Drug Safety: Preliminary Findings Suggest Weaknesses in FDA's Program for Inspecting Foreign Drug Manufacturers
Published: 2007-11-01T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: Many drugs marketed in the United States are manufactured in foreign countries and the value of such products entering the country is increasing. The Food and Drug Administration (FDA) is responsible for overseeing the safety and effectiveness of human drugs that are marketed in the United States, whether they are manufactured in foreign or domestic establishments. Foreign establishments that market their drugs in the United States must register with FDA and FDA inspects foreign establishments to ensure that they meet the same standards that are required of domestic ones. GAO reported 9 years ago that FDA needed to improve its foreign drug inspection program (GAO/HEHS-98-21). Questions remain as to whether FDA has improved its management of the foreign drug inspection program. This statement discusses preliminary information on (1) the extent to which FDA has accurate data to manage the foreign drug inspection program, (2) the frequency of foreign inspections and factors influencing the selection of establishments to inspect, and (3) issues unique to conducting foreign inspections. To address these issues GAO interviewed FDA officials; reviewed pertinent statutes, regulations, and guidance; and analyzed information from FDA databases. Because of the preliminary nature of our work, we are not making recommendations at this time.
section_title: What GAO Found
paragraphs: FDA's effectiveness in managing the foreign drug inspection program continues to be hindered by weaknesses in its databases. FDA does not know how many foreign establishments are subject to inspection. Instead, FDA relies on databases that were not designed for this purpose. Further, these databases contain inaccuracies that FDA cannot easily reconcile. One database indicates there were about 3,000 foreign establishments registered to market drugs in the United States in fiscal year 2007, while another indicates that about 6,800 foreign establishments actually imported drugs in that year. FDA recognizes these flaws. Further, because the databases cannot exchange information, any comparisons of the data are performed manually, on a case-by-case basis. FDA officials told GAO that they have not generated an accurate count of foreign establishments whose drugs are imported into the United States. FDA inspects relatively few foreign establishments. Data from FDA suggest that the agency may inspect about 7 percent of foreign establishments in a given year. At this rate, it would take FDA more than 13 years to inspect each foreign establishment once, assuming that no additional establishments require inspection. However, FDA cannot provide an exact number of foreign establishments that have never been inspected. Most of the foreign inspections performed are conducted as part of a review associated with processing an application to market a new drug, rather than inspections for monitoring the quality of marketed drugs. Although FDA uses a risk-based process to develop a prioritized list of foreign establishments for inspections to monitor the quality of marketed drugs, few are completed in a given year. This prioritized list was used to select foreign establishments for inspection in fiscal year 2007. According to FDA, about 30 such inspections were completed in that year and at least 50 are targeted for inspection in fiscal year 2008. The foreign inspection process involves unique circumstances that are not encountered domestically. For example, FDA relies on staff that inspect domestic establishments to volunteer for foreign inspections. Unlike domestic inspections to monitor the quality of a marketed drug, FDA does not arrive unannounced at a foreign establishment. It also lacks the flexibility to easily extend foreign inspections if problems are encountered, due to the need to adhere to an itinerary that typically involves multiple inspections in the same country. Finally, language barriers can make foreign inspections more difficult than domestic ones. FDA does not generally provide translators to its inspection teams. Instead, they may have to rely on an English-speaking representative of the foreign establishment being inspected, rather than an independent translator.

section_title: Letter
paragraphs: I am pleased to be here today as you examine the Food and Drug  Administration’s (FDA) inspections of foreign drug manufacturers whose  products are imported into the United States. In 1998, we reported that  FDA needed to improve its foreign drug inspection program. Among other  things, we noted that FDA had serious problems managing its foreign  inspection data and that it lacked a comprehensive automated system for  tracking this important information. We were also critical of the number of  inspections FDA conducted at foreign manufacturers. At that time, FDA  reported on our growing dependence on imported pharmaceutical  products, noting that as much as 80 percent of the bulk drug substances  used by manufacturers in the United States to produce prescription drugs  was imported and that the number of finished drug products  manufactured abroad for the U.S. market was increasing. Today, we are  still dependent on foreign establishments manufacturing drugs for the  U.S. market as the value of pharmaceutical products coming into the  United States from abroad continues to increase.
