Department of Health and Human Services
 
OFFICE OF 
 
INSPECTOR GENERAL 
 
 
 
 
 
 
 
 
C FDA A T
  HALLE NGES TO  S  BILITY  O 
 
M I F
ONITOR AND  NSPECT  OREIGN 
 
C T  
  LINICAL  RIALS 
 
 
 
 
 
 
 
Daniel R. Levinson  
Inspector General 
 
June 2010 
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 E X E C U T I V E   S U M M A R Y  
OBJECTIVE
 
1. To determine the extent to which sponsors submitted data from 
foreign clinical trials to support drug- and biologic-marketing 
applications approved by the Food and Drug Administration (FDA) in 
fiscal year (FY) 2008. 
2. To determine the extent to which FDA monitors and inspects foreign 
clinical trials that support marketing applications. 
BACKGROUND 
The Food, Drug, and Cosmetic Act requires all new investigational 
drugs and biologics to undergo clinical trials on human subjects to 
demonstrate the safety and efficacy of these products prior to approval 
for sale in the United States.  Through its review of the clinical trial 
protocol and sponsors marketing applications and its inspections of 
clinical trial sites, FDA ensures the rights, safety, and well-being of 
subjects who participate in these trials and verifies that the clinical trial 
data collected are both accurate and reliable. 
Sponsors that wish to market drugs or biologics in the United States 
must submit marketing applications to FDA.  Sponsors may submit 
data from foreign and domestic clinical trials to support marketing 
applications.  Sources have estimated that between 40 percent and        
65 percent of clinical trials investigating FDA-regulated products are 
conducted outside the United States.  Sponsors may realize benefits 
from conducting research abroad, such as lower costs in some countries 
or the ability to conduct larger trials in less time.  Despite benefits to 
sponsors, critics have raised concerns about the increased prevalence of 
foreign clinical trials, particularly those conducted in developing 
countries.  The concerns cited by medical ethicists include the ability of 
local regulatory bodies and institutional review boards to adequately 
monitor clinical trials to protect the rights and welfare of subjects and to 
ensure data integrity.  Other critics question the extent to which the 
results from foreign clinical trials conducted in developing countries are 
generalizable to the U.S. population.   
We reviewed all marketing applications for drugs and biologics 
approved in FY 2008 that contained clinical trial data.  We used five 
sources of data in our review:  approved FDA marketing applications 
and corresponding review documents; FDA inspection documents; 
structured interviews; database of clinical investigators involved with 
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FFIINNDDIINNGGSS  
In FY 2008, sponsors relied heavily on data from foreign clinical 
trials to support their marketing applications for drugs and 
biologics.  Eighty percent of approved marketing applications for drugs 
and biologics contained data from foreign clinical trials.  Over half of 
clinical trial subjects and sites were located outside the United States.  
Western Europe accounted for most foreign clinical trial subjects and 
sites; however, Central and South America had the highest average 
number of subjects per site.  Based on the increase in foreign clinical 
investigators conducting clinical trials under INDs over the last10 years 
and the observations of FDA reviewers, sponsors reliance on foreign 
clinical trials for FDA-regulated drugs and biologics appears likely to 
grow.  
FDA inspected clinical investigators at less than 1 percent of foreign 
sites.  FDA inspected clinical investigators at only 1.2 percent of clinical 
trial sites for applications approved in FY 2008.  FDA inspected               
1.9 percent of domestic clinical trial sites and 0.7 percent of foreign 
clinical trial sites.  The agency targeted domestic sites and original 
applications, although inspection files and interviews with medical 
reviewers indicated the main reason for inspecting a specific site was a 
large number of enrolled subjects.  
Challenges to conducting foreign inspections and data limitations 
inhibit FDAs ability to monitor foreign clinical trials.  FDA may be 
unaware of some ongoing, early-phase clinical trials because sponsors 
are increasingly conducting early-phase clinical trials outside the 
United States without INDs.  Logistical challenges and sponsors 
submission of clinical trial data in a nonstandard format also hinder 
FDAs ability to monitor foreign clinical trials.  FDA was also unable to 
account for all clinical trial information because application files were 
missing or the sponsors failed to provide site locations and subject 
enrollment in the clinical study reports.   
 
 
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RECOMMENDATIONS 
FDA should take steps to improve its system for overseeing foreign 
clinical trial data.  Toward that end, we recommend that: 
FDA should require standardized electronic clinical trial data and 
create an internal database.  Requiring sponsors to submit their clinical 
trial data in a standardized electronic format would help ensure that 
reviewers had all necessary information from sponsors to effectively 
analyze the data, enable FDA to create an internal database to 
systematically cull clinical trial information, and enable FDA to more 
effectively select sites for inspection and meet its review timelines.   
FDA should monitor trends in foreign clinical trials not conducted 
under INDs and, if necessary, take steps to encourage sponsors to file 
INDs.  As sponsors submit future marketing applications with the results of 
foreign clinical trials that were not conducted under INDs, FDA should 
assess whether enrolled subjects were at additional risk and whether 
clinical trial data collected were both accurate and reliable.  Should FDA 
determine that clinical trials not conducted under INDs compromised the 
rights, safety, and well-being of subjects or the integrity of the data 
submitted by sponsors, it should consider taking steps to encourage 
sponsors to voluntarily consult with FDA on their clinical trial protocols or 
submit INDs to the agency.  FDA could also explore providing incentives to 
promote these, if it deems them appropriate.   
FDA should continue to explore ways to expand its oversight of 
foreign clinical trials.  To improve its oversight of foreign clinical trials, 
FDA could take the following additional actions: 
Continue to develop inspectional agreements with foreign regulatory bodies.  
By sharing past inspection details as well as future plans, FDA would 
be better able to maximize its resources allocated to inspections of 
foreign clinical trial sites.  FDAs recent agreement with the European 
Medicines Agency is a positive step for the agency to extend its 
oversight capability outside the United States.   
Inspect clinical trials in more countries.  FDA could target clinical trials in 
more countries, such as those in countries that the agency has not 
previously inspected or where Good Clinical Practice standards have 
only recently been adopted.  
Look to new models of oversight.  FDA could explore other oversight 
models, such as a quality risk management approach, to oversee clinical 
trials.   
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E X E C U T I V E   S U M M A R Y  
AGENCY COMMENTS AND OFFICE OF INSPECTOR GENERAL 
RESPONSE  
FDA agreed with all three of our recommendations.  It also stated that 
it has ongoing efforts or is developing new procedures to address each 
recommendation.   
Where appropriate, we made changes to the report based on FDAs 
technical comments.
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 T A B L E   O F   C O N T E N T S  
EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i
 
 
I N T RO DUC T IO N . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 
 
 
F I N D IN G S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 
In FY 2008, sponsors relied heavily on data from foreign clinical  
trials to support their marketing applications for drugs and     
biologics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 
FDA inspected clinical investigators at less than 1 percent of     
foreign sites  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 
Challenges to conducting foreign inspections and data limitations 
inhibit FDAs ability to monitor foreign clinical trials. . . . . . . . . . 17 
 
 
R E C O MMEN D A T ION S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 
Agency Comments and Office of Inspector General Response . . . 22 
 
 
APPENDIXES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 
  A:  Detailed Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 
  B:  Region Definitions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 
C:  Subjects and Sites by Country for Marketing  Applications 
Approved in Fiscal Year 2008. . . . . . . . . . . . . . . . . . . . . . . . . . 30 
D:  Number of Subjects and Number of Inspections per Country       
for Marketing Applications Approved in Fiscal Year 2008. . . 33 
E:  Agency Comments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 
 
 
A C K NO WL E D G M E N T S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43    
   
 I N T R O D U C T I O N  
OBJECTIVE 
1. To determine the extent to which sponsors submitted data from 
foreign clinical trials to support drug- and biologic-marketing 
applications approved by the Food and Drug Administration (FDA) in 
fiscal year (FY) 2008. 
2. To determine the extent to which FDA monitors and inspects foreign 
clinical trials that support marketing applications. 
BACKGROUND 
The Federal Food, Drug, and Cosmetic Act requires all new 
investigational drugs and biologics to undergo clinical trials on human 
subjects (hereinafter referred to as subjects) to demonstrate the safety 
and efficacy of these products prior to approval for sale in the United 
States.1  Through its review of the clinical trial protocol and sponsors 
marketing applications and its inspections of clinical trial sites, FDA 
ensures the rights, safety, and well-being of subjects who participate in 
these trials and verifies that the clinical trial data collected are both 
accurate and reliable. 
Sponsors that wish to market drugs or biologics in the United States 
must submit marketing applications to FDA.2  Sponsors may submit 
data from foreign and domestic clinical trials to support marketing 
applications.  Sources have estimated that between 40 percent and        
65 percent of clinical trials investigating FDA-regulated products are 
conducted outside the United States.3, 4  A recent analysis of the 
ClinicalTrial.gov Web site found that the 20 largest United States-based 
pharmaceutical companies were conducting one-third of their clinical 
trials exclusively at foreign sites.5   
 
