Drug Safety:

Better Data Management and More Inspections Are Needed to Strengthen FDA's Foreign Drug Inspection Program

GAO-08-970: Published: Sep 22, 2008. Publicly Released: Oct 22, 2008.

Additional Materials:

Contact:

Marcia G. Crosse
(202) 512-3407
contact@gao.gov

 

Office of Public Affairs
(202) 512-4800
youngc1@gao.gov

The Food and Drug Administration (FDA), an agency within the Department of Health and Human Services (HHS), oversees the safety and effectiveness of human drugs marketed in the United States, including those manufactured in foreign establishments. FDA inspects foreign establishments in order to ensure that the quality of drugs is not jeopardized by poor manufacturing processes. This report examines (1) the extent to which FDA has accurate data on the number of foreign establishments subject to inspection, (2) the frequency of foreign inspections, and (3) oversight by FDA to ensure that foreign establishments correct serious problems identified during inspections. GAO analyzed information from FDA databases, reviewed inspection reports which identified serious deficiencies, and interviewed FDA officials.

FDA databases contain inaccurate information on foreign establishments subject to inspection. FDA uses information from a database of establishments registered to market drugs in the United States and a database of establishments that shipped drugs to the United States to compile a list of establishments subject to inspection, but these databases contain divergent estimates--about 3,000 and 6,800, respectively. FDA's registration database contains information about establishments not subject to FDA inspection. Although annual reregistration is required, FDA does not deactivate in its database establishments that do not fulfill this requirement. The agency also does not routinely verify that a registered establishment manufactures a drug for the U.S. market. The accuracy of this information is important in FDA's identification of foreign establishments subject to inspection. FDA inspects relatively few foreign establishments each year to assess the manufacturing of drugs currently marketed in the United States. FDA inspected 1,479 foreign drug manufacturing establishments from fiscal years 2002 through 2007.Because FDA does not know the number of establishments subject to inspection, the percentage of those inspected cannot be calculated with certainty. However, using a list FDA developed to prioritize foreign establishments for inspection in fiscal year 2007, GAO estimated that FDA may inspect about 8 percent of foreign establishments in a given year. At this rate, it would take the agency more than 13 years to inspect these establishments once. In contrast, FDA estimates that it inspects domestic establishments about once every 2.7 years. Unlike domestic establishments, foreign establishments were generally only inspected if they were named in an application for a new drug. While FDA made progress in fiscal year 2007 in conducting more foreign inspections, GAO estimated it still inspected less than 11 percent of such establishments. As FDA plans additional inspections, it is important that it ensure that foreign and domestic establishments with similar characteristics are inspected at a similar frequency. FDA's identification of serious deficiencies has led foreign establishments to take corrective actions, but inspections to determine continued compliance are not always timely. FDA identified deficiencies during most foreign inspections, but determining how the agency classified the results of a specific inspection is hindered by inconsistencies in its databases, particularly on the classification of inspections with serious deficiencies. From fiscal years 2002 through 2007, FDA issued 15 warning letters to foreign establishments at which it identified serious deficiencies. FDA generally determined the adequacy of actions taken in response to these letters by reviewing information provided by the establishments. FDA's subsequent inspections to determine establishments' continued compliance were not always timely. Of establishments named in the 15 warning letters, FDA subsequently inspected 4 establishments 2 to 5 years later, generally because these establishments were named in a new drug application. At 3 of these 4 inspections, FDA verified that corrective actions had been taken but identified additional deficiencies.

Status Legend:

More Info
  • Review Pending-GAO has not yet assessed implementation status.
  • Open-Actions to satisfy the intent of the recommendation have not been taken or are being planned, or actions that partially satisfy the intent of the recommendation have been taken.
  • Closed-implemented-Actions that satisfy the intent of the recommendation have been taken.
  • Closed-not implemented-While the intent of the recommendation has not been satisfied, time or circumstances have rendered the recommendation invalid.
    • Review Pending
    • Open
    • Closed - implemented
    • Closed - not implemented

    Recommendations for Executive Action

    Recommendation: To address weaknesses in FDA's oversight of foreign establishments manufacturing drugs for the U.S. market, the Commissioner of FDA should conduct more inspections to ensure that foreign establishments manufacturing drugs currently marketed in the United States are inspected at a frequency comparable to domestic establishments with similar characteristics.

    Agency Affected: Department of Health and Human Services: Public Health Service: Food and Drug Administration

    Status: Open

    Comments: In 2010 and 2011, FDA reported increasing the number of foreign establishments that it inspected. It also outlined steps it was taking it enhance the quality of information it maintained on foreign establishments by leveraging its inspectional resources to obtain inspectional and other information from trusted foreign counterparts. For example, FDA cited a pilot program to leverage inspections of establishments of manufacturers of active pharmaceutical ingredients by collaborating with European and Australian authorities. However, it also stated that it did not have the financial resources to inspect foreign establishments as frequently as domestic ones, due to the requirement that FDA inspect domestic inspections every 2 years. However, in 2012, FDA reported that the recently enacted Food and Drug Administration Safety and Innovation Act eliminated the requirement to conduct domestic inspections every 2 years. Instead, it mandates that FDA inspect drug establishments on a risk-based schedule. The legislation also includes a provision that prohibits establishments from delaying, denying, limiting or refusing inspections, and provides additional resources for the inspection of generic drug manufacturers. In July 2012, the Food and Drug Administration Safety and Innovation Act (FDASIA), (P.L. 112-144) was enacted directing FDA to take a risk-based approach to inspecting both foreign and domestic establishments, consistent with our recommendation.