Given the importance of FDA’s foreign drug inspection program, you  expressed concern about FDA’s ability to oversee foreign establishments  manufacturing drugs and asked whether FDA has improved its  management of the foreign drug inspection program since our previous  report was issued. My testimony today will summarize preliminary  findings from our ongoing work to update our 1998 report. My remarks  will focus on (1) the extent to which FDA has accurate data to manage its  foreign drug inspection program, (2) the frequency of foreign inspections  and factors influencing the selection of establishments to inspect, and   (3) issues unique to conducting foreign inspections.
To address these issues, we interviewed officials from FDA’s Center for  Drug Evaluation and Research (CDER) and Office of Regulatory Affairs  (ORA), which each have responsibilities for managing the foreign drug  inspection program. We 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 practices  (GMP). These documents included FDA’s Compliance Program Guidance  Manuals, its Guide to Inspections of Foreign Pharmaceutical  Manufacturers, and its Investigations Operations Manual 2007. We also  obtained information from FDA databases on establishments whose drugs  have been imported into the United States. Specifically, we obtained data  from the Drug Registration and Listing System (DRLS), the Field  Accomplishments and Compliance Tracking System (FACTS), and the  Operational and Administrative System for Import Support (OASIS). 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 from FACTS. We found the data in the  FACTS database reliable for our purposes. We also found that DRLS was  reliable, 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. In  addition, we found that OASIS is likely to over-estimate the number of  foreign establishments whose drugs have been imported into the United  States, due to uncorrected errors in the data. 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. Our ongoing  work is focused on human drugs regulated by CDER and not on biologics,  medical devices, veterinary medicines, or other items or products for  which FDA conducts inspections. We received technical comments on a  draft of this statement from FDA, which we incorporated as appropriate.
Our work is being performed in accordance with generally accepted  government auditing standards.
In summary, our preliminary results indicate that more than 9 years after  we issued our last report on this topic, FDA’s effectiveness in managing  the foreign drug inspection program continues to be hindered by  weaknesses in its data systems. FDA does not know how many foreign  establishments are subject to inspection. FDA relies on information from  several databases that were not designed for this purpose. One of these  databases contains information on foreign establishments that have  registered to market drugs in the United States, while another contains  information on drugs imported into the United States. One database  indicates about 3,000 foreign establishments could have been subject to  inspection in fiscal year 2007, while another indicates that about 6,800  foreign establishments could have been subject to inspection in that year.  Despite the divergent estimates of foreign establishments subject to  inspection generated by these two databases, FDA does not verify the data  within each database. For example, the agency does not routinely confirm  that a registered establishment actually manufactures a drug for the U.S.  market. However, FDA used these data to generate a list of 3,249  establishments from which it prioritized establishments for inspection.
Because FDA is not certain how many foreign establishments are actually  subject to inspection, the percentage of foreign establishments that have  been inspected cannot be calculated with certainty. We found that FDA  inspects relatively few foreign establishments. Using the list of 3,249  establishments from which FDA prioritized establishments for inspection,  we found that the agency may inspect about 7 percent of foreign  establishments in a given year. At this rate, it would take FDA more than  13 years to inspect each foreign establishment on this list once, assuming  that no additional establishments are subject to inspection. FDA cannot  provide the exact number of foreign establishments that have never been  inspected. Most of the foreign inspections are conducted as part of  processing a new drug application (NDA) or an abbreviated new drug  application (ANDA), rather than as GMP surveillance inspections, which  are used to monitor the quality of marketed drugs. Although FDA used a  risk-based process to develop a prioritized list of foreign establishments  for GMP surveillance inspections in fiscal year 2007, few such inspections  are completed in a given year. According to FDA, about 30 such  inspections were completed in fiscal year 2007 and at least 50 are targeted  for inspection in fiscal year 2008. Further, the data on which this risk- based process depends limits its effectiveness.
Finally, the very nature of the foreign inspection process involves unique  circumstances that are not encountered domestically. For example, FDA  does not have a dedicated staff to conduct foreign inspections and relies  on those inspecting domestic establishments to volunteer. While FDA may  conduct unannounced GMP surveillance inspections of domestic  establishments, it does not arrive unannounced at foreign establishments.  It also lacks the flexibility to easily extend foreign inspections if problems  are encountered, due to the need to adhere to an itinerary that typically  involves multiple inspections in the same country. Finally, language  barriers can make foreign inspections more difficult to conduct than  domestic ones. FDA does not generally provide translators to its  inspection teams. Instead, they may have to rely on an English-speaking  representative of the foreign establishment being inspected, rather than an  independent translator.
