Foreign Affairs

The heparin debacle and other food and drug import scandals have generated considerable skepticism about industry reliance on imported drug ingredients—and on the FDA's ability to adequately monitor foreign drug manufacturing. Policymakers are blasting FDA for going after US tomato growers while Mexican peppers were the real culprit in this summer's salmonella outbreak. Allegations of manufacturing violations and fraud by Indian drugmaker Ranbaxy prompted the House Energy & Commerce Committee to question whether FDA took appropriate action to keep adulterated Ranbaxy drugs out of the United States. Moreover, the case has generated murmurs about another generic drug scandal—20 years after fraudulent activity rocked FDA and the then-nascent generic drug industry.

Jill Wechsler

The good news from the foreign enforcement front is that Congress finally is giving FDA some additional resources to expand overseas inspections and oversight. The agency received a $150 million budget supplemental in June to boost food and drug inspections and enhance drug safety, and there's support on Capitol Hill for further increases in FDA's 2009 budget.

Legislators are also crafting laws to strengthen FDA's ability to block suspect imports and crack down on fraudulent operators. FDA agrees on the need for subpoena power, as well as authority to destroy unsafe products at the border, impose stiffer penalties for criminal acts and counterfeiting, and block imports from plants that refuse access to FDA inspectors. Congress might even give FDA a more realistic four-year cycle for inspecting manufacturing plants, instead of retaining the two-year requirement that it seldom meets.

But any FDA legislation moving through Congress next year is likely to go beyond a few agreed-upon improvements. Even though FDA is just barely digesting last year's massive FDA Amendments Act, another hefty reform bill may emerge that also curbs drug advertising and reorganizes how the agency evaluates and monitors drug safety; follow-on biologics could join the party. E&C chairman Rep. John Dingell (D-MI) and Sen. Edward Kennedy (D-MA), chairman of the Senate Health, Education, Labor and Pensions (HELP) Committee, have been crafting food and drug import legislation this year, while Sen. Chuck Grassley (R-IA) still wants to split FDA operations for approving new drugs from postmarket surveillance. One bone of contention is whether to levy new user fees on importers to finance expanded foreign inspections. Dingell wants the fees, but FDA fears an administrative nightmare.

Meanwhile, pharma companies are under the gun to better monitor foreign contractors and ensure the safety and quality of imported ingredients and products. Sen. Sherrod Brown (D-OH) wants to know whether drugmakers are expanding outsourcing largely to obtain cheaper, less stringently regulated imports at the expense of lost jobs and additional health risks for Americans. Brown has asked FDA to address this issue, and has queried Pfizer and Merck on the ramifications of their outsourcing programs. And if overseas operations do save money, Brown expects those cost reductions to translate into savings for US consumers.

Beyond Our Borders

Everyone agrees that FDA's current system for monitoring foreign drug manufacturing—to say nothing of food imports—cannot cope with the surge in active ingredients and drug products imported from overseas. (See "Global Enterprise") Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), told the E&C Committee in May that inspections alone cannot fully evaluate if manufacturing facilities can produce safe, high-quality products. And we can no longer "inspect out" bad products at the border, said FDA deputy commissioner Murray Lumpkin at the Drug Information Association (DIA) annual meeting in June.

Global enterprise

FDA commissioner Andrew von Eschenbach's solution is the high profile "Beyond our Borders Initiative," which is establishing on-the-ground regulatory offices in critical parts of the world. The first in-country operation will be in China, with offices in Beijing, Shanghai, and Guangzhou by year's end. A relatively small staff of 13 will conduct some site inspections, but they will work primarily with Chinese regulatory authorities to better track local enforcement activities, become more informed of legal and political issues affecting drug regulation, and further acquaint Chinese regulators and manufacturers with US drug quality standards and clinical research requirements. An additional $20 million from the June supplemental appropriation will enable FDA to establish the Chinese offices, plus operations in India, Europe, and Latin America by the end of next year; a Middle East office in Amman, Jordan may follow.

Establishing official foreign operations takes time and patience. In December 2007, FDA signed a Memoranda of Agreement (MOA) with the Chinese to improve the safety of drugs and medical devices. It calls for registration of Chinese firms exporting to the US, enhanced drug tracking by Chinese authorities, and FDA notification of inspection failures involving plants that export to the US. The State Department approved the assignment of FDA staffers to Chinese offices in March, but a final agreement was delayed by a request from the Chinese for a similar presence in the US, which the State Department has yet to approve.

In addition, FDA will be sending more inspectors to foreign plants and research sites in the coming year. FDA conducted 322 foreign inspections in fiscal year 2007—a big jump up from 212 in FY 2006, and 260 in 2004. The plan is to carry out 500 foreign inspections in 2009. Most of these visits involve pre-approval inspections that are required for every new plant listed on market applications or supplements before a new product can be distributed in the US.

FDA also aims to boost routine inspections of overseas manufacturers, implementing a risk-based approach for scheduling site visits: At the top of the list will be facilities producing higher risk dosage forms, without an inspection in the last three years, with high shipping volumes, and with a history of past compliance issues with either FDA or local regulators. The agency is establishing an international cadre of inspectors to conduct site visits around the world, and to be ready to conduct "for cause" inspections when problems emerge about the safety of a regulated product.

Internal IT modernization may further help FDA cope with the globalization of the pharmaceutical supply chain with its ever-growing number of brokers, traders, distributors, repackagers, and manufacturers. A top priority is to build an interoperable electronic data system for facility registration and product listing that can identify more accurately who manufactures which products, and what is being distributed in the US.

More cooperation

Because FDA will never have enough resources to inspect all facilities frequently enough to catch all safety and quality problems, FDA officials seek to leverage resources and reduce redundant oversight activities through collaborative initiatives with other regulators:

» Sharing foreign inspection reports FDA has more than 70 cooperative arrangements with foreign counterparts that permit mutual access to certain manufacturing information. Some 30 confidentiality agreements allow FDA to share actual inspection reports, which provide information on foreign facilities that can help target foreign inspection activities.

» Joint inspection pilot FDA is teaming up with the European Medicines Agency (EMEA) and Australia's Therapeutic Goods Administration to consult on inspection schedules and reports, initially for API manufacturers in China and India. The aim is to avoid redundant site visits and to cover more facilities. The three agencies will review which facilities are on each other's lists and agree on which agency should go in first. In some important cases, all three regulators may visit a certain plant together. If successful, the program could expand from APIs to drug products.

» Third party certification FDA wants to accredit more government and independent entities as capable of verifying company or product compliance with US safety standards. Drug import legislation could support these efforts, but there is skepticism on Capitol Hill about this approach because such programs for medical devices have not been very successful.

Even with more information sharing and joint inspections, neither FDA, EMEA, nor other regulatory authorities are ceding the right to evaluate and make independent enforcement decisions regarding any drug product or facility. The hope is that these collaborations will breed confidence in the approaches and decisions of colleagues, explained EMEA head of inspections Emer Cooke at the DIA meeting. Cooke anticipates that such joint efforts eventually will lead to increased reliance on each other's decisions.

Jill Wechsler is Pharmaceutical Executive's Washington correspondent. She can be reached at jwechsler@advanstar.com