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Trying Times at the FDA — The Challenge of Ensuring the Safety of Imported Pharmaceuticals

Stuart O. Schweitzer, Ph.D.
http://content.nejm.org/cgi/content/full/358/17/1773?query=TOC

In recent years, the Food and Drug Administration (FDA) has faced three serious challenges to its ability to ensure the safety of the country's medical devices and drugs. The first arose when the widely marketed drug Vioxx (rofecoxib) was shown to be dangerous enough for its manufacturer to withdraw it from the market. Previously, consumers and most physicians had assumed that the FDA's drug-approval process, though not legally guaranteeing a product's safety, could be trusted to assure the public of its relative safety.
The challenge to physicians, who were forced to confront their prescribing habits, was no less than that to patients, whose assumption that an approved drug, taken as directed, would be safe was proven invalid. In response, Congress and the Institute of Medicine have called on the FDA to prioritize safety monitoring.

The second challenge recently came from the Supreme Court, which ruled in February that FDA approval of a medical device precludes lawsuits brought by patients against the manufacturer over adverse events in state courts. Courts had previously ruled that patients harmed by a device or drug through no fault of their own could claim compensation from the manufacturer. Such cases were, admittedly, difficult, because usually the manufacturer had done nothing wrong; the courts simply took the position that the party with the deeper pockets should compensate the party with the shallower ones. The Supreme Court has changed this situation, leaving patients without recourse if the FDA has certified that a medical device is generally safe and effective. In effect, FDA approval is now a shield protecting a manufacturer from subsequent claims — a role the agency undoubtedly never intended to play. A similar case, involving drugs, will be argued before the Court this fall.

A third challenge has now arrived from China. Baxter International has recalled its entire production of certain forms of Heparin after hundreds of patients had allergic reactions and at least 19 died (the FDA has since reported a death count of 62).
The FDA has identified the cause of the problem as an altered form of a dietary supplement that mimics heparin when tested. The impurity was introduced — whether intentionally or not is not yet clear — into the active ingredient at a Chinese factory before it was exported to Baxter, which manufactured the final product. This sort of problem should theoretically have been prevented by the FDA, which inspects foreign factories producing drugs and chemical components that are intended for export to the United States. Investigations are continuing, but preliminary information shows that the FDA did not inspect the plant, though it had intended to do so. The FDA's program for inspecting foreign drug manufacturers has been swamped by a rapid increase in overseas manufacturing of both finished drugs and chemical components.

The FDA has a mandate to inspect producers of both drugs and chemicals used to manufacture drugs (active pharmaceutical ingredients, or APIs) in order to certify that plants meet the current Good Manufacturing Practice (GMP) standards. Data on the number of foreign drug and API manufacturers are difficult to obtain. The FDA uses two databases listing foreign plants that are subject to inspection. According to a 2007 report by the Government Accountability Office (GAO), one database lists approximately 3200 establishments, whereas the other lists 6800. Even if the smaller number is accurate, the agency inspects only approximately 7% of foreign establishments in a given year, meaning that it could take at least 13 years to inspect them all — once. The FDA cannot say how many foreign plants have never been inspected.

These inspections are conducted during the drug-development process and the preapproval stage, as well as after FDA approval. Between fiscal years 2002 and 2007, the FDA conducted 11,384 inspections, only 1445 (12.7%) of which were in foreign countries (see graph). The overwhelming majority of these foreign inspections were conducted as part of a drug-preapproval process; only 179 of them were GMP inspections. Funding has also been tilted toward drug approval: total expenditures for facility inspections during this period were just over $80 million, 39% of which was for postapproval monitoring.

Number of FDA Inspections of Foreign Establishments Involved in the Manufacture of Drugs for the U.S. Market, Fiscal Years (FY) 2002–2007/b]
The 10 countries listed are those with the most frequent inspections. The total number of establishments in each country is the number that was used by the FDA to plan its fiscal year 2007 prioritized surveillance inspections. The agency bases these counts on information obtained from previous inspections and from two databases, both of which were designed for other purposes. Data are from the Government Accountability Office.

