FDA inspected more foreign drug establishments in fiscal 2007 than in each of the five previous years, but visited less than 11 percent of such facilities, the Government Accountability Office estimates in a report released Oct. 22.

The number of foreign inspections increased from 220 in fiscal year 2002 to 332 in fiscal year 2007, GAO says. Overall during the fiscal 2002-2007 period, FDA conducted 1,479 foreign inspections at 1,119 unique establishments in 51 countries. The list used by FDA to plan its 2007 foreign inspections included 3,249 facilities (see chart: " ¹ FDA Inspections of Foreign Establishments Involved in the Manufacture of Drugs for the U.S. Market ").

Domestically, FDA conducted about 1,528 inspections per year during the six years audited by GAO and estimates about 3,000 establishments manufactured drugs in the U.S. in fiscal 2007.

With additional money provided for fiscal 2009 by a supplemental appropriations package, the agency plans to further increase inspections - by 143 overseas and 75 in the U.S. - GAO says.

The statistics suggest that FDA has taken the criticism of its foreign oversight procedures to heart but is struggling to improve performance, given the financial pressures it is facing.

The report, commissioned by leaders of the House Energy and Commerce Committee and Sen. Chuck Grassley, R-Iowa, ranking member of the Finance Committee, is the final version of an assessment of FDA's foreign inspections program presented to the House panel in preliminary form in November 2007 (² Also see "FDA IT Infrastructure Inadequate For Managing Foreign Inspections, GAO Says" - Pink Sheet, 5 November, 2007., p. 30).

The findings confirm that there is "reason to be concerned about the safety of imported drugs," noted John Dingell, D-Mich., chairman of the Energy and Commerce Committee.

Dingell has drafted several versions of a bill to authorize greater FDA oversight over imported drugs, devices and food, and Grassley and Sen. Ted Kennedy, D-Mass., introduced their Drug and Device Accountability Act in August (³ Also see "Kennedy/Grassley Imports Criminal Liability To Global Drug Safety Efforts" - Pink Sheet, 11 August, 2008., p. 28).

Reintroducing the import safety bill "will be a top priority next year," a House Energy and Commerce Committee staffer said.

Based on its findings, GAO recommends that FDA:

Inspect foreign facilities at the same frequency as domestic establishments;

Conduct timely re-inspections of foreign facilities that have received a warning letter;

Enforce a requirement that manufacturers of drugs for the U.S. market update their registration annually;

Institute mechanisms for verifying facility information at the time of registration; and

Ensure that information on classification of inspections with serious deficiencies is accurate in all FDA databases.

A problem with FDA's foreign inspections program is that most resources go toward inspections related to drug applications rather than toward monitoring facilities producing drugs exported to the U.S., according to the government watchdog agency.

In fiscal years 2002 through 2007, about 13 percent of foreign inspections were to monitor compliance with good manufacturing practices, GAO points out. During the same time period, 85 percent of U.S. inspections were to evaluate GMP compliance.

Yet, GAO notes, FDA "identifies deficiencies at foreign establishments at least as often as at domestic establishments."

Therefore, the report continues, "it is important that the agency reassess its priorities to ensure that foreign and domestic establishments with similar characteristics are inspected at a similar frequency."

Recurring Deficiencies

GAO auditors found that warning letters with regard to serious deficiencies were issued at a similar rate to both foreign and domestic establishments.

During the six-year audit period, foreign facilities received 15 warning letters. In four of the 15 cases, FDA issued an import alert for drugs from the facilities. Twelve recipients of the letters had been inspected previously. At 10 sites, the previous inspections found deficiencies classified as voluntary action indicated, and one found deficiencies classed as official action indicated.

At seven sites, the inspections leading to the warning letters found the same deficiencies that had been present at the previous inspections, GAO says.

As of July 2008, FDA had determined that 11 of the 15 facilities had taken adequate corrective action. In seven cases, that determination was based on information provided by the establishment. In three cases, the determination was based on a re-inspection by FDA; one determination was based on re-inspection by a private consultant.

As of June 2008, GAO notes, FDA had conducted new inspections at only four of the 11 facilities determined to have taken adequate corrective actions. Three of the four were not re-inspected until four or five years after the inspection that sparked the warning letter, GAO points out.

Although foreign facilities have been responsive to warning letters, the identification of more deficiencies at subsequent inspections "points to the need for FDA to promptly inspect establishments with a history of serious deficiencies so problems do not go undetected for extended periods."

Because of discrepancies among its data systems, the exact number of foreign establishments that should be inspected is unclear, GAO points out. However, FDA has reviewed the list of 3,249 facilities used for FY '07 planning purposes and found 2,133 sites for which there was no indication of an inspection being conducted.

Of the other 1,116 establishments, 242 had been inspected at least once since fiscal 2000, but not for GMP. A GMP inspection was conducted at least once since fiscal 2000 at the remaining 874.

The GAO audit determined that FDA identified VAI or OAI deficiencies at about 62 percent of foreign sites inspected during fiscal years 2002 through 2006. Such deficiencies were found at about 51 percent of inspected domestic facilities during the same period. Inconsistencies in the agency's databases prevent determination of the foreign inspections that identified serious deficiencies, GAO adds.

GAO reviewed a number of FDA initiatives to improve its oversight of foreign drug makers, but noted that "the extent to which these proposals will improve FDA's program is unclear."

Improvements In FDA Oversight Capabilities

A pilot program to measure the effectiveness of a specialized foreign inspection force is slated to begin in early fiscal 2009. Fifteen investigators with foreign inspection experience are to be hired. Based on the pilot program, the full size of the foreign inspectorate is to be determined in fiscal 2010.

FDA is taking several actions to improve its information technology to better identify foreign facilities for inspection, GAO reports, but the steps "do not fully address this weakness."

The agency plans changes to the Drug Registration and Listing System but these still will not provide an accurate count of foreign facilities, GAO says.

In July, FDA initiated a pilot program in which facilities that manufacture drugs can register electronically. Beginning in June 2009, only electronic registrations will be accepted and FDA plans to require use of a unique identifier from the Dun and Bradstreet Data Universal Number System.

FDA hopes the electronic registration process will allow resources to be shifted from data entry to assuring the quality of the databases, GAO says.

Use of a unique identifier could provide assurance about certain information, but will not prevent foreign establishments that do not make drugs for the U.S. market from registering, so the "database will continue to contain inaccuracies when FDA selects establishments for inspection," GAO adds.

FDA and other agencies are working to set up a unique establishment identifier for use on imports, but as yet there is no timeline for its operation.

FDA has solicited proposals for a contractor to conduct on-site verification of registration data and product listing information for foreign establishments that ship drugs and other FDA-regulated products to the U.S.

The agency, however, has not yet formalized criteria to identify establishments to be visited for verification purposes, or determined how many establishments would be verified annually.

FDA also is installing a Mission Accomplishments and Regulatory Compliance Services system to help FDA electronically integrate data from multiple systems. This, with improvements in the DRLS, could help FDA obtain an accurate count of establishments subject to inspection, GAO says.

MARCS is being implemented in stages and could be fully in place by 2011 or 2012. However, implementation "has been slow because the agency has been forced to shift resources away from MARCS and toward the maintenance of current systems that are still heavily used."

- Cathy Dombrowski (c.dombrowski@elsevier.com)

FDA Ups Foreign Inspections In FY ’07; Visits 11% Of Foreign Establishments

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