1 The Federal Food, Drug, and Cosmetic Act of 1938, P.L. 75-717, 52 Stat. 1040 (1938) 
(amended 2004); 21 U.S.C.  355(i) and 360(j). 
2 21 CFR  314.50 (drugs) and 21 CFR  601.2 (biologics). 
3 Anand, G.; Wang, S.; Whalen, J., Scrutiny Grows for Drug Trials Abroad, The Wall 
Street Journal, December 1, 2008. 
4 Tufts Center for the Study of Drug Development, Outlook 2009, 2009, p. 6.   
5 Cairns, C.; Califf, R.; Glickman, S.; Harrington, R.; McHutchison, J.; and Peterson, E., 
Ethical and Scientific Implications of the Globalization of Clinical Research, New England 
Journal of Medicine, 2009, 360: 816.  
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I N T R O D U C T I O N  
Sponsors may realize benefits from conducting research abroad, such as 
lower costs in many countries.6  Foreign clinical trials may also allow 
sponsors to conduct larger trials in less time because of access to a 
larger population.7  In addition, sponsors may conduct clinical trials in 
particular countries because it could be a requirement to file for 
marketing approval in those countries.8 
Despite benefits to sponsors, critics have raised concerns about the 
increased prevalence of foreign clinical trials, particularly those 
conducted in developing countries.  The concerns cited by medical 
ethicists include the ability of local regulatory bodies and institutional 
review boards (IRB) to adequately monitor clinical trials to protect the 
rights and welfare of subjects and to ensure data integrity.9, 10  Other 
critics question the extent to which the results from foreign clinical 
trials conducted in developing countries are generalizable to the U.S. 
population.11   
Clinical Trials  
Sponsors generally conduct clinical trials in multiple trial sites 
(hereinafter referred to as multisite trials).  These multisite trials 
often take place in many countries.  Sponsors hire clinical investigators 
to manage the trial at each site.  Typically, a single clinical investigator 
may enroll anywhere from one to hundreds of subjects, depending on 
the trial phase.    
As a drug or biologic proceeds through development, sponsors conduct 
clinical trials in three phases.  Phase 1 evaluates small groups of 
healthy volunteers to assess the safety of a product and determine 
dosage.  Phase 2 evaluates the efficacy of the product in patients with 
the condition to be treated.  Phase 3 evaluates the safety and efficacy of 
a product within a larger population.12   
 
6 Gregory Lopes, Drug Makers Look East For Testing, The Washington Times, 
December 8, 2007. 
7 Ibid. 
8 Cairns, C., et al., op. cit., p. 817. 
9 Buchanan, D.; Sifunda, S.; Naidoo, N.; James, S.; and Reddy, P., Assuring Adequate 
Protections in International Health Research:  A Principled Justification and Practical 
Recommendations for the Role of Community Oversight, Public Health Ethics, 2008, 1:3 
246257. 
10 Cairns, C., et al., op. cit., pp. 818819. 
11 Ibid, p. 819. 
12 21 CFR  312.21. 
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I N T R O D U C T I O N  
FDA bases its approval to market a new drug or biologic largely on a 
review of the pivotal trial results that sponsors submit with marketing 
applications.13  Pivotal trials are generally Phase 3 trials that support 
the safety and efficacy of the drug or biologic.  FDA requires sponsors to 
submit all other clinical trial results in their marketing applications, in 
addition to the pivotal trial results.14 
FDA Oversight of Clinical Trials  
Investigational New Drug Application.  FDAs oversight of a clinical trial 
begins when a sponsor submits an Investigational New Drug 
Application (IND) to the agency.  Federal law prohibits unapproved 
drugs and biologics from interstate commerce.  The IND provides an 
exemption from that law.15  Because interstate commerce laws do not 
extend to foreign countries, INDs are not necessary for clinical trials 
conducted exclusively outside the United States. 
INDs provide FDA with information on the clinical trial protocol, the 
qualifications of trial personnel, and assurances that trials will protect 
subjects welfare, among other details.  FDA has 30 days to review the 
IND for safety to ensure that research subjects will not be subjected to 
unreasonable risk.16  A sponsor may begin its clinical trial 30 days after 
FDA receives an IND, provided that the agency does not place the study 
on clinical hold.17  Thereafter, FDA may choose to inspect a clinical trial 
while the trial is ongoing.   
FDA regulations permit sponsors to submit marketing applications with 
data exclusively from foreign clinical trials even if they are not 
conducted under INDs.18  Sponsors may also submit the results of 
earlier foreign clinical trials that were not conducted under INDs in 
support of current INDs.19  In both instances, FDA regulations require 
that sponsors conducted the clinical trials in accordance with Good 
Clinical Practice, which is defined as a standard for the design, 
conduct, performance, monitoring, auditing, recording, analysis, and 
reporting of clinical trials in a way that provides assurance that the 
 
13 The term pivotal trial is not defined in statute or regulations.   
14 21 CFR  314.50(d)(5). 
15 Federal Food, Drug, and Cosmetic Act, op. cit.; 21 U.S.C.  355(i) and Public Health 
Service Act of 1944; 42 U.S.C. 262(a). 
16 21 CFR  312.42. 
17 21 CFR  312.40 and 312.42.    
18 21 CFR  312.120 and 21 CFR  314.106. 
19 21 CFR  312.23. 
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I N T R O D U C T I O N  
data and reported results are credible and accurate and that the rights, 
safety, and well-being of trial subjects are protected.20  FDA regulations 
also require that sponsors submit information retrospectively that is 
largely similar to what would otherwise be required by an IND.21   
FDA inspections of clinical trial sites.  FDA uses onsite inspections to ensure 
that clinical investigators, sponsors, and IRBs comply with FDA 
regulations while developing investigational drugs or biologics.  
Although FDA has the authority to conduct site inspections, it is not 
required to do so.   
In 1977, FDA established the Bioresearch Monitoring Program to 
develop cross-center guidelines for inspections of clinical investigators, 
sponsors, and IRBs.22  The main objectives of this program are to 
protect the rights, safety and welfare of subjects involved in           
FDA-regulated clinical trials and to verify the accuracy and reliability of 
clinical trial data submitted to FDA in support of research or marketing 
applications.23  The Bioresearch Monitoring Program for drugs is 
managed by the Division of Scientific Investigations and for biologics by 
the Division of Inspections and Surveillance.  Medical reviewers, who 
are responsible for approving or disapproving a product, consult with 
Bioresearch Monitoring reviewers to choose which clinical trial sites to 
inspect.  Bioresearch Monitoring reviewers analyze various factors, such 
as the clinical trial protocol risk, high subject enrollment at one site, 
and the clinical investigators inspection history to determine which 
sites to inspect.   
FDA may conduct inspections at foreign or domestic sites.  Most 
inspections occur after FDA receives a marketing application and 
largely verify the accuracy of the clinical trial data submitted with the 
application.  FDA may choose to conduct an inspection while a clinical 
trial is ongoing.       
After the inspection, the medical reviewers and Bioresearch Monitoring 
reviewers discuss inspection findings.  FDA may disqualify data from a 
 
20 21 CFR  312.120(a)(i).  
21 For example, 21 CFR  312.120 includes requirements that sponsors submit the 
qualifications of all clinical investigators, a record of an independent review committee 
oversight, an attestation of the study being conducted according to ethical principles, and a 
detailed summary of the protocol. 
22 21 U.S.C.  355(i), 360(i). 
23 FDA, Compliance Program Guidance Manual, Chapter 48.811:  Bioresearch 
MonitoringClinical Investigators and Sponsor-Investigators (December 8, 2008). 
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specific subject, site, or trial based on inspection findings.24  FDA also 
has the authority to disqualify clinical investigators in cases of 
deliberate and repeated noncompliance.25   
Foreign Oversight of Clinical Trials 
International guidelines.  The World Medical Association developed the 
Declaration of Helsinki in 1964 to prescribe ethical standards for 
clinical research.26  The International Conference on Harmonization 
developed its Guideline for Good Clinical Practice as a unified standard 
for clinical trials in the European Union, Japan, and the United States.  
The objective of this guideline is to establish an international ethical 
and scientific quality standard for designing, conducting, recording, and 
reporting trials that involve the participation of subjects.  Compliance 
with this standard provides public assurance that the rights, safety and 
well-being of trial subjects are protected.27  The guideline has been 
credited as a model for some countries laws and regulations related to 
clinical trials.   
Foreign regulatory agencies.  In addition to observing international 
standards and guidelines, sponsors conducting clinical trials in foreign 
countries must comply with the applicable local laws and regulations.  
Regulatory agencies in each country may monitor clinical trials and 
conduct inspections, but they are not required to share their findings 
with FDA. 
Marketing Application Review Process 
To market drugs in the United States, sponsors must submit marketing 
applications to FDAs Center for Drug Evaluation and Research 
(CDER).  To market biologics in the United States, sponsors must 
submit marketing applications to FDAs Center for Biologics Evaluation 
and Research (CBER).28  Before sponsors may begin marketing drugs or 
biologics, CDER or CBER, as appropriate, must approve the 
 
24 Ibid. 
25 21 CFR  312.70(a) 
26 World Medical Association, World Medical Association Declaration of Helsinki:  
Ethical Principles for Medical Research Involving Human Subjects, June 1964. 
27 European Medicines Agency, Harmonized Guideline, Tripartite International 
Committee on Harmonization Topic E6 (R1):  Guideline for Good Clinical Practice, June 10, 
1996. 
28 CDER also regulates biologic therapeutics.  Hereinafter, we include biologic 
therapeutics in our discussion and analyses of drugs.   
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I N T R O D U C T I O N  
applications, which consist of information on the products, their 
manufacturing, clinical trials, and labeling.29    
A drug-marketing application for a chemical compound previously 
unapproved by FDA (i.e., a New Molecular Entity) is called a New Drug 
Application.  A marketing application for a biologic is called a Biologic 
Licensing Application.  (Hereinafter, these two application types will be 
referred to as original applications.)  Sponsors may also submit data 
from clinical trials to support efficacy supplements for approved 
applications.  An efficacy supplement proposes a change to an approved 
drugs labeling, such as the indication, dosing, or route of 
administration.30   
Regardless of whether a marketing application contains data from 
foreign sites, FDAs review process remains the same.  When CDER or 
CBER receives an application, a medical reviewer first determines 
whether the sponsor has submitted everything necessary to complete its 
review.  Sponsors identify which clinical trials are the pivotal trials.  
Clinical study reports that provide results and data analyses from these 
trials and other pertinent trials must be included in the application.  If 
the application is complete, reviewers conduct a series of scientific 
analyses on the pivotal trial(s) and other supporting data.  These 
analyses include medical, chemistry, pharmacology, and statistical 
reviews. 
Medical reviewers rely primarily on attestations from sponsors that 
Good Clinical Practices were followed.  These attestations are supported 
by descriptions of the procedures used to ensure compliance with Good 
Clinical Practices.  FDA reviewers also rely on access to all the data and 
pertinent case reports forms.  Meanwhile, Bioresearch Monitoring 
reviewers analyze data collected from clinical trial site inspections.  
These reviewers attempt to verify that informed consent was collected, 
that protocols were followed, and that the clinical trials were conducted 
in accordance with standard ethical principles.31   
If the clinical trial results demonstrate the new drug or biologic to be 
safe and effective and if FDA reviewers determine that the trial was 
 
