Drug Safety
Better Data Management and More Inspections Are Needed to Strengthen FDA's Foreign Drug Inspection Program Gao ID: GAO-08-970 September 22, 2008The Food and Drug Administration (FDA), an agency within the Department of Health and Human Services (HHS), oversees the safety and effectiveness of human drugs marketed in the United States, including those manufactured in foreign establishments. FDA inspects foreign establishments in order to ensure that the quality of drugs is not jeopardized by poor manufacturing processes. This report examines (1) the extent to which FDA has accurate data on the number of foreign establishments subject to inspection, (2) the frequency of foreign inspections, and (3) oversight by FDA to ensure that foreign establishments correct serious problems identified during inspections. GAO analyzed information from FDA databases, reviewed inspection reports which identified serious deficiencies, and interviewed FDA officials.
FDA databases contain inaccurate information on foreign establishments subject to inspection. FDA uses information from a database of establishments registered to market drugs in the United States and a database of establishments that shipped drugs to the United States to compile a list of establishments subject to inspection, but these databases contain divergent estimates--about 3,000 and 6,800, respectively. FDA's registration database contains information about establishments not subject to FDA inspection. Although annual reregistration is required, FDA does not deactivate in its database establishments that do not fulfill this requirement. The agency also does not routinely verify that a registered establishment manufactures a drug for the U.S. market. The accuracy of this information is important in FDA's identification of foreign establishments subject to inspection. FDA inspects relatively few foreign establishments each year to assess the manufacturing of drugs currently marketed in the United States. FDA inspected 1,479 foreign drug manufacturing establishments from fiscal years 2002 through 2007.Because FDA does not know the number of establishments subject to inspection, the percentage of those inspected cannot be calculated with certainty. However, using a list FDA developed to prioritize foreign establishments for inspection in fiscal year 2007, GAO estimated that FDA may inspect about 8 percent of foreign establishments in a given year. At this rate, it would take the agency more than 13 years to inspect these establishments once. In contrast, FDA estimates that it inspects domestic establishments about once every 2.7 years. Unlike domestic establishments, foreign establishments were generally only inspected if they were named in an application for a new drug. While FDA made progress in fiscal year 2007 in conducting more foreign inspections, GAO estimated it still inspected less than 11 percent of such establishments. As FDA plans additional inspections, it is important that it ensure that foreign and domestic establishments with similar characteristics are inspected at a similar frequency. FDA's identification of serious deficiencies has led foreign establishments to take corrective actions, but inspections to determine continued compliance are not always timely. FDA identified deficiencies during most foreign inspections, but determining how the agency classified the results of a specific inspection is hindered by inconsistencies in its databases, particularly on the classification of inspections with serious deficiencies. From fiscal years 2002 through 2007, FDA issued 15 warning letters to foreign establishments at which it identified serious deficiencies. FDA generally determined the adequacy of actions taken in response to these letters by reviewing information provided by the establishments. FDA's subsequent inspections to determine establishments' continued compliance were not always timely. Of establishments named in the 15 warning letters, FDA subsequently inspected 4 establishments 2 to 5 years later, generally because these establishments were named in a new drug application. At 3 of these 4 inspections, FDA verified that corrective actions had been taken but identified additional deficiencies.
RecommendationsOur recommendations from this work are listed below with a Contact for more information. Status will change from "In process" to "Open," "Closed - implemented," or "Closed - not implemented" based on our follow up work.
Director: Team: Phone:GAO-08-970, Drug Safety: Better Data Management and More Inspections Are Needed to Strengthen FDA's Foreign Drug Inspection Program
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Report to Congressional Requesters:
United States Government Accountability Office:
GAO:
September 2008:
Drug Safety:
Better Data Management and More Inspections Are Needed to Strengthen
FDA's Foreign Drug Inspection Program:
FDA Foreign Drug Inspection:
GAO-08-970:
GAO Highlights:
Highlights of GAO-08-970, a report to congressional requesters.
Why GAO Did This Study:
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.
What GAO Found:
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.
What GAO Recommends:
GAO recommends that FDA improve the data that it uses to manage its
foreign inspection program, conduct more inspections of foreign
establishments, and ensure more timely inspection of foreign
establishments where FDA has identified serious deficiencies. HHS
agreed that FDA should conduct more foreign inspections but did not
comment on the other recommendations. HHS noted that additional
inspections are only one component of FDA‘s strategy to enhance
oversight and elaborated on other initiatives, such as database
improvements, discussed in this report.
To view the full product, including the scope and methodology, click on
[hyperlink, http://www.gao.gov/cgi-bin/getrpt?GAO-08-970]. For more
information, contact Marcia Crosse at (202) 512-7114 or
crossem@gao.gov.
