Drug Safety: Better Data Management and More Inspections Are Needed to Strengthen FDA's Foreign Drug Inspection Program
Published: 2008-09-22T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: 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.
section_title: What GAO Found
paragraphs: 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.

section_title: Letter
paragraphs: The United States is becoming increasingly dependent on drug products  and drug ingredients manufactured in foreign countries. Whether drugs  are manufactured in foreign or domestic establishments, oversight of the  safety and effectiveness of drugs marketed in the United States is the  responsibility of the Food and Drug Administration (FDA), an agency  within the Department of Health and Human Services (HHS). In fulfilling  its responsibility, FDA may inspect foreign establishments whose drugs  are imported into the United States. Testing a drug at the border cannot  reliably determine safety or quality, and FDA relies on establishment  inspections to determine compliance with current good manufacturing  practice regulations (GMP) and assure that the safety and quality of drugs  are not jeopardized by poor manufacturing practices.
Ten years ago, we reported that FDA needed to improve its foreign drug  inspection program. Among other things, we noted that FDA had  significant problems managing its foreign inspection data, and we were  critical of the small number of inspections FDA conducted at foreign  establishments. For example, we found that a database FDA used to track  inspections did not always contain correct information about how FDA  classified the results of a given foreign establishment inspection. We also  found that the agency did not promptly issue warning letters asking  establishments to correct serious GMP deficiencies identified during  inspections.
Given the importance of FDA’s foreign drug inspection program, you  raised questions about the safety of imported drugs and the agency’s  ability to adequately oversee foreign establishments manufacturing such  products. In response, we began work and presented our preliminary  findings in a November 2007 hearing before the Subcommittee on  Oversight and Investigations, House Committee on Energy and Commerce,  suggesting that there were serious weaknesses in FDA’s foreign drug  inspection program similar to those we reported on in 1998. Following  that hearing, questions regarding the safety of drugs manufactured at  foreign establishments continued to mount. In January 2008, FDA began  an investigation after receiving reports of serious adverse events in people  receiving heparin sodium, a commonly used blood thinner. The agency  later learned that an active pharmaceutical ingredient (API) found in this  drug contained a contaminant and had been manufactured at a Chinese  establishment never inspected by FDA. Since we started our work, FDA  began or proposed several initiatives to strengthen its foreign drug  inspection program. In April 2008, we testified before this same  subcommittee on our preliminary assessment of how these initiatives  might address some of the weaknesses we identified in our November  2007 testimony.
In this report, we discuss FDA’s foreign drug inspection program,  including updates to information presented in our November 2007 and  April 2008 testimonies. Specifically, this report examines (1) the extent to  which FDA has accurate data on the number of foreign manufacturing  establishments subject to inspection, (2) the frequency of foreign  inspections, (3) oversight by FDA to ensure that foreign manufacturing  establishments correct serious deficiencies identified during inspections  and to monitor establishments’ continued compliance, and (4) issues  unique to conducting foreign inspections.
To address these objectives, we interviewed officials from FDA, including  its Center for Drug Evaluation and Research (CDER) and Office of  Regulatory Affairs (ORA), which each have responsibilities for managing  the foreign inspection program. To examine the extent to which FDA has  accurate data on the number of foreign manufacturing establishments  subject to inspection, we obtained information from an FDA database on  the number of establishments registered to market their drugs in the  United States. We also obtained from FDA’s import database data on the  number of establishments manufacturing drugs shipped to the United  States. We found information about the types of drugs shipped to the  United States sufficiently reliable for the purposes of our report. We  identified inaccuracies with some parts of FDA’s registration and import  databases, and we present these data to illustrate the variability in  information that FDA’s databases provide to agency officials on this topic.  To examine the frequency of foreign inspections, we obtained information  from another FDA database on the number of inspections conducted by  FDA of foreign drug manufacturing establishments. We found counts of  inspections sufficiently reliable for the purposes of our report. We also  examined methods used by FDA to select establishments for inspection.  To examine FDA’s response to serious deficiencies identified during  inspections of foreign manufacturing establishments, we examined FDA  data indicating how the agency classified establishments’ compliance with  agency requirements. We identified inconsistencies with these data, and  we present them to illustrate the variability in information that FDA’s  databases provide to agency officials on this topic. We also reviewed FDA  files on inspections of foreign establishments that occurred from fiscal  years 2002 through 2007, during which FDA identified serious deficiencies  and subsequently issued warning letters. The files contained information  about these establishments, their inspections, and their correspondence  with FDA. To examine issues unique to conducting foreign inspections, we  obtained information on agency initiatives that may have the potential to  improve its program for inspecting foreign establishments. Our work  focuses on human drugs regulated by CDER and not on biologics,  medical devices, veterinary medicines, or other items or products for  which FDA conducts inspections. (See app. I for a more detailed  discussion of the scope and methodology for this report.) We conducted  our work from September 2007 through September 2008 in accordance  with generally accepted government auditing standards. Those standards  require that we plan and perform the audit to obtain sufficient, appropriate  evidence to provide a reasonable basis for our findings and conclusions  based on our audit objectives. We believe that the evidence obtained  provides a reasonable basis for our findings and conclusions based on our  audit objectives.
subsections: section_title: Background
paragraphs: FDA is responsible for overseeing the safety and effectiveness of human  drugs marketed in the United States, whether they are manufactured in  foreign or domestic establishments. As part of its efforts to ensure the  safety and quality of imported drugs, FDA may inspect foreign  establishments whose drugs are imported into the United States. The  purpose of these inspections is to ensure that foreign establishments meet  the same manufacturing standards for quality, purity, potency, safety, and  efficacy as required of domestic establishments.
Requirements governing FDA’s inspection of foreign and domestic  establishments differ. Specifically, FDA is required to inspect every 2 years  those domestic establishments that manufacture drugs marketed in the  United States, but there is no comparable requirement for inspecting  foreign establishments. However, drugs manufactured by foreign  establishments that are offered for import may not enter the United States  if FDA determines—through the inspection of an establishment, a physical  examination of drugs offered for import, or otherwise—that there is  sufficient evidence of a violation of applicable laws or regulations.
Within FDA, CDER sets standards and evaluates the safety and  effectiveness of prescription and over-the-counter (OTC) drugs. Among  other things, CDER requests that ORA inspect both foreign and domestic  establishments to ensure that drugs are produced in conformance with  federal statutes and regulations, including current GMPs. CDER requests  that ORA conduct inspections of establishments that produce drugs in  finished-dosage form as well as APIs used in finished drug products. These  inspections are performed by investigators and, as needed, laboratory  analysts. ORA conducts two primary types of drug manufacturing  establishment inspections:    Preapproval inspections of domestic and foreign establishments are  conducted before FDA will approve a new drug to be marketed in the  United States. These inspections occur following FDA’s receipt of a new  drug application or an abbreviated new drug application and focus on the  manufacture of a specific drug. Preapproval inspections are designed to  verify the accuracy and authenticity of the data contained in these  applications to determine that the establishment is following commitments  made in the application. FDA also determines that the establishment  manufacturing the finished drug product, as well as each manufacturer of  an API used in the finished product, manufactures, processes, packs, and  labels the drug adequately to preserve its identity, strength, quality, and  purity.
GMP inspections focus on an establishment’s systemwide controls for  ensuring that the processes it uses to manufacture drugs marketed in the  United States produce drugs that are of high quality. Systems examined  during these inspections include those related to materials, quality control,  production, facilities and equipment, packaging and labeling, and  laboratory controls. These systems may be involved in the manufacture of  multiple drugs. For the purpose of surveillance, FDA conducts GMP  inspections of establishments manufacturing drugs currently marketed in  the United States to determine establishments’ ongoing compliance with  laws and regulations. FDA conducts for-cause GMP inspections when it  receives information indicating problems in the manufacture of approved  drugs, as well as when it follows up on establishments that were not in  compliance with GMPs during previous inspections.
FDA may conduct an inspection that combines both preapproval and GMP  components during a single visit to an establishment. As the results of a  GMP inspection can often be generalized to all drugs manufactured at a  particular establishment, FDA can use the results of the combined  inspection to make decisions in the future if the establishment is listed in  another application.