29 21 CFR  314.50 (drugs) and 21 CFR  601.2 (biologics). 
30 21 CFR  314.3(b) and 314.60.   
31 FDA, CDER, Manual of Policies and Procedures, MAPP 6010.3, Clinical Review 
Template, July, 9, 2004, p. 13.  
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 I N T R O D U C T I O N  
conducted properly and the data are valid, FDA grants approval for the 
sponsor to market the product in the United States. 
The Prescription Drug User Fee Act of 1992 requires FDA to complete 
its review of drug- and biologic-marketing applications in a timely 
manner.32  FDA generally has 6 months to review a priority marketing 
application and 10 months to complete a review of a standard 
marketing application.   
Previous Work 
A 2001 Office of Inspector General (OIG) report on the globalization of 
clinical trials found that the number of clinical investigators conducting 
research outside the United States under INDs increased from          
1990 to 1999.  The report also found that research was occurring 
increasingly in countries with little clinical trial experience.  The report 
raised concerns regarding FDAs ability to ensure the same level of 
protection to subjects enrolled in foreign trials as domestic trials.33 
A 2007 OIG report highlighted data limitations that inhibit FDAs 
ability to effectively manage inspections of clinical trials.  The report 
found that FDA had limited authority over foreign trials and often did 
not know that a foreign trial had been conducted until it was completed 
and its results were submitted to FDA to support a marketing 
application.34 
METHODOLOGY 
Scope 
We reviewed clinical trial data from all original applications and 
efficacy supplements for drugs and biologics approved in FY 2008.   
Data Sources and Analyses 
We used five sources of data in our review:  approved FDA marketing 
applications and corresponding review documents; FDA inspection 
documents; clinical investigator information from INDs; structured 
interviews; and FDA policies, procedures, and guidance documents.  
(See Appendix A for a detailed methodology.) 
 
32 P.L. 102-571.  
33 OIG, The Globalization of Clinical Trials (OEI-01-00-00190), September 2001. 
34 OIG, The Food and Drug Administrations Oversight of Clinical Trials                   
(OEI-01-06-00160), September 2007. 
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I N T R O D U C T I O N  
Approved FDA marketing applications and corresponding review documents. 
We requested from CDER and CBER a list of all marketing applications 
for drugs and biologics approved in FY 2008.   
CDERs list consisted of 169 marketing applications for drugs.  CDER 
reported that 114 of these marketing applications contained clinical 
trial data.   
CBERs list consisted of 15 marketing applications for biologics.  All of 
these marketing applications contained clinical trial data.   
We reviewed the 129 marketing applications reported to contain clinical 
trial data and corresponding review documents.  We used FDA 
databases to locate the review documents for each application.   
We excluded 8 marketing applications from the original 129 that 
lacked information on clinical trial locations.  This resulted in                     
121 applications from which we calculated the percentage that 
contained foreign data.   
Our populations included 193 complete clinical trials.  We used these 
clinical trials to calculate the number of subjects, sites, and regions.  
FDA inspection documents.  We obtained from FDA a list of all inspections 
it conducted for the marketing applications approved in FY 2008 and 
their corresponding inspection files.  We determined that FDA inspected        
147 clinical investigators for the marketing applications in our 
population. 
We used a logistic multivariate regression model to predict the 
probability of FDA inspecting a clinical investigator at a domestic site 
as opposed to a foreign site for a specific clinical trial within an 
application. 
Clinical investigator information from INDs.  We used the Bioresearch 
Monitoring Information System to identify and conduct a trend 
analysis of clinical investigators involved in the conduct of IND 
studies from 1998 to 2008. 
Structured interviews.  We interviewed 1 reviewer in each of FDAs 18 review 
divisions responsible for the marketing applications in our population.  
The interview questions focused on the processes and challenges, if any, 
when evaluating data from foreign clinical trials.  We also interviewed two 
senior FDA officials to discuss the processes for determining which sites to 
inspect and challenges to conducting foreign clinical trial inspections. 
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FDA policies, procedures, and guidance documents.  We obtained and 
reviewed all relevant policies, procedures, and guidance documents issued 
by FDA for accepting marketing applications supported by foreign clinical 
trials.  
Limitations  
Our analysis of marketing applications was limited to 1 year of data.  
Additionally, we did not verify the information provided by FDA, such 
as the number of applications approved and the number of inspections.  
Lastly, we were unable to collect information about the number of 
subjects at the site level, so we could not identify the largest sites for a 
clinical trial.  
Standards  
This study was conducted in accordance with the Quality Standards for 
Inspections approved by the Council of the Inspectors General on 
Integrity and Efficiency. 
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 F I N D I N G S  
In FY 2008, sponsors relied heavily on data from  In FY 2008, FDA approved          
foreign clinical trials to support their marketing  129 marketing applications 
containing clinical trial data:      
applications for drugs and biologics 
114 for drugs and 15 for biologics.  
Of these, 121 applications contained sufficient information to determine 
whether sponsors submitted foreign or domestic clinical trial data:     
106 for drugs and all 15 for biologics.  FDA was unable to locate the 
other eight marketing applications. 
Eighty percent of approved marketing applications for drugs and biologics 
contained data from foreign clinical trials 
Sponsors submitted 91 marketing applications for drugs containing at 
least 1 foreign clinical trial site (86 percent).  Nine of these applications 
had exclusively foreign data.   
Sponsors submitted six marketing applications for biologics containing 
at least one foreign clinical trial site (40 percent).  One of these 
applications contained exclusively foreign data.  (See Table 1 for 
details.)   
Table 1:  FDA Marketing Applications for Drugs and Biologics 
Containing Clinical Data Approved in FY 2008 
Drugs and 
Marketing Applications Drugs Biologics
Biologics
Applications With Only Domestic Data 15 9 24
Applications With Foreign and Domestic Data 82 5 87
Applications With Only Foreign Data 9 1 10
     Totals  106 15 121
Note:  These numbers are based on 121 applications with sufficient information to determine whether the data were 
foreign or domestic.
Source:  OIG analysis of FDA marketing applications approved in FY 2008.
Over half of all clinical trial subjects and sites were located outside the 
United States 
Seventy-eight percent of all subjects who participated in clinical trials 
were enrolled at foreign sites; 54 percent of all trial sites were foreign.  
Marketing applications for both drugs and biologics had about half 
foreign and half domestic trial sites; however, marketing applications 
for biologics had a much higher percentage of subjects enrolled at 
foreign sites.  (See Table 2 for details.) 
 
  OEI-01-08-00510  CHALLENGES TO FDAS ABILITY TO MONITOR AND INSPECT FOREIGN CLINICAL TRIALS  10    
   
FF II NN DD II NN GG SS   
Table 2:  Number and Percentage of Foreign Subjects and Sites 
From Clinical Trials Supporting Drug- and Biologic-Marketing 
Applications Approved in FY 2008 
Drugs and 
Drugs Biologics
Biologics
Number of Foreign and Domestic Subjects 92,859 206,842 299,701
Number of Foreign Subjects 52,820 179,712 232,532
Percentage of Foreign Subjects 56.9% 86.9% 77.6%
Number of Foreign and Domestic Trial Sites 11,227 717 11,944
Number of Foreign Trial Sites 6,129 356 6,485
Percentage of Foreign Trial Sites 54.6% 49.7% 54.3%
Note: These numbers are based on data from 193 clinical trials with complete subject and site information.
Source:  OIG analysis of FDA marketing applications approved in FY 2008.
Fifty-seven percent of subjects participating in clinical trials supporting 
marketing applications for drugs were enrolled at foreign sites.  These 
sites accounted for 55 percent of all trial sites in marketing applications 
for drugs.  The average number of subjects per trial site was similar for 
foreign and domestic sites:  nine at foreign sites and eight at domestic 
sites. 
Eighty-seven percent of subjects who participated in clinical trials 
supporting marketing applications for biologics were enrolled at foreign 
sites.  These sites accounted for half of all trial sites in marketing 
applications for biologics.  The average number of subjects per site was 
much greater at foreign sites:  505 at foreign sites versus 75 at domestic 
sites.   
Marketing applications for biologics often contain extremely large 
clinical trials.  For example, 1 trial in Sweden enrolled almost       
83,000 subjects at 14 sites, with an average number of subjects per site 
of almost 6,000.  This trial partially explains the large difference in the 
number and percentage of foreign subjects in applications for biologics 
compared to drugs.   
Western Europe accounted for most foreign clinical trial subjects and sites 
Sponsors submitted marketing applications with over 200,000 subjects 
enrolled at over 6,500 foreign sites.  Within these applications, Western 
Europe accounted for 58 percent of subjects enrolled at foreign sites and 
60 percent of foreign sites.  Although Western Europe accounted for 
  OEI-01-08-00510  CHALLENGES TO FDAS ABILITY TO MONITOR AND INSPECT FOREIGN CLINICAL TRIALS  11    
   
F I N D I N G S  
most of the subjects enrolled at foreign sites, Central and South 
America also enrolled a significant number.  This region contained        
26 percent of all subjects enrolled at foreign trial sites, but it accounted 
for only 7 percent of foreign sites.  (See Graph 1 for details.  Also see 
Appendix B for regional definitions.) 
Graph 1:  Percentage of Foreign Clinical Trial Subjects and 
Sites by Region for FDA Marketing Applications Approved in    
FY 2008 
70%
60%
50%
40%
30%
20%
10%
0%
Western Eastern Asia North America Central and Africa and
Europe Europe (Non-U.S.) South America Middle East
Percentage of Subjects Percentage of Sites
 
Note:  These numbers are based on data from 193 clinical trials with complete subject and site information. 
Source:  OIG analysis of FDA marketing applications approved in FY 2008. 
Central and South America had the highest average number of subjects 
per site compared to other foreign regions that enrolled clinical trial 
subjects.  The average number of subjects per site was more than three 
times as large for Central and South American countries as for Western 
European countries.  (See Graph 2 for more details.  Also see Appendix 
C for country-specific data.) 
 