[End of section]
Contents:
Letter:
Results in Brief:
Background:
FDA Lacks Accurate Information to Effectively Manage the Foreign Drug
Inspection Program:
FDA Inspects Relatively Few Foreign Establishments to Assess the
Manufacture of Drugs Currently Marketed in the United States:
FDA's Identification of Serious Deficiencies Has Led Establishments to
Take Corrective Actions, but Subsequent Inspections Were Not Always
Timely:
Challenges Unique to Foreign Inspections Influence the Manner in which
FDA Conducts Such Inspections:
Conclusions:
Recommendations for Executive Actions:
Agency Comments and Our Evaluation:
Appendix I: Scope and Methodology:
Appendix II: Comments from the Department of Health and Human Services:
Appendix III: GAO Contact and Staff Acknowledgments:
Related GAO Products:
Tables:
Table 1: Number of FDA Inspections of Foreign Establishments Involved
in the Manufacture of Drugs for the U.S. Market, by Country for the 10
Most Frequently Inspected Countries, Fiscal Years 2002 through 2007:
Table 2: Warning Letters Issued by FDA to Foreign Establishments in
Response to Inspections Conducted from Fiscal Years 2002 through 2007:
Figures:
Figure 1: FDA's Process for Managing Inspections of Foreign
Establishments:
Figure 2: Foreign Establishments Registered to Manufacture Drugs for
the U.S. Market by Country, Fiscal Year 2007:
Figure 3: FDA Foreign Establishment Inspections by Type of Inspection,
Fiscal Years 2002 through 2007:
Figure 4: FDA's Methods for Determining the Adequacy of Corrective
Actions for 15 Warning Letters Issued Following Foreign Inspections
Conducted from Fiscal Years 2002 through 2007:
Abbreviations:
API: active pharmaceutical ingredient:
CBP: Customs and Border Protection:
CDER: Center for Drug Evaluation and Research:
DRLS: Drug Registration and Listing System:
D-U-N-SŪ: Data Universal Numbering System:
FACTS: Field Accomplishments and Compliance Tracking System:
FDA: Food and Drug Administration:
GMP: good manufacturing practice regulations:
HHS: Department of Health and Human Services:
MARCS: Mission Accomplishments and Regulatory Compliance Services:
NAI: no action indicated:
OAI: official action indicated:
OASIS: Operational and Administrative System for Import Support:
OCFITS: Office of Compliance Foreign Inspection Tracking System:
ORA: Office of Regulatory Affairs:
OTC: over-the-counter:
SEDS: Shared Establishment Data Service:
VAI: voluntary action indicated:
United States Government Accountability Office:
Washington, DC 20548:
September 22, 2008:
The Honorable John D. Dingell:
Chairman:
The Honorable Joe Barton:
Ranking Member:
Committee on Energy and Commerce:
House of Representatives:
The Honorable Bart Stupak:
Chairman:
The Honorable John Shimkus:
Ranking Member:
Subcommittee on Oversight and Investigations:
Committee on Energy and Commerce:
House of Representatives:
The Honorable Charles E. Grassley:
Ranking Member:
Committee on Finance:
United States Senate:
The Honorable Ed Whitfield:
House of Representatives:
The United States is becoming increasingly dependent on drug products
and drug ingredients manufactured in foreign countries.[Footnote 1]
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),[Footnote 2] 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)[Footnote 3] 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.[Footnote 4] 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.[Footnote 5] We also found that the agency did not promptly
issue warning letters asking establishments to correct serious GMP
deficiencies identified during inspections.[Footnote 6]
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.[Footnote 7]
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.[Footnote 8] 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.[Footnote
9]
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.[Footnote 10] 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,[Footnote 11] 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.
Results in Brief:
FDA databases contain inaccurate information on foreign establishments
subject to inspection and recent initiatives do not fully address this
weakness. FDA uses databases of registered establishments and imported
drugs to help it select establishments for inspection, but these
databases contain inaccuracies and were not designed for this purpose.
FDA's registration database indicates about 3,000 foreign
establishments could have been subject to inspection in fiscal year
2007, while its import database contains information indicating that
about 6,800 establishments shipped drugs to the United States in that
year. FDA's registration database contains information about
establishments that are not actually subject to FDA inspection.
Although establishments that manufacture drugs for the U.S. market are
required to reregister annually, FDA does not enforce this requirement
by deactivating in its database establishments that do not fulfill this
requirement. Therefore, foreign establishments that are no longer
subject to FDA inspection may be included in the database. In addition,
the agency does not routinely verify that a registered establishment
actually manufactures a drug for the U.S. market. For example, foreign
drug manufacturing establishments may register with FDA because, in
some foreign markets, registration may appear to convey an "approval"
or endorsement by the agency. FDA is making improvements to this
database. However, these changes will not ensure that FDA enforces the
requirement that establishments update their registration annually or
that the agency verifies information provided by establishments. To
reduce duplication in its import database, FDA supported a proposal to
create a unique identifier for all establishments whose products,
including drugs, are imported into the United States that would be used
by all federal agencies involved in the oversight of imported products.
However, the implementation of this identifier would require action
from multiple federal agencies in addition to FDA and the timeline for
its implementation is unclear. Finally, initiatives to improve the
integration of these databases could be beneficial, but it is too early
to know their impact.
FDA inspects few foreign establishments, relative to domestic
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.
Although FDA does not know how many foreign establishments are actually
subject to inspection, using the list of 3,249 establishments from
which FDA prioritized establishments for inspection in fiscal year
2007, we found that the agency may inspect about 8 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.
In comparison, the agency estimates that it inspects domestic
establishments manufacturing drugs about once every 2.7 years. From
fiscal years 2002 through 2007, FDA selected few foreign establishments
for inspections to conduct surveillance of drugs currently marketed in
the United States. FDA generally only inspects foreign establishments
if they are named in an application for new drug approval. In
comparison, most of the domestic establishments inspected by FDA are
selected for surveillance purposes to examine the manufacture of drugs
currently marketed in the United States. While FDA made progress in
fiscal year 2007 in conducting more foreign inspections, it still
inspected relatively few establishments. The agency has proposed plans
for conducting many more foreign inspections in fiscal year 2009, but
these plans will require the agency to dedicate substantially more
resources to such inspections than in the past.
FDA's identification of serious deficiencies has led foreign
establishments to take corrective actions, but subsequent inspections
to determine continued compliance are not always timely. FDA identified
deficiencies during most of its inspections of foreign establishments,
but determining the number of such inspections during which the agency
identified serious deficiencies is hindered by classification
inconsistencies in FDA's databases. As a result, consistent information
may not be readily accessible to FDA staff responsible for the
oversight of those establishments manufacturing drugs marketed in the
United States. In response to serious deficiencies that FDA identified
at establishments inspected from fiscal years 2002 through 2007, the
agency issued 15 warning letters requesting corrective actions; the
agency generally did not restrict importation of drugs manufactured by
these establishments. FDA had previously identified deficiencies that
required corrective actions at establishments named in most of these
letters, but had not issued a warning letter at that time. According to
FDA files, corrective actions were taken by establishments that
received warning letters. As of July 2008, FDA had deemed adequate the
corrective actions of establishments named in 11 of the 15 warning
letters; corrective actions taken by establishments referenced in the
other 4 warning letters had not yet been accepted by FDA. Most often,
FDA deemed an establishment's corrective actions adequate by reviewing
documentation and other information provided by the establishment.
Subsequent inspections by FDA to determine establishments' continued
compliance were not always timely. Since deeming their corrective
actions adequate, FDA subsequently inspected 4 of these 11
establishments. In 1 case, FDA met its recommendation to inspect the
establishment within 2 years by conducting a surveillance inspection.