FDA uses a risk-based process to select some domestic and foreign  establishments for GMP inspections to conduct surveillance of drugs  currently marketed in the United States. According to an FDA report, the  agency developed the process after recognizing that it did not have the  resources to meet the requirement for inspecting domestic establishments  every 2 years. The process uses a risk-based model to identify those  establishments that, based on characteristics of the establishment and of  the drug being manufactured, have the greatest public health risk potential  should they experience a manufacturing defect. Through this process,  CDER annually prepares a prioritized list of domestic establishments and a  separate, prioritized list of foreign establishments. FDA began applying  this risk-based process to domestic establishments in fiscal year 2006 and  expanded it to foreign establishments in fiscal year 2007.
FDA’s process for determining whether a foreign establishment complies  with GMPs involves both CDER and ORA. During an inspection, ORA staff  report observations of significant objectionable conditions and practices  that do not conform to GMPs on the list-of-observations form, commonly  referred to as an FDA Form 483. They provide this Form 483 to the  establishment, along with a briefing on the inspection’s results, on the last  day of the inspection. ORA staff discuss the observations on the Form 483  with the establishment’s management to ensure that they are aware of any  deficiencies that were observed during the inspection and suggest that the  establishment respond to FDA in writing concerning all actions taken as a  result of the observations.
Once ORA staff complete the inspection, they prepare an establishment  inspection report to document their inspection findings. Inspection reports  describe the manufacturing operations observed during the inspection and  any conditions that may violate federal statutes and regulations. Based on  its inspection findings, ORA recommends whether the establishment is  acceptable to supply drug products or drug ingredients to the United  States.
ORA makes a recommendation regarding the classification of the  inspection. All inspection reports and classification recommendations  related to inspections of foreign establishments are forwarded to CDER.  CDER reviews the ORA recommendation and determines the final  classification and whether regulatory action is necessary.
A classification of no action indicated (NAI) means that insignificant or no  deficiencies were identified during the inspection.
A classification of voluntary action indicated (VAI) means that deficiencies  were identified during the inspection, but the agency is not prepared to  take regulatory action. Therefore, any corrective actions are left to the  establishment to take voluntarily.
A classification of official action indicated (OAI) means that serious  deficiencies were found that warrant regulatory action.
Inspections classified as OAI may result in regulatory action, such as the  issuance of a warning letter. FDA issues warning letters to those foreign  establishments manufacturing drugs for the U.S. market that are in  violation of the law or implementing regulations and may be subject to  enforcement action if the violations are not promptly and adequately  corrected. In addition, warning letters notify the establishment that FDA  may refuse entry of the establishment’s drugs at the border and will  recommend disapproval of any new drug applications listing the  establishment until sufficient corrections are made. It is FDA policy to  consider many factors in determining whether to issue a warning letter.  For example, the agency is to consider corrective actions taken or  promised by the establishment since the inspection, and it may decide to  not issue a letter if an establishment’s corrective actions are adequate and  the violations that would have supported the letter have been corrected.  Warning letters are issued after the review and approval of FDA’s Office of  Chief Counsel. FDA policy states that the agency will strive to issue  warning letters within 4 months of the last day of the inspection.
In addition to a warning letter, FDA may take other regulatory actions if it  identifies serious deficiencies during the inspection of a foreign  establishment. For example, FDA may issue an import alert, which  instructs FDA staff that they may detain drugs manufactured by the  violative establishment that have been offered for entry into the United  States. In addition, FDA may conduct regulatory meetings with the  violative establishment. Regulatory meetings may be held in conjunction  with the issuance of a warning letter to emphasize the significance of the  deficiencies or for the purpose of obtaining prompt voluntary compliance  in those instances in which the deficiencies do not warrant the issuance of  a warning letter.
FDA uses multiple sources of information to determine whether the  actions taken by an establishment to correct violations are adequate. FDA  may, for example, review documentation describing completed or  proposed corrective actions; hold meetings with representatives of the  establishment to discuss corrective actions; agree to consider reports of  inspections conducted by private consultants; obtain inspection reports  from foreign regulatory bodies; and reinspect the establishment itself,  though it is not required to do so. As part of this process, agency staff may  also make a recommendation for when the establishment should next  receive a surveillance inspection. See figure 1 for a description of this  process.
FDA uses multiple databases to manage its foreign drug inspection  program.
The Drug Registration and Listing System (DRLS) contains information on  foreign and domestic drug establishments that have registered with FDA  to market their drugs in the United States. These establishments provide  information, including company name and address and the drugs they  manufacture for commercial distribution in the United States, on paper  forms, which are entered into DRLS by FDA staff.
The Operational and Administrative System for Import Support (OASIS)  contains information on drugs and other FDA-regulated products offered  for entry into the United States, including information on the  establishment that manufactured the drug. The information in OASIS is  automatically generated from data managed by Customs and Border  Protection (CBP). The data are originally entered by customs brokers  based on the information available from the importer. CBP specifies an  algorithm by which customs brokers generate a manufacturer  identification number from information about an establishment’s name  and address.
The Field Accomplishments and Compliance Tracking System (FACTS)  contains information on foreign and domestic establishments inspected by  ORA, the type of inspection conducted, and the outcome of those  inspections. Investigators and laboratory analysts enter information into  FACTS following completion of an inspection.
The Office of Compliance Foreign Inspection Tracking System (OCFITS)  contains information that CDER uses to track its review of foreign  inspection reports submitted by ORA staff, such as information on the type  of inspection conducted, CDER actions taken in connection with its  review of inspection reports, and the outcome of those inspections.  Information in OCFITS is entered by CDER staff.
According to DRLS, in fiscal year 2007, foreign countries that had the  largest number of registered establishments were China, India, Canada,  France, Germany, Japan, the United Kingdom, and Italy (see fig. 2). These  countries are also listed in OASIS as having the largest number of  establishments offering drugs for import into the United States.  Specifically, according to OASIS, China had more establishments  manufacturing drugs that were offered for import into the United States  than any other foreign country. According to OASIS, in fiscal year 2007, a  wide variety of prescription and OTC drugs manufactured in China were  offered for import into the United States, including pain killers, antibiotics,  blood thinners, and hormones.
section_title: FDA Lacks Accurate Information to Effectively Manage the Foreign Drug Inspection Program
paragraphs: FDA does not know how many foreign establishments are subject to  inspection, and the agency’s recently announced initiatives do not fully  address this weakness. The databases that FDA uses to select  establishments for inspection do not contain accurate information on the  number of establishments manufacturing drugs for the U.S. market.  Instead of maintaining a list of establishments subject to inspection, FDA  relies on information from databases that contain inaccuracies and that  were not designed for this purpose. Furthermore, officials indicated that  these databases cannot be electronically integrated or readily interact with  one another to compare data, so some comparisons are done manually for  each individual establishment. FDA has supported initiatives that could  provide it with more accurate information about foreign establishments  subject to inspection, but it is too early to tell if these efforts will provide  the agency with an accurate count.
subsections: section_title: FDA’s Drug Registration Database Contains Inaccuracies and Planned Changes Will Not Ensure the Availability of Accurate Information on Foreign Establishments
paragraphs: DRLS provides FDA with some information that the agency uses to select  establishments for inspection, but contains inaccuracies and does not  provide a complete count of establishments subject to inspection. DRLS,  established in 1991, is intended to list the registered establishments that  manufacture drugs for the U.S. market. Requirements for the registration  of foreign establishments were implemented in 2002. FDA expected that  requiring foreign establishments to register would provide it with a  comprehensive list of establishments that manufacture drugs for the U.S.  market. In fiscal year 2007, approximately 3,000 foreign establishments  that reported manufacturing human drugs, biologics, or veterinary drugs  were registered with FDA; FDA was unable to determine from this  database the number of registered establishments specifically  manufacturing human drugs.