 
 
 
 
 
  OEI-01-08-00510  CHALLENGES TO FDAS ABILITY TO MONITOR AND INSPECT FOREIGN CLINICAL TRIALS  12    
   
F I N D I N G S  
Graph 2:  Average Number of Subjects per Foreign Site 
Contrasted With Percentage of Foreign Subjects and Sites by 
Region for FDA Marketing Applications Approved in FY 2008 
     Average Number of Foreign     Percentage of Foreign  
Subjects per Site                        Subjects and Sites   
Central and South America 
North America (Non-U.S.) 
Africa and Middle East 
     Asia 
Eastern Europe 
Western Europe 
         
140 120 100 80 60 40 20 0 10% 20% 30% 40% 50% 60% 70%
Percentage of Foreign Subjects Percentage of Foreign Sites Average Number of Subjects per Site
Note:  These numbers are based on data from 193 clinical trials with complete subject and site information. 
Source:  OIG analysis of FDA marketing applications approved in FY 2008. 
Reliance on foreign clinical trials for FDA-regulated drugs and biologics 
appears likely to grow 
The percentage of foreign clinical investigators conducting clinical trials 
under INDs has more than doubled over the past decade.35  (See Graph 
3 for details.)  Clinical trials may take several years to complete before 
they appear in a marketing application.  Therefore, the increase in 
foreign clinical investigators conducting trials under INDs will not lead 
to an immediate increase in the use of foreign clinical trial data.  
Rather, this increase in foreign clinical investigators suggests a possible 
increase in foreign clinical trial data in future marketing applications.  
 
 
 
 
 
35 Only CDER tracks the number of foreign clinical investigators who are conducting 
research under INDs.    
  OEI-01-08-00510  CHALLENGES TO FDAS ABILITY TO MONITOR AND INSPECT FOREIGN CLINICAL TRIALS  13    
   
FFF III NNN DDD III NNN GGG SSS    
Graph 3:  Trend in Foreign Clinical Investigators as a 
Percentage of All Clinical Investigators Identified in INDs From 
1998 to 2008  
40.0%
s
or 35.0%
at
g
esti 30.0%
v
n
al I 25.0%
c
ni
n Cli 20.0%
g
ei
or 15.0%
F
of 
e  10.0%
g
a
nt
ce 5.0%
er
P
0.0%
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Year
Source:  OIG analysis of FDAs Bioresearch Monitoring Information System data from 1998 through 2008. 
FDA reviewers indicated the trend is likely to continue.  Twelve of 
eighteen medical reviewers who commented on trends noted that 
sponsors use of foreign data is increasing.  Reviewers cited Western and 
Eastern Europe, Central and South America, and China and India as 
regions or countries in which sponsors are conducting more clinical 
trials.  FDA reviewers expect more clinical trials from these regions or 
countries to support marketing applications in the coming years.  
 
FDA inspected clinical investigators at less than      Clinical trial site inspections are 
1 percent of foreign sites  an important part of FDAs 
oversight of clinical trials, both 
foreign and domestic.  The agency uses them to verify the quality and 
integrity of clinical trial data and to ensure that subjects were 
protected.  However, inspections are not the only oversight mechanism 
available.  FDA also reviews study protocols during the IND phase.  In 
addition, regulatory authorities in other countries sometimes conduct 
inspections, although the results of these inspections are not necessarily 
  OEI-01-08-00510  CHALLENGES TO FDAS ABILITY TO MONITOR AND INSPECT FOREIGN CLINICAL TRIALS  14    
   
F I N D I N G S  
shared with FDA.  However, according to FDA, the possibility of an 
inspection helps keep involved parties aware of their responsibilities.36   
FDA inspected clinical investigators at few clinical trial sites overall 
FDA inspected clinical investigators at 1.2 percent of clinical trial sites 
for drug- and biologic-marketing applications approved in FY 2008.37  
FDA inspected investigators at 0.7 percent of foreign clinical trial sites 
compared to 1.9 percent of domestic clinical trial sites.  (See Table 3 for 
more details and Appendix D for additional information.)   
Table 3:  Number and Percentage of Clinical Investigator 
Inspections at Domestic and Foreign Sites for FDA Marketing 
Applications Approved in FY 2008 
Number of  Percentage of Sites 
Site Location Number of Sites
Inspections Inspected
Domestic 5,459 102 1.9%
Foreign 6,485 45 0.7%
     Overall Total 11,944 147 1.2%
Note:  These numbers are based on data from 193 clinical trials with complete subject and site information.
Source:  OIG analysis of FDA marketing applications approved in FY 2008.
FDA inspected clinical investigators at trial sites in 20 of the                
72 countries identified in our review.  For the clinical trials in our 
population, of the almost 12,000 clinical trial sites, 16 percent were 
located in the 52 countries in which FDA conducted no inspections.  Of 
the almost 300,000 subjects, 21 percent were located in these countries.  
Of note, some of the countries in which FDA conducted no inspections 
had clinical trials that enrolled a large number of subjects.  (See Table 4 
for details.)  For example, Peru had the fourth largest subject 
enrollment in our review, yet FDA inspected no trials there for 
marketing applications in our population. 
 
 
36 OIG, The Food and Drug Administrations Oversight of Clinical Trials  
(OEI-01-06-00160), September 2007, p. 32. 
37 This percentage is similar to that presented in the September 2007 OIG report entitled 
The Food and Drug Administrations Oversight of Clinical Trials.  That report estimated 
that FDA inspected about 1 percent of clinical trial sites from FYs 20002005.  This 
estimate was based on all clinical trial sites, not just those used to support approved 
marketing applications, and included all inspection types.  
  OEI-01-08-00510  CHALLENGES TO FDAS ABILITY TO MONITOR AND INSPECT FOREIGN CLINICAL TRIALS  15    
   
 F   I N D I N G S  
TTaabbllee  44::    CCoouunnttrriieess  WWiitthh  aa  LLaarrggee  NNuummbbeerr  ooff  SSuubbjjeeccttss  EEnnrroolllleedd  iinn  
CClliinniiccaall  TTrriiaallss  TThhaatt  WWeerree  NNoott  IInnssppeecctteedd  ffoorr  FFDDAA  MMaarrkkeettiinngg  
AApppplliiccaattiioonnss  AApppprroovveedd  iinn  FFYY  22000088  
Country Number of Subjects
Peru 13,628
Colombia 5,480
Chile 4,949
Panama 4,310
Venezuela 4,258
Nicaragua 4,057
Dominican Republic 4,056
Denmark 3,089
Norway 2,513
Poland 2,306
     Total 48,646
Note:  These numbers are based on data from 193 clinical trials with complete subject and site information.
Source:  OIG analysis of FDA marketing applications approved in FY 2008.
FFDDAA  iinnssppeeccttiioonnss  ttaarrggeetteedd  cclliinniiccaall  iinnvveessttiiggaattoorrss  aatt  ddoommeessttiicc  ssiitteess  aanndd  
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tthhaatt  FFDDAA  wwaass  99  ttiimmeess  mmoorree  lliikkeellyy  ttoo  ccoonndduucctt  aann  iinnssppeeccttiioonn  ffoorr  aann  
oorriiggiinnaall  aapppplliiccaattiioonn  tthhaann  ffoorr  aann  eeffffiiccaaccyy  ssuupppplleemmeenntt  ffoorr  ddrruuggss  aanndd  
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iinnddiiccaatteedd  tthhee  mmaaiinn  rreeaassoonn  ffoorr  iinnssppeeccttiinngg  aa  ssppeecciiffiicc  cclliinniiccaall  iinnvveessttiiggaattoorr  
wwaass  aa  llaarrggee  nnuummbbeerr  ooff  eennrroolllleedd  ssuubbjjeeccttss  aatt  hhiiss  oorr  hheerr  ssiittee..    AAddddiittiioonnaall  
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hhaadd  aa  llaarrggee  eeffffeecctt  oonn  eeffffiiccaaccyy  rreessuullttss,,  hhaadd  ddaattaa  iinnccoonnssiisstteenncciieess,,  hhaadd  
ssttaattiissttiiccaall  oouuttlliieerrss,,  oorr  wwaass  ppaarrtt  ooff  aann  oorriiggiinnaall  aapppplliiccaattiioonn..    
AAddddiittiioonnaall  aannaallyyssiiss  aallssoo  iinnddiiccaatteedd  tthhaatt  FFDDAA  iinnssppeecctteedd  cclliinniiccaall  
iinnvveessttiiggaattoorrss  aatt  aallmmoosstt  tthhrreeee  ttiimmeess  aass  mmaannyy  ssiitteess  wwiitthh  llaarrggee  
eennrroollllmmeennttss  tthhaann  wwiitthh  ssmmaallll  eennrroollllmmeennttss..3388    ((SSeeee  TTaabbllee  55  ffoorr  ddeettaaiillss..))      
TThhiiss  ccoorrrreessppoonnddss  wwiitthh  rreevviieewweerrss  ssttaatteemmeennttss  tthhaatt  ssiitteess  wwiitthh  aa  llaarrggee  
nnuummbbeerr  ooff  ssuubbjjeeccttss  aarree  ttaarrggeetteedd  ffoorr  iinnssppeeccttiioonn..        
  
