Department of Health and Human Services

OFFICE OF 

INSPECTOR GENERAL 

 

 CHALLENGES TO FDA’S ABILITY TO 

MONITOR AND INSPECT FOREIGN 

CLINICAL TRIALS 

 

 

Daniel R. Levinson 

Inspector General 

June 2010 

OEI-01-08-00510 
 

 

INTRODUCTION EXECUTIVE S UMMARY 

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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E XECUTIVE SUMMARY 

Investigational New Drug Application (IND) clinical trials; and FDA 

policies, procedures, and guidance documents. Using these data sources 

we calculated the number of foreign trials, sites, subjects, and 

inspections. 

FINDINGS FINDINGS 

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 FDA’s 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 

FDA’s 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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EXECUTIVE SUMMARY 

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. FDA’s 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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EXECUTIVE SUMMARY 

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 FDA’s 

technical comments.
 

 TABLE OF CONTENTS 

EXECUTIVE SUMMARY .....................................i

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 

FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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 FDA’s ability to monitor foreign clinical trials. . . . . . . . . . 17 

RECOMMENDATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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 

ACKNOWLEDGMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
 

 

 INTRODUCTION 

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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INTRODUCTION 

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 

2 

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 

246–257. 

10 Cairns, C., et al., op. cit., pp. 818–819. 

11 Ibid, p. 819. 

12 21 CFR § 312.21. 

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INTRODUCTION 

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. FDA’s 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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INTRODUCTION 

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 investigator’s 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 

Monitoring—Clinical Investigators and Sponsor-Investigators” (December 8, 2008). 

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INTRODUCTION 

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 FDA’s Center for Drug Evaluation and Research 

(CDER). To market biologics in the United States, sponsors must 

submit marketing applications to FDA’s 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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INTRODUCTION 

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 

drug’s labeling, such as the indication, dosing, or route of 

administration.30 

Regardless of whether a marketing application contains data from 

foreign sites, FDA’s 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 

6 

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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INTRODUCTION 

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 FDA’s 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 FDA’s 

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 Administration’s Oversight of Clinical Trials 

(OEI-01-06-00160), September 2007. 

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INTRODUCTION 

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. 

CDER’s list consisted of 169 marketing applications for drugs. CDER 

reported that 114 of these marketing applications contained clinical 

trial data. 

CBER’s 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 FDA’s 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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INTRODUCTION 

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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In FY 2008, sponsors relied heavily on data from 

foreign clinical trials to support their marketing 

applications for drugs and biologics 

 FINDINGS 

In FY 2008, FDA approved 

129 marketing applications 

containing clinical trial data: 

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 

Marketing Applications Drugs Biologics Drugs and 

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.) 

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FINDINGS 

Table 2: Number and Percentage of Foreign Subjects and Sites 

From Clinical Trials Supporting Drug- and Biologic-Marketing 

Applications Approved in FY 2008 

Drugs Biologics Drugs and 

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 

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FINDINGS 

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

0%

10%

20%

30%

40%

50%

60%

70%

Western

Europe

Eastern

Europe

Asia North America

(Non-U.S.)

Central and

South America

Africa and

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.) 

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FINDINGS 

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 

Central and South America

North America (Non-U.S.)

Africa and Middle East

 Asia

Eastern Europe

Western Europe

 Average Number of Foreign Percentage of Foreign 

Subjects per Site Subjects and Sites 

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. 

13 

35 Only CDER tracks the number of foreign clinical investigators who are conducting 

research under INDs. 

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FINDINGS 

Graph 3: Trend in Foreign Clinical Investigators as a 

Percentage of All Clinical Investigators Identified in INDs From 

1998 to 2008 

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

35.0%

40.0%

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Year

Percentage of Foreign Clinical Investigators

Source: OIG analysis of FDA’s 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. 