FDA officials told us that the count of registered foreign establishments in  DRLS does not reflect the actual number whose drugs are being imported  into the United States for several reasons. First, although foreign  establishments are required to renew their registration information  annually, FDA does not enforce this requirement by deactivating the  registration of establishments that do not fulfill this requirement. Agency  officials told us that some foreign establishments may not report to FDA if  they stop manufacturing drugs for the U.S. market or go out of business,  although establishments are required to do so. Thus, these establishments  may still be listed in DRLS as actively registered establishments. Second,  foreign establishments may register with FDA whether or not they actually  manufacture drugs for the U.S. market. FDA officials told us that this is  made more likely by the fact that FDA does not charge foreign  establishments a fee to register. FDA officials pointed out that some  foreign establishments register because, in foreign markets, registration  may erroneously convey an “approval” or endorsement by FDA. FDA  officials told us that the agency does not routinely verify the information  provided by establishments to ensure that it is accurate. Nor does FDA  confirm that the establishment actually manufactures drugs for the U.S.  market. FDA does not know how many foreign establishments are  erroneously registered. In addition, DRLS does not provide the agency  with a complete count of establishments subject to inspection because  foreign establishments that manufacture APIs are not required to register  if their products are not directly imported into the United States.
Planned changes to DRLS could help FDA improve this database but will  not provide an accurate count. In July 2008, FDA initiated a pilot of a  voluntary electronic registration and listing system for establishments that  manufacture drugs; the agency plans to accept only electronic  registration beginning June 2009. The new system allows drug  manufacturing establishments to submit registration and listing  information electronically, rather than submitting it on paper forms. FDA  hopes that electronic registration will result in efficiencies allowing the  agency to shift resources from data entry to assuring the quality of the  databases. Through this new system, FDA also plans to require  establishments to update their registration information every 6 months,  rather than annually, as is currently required. In addition, FDA has asked  establishments to voluntarily submit a unique identification number—a  Dun and Bradstreet Data Universal Numbering System (D-U-N-S®)  Number—as part of their registration. An official said the agency plans to  make this a requirement after it implements electronic registration in June  2009. This identification number could provide FDA with confidence  regarding certain information about the establishment, such as its name  and location. However, it will not prevent foreign establishments that do  not manufacture drugs for the U.S. market from registering. As a result,  the registration database will continue to contain inaccuracies when FDA  selects establishments for inspection.
FDA has also proposed, but not yet implemented, initiatives that could  help improve the accuracy of information FDA maintains on registered  establishments. FDA proposed a program to contract with an external  organization to help manage and improve DRLS, which it describes in its  proposal as fragmented and unreliable. As part of the contract, FDA states  that the contractor would “establish reasonable credibility” of some of the  information provided by establishments. However, as of June 2008, the  agency had not yet solicited proposals for this program. In addition, the  agency has proposed the Foreign Vendor Registration Verification  Program. Through this program, FDA plans to contract with an external  organization to conduct on-site verification of the registration data and  product listing information of foreign establishments shipping drugs and  other FDA-regulated products to the United States. FDA has solicited  proposals for this contract but is still developing the specifics of the  program. For example, the agency has not yet formalized the criteria it  would use to determine which establishments would be visited for  verification purposes or determined how many establishments it would  verify annually. As of July 2008, FDA had not yet awarded this contract.  Given the early stages of these proposals, it is too soon to determine  whether they will improve the accuracy of the data FDA maintains on  foreign drug establishments.
section_title: FDA’s Import Database Contains Inaccurate Data on Establishments Offering Drugs for Import into the United States
paragraphs: OASIS, which FDA also uses to help it select establishments for  inspection, provides an inaccurate count of foreign establishments  manufacturing drugs offered for import into the United States. According  to OASIS, 6,760 foreign establishments manufactured drugs that were  offered for import into the United States in fiscal year 2007. However, this  count is inaccurate as a result of unreliable manufacturer identification  numbers generated by customs brokers when a drug is offered for  import. FDA officials told us that these errors result in the creation of  multiple records for a single establishment, which results in inflated  counts of establishments offering drugs for import into the U.S. market.  FDA officials acknowledged this problem but were unable to provide us  with an estimate of the extent of these errors. In addition, the agency does  not have a process for systematically identifying and correcting these  errors. To mitigate this problem, the officials told us that FDA has  provided training to brokers as a way to improve accuracy.
FDA has supported a proposal with the potential to address weaknesses in  OASIS, but FDA does not control the implementation of this proposed  change. FDA, in conjunction with other federal agencies, is pursuing the  creation of a governmentwide unique establishment identifier that could  minimize duplication. Agencies currently rely on the creation and entry of  an identifier at the time of import. Under this new proposal,  establishments offering products, including drugs, for import into the  United States would obtain a unique establishment identifier through a  commercial service that would verify certain information about the  establishment. This unique identifier would then be stored within the  proposed Shared Establishment Data Service (SEDS) and submitted as  part of import entry data when required by FDA or other government  agencies. The unique identifier could thus eliminate the problems that  have resulted in multiple identifiers associated with an individual  establishment. The implementation of SEDS is dependent on action from  multiple federal agencies, including the integration of the concept into a  CBP import and export system that is under development and scheduled  for implementation in 2010. In addition, once implemented by CBP, FDA  and other participating federal agencies would be responsible for bearing  the cost of integrating SEDS with their own operations and systems. FDA  officials are not aware of a specific time line for the implementation of  SEDS.
section_title: FDA’s Databases Are Not Currently Electronically Integrated, which Could Help Reconcile Data Inaccuracies
paragraphs: The databases FDA uses to select establishments for inspection are not  electronically integrated, and their integration could help reconcile data  inaccuracies. To create a list of foreign establishments subject to  inspection, the agency relies on information from databases that were not  designed for that purpose and contain divergent estimates—about 3,000  and 6,760 from DRLS and OASIS, respectively. FDA officials told us that  these databases are not electronically integrated and do not readily  interact with one another to help reconcile the data. FDA indicated that  any electronic comparison of the data in these databases is complex and  the agency conducts some comparisons manually for each individual  establishment. For example, for fiscal year 2007, FDA used DRLS and  other data to develop a list of 3,249 foreign establishments ranked by their  risk level in order to select establishments for surveillance inspection.  However, due to inaccuracies in DRLS, FDA must also check OASIS to  determine which of these establishments actually had imported drugs into  the United States and were subject to inspection. FDA officials indicated  that they had to manually compare establishments on this list with  establishments in OASIS. Because these databases are not electronically  integrated, DRLS and OASIS are not conducive to routine analysis to  compare the data and identify errors.
FDA is in the process of improving the integration of some of its current  data systems, which could make it easier for the agency to establish an  accurate count of foreign drug manufacturing establishments subject to  inspection. The agency’s Mission Accomplishments and Regulatory  Compliance Services (MARCS) is intended to help FDA electronically  integrate data from multiple systems. It is specifically designed to give  individual users a more complete picture of establishments but could also  help the agency compare information in multiple databases to obtain an  accurate count of establishments subject to inspection. For example, an  FDA official indicated that MARCS in combination with planned  improvements to the agency’s registration database will allow FDA to  electronically integrate FDA’s drug registration and import data. FDA  officials estimate that MARCS, which is being implemented in stages,  could be fully implemented by 2011 or 2012. An FDA official told us that  the agency may be able to electronically integrate its registration and  import data by the end of fiscal year 2009, but this implementation has  previously faced delays. FDA officials told us that 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, such as FACTS and OASIS. It is too early to tell whether the  implementation of MARCS will improve FDA’s management of its  inspection program.
section_title: FDA Inspects Relatively Few Foreign Establishments to Assess the Manufacture of Drugs Currently Marketed in the United States
paragraphs: FDA inspects few foreign establishments, relative to domestic  establishments, each year to assess the manufacture of drugs currently  marketed in the United States. The percentage of such foreign  establishments that have been inspected cannot be calculated with  certainty because FDA does not know how many foreign establishments  manufacture drugs for the U.S. market and are thus actually subject to  inspection. Of the foreign establishments that FDA inspected, few were  selected to conduct surveillance of drugs currently marketed in the United  States. Instead, most foreign establishments are selected for inspection as  part of the agency’s review process associated with applications for  approving a new drug.
subsections: section_title: FDA Inspects Few Foreign Establishments Each Year, Relative to Its Inspection of Domestic Establishments
paragraphs: In each year we examined, FDA inspected fewer foreign establishments  manufacturing drugs for the U.S. market than it inspected domestically.  However, its lack of an accurate count of foreign establishments subject to  inspection makes it difficult to exactly determine the relative size of that  portion. Based on our review of data on inspections, FDA conducted an  average of 247 foreign establishment inspections per year from fiscal years  2002 through 2007. Comparing this average number of inspections with  FDA’s count of 3,249 foreign establishments that it used to prioritize its  fiscal year 2007 surveillance inspections suggests that the agency inspects  about 8 percent of foreign establishments in a given year. At this rate it  would take FDA more than 13 years to inspect this group of  establishments once, assuming that no additional establishments are  subject to inspection. In contrast, from fiscal years 2002 through 2007 FDA  conducted about 1,528 inspections of domestic establishments each year.  FDA officials estimated that there were about 3,000 domestic  establishments manufacturing drugs in fiscal year 2007. They told us that  the agency inspects these domestic establishments about once every   2.7 years.
