidance on Real-Time PMA Supplements

FDA has published a guidance for industry and FDA staff called “Real-Time Premarket Approval Application (PMA) Supplement.” It provides information about the real-time review process for medical device premarket approval (PMA) supplements and outlines the procedures for requesting and submitting these types of documents.

The new guidance supersedes a 1997 document. It incorporates comments submitted on the earlier document as well as other comments about real-time review from annual Medical Device User Fee and Modernization Act of 2002 (MDUFMA) stakeholder meetings. The revision includes the real-time PMA supplements from section 737(4)(D) of the Federal Food, Drug, and Cosmetic Act and clarifies the kinds of device modifications that are appropriate for real-time review. The agency said it welcomes additional comments.

The guidance covers which modifications are appropriate for real-time PMA supplements, how to request a real-time review, and user fees for real-time PMA supplements. It also covers submitting a real-time PMA supplement, contents of a real-time PMA supplement, and the format of a real-time review meeting, along with a sample real-time review request.

To download the guidance, visit www.fda.gov/cdrh/ode/guidance/673.html.

B&L Abandons MoistureLoc, Is Cited by FDA

FDA reported in May that Bausch & Lomb (B&L; Rochester, NY) has decided to permanently remove its ReNu with MoistureLoc contact lens cleaner from the market. In an announcement that followed shortly, FDA said that it had cited the company in a 10-page FDA-483 for quality system regulation (QSR) deviations at the product's manufacturing facility.

The firm withdrew ReNu with MoistureLoc from the U.S. market in April and later worldwide, FDA announced. There is concern that a characteristic of the product's formulation in certain unusual circumstances can increase the risk of Fusarium keratitis infection.

The agency said it supported B&L's decision. CDRH director Daniel Schultz told a news conference that the concern was brought about by a complex relationship between the design of ReNu with MoistureLoc and some use patterns. The withdrawal had no apparent relationship to CGMP problems that FDA had found at B&L's Greenville, SC, plant, where the product was made.

After more than eight weeks in the facility, three investigators checking for Fusarium contamination made 18 observations at the manufacturing facility at 8507 Pelham Rd. FDA cited the company for a design plan that did not adequately describe the design and development activities for ReNu with MoistureLoc, and for medical device reporting (MDR) deficiencies involving failure to notify FDA of 35 injury reports. In addition, failures to revalidate process changes, to prevent contamination, and to define and document procedures were cited.

Two observations were aimed at the firm's repackaging and relabeling facility at 130 Commerce Ctr. They cited the company for not having procedures to prevent product “mix-ups, damage, and other adverse effects.” The facility was also cited for not documenting procedures to prevent contamination “by certain substances.” Packaging equipment for ReNu with MoistureLoc, including equipment coverings, “on both lines was dirty and dusty. Additionally, the entire packaging area was in need of cleaning.”

In a news release announcing the inspectional findings, FDA gave no details. It simply described the FDA-483 as detailing “observations of procedures found to deviate from FDA quality system regulations.” Earlier, officials had praised B&L's cooperativeness as the story of the Fusarium keratitis infections gradually unfolded in the media. The FDA release said that after “extensive inspection and testing of environmental factors, raw materials, in-line manufacturing processes, and finished products, these preliminary results do not provide evidence of Fusarium contamination.

“Bausch & Lomb has proposed the ReNu with MoistureLoc formulation as the potential root cause of the increased relative risk of Fusarium keratitis. The observations from the FDA inspection, which may indicate deviations from current good manufacturing practice, do not necessarily support a connection between the formulation of the ReNu with MoistureLoc product and the Fusarium keratitis infections. It is important to point out FDA's inspectional observations are preliminary and will need to be further evaluated before any conclusions can be drawn about such a connection.”

During a press briefing four days earlier, Schultz was asked if there was more that FDA could have done during the approval process for the ReNu with MoistureLoc solution. He said agency officials will go back and look at the process, but he also said he doubted anything could have been seen or changed. “I don't think this is the kind of problem that could be seen during even a very extensive premarket review,” he said. He added that the case shows the importance of continuing to look for signals and make decisions based on sound science.

