The globalisation of the supply chain increasingly challenges the US Food and Drug Administration's ability to ensure the quality of pharmaceuticals on the US market, acknowledges the acting director of the agency's Center for Drug Evaluation and Research.
Addressing a hearing of the House Agriculture, Rural Development, Food and Drug Administration and Related Agencies Appropriations Subcommittee last week, Dr Janet Woodcock, who is also the FDA's chief medical officer and deputy commissioner for scientific and medical programmes, noted that the agency now routinely reviews and monitors drugs - from both innovator and generic companies - that are "studied or manufactured, at least in part, outside the United States".
The supply chain for finished drugs and active pharmaceutical ingredients "frequently links to manufacturing sites in countries such as China and India", Dr Woodcock pointed out, adding: "With the globalisation of the supply chain, FDA faces an ever-growing number of brokers, traders, distributors, repackagers, and other players involved in the import of pharmaceuticals."
This changing environment, which included "the fundamental challenges of many different languages and protocols", meant the agency had to "devise and evaluate more complex risk scenarios and apply more sophisticated technologies to screen and evaluate drugs entering the United States to ensure their quality", she said.
Dr Woodcock's comments came in the wake of the safety scare over Baxter's blood-thinning drug heparin, which partially implicated a Chinese manufacturing facility. Production of the drug in multi-dose vials was suspended after heparin was linked to four deaths and 350 reports of severe allergic reactions in the US.
It subsequently emerged that some of the active pharmaceutical ingredient (API) for heparin was sourced from the Changzhou SPL plant in China, which the FDA has never inspected. According to the Associated Press, Rose DeLauro, Democrat chair of the appropriations subcommittee, told the hearing the FDA had apparently inspected the wrong facility, details of which were then entered into the agency's database.
The "dramatic changes" of the last 10-15 years were exemplified by the FDA's generic drug programme, Dr Woodcock observed. Since 1992, the agency had witnessed a 400 per cent increase in the number of foreign establishments named in generic drug marketing applications. In India alone, there were nearly 25 times as many drug establishments as there were eight years ago (867 versus 37).
Moreover, growth in the FDA's capacity to inspect generic drug manufacturing facilities "has not been commensurate with this global expansion", Dr Woodcock warned. While President Bush's budget proposal for generic drug user fees in fiscal year 2009 would help the agency respond to some of these challenges, it still needed to be in a position "to determine that facilities named in drug applications will meet FDA standards for marketed drug safety, effectiveness, and quality, no matter where they are located".
The president's FY 2009 proposal envisages a total budget of $739 million for the FDA's Human Drugs Program. This includes a $5 million increase in budget authority and a $54 million hike in fees under the Prescription Drug User Fees Act (PDUFA) and the proposed Generic Drug User Fee Program.
Critics have variously denounced the FDA's heavy reliance on industry fees and insisted that the agency needs a far more generous injection of funds - as much as $375 million, according to the FDA's Science Board - if it is to dispel its responsibilities effectively. According to press reports, though, DeLauro also accused the FDA of using inadequate resources as a front for poor management and regulatory weaknesses.
Dr Sidney Wolfe, director of Public Citizen's Health Research Group, said the FDA's pre-market inspection budget for foreign drug companies had fallen by 30 per cent from $8.27 million in FY 2002 to $5.84 million in FY 2007, while its post-approval inspection budget had dropped by 17 per cent from $5.26 million to $4.35 million. Overall, 25 per cent had been shaved off the foreign inspection budget over this five-year period.
The "situation with respect to inspections of foreign drug facilities is desperate and the consequences are increasingly being brought to attention in the form of dangerous products being produced by these inadequately inspected plants", Dr Wolfe told the hearing.
He also highlighted the findings of last November's damning report by the Government Accountability Office (GAO) on the FDA's record of inspecting foreign drug manufacturing plants, in particular the wide disparity between the number of manufacturing facilities eligible for inspection and actually inspected in China and India respectively.
China's 714 drug-producing establishments made up 22% of all foreign facilities eligible for FDA inspection in FY 2007. But the agency conducted only 13 inspections in China that year, representing just 4 per cent of all inspections outside the US. Meanwhile, India had the second-highest number of eligible establishments - 410 or 12.65 per cent of the total - and was the subject of 65 inspections in FY 2007, 22 per cent of that total.
David Horowitz, the FDA's deputy associate commissioner for compliance policy in the Office of Regulatory Affairs, reportedly told the hearing that the agency's 232 inspectors in the field visited 300 foreign manufacturing facilities (about 10 per cent of the total) in 2007, compared with 1,200 facilities within the US.
According to Dr Woodcock, the FDA conducted 498 foreign inspections during FY 2007, 45 per cent more than in the previous year. But that included pre-approval, current Good Manufacturing Practice and bioresearch monitoring inspections.
The agency would also shortly begin implementing an electronic system for accepting and processing the registration and listing of drug establishments, Dr Woodcock noted. This would "provide FDA with a more accurate and thorough accounting of drug manufacturing firms and locations".
In addition, the agency had "entered into a number of co-operative relationships with foreign regulators, ranging from co-operation under a Free Trade Agreement, to agency-to-agency Memoranda of Understanding, to more informal arrangements to advance drug quality".
One of those regulators was China's State Food and Drug Administration, which last December agreed that Chinese manufacturers exporting to the US any API on a newly drawn-up list, including atorvastatin (the active pharmaceutical ingredient in Lipitor) and sildenafil (Viagra), would have to register with the national agency.
Meanwhile, there are rumblings of more decisive congressional action in the form of legislation that would require the FDA to inspect US and foreign drug manufacturing facilities at the same rate.