In the other 3 cases, the establishments were inspected about 4 to 5
years after the inspection that resulted in the warning letter,
although it had been recommended that they be inspected within 1 year.
These 3 inspections were not conducted as part of routine surveillance,
but rather because the establishment was named in an application for a
new drug. Although FDA verified at 3 of the 4 subsequent inspections
that the establishments had taken the promised corrective actions, the
agency also identified additional deficiencies that required corrective
actions. However, these additional deficiencies did not result in the
issuance of a warning letter.
Human resource and logistical challenges unique to foreign inspections
influence the manner in which FDA conducts those inspections. For
example, FDA does not have a dedicated staff to conduct foreign
inspections and relies on those inspecting domestic establishments to
volunteer. In addition, while FDA may conduct unannounced GMP
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.
FDA is pursuing initiatives that could address some of these
challenges. For example, the agency plans to establish an office in
China and has proposed overseas offices in other locations, but the
impact that these offices will have on overcoming these challenges is
unknown.
Initiatives proposed by FDA could help address weaknesses in the
agency's oversight of foreign establishments manufacturing drugs for
the U.S. market, but additional actions are needed. Improving the
accuracy of its databases could allow the agency to make better
informed selections of foreign establishments for inspection. FDA's
plans for additional inspections could provide it with an opportunity
to conduct the inspections that are vital to its oversight of
establishments manufacturing drugs that are currently marketed in the
United States. Although the agency identifies deficiencies at foreign
establishments at least as often as domestic establishments, foreign
establishments are unlikely to be selected in order to inspect the
manufacturing of drugs currently marketed in the United States.
Therefore, it is important that the agency reassess its priorities to
ensure that foreign and domestic establishments with similar
characteristics are inspected at a similar frequency. Further, the
continued identification of deficiencies at foreign establishments that
previously received warning letters points to the need for FDA to
promptly conduct subsequent inspections of establishments with a
history of serious deficiencies so problems do not go undetected for
extended periods. Therefore, we recommend that FDA take the following
five actions: (1) enforce the requirement that establishments
manufacturing drugs for the U.S. market update their registration
annually, (2) establish mechanisms for verifying information provided
by the establishment at the time of registration, (3) ensure that
information on the classification of inspections with serious
deficiencies is accurate in all FDA databases, (4) 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, and
(5) conduct timely inspections of foreign establishments that have
received warning letters to determine continued compliance.
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 noted that conducting
additional inspections is only one component of FDA's overall strategy
to enhance oversight of imported drugs. It also elaborated on some of
the other FDA initiatives--such as database improvements and
establishing foreign offices--that were discussed in our report.
Background:
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,[Footnote 12] 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.[Footnote 13] 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.[Footnote 14] 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.[Footnote
15] 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,[Footnote 16] 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.[Footnote 17]
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.[Footnote 18] 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.[Footnote 19] 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.
Figure 1: FDA's Process for Managing Inspections of Foreign
Establishments:
This figure is a diagram showing FDA's process of managing inspections
of foreign establishments.
[See PDF for image]
Source: GAO.
[End of figure]
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.[Footnote 20] 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).[Footnote 21] 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.
Figure 2: Foreign Establishments Registered to Manufacture Drugs for
the U.S. Market by Country, Fiscal Year 2007:
This figure is a shaded map of the world showing foreign establishments
registered to manufacture drugs for the U.S. market by country, fiscal
year 2007.
[See PDF for image]
Source: Copyright Corel Corp. All rights reserved (map); GAO analysis
of FDA data.
Note: The counts include foreign establishments that were registered to
manufacture human drugs, biologics, and veterinary drugs; FDA was
unable to provide the number of registered establishment specifically
manufacturing human drugs.
[End of figure]
FDA Lacks Accurate Information to Effectively Manage the Foreign Drug
Inspection Program:
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.
FDA's Drug Registration Database Contains Inaccuracies and Planned
Changes Will Not Ensure the Availability of Accurate Information on
Foreign Establishments:
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.[Footnote 22] 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.[Footnote 23] 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.[Footnote 24]
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;[Footnote 25] 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-SŪ) Number--as part of their registration.[Footnote 26]
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.[Footnote 27]
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.
FDA's Import Database Contains Inaccurate Data on Establishments
Offering Drugs for Import into the United States:
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.[Footnote 28] 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.[Footnote 29] This unique identifier would then be stored
within the proposed Shared Establishment Data Service (SEDS)[Footnote
30] 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.[Footnote 31] 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.
FDA's Databases Are Not Currently Electronically Integrated, which
Could Help Reconcile Data Inaccuracies:
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.
FDA Inspects Relatively Few Foreign Establishments to Assess the
Manufacture of Drugs Currently Marketed in the United States:
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.
FDA Inspects Few Foreign Establishments Each Year, Relative to Its
Inspection of Domestic Establishments:
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.[Footnote 32]
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.[Footnote 33] 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.[Footnote 34] 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.
Table 1: Number of FDA Inspections of Foreign Establishments Involved
in the Manufacture of Drugs for the U.S. Market, by Country for the 10
Most Frequently Inspected Countries, Fiscal Years 2002 through 2007:
Country: India;
Number of inspections: FY2002: 11;
Number of inspections: FY2003: 19;
Number of inspections: FY2004: 38;
Number of inspections: FY2005: 33;
Number of inspections: FY2006: 34;
Number of inspections: FY2007: 64;
Number of inspections: Total: 199;
Number of unique establishments inspected: 152;
Estimated number of establishments[A]: 410.
Country: Germany;
Number of inspections: FY2002: 24;
Number of inspections: FY2003: 15;
Number of inspections: FY2004: 35;
Number of inspections: FY2005: 25;
Number of inspections: FY2006: 19;
Number of inspections: FY2007: 25;
Number of inspections: Total: 143;
Number of unique establishments inspected: 95;
Estimated number of establishments[A]: 199.
Country: Italy;
Number of inspections: FY2002: 17;
Number of inspections: FY2003: 30;
Number of inspections: FY2004: 26;
Number of inspections: FY2005: 21;
Number of inspections: FY2006: 18;
Number of inspections: FY2007: 28;
Number of inspections: Total: 140;
Number of unique establishments inspected: 98;
Estimated number of establishments[A]: 150.