3388  LLaarrggeerr  eennrroollllmmeennttss  iiss  ddeeffiinneedd  aass  aavveerraaggee  nnuummbbeerr  ooff  ssuubbjjeeccttss  ppeerr  ssiittee  ggrreeaatteerr  tthhaann  oorr  
equal to the median, 7. 
  OEI-01-08-00510  CHALLENGES TO FDAS ABILITY TO MONITOR AND INSPECT FOREIGN CLINICAL TRIALS  16   
  
   
FF II NN DD II NN GG SS   
Table 5:  Inspections Conducted at Clinical Trial Sites With 
Larger and Smaller Enrollments for FDA Marketing Applications 
Approved in FY 2008  
Average Number of Subjects Per Site Less  Average Number of Subjects Per Site Greater 
Than Seven Than or Equal to Seven
Application Type
Sites  Total  Percentage  Sites  Total  Percentage 
Inspected   Sites Inspected Inspected Sites Inspected
Original Application 19 224 8.5% 39 151 25.8%
Efficacy Supplement 4 534 0.7% 24 644 3.7%
     Total 23 758 3.0% 63 795 7.9%
Note:  Seven is the median number of subjects per site for all clinical trials in our population.
Note:  The number of sites and the number of inspections in Table 5 are different from those in Table 3.  The number of sites in Table 3 is based on the 
193 clinical trials with complete subject and site information, and the number of inspections is based on clinical investigator inspections for these clinical 
trials.  The number of sites in Table 5 is based on a count of the countries in which trials were conducted to support each application, and the number of 
inspections is based on whether an inspection occurred in these countries.
Source:  OIG analysis of FDA marketing applications approved in FY 2008 and associated clinical inspections.
 
 
Challenges to conducting foreign inspections 
 
and data limitations inhibit FDAs ability to 
 
monitor foreign clinical trials 
 
FDA is unaware of some ongoing, early-phase foreign clinical trials  
If a sponsor has not submitted an IND or consulted with FDA in some 
other way about its foreign clinical trials, FDA has no way of knowing 
whether and where clinical trials are taking place.  Current regulations 
allow sponsors to submit data from these trials in support of future 
INDs or marketing applications.  Several medical reviewers reported 
that sponsors are increasingly conducting early-phase clinical trials 
outside the United States without INDs.  Because it takes several years 
for sponsors to complete all the clinical trials needed to support safety 
and efficacy, FDA will be unable to determine the extent of this trend 
until sponsors submit clinical trial results in their marketing 
applications several years from the start of the trials. 
Early-phase trials may pose more risk for subjects because the drugs or 
biologics have not been tested widely in humans and because they are 
being tested in an otherwise healthy population, the members of which 
have nothing to gain therapeutically.  If FDA was aware of early-phase 
  OEI-01-08-00510  CHALLENGES TO FDAS ABILITY TO MONITOR AND INSPECT FOREIGN CLINICAL TRIALS  17    
   
F I N D I N G S  
trials through an IND, it could potentially conduct inspections to ensure 
that all parties comply with applicable regulations and that subjects are 
protected.  However, without an IND, FDA is unaware that these trials 
are occurring and has no authority to oversee them.39     
Logistical challenges complicate foreign inspections   
FDA officials reported on a variety of logistical challenges FDA faces 
when inspecting clinical investigators at foreign sites.  According to 
these officials, inspectors are generally allowed 1 week, including travel 
time, to conduct these inspections.  FDA is unable to easily extend the 
inspections if significant compliance issues or other problems arise.  
Officials also reported that obtaining work visas and translators are 
obstacles to conducting foreign inspections.  Lastly, inspections are 
expensive and may not always be cost effective.  One FDA official told 
us that as sponsors conduct multisite trials at increasingly more sites, 
fewer subjects are enrolled at any one site.  With inspections costing 
about $40,000 each and the additional logistical challenges of 
conducting inspections at foreign sites, it may be more difficult for FDA 
to justify a foreign inspection.40 
FDA is taking steps to maximize its resources for inspecting foreign 
clinical trials.  The agency is piloting a computer-based tool (hereinafter 
referred to as site selection tool) to select inspection sites based on risk 
factors unique to a particular clinical trial.  Further, FDA recently 
announced an initiative with its European counterpart in which both 
agencies will share information concerning the planning of and results 
from Good Clinical Practice inspections.  Both initiatives could enable 
FDA to more efficiently target its resources for riskier foreign clinical 
trials. 
Sponsors submitted clinical trial information in a nonstandard format  
FDA recommends that sponsors follow Good Clinical Practice guidelines 
for submitting clinical trial study reports, in addition to requiring that 
sponsors submit the complete raw data sets of all clinical trials.  These 
guidelines recommend that sponsors submit trial data displayed by 
 
39 FDA may become aware of a foreign clinical trial not conducted under an IND if the 
sponsor requests a meeting before filing a marketing application.  Sponsors sometimes use 
such a meeting to resolve questions and issues raised during the course of a clinical 
investigation.  See 21 CFR  312.47.   
40 A budget official from the Office of Regulatory Affairs provided the budgeted cost for 
inspections in FY 2008.  The inspection cost is about the same for domestic and foreign 
inspections.        
  OEI-01-08-00510  CHALLENGES TO FDAS ABILITY TO MONITOR AND INSPECT FOREIGN CLINICAL TRIALS  18    
   
FFF III NNN DDD III NNN GGG SSS    
clinical trial sites when the sites have enough subjects to make such an 
analysis valuable.41 
Despite the Good Clinical Practice guidelines, sponsors generally 
submitted clinical study reports in portable document formats, which 
FDA is unable to directly analyze.  Within these documents, the data 
are presented inconsistently, making it difficult to locate clinical trial 
information, particularly site locations and subject enrollment.  As a 
result, reviewers generally use the raw data submitted by the sponsors 
to analyze clinical trial results.  Although we did not evaluate raw data 
files, an FDA official told us these files could be as varied and time 
consuming to analyze as the clinical study reports.  In many cases, FDA 
staff contacted sponsors multiple times to request data in a format they 
could analyze.  The FDA official reported that nonstandard and missing 
data adversely affect FDAs ability to review marketing applications and 
meet timelines prescribed by the Prescription Drug User Fee Act of 
1992.42 
FDA is taking steps to address nonstandard data submissions.  The 
agency is currently piloting a data management system, which would 
potentially require sponsors to submit standardized clinical trial data.  
This data management system would enable medical reviewers to 
review safety and efficacy data more effectively.43 
FDA was unable to account for all clinical trial information  
FDA was unable to provide detailed clinical trial data for 29 of the     
129 applications within our review.  FDA was unable to locate any 
portion of 8 of these 29 applications.  All eight applications were paper.   
For the other 21 applications, FDA provided incomplete clinical study 
reports.  Four of these applications were paper and the rest were 
electronic.  In some cases, the sponsors failed to provide site locations 
and subject enrollment in the clinical study reports, and in other cases, 
appendixes that were supposed to contain the information were missing.   
 
 
 
41 European Medicines Agency, International Committee on Harmonization, Topic 3, 
Structure and Content of Clinical Study Reports, p. 22, July 1996. 
42 21 U.S.C.  301. 
43 OIG interview with an Office of Critical Path Programs official. 
  OEI-01-08-00510  CHALLENGES TO FDAS ABILITY TO MONITOR AND INSPECT FOREIGN CLINICAL TRIALS  19    
   
 R E C O M M E N D A T I O N S  
Sponsors relied heavily on data from foreign clinical trials to support 
their marketing applications for drugs and biologics approved in  
FY 2008.  The percentage of foreign clinical investigators conducting 
drug research under INDs has more than doubled over the past decade, 
and FDA reviewers indicated that the number of marketing applications 
supported by foreign clinical trials will likely continue to increase.   
Meanwhile, FDA inspected few clinical investigators at foreign sites.  
Our review identified shortcomings, such as data limitations and 
logistical challenges, that also inhibited FDAs ability to monitor foreign 
clinical trials effectively. 
FDA has taken several steps to address these vulnerabilities, such as 
developing a site selection tool and drafting industry guidance for 
standardized clinical trial data.  Our review shows that FDA should 
take additional steps to improve its system for overseeing foreign 
clinical trial data.  Toward that end, we recommend that: 
FDA should require standardized electronic clinical trial data and create an 
internal database  
Requiring sponsors to submit all necessary clinical trial data in a 
standardized electronic format would help ensure that reviewers had all 
information from sponsors to effectively review the data.  It would also 
enable FDA to create an internal database to systematically cull clinical 
trial information.  Standardized clinical trial data would also enable 
FDA to more effectively select sites for inspection and meet its review 
timelines.  FDAs data management system under development is a 
positive step to collecting standardized clinical trial data.    
An internal database would enable FDA to conduct trend analyses to 
determine where sponsors were conducting clinical trials as well as 
identify areas of risk, such as the number of adverse events at any 
specific site or the numbers of subjects enrolled at clinical trial sites 
with histories of noncompliance, more quickly.   
FDA should monitor trends in foreign clinical trials not conducted under 
INDs and, if necessary, take steps to encourage sponsors to file INDs  
As sponsors submit future marketing applications with the results of 
foreign clinical trials that were not conducted under INDs, FDA should 
assess whether enrolled subjects were at additional risk and whether 
clinical trial data collected were both accurate and reliable. 
Conducting a trial under an IND provides an additional layer of 
oversight.  An IND enables FDA to review the protocol before any 
  OEI-01-08-00510  CHALLENGES TO FDAS ABILITY TO MONITOR AND INSPECT FOREIGN CLINICAL TRIALS  20    
   
