THE GLOBAL DRUG SAFETY DILEMMA

The FDA only inspects about 7% of foreign manufacturers in any given year

T he Food and Drug Administration (FDA), amid mounting criticism from Congress, is pressing ahead with plans to beef up inspections of facilities in foreign countries that manufacture and export finished drugs and active pharmaceutical ingredients (APIs) to the United States. But some U.S. lawmakers, citing ongoing safety concerns over drugs and APIs made in China, India, and other developing countries, say the FDA's efforts are not enough to prevent contaminated products from reaching the public.

"American lives are unnecessarily being placed at risk," Michigan Democrats Rep. Bart Stupak, chairman of the House Committee on Energy and Commerce Subcommittee on Oversight and Investigations, and Rep. John D. Dingell, full committee chairman, wrote in a February letter to FDA Commissioner Andrew C. von Eschenbach, MD. "Clearly, to date, you have been unable to assure the public these products are safe because you have been unable to competently address the systemic weaknesses in this [foreign inspection] program."

The lawmakers were seeking safety information about Baxter Healthcare Corporation's (Deerfield, Ill.) heparin, a blood thinner that has been tied to at least 350 adverse reactions-and possibly four deaths-in the United States since December, primarily at hospitals and dialysis centers. While the cause is still undetermined and tests continue, suspicion centers around an API manufactured for Baxter at a plant in China, one of hundreds or perhaps thousands of facilities-many of them unregulated-that produce finished drugs and active ingredients for export to the United States and other countries.

Changzhou SPL, a joint venture with Scientific Protein Laboratories LLC (Waunakee, Wis.), has been producing the heparin API, derived from pig intestines, for Baxter since 2004. Scientific Protein Laboratories says the Chinese processes and quality control measures meet FDA standards. Baxter officials say they inspected the facility last year and routinely tested the imported product for quality. But the facility, located near Shanghai, has not been inspected by Chinese or U.S. regulators. The FDA finally did so in February after acknowledging it had previously inspected the wrong facility due to a data entry error. Baxter voluntarily recalled nine lots of the drug and went on to recall single-dose vials and a diluted solution.

CHINA: POWERHOUSE AND PROBLEM

Dozens of major U.S. and European drug makers have opened manufacturing facilities in China, while scores of other manufacturers-large and small-purchase APIs from hundreds of new Chinese companies. China has become the world's largest supplier of active ingredients, producing 14% ($4.4 billion) of the $31.0 billion total in 2005. If its share grows as expected at 17.2% annually, by 2010 China will be producing 21.5% ($9.9 billion) of the world's $46.0 billion API market, according to the Chemical Pharmaceutical Generic Association (CPA; Milan, Italy).

Despite this explosive growth, the Chinese State Food and Drug Administration (SFDA) does not inspect companies that produce finished drugs and APIs solely for export, says Murray Lumpkin, MD, deputy FDA commissioner for international and special programs. Rather, SFDA's responsibility is confined to drugs and materials destined for domestic consumption. While China's provincial governments can inspect these facilities, they are not required to do so. "We have never investigated a chemical company," a senior SFDA official told The New York Times in October 2007. "We don't have the jurisdiction."

The situation is eerily similar for the FDA. Nearly 80% of all APIs used by U.S. drug manufacturers are imported, mainly from China and India, and 40% of all finished drugs come from facilities around the world, including developing nations, where fake and counterfeit drug products are most prevalent. But, unlike U.S. drug manufacturers, which the FDA is required to inspect at least every two years, the agency is not obligated to regularly inspect overseas manufacturing facilities for current good manufacturing practices (cGMP).

The FDA performs more than 200 foreign drug manufacturing inspections annually for new drug applications, abbreviated new drug applications, and biological license applications. But 90% of these are for pre-approval, while only 10% are for cGMP, according to the Synthetic Organic Chemical Manufacturers Association (SOCMA; Washington, D.C.), which represents the batch, custom, and specialty chemical industry and has been pushing for more foreign inspections.