Country: Canada;
Number of inspections: FY2002: 29;
Number of inspections: FY2003: 12;
Number of inspections: FY2004: 17;
Number of inspections: FY2005: 23;
Number of inspections: FY2006: 23;
Number of inspections: FY2007: 20;
Number of inspections: Total: 124;
Number of unique establishments inspected: 88;
Estimated number of establishments[A]: 288.
Country: United Kingdom;
Number of inspections: FY2002: 17;
Number of inspections: FY2003: 21;
Number of inspections: FY2004: 15;
Number of inspections: FY2005: 18;
Number of inspections: FY2006: 15;
Number of inspections: FY2007: 16;
Number of inspections: Total: 102;
Number of unique establishments inspected: 84;
Estimated number of establishments[A]: 169.
Country: China;
Number of inspections: FY2002: 11;
Number of inspections: FY2003: 9;
Number of inspections: FY2004: 17;
Number of inspections: FY2005: 21;
Number of inspections: FY2006: 17;
Number of inspections: FY2007: 19;
Number of inspections: Total: 94;
Number of unique establishments inspected: 80;
Estimated number of establishments[A]: 714.
Country: France;
Number of inspections: FY2002: 14;
Number of inspections: FY2003: 15;
Number of inspections: FY2004: 13;
Number of inspections: FY2005: 12;
Number of inspections: FY2006: 16;
Number of inspections: FY2007: 24;
Number of inspections: Total: 94;
Number of unique establishments inspected: 71;
Estimated number of establishments[A]: 162.
Country: Japan;
Number of inspections: FY2002: 11;
Number of inspections: FY2003: 13;
Number of inspections: FY2004: 14;
Number of inspections: FY2005: 21;
Number of inspections: FY2006: 13;
Number of inspections: FY2007: 22;
Number of inspections: Total: 94;
Number of unique establishments inspected: 82;
Estimated number of establishments[A]: 196.
Country: Switzerland;
Number of inspections: FY2002: 12;
Number of inspections: FY2003: 12;
Number of inspections: FY2004: 11;
Number of inspections: FY2005: 17;
Number of inspections: FY2006: 9;
Number of inspections: FY2007: 17;
Number of inspections: Total: 78;
Number of unique establishments inspected: 50;
Estimated number of establishments[A]: 83.
Country: Ireland;
Number of inspections: FY2002: 11;
Number of inspections: FY2003: 5;
Number of inspections: FY2004: 11;
Number of inspections: FY2005: 14;
Number of inspections: FY2006: 3;
Number of inspections: FY2007: 14;
Number of inspections: Total: 58;
Number of unique establishments inspected: 43;
Estimated number of establishments[A]: 61.
Country: All other countries;
Number of inspections: FY2002: 63;
Number of inspections: FY2003: 38;
Number of inspections: FY2004: 63;
Number of inspections: FY2005: 61;
Number of inspections: FY2006: 45;
Number of inspections: FY2007: 83;
Number of inspections: Total: 353;
Number of unique establishments inspected: 276;
Estimated number of establishments[A]: 817.
Country: Total;
Number of inspections: FY2002: 220;
Number of inspections: FY2003: 189;
Number of inspections: FY2004: 260;
Number of inspections: FY2005: 266;
Number of inspections: FY2006: 212;
Number of inspections: FY2007: 332;
Number of inspections: Total: 1,479;
Number of unique establishments inspected: 1,119;
Estimated number of establishments[A]: 3,249.
Source: GAO analysis of FDA data.
[A] This count represents the number of establishments FDA used to plan
its fiscal year 2007 prioritized surveillance inspections.
[End of table]
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.[Footnote 35] 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.[Footnote 36]
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.
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:
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.[Footnote 37]
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.[Footnote
38]
Figure 3: FDA Foreign Establishment Inspections by Type of Inspection,
Fiscal Years 2002 through 2007:
This figure is a pie graph showing FDA foreign establishment
inspections by type of inspection, fiscal years 2002 through 2007.
Both preapproval and GMP: 68%;
Preapproval only: 19%;
GMP only: 13%.
[See PDF for image]
Source: GAO analysis of FDA data.
[End of figure]
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.[Footnote 39]
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.
FDA's Identification of Serious Deficiencies Has Led Establishments to
Take Corrective Actions, but Subsequent Inspections Were Not Always
Timely:
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.
FDA Identified Deficiencies during Most of Its Inspections of Foreign
Establishments, but FDA's Databases Contain Inconsistent Information
about Inspection Classifications:
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,[Footnote 40] 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,[Footnote 41] 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.[Footnote 42] 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.[Footnote 43]
FDA Issued Warning Letters to Establishments, Most of which Had
Previous Deficiencies:
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,[Footnote 44] the agency issued a warning letter following 15
inspections in which serious deficiencies were identified (see table
2).[Footnote 45] The rate of warning letters issued to foreign
establishments was similar to that for domestic
establishments.[Footnote 46] 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.
Table 2: Warning Letters Issued by FDA to Foreign Establishments in
Response to Inspections Conducted from Fiscal Years 2002 through 2007:
Date inspection ended: Fiscal year 2002: April 16, 2002;
Date warning letter issued: November 21, 2002;
Location of establishment: Australia;
Import alert issued: No;
Time from inspection to warning letter issuance: 7 months, 5 days.
Date inspection ended: Fiscal year 2003: September 10, 2003;
Date warning letter issued: January 15, 2004;
Location of establishment: Czech Republic;
Import alert issued: No;
Time from inspection to warning letter issuance: 4 months, 5 days.
Date inspection ended: Fiscal year 2004: October 29, 2003;
Date warning letter issued: January 5, 2004;
Location of establishment: Taiwan, Republic of China;
Import alert issued: No;
Time from inspection to warning letter issuance: 2 months, 7 days.
Date inspection ended: Fiscal year 2004: October 31, 2003;
Date warning letter issued: February 10, 2004;
Location of establishment: China;
Import alert issued: Yes;
Time from inspection to warning letter issuance: 3 months, 10 days.