RR EE CC OO MM MM EE NN DD AA TT II OO NN SS   
subjects are enrolled in the trial.  An IND also gives FDA more 
opportunity to ensure data integrity through real-time inspections.    
FDA may require sponsors to change the protocol or may even prevent 
the trial from starting if it identifies concerns.  
Should FDA determine that clinical trials not conducted under INDs 
compromise the rights, safety, and well-being of subjects or the integrity 
of the data submitted by sponsors, it should consider taking steps to 
encourage sponsors to voluntarily consult with FDA on their clinical 
trial protocols or submit INDs to the agency.  FDA could also explore 
providing incentives to promote these, if it deems them appropriate.  
Such incentives may require FDA to seek new legislative authority.  
FDA should continue to explore ways to expand its oversight of foreign 
clinical trials 
As sponsors increase the number of foreign clinical trials in support of 
FDA marketing applications, the agencys current method of using 
inspections to ensure human subject protections and data validity is 
becoming increasingly strained.  To improve its oversight of foreign 
clinical trials, FDA could take the following additional actions:  
Continue to develop inspectional agreements with foreign regulatory bodies.  
By sharing past inspection details as well as future plans, FDA would 
be better able to maximize its resources allocated to inspections of 
foreign clinical trial sites.  FDAs recent agreement with the European 
Medicines Agency is a positive step for the agency to extend its 
oversight capability outside the United States.     
Inspect clinical trials in more countries.  FDA could target clinical trials in 
more countries, such as those in countries that the agency has not 
previously inspected or where Good Clinical Practice standards have 
only recently been adopted.   
We recognize that inspecting more foreign sites would require 
additional resources; however, doing so would communicate to sponsors, 
clinical investigators, and IRBs the importance of complying with FDA 
regulations.       
Look to new models of oversight.  FDA could explore other oversight 
models, such as a quality risk management approach, to oversee clinical 
trials.  Although not required to, FDA currently inspects clinical trials 
sites for almost all original applications.  A quality risk management 
approach could focus on identifying and analyzing risk factors unique to 
each investigational drug or biologic.  After assessing the degree of risk, 
  OEI-01-08-00510  CHALLENGES TO FDAS ABILITY TO MONITOR AND INSPECT FOREIGN CLINICAL TRIALS  21    
   
R E C O M M E N D A T I O N S  
FDA would then be able to determine the appropriate level of oversight.  
FDAs new site selection tool is a positive example of taking steps to 
utilize quality risk management principles. 
 
AGENCY COMMENTS AND OFFICE OF INSPECTOR GENERAL 
RESPONSE 
FDA agreed with all three of our recommendations.  It also stated that 
it has ongoing efforts or is developing new procedures to address each 
recommendation.   
To address our recommendation that it require standardized clinical 
trial data and create an internal database, FDA said that it will 
continue piloting its site selection tool, and, if the pilot is successful, 
expand its use of the tool within FDA.  The agency added that the data 
captured by the site selection tool represent a partial solution and that 
it is considering long-term solutions.   
FDA agreed with our second recommendation, that trends in clinical 
trials should be monitored to assess whether differences exist in data 
integrity and human subject protections between domestic and foreign 
clinical trial sites.  FDA said that it will continue to assess these trends 
through inspection data.  The agency added that it will explore whether 
tracking the number of applications with clinical trial data not collected 
under INDs is feasible, and if so, initiate such tracking.   
FDA agreed with our third recommendation and highlighted steps it is 
taking to expand its oversight of foreign clinical trials.  The agency 
stated that if these steps are successful, it plans to leverage its 
partnership with the European Medicines Agency to work with other 
regulatory bodies.  In addition, FDA highlighted its efforts to expand 
outreach and training in Good Clinical Practice concepts worldwide.     
Where appropriate, we made changes to the report based on FDAs 
technical comments.   
The full text of FDAs comments is provided in Appendix E. 
  OEI-01-08-00510  CHALLENGES TO FDAS ABILITY TO MONITOR AND INSPECT FOREIGN CLINICAL TRIALS  22    
   
 A P P E N D I X ~ A  
Detailed Methodology 
Scope  
We reviewed data from all New Molecular Entities, Biologic Licensing 
Applications, and efficacy supplements (hereinafter referred to 
collectively as marketing applications) approved in fiscal year (FY) 
2008.  We reviewed all marketing applications approved in                  
FY 2008 from two Food and Drug Administration (FDA) Centers:  the 
Center for Drug Evaluation and Research (CDER) and the Center for 
Biologics Evaluation and Research (CBER).   
Data Sources and Data Analyses 
We used five sources of data in our review:  approved FDA marketing 
applications and corresponding review documents; clinical investigator 
information from Investigational New Drug Applications (IND); FDA 
inspection documents; structured interviews; and FDA policies, 
procedures, and guidance documents. 
Approved FDA Marketing Applications and Corresponding Review Documents 
We requested from CDER and CBER a list of all marketing applications 
for drugs and biologics approved in FY 2008, indicating which 
marketing applications were supported by clinical trial data.  We 
received the list from CDER in March 2009 and from CBER in         
June 2009.   
CDERs list consisted of 169 marketing applications for drugs.  CDER 
reported that 114 of these marketing applications contained clinical 
trial data.   
CBERs list consisted of 15 marketing applications for biologics.  All of 
these marketing applications contained clinical trial data.   
We reviewed the 129 marketing applications reported to contain clinical 
trial data and corresponding review documents.  We used one of three 
FDA databases to locate the review documents for each approved 
marketing application:  the CDER Division File System, the Biologic 
Licensing Application Action Package Files, or the public online 
database.44   
For each marketing application in our population, we used the medical 
review to determine the pivotal clinical trials that supported the drugs 
 
44 Accessed online at http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/ on    
March 12, 2010. 
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efficacy and safety.  For New Molecular Entities and Biologic Licensing 
Applications, when the medical reviews did not specify which trials 
were pivotal, we instead determined which trials supported the entities 
efficacy and safety and considered them the pivotal trials.  For efficacy 
supplements, we reviewed all submitted clinical trials.  We recorded the 
pivotal trials in an Access database.    
We located the sponsors marketing applications in one of the following 
places:  Electronic Common Technical Document System, 
GlobalSummit, or Electronic or Paper Document Rooms.  We reviewed 
the sponsors marketing application packages for all pivotal clinical 
trials.  Our review of the Clinical Study Reports within the application 
packages provided information on the number of subjects, sites, and 
countries in which the trials were conducted for each pivotal trial.  We 
recorded all information in an Access database. 
  Approved marketing application calculations:  According to FDA, 
129 marketing applications contained clinical trial data.  We 
excluded eight marketing applications that lacked information on 
clinical trial locations.  This resulted in 121 marketing 
applications from which we calculated the percentage that 
contained foreign data.  Twenty-one additional marketing 
applications included only enough information to determine 
whether they contained foreign or domestic clinical trials.   
  Clinical trial calculations:  The 129 approved marketing 
applications had 252 clinical trials.  To avoid double counting, we 
excluded 32 trials that supported multiple marketing applications, 
leaving 220 clinical trials.  We excluded 27 clinical trials that 
lacked complete data on trial locations, sites, or subjects.  We used 
the resulting 193 complete clinical trials to calculate the number 
of sites, subjects, and regions.   
  Subject and site calculations:  We counted all randomized subjects 
for each of the pivotal trials in the original 129 marketing 
applications.  We counted each site that randomized subjects for 
each of the pivotal trials in our population.  
FDA Inspection Documents 
We obtained from CDERs Division of Scientific Investigations (DSI) 
and CBERs Division of Inspections and Surveillance (DIS) a list of all 
inspections conducted for the marketing applications approved in        
FY 2008 and their corresponding inspection files.  Based on the files 
provided by the Bioresearch Monitoring Programs at DSI and DIS, we 
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AA PP PP EE NN DD II XX ~~ AA   
determined the number of inspections conducted for the 129 approved 
marketing applications.  The files also provided insight into FDAs 
process for determining which sites to inspect, inspection locations, and 
the outcomes of these inspections.  We received the following: 
  DSI Data:  We received one spreadsheet in April 2009.  The 
spreadsheet contained 152 inspection records for marketing 
applications for drugs in our review.   
For 15 of these inspections, DSI records indicated that multiple 
clinical trial records were reviewed at 1 site.  To account for this, we 
added 21 records, bringing the total inspection records to 173. 
We eliminated all inspections classified as Withdrawn or 
Canceled.  We also eliminated inspections with clinical trial names 
that failed to match the clinical trials in our population.  We ended 
up with 134 CDER inspections. 
  DIS Data:  We received one spreadsheet in April 2009.  The file 
contained 27 inspection records for marketing applications for 
biologics; we did not eliminate any inspections because of their 
status classifications. 
Table A-1 shows the inspection information for our population. 
Table A-1:  FDA Inspection Types 
Percentage of 
Inspection Type Number of Inspections
Inspections
Clinical Investigator 147 91.30%
Clinical Research Organization 4 2.48%
Sponsor 10 6.21%
     Overall Total 161 100.00%
Source:  Office of Inspector General (OIG) analysis of FDA clinical inspections for applications approved in FY 2008.
  
