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.

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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.

Recommendations for Executive Action

  1. Status: Closed - Implemented

    Comments: FDA has been taking steps in response to this recommendation for several years and its implementation is now complete. These steps included two phases of action and enforcement. The first phase began in the latter half of 2011 when FDA started a cleanup initiative of its registration data to eliminate inactive establishments from the database and bring active establishments into compliance by getting them to update their records. According to FDA, it sent letters to foreign establishments reminding them of their annual obligation to renew their registration and information on how to do so. The agency specifically contacted drug establishments that had let their registration expire or that had failed to notify FDA that they no longer performed drug operations at the facility. It ultimately deactivated the registration of 1,623 foreign establishments that failed to re-register or otherwise respond to FDA. The second phase of enforcement, which began in fiscal year 2012, involved identifying and contacting establishments that had let their registrations expire, but were still actively engaged in drug manufacturing. These establishments were sent official warning letters with a charge of misbranding. These letters indicated that the agency had identified violations that may lead it to initiate enforcement action if not promptly and adequately corrected, based on the distribution of a drug produced at a facility that is not duly registered. FDA has taken the additional step of issuing import alerts aimed at stopping the importation of drugs from establishments that fail to properly register. These import alerts subject the establishments to detention of their products without physical examination at the U.S. border.

    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

  2. Status: Closed - Implemented

    Comments: FDA has now implemented this recommendation. After GAO's report was issued, FDA requested that establishments submit a unique identification number?a Dun and Bradstreet Data Universal Numbering System (D-U-N-S) Number. The use of this unique identifier and the associated data had the potential to enhance FDA's ability to verify information about foreign establishments, including whether they have gone out of business or relocated, as well as help the agency avoid duplications and errors in its data systems. However, FDA could not require it the D-U-N-S Number be used and so an establishment's use of it was voluntary. Several years later, in July 2012, The Food and Drug Administration Safety and Innovation Act mandated that the Secretary of HHS designate a unique facility identifier and require its use in establishment registration. The Secretary designated the D-U-N-S Number as the identifier to be used. FDA issued draft guidance in September 2013 that, when finalized, will implement this provision.

    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

  3. 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 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

  4. Status: Open

    Comments: FDA is continuing to implement this recommendation, which is consistent with a requirement in the July 2012 Food and Drug Administration Safety and Innovation Act. This law mandated the incorporation of a risk-based model to scheduling drug inspections. The model is to include specific factors, such as facility manufacturing metrics and foreign government inspection findings. In August 2015, FDA reported it has refined its risk-based model to include the achievement of "risk-adjusted parity" by using the same risk factors to identify both domestic and foreign establishments to inspect. One combined model is now used for all identified establishments. FDA said it is now scheduling inspections based solely on these risk factors, rather than on geography. FDA also explained it has taken several steps to enhance its foreign drug inspection capacity. The dedicated foreign cadre of drug investigators, established in 2009, increased from 15 to 20 full-time equivalents (FTE). In addition, FDA committed to increased hiring of investigators to conduct inspections. In 2015, the agency hired 80 FTEs whose inspection work is primarily focused on generic drug facilities. Because a significant number of generic drug facilities are located abroad, these new investigators are expected--after a period of training--to focus their inspection portfolio mostly on foreign sites. In addition, FDA emphasized that it has steadily increased the number of foreign inspections it has conducted since 2011. FDA also cited a report by the HHS-OIG which indicated the agency had made progress in achieving parity. We are leaving this recommendation open until it is clear that parity has been achieved.

    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

  5. Status: Open

    Comments: In August 2015, FDA stated that, in order to ensure that re-inspections are occurring in a timely manner, the need for a compliance follow-up inspection at a particular facility is now routinely identified as part of the surveillance list that the Center for Drug Evaluation and Research provides to the Office of Regulatory Affairs to accomplish. FDA reported that of the 22 warning letters issued to establishments in 2013, 13 have been re-inspected while the other 9 remain on import alert, which allows FDA to detain products or to refuse admission of future shipments. For the 19 warning letters issued in 2014, 2 establishments have been re-inspected, 6 remain on import alert, and FDA is assessing the responses to the warning letters for the other 9 establishments. Regarding the 5 warning letters issued to date in 2015, none of the establishments have been re-inspected, but FDA is reviewing responses to 4 of the warning letters. FDA did not provide information about the status of the fifth establishment. For those warning letters issued in 2013 and 2014 that have been officially closed, the average number of days elapsed from the issuance of the letter until the matter was closed exceeded 200 days in both years--the average was 279 days for letters issued in 2013 and 211 days for those issued in 2014.

    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

 

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