Attorney on Lessons Learned from the Utah Medical Case

There are lessons that industry can take away from last year's FDA defeat in the Utah Medical Products federal court trial, according to defense counsel Larry R. Pilot of McKenna, Long & Aldridge. First, seek explanations from FDA whenever you don't understand its position. In addition, seek competent independent review of the dispute and always support your beliefs.

Addressing the Medical Device Quality Congress in San Diego in May, Pilot said that there are also lessons for FDA, which he said has shown no willingness to learn from the case. First, FDA failed. Just as the QSR's goal for industry is the release of safe and effective medical devices, the FDA goal for compliance through enforcement by litigation is success through the court's opinion. In other words, FDA lost on both counts, as it has lost all four QSR/GMP cases it has brought to court (Utah Medical, Laerdal in 1994, Andersen in 1997, and BioClinical in 1988). FDA and CDRH should apply the QSR approach to their own performance with respect to their inspections, supervisory reviews of inspection results, internal decision making, and pursuit of successful litigation.

The central issue in the trial was FDA's belief—which was not accepted by the court—that a new GMP becomes a regulatory requirement when it's generally accepted throughout the industry. To the agency, that would be true even if it were not written down and even if a majority of firms did not follow it. By contrast, the court said CGMP requirements “are set forth in this quality system regulation...[and] it is fundamental that the regulations state applicable law.”

Why did FDA fail in the Utah Medical case? In Pilot's opinion, there are many reasons. Pilot cited poorly trained investigators and associated personnel; poor supervisory review; a multilevel unwillingness to listen to, talk to, and understand the company; and a resistance to differences of opinion. In addition, he said, FDA showed an internal inability to challenge lower-level decisions and recommendations, performed no risk analysis, and held an attitude of superiority combined with an ends-justifies-the-means philosophy. FDA's unwillingness to learn from mistakes and a refusal to apply corrective and preventive actions to its own mistakes, as well as an absence of oversight from HHS, also contributed, Pilot said.

Pilot's advice for FDA: Seek objective internal and external evaluation of the failures in the Utah Medical case. Adopt a code of ethics, use the GMP Advisory Committee to examine what went wrong, and restore quality as the GMP objective, as opposed to enforcement.

Guidance on Reprocessors' Product IDs

CDRH has published a guidance outlining how device reprocessors should label reprocessed devices with their name or a symbol for identification purposes. The document says that the original device should “prominently and conspicuously bear the name of the manufacturer of the original device, a generally recognized abbreviation of such name, or a unique and generally recognized symbol identifying the manufacturer.” In addition, if the original device does not display the name, the manufacturer that reprocesses the single-use device “may identify itself using a detachable label on the device's packaging.”

The detachable label is then intended to be removed and affixed to the patient's medical record by the reprocessed-device user. The labeling of such devices should help users accurately report adverse events and device malfunctions related to reprocessed devices, FDA says. To view the guidance, visit www.fda.gov/OHRMS/DOCKETS/98fr/05d-0401-gdl0002.pdf.

Guidance on Postmarket Surveillance

CDRH has released a guidance on postmarket surveillance. It consolidates previously released documents and updates requirements mandated by the FDA Modernization Act of 1997 (FDAMA). The document, “Postmarket Surveillance Under Section 522 of FDAMA,” describes the regulatory requirements for manufacturers that are ordered to conduct postmarket surveillance (PS). FDAMA gave FDA authority to order PS if a device failure could have serious adverse health consequences or if the device is to be implanted or used for life-sustaining purposes.

The guidance outlines CDRH's general approach to placing a PS order. It explains how FDA decides when PS is necessary, the process for notifying and involving the manufacturer, which different types of PS tools may be appropriate, how the manufacturer should conduct and report PS activities, and how FDA will review and follow up orders for PS.

To view the guidance, visit www.fda.gov/cdrh/osb/guidance/316.html.

Class 1 Recall by Respironics

A Respironics recall of its PLV Continuum ventilator has been classified as Class 1 because of its potential for serious injury or death. The company issued a recall notice in March because a design flaw could cause lead wires in the airflow valve to break during use, ending mechanical ventilation.

Customers were told to quarantine units in their possession and not use them with patients. Company representatives are said to be contacting all customers to arrange for the return of all affected units. Customers were told to safely transition patients in their care from the PLV Continuum ventilator to other comparable patient support devices.

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