Clinical trial site inspections are 

an important part of FDA’s 

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 

FDA inspected clinical investigators at less than 

1 percent of foreign sites 

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FINDINGS 

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 

Site Location Number of Sites Number of 

Inspections

Percentage of Sites 

Inspected

Domestic 5,459 102 1.9%

Foreign 6,485 45 0.7%

 Overall Total 11,944 147 1.2%

Source: OIG analysis of FDA marketing applications approved in FY 2008.

Note: These numbers are based on data from 193 clinical trials with complete subject and site information.

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. 

15 

36 OIG, The Food and Drug Administration’s 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 Administration’s Oversight of Clinical Trials. That report estimated 

that FDA inspected about 1 percent of clinical trial sites from FYs 2000–2005. This 

estimate was based on all clinical trial sites, not just those used to support approved 

marketing applications, and included all inspection types. 

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 F INDINGS 

Table 4: Countries With a Large Number of Subjects Enrolled in 

Clinical Trials That Were Not Inspected for FDA Marketing 

Applications Approved in FY 2008 

Table 4: Countries With a Large Number of Subjects Enrolled in 

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

Source: OIG analysis of FDA marketing applications approved in FY 2008.

Note: These numbers are based on data from 193 clinical trials with complete subject and site information.

FDA inspections targeted clinical investigators at domestic sites and 

original applications 

FDA inspections targeted clinical investigators at domestic sites and 

Our regression analysis indicated that FDA was 16 times more likely to 

inspect a clinical investigator at a domestic site than a foreign site and 

that FDA was 9 times more likely to conduct an inspection for an 

original application than for an efficacy supplement for drugs and 

biologics. (See Appendix A for details.) 

Our regression analysis indicated that FDA was 16 times more likely to 

inspect a clinical investigator at a domestic site than a foreign site and 

that FDA was 9 times more likely to conduct an inspection for an 

original application than for an efficacy supplement for drugs and 

biologics. (See Appendix A for details.) 

However, inspection files and interviews with medical reviewers 

indicated the main reason for inspecting a specific clinical investigator 

was a large number of enrolled subjects at his or her site. Additional 

reasons for choosing to inspect an investigator included whether the site 

had a large effect on efficacy results, had data inconsistencies, had 

statistical outliers, or was part of an original application. 

However, inspection files and interviews with medical reviewers 

indicated the main reason for inspecting a specific clinical investigator 

was a large number of enrolled subjects at his or her site. Additional 

reasons for choosing to inspect an investigator included whether the site 

had a large effect on efficacy results, had data inconsistencies, had 

statistical outliers, or was part of an original application. 

Additional analysis also indicated that FDA inspected clinical 

investigators at almost three times as many sites with large 

enrollments than with small enrollments.38 (See Table 5 for details.) 

This corresponds with reviewers’ statements that sites with a large 

number of subjects are targeted for inspection. 

Additional analysis also indicated that FDA inspected clinical 

investigators at almost three times as many sites with large 

enrollments than with small enrollments.38 (See Table 5 for details.) 

This corresponds with reviewers’ statements that sites with a large 

number of subjects are targeted for inspection. 

16 

38 “Larger enrollments” is defined as average number of subjects per site greater than or 

equal to the median, 7. 

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FINDINGS 

Table 5: Inspections Conducted at Clinical Trial Sites With 

Larger and Smaller Enrollments for FDA Marketing Applications 

Approved in FY 2008 

Sites 

Inspected 

Total 

Sites

Percentage 

Inspected

Sites 

Inspected

Total 

Sites

Percentage 

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%

Source: OIG analysis of FDA marketing applications approved in FY 2008 and associated clinical inspections.

Note: Seven is the median number of subjects per site for all clinical trials in our population.

Average Number of Subjects Per Site Less 

Than Seven

Average Number of Subjects Per Site Greater 

Than or Equal to Seven

Application Type

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.

Challenges to conducting foreign inspections 

and data limitations inhibit FDA’s 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 

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FINDINGS 

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 

18 

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. 

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FINDINGS 

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 FDA’s 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. 

19 

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. 