FDA’s data indicate that some foreign establishments have never received  an inspection, but the exact number of such establishments is unclear. Of  the list of 3,249 foreign establishments, there were 2,133 foreign  establishments for which the agency could not identify a previous  inspection. Agency officials told us that this count included registered  establishments whose drugs are being imported into the United States that  have never been inspected, as well as establishments whose drugs were  never imported into the United States or those who have stopped  importing drugs into the United States without notifying FDA. FDA was  unable to provide us with counts of how many establishments fall into  each of these subcategories. Of the remaining 1,116 establishments on  FDA’s list, 242 had received at least one inspection, but had not received a  GMP inspection since at least fiscal year 2000. The remaining 874  establishments had received at least one GMP inspection since fiscal year  2000. Of these 874 establishments, 326 had last been inspected in fiscal  years 2005 or 2006, 292 were last inspected in fiscal years 2003 or 2004,  and the remaining 256 received their last inspection in fiscal years 2000  through 2002.
FDA recently increased the number of foreign establishments it inspects,  most of which are concentrated in a small number of countries. From  fiscal years 2002 through 2007, the number of foreign establishment  inspections FDA conducted varied from year to year, but increased overall  from 220 in fiscal year 2002 to 332 in fiscal year 2007. During this period,  FDA inspected establishments in a total of 51 countries. More than three  quarters of the 1,479 foreign inspections the agency conducted during this  period were of establishments in 10 countries, as shown in table 1.  Because some establishments were inspected more than once during this  time period, FDA actually inspected 1,119 unique establishments. For  example, of the 94 inspections that FDA conducted of Chinese  establishments, it inspected 80 unique establishments. The proportion of  establishments inspected in each of these 10 countries varied. The country  with the lowest proportion of establishments inspected was China, for  which FDA inspected 80 of its estimated 714 establishments. In contrast,  the agency inspected 43 of the estimated 61 establishments in Ireland.
While FDA has recently made progress in conducting more foreign  inspections, it still inspects relatively few such establishments. FDA  conducted more foreign establishment inspections in fiscal year 2007 than  it had in each of the 5 previous fiscal years. However, the agency still  inspected less than 11 percent of the foreign establishments on the  prioritized list that it used to plan its fiscal year 2007 surveillance  inspections.
In order to inspect foreign establishments biennially, as is required for  domestic establishments, FDA would have to dedicate substantially more  resources than it has dedicated to such inspections in the past. In fiscal  year 2007, FDA dedicated about $10 million to inspections of foreign  establishments. FDA estimates that, based on the time spent conducting  inspections of foreign drug manufacturing establishments in fiscal year  2007, the average cost of such an inspection ranged from approximately  $41,000 to $44,000. If these estimates are applied to the 3,249 foreign drug  establishments on the list FDA used to plan its fiscal year 2007  surveillance inspections, it could cost the agency $67 million to $71 million  each year to inspect each of those establishments biennially. Using FDA’s  estimates for the cost of each inspection also suggests that it could cost  the agency $15 million to $16 million each year to biennially inspect the  estimated 714 drug manufacturing establishments in China, the country  estimated to have the largest number of establishments. According to FDA  budget documents, the agency estimates that it will dedicate a total of  about $11 million in fiscal year 2008 to foreign drug inspections.
Significant changes were recently made to the fiscal year 2009 budget  request for FDA. The President’s original budget request to the Congress  called for $2.4 billion in fiscal year 2009 for FDA, including $13 million to  conduct all inspections of foreign drug establishments. However, in June  2008, the President submitted an amendment requesting an additional   $275 million for fiscal year 2009, an approximately 11 percent increase  over the original request. According to the submission, some of these  additional funds were requested to allow FDA to conduct an additional 143  inspections of foreign drug establishments and 75 inspections of domestic  drug establishments.
FDA is pursuing initiatives with drug regulators in foreign countries that  are intended to help the agency improve its inspectional coverage. FDA  has announced an initiative with the regulatory body of the European  Union to pilot joint inspections of establishments that manufacture  finished drug products in either the United States or the European Union  and supply both of these markets. FDA indicated that these joint  inspections could help it leverage resources by allowing the agency to  utilize staff from the E.U. regulatory body when forming joint inspection  teams. According to FDA, the joint inspections will help the agency and  the E.U. regulatory body build confidence in each other’s inspections,  which could allow FDA to review an inspection report completed by E.U.  regulators instead of conducting its own inspection. As of July 2008, no  joint inspections had been scheduled under this program, but they were in  preliminary discussions with one establishment to conduct a joint  inspection. In addition, FDA has announced an initiative with the  regulatory bodies of the European Union and Australia to share their plans  for and results of inspections of API manufacturing establishments in  these and other countries. For example, FDA could receive the results of  inspections conducted by these regulatory bodies and then determine if  regulatory action or a follow-up inspection is necessary. FDA contends  that prospectively sharing information about inspection plans will allow  these regulatory bodies to more efficiently use their resources by  minimizing the overlap in their plans. FDA and the other regulatory bodies  held initial discussions in July 2008 and plan to further discuss the  program in September 2008. While both initiatives are intended to improve  FDA’s knowledge of foreign establishments, both were recently  announced and their impact will depend on the extent to which FDA  effectively utilizes the information that it receives from the other  regulatory bodies.
section_title: FDA Selects Few Foreign Establishments to Inspect the Manufacturing of Drugs Currently Marketed in the United States, in Contrast to Its Inspections of Domestic Establishments
paragraphs: FDA selected few foreign establishments for inspection in order to  examine the manufacturing of drugs currently marketed in the United  States. We reported in 1998 that 20 percent of the agency’s foreign  inspections were for the purpose of routine surveillance. For fiscal years  2002 through 2007, we found that about 13 percent of foreign inspections  were GMP inspections conducted to examine the manufacturing of drugs  currently marketed in the United States, rather than to inspect an  establishment listed in a new drug application. (See fig. 3.) In comparison,  for fiscal years 2002 through 2007, about 85 percent of FDA’s inspections  of domestic establishments were GMP inspections conducted to examine  the manufacturing of drugs currently marketed in the United States. FDA  conducts a similar number of preapproval inspections in domestic and  foreign establishments each year, but many more domestic GMP  inspections. Agency officials said that preapproval inspections are driven  by specific goals for the timely review of new drug applications, which  may necessitate the inspection of establishments referenced in those  applications.
FDA often included a systemwide GMP inspection when it visited a foreign  establishment for a preapproval inspection. From fiscal years 2002 through  2007, the majority of FDA’s foreign inspections combined a preapproval  inspection with a broader GMP inspection. According to FDA officials,  because foreign establishments are inspected infrequently, it is expedient  for the agency to conduct preapproval inspections and GMP inspections  during the same visit to a foreign establishment.