Because of the preliminary nature of our work, we are not making  recommendations at this time.
subsections: section_title: Background
paragraphs: FDA is responsible for overseeing the safety and effectiveness of human  drugs that are marketed in the United States, whether they are  manufactured in foreign or domestic establishments. Foreign  establishments that market their drugs in the United States must register  with FDA. As part of its efforts to ensure the safety and quality of imported  drugs, FDA is responsible for inspecting foreign establishments whose  products 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 foreign and domestic inspections differ.  Specifically, FDA is required to inspect registered domestic establishments  that have been previously approved to market their drugs in the United  States every 2 years, but there is no comparable requirement for  inspecting foreign establishments. FDA does not have authority to require  foreign establishments to allow the agency to inspect their facilities.  However, FDA has the authority to conduct physical inspections of the  imported product or prevent its entry at the border.
Within FDA, CDER sets standards for and evaluates the safety and  effectiveness of prescription drugs and over-the-counter 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 finished  drug products. CDER also requests inspections of those that produce bulk  drug substances, including the active pharmaceutical ingredients (API)  used in finished drug products. These inspections are performed by  investigators and laboratory analysts. ORA conducts two primary types of  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 an NDA  or ANDA and focus on the manufacture of a specific drug product.  Preapproval inspections are designed to verify the accuracy and  authenticity of the data contained in these applications and ensures that  the manufacturer of the finished drug product, as well as each  manufacturer supplying a bulk drug substance used in the finished  product, manufactures, processes, and packs the drug adequately to  preserve its identity, strength, quality, and purity.
Postapproval GMP surveillance inspections are conducted to ensure  compliance with applicable laws and regulations pertaining to the  manufacturing processes used by domestic and foreign establishments in  the manufacture of finished drug products marketed in the United States  and bulk drug substances used in the manufacture of those products.  These inspections focus on a manufacturer’s systemwide controls for  ensuring that drug products are high in quality. Systems examined during  these inspections include those related to quality control, production, and  packaging and labeling. These systems may be involved in the  manufacture of multiple drug products.
FDA allocates funds to ORA to carry out preapproval and postapproval  inspections of foreign and domestic establishments. ORA develops an  annual work plan and a budget that estimates human resources available  to conduct activities related to foreign inspections. ORA also develops  estimates for inspections of domestic establishments. Typically, ORA  investigators and laboratory analysts travel abroad for about 3 weeks at a  time, during which they inspect approximately three establishments. Each  establishment inspection typically lasts a week, with 1 day of each week  set aside for documenting the inspection or for extending the inspection, if  necessary.
CDER uses a risk-based process to select some domestic and foreign  establishments for postapproval GMP surveillance inspections. 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 model to  identify those establishments that, based on characteristics of the  establishment and of the product being manufactured, have the greatest  public health risk potential should they experience a manufacturing  defect. (See table 1 for a description of the risk-based site selection model  used by FDA in fiscal year 2007.) For example, FDA considers the risk to  public health from poor quality over-the-counter drugs to be lower than for  prescription drugs, and consequently establishments manufacturing only  over-the-counter drugs receive a lower score on this factor than other  manufacturers. Through this process, CDER annually prepares a  prioritized list of domestic establishments and a separate, prioritized list of  foreign establishments. CDER began applying this risk-based process to  domestic establishments in fiscal year 2006 and expanded it to foreign  establishments in fiscal year 2007.
FDA relies on multiple databases to manage the foreign drug inspection  program. FDA assigns unique numeric identifiers to establishments,  known as the FDA establishment identifier (FEI) number. An FEI number  could be assigned at the time of registration, importation, or inspection.
DRLS contains information on foreign and domestic drug establishments  that have registered with FDA. Establishments that market their drugs in  the United States must register with FDA. These establishments provide  information, such as company name and address and the drug products  they manufacture for commercial distribution in the United States, on  paper forms that are entered into DRLS by FDA.