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 RECOMMENDATIONS 

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 FDA’s 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. FDA’s 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 

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RECOMMENDATIONS 

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 agency’s 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. FDA’s 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, 

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RECOMMENDATIONS 

FDA would then be able to determine the appropriate level of oversight. 

FDA’s 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 FDA’s 

technical comments. 

The full text of FDA’s comments is provided in Appendix E. 

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 APPENDIX~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. 

CDER’s list consisted of 169 marketing applications for drugs. CDER 

reported that 114 of these marketing applications contained clinical 

trial data. 

CBER’s 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 drug’s 

44 Accessed online at http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/ on 

March 12, 2010. 

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APPENDIX~A 

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 CDER’s Division of Scientific Investigations (DSI) 

and CBER’s 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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APPENDIX~A 

determined the number of inspections conducted for the 129 approved 

marketing applications. The files also provided insight into FDA’s 

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 

Inspection Type Number of Inspections Percentage of 

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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APPENDIX~A 

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 α = 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.) 

26 

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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APPENDIX~A 

Table A-3: Regression Statistics for Significant Predictors 

Explanatory Variable Coefficient 

Estimate P-value Odds Ratio

95%-Confidence 

Interval

Domestic vs. Foreign Site 2.76 < 0.0001 15.87 9.69–25.99

Original Application vs. Efficacy Supplement 2.15 < 0.0001 8.57 5.19–14.13

Pearson Goodness-of-Fit Test P-value: 0.62*

Source: OIG analysis of FDA marketing applications approved in FY 2008 and associated clinical inspections.

* The Pearson Goodness-of-Fit test’s large p-value indicates insufficient evidence for rejecting the null hypothesis that the 

model fits.

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 14.56–110.75

Domestic, Avg. Subj. Per Site >= 7 10.96 5.92–20.27

Original Application vs. Efficacy Supplement 9.64 5.71–16.29

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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APPENDIX~A 

Structured Interviews

We interviewed 1 reviewer in each of FDA’s 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 guide’s 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 CDER’s 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 ~ B 

APPENDIX~B 

Region Definitions 

Africa and Middle East Africa and Middle East

 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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 APPENDIX~C 

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 

Trial Location Number of 

Subjects

Percentage of 

Subjects

Number of 

Sites

Percentage of 

Sites

Average Number of 

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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APPENDIX~C 

Table C-1: Country Breakdown for Drug-Marketing Applications 

Approved in FY 2008 (Continued) 

Trial Location Number of 

Subjects

Percentage of 

Subjects

Number of 

Sites

Percentage of 

Sites

Average Number of 

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

Source: Office of Inspector General (OIG) analysis of Food and Drug Administration (FDA) marketing applications.approved in FY 2008.

Note: These numbers are based on data from 193 clinical trials with complete subject and site information.

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APPENDIX~C 

Table C-2: Country Breakdown for Biologic-Marketing 

Applications Approved in FY 2008

Trial Location Number of 

Subjects

Percentage of 

Subjects

Number of 

Sites

Percentage of 

Sites

Average Number of 

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

Source: OIG analysis of FDA marketing applications approved in FY 2008.

Note: These numbers are based on data from 193 clinical trials with complete subject and site information.

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33 

 APPENDIX~D 

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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

Source: Office of Inspector General analysis of Food and Drug Administration marketing applications approved in fiscal year 2008 and associated clinical trial inspections. 

5,000-10,000 Subjects1,000-5,000 Subjects500-1,000 Subjects100-500 Subjects1-100 Subjects

Legend

Greater than 10,000 Subjects

1 inspection

4 inspections

2 inspections

5 inspections

5 inspections

1 inspection

1 inspection

3 inspections

1 inspection

3 inspections

1 inspection

3 inspections

2 inspections

1 inspection

2 inspections

1 inspection

1 inspection

2 inspections

102 inspections

6 inspections
A P PEN 0 x E 


Agency Comments 

DEPARTMENT OF HEALTH & HUMAN SERVICES 

Food and Drug Administration 

Silver Spring