  Inspection data at a site level:  DSI and DIS conducted              
161 inspections for the marketing applications in our population.  
We excluded 14 sponsor and contract research organization 
inspections that were not clinical investigator inspections, leaving 
147 clinical investigator inspections.   
We used a logistic multivariate regression model to predict the 
probability of FDA inspecting a clinical investigator at a domestic site 
as opposed to a foreign site for a specific clinical trial within an 
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application.45   Our regression model employed a dichotomous response 
variable that indicates whether FDA inspected a clinical investigator at 
the site.  We considered the following explanatory variables when 
building our model:  domestic versus foreign site, application type, 
review division, review class, presence of an IND, and average number 
of subjects per site.46  (See Table A-2 for more details.)  
Table A-2:  Regression Variables 
Variables Type of Variable Values of Variables
Response Variable:
Inspection Conducted Dichotomous 0=No, 1=Yes
Explanatory Variables:
Review Division Categorical CDER or CBER
Review Type Categorical Orphan, Priority, or Standard
Average Number of Subjects per Site Continuous Range=0.4-12,400
IND Dichotomous 0=No, 1=Yes
Application Type Dichotomous 1=Original Application, 2=Efficacy Supplement
Foreign or Domestic Country Dichotomous 0=Foreign, 1=Domestic
Source:  OIG analysis of FDA marketing applications approved in FY 2008 and associated clinical inspections.
We tested the significance of each explanatory variable using the Wald  
Chi-Square statistic at the  = 0.05 level.  We also used the Pearson  
Goodness-of-Fit statistic to evaluate the fit of the model as a whole. 
The most parsimonious model consisted only of foreign or domestic 
country and application type as explanatory variables.47  (See Table A-3 
for the statistics for the significant predictors in our regression model.) 
 
 
45 The denominator of our regression analysis is different from the denominator used to 
calculate the percentage of clinical trial sites inspected.  The number of clinical trial sites 
for the latter is 12,039, which is the total number of sites for each clinical trial.  The 
regression uses the total number of countries for a specific clinical trial within an 
application.  Further, clinical trials may be duplicated when they are used to support 
different applications.  The denominator of our regression was 1,632. 
46 Because of data limitations, we were not able to collect the number of subjects enrolled 
in each site, but were able to calculate the average number of subjects per site for each 
country. 
47 The model had a max-rescaled R-square value of 0.34. 
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Table A-3:  Regression Statistics for Significant Predictors 
Coefficient  Odds  95%-Confidence 
Explanatory Variable P-value
Estimate Ratio Interval
Domestic vs. Foreign Site 2.76 < 0.0001 15.87 9.6925.99
Original Application vs. Efficacy Supplement 2.15 < 0.0001 8.57 5.1914.13
Pearson Goodness-of-Fit Test P-value:  0.62*
* The Pearson Goodness-of-Fit tests large p-value indicates insufficient evidence for rejecting the null hypothesis that the 
model fits.
Source:  OIG analysis of FDA marketing applications approved in FY 2008 and associated clinical inspections.
We found that review division, review type, and IND did not have a 
significant role in predicting the likelihood of an inspection when 
modeled with foreign or domestic country, application type, and average 
number of subjects per site.   
We discovered an interaction between foreign or domestic country and 
average number of subjects per site and tested a model that included 
the interaction along with application type.  However, we were unable 
to produce estimates for that model with confidence because of small 
population sizes and ultimately chose to present the simpler model 
described above.  (See Table A-4 for the odds ratios from that model.)   
Table A-4:  Odds Ratios for Model With Interaction 
Explanatory Variable Odds Ratio 95%-Confidence Interval
Domestic, Avg. Subj. Per Site < 7 40.16 14.56110.75
Domestic, Avg. Subj. Per Site >= 7 10.96 5.9220.27
Original Application vs. Efficacy Supplement 9.64 5.7116.29
Source:  OIG analysis of FDA marketing applications approved in FY 2008 and associated clinical inspections.
Clinical Investigator Information From INDs 
We used the Bioresearch Monitoring Information System (BMIS) to 
identify clinical investigators, contract research organizations, and 
institutional review boards listed on INDs from 1998 to 2008.  BMIS 
identified a total of 878,419 clinical investigators, contract research 
organizations, and institutional review boards in this time period.  We 
eliminated all contract research organizations and institutional review 
boards, leaving 382,491 clinical investigators.  Using these data, we 
then calculated the percentage of foreign investigators. 
 
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Structured Interviews 
We interviewed 1 reviewer in each of FDAs 18 review divisions 
responsible for marketing applications in our population.  Most were 
team leaders, who oversaw a group of medical reviewers in their 
division.   
The interview questions focused on the processes and challenges, if any, 
when evaluating data from foreign clinical trials.  We developed and 
used a structured interview guide.  After concluding our first two 
interviews, we solicited comments from the medical reviewers about the 
interview guides content and clarity.  We incorporated feedback into 
the final interview guide used for the remaining 16 medical reviewers.  
We conducted the interviews in May and June of 2009.  At least two 
OIG staff participated in each telephone interview.   
To add context to our understanding, we also interviewed two senior 
FDA officials from DSI and DIS to discuss the processes for and their 
experiences with conducting foreign clinical trial inspections.  Again, we 
used a structured interview guide.  At least two OIG staff participated 
in each interview. 
FDA Policies, Procedures, and Guidance Documents 
We obtained and reviewed all relevant policies, procedures, and 
guidance documents issued by FDA for accepting marketing 
applications supported by foreign clinical trials.  
Data Analysis Software 
We used SAS Software for most of our data analyses. 
Limitations  
Our analysis of marketing applications was limited to 1 year of data.  
Therefore, we were unable to conduct a trend analysis of foreign data 
supporting marketing applications; instead we present a trend of 
clinical investigators named on CDERs INDs.  
Additionally, we did not verify the information provided by FDA, such 
as the number of applications approved and the number of inspections. 
Lastly, we were unable to collect information about the number of 
subjects at the site level, so we created a variable to represent the 
average number of subjects per site at the country level.  This is a 
limitation of the regression model, because the average number of 
subjects per site does not identify the largest sites in a country. 
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A   P P E N D I X ~~ BB   
RReeggiioonn  DDeeffiinniittiioonnss  
  
AAffrriiccaa  aanndd  MMiiddddllee  EEaasstt 
  Cyprus, Egypt, Israel, Lebanon, South Africa, Tunisia, Turkey  
Asia  
  Australia, China, Hong Kong, India, Indonesia, Japan, Malaysia, New Zealand, 
Philippines, Republic of Korea, Singapore, Taiwan, and Thailand 
Central and South America 
  Argentina, Brazil, Chile, Colombia, Costa Rica, Dominican Republic, Ecuador, 
Guatemala, Honduras, Nicaragua, Panama, Peru, Uruguay, Venezuela 
Eastern Europe 
  Belarus, Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Estonia, Georgia, 
Hungary, Latvia, Lithuania, Montenegro, Poland, Romania, Russia, Serbia, Slovakia, 
Slovenia, and Ukraine 
North America (Non-United States) 
  Canada and Mexico 
Western Europe 
  Austria, Belgium, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Italy, 
Netherlands, Norway, Portugal, Spain, Sweden, Switzerland, and United Kingdom 
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Subjects and Sites by Country for Marketing Applications Approved in 
Fiscal Year 2008 
 
Table C-1:  Country Breakdown for Drug-Marketing Applications 
Approved in Fiscal Year (FY) 2008 
Number of  Percentage of  Number of  Percentage of  Average Number of 
Trial Location
Subjects Subjects Sites Sites Subjects Per Site
Argentina 1,551 1.7% 113 1.0% 14
Australia 1,586 1.7% 228 2.0% 7
Austria 645 0.7% 71 0.6% 9
Belarus 18 0.0% 3 0.0% 6
Belgium 1,571 1.7% 206 1.8% 8
Bosnia and Herzegovina 3 0.0% 1 0.0% 3
Brazil 1,863 2.0% 187 1.7% 10
Bulgaria 507 0.5% 43 0.4% 12
Canada 3,294 3.5% 363 3.2% 9
Chile 454 0.5% 26 0.2% 17
China 424 0.5% 32 0.3% 13
Colombia 177 0.2% 20 0.2% 9
Costa Rica 1,436 1.5% 15 0.1% 96
Croatia 226 0.2% 24 0.2% 9
Cyprus 3 0.0% 1 0.0% 3
Czech Republic 670 0.7% 69 0.6% 10
Denmark 684 0.7% 83 0.7% 8
Ecuador 50 0.1% 4 0.0% 13
Egypt 17 0.0% 2 0.0% 9
Estonia 345 0.4% 27 0.2% 13
Finland 973 1.0% 74 0.7% 13
France 3,960 4.3% 560 5.0% 7
Georgia 1 0.0% 1 0.0% 1
Germany 7,086 7.6% 1,064 9.5% 7
Greece 538 0.6% 68 0.6% 8
Guatemala 138 0.1% 12 0.1% 12
Hong Kong 190 0.2% 18 0.2% 11
Hungary 930 1.0% 79 0.7% 12
Iceland 59 0.1% 8 0.1% 7
India 384 0.4% 49 0.4% 8
Indonesia 20 0.0% 3 0.0% 7
Ireland 209 0.2% 26 0.2% 8
Israel 720 0.8% 81 0.7% 9
Italy 2,910 3.1% 388 3.5% 8
Japan 481 0.5% 75 0.7% 6
continued on next page
 