OASIS contains information on drugs and other FDA-regulated products  imported into the United States, including information on the  establishment that manufactured the drug. The information in OASIS is  automatically generated from data managed by U.S. Customs and Border  Protection, which are originally entered by customs brokers based on the  information available from the importer. Each establishment is assigned a  manufacturer identification number that is generated from key  information entered about an establishment’s name, address, and location.
FACTS contains information on FDA’s inspections of domestic and foreign  drug establishments. FDA investigators and laboratory analysts enter  information into FACTS, following completion of an inspection.
According to DRLS, in fiscal year 2007, China and India had more  establishments registered to manufacture drugs for the U.S. market than  any other country. Other countries that had a large number of  establishments registered to manufacture drugs for the U.S. market in this  year were Canada, France, Germany, Italy, Japan, and the United  Kingdom. (See fig. 1.) These countries are also listed in OASIS as having  the largest number of manufacturers importing drugs into the United  States.
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; including the number of establishments that are registered and  whose products are currently imported into the United States and  establishments that are not required to register but whose products are  ultimately used in drugs that are marketed here. Instead of maintaining a  list of such establishments, FDA relies on information from several  databases that were not designed for this purpose.
DRLS, established in 1991, is intended to list the establishments registered  that manufacture drugs for the U.S. market. However, requirements for the  registration of foreign establishments were not implemented until 2002.  FDA expected that requiring foreign establishments to register would  provide it with a comprehensive list of such establishments. In fiscal year  2007, approximately 3,000 foreign establishments were registered with  FDA that manufactured human drugs, biologics, or veterinary drugs; FDA  was unable to determine from this database the number of registered  establishments specifically manufacturing human drugs.
DRLS provides FDA with some information about establishments subject  to inspection, but contains inaccuracies and does not provide a complete  count. FDA officials told us that the count of registered foreign  establishments in DRLS does not reflect the actual number whose  products are being imported into the United States for several reasons.  First, 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. Second,  foreign establishments may not renew their registration information,  although they are required by FDA to do so annually. Agency officials told  us that if foreign establishments stop manufacturing drugs for the U.S.  market or go out of business they may not report the change to FDA, even  though it is required. FDA officials told us that the agency does not  routinely verify the information provided by the establishment to ensure  that it is accurate or confirm that the establishment actually manufactures  drugs for the U.S. market. FDA does not know how many foreign  establishments are erroneously registered. Third, foreign establishments  that manufacture APIs are not required to register if their products are not  directly imported into the United States.
OASIS also provides FDA with some information about establishments  subject to inspection, but this database contains inaccurate data on the  count of foreign establishments manufacturing drugs imported into the  United States. According to OASIS, 6,760 foreign establishments  manufactured drugs that were imported into the United States in fiscal  year 2007. However, FDA officials told us that errors in data entry result in  inaccurate counts of establishments whose drugs are imported into the  United States. FDA officials told us that if information about an  establishment—such as its name—was entered by customs brokers  incorrectly, a new manufacturer identification number, and thus a new  FEI number, could be assigned to an establishment that already has an FEI  number. For example, a customs broker may enter an establishment’s  name slightly differently from the way it is displayed in OASIS, such as  using “Inc.” instead of “Incorporated,” which would lead to the creation of  a second FEI number for the establishment. Therefore, a single  establishment may be counted more than once in OASIS, which would  result in an artificially high count of foreign establishments importing  drugs into the United States. FDA officials acknowledge this problem but  were unable to provide us with an estimate of the extent of that error. 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 regional training to brokers as a way to improve  accuracy. FDA officials also told us that the agency is pursuing a new  government-wide initiative that would address this problem by providing a  unique identifier for each foreign establishment involved in the import  supply chain.
FDA’s data suggest that between 3,000 and 6,760 establishments could be  subject to FDA inspection. However, FDA officials told us that the two  databases—DRLS and OASIS—cannot be electronically integrated or  interact with one another, so any comparisons are done manually for each  individual establishment. Because comparisons of the data and error  identification are done manually, the databases are not conducive to  routine data analysis. FDA officials told us that they have not generated an  accurate count of the establishments whose drugs are imported into the  United States.