    Recommendation: To address weaknesses in FDA's oversight of foreign establishments manufacturing drugs for the U.S. market, the Commissioner of FDA should ensure that information on the classification of inspections with serious deficiencies is accurate in all FDA databases.

    Agency Affected: Department of Health and Human Services: Public Health Service: Food and Drug Administration

    Status: Closed - Implemented

    Comments: In 2011, FDA reported that it would be replacing its Office of Compliance's Foreign Inspections Tracking System (OCFITS) database with a new database--the compliance management system (CMS). In 2012, FDA reported that the new CMS module became operational in October 2011. CMS is linked directly to FDA's Field Accomplishments and Compliance Tracking System (FACTS), thereby, eliminating any possible discrepancy between the two systems. The implementation of CMS allows FDA to generate consistent and reliable information about foreign inspections. When a firm's information is updated in FACTS, the same information is updated in CMS. This allows FDA to generate a variety of reports, such as inspections by countries inspected and the inspection outcome and also enables FDA to generate timeline metrics. FDA is considering adding more functionality to CMS such as identifying inspection reports not yet received or reviewed by agency officials. FDA's new reliance on CMS should enhance its oversight of foreign drug establishments and improved the overall management of its foreign drug inspection program.

    Recommendation: To address weaknesses in FDA's oversight of foreign establishments manufacturing drugs for the U.S. market, the Commissioner of FDA should establish mechanisms for verifying information provided by the establishment at the time of registration.

    Agency Affected: Department of Health and Human Services: Public Health Service: Food and Drug Administration

    Status: Open

    Comments: As of the 2nd quarter of 2012, FDA had taken actions against establishments that failed to fulfill their obligation to register annually. First, FDA 1,759 letters to foreign establishments reminding them of their annual obligation to renew registration. The letters and subsequent responses or non-responses from those foreign establishments culminated in deactivating 1,623 establishments from FDA's Registration and Listing data sources. In addition, 136 of those establishments provided registration information to fulfill their annual registration obligation. FDA also began an effort to take action against unregistered firms that are importing products into the United States. As a result, six warning letters were issued to establishments that either imported products into the United States without registering annually or that imported products but never registered. In addition, FDA is continuing to use the D-U-N-S number, a universal identifier issued by Dun and Bradstreet. The D-U-N-S number allows FDA to use other established databases to verify the accuracy of registration information. In 2012 FDA reported that there are 3,170 foreign establishments that have fulfilled their annual registration obligation with a corresponding D-U-N-S number. FDA also stated that a pilot program it developed in conjunction with Dun & Bradstreet in 2011 has contributed to the agency formulating a more accurate list of establishments subject to inspection. This pilot produces detailed reports of targeted foreign establishments by using Dun & Bradstreet staff to provide face-to-face verification of registration information submitted by these establishments to the FDA. As a result, FDA has obtained information on out-of-business establishments, location changes and other inaccurate reporting, allowing FDA to take correct its data.

    Recommendation: To address weaknesses in FDA's oversight of foreign establishments manufacturing drugs for the U.S. market, the Commissioner of FDA should enforce the requirement that establishments manufacturing drugs for the U.S. market update their registration annually.

    Agency Affected: Department of Health and Human Services: Public Health Service: Food and Drug Administration

    Status: Open

    Comments: In prior years, FDA described its efforts to institute a new electronic drug registration and listing system that it made it mandatory for all drug establishments shipping drugs to the United States. It also outlined its plans to develop software "rules" for PREDICT, the agency's new risk-based screening system for imports. FDA said that PREDICT may include a review of characteristics of manufacturer registrations in order to identify firms who were overdue for annual drug registration. In 2012 FDA reported that it had started a cleanup initiative of the registration data to eliminate inactive establishments from the database and bring active establishments into compliance by getting them to update their records. The effort includes two levels of action and enforcement. The first is to identify and contact establishments that had let their registrations expire or had failed to notify FDA that they no longer performed drug operations at the facility. The second is to identify and contact establishments that had let their registrations expire, but were still actively engaged in drug manufacturing. These establishments are sent an official warning letter with a charge of misbranding, based on the distribution of a drug produced at a facility that is not duly registered. The first warning letter was sent in December of 2011. FDA said that warning letters will continue to be issued in 2012, as resources permit.

    Recommendation: To address weaknesses in FDA's oversight of foreign establishments manufacturing drugs for the U.S. market, the Commissioner of FDA should conduct timely inspections of foreign establishments that have received warning letters to determine continued compliance.

    Agency Affected: Department of Health and Human Services: Public Health Service: Food and Drug Administration

    Status: Open

    Comments: In 2012, FDA reported that it had been issuing warning letters--19 in 2010 and 20 in 2011--to foreign manufacturing or testing facilities. As of May 9, 2012, ten warning letters were issued. FDA continues to monitor and track manufacturers' readiness for a warning letter reinspection. Sites no longer remain under OAI (official action indicated) status--the most negative and critical status--indefinitely. FDA said that it removes the OAI status of the firm once it is verified that the manufacturer has implemented appropriate corrective actions. Under special circumstances, a site that receives a warning letter may not be placed under import alert, such as if doing so would cause a shortage of a life saving drug. In such cases, FDA reported that it works with the firm to conduct additional testing, suggests that they consider having an independent third party to assist the firm, and/or continues to work with foreign regulatory partners on updated information they may have about the facility.

    Jul 16, 2014

    Jul 15, 2014

    Jul 10, 2014

    Jun 30, 2014

    Jun 25, 2014

    Jun 24, 2014

    Jun 23, 2014

    Jun 18, 2014

    Jun 13, 2014

    Looking for more? Browse all our products here