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Table C-1:  Country Breakdown for Drug-Marketing Applications 
Approved in FY 2008 (Continued) 
Number of  Percentage of  Number of  Percentage of  Average Number of 
Trial Location
Subjects Subjects Sites Sites Subjects Per Site
Latvia 133 0.1% 11 0.1% 12
Lebanon 42 0.0% 4 0.0% 11
Lithuania 262 0.3% 19 0.2% 14
Malaysia 142 0.2% 23 0.2% 6
Mexico 892 1.0% 94 0.8% 9
Montenegro 8 0.0% 1 0.0% 8
Netherlands 1,248 1.3% 134 1.2% 9
New Zealand 365 0.4% 38 0.3% 10
Norway 682 0.7% 78 0.7% 9
Panama 249 0.3% 10 0.1% 25
Peru 234 0.3% 26 0.2% 9
Philippines 367 0.4% 23 0.2% 16
Poland 1,849 2.0% 194 1.7% 10
Portugal 371 0.4% 58 0.5% 6
Republic of Korea 409 0.4% 32 0.3% 13
Romania 286 0.3% 23 0.2% 12
Russia 1,226 1.3% 141 1.3% 9
Serbia 75 0.1% 7 0.1% 11
Singapore 170 0.2% 22 0.2% 8
Slovakia 348 0.4% 25 0.2% 14
Slovenia 141 0.2% 10 0.1% 14
South Africa 1,140 1.2% 130 1.2% 9
Spain 2,993 3.2% 378 3.4% 8
Sweden 818 0.9% 83 0.7% 10
Switzerland 262 0.3% 50 0.4% 5
Taiwan 721 0.8% 66 0.6% 11
Thailand 314 0.3% 40 0.4% 8
Tunisia 4 0.0% 2 0.0% 2
Turkey 278 0.3% 28 0.2% 10
Ukraine 69 0.1% 12 0.1% 6
United Kingdom 2,564 2.8% 337 3.0% 8
United States 40,039 43.1% 5,098 45.4% 8
Uruguay 27 0.0% 3 0.0% 9
Venezuela 8 0.0% 3 0.0% 3
Foreign Countries 52,820 56.9% 6,129 54.6% 9
United States 40,039 43.1% 5,098 45.4% 8
     All Countries 92,859 100.0% 11,227 100.0% 8
Note:  These numbers are based on data from 193 clinical trials with complete subject and site information.
Source:  Office of Inspector General (OIG) analysis of Food and Drug Administration (FDA) marketing applications.approved in FY 2008.
 
 
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Table C-2:  Country Breakdown for Biologic-Marketing 
Applications Approved in FY 2008
Number of  Percentage of  Number of  Percentage of  Average Number of 
Trial Location
Subjects Subjects Sites Sites Subjects Per Site
Argentina 4,686 2.3% 5 0.7% 937
Australia 143 0.1% 2 0.3% 72
Austria 115 0.1% 2 0.3% 58
Belgium 1 0.0% 1 0.1% 1
Brazil 5,747 2.8% 24 3.3% 239
Canada 2,138 1.0% 14 2.0% 153
Chile 4,495 2.2% 3 0.4% 1,498
Colombia 5,303 2.6% 10 1.4% 530
Czech Republic 590 0.3% 21 2.9% 28
Denmark 2,405 1.2% 12 1.7% 200
Dominican Republic 4,056 2.0% 1 0.1% 4,056
Finland 6,776 3.3% 33 4.6% 205
France 146 0.1% 21 2.9% 7
Germany 679 0.3% 35 4.9% 19
Honduras 4,195 2.0% 1 0.1% 4,195
Hong Kong 100 0.0% 1 0.1% 100
Hungary 13 0.0% 1 0.1% 13
Iceland 710 0.3% 1 0.1% 710
Israel 15 0.0% 3 0.4% 5
Italy 102 0.0% 11 1.5% 9
Mexico 14,078 6.8% 13 1.8% 1,083
New Zealand 170 0.1% 5 0.7% 34
Nicaragua 4,057 2.0% 1 0.1% 4,057
Norway 1,831 0.9% 24 3.3% 76
Panama 4,061 2.0% 1 0.1% 4,061
Peru 13,394 6.5% 5 0.7% 2,679
Poland 457 0.2% 14 2.0% 33
Portugal 9 0.0% 2 0.3% 5
Romania 2 0.0% 1 0.1% 2
Russia 93 0.0% 3 0.4% 31
Serbia 11 0.0% 1 0.1% 11
Singapore 181 0.1% 1 0.1% 181
Spain 435 0.2% 19 2.6% 23
Sweden 93,599 45.3% 47 6.6% 1,991
Taiwan 52 0.0% 2 0.3% 26
Thailand 160 0.1% 1 0.1% 160
United Kingdom 457 0.2% 13 1.8% 35
United States 27,130 13.1% 361 50.3% 75
Venezuela 4,250 2.1% 1 0.1% 4,250
Foreign Countries 179,712 86.9% 356 49.7% 505
United States 27,130 13.1% 361 50.3% 75
     All Countries 206,842 100.0% 717 100.0% 288
Note:  These numbers are based on data from 193 clinical trials with complete subject and site information.
Source:  OIG analysis of FDA marketing applications approved in FY 2008.
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 A P P E N D I X ~ D  
Number of Subjects and Number of Inspections per Country for Marketing 
Applications Approved in Fiscal Year 2008 
Figure D-1:  Map of Subjects and Inspections per Country
S
o L
u e
rc g
e:  Office of Inspector General analy Greater than 10,000 Subjects 5,000-10,000 Subjects 1,000-5,000 Subjects500-1,000 Subjects 100-500 Subjects1-100 Subjects end 1 inspection 1 inspection 102 inspections 1 inspection
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rug A 4 ins
dministration marketing applications ap pections 2 inspections5 inspections 2 inspections1 inspection 2 inspections 1 inspection 3 inspections 3 inspections 2 inspections 5 inspections 6 inspections 1 inspection 3 inspection
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. 
  OEI-01-08-00510  CHALLENGES TO FDAS ABILITY TO MONITOR AND INSPECT FOREIGN CLINICAL TRIALS  33  x 
A  P  PEN  0  E 

Agency Comments 
DEPARTMENT OF HEALTH & HUMAN SERVICES 
Food and Drug Administration 
Silver Spring, MD 20993 
DATE:  April 23,  2010 
TO:  inspector General 
FROM:  Principal Deputy Commissioner ofFood and Drugs 
SUBJECT:  FDA's Response to OIG's Draft Report Entitled, Challmges 10 FDA '.\' 
Ahilily 10 Monilor and fnspecl Foreign Clinical Trials 
FDA is providing the attached response to the Office of Inspector General's Draft Report 
entitled, Challenges to FDA's Ability 10 Monitor /ntl ImpecI Foreign Clinical Trials 
(OEI-Of -08-{)051 0). 
FDA appreciates the opportunity to review and comment on this repOJ1. 
Joshua M. Sharfstein, M,D. 

Principal Deputy Commissioner of Food and Drugs 

Attachment 
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 A P AP EC NK DN IOX W~ LE E  D G M E N T S  
 
This report was prepared under the direction of Joyce M. Greenleaf, 
Regional Inspector General for Evaluation and Inspections in the 
Boston regional office, and Russell W. Hereford, Deputy Regional 
Inspector General.   
Chris Galvin served as the team leader for this study.  Other principal 
Office of Evaluation and Inspections staff from the Boston regional 
office who contributed to the report include Carolyn Kenline and Rose 
Lichtenstein; other central office staff who contributed include Talisha 
Searcy, Megan Ruhnke, and Heather Barton. 
  OEI-01-08-00510  CHALLENGES TO FDAS ABILITY TO MONITOR AND INSPECT FOREIGN CLINICAL TRIALS  43    
 
 
Office of Inspector General 
http://oig.hhs.gov 
 
The mission of the Office of Inspector General (OIG), as mandated by Public Law 95-452, as 
amended, is to protect the integrity of the Department of Health and Human Services 
(HHS) programs, as well as the health and welfare of beneficiaries served by those 
programs.  This statutory mission is carried out through a nationwide network of audits, 
investigations, and inspections conducted by the following operating components: 
Office of Audit Services 
The Office of Audit Services (OAS) provides auditing services for HHS, either by conducting 
audits with its own audit resources or by overseeing audit work done by others.  Audits 
examine the performance of HHS programs and/or its grantees and contractors in carrying 
out their respective responsibilities and are intended to provide independent assessments of 
HHS programs and operations.  These assessments help reduce waste, abuse, and 
mismanagement and promote economy and efficiency throughout HHS. 
Office of Evaluation and Inspections 
The Office of Evaluation and Inspections (OEI) conducts national evaluations to provide 
HHS, Congress, and the public with timely, useful, and reliable information on significant 
issues.  These evaluations focus on preventing fraud, waste, or abuse and promoting 
economy, efficiency, and effectiveness of departmental programs.  To promote impact, OEI 
reports also present practical recommendations for improving program operations.  
Office of Investigations 
The Office of Investigations (OI) conducts criminal, civil, and administrative investigations 
of fraud and misconduct related to HHS programs, operations, and beneficiaries.  With 
investigators working in all 50 States and the District of Columbia, OI utilizes its resources 
by actively coordinating with the Department of Justice and other Federal, State, and local 
law enforcement authorities.  The investigative efforts of OI often lead to criminal 
convictions, administrative sanctions, and/or civil monetary penalties. 
Office of Counsel to the Inspector General 
The Office of Counsel to the Inspector General (OCIG) provides general legal services to 
OIG, rendering advice and opinions on HHS programs and operations and providing all 
legal support for OIGs internal operations.  OCIG represents OIG in all civil and 
administrative fraud and abuse cases involving HHS programs, including False Claims Act, 
program exclusion, and civil monetary penalty cases.  In connection with these cases, OCIG 
also negotiates and monitors corporate integrity agreements.  OCIG renders advisory 
opinions, issues compliance program guidance, publishes fraud alerts, and provides other 
guidance to the health care industry concerning the anti-kickback statute and other OIG 
enforcement authorities.