Just a decade ago, FDA was accused of dragging its feet on new drug applications. Now, supposedly, the agency is moving so fast that it's letting unsafe, insufficiently tested products into the marketplace.
The cherry blossoms bloomed in Washington last month, but it was not a cheery time for FDA—or pharma companies. Prospects for a speedy Senate confirmation of Lester Crawford as the next FDA commissioner were put on hold by Senators demanding that FDA first take action on the application for an OTC version of Duramed's "morning-after" contraceptive, Plan B (levonorgestrel).
As legislators accelerated efforts to shore up FDA's oversight of drug safety, agency officials showed their muscle by seizing a massive quantity of drugs produced in Puerto Rico by GlaxoSmithKline (GSK), and forcing Pfizer to halt sales of its COX-2 inhibitor Bextra (valdecoxib). While many observers fear that the seizures and withdrawal actions signal a more risk-averse stance at FDA, cynics regard these actions as just another swing of the regulatory pendulum. A decade ago, FDA was accused of dragging its feet over new drug applications; now the agency is accused of moving so fast that it's letting unsafe and insufficiently tested products onto the market. Meanwhile, despite the current focus on safety, legislators and others remain oddly focused on opening the door to broader importation of drugs (see "Matters of Import").
Meanwhile, FDA has demonstrated that it already has the power and will to pull unsafe drugs off the market. At the annual meeting of the Food and Drug Law Institute in April, Senator Mike Enzi (R-WY), chairman of the Senate Health, Education, Labor and Pensions Committee, reported that he is working with ranking Democrat Edward Kennedy (D-MA) on a "comprehensive response" to drug safety problems. They are evaluating recommendations made by FDA officials and other experts at committee hearings this past February, including legislative proposals to establish a more independent drug safety oversight system.
Matters of Import
Not coincidentally, FDA cracked down on GSK in March for failing to fully recall deficient lots of controlled release Paxil (paroxetine) and the diabetes drug Avandamet (metformin) made in Puerto Rico. The seizure, which FDA says is the largest in its history, aimed to send a message to manufacturers to pay attention to warning letters and citations for violating good manufacturing practices.
The loss of these blockbuster products should cost GSK more than $1 billion in annual revenues for as long as the plant remains shut down, and more if the feds seek disgorgement of past revenues and profits. Negotiations of a consent decree were rumored at press time. This could involve a very long and costly process of overhauling the plant to meet manufacturing standards.
In addition to telling Pfizer to halt sales of Bextra, FDA required black-box warnings for Pfizer's other COX-2, Celebrex (celecoxib), and for all prescription NSAIDs (non-steroidal anti-inflammatory drugs). Pfizer objected, but FDA's decision may be a boost for Celebrex, which now appears no riskier than widely used painkillers.
FDA is allowing nonprescription NSAIDs to remain on the market, albeit with more warnings on labels, because the OTC versions are used in low doses and generally for short periods.
Pfizer moved to shore up its position in pain relief by promising a long-term study comparing Celebrex's safety to other drugs', and suggesting that it might even resume DTC advertising. The company acknowledged hopes to renew limited sales of Bextra, despite speedy moves by trial lawyers to file new suits against the drug.
FDA's decision to halt Bextra sales went beyond the recommendations of its advisory committees, which in February voted by a narrow margin to keep the drug on the market. Some Congressional critics praised FDA for taking an aggressive stance with high-risk drugs—and for throwing the book at pharma marketers—but industry fears that the agency is tipping the delicate risk-benefit balance for prescription drugs too much to the risk side.
To further demonstrate that it has policies and programs to ensure drug safety, FDA issued three final guidances in March designed to improve the collection of data on drug safety prior to approval, to enhance adverse event tracking, and to ensure the safe use of medications. A main theme of these documents, plus a separate Good Review Management Guidance, is to encourage more consistent review practices and approval policies across drug review divisions. The guidances (
Premarket risk assessment The guidance outlines testing approaches likely to enhance a sponsor's understanding of product safety concerns, noting the need for longer and larger trials for drugs intended for long-term use.
RiskMAPs The guidance emphasizes that only a limited number of high-risk products will warrant the use of a Risk Minimization Action Plan (RiskMAP) to educate patients. This reflects concerns of doctors and pharmacists about dealing with too many special prescribing and dispensing programs.
Pharmacovigilance The guidance discusses ways in which pharma companies can establish good pharmacovigilance programs for marketed drugs. In identifying strategies for identifying and analyzing safety signals, FDA recommends that manufacturers also investigate signs of confusion about a product's name, labeling, packaging, or use.
In addition to Congressional hearings, drug safety is the prime topic at a number of public meetings on policies affecting FDA and drug marketers. The Institute of Medicine Committee on Identifying and Preventing Medical Errors discussed drug safety reporting systems at its April meeting. At the same time, FDA's Science Board devoted much of its April session to pre- and post-marketing safety programs for drugs and biologics.
Also last month, scientists from industry, academia, NIH, and FDA discussed a guidance on how pharma and biotech companies may submit pharmacogenomic data to FDA (see "A Push for Personalized Medicine," page 28). FDA acting deputy director Janet Woodcock opened the meeting by outlining the "real imperative" for improving the current wasteful and uninformative system for testing drug candidates, and shifting to research methods that use biomarkers to predict drug side effects and benefits. Success in this area can address the current crisis over affordability and access, she said, as well as the need for a more agile process to produce medical countermeasures in response to public health emergencies.
Perhaps in the end, the public will have a better understanding of the dangers associated with all pharmaceuticals and how virtually impossible it is to guarantee a risk-free medical treatment.
Jill Wechsler is Pharmaceutical Executive's Washington correspondent.