Date inspection ended: Fiscal year 2004: May 13, 2004;
Date warning letter issued: August 3, 2004;
Location of establishment: Switzerland;
Import alert issued: No;
Time from inspection to warning letter issuance: 2 months, 21 days.
Date inspection ended: Fiscal year 2005: October 15, 2004;
Date warning letter issued: February 15, 2005;
Location of establishment: Canada;
Import alert issued: Yes;
Time from inspection to warning letter issuance: 4 months.
Date inspection ended: Fiscal year 2005: March 24, 2005;
Date warning letter issued: July 21, 2005;
Location of establishment: Italy;
Import alert issued: No;
Time from inspection to warning letter issuance: 3 months, 27 days.
Date inspection ended: Fiscal year 2005: April 8, 2005;
Date warning letter issued: August 16, 2005;
Location of establishment: Switzerland;
Import alert issued: No;
Time from inspection to warning letter issuance: 4 months, 8 days.
Date inspection ended: Fiscal year 2006: November 11, 2005;
Date warning letter issued: February 21, 2006;
Location of establishment: India;
Import alert issued: No;
Time from inspection to warning letter issuance: 3 months, 10 days.
Date inspection ended: Fiscal year 2006: February 8, 2006;
Date warning letter issued: April 28, 2006;
Location of establishment: Croatia;
Import alert issued: No;
Time from inspection to warning letter issuance: 2 months, 20 days.
Date inspection ended: Fiscal year 2006: February 25, 2006;
Date warning letter issued: June 15, 2006;
Location of establishment: India;
Import alert issued: No;
Time from inspection to warning letter issuance: 3 months, 21 days.
Date inspection ended: Fiscal year 2006: September 13, 2006;
Date warning letter issued: February 23, 2007;
Location of establishment: Canada;
Import alert issued: No;
Time from inspection to warning letter issuance: 5 months, 10 days.
Date inspection ended: Fiscal year 2007: April 25, 2007[A];
Date warning letter issued: September 6, 2007;
Location of establishment: China;
Import alert issued: Yes[B];
Time from inspection to warning letter issuance: 4 months, 12 days.
Date inspection ended: Fiscal year 2007: August 30, 2007;
Date warning letter issued: October 31, 2007;
Location of establishment: China;
Import alert issued: Yes;
Time from inspection to warning letter issuance: 2 months, 1 day.
Date inspection ended: Fiscal year 2007: August 2, 2007;
Date warning letter issued: January 14, 2008;
Location of establishment: Japan;
Import alert issued: No;
Time from inspection to warning letter issuance: 5 months, 12 days.
Source: GAO review of FDA warning letters.
[A] This warning letter related to inspections of two establishments as
drug production was being moved from one establishment to the other. As
FDA referred to both establishments in its warning letter, we count the
end date of the inspection of the second establishment as the relevant
end date.
[B] The import alert only applied to drugs manufactured at the
establishment from which production was being moved.
[End of table]
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;[Footnote 47] 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.[Footnote 48] 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.[Footnote 49] 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.[Footnote 50] 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.
FDA Oversight Has Led Establishments to Take Corrective Actions, but
Subsequent Inspections to Determine Continued Compliance Are Not always
Timely:
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.[Footnote 51] (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.
Figure 4: FDA's Methods for Determining the Adequacy of Corrective
Actions for 15 Warning Letters Issued Following Foreign Inspections
Conducted from Fiscal Years 2002 through 2007:
This figure is a diagram showing FDA's methods for determining the
adequacy of corrective actions for 15 warning letters issued following
foreign inspections conducted from fiscal years 2002 through 2007.
[See PDF for image]
Source: GAO analysis of FDA documents.
[End of figure]
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.
Challenges Unique to Foreign Inspections Influence the Manner in which
FDA Conducts Such Inspections:
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.
Inspections of Foreign Drug Establishments Pose Unique Challenges to
FDA:
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.[Footnote 52]
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.[Footnote
53] 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.[Footnote 54] 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.
Unclear if Recent FDA Proposals Will Address All Challenges Unique to
Foreign Inspections:
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.[Footnote 55] 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.[Footnote 56] 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.
Conclusions:
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.
Recommendations for Executive Actions:
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.
Agency Comments and Our Evaluation:
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
[hyperlink, 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.
Signed by:
Marcia Crosse:
Director, Health Care:
[End of section]
Appendix I: Scope and Methodology:
To address 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.[Footnote 57] 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.
[End of section]
Appendix II: Comments from the Department of Health and Human Services:
Department Of Health At Human Services:
Office Of The Secretary:
Assistant Secretary for Legislation:
Washington, DC 20201:
September 2, 2008:
Marcia Crosse:
Director, Health Care:
441 G Street NW:
U.S. Government Accountability Office:
Washington, D.C. 20548:
Dear Ms. Crosse:
Enclosed are the Department's comments on the U.S. Government
Accountability Office's (GAO) draft report entitled, "Drug Safety:
Better Data Management and More Inspections Are Needed to Strengthen
FDA's Foreign Drug Inspection Program" (GAO 08-970).
The Department appreciates the opportunity to comment on this draft
before its publication.
Sincerely,
Jennifer R. Luong:
for:
Vincent J. Ventimiglia, Jr.:
Assistant Secretary for Legislation:
Attachment:
Comments Of The U.S. Department Of Health And Human Services (HHS) On
The U.S. Government Accountability Office's (GAO) Draft Report
Entitled, "Drug Safety: Better Data Management And More Inspections Are
Needed To Strengthen FDA's Foreign Drug Inspection Program" (GAO 08-
970):
The Food and Drug Administration (FDA) appreciates the opportunity to
review and comment on the Government Accountability Office's (GAO)
draft report. GAO has raised some important issues regarding FDA's
foreign drug inspection program. FDA strives continually to advance its
public health mission, and this includes significant efforts to improve
the foreign drug inspection program. As stated in the report's title,
GAO is recommending that more inspections are needed to strengthen this
program. Although FDA recognizes the need for additional risk-based
targeted foreign inspections, this is only one component of FDA's
overall strategy to enhance oversight of imported drugs. The overall
approach is multi-faceted and includes conducting risk-based targeted
inspections of foreign firms, working collaboratively with the
importing community and state and local governments, reaching out to
foreign producers, exporters and governments, improving information
technology (IT), and expanding FDA's foreign presence. FDA believes
that strategic use of resources for this multi-faceted approach to
foreign firms, as opposed to simply increasing numbers of inspections,
will provide the greatest public health protection. With our Import
Safety Action Plan, FDA is adopting a strategy that shifts the primary
emphasis for import safety from intervention to a risk-based
"prevention with verification" model. GAO acknowledges that there are
unique challenges to foreign inspections not present in the domestic
arena. Therefore, the conclusion that FDA should endeavor to conduct
foreign inspections based on the same criteria as domestic inspections
is also problematic because of the differences in regulatory
methodology and resources.