Relatively few foreign establishments identified through CDER’s risk- based process are selected for the agency to conduct surveillance of drugs  currently marketed in the United States. In fiscal year 2007, after using this  process to rank the 3,249 establishments by their potential risk level,  CDER forwarded to ORA a list of 104 foreign establishments that it  considered to be a high priority for inspection and requested that ORA  complete surveillance inspections of 25 of them. FDA officials indicated  that 29 such inspections were actually completed in fiscal year 2007. In  fiscal year 2008, CDER submitted a list of 110 foreign establishments to  ORA, with a target of at least 50 inspections.
section_title: FDA’s Identification of Serious Deficiencies Has Led Establishments to Take Corrective Actions, but Subsequent Inspections Were Not Always Timely
paragraphs: Though FDA oversight resulted in foreign establishments taking actions to  address serious deficiencies identified during inspections, FDA’s  subsequent inspections of these establishments were not always timely.  FDA identified deficiencies during most of its inspections of foreign  establishments. However, determining the number of inspections during  which FDA identified serious deficiencies is hindered by inconsistent data  on inspection classifications. FDA issued 15 warning letters to foreign  drug establishments found to be out of compliance with GMPs. To  determine the adequacy of an establishment’s corrective actions, FDA  often relied on information provided by the establishment, rather than  information obtained from another FDA inspection. Although FDA verified  these corrective actions during subsequent inspections, FDA inspections  to determine establishments’ continued compliance were not always  timely and identified additional deficiencies.
subsections: section_title: FDA Identified Deficiencies during Most of Its Inspections of Foreign Establishments, but FDA’s Databases Contain Inconsistent Information about Inspection Classifications
paragraphs: FDA identified deficiencies during most of its inspections of foreign  establishments. Based on our review of classification data in FACTS, FDA  identified deficiencies necessitating a classification of VAI or the more  serious OAI in about 62 percent of foreign inspections conducted from  fiscal years 2002 through 2006, compared to about 51 percent of  inspections of domestic establishments. However, we determined that  FDA’s data did not provide reliable information about the number of  foreign inspections with serious deficiencies classified specifically as OAI.
Determining the number of inspections during which FDA identified  serious deficiencies is hindered by inconsistencies in databases used by  FDA to track inspections. FDA uses two databases to track information  about foreign inspections—FACTS, which is accessible to ORA staff and  staff in CDER and other FDA centers, and OCFITS, which is only  accessible to CDER staff who review foreign inspection reports. In  comparing inspection classification information for foreign inspections  conducted from fiscal years 2002 through 2006, we found that of the  inspections that could be identified in both databases, 92 percent were  consistently classified. However, for inspections that identified serious  deficiencies, this rate was much lower. Of inspections classified as OAI in  FACTS, 53 percent were identified in OCFITS as receiving the less serious  classification of VAI. CDER officials told us that the final inspection  classification should be the same in both FACTS and OCFITS.
FDA officials suggested that inconsistencies between FACTS and OCFITS  may result when changes in inspection classifications are not  appropriately updated by FDA staff during the review process. Following  an inspection of a foreign establishment, ORA staff enter classification  recommendations into FACTS. However, CDER makes the final  classification decision, which may be either more or less serious than  ORA’s recommendation. CDER officials enter this final classification into  OCFITS and, according to FDA policy, should also update this information  in FACTS. However, FDA officials indicated that CDER staff may not  always update FACTS. FACTS is the database used by ORA investigators  and staff in other FDA centers to check establishments’ compliance  history. When FACTS is not always updated consistent information on  foreign establishments may not be readily accessible to FDA staff  responsible for the oversight of foreign establishments manufacturing  drugs marketed in the United States.
section_title: FDA Issued Warning Letters to Establishments, Most of which Had Previous Deficiencies
paragraphs: FDA issued warning letters to establishments at which it identified serious  deficiencies. Of the 1,479 inspections of foreign drug establishments that  FDA conducted from fiscal years 2002 through 2007, the agency issued a  warning letter following 15 inspections in which serious deficiencies were  identified (see table 2). The rate of warning letters issued to foreign  establishments was similar to that for domestic establishments. Foreign  establishments that received warning letters were located in 10 countries.  For establishments listed in 4 of the 15 warning letters, in addition to  issuing a warning letter, FDA also issued import alerts authorizing  detention of the establishments’ drugs if they were offered for import into  the United States. When issuing the other 11 warning letters, FDA did not  restrict importation of the establishments’ drugs, but notified the  establishments that failure to correct the identified deficiencies could  result in the agency denying entry of their drugs when they were offered  for import into the United States.
During the inspections that resulted in these 15 warning letters, FDA  identified various deficiencies. Identified deficiencies included those  related to: laboratory controls, such as lack of an adequate impurity  profile; documentation and records, such as records that did not include  complete and accurate information relating to the production of each  batch of drug produced; and facilities and equipment, such as an  “unknown soft, yet flaking, black residue” inside a piece of equipment.
FDA generally met its internal goal for the timely issuance of warning  letters, and establishments usually began responding to deficiencies  identified on the Form 483 prior to receiving the warning letter. FDA  issued 9 of the 15 warning letters within 4 months of completing its  inspection—as is FDA’s policy—and issued 3 other letters in just over   4 months. While FDA was reviewing the results of the inspection and  drafting the warning letters, inspected establishments generally responded  in writing to deficiencies identified on the Form 483, which establishments  receive on the last day of an inspection. In all but one instance, the  establishments responded in writing to Form 483 observations within   5 weeks following the completion of the inspection. These written  responses included information on the establishments’ proposed,  completed, or soon to be implemented corrective actions taken to address  deficiencies identified during the FDA inspection. In more than half of the  cases, FDA noted that more comprehensive corrective actions were  needed than those outlined in the establishments’ responses or that the  responses lacked sufficient details, explanation, or documentation. The  agency proceeded to issue the warning letters after finding the  establishments did not provide sufficient written responses to the  deficiencies identified during the inspection.
Most of the foreign drug establishments to which FDA issued the 15  warning letters had previously been found by the agency to be out of  compliance with GMPs. FDA had previously inspected establishments  named in 12 of the 15 warning letters. These previous inspections had  been conducted 1 to 7 years prior to the inspection that resulted in the  issuance of the warning letter, with 9 of the 12 previous inspections  occurring within 4 years of the warning letter inspection. FDA identified  deficiencies in almost all of the 12 previous inspections, classifying 10 as  VAI and 1 as OAI, but did not issue any warning letters. For 7 of these  inspections, the deficiencies FDA identified at these establishments were  again identified during the inspection that led to the issuance of a warning  letter.
FDA often identified the warning letter deficiencies, which relate to the  manufacture of a currently marketed drug, when it inspected the  establishment as part of its review of a new drug application. In 7 of the   15 cases, FDA selected the establishment for inspection as part of its  review of a drug application. In 3 cases, FDA conducted the inspection for  surveillance purposes. In 3 other cases, FDA conducted the inspections  following the receipt of information from an informant, such as allegations  of insanitary conditions. In the 2 remaining cases, FDA conducted the  inspection to follow up on a previous inspection performed by FDA or a  foreign government that identified deficiencies.
section_title: FDA Oversight Has Led Establishments to Take Corrective Actions, but Subsequent Inspections to Determine Continued Compliance Are Not always Timely
paragraphs: FDA oversight resulted in establishments taking actions to correct serious  deficiencies, but the agency has not always conducted timely subsequent  inspections to determine whether establishments continued to comply  with agency requirements. FDA often relied on information provided by  the establishment, rather than obtained from an FDA inspection, to  determine the adequacy of an establishment’s corrective actions. As of  July 2008, FDA had determined that the corrective actions taken by  establishments referenced in 11 of the 15 warning letters were adequate.  (See fig. 4.) For 7 of these 11 establishments, FDA relied on information  provided by the establishment to make this determination. For example,  establishments provided FDA with an outline of corrective actions to be  taken. In some of these cases, FDA also met with officials from the  establishments or held telephone conferences to discuss the corrective  actions. This process often involved multiple communications between  FDA and the establishment. FDA typically notified these establishments  that their corrective actions were adequate within 4 months of issuing the  warning letter. In this notification, the agency generally stated that it  would verify the corrective actions taken at the time of the next  inspection.