Because FDA does not have a list of all foreign establishments subject to  inspection, in fiscal year 2007 it created a list of such establishments for  the purpose of applying its risk-based process. In preparing this list, FDA  draws on information from DRLS. It also obtains information from  previous inspections to help it identify establishments that are subject to  inspections but are not required to register—such as the manufacturer of  an API whose product is not directly imported into the United States. For  fiscal year 2007, this list consisted of 3,249 foreign establishments.  However, as a result of the inaccuracies in DRLS, FDA recognizes that this  list does not provide an accurate count of establishments subject to  inspection.
section_title: FDA Conducts Relatively Few Foreign Establishment Inspections and Relies on the NDA and ANDA Review Process as the Primary Selection Factor
paragraphs: FDA conducts relatively few inspections of foreign drug establishments.  However, because FDA is not certain how many foreign establishments  are actually subject to inspection, the percentage of foreign establishments  that have been inspected cannot be calculated with certainty. Most foreign  establishments are selected for inspection as part of the agency’s review  process associated with an NDA or ANDA. Therefore, the vast majority of  foreign inspections include a preapproval inspection. In addition, although  FDA has implemented a risk-based process in selecting foreign  establishments for GMP surveillance inspections, relatively few such  inspections are conducted. FDA tries to make efficient use of its resources  by selecting establishments for these inspections that allow it to  coordinate travel with preapproval inspections.
subsections: section_title: Relatively Few Foreign Establishments Are Inspected by FDA Each Year
paragraphs: In each year we examined, FDA inspected a small portion of foreign  establishments through either preapproval or GMP surveillance  inspections. However, its lack of a list of foreign establishments subject to  inspection makes it difficult to determine an exact percentage. Based on  our review of data on inspections, FDA conducted an average of 241  foreign establishment inspections per year from fiscal year 2002 through  fiscal year 2007. Comparing this average number of inspections with  FDA’s count of 3,249 foreign establishments it used to plan its fiscal year  2007 prioritized GMP surveillance inspections suggests that the agency  inspects about 7 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.
FDA’s data indicate that some foreign drug manufacturers have not  received an inspection, but the exact number of establishments not  inspected was 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 but also included other types of  establishments, such as those whose products 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 surveillance inspection  since fiscal year 2000, and 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 from fiscal year 2000 through fiscal year  2002.
FDA has increased the number of foreign establishments it inspects, most  of which are concentrated in a small number of countries. From fiscal year  2002 through fiscal year 2007, the number of foreign establishment  inspections FDA conducted annually varied from year to year, but  increased overall from 222 in fiscal year 2002 to 295 in fiscal year 2007.  During this period, FDA inspected establishments in a total of 51  countries. More than three quarters of the 1,445 foreign inspections the  agency conducted during this period were of establishments in ten  countries, as shown in table 2. The country with the most inspections  during this period was India, which had 200 inspections. Inspections of  establishments located in India increased from 11 in fiscal year 2002 to 65  in fiscal year 2007.
section_title: The Need to Conduct Preapproval Inspections Associated with NDAs and ANDAs Drives FDA’s Selection of Foreign Establishments
paragraphs: While enforcing GMP compliance through surveillance inspections is  FDA’s most comprehensive program for monitoring the quality of  marketed drugs, FDA’s inspections of most foreign establishments occur  as part of the agency’s review of an NDA or ANDA. Agency officials said  that FDA may need to inspect establishments involved in the manufacture  of the drug referenced in an NDA or ANDA in order to meet specific goals  for the timely review of these applications. As we reported in 1998 and we  still found in 2007, most inspections of foreign manufacturers occur only  when they are listed in an NDA or ANDA. For fiscal years 2002 through  2007, 88 percent of FDA’s inspections of foreign establishments were  conducted as part of the preapproval process. When FDA receives an NDA  or ANDA, CDER officials review the inspection history of each  establishment listed on the application. According to FDA officials, if an  establishment listed on the NDA or ANDA has received a satisfactory GMP  inspection in the previous 2 years and the agency has no new concerns,  FDA will consider this inspection sufficient and will not perform a  preapproval inspection of this establishment.