FDA has many initiatives underway focused on improving the foreign drug
inspection program. The FDA "Beyond Our Borders" initiative is a multi-
pronged approach to promote and verify compliance of imported food,
cosmetics, and medical products with FDA requirements. Key components
of this initiative are establishing an FDA presence in China, India,
Latin America, Europe and the Middle East; increased FDA inspections;
greater laboratory capacity; greater sharing and use of foreign
regulatory authority inspection reports and other information; use of
third party certification; and increased capacity building with
countries that have less developed regulatory systems to ensure product
safety. FDA plans to establish offices in several countries around the
world, starting with China and India. On July 25, 2008, seven new
positions within FDA's China Office were announced in addition to the
previously selected country director. Consumer safety officer positions
in India were also recently announced. These positions demonstrate
FDA's efforts toward a more global approach to our regulatory
responsibilities. FDA also plans to establish a foreign inspection
cadre, which will consist of highly qualified consumer safety officers
with relevant skills and experience to conduct foreign inspections. The
supervisory position in the Division of Field Investigations for the
cadre has also been announced.
FDA also has several plans to enhance its IT systems in ways that will
enable the Agency to better utilize risk-based information from the
entire life-cycle of imported products. These projects will improve
databases, enhance interoperability of systems within the Agency and
among other regulatory agencies, and provide better analytical function
to assess and control risk. The following are specific examples of
ongoing IT projects:
* One of many activities proceeding under the auspices of the
Bioinformatics Board and in particular the Product Quality Business
Review Board is the Harmonized Inventory project, which is bringing
together many databases to have a common identifier for each
establishment, a problem most acute for foreign establishments.
* The Center for Drug Evaluation and Research (CDER) is working
vigorously to establish electronic Drug Registration and Listing
(eDRLS) which will, among other things, require firms to update their
registration electronically every 6 months to be active. Overall, these
efforts will modernize our databases to prevent outdated, inaccurate,
and duplicative information.
* CDER has recently published a draft guidance on eDRLS which is
piloting its use prior to the actual regulatory implementation date.
One of the features of this pilot will be to have establishments enter
their Dun and Bradstreet number (DUNS) to serve as a recognized
identifier to avoid duplications and error. The link to this draft
guidance is provided here--[hyperlink,
http://www.fda.gov/cder/guidance/OC2008145.htm].
All of these activities will improve FDA's ability to ensure the safety
and efficacy of human drugs, regardless of where they are manufactured.
[End of section]
Appendix III GAO Contact and Staff Acknowledgments:
GAO Contact:
Marcia Crosse, (202) 512-7114, crossem@gao.gov.
Acknowledgments:
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.
[End of section]
Related GAO Products:
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.
[End of section]
Footnotes:
[1] According to GAO analysis of International Trade Centre data, the
value of pharmaceutical imports increased 42 percent from 2001 to 2005,
adjusted for pharmaceutical inflation. The International Trade Centre
is a joint agency of the United Nations Conference on Trade and
Development and the World Trade Organization.
[2] Drugs are defined to include, among other things, articles intended
for use in the diagnosis, cure, mitigation, treatment, or prevention of
disease, and include components of those articles. 21 U.S.C. §
321(g)(1)(B), (D). FDA regulations define manufacturing to include the
manufacture, preparation, propagation, compounding, or processing of a
drug. 21 C.F.R. § 207.3(a)(8) (2007). In addition, FDA regulations
define an establishment as a place of business under one management at
one general physical location. 21 C.F.R. § 207.3(a)(7) (2007). Drug
firms may have more than one establishment.
[3] GMPs provide a framework for a manufacturer to follow to produce
safe, pure, and high-quality drugs. See 21 C.F.R. pts. 210, 211 (2007).
[4] GAO, Food and Drug Administration: Improvements Needed in the
Foreign Drug Inspection Program, GAO/HEHS-98-21 (Washington, D.C.: Mar.
17, 1998).
[5] FDA classifies inspections based on the seriousness of the
deficiencies identified during the inspection.
[6] FDA issues warning letters to those establishments manufacturing
drugs for the U.S. market where it has identified violations that may
lead the agency to initiate enforcement action if not promptly and
adequately corrected.
[7] GAO, Drug Safety: Preliminary Findings Suggest Weaknesses in FDA's
Program for Inspecting Foreign Drug Manufacturers, GAO-08-224T
(Washington, D.C.: Nov. 1, 2007).
[8] An API is any component that is intended to provide pharmacological
activity or other direct effect in the diagnosis, cure, mitigation,
treatment, or prevention of disease. FDA defines inactive ingredients
as any component of a drug product other than the API, such as
materials that improve the appearance, stability, and palatability of
the product. See 21 C.F.R. § 210.3(b)(7), (8) (2007). According to FDA
officials, the agency typically only inspects establishments
manufacturing inactive ingredients when it receives information
indicating potential problems with their manufacture.
[9] GAO, 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.: Apr.
22, 2008).
[10] Foreign and domestic establishments that manufacture drugs for the
U.S. market are required to register annually with FDA. Establishments
provide FDA with, among other things, their names and addresses and a
listing of the drugs that they manufacture for the U.S. market. 21
U.S.C. §360(b), (i), (j).
[11] Biologics are materials, such as vaccines, derived from living
sources such as humans, animals, and microorganisms. Biologics are
generally regulated by FDA's Center for Biologics Evaluation and
Research. Biologics regulated by this center are not addressed in this
report. However, some biologics are regulated by CDER and inspections
related to those products are included in our work.
[12] 21 U.S.C. § 360(h).