FDA conducted an inspection or used the results of an inspection  conducted by a private consultant to determine the adequacy of the  establishments’ corrective actions for the other four establishments it  deemed adequate. FDA inspected three of these establishments between 8  and 21 months after the issuance of the warning letter. Based on these  inspections and other documentation, FDA determined that the  deficiencies that led to the warning letter had been corrected. In two of  those three inspections, FDA also found additional deficiencies that led to  a classification of VAI. For one establishment, instead of waiting for FDA  to conduct an inspection to determine the adequacy of its corrective  actions, FDA agreed that the establishment could arrange for an  inspection by a private consultant. The consultant found that the  establishment had made the corrective actions requested by FDA. The  agency stated that it would verify the corrective actions during its next  inspection.
FDA inspections to determine establishments’ continued compliance were  not always timely. As of June 2008, FDA had subsequently inspected 4 of  the 11 establishments it determined had taken adequate corrective actions  in response to the warning letters. For 3 establishments, FDA had  previously determined the adequacy of their corrective actions by  reviewing information provided by the establishment. Although CDER  staff had recommended that they be inspected within 1 year, these 3  establishments were inspected about 4 to 5 years after the inspection that  resulted in the warning letter. However, FDA officials told us that dates  recommended by CDER staff for subsequent inspections are only regarded  as suggestions and scheduling inspections must be considered in light of  other priorities. They noted that the selection of foreign establishments for  inspection is driven by the drug approval process. We found that, in these  3 cases, FDA next selected the establishment for inspection as part of  processing an application for a new drug, rather than for the purpose of  surveillance. For the fourth establishment, FDA had previously  determined the adequacy of the establishment’s corrective actions by  reviewing an audit report from a private consultant’s inspection. CDER  staff had recommended that this establishment be inspected within 2 years  and the agency met this recommendation by conducting a surveillance  inspection.
FDA verified corrective actions during three of these four inspections  subsequent to deeming the establishments’ corrective actions adequate,  but it also identified additional deficiencies. The agency found that the  three establishments had taken the corrective actions indicated in their  response to the warning letters. However, FDA found other deficiencies  requiring correction at those establishments. FDA classified all four of  these inspections as VAI and none resulted in the issuance of a warning  letter.
section_title: Challenges Unique to Foreign Inspections Influence the Manner in which FDA Conducts Such Inspections
paragraphs: Inspections of foreign drug establishments pose unique challenges to  FDA—in both human resources and logistics—that influence the manner  in which such inspections are conducted. For example, FDA does not have  a dedicated staff devoted to conducting foreign inspections and relies on  staff to volunteer. In addition, unlike domestic surveillance inspections,  foreign surveillance inspections are announced in advance and inspections  cannot be easily extended due to travel itineraries that involve more than  one establishment. Other factors, such as language barriers, can also add  complexity to the challenge of completing foreign establishment  inspections. FDA has recently announced proposals to address some of  the challenges unique to conducting foreign inspections, but it is unclear if  these proposals will address all of these challenges.
subsections: section_title: Inspections of Foreign Drug Establishments Pose Unique Challenges to FDA
paragraphs: Human resource and logistical challenges unique to foreign inspections  influence the manner in which FDA conducts those inspections. According  to FDA officials, the agency does not have a dedicated staff to conduct  foreign inspections. Instead FDA relies on investigators and laboratory  analysts to volunteer to conduct foreign inspections. Officials explained  that the same investigators and laboratory analysts are responsible for  conducting both foreign and domestic inspections. These staff members  must meet certain criteria in terms of their experience and training in  order to conduct inspections of foreign establishments. For example, they  are required to take certain training courses and must have at least 3 years  of experience conducting domestic inspections before they are considered  qualified to conduct a foreign inspection. FDA reported that in fiscal year  2007 it had approximately 335 employees who were qualified to conduct  foreign inspections of drug manufacturing establishments. Approximately  250 of these employees were investigators and 85 were laboratory  analysts.
FDA officials told us that it is difficult to recruit investigators and  laboratory analysts to voluntarily travel to certain countries and FDA does  not mandate that they do so. However, officials noted that the agency  provides various incentives to recruit employees for foreign inspection  assignments. For example, employees receive a $300 bonus for each   3-week foreign inspection trip completed, when their inspection reports  are submitted within established time frames. FDA indicated that if the  agency could not find an individual to volunteer for a foreign inspection  trip, it would mandate that travel. However, FDA has not typically sent  investigators and laboratory analysts to countries for which the  Department of State has issued a travel warning. We found that 49 foreign  establishments registered as manufacturers of drugs for the U.S. market  were located in 10 countries that had travel warnings posted as of October  2007. However, FDA officials told us that they have conducted  inspections in countries with travel warnings. They also provided us with  one example in which an establishment in a country with a travel warning  hired security through the Department of State to protect the inspection  team.
FDA also faces several logistical challenges in conducting inspections of  foreign drug manufacturing establishments. FDA guidance states that  inspections of foreign establishments are to be approached in the same  manner as domestic inspections. However, the guidance notes that  logistics pose a significant challenge to the inspection team abroad. For  example, FDA is unable to conduct unannounced inspections of foreign  drug establishments, as it does with domestic establishments. FDA policy  states that the agency, with few exceptions, initiates inspections of  establishments without prior notification to the specific establishment or  its management so that the inspection team can observe the establishment  under conditions that represent normal day-to-day activities. However,  prior notification is routinely provided to foreign establishments. FDA  officials noted that the time and expense associated with foreign travel  require them to ensure that managers of the foreign establishments are  available and that the production line being inspected is operational  during the inspection. In addition, FDA often needs the permission of the  foreign government prior to the inspection. FDA officials explained that in  some cases investigators and laboratory analysts may need to obtain a visa  or letters of invitation to enter the country in which the establishment is  located. Furthermore, FDA does not have the same flexibility to extend  the length of foreign inspection trips if problems are encountered as it  does with domestic inspections because of the need to maintain the  inspection schedule, which FDA officials told us typically involves  inspections of multiple establishments in the same country. In our review  of FDA inspection reports, we identified instances in which FDA was  unable to fully complete inspections of foreign establishments in the  allotted time. For example, in one instance, the FDA staff had a  commitment to travel to another city to inspect another establishment. In  this instance, an unexpected cancellation during that same trip allowed  FDA staff to return to the establishment at a later date to complete the  inspection.
FDA officials also told us that language barriers can make foreign  inspections more difficult to complete than domestic inspections. The  agency does not generally provide translators in foreign countries, nor  does it require that foreign establishments provide independent  interpreters. Instead, FDA staff may have to rely on an English-speaking  employee of the foreign establishment being inspected, who may not be a  translator by training, rather than rely on an independent translator. In our  review of FDA inspection reports, we identified instances in which the  translational support provided by an establishment created challenges. For  example, an FDA investigator noted that during one inspection it was  difficult to get an interpreter provided by the establishment to translate  employee statements verbatim. FDA officials told us that while the  presence of a translator is helpful, it is not necessary. They also pointed  out that for inspections related to the review of a drug application, the  establishment is required to submit its documentation in English.
section_title: Unclear if Recent FDA Proposals Will Address All Challenges Unique to Foreign Inspections
paragraphs: FDA has recently announced proposals to address some of the challenges  unique to conducting foreign inspections, but the extent to which these  proposals will improve FDA’s program is unclear. FDA is exploring the  creation of a cadre of investigators who would be dedicated to conducting  foreign inspections. FDA officials indicated that the agency plans to begin  a pilot of the foreign cadre in early fiscal year 2009. As of July 2008, FDA  had not yet begun recruiting investigators to participate in the foreign  cadre, but officials expected the pilot group to consist of 15 investigators  specializing in the inspection of drug establishments. An FDA official told  us, however, that it may recruit investigators specializing in other FDA- regulated products, such as food or medical devices, if it is unable to  recruit 15 drug investigators. The official also stated that the foreign cadre  will be composed of investigators who have experience conducting foreign  inspections. FDA has indicated that it would take approximately 4 years  before a newly hired investigator would be able to complete independent  inspections of foreign drug manufacturing establishments. According to  FDA, the full size of the foreign cadre will be determined in fiscal year  2010, taking lessons learned from the fiscal year 2009 pilot and resources  into consideration.
