Drug Safety
Better Data Management and More Inspections Are Needed to Strengthen FDA's Foreign Drug Inspection Program
GAO-08-970, 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.
Status Legend:
Status will change from "In process" to "Open," "Closed - implemented," or "Closed - not implemented" based on our follow up work.
- In Process
- 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 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 its agency comments on a draft of our report, FDA noted that it plans to require establishments to update their registration at 6-month intervals, which is more frequent than is currently required. However, it did not specifically address its plans to enforce this requirement. In its 2010 recommendations update, FDA indicated it has recently implemented the electronic drug registration and listing system (eDRLS) and has made it mandatory for all drug establishments shipping drugs to the United States to register with FDA using this electronic system. According to FDA, eDRLS submissions will require more comprehensive information than the old, paper registration system and the potential for human transcription errors will be reduced. The implementation of eDRLS will help FDA to identify foreign establishments that have not registered and to assemble more reliable information about drug establishments. eDRLS is updated daily.
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: In its agency comments on a draft of our report, FDA described plans to pilot a new unique numeric identifier to avoid duplications and errors during the registration process. Also, as of June 1, 2009, in most instances FDA will no longer accept paper submissions for drug establishment registrations. FDA said that moving from a paper-based format to an electronic system will improve the accuracy of submissions. In its September 2010 recommendations update, FDA stated that the new electronic registration system requires the submission of more comprehensive information than the old paper registration system and the implementation of electronic registration allows for better and automatic validation of import information against FDA's records. The validation process includes confirmation that the drug being imported corresponds with a drug approved for marketing by FDA. In addition, FDA indicated that it has also taken steps to use secondary verification of drug establishments in eDRLS (the electronic registration system) through a widely used universal establishment identifier. Although FDA does not have statutory authority to mandate that establishments provide it with such an identifier at this time, in May 2009 FDA published a guidance requesting the submission of a Data Universal Number System (DUNS) number during the electronic registration process. Finally, FDA indicated that it has also begun to implement the Foreign Facility Registration Verification Project. Through this project, FDA contractors will verify and document the existence of foreign firms registered with FDA and confirm that such firms manufacture the products that U.S. import records reflect they export to the United States. Despite the implementation of the above initiatives, FDA acknowledged that they are not a comprehensive solution to correcting existing problems raised by GAO in connection with its first and second recommendations regarding the need to correct inaccurate information in its registration database.
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: Open
Comments: In its agency comments on a draft of our report, FDA said that it has plans to enhance its IT systems in ways that will improve its databases and enhance the interoperability of systems within the agency. However, it did not specifically address its plans to enhance the IT system that stores inspections results or classifications. In it's 2010 recommendations update, FDA indicated that the discrepancies identified were largely the result of omission and human error. To resolve these errors, FDA has implemented a revised procedure for its compliance officers to underscore the importance of their data entry responsibilities. The procedure was finalized in May 2010, and training has been provided to staff to ensure that data entry is properly conducted in both the Field Accomplishments and Compliance Tracking System (FACTS) and Office of Compliance Foreign Inspection Tracking System (OCFITS) databases, in accordance with the policy. FDA reported that to date, the new procedure and training have been effective. Since the implementation of the new procedure and compliance officer training, adequate information is being entered into the appropriate databases. Additionally FDA is in the process of replacing OCFITS with a new compliance management system referred to as CMS. The new system will be linked directly to FACTS, thereby, further reducing, if not eliminating, discrepancies between databases.
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 its agency comments on a draft of our report, FDA agreed that additional inspections are needed to strengthen its foreign drug inspection program. However, the agency also said that conducting foreign inspections based on the same criteria as domestic inspections is problematic because foreign inspections pose unique challenges. In its 2010 recommendation update, FDA indicated that it has increased the frequency of its foreign current good manufacturing practice (CGMP) surveillance inspections from 318 in fiscal year 2008 to a minimum of 392 in fiscal year 2009. FDA also reported that it has been able to target additional inspections in geographic regions and establishments where the need is greatest. For example, over the past two years FDA has more than doubled the number of FDA CGMP surveillance inspections in China. FDA also cited numerous other initiatives to enhance its oversight of foreign establishments including the opening of its overseas offices, the creation of a dedicated cadre of investigators to conduct foreign inspections, and collaborative efforts with foreign governments.
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: FDA has not provided a specific response to this recommendation. In its 2010 recommendation update, FDA indicated that after the agency issues a warning letter or a major product recall occurs, it will make it a priority to follow-up promptly with appropriate action, including inspection and investigation, as appropriate, to assess whether a company has made required changes in its practices. FDA reported that, of the 13 foreign firms to which the agency issued warning letters in 2009, the agency has already reinspected four and found them acceptable. The remaining nine firms are either implementing corrective action plans or will be reinspected, and three remain on import alert. Additionally, FDA is no longer issuing multiple warning letters to noncompliant firms before taking enforcement action. FDA said it may consider immediate action, even before it has issued a formal warning letter. FDA cited one example from August 2009, when it issued an import alert regarding products made at two facilities of Apotex, Inc., the largest Canadian-owned pharmaceutical firm. The agency took this action just fourteen days after it completed an inspection of the company's Ontario facility. During that inspection, the agency uncovered several CGMP violations that were similar to those it found during its December 2008 inspection at another of the firm's manufacturing sites and for which the agency issued a warning letter in June 2009. FDA placed both sites under import alert in August 2009, informing agency staff that they may detain without physical examination all finished drug products offered for entry into the United States and manufactured at both facilities.