[13] ORA investigators lead inspections. Investigators are responsible
for performing or overseeing all aspects of an inspection. ORA
laboratory analysts are chemists or microbiologists and have expertise
in laboratory testing. In some instances, staff from CDER may
participate in inspections.
[14] When FDA receives an application for drug approval, officials
review the inspection history of each establishment listed on the
application. According to FDA officials, if an establishment listed on
the application 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.
[15] FDA must approve an application for a new drug before it can be
marketed in the United States. FDA reviews scientific and clinical data
contained in these applications as part of its process in considering
them for approval to be marketed. Approval for a generic drug is sought
through an abbreviated new drug application, which generally does not
require preclinical and clinical data but which must demonstrate that
the generic drug performs in the same manner as the new drug on which
the generic is based. While new OTC drugs may reach the market through
FDA's review of a new drug or abbreviated new drug application, the
majority of OTC drugs are marketed today through a different process,
which has established the marketing conditions for various categories
of OTC drugs with particular active ingredients. Drugs marketed through
this different process may be marketed without FDA preapproval and
establishments that manufacture such drugs may not receive a
preapproval inspection.
[16] Department of Health and Human Services, U.S. Food and Drug
Administration, "Risk-Based Method for Prioritizing CGMP Inspections of
Pharmaceutical Manufacturing Sites--A Pilot Risk Ranking Model"
(September 2004), [hyperlink,
http://www.fda.gov/cder/gmp/gmp2004/risk_based_method.htm] (accessed
June 26, 2008).
[17] For more information about this process, see GAO-08-224T.
[18] FDA issues untitled letters to violative foreign establishments
that were inspected as part of the agency's review of an application
and intend to market a drug in the United States but do not yet do so.
[19] An import alert can apply to specific drugs or all drugs
manufactured by an establishment.
[20] Customs brokers are private individuals, partnerships,
associations, or corporations that are licensed, regulated, and
empowered by CBP to assist in meeting federal requirements governing
imports and exports.
[21] The counts include foreign establishments that were registered to
manufacture human drugs, biologics, and veterinary drugs; FDA was
unable to provide the number of registered establishment specifically
manufacturing human drugs.
[22] See Pub. L. No. 105-115, §§ 417; 111 Stat. 2296, 2379 (1997). FDA
issued implementing regulations in 2001 (21 C.F.R. § 207.40), which
were effective February 11, 2002. 66 Fed. Reg. 59138 (Nov. 27, 2001).
[23] If the agency learns of an error, it asks the establishment to
submit corrected information.
[24] For example, an establishment in China may export an API to
Germany. The German establishment may use the API in its production of
a drug that is imported into the United States. Although the German
establishment would be required to notify FDA of its arrangement with
the Chinese establishment, and the Chinese establishment would be
subject to inspection by FDA, the Chinese establishment is not required
to register.
[25] This voluntary program was established through release of draft
FDA guidance in July 2008. See "Guidance for Industry: Providing
Regulatory Submissions in Electronic Format--Drug Establishment
Registration and Drug Listing" at [hyperlink,
http://www.fda.gov/cder/guidance/index.htm] (accessed July 30, 2008).
[26] The D-U-N-SŪ Number is a unique nine-digit sequence recognized as
the federal government's universal standard for identifying and keeping
track of business entities. Submitting the site-specific number for an
entity would provide, by reference to the number, certain business
information for that entity that is otherwise required for drug
establishment registration. For example, a D-U-N-SŪ Number could be
used to identify trade names used by the entity; addresses; additional
ownership information, such as the name of each partner or the name of
each corporate officer and director; and the state of incorporation.
[27] In fiscal year 2008, another FDA center implemented changes
affecting the registration of medical device manufacturing
establishments, an activity for which we previously identified problems
similar to those found in DRLS. See Medical Devices: FDA Faces
Challenges in Conducting Inspections of Foreign Manufacturing
Establishments, GAO-08-780T (Washington, D.C.: May 14, 2008). Officials
indicated that the Center for Devices and Radiological Health began
deactivating the registrations of those establishments that fail to
complete the annual registration process. In addition, it implemented
an electronic registration system and began charging an annual user
fee, $1,706 in fiscal year 2008, per registration for certain medical
device establishments. (CDER does not have authority to charge such a
fee to drug establishments.) Officials found that, combined, these
changes resulted in the elimination of establishments from the
database. They anticipated that this would provide FDA with a smaller,
more accurate database of medical device establishments.
[28] The algorithm currently used by customs brokers to assign the
manufacturer identification number does not provide for a number that
is reliably reproduced or inherently unique.
[29] If an establishment did not already have an identification number,
it would request an identification number and data about the
establishment would be verified through a commercial service. This
commercial service would provide federal agencies with researched and
validated records on domestic and foreign establishments.
[30] The SEDS proposal was developed by the Federal Health Architecture
Food Safety Work Group, which is comprised of representatives from FDA,
the Environmental Protection Agency, and the departments of
Agriculture, Commerce, Defense, and Homeland Security. These agencies
are involved in the oversight of products imported into the United
States. In addition, developing an implementation plan for SEDS was
recommended by the Interagency Working Group on Import Safety in 2007.
In July 2007, the Interagency Working Group on Import Safety was
established to conduct a comprehensive review of current import safety
practices and determine where improvements could be made. Interagency
Working Group on Import Safety, Action Plan for Import Safety: A
Roadmap for Continual Improvement (November 2007) ([hyperlink,
http://www.importsafety.gov/report/actionplan.pdf], accessed May 6,
2008).
[31] In October 2007, we reported on CBP's implementation of its import
and export system, known as the Automated Commercial Environment. We
found that CBP has made progress but warned that further efforts were
needed to avoid major program schedule delays and cost overruns. See
Information Technology: Improvements for Acquisition of Customs Trade
Processing System Continue, but Further Efforts Needed to Avoid More
Cost and Schedule Shortfalls, GAO-08-46 (Washington, D.C.: Oct. 25,
2007).
[32] Our analysis includes all foreign and domestic inspections that
were identified in FDA's FACTS database as being either related to the
drug application approval process or GMP. It does not include a small
number of other inspections, such as inspections conducted to determine
whether drug manufacturers are submitting to FDA, as required, complete
and accurate data on adverse drug experiences associated with marketed
drugs.