"We recognize that the world is evolving and our local markets now provide products largely from a global marketplace," Dr. von Eschenbach told the House subcommittee in November. But lawmakers were unimpressed. "How do you allow these drugs into this country when you don't even inspect?" Stupak asked. "Where is the enforcement to make sure you are doing things right?"

Frustrated at the slow pace of the FDA's response to the heparin problem and other foreign inspection issues, as well as ongoing concerns over safety issues surrounding some other drugs, Stupak called in February for Dr. von Eschenbach to resign. "It's just a total lack of leadership," he told the Associated Press.

FDA and European officials say their respective drug industries must also take ownership and responsibility for quality. "FDA, from a risk-based perspective, targets firms that warrant pre-approval inspections and should be targeted as part of a surveillance program," says Michael Rogers, director of field investigations in the FDA's Office of Regulatory Affairs. "But this does not obviate industry's responsibility to qualify their suppliers, establish criteria, and evaluate products upon receipt, and their role in overall GMPs with respect to products and raw materials they receive from foreign sources," Rogers tells Pharmaceutical Formulation and Quality.

European Union directives require finished product manufacturers to use only active substances that have been manufactured in accordance with GMP principles, says Valvanera Valero, spokesman for the European Medicines Agency (EMEA) in London. "There is no routine requirement for competent authorities to inspect the active substance manufacturers, although they may do so if they suspect serious non-compliance," he tells Pharmaceutical Formulation and Quality.

THE PROBLEM IN MICROCOSM

The heparin situation is the latest example of what can go wrong when manufacturers fail to employ adequate quality control measures. It is also just one in a series of recent safety scandals in which hundreds of people around the world have died from or been injured by taking contaminated drugs or drug products made in China.

Since 2006, more than 100 people in Panama, Central America, and the Caribbean have died from ingesting contaminated Chinese drugs. Two years ago, five people in China died after taking a drug made by Qiqihar No. 2 Pharmaceutical Company after the company substituted diethylene glycol for a key ingredient to save money. Last year, nearly 200 Chinese cancer patients were paralyzed or harmed after injecting two leukemia drugs-cytarabin hydrochloride and methotrexate-that had been contaminated with a third cancer drug, vincristine sulfate, during production.

SFDA officials have since closed the cancer drug facility, run by state-owned manufacturer Shanghai Hualian, and have accused two company officials of engaging in a cover-up. Shanghai Hualian is the sole supplier to the United States of the abortion drug mifepristone (RU-486), distributed by Danco Laboratories LLC (New York, N.Y.). The factory that manufactures the abortion drug is different from the one involved in the tainted cancer drugs scandal, Chinese officials say. Last year, former SFDA chief Zheng Xiaoyu was executed for taking bribes to speed drug approvals.

HOW DO YOU ALLOW THESE DRUGS INTO THIS COUNTRY WHEN YOU DON'T EVEN INSPECT? WHERE IS THE ENFORCEMENT TO MAKE SURE YOU ARE DOING THINGS RIGHT?

-Rep. Bart Stupak, chair of the House Committee on Energy and Commerce, Subcommittee on Oversight and Investigations

The FDA was supposed to have conducted a pre-approval inspection of the Changzhou SPL plant, which produced Baxter's API, but failed to do so "due to human error and inadequate information technology systems," an FDA spokesperson told The Wall Street Journal in January.

NO 7% SOLUTION

That admission appears to be the tip of the iceberg. The Changzhou SPL plant is just one of hundreds never inspected by the FDA. According to a recent report by the Government Accountability Office (GAO), the investigative arm of Congress, the FDA only inspects about 7% of foreign manufacturers in any given year.

"More than nine years after we issued our last report on this topic, FDA's effectiveness in managing the foreign drug inspection program continues to be hindered by weaknesses in its data systems," Marcia Crosse, GAO's director of health care, said in congressional testimony in November. Auditors found that the FDA relied on information from two databases of foreign companies that supply finished medicines or APIs to U.S. manufacturers. One database contained about 3,000 foreign companies and the other 6,800.