FDA also recently announced plans to establish a permanent foreign  presence overseas, although little information about these plans is  available. Through an initiative known as “Beyond our Borders,” FDA  intends to establish foreign offices to improve cooperation and  information exchange with foreign regulatory bodies, improve procedures  for expanded inspections, allow it to inspect facilities quickly in an  emergency, and facilitate work with private and government agencies to  assure standards for quality. FDA’s proposed foreign offices are intended  to expand the agency’s capacity for regulating, among other things, drugs,  medical devices, and food. The extent to which the activities conducted by  foreign offices are relevant to FDA’s foreign drug inspection program is  uncertain. Initially, FDA plans to establish a foreign office in China with  three locations—Beijing, Shanghai, and Guangzhou—composed of a total  of eight FDA employees and five Chinese nationals. The Beijing office,  which the agency expects will be partially staffed by the end of 2008, will  be responsible for coordination between FDA and the Chinese regulatory  agencies. FDA staff located in Shanghai and Guangzhou, who the agency  announced it will hire in 2009, will be focused on conducting inspections  and working with Chinese inspectors to provide training as necessary.  FDA has noted that the Chinese nationals will primarily provide support to  FDA staff including translation and interpretation. The agency also plans  to begin staffing offices in Central America, Europe, and India by the end  of 2008 and in the Middle East in 2009. While the establishment of both a  foreign inspection cadre and offices overseas has the potential for  improving FDA’s oversight of foreign establishments and providing the  agency with better data on foreign establishments, it is too early to tell  whether these steps will be effective or will increase the number of foreign  drug inspections.
Agreements with foreign governments, such as one recently reached with  China’s State Food and Drug Administration as part of Beyond our  Borders, may help the agency address certain logistical issues unique to  conducting inspections of foreign establishments. We have noted that  one challenge facing FDA involved the need for its staff to obtain a visa or  letter of invitation to enter a foreign country to conduct an inspection.  However, FDA officials told us that the agency’s agreement with China  recently helped FDA expedite this process when it learned of the adverse  events associated with a Chinese heparin manufacturing establishment.  According to these officials, the agreement with China greatly facilitated  FDA’s inspection of this establishment by helping the agency send  investigators much more quickly than was previously possible.
section_title: Conclusions
paragraphs: Americans depend on FDA to ensure the safety and effectiveness of drugs  marketed in the United States. More than 10 years ago we reported that  FDA needed to make improvements in its foreign drug inspection  program. Our current work indicates that flaws we identified at that time  persist. The recent incident involving contaminated heparin sodium also  underscores the need for FDA to obtain more information about foreign  drug establishments, conduct more inspections overseas, and improve its  overall management of this critical program. FDA recently announced  initiatives that represent important steps for the agency and, if fully  implemented, could address some of the concerns we identified in 1998  and reiterated in recent testimonies. However, given the growth in foreign  drug manufacturing for the U.S. market and the large gaps in FDA’s foreign  drug inspection program, significant challenges—such as improving its  data systems and increasing the rate of inspection—remain.
FDA’s oversight of its foreign inspection program is hampered by  inaccurate and inconsistent data on foreign establishments. An important  component of selecting establishments for inspection is an accurate list of  establishments subject to inspection, which currently is not readily  available to the agency. To reduce the creation of duplicate counts in its  import database, FDA supports the establishment of a unique  governmentwide identifier for foreign establishments. Such an identifier  has the potential to improve the accuracy of the data that FDA maintains  on foreign drug manufacturing establishments, and FDA’s continued  exploration of this option is an important step to improving the accuracy  of its data. However, the establishment and utilization of a unique  governmentwide identifier would be dependent on the actions of multiple  agencies and would not provide an immediate solution to correcting the  inaccuracies in FDA’s databases. In addition, the agency’s plan to institute  electronic registration may provide FDA with a more efficient way to  maintain information on each establishment, but it is unlikely to make a  meaningful improvement in FDA’s registration database by preventing  erroneous registration and providing an accurate count of establishments  subject to inspection. Enforcing the requirement that establishments  update their registration annually, or biannually, as planned, is an  important step towards keeping this database up to date. However, it is  also important that FDA verify the information provided by establishments  at the time of registration to ensure that establishments are appropriately  registered. In addition, inconsistencies in databases that FDA uses to track  inspections of foreign drug manufacturing establishments provide it with  unreliable data on those establishments for which it identified serious  manufacturing deficiencies. As a result, the different FDA staff responsible  for oversight of these foreign establishments may not have ready access to  accurate information on their compliance history when carrying out  regulatory responsibilities.
Conducting additional surveillance inspections of foreign establishments  manufacturing drugs currently marketed in the United States is vital, but  FDA’s selection of foreign establishments for inspection has instead been  driven by the need to inspect establishments named in an application for a  new drug. While these preapproval inspections are an important  component of FDA oversight, without additional surveillance inspections  FDA has little opportunity to monitor the ongoing compliance of  establishments manufacturing drugs currently marketed in the United  States. In addition, FDA has not utilized its risk-based process to select  foreign establishments for inspection to the extent it has for selecting  domestic establishments. However, both FDA’s inspection classifications  and issuance of warning letters indicate that deficiencies, including  serious GMP deficiencies, are found in foreign establishments at least as  often as in domestic ones. Therefore, it is important that FDA inspect  foreign and domestic establishments with similar characteristics at  comparable frequencies. A reassessment of FDA’s inspection priorities  could help the agency to ensure that it is frequently inspecting those  establishments, foreign or domestic, that pose the greatest potential risk to  public health should they experience a manufacturing defect.
Although foreign establishments have been responsive to FDA warning  letters, the agency’s subsequent inspections have often identified  additional deficiencies. This 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. FDA’s plans to establish  overseas offices and a cadre of investigators dedicated to foreign  inspections are promising and have the potential to address many of the  challenges unique to conducting foreign inspections. However, it is too  early to tell whether these steps will be effective in improving the agency’s  foreign drug inspection program.
section_title: Recommendations for Executive Actions
paragraphs: To address weaknesses in FDA’s oversight of foreign establishments  manufacturing drugs for the U.S. market, we recommend that the  Commissioner of FDA take the following five actions:    Enforce the requirement that establishments manufacturing drugs for the  U.S. market update their registration annually.
Establish mechanisms for verifying information provided by the  establishment at the time of registration.
Ensure that information on the classification of inspections with serious  deficiencies is accurate in all FDA databases.
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.
Conduct timely inspections of foreign establishments that have received  warning letters to determine continued compliance.
section_title: Agency Comments and Our Evaluation
paragraphs: HHS reviewed a draft of this report and provided comments, which are  reprinted in appendix II. HHS also provided technical comments, which  we incorporated as appropriate. HHS commented on one of our  recommendations and agreed that FDA should conduct more inspections  of foreign establishments. It did not comment on the other four  recommendations we made. HHS also stated that our report raises some  important issues regarding FDA’s foreign drug inspection program and  noted that FDA has made efforts to improve this program.
HHS agreed that additional inspections are needed to strengthen its  foreign drug inspection program. The agency did not provide a specific  plan or timeframe for conducting additional foreign inspections. HHS  noted that these inspections represent only one component of its overall  strategy to enhance oversight of imported drugs. HHS also said that  conducting foreign inspections based on the same criteria as domestic  inspections is problematic because of challenges associated with foreign  inspections. As we noted in our draft report, we recognize that inspections  of foreign establishments pose unique challenges to FDA. Nevertheless,  foreign and domestic establishments with characteristics that pose similar  potential risks to public health need to be inspected at comparable  frequencies. As we noted, FDA finds serious GMP deficiencies in foreign  establishments at least as often as in domestic ones. Therefore, we believe  that it is important for the agency to use its resources, in coordination with  its other initiatives, to prioritize for inspection those establishments,  whether they are located in the United States or a foreign country, that  have the greatest potential to negatively impact public health.