[33] In preparing this list, FDA drew on information from DRLS. It also
obtained information from previous inspections to help it identify
establishments that are subject to inspection but are not required to
register--such as the manufacturer of an API whose product is not
directly imported into the United States. However, as a result of the
inaccuracies in its data, FDA recognizes that this list does not
provide an accurate count of establishments subject to inspection.
[34] According to FDA officials, some of these establishments may have
received an inspection for another type of product, such as a
veterinary drug.
[35] According to FDA, the cost of conducting foreign inspections
varies, depending on the time spent at an establishment, the number of
FDA staff conducting the inspection, the costs associated with
traveling to the country in which the establishment is located, and
whether the type of inspection was a preapproval or GMP surveillance
inspection.
[36] The submission requested funds for FDA to conduct a total of 2,100
inspections in addition to those the agency already planned to conduct.
Of the 2,100 inspections, 1,050 would be of foreign establishments
manufacturing food, drugs, and other medical products and 1,050 would
be of domestic establishments manufacturing food, drugs, and other
medical products.
[37] GAO/HEHS-98-21, 23.
[38] When FDA receives a new drug application, CDER officials review
the inspection history of each establishment listed on the application.
According to FDA officials, if an establishment listed on the
application has received a satisfactory GMP inspection in the previous
2 years and the agency has no new concerns, FDA will consider this
inspection sufficient for the review of the application and will not
perform a preapproval inspection of this establishment. Otherwise, the
agency may inspect the establishment as part of the application review
process.
[39] Because a GMP inspection examines the major manufacturing systems
at an establishment, the results of such an inspection can often be
generalized to all drugs 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 in another new
drug application.
[40] We present data from fiscal years 2002 through 2006 because, at
the time we received these data, some inspections conducted in fiscal
year 2007 may not have received their final classification.
[41] We were unable to match all inspection information in the two
databases. For fiscal years 2002 through 2006, we identified 1,147
inspections in FACTS and 1,128 inspections in OCFITS. Of these, we were
able to reliably determine that 1,060 inspections in each database were
indeed the same inspections.
[42] We identified a similar weakness in our 1998 report. We reported
that a 1988 FDA evaluation of its foreign inspection program found that
an inspection tracking database that served as a precursor to FACTS
contained incomplete information for 37 percent of foreign inspections
conducted between fiscal years 1982 and 1987. The evaluation attributed
this error to CDER staff not updating the inspection tracking database
after reviewing and classifying inspection reports. In addition, our
review of data on inspections conducted between January 1, 1994, and
May 15, 1996, found that these data were missing or incorrect in 15
percent of inspections. Similar to FDA's 1988 findings, we attributed
some of these errors to staff not updating the database after reviewing
and classifying inspection reports. GAO/HEHS-98-21.
[43] Although we have concerns about the consistency with which CDER
staff update final classification information in FACTS, we use FACTS,
rather than OCFITS, as our source for this information. FDA inspections
of both domestic and foreign establishments are tracked in FACTS, while
only foreign inspections are tracked in OCFITS. Thus, for purposes of
comparison, we report both domestic and foreign inspection counts from
FACTS. For consistency, we used that same count of inspections to
conduct our analysis of classification information. As we report, our
analysis of FACTS data suggested that about 62 percent of foreign
inspections conducted from fiscal year 2002 through 2006 were
classified as VAI or OAI. Similarly, about 61 percent of foreign
inspections in OCFITS were classified as VAI or OAI, though
classifications of individual inspections differed between the two
databases.
[44] FDA only issues warning letters to those foreign establishments
manufacturing drugs for the U.S. market at which it has identified
violations that could lead to enforcement action. If the violative
foreign establishment is not yet manufacturing any drugs for the U.S.
market, but intends to, the agency may issue an untitled letter.
Because our analysis may have included inspections of establishments
named in a new drug application that did not yet manufacture a drug for
the U.S. market, in some instances the identification of serious
deficiencies could have resulted in an untitled letter and not a
warning letter.
[45] One warning letter related to the inspection of two establishments
as drug production was being moved from one establishment to the other.
As FDA referred to both inspections in its warning letter, we count
this as a single inspection.
[46] We base this statement on a comparison of inspections conducted
and warning letters issued from fiscal years 2004 through 2007. The
number of domestic warning letters issued prior to fiscal year 2004 was
not readily available.
[47] An impurity profile describes the identified and unidentified
impurities present in an API. GMP guidance notes that impurity profiles
should be compared with historical data at appropriate intervals to
detect changes in the API.
[48] One establishment did not respond to the identified deficiencies
until 6 months after the FDA inspection. FDA did not receive a response
from the establishment until after it issued the warning letter.
[49] In the case of three establishments that received warning letters
but that FDA had not previously inspected, the establishments
manufactured OTC drugs. FDA does not generally conduct preapproval
inspections for establishments manufacturing OTC drugs because the
majority of OTC drugs may be marketed without FDA preapproval. FDA
generally considers establishments manufacturing OTC drugs to have a
lower inspection priority.
[50] None of the inspections that directly preceded the warning letter
inspection resulted in a warning letter. However, FDA indicated that
two of the establishments in our review had received a previous warning
letter since fiscal year 1995, the year from which FDA could reliably
determine warning letter issuance.
[51] As of July 2008, the corrective actions of establishments
referenced in the other four warning letters had not been accepted by
FDA.
[52] These counts do not represent the number of individuals who
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 other qualified
investigators and laboratory analysts may perform multiple inspections
during the same period. While an investigator and laboratory 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.
[53] Travel warnings are issued when the Department of State recommends
that Americans avoid travel to a certain country.
[54] These 10 countries were Colombia, the Democratic Republic of the
Congo, Haiti, Indonesia, Israel, Kenya, Nigeria, Pakistan, the
Philippines, and Saudi Arabia.
[55] See Food and Drug Administration, Revitalizing ORA: Protecting the
Public Health Together In a Changing World (Rockville, Md.: January
2008).
[56] For additional information about FDA's agreements with foreign
regulatory bodies, see GAO-08-701T.
[57] GAO-08-224T, 15.
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