From these lists, the agency compiled its own list of 3,249 foreign drug establishments from which to prioritize inspections. But the FDA only conducts around 200 inspections in any given year, a little more than 7% of the total, meaning that it would take the agency 13 years to inspect each facility once, assuming no additional establishments are subject to inspection. The auditors also said the FDA could not determine the exact number of foreign companies it oversees and "could not identify a previous inspection" for 2,133 of the companies.

THERE IS NO ROUTINE REQUIREMENT FOR COMPETENT AUTHORITIES TO INSPECT THE ACTIVE SUBSTANCE MANUFACTURERS, ALTHOUGH THEY MAY DO SO IF THEY SUSPECT SERIOUS NON-COMPLIANCE.

-Valvanera Valero, spokesman for the European Medicines Agency

"How can we have any confidence FDA is truly managing the risk that may come from foreign-made drug products if the FDA doesn't know the exact number or location of foreign drug manufacturers?" Stupak asked. Conducting foreign inspections can be "challenging," Dr. von Eschenbach acknowledged. "In some countries, we need authorization from the relevant government to enter and inspect facilities. Other countries have travel alerts that require FDA to take special precautions to ensure the safety of our investigators."

The agency, he continued, relies on volunteers from a pool of about 800 domestic investigators to conduct foreign inspections. The task can be grueling. One investigator typically conducts three five-day inspections consecutively, often relying on each of the three inspected facilities to help with logistics and supply translators. As a result, surprise visits are often not possible, in contrast to the unannounced inspections common in the United States.

FDA resources for overseas inspections have also been diminished, congressional investigators report. In 2002, the FDA spent $16.7 million and devoted 149 staffers to foreign inspections, while in fiscal year 2008 the agency will spend only $16 million and pay 102 staffers, despite the approximate doubling in volume of FDA-regulated imports every five years. The FDA estimates that 714 companies in China produce drug products for export to the United States, yet it conducted only 13 inspections in 2007, less than 2% of the total.

TARGETS FOR IMPROVEMENT

FDA officials have outlined a number of targeted improvement areas. The agency has requested $247 million in fiscal year 2008 to improve its information technology and other infrastructure. The FDA and SFDA agreed in December to align inspections and regulatory standards, combine databases to track drugs, and share information on inspections and approvals, Dr. Lumpkin says.

FDA officials are talking with their counterparts about opening offices in China, India, and other countries (See PFQ "News and Notes," December/January 2008, p. 14). In January, Dr. von Eschenbach told reporters he wanted to have a presence in nations like India and China, as well as in such regions as Central and South America and theMiddle East, so that plants can be inspected on an "ongoing and continuous basis" rather than on an episodic and periodic basis.

For fiscal year 2009, which begins October 1, the White House has requested $2.4 billion for the FDA, a 5.7% increase. Part of the increased funding will allow the FDA to perform an additional 23 domestic cGMP inspections, 50 more foreign pre-approval inspections, and 64 more foreign GMP inspections. Like most regulatory agencies around the world, the FDA faces budget constraints. "FDA is in the same situation from the resource perspective as all of our other regulatory partners in the international arena," Rogers says.

But the FDA's own scientific advisers have recommended doubling the budget over the next two years to address glaring deficiencies and increase the number of employees by 50%. "We found that FDA's shortfalls have resulted in a plethora of inadequacies that threaten our society," says Gail Cassell, PhD, chair of the FDA's Science Board and an Eli Lilly executive. These include "inadequate inspections of manufacturers" and "an import system that is badly broken," as well as "an information technology infrastructure that was identified as a source of risk in every [FDA] Center and program reviewed" by the board, Cassell told lawmakers in January.

Dr. von Eschenbach disagreed with many of the Science Board's dire assessments. "It's not that it's bad" at the FDA, he said, "it's that it is at a level of excellence that needs to continue to improve and that needs to expand." Nevertheless, he said he takes the board's recommendations "very seriously." �