HHS also elaborated on some of the initiatives to improve FDA’s foreign  drug inspection program that were discussed in our report—such as  initiatives to improve FDA databases, establish foreign offices, and  collaborate with foreign governments. In particular, HHS noted that as  FDA implements electronic registration, it also plans to require  establishments to update their registration at 6-month intervals, which is  more frequent than is currently required. We have revised our report to  reflect this proposed change. While requiring establishments to update  their registration more often could enhance the accuracy of FDA’s  registration information, we remain concerned about the agency’s  enforcement of this provision. There is already a requirement for  establishments to update this information annually, but FDA has not  enforced it. FDA’s proposal to direct establishments to update their  registration information at more frequent intervals will only be meaningful  if the agency takes steps to actively enforce this requirement.
As arranged with your office, unless you publicly announce its contents  earlier, we plan no further distribution of this report until 30 days after its  issue date. At that time, we will send copies of this report to the  Commissioner of FDA and appropriate congressional committees. We will  also make copies available to others on request. In addition, the report will  be available at no charge on the GAO Web site at http://www.gao.gov.
If you or your staff have any questions about this report, please contact me  at (202) 512-7114 or crossem@gao.gov. Contact points for our offices of  Congressional Relations and Public Affairs may be found on the last page  of this report. GAO staff who made major contributions to this report are  listed in appendix III.
section_title: Appendix I: Scope and Methodology
paragraphs: To adress our reporting objectives, we interviewed officials from several  components of the Food and Drug Administration (FDA), including the  Center for Drug Evaluation and Research (CDER) and the Office of  Regulatory Affairs (ORA). We also reviewed pertinent statutes and  regulations as well as agency documents that provide guidance on  conducting inspections and provide the basis for FDA’s assessment of an  establishment’s compliance with current good manufacturing practice  regulations (GMP). These documents included FDA’s Compliance  Program Guidance Manuals; Guide to Inspection of Foreign  Pharmaceutical Manufacturers; Investigations Operations Manual  2008; Regulatory Procedures Manual, March 2008; and Field  Management Directives. To obtain perspectives from relevant  stakeholders, we also interviewed officials from the Generic  Pharmaceutical Association, Pharmaceutical Research and Manufacturers  of America, and Synthetic Organic Chemical Manufacturers Association.
To examine the extent to which FDA has accurate data on the number of  foreign manufacturing establishments subject to inspection, we obtained  information from FDA databases on establishments whose drugs have  been imported into the United States. Specifically, we obtained data from  CDER’s Drug Registration and Listing System (DRLS) and ORA’s  Operational and Administrative System for Import Support (OASIS).
From DRLS, we obtained counts of establishments registered with FDA in  fiscal year 2007 to market drugs in the United States. We assessed the  reliability of these data by (1) reviewing existing information about the  data and the databases that produced them and (2) interviewing agency  officials knowledgeable about the data. We found that DRLS was reliable  for our purposes, to the extent that it accurately reflects information  provided by foreign establishments that register to market drugs in the  United States. However, we determined that these data do not necessarily  reflect all foreign establishments whose drugs are imported into the  United States.
From OASIS, we obtained counts of establishments that offered drugs for  import into the United States in fiscal year 2007. We also obtained fiscal  year 2007 data from OASIS to determine the types of drugs manufactured  in China and offered for import into the United States. We assessed the  reliability of these data by (1) reviewing existing information about the  data and the databases that produced them, (2) interviewing agency  officials knowledgeable about the data, and (3) performing electronic  testing of data elements. We found that while OASIS is likely to  overestimate the number of foreign establishments involved in the  manufacture of those drugs because of uncorrected errors in the data, it  provides sufficiently reliable information about the types of drugs offered  for import into the United States.
Therefore, we present information from both DRLS and OASIS to illustrate  the variability in information that FDA’s databases provide to agency  officials on this topic. This represents the best information available and is  what FDA relies on to manage its foreign drug inspection activities. We  examined FDA’s plans to improve these and other databases. We also  obtained information from the Center for Devices and Radiological Health  to learn about changes to one of its databases that address problems  similar to CDER’s problems with DRLS.
To examine the frequency of foreign inspections and factors influencing  the selection of such establishments for inspection, we obtained data on  foreign and domestic inspections from ORA’s Field Accomplishments and  Compliance Tracking System (FACTS). Our analysis includes all foreign  and domestic inspections that were identified in FACTS as being either  related to the drug application approval process or GMP. Our November  2007 testimony included the number of inspections from FACTS as of  September 26, 2007. Therefore, we obtained FACTS data that contained  information on fiscal year 2007 inspections conducted or entered into this  database since September 26, 2007, to update the data presented in our  November 2007 testimony. We assessed the reliability of these data by   (1) reviewing existing information about the data and the databases that  produced them, (2) interviewing agency officials knowledgeable about the  data, and (3) performing electronic testing of data elements. We found  these data from the FACTS database reliable for our purposes. In addition,  we examined methods used by FDA to help it select foreign and domestic  establishments for inspection, including its risk-based site selection  process.
To examine FDA’s response to serious deficiencies identified during  inspections of foreign manufacturing establishments and FDA’s  monitoring of establishments’ corrective actions and continued  compliance, we examined data in two sources, FACTS and CDER’s Office  of Compliance Foreign Inspection Tracking System, which each contain  information on how the agency classified establishments’ compliance with  agency requirements. We assessed the reliability of these data by  interviewing agency officials knowledgeable about the data and  performing electronic testing to compare the data from each of these  databases. We found that these databases sometimes presented  inconsistent information about the final classification of foreign  inspections. Therefore, we present data from these databases on  inspection classification to illustrate the variability in information that  FDA’s databases provide to agency officials on this topic. We also  reviewed case files provided by FDA that relate to inspections of foreign  establishments conducted from fiscal years 2002 through 2007, during  which FDA identified serious deficiencies and subsequently issued  warning letters. The case files contained information about these  establishments, their inspections, and their correspondence with FDA.
To examine issues unique to conducting foreign inspections, we reviewed  FDA practices and policies related to the conduct of foreign inspections  and interviewed FDA officials about these topics. We also obtained  information about recent or proposed FDA initiatives that may have the  potential to improve the agency’s foreign drug inspection programs.
We conducted the work for this report from September 2007 through  September 2008 in accordance with generally accepted government  auditing standards. Those standards require that we plan and perform the  audit to obtain sufficient, appropriate evidence to provide a reasonable  basis for our findings and conclusions based on our audit objectives. We  believe that the evidence obtained provides a reasonable basis for our  findings and conclusions based on our audit objectives.
section_title: Appendix II: Comments from the Department of Health and Human Services
section_title: Appendix III: GAO Contact and Staff Acknowledgments
paragraphs: Marcia Crosse, (202) 512-7114, crossem@gao.gov.
subsections: section_title: Acknowledgments
paragraphs: In addition to the contact named above, Geraldine Redican-Bigott,  Assistant Director; Katherine Clark; Andrew Fitch; William Hadley;  Cathleen Hamann; Julian Klazkin; Daniel Ries; and Monique B. Williams  made key contributions to this report.
section_title: Related GAO Products
paragraphs: Medical Devices: FDA Faces Challenges in Conducting Inspections of  Foreign Manufacturing Establishments. GAO-08-780T. Washington, D.C.:  May 14, 2008.
Drug Safety: Preliminary Findings Suggest Recent FDA Initiatives Have  Potential, but Do Not Fully Address Weaknesses in Its Foreign Drug  Inspection Program. GAO-08-701T. Washington, D.C.: April 22, 2008.
Medical Devices: Challenges for FDA in Conducting Manufacturer  Inspections. GAO-08-428T. Washington, D.C.: January 29, 2008.
Drug Safety: Preliminary Findings Suggest Weaknesses in FDA’s  Program for Inspecting Foreign Drug Manufacturers. GAO-08-224T.  Washington, D.C.: November 1, 2007.
Food and Drug Administration: Improvements Needed in the Foreign  Drug Inspection Program. GAO/HEHS-98-21. Washington, D.C.:   March 17, 1998.