Modernizing Drug Safety Laws

The Prescription Drug User Fee Act (PDUFA), the law that allows the Food & Drug Administration to collect fees from pharmaceutical companies to help expedite drug reviews, is set to expire in September 2012. But as Congress begins to deliberate on reauthorizing PDUFA, an event that has occurred every five years since 1992, some lawmakers are taking the opportunity to address prescription drug shortages and safety concerns related to the globalization of the U.S. drug supply chain.

This broadening of focus beyond user fees was evident at a recent Senate hearing and promises to garner continued attention as the reauthorization of PDUFA moves forward.

In draft recommendations released last month, FDA proposed raising drug user fees by 6% above the current level, bringing the total drug user fee budget to about $693 million in fiscal 2013 (C&EN, Sept. 12, page 17). Such fees provide about 60% of FDA’s drug review budget.

It is now up to Congress to approve the user fee hike. As part of that process, the Senate Committee on Health, Education, Labor & Pensions (HELP) held a hearing last month to examine the safety and integrity of the U.S. pharmaceutical supply chain.

A recurring theme at the hearing was the need to level the playing field so that U.S. pharmaceutical companies are not inspected more frequently and held to higher standards than foreign drugmakers. FDA estimates that 80% of the active ingredients in pharmaceuticals sold in the U.S. and 40% of prescription drugs taken by Americans are manufactured abroad (C&EN, May 16, page 11).

“U.S. companies that source and manufacture drugs in this country should not be placed at a competitive disadvantage by foreign firms that operate with less oversight and sell substandard ingredients into this country at reduced prices,” said Sen. Tom Harkin (D-Iowa), HELP Committee chairman. “FDA does not have the authority and flexibility it needs to make sure that foreign facilities adhere to the same quality standards as U.S. facilities,” he stressed.

The current system does not reward pharmaceutical companies for complying with Good Manufacturing Practices, testified Deborah M. Autor, FDA’s deputy commissioner for global regulatory operations and policy. “Companies that choose to skirt the law can do so beyond regulators’ reach and thereby make more money,” she said. Autor pointed to recent incidents of drug adulteration, counterfeiting, and cargo theft, all of which, she said, “have posed serious threats to public health.”

The increasing complexity of the drug supply chain has made it more difficult for regulators to catch bad actors. “In addition to the sheer volume of imports and foreign facilities, there has been an increase in the variety of sources, shippers, and methods of transportation,” Autor pointed out. “Our current authorities have not kept pace with the challenges of the current global marketplace,” she said.

Autor suggested several ways that Congress could help remedy the situation, including giving FDA the authority to recall drugs that appear to be unsafe, increasing criminal penalties for violating drug safety laws, and requiring drug manufacturers and pharmacies to use a track-and-trace system that tells them who has handled a drug along the supply chain. She also urged Congress to give FDA the authority to refuse products at the border from foreign facilities that refuse or delay FDA inspections.

Currently, the burden is on FDA to show that a drug product appears to be adulterated, misbranded, or unapproved to keep it out of the country, Autor told lawmakers. FDA has begun using portable spectrometers to rapidly screen products at the border, but such tests still need to be confirmed by laboratory analyses. In most other countries the burden is on drug companies to show that their product meets minimal safety standards to be imported.

Another problem, Autor noted, is the need to obtain a letter of invitation from some countries, such as China, just to get a visa to enter the country to do inspections. As a result, FDA cannot perform unannounced inspections of drug manufacturing facilities in such countries, unless it has inspectors already stationed there.

FDA does have 13 posts around the world, but those offices are insufficiently staffed to inspect all foreign facilities at the same frequency that domestic facilities are inspected—which happens once every two years. FDA typically inspects foreign facilities once every three to five years.

To help level the playing field, “we need to form global coalitions of regulators,” Autor emphasized. “To some extent that means harmonizing standards; to some extent it means simply being able to rely on each other,” she said. Such collaborations would have benefits for industry, including fewer inspections and streamlined requirements, she pointed out. The global pharma industry recognizes such benefits and is interested in working with regulators toward a safer drug supply (see page 30).

Industry supports the use of third-party inspectors and foreign regulatory bodies to ensure that foreign facilities are complying with U.S. standards. “We recognize that there will never be enough resources for the agency to get to all the places it needs to get,” Kendra A. Martello, assistant general counsel with the industry group Pharmaceutical Research & Manufacturers of America, said at the hearing. She urged FDA to inspect high-risk facilities more often than low-risk ones.

Another challenge for FDA is that it lacks complete information about drug manufacturing facilities, pointed out Marcia Crosse, director of health care at the Government Accountability Office, the investigative arm of Congress. FDA asks companies to submit a unique facility identifier with all drug applications, but it can’t require them to do so.

But some Republican senators are hesitant to give FDA additional authorities. Sen. Michael B. Enzi (R-Wyo.), ranking minority member of the HELP Committee, is particularly concerned about giving FDA the power to require a drug track-and-trace system.

Enzi pointed out at the hearing that a full track-and-trace system is estimated to cost about $110,000 for an individual pharmacy. “Small-business pharmacists can’t afford this additional cost,” he noted. “Right now my concern is FDA overregulating, not underregulating,” he said.

Autor reassured lawmakers that FDA would take into consideration both the benefits and costs of a track-and-trace system. She also pointed out that such a system would help slow down the growing problem of drug shortages in the U.S.

Sen. Richard Blumenthal (D-Conn.), cosponsor of the Preserving Access to Life-Saving Medications Act (S. 296), used the hearing to address his concerns about the rapidly growing number of drugs that are in short supply.

Drug shortages have allowed the gray market—secondary suppliers selling substandard drugs at exorbitant prices—to flourish, Blumenthal said. Sterile injectable drugs, including anesthesia, antibiotics, and some cancer drugs, have been particularly prone to shortages.

S. 296 would help prevent future shortages by requiring manufacturers to give FDA six months’ notice before discontinuing or interrupting drug production. Currently, companies voluntarily provide FDA with such information.

FDA has prevented 99 drug shortages so far this year, thanks to companies notifying the agency of production changes. In 2010, FDA prevented 38 shortages, according to agency officials. But overall, the number of drugs in short supply has tripled in the past five years.

The reason drug shortages are on the rise is complex and controversial. At a public meeting last month, FDA officials stated that 54% of drug shortages in the U.S. in 2010 were caused by product quality concerns, such as sterility problems and the presence of foreign matter; 21% were due to production delays; 11% were caused by discontinuations; 5% were attributed to raw material issues; 4% were associated with increased demand due to another shortage; 3% were due to loss of a manufacturing site; and 2% were due to component problems.

not everyone agrees with FDA’s analysis. At the public meeting, Erin R. Fox, manager of drug information services at the University of Utah Hospitals & Clinics, reported that 55% of drug shortages have unknown causes, 23% are due to manufacturing problems, 13% are related to supply-and-demand issues, 6% are caused by discontinuations, and 3% are due to raw material issues.

Congress and the Obama Administration are taking drug shortages seriously. In addition to S. 296, a bill to address drug shortages has been introduced this year in the House of Representatives (H.R. 2245). And now, some lawmakers are eyeing reauthorization of drug user fees as an alternative vehicle to get the legislation passed.

Sen. Michael F. Bennet (D-Colo.), for example, is considering adding language to the PDUFA reauthorization bill that would require a “uniform pedigree standard” that allows FDA to monitor individual drugs throughout the supply and distribution chain. Such a standard would ensure that all drugs are manufactured, stored, and distributed safely and legally.

Sens. Harkin and Enzi plan to have PDUFA legislation ready for a Senate vote by early spring.