Safety, Surveillance, and Product Shortages

Does FDA harm patients by rushing unsafe products to market or by slowing product development and approval? That debate came to the fore recently with the almost simultaneous release of competing studies.

Public Citizen director Sidney Wolfe and Harvard Medical School researchers published a report in the Journal of the American Medical Association (JAMA) accusing FDA of approving too many unsafe new drugs. Reseachers had examined the number of new therapies approved between 1975 and 2000 that were subsequently withdrawn from the market or had black-box warnings added to their labels. The take-home message is that physicians should avoid prescribing any therapy that is less than seven years old if an alternative treatment is available and that FDA should be much more careful in approving new medicines.

Around the same time, a Washington think tank unveiled a survey of 160 oncologists, many of whom believe that FDA is too slow in approving new medical products. Although almost half (48 percent) said FDA's approval process has improved, 60 percent agreed that the agency takes too long to approve new therapies, and about half also believe that FDA regulations prevent them from using promising new treatments. The Competitive Enterprise Institute (CEI), which sponsored the poll, wants FDA to speed new products to market and let physicians decide what treatments are appropriate for patients. Insisting on absolute knowledge would be a disaster, says CEI attorney Sam Kazman: "Zero drug recalls equal zero drug approvals."

A similar debate took place at the annual meeting of the Food and Drug Law Institute (FDLI) in April. Robert Temple, director of the Office of Medical Policy at FDA's Center for Drug Evaluation and Research (CDER), defended FDA against attorney Peter Barton Hutt's charges that the agency is too conservative in bringing new therapies to market. Hutt argued that, even though application review times have declined, FDA now asks for more and more clinical information, which slows down product development. Temple responded that his review of 29 new drug applications, each of which took more than 12 months to be approved, provides no evidence that FDA is hindering the process and that most delays arise from safety concerns that require additional data.

Agency Bottleneck?

FDA officials acknowledge that the average review time for standard applications has increased in recent years, despite a reduction in the "action deadline" under the Prescription Drug User Fee Act (PDUFA). The trend has generated charges that FDA issues "approvable" letters to meet user fee deadlines, then takes a long time to finalize labeling and other issues before letting the new product enter the market.

Although industry is concerned about any slowdown in application approvals, the real problem appears to be an actual decline in the number of new therapies coming to market. CDER deputy director Steven Galson agrees with that assessment. CDER approved only 24 new molecular entities last year, the smallest number since 1995.

The decline is particularly noticeable for biotech therapies, according to Carl Feldbaum, president of the Biotechnology Industry Organization (BIO). At a recent meeting he described FDA as once again "a choke point in the development pipeline," possibly because of the lack of a strong leader in the commissioner's office.

Separately, Kathryn Zoon, director of FDA's Center for Biologics Evaluation and Research (CBER), acknowledged the recent drop in approvals and also in products under development. Manufacturers and researchers filed only 326 investigational new drug applications for biologics and investigational device exemptions with CBER in 2001, compared with more than 400 during each of the previous two years.

Product Woes

In light of soaring public and private investment in biomedical research, that trend is distressing. The federal government is about to double the National Institutes of Health budget to $27 billion. Many states are offering tax and other incentives to spur biotech development, and investors continue to boost support for the industry. Public offerings provided $5.7 billion for biotech companies in the first quarter of 2002 alone.

Questions about the declining productivity of pharma R&D arose during a hearing on generic drug competition before the Senate Commerce Committee in April. Senator Ron Wyden (D, Oregon) noted that some members of Congress question industry demands for strong patent protection and high prices for brand-name medicines when companies are failing to deliver anticipated new cures. Wyden cited industry mergers as a possible factor underlying the drop in R&D productivity, as well as increased spending on direct-to-consumer (DTC) advertising. Pharma companies point to FDA regulatory policies plus an increased focus on finding therapies for more hard-to-treat diseases. Wyden said he planned to explore research productivity more fully as a central development affecting policies governing patents and generic drug competition.

Supply Crises

A serious concern for both FDA and the industry is that overly strict good manufacturing practices (GMP) enforcement will lead to plant closures and shortages of important therapies. Most of the products listed on the "drug shortages" page of the FDA website are there because of production problems. The Centers for Disease Control and Prevention (CDC) warns that there are shortages of most childhood vaccines, largely because of manufacturing difficulties or company decisions to exit certain market categories. Industry consolidation, as well as new vaccine formulation requirements, also have taken a serious toll on vaccine supplies.

Typically, FDA develops action plans to cope with critical therapy shortages. That may involve helping a company resolve GMP issues or expediting review of new data or of another supplier's application. FDA also seeks advance notice of company plans to halt production of important sole-source products. Pharmacists have been clamoring for earlier information about anticipated shortages so they can deal with a growing list of hard-to-obtain medicines. The American Society of Health System Pharmacists lists shortages tracked by the University of Utah Drug Information Center to keep pharmacists informed about the duration of current shortages and efforts to restore supplies.

Some policy makers are urging increased government intervention to prevent shortages of critical drugs and vaccines. Enlarging government stockpiles is one possibility; another might be to establish a government-owned vaccine manufacturing operation. A Department of Defense panel recommended such action last year, and the Institute of Medicine issued a similar proposal. Congress is slated to review such initiatives later this year when the General Accounting Office issues a new report on vaccine shortages.

Although FDA wants to avoid medical product shortages, it still plans to enforce manufacturing requirements. FDA needs to "balance supply with the need to comply with GMPs," commented Zoon of CBER. But, she said, allowing companies to ignore GMPs is equally troubling: "With millions of vaccines going into babies every year, we have to do our job."