FDA often includes a GMP inspection when it visits an establishment for a  preapproval inspection. As presented in figure 2, from fiscal year 2002  through fiscal year 2007, the majority of FDA’s foreign inspections  combined a preapproval inspection with a GMP inspection. According to  FDA officials, because foreign establishments are inspected infrequently, it  is expedient for investigators and laboratory analysts to conduct  preapproval inspections and GMP inspections during the same visit to a  foreign establishment. During one establishment visit, FDA investigators  can conduct inspections related to multiple compliance programs.  Because a GMP surveillance inspection examines the major manufacturing  systems at an establishment, the results of such an inspection can be  generalized to all products manufactured at a particular establishment.  FDA can thus use the results of the combined inspection to make  decisions in the future if that establishment is listed again in another NDA  or ANDA.
FDA conducts fewer GMP surveillance inspections of foreign  establishments than it does of domestic ones. Of the 1,445 foreign  establishment inspections conducted from fiscal year 2002 through fiscal  year 2007, 1,177 inspections included a GMP component, of which 998  were conducted in conjunction with a preapproval inspection. In contrast,  FDA conducted 9,694 domestic establishment inspections that included a  GMP component, of which 7,742 were not conducted in conjunction with a  preapproval inspection. Figure 3 shows a comparison of foreign and  domestic inspections, by type of inspection.
FDA’s funding for its domestic and foreign inspection programs is  consistent with this approach. From fiscal year 2002 through fiscal year  2007, FDA dedicated more funding to domestic establishment inspections  than foreign establishment inspections. The agency dedicated more  funding to conduct foreign preapproval inspections than foreign GMP  surveillance inspections, as shown in table 3.
section_title: FDA’s Risk-Based Process Is Used to Select Relatively Few Foreign Establishments for GMP Surveillance Inspections
paragraphs: Relatively few foreign establishments identified through CDER’s risk- based site selection process are selected for GMP surveillance inspections.  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. Of these, CDER requested that ORA complete GMP  surveillance inspections of 25 establishments and FDA officials estimated  that about 30 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 negotiated target of at least 50 inspections.
The application of the risk-based site selection process does not ensure  that the foreign establishments posing the greatest potential risk are  selected for GMP surveillance inspections. First, FDA officials  acknowledge that they do not have an accurate list of foreign  establishments manufacturing drugs for the U.S. market to use in the  application of the risk-based process. Second, the usefulness of the risk- based process is weakened by the incomplete and possibly inaccurate  information on those foreign establishments that FDA has not inspected  recently, as well as those that have never been the subject of a GMP  surveillance inspection. As a consequence, FDA lacks sufficient data to  make an accurate assessment of the potential risk of such establishments.  FDA recognized the effect of such data limitations on the domestic  application of the risk-based process and undertook a data quality  improvement initiative in fiscal year 2005, but it has yet to make a  comparable effort to improve its data on foreign establishments.
To help account for the differences in information available to FDA  between foreign establishments that have and have not been inspected,  the agency categorizes establishments into one of three groups for the  purposes of examining risk scores: (1) those that have received a GMP  surveillance inspection since fiscal year 2000; (2) those that have not  received a GMP surveillance inspection since fiscal year 2000, but have  received another type of inspection in that time (for example, a  preapproval inspection or a veterinary drugs inspection); and (3) those  that may never have received an inspection. These groups were created  to account for limitations in the data and are not designed to indicate  relative risk among groups. FDA officials told us that risk scores can be  more readily compared within a group, than among groups. In 2007, FDA  selected 33 establishments from the first group, 31 from the second group,  and 40 from the third group to create the list of 104 establishments it  submitted to ORA.
FDA officials indicated that they do not know if the establishments on the  prioritized list forwarded to ORA differ significantly from each other in  risk level. Consequently, they do not necessarily select the highest ranked  establishments and therefore consider the locations of other planned  inspections in making a final determination of foreign establishments from  the prioritized list for GMP surveillance inspections. According to FDA  officials, this gives them needed flexibility to make selections that will  make efficient use of available resources. For example, if ORA is sending  an investigator and laboratory analyst to a particular region in China for a  preapproval inspection and an establishment in the same region appears  on the prioritized list for GMP surveillance inspections, ORA might add  this establishment to the inspection itinerary.
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. For example, unlike  domestic inspections, FDA does not have a dedicated staff devoted to  conducting foreign inspections and relies on volunteers. In addition, unlike  domestic GMP surveillance inspections, foreign establishment GMP  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.