According to the GAO report, the number of FDA employees who conduct GMP inspections has decreased by nearly 25% since 2002, when there were 587 such employees, though the number covering foreign sites increased from 100 to 141. The report also notes a number of difficulties that inspectors face at foreign sites. For instance, agency inspectors cannot conduct unannounced inspections, despite policy guidelines stipulating that inspections be conducted "without prior notification."
The agency explains that inspectors must visit a number of facilities within a country during each overseas visit, which requires verification that the appropriate people in each plant will be available. Language barriers also hinder rigorous inspections, since inspectors must often "rely on an English-speaking representative of the foreign establishment being inspected, who may not be a translator by training."

Given its limited resources, the FDA has devised a "risk-based" method for prioritizing GMP inspections. It developed a model to predict which establishments are more likely to have problems maintaining GMP standards, and inspections are focused on those facilities. Although this represents a rational strategy for maximizing the effectiveness of screening within tight resource constraints, the evidence suggests that inspection needs have overwhelmed the agency's capacity.
A 2004 FDA report on the risk-based method indicated that the number of "registered human drug establishments" had more than quadrupled during the previous 25 years, whereas the number of GMP inspections conducted dropped by more than 60%. As a result, the agency could not possibly achieve "uniformly intensive . . . inspectional coverage" for all facilities.

The pharmaceutical industry is increasingly turning to overseas producers for both finished drugs and APIs. According to a report by U.S. and European fine-chemical manufacturing trade associations, the proportion of "API needs" supplied by U.S. and European Union manufacturers has declined from 90% two decades ago to less than 20% today.5

These production trends imply that the FDA faces a growing burden even if it merely maintains its role in testing foreign pharmaceuticals and chemicals for purity. If it must hold products to an ever-higher safety standard — given public expectations and the responsibilities implicit in court rulings — its job becomes even more daunting.

bWhat can be done? One approach is to attempt to boost the FDA's efficiency — an objective the agency has pursued by targeting its inspections to facilities least likely to comply with GMP standards. Hoping to increase its resources, the agency has asked Congress for large budget increases; Congress is now considering augmented funding, but neither congressional passage nor White House approval is by any means certain. Another possible source of funding is suggested by experience with the Prescription Drug User Fee Act: charging manufacturers fees to help cover the costs of the drug-approval review process increased the agency's resources, primarily for premarketing review; manufacturers could also be charged to help cover the cost of GMP reviews. Of course, no addition to the budget will be without cost. Federal funding would come at a time of severe budget restrictions and competing demands for scarce public funds, and increased user charges would push drug costs higher.

Alternatively, we could reconsider the FDA's responsibilities. The expectation that FDA approval can guarantee drug safety is naive, since drug trials can never uncover all risks. No drug is completely safe for everyone, nor are people entitled to drugs that are entirely safe. Rather, patients and physicians are entitled to know a drug's risks in order to weigh those risks against its expected benefits. FDA approval should not be interpreted as signaling an absence of risk. Furthermore, when a manufacturer attempts to reduce production or development costs, increased profitability must be balanced against the increased risk to consumers. Manufacturers thus have greater responsibility when production is streamlined or component chemicals are outsourced. Ultimately, the manufacturer ought to be held accountable for any increased risk of adverse events — though the recent Supreme Court decision has made it less likely that cost-cutting actions will expose companies to financial risk.

With all these pressures coming to a head, this may be an opportune time not only to seek ways of increasing the FDA's efficiency but to consider again exactly what we expect the agency to do.

No potential conflict of interest relevant to this article was reported.


Source Information

Dr. Schweitzer is a professor in the Department of Health Services at the UCLA School of Public Health, Los Angeles.

References


Bogdanich W. Blood thinner might be tied to more deaths. New York Times. February 29, 2008.
Idem. Heparin find may point to Chinese counterfeiting. New York Times. March 20, 2008.
Drug safety — preliminary findings suggest weakness in FDA's program for inspecting foreign drug manufacturers. Testimony of Marcia Crosse, director health care, before the Subcommittee on Oversight and Investigations, Committee on Energy and Commerce, House of Representatives, November 1, 2007. Washington, DC: Government Accountability Office. (GAO-08-224T.) (Accessed April 4, 2008, at http://www.gao.gov/htext/d08224t.html.)
Risk-based method for prioritizing CGMP inspections of pharmaceutical manufacturing sites — a pilot risk ranking model. Rockville, MD: Food and Drug Administration, September 2004. (Accessed April 4, 2008, at http://www.fda.gov/cder/gmp/gmp2004/risk_based.pdf.)
Barnes K. US and EU pharma trade bodies slam poor regulation of foreign APIs. LabTechnologist.com, October 20, 2006.