Washington Report

New FDA Policies Shape Pharma Development and Production - continued

Cracking down Perhaps to demonstrate that FDA can be a tough enforcer, FDA took the unusually severe action of seizing two major drugs produced at GlaxoSmith- Kline’s manufacturing facility in Cidra, Puerto Rico. FDA and the Justice Department cited ongoing manufacturing quality problems and the company’s failure to take requested action on “significant violations” of GMPs. The agency explained that it had cited manufacturing issues at the Cidra plant in a 2002 warning letter and subsequent inspection reports. These included deficiencies in process controls, process validation, personnel training, and documentation of investigations into batch failures. The regulators specifically noted a lack of product uniformity in lots of the two-drug combination diabetes treatment “Avadamet” (rosiglitazone/metformin), which raised the possibility of inaccurate dosing. The investigators also found evidence that some “Paxil” (paroxetine) controlled-release tablets could split apart, giving patients either no drug or too much active ingredient in some cases. Glaxo explained that it had taken steps to recall supplies of the troubled products as FDA had requested and was working to identify and fix its manufacturing problems. The company subsequently reported efforts to negotiate a consent decree with FDA to resume production as soon as possible, but this is likely to involve a lengthy upgrade and validation process. The problems also threaten production delays for other Glaxo products made at the Puerto Rico plant and possible postponement in FDA approval of new Glaxo drugs. FDA compliance officials acknowledged that this high-profile seizure was designed to prompt all manufacturers to take GMP violations and warning letters more seriously and to carry out requested recalls without delay. FDA Associate Commissioner for Regulatory Affairs John Taylor said that once FDA discovers a company is not following safety and quality standards, “we expect them to correct the deficiencies in an expedited manner.” FDA had more benign ways to deal with the Glaxo manufacturing problems, but the decision to seize these widely used products was guaranteed to generate press coverage of FDA as a tough enforcer of drug safety rules—the kind of story that could help Crawford demonstrate his bona fides to senators eager to crack down on lax FDA enforcement. FDA’s enforcement action also may seek to address concerns that the agency issuedfewer GMP warning letters in recent years. Although nearly 30 warning letters were directed at drug manufacturing issues in 2003 and 2004—compared with more than 70 in previous years—FDA says that the warnings it issues raise more serious problems and are likely to generate more aggressive agency responses, as seen in the Glaxo seizure. In March, the agency demonstrated that it can take action when needed by issuing warning letters citing GMP violations to a manufacturer of antibiotics (Patient First Corp.) and to a firm that produces herbal tinctures intended for ophthalmic use (Alternative Health & Herbs Remedies) but that the agency claims are actually drugs. A few weeks later, FDA made another bold move by telling Pfizer to halt sales of “Bextra” (valdexocib). The agency also required black-box warnings for Pfizer’s “Celebrex” (celecoxib), the only remaining COX-2, and for all prescription nonsteroidal anti-inflammatory drugs (NSAIDs). In what is probably a regulatory first, FDA decided to allow nonprescription NSAIDs to share the market with products carrying black-box warnings. Over-the-counter NSAIDs must add more warnings to their labels, but FDA officials decided that they should remain available because they provide lower doses and patients generally use them on a short-term basis. Pfizer moved to shore up its position in the pain-relief category by promising a long-term study comparing Celebrex’s safety to other drugs and suggesting that it might even resume direct-to-consumer advertising, an activity that FDA may permit if the marketer can address all risks clearly and completely. Pfizer acknowledged hopes to renew limited sales of Bextra, despite speedy moves by trial lawyers to file new suits against the drug. FDA’s actions, heralded as the agency’s most sweeping challenge to marketed drugs ever, went beyond the recommendations of its advisory committees, which had voted by a narrow margin in February to keep Bextra on the market. Members of Congress praised FDA’s more aggressive stance for dealing with high-risk drugs, but many manufacturers fear that these actions signal a more risk-averse regulatory stance. A decade ago, FDA was accused of dragging its feet over new drug applications; now the charge is that the agency is moving so fast that it’s letting unsafe and insufficiently tested products on the market. The question is whether FDA is tipping the delicate risk–benefit balance for prescription drugs and biologics too much to the risk side and how that will affect the development of new therapies. (continued)