According to FDA officials, the agency does not have a dedicated staff to  conduct foreign inspections. They 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 to conduct inspections of foreign  establishments. For example, they are required to take certain training  courses and have at least 3 years of experience conducting domestic  inspections before they can be considered to conduct a foreign inspection.  FDA reported that it currently has approximately 335 employees who are  qualified to conduct foreign inspections of drug manufacturers.  Approximately 250 of these employees are investigators and 85 are  laboratory analysts. These counts do not represent the number of  individuals that actually conduct foreign inspections in a given year. Not  all investigators and laboratory analysts who are qualified to conduct a  foreign inspection do so in a given year, while others may perform  multiple inspections during the same period. Using data from FACTS, we  found that the total number of employees conducting pre-approval and  GMP surveillance inspections of drug manufacturing establishments,  either foreign or domestic, decreased from 587 in fiscal year 2002 to 446 in  fiscal year 2007, as shown in table 4. However, of these, the number of  employees who conducted foreign inspections of drug manufacturers  increased from 100 to 141 during that same period. While an investigator  and analyst team may participate in foreign inspections, FDA officials  stated that in certain circumstances, such as inspections that do not  involve the review of laboratory facilities, only an investigator is sent.
FDA relies on investigators and laboratory analysts to volunteer to  conduct foreign inspections. FDA officials told us that it is difficult to  recruit investigators and laboratory analysts to voluntarily travel to certain  countries. 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 three week trip  completed. FDA indicated that if the agency could not find an individual to  volunteer for a foreign inspection trip, it would mandate the travel.  However, FDA does not typically send investigators and laboratory  analysts to countries for which the U.S. Department of State has issued a  travel warning nor would it mandate travel to such a country. 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 in the past 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 U.S. 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 at foreign facilities are to be approached in the same manner  as domestic inspections. However, the guidance notes that one main  difference posing a significant challenge to the inspection team abroad is  the logistics borne by the program itself. For example, FDA is unable to  conduct unannounced inspections of foreign drug manufacturers, as it  sometimes does with domestic manufacturers. 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  recognizes that the time and expense associated with foreign travel  requires them to ensure that the foreign establishment’s managers are  available and that the production line being inspected is operational  during the inspection. In addition, FDA does not have explicit authority to  inspect establishments in foreign countries, and it therefore may have to  obtain permission from the government and company 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. In addition, 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.
FDA officials also told us that language barriers can make foreign  inspections more difficult to conduct than domestic inspections. The  agency does not generally provide translators in foreign countries, nor  does it require that foreign establishments provide independent  interpreters. Instead, they may have to rely on an English-speaking  representative of the foreign establishment being inspected, who may not  be a translator by training, rather than rely on an independent translator.
section_title: Concluding Observations
paragraphs: Millions of Americans depend on the safety and effectiveness of the drugs  they take. More than nine years ago we reported that FDA needed to make  improvements in its foreign drug inspection program. Yet, our preliminary  work indicates that fundamental flaws that we identified in the  management of this program in 1998, continue to persist. FDA still does  not have a reliable list of foreign establishments that are subject to  inspection. As more imported drugs enter the United States, it becomes  increasingly important that foreign establishments receive appropriate  scrutiny. We understand that FDA currently cannot inspect all foreign  establishments every few years. We also recognize that FDA has taken  steps to improve its management of the foreign drug inspection program  by enhancing the risk-based process it uses to select establishments for  GMP surveillance inspections. In addition, FDA is pursuing an initiative  that is intended to improve its identification of foreign drug  establishments. However, until FDA responds to systemic weaknesses in  the management of this important program, it cannot provide the needed  assurance that the drug supply reaching our citizens is appropriately  scrutinized, and safe.
Mr. Chairman, this completes my prepared statement, I would be happy to  respond to any questions you or the other Members of the subcommittee  may have at this time.
section_title: Contacts and Acknowledgments
paragraphs: For further information about this testimony, please contact Marcia  Crosse 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 testimony. Geraldine Redican-Bigott, Assistant Director;  Katherine Clark; Robert Copeland; William Hadley; Cathleen Hamann;  Julian Klazkin; Romonda McKinney; Lisa Motley; and Suzanne Worth made  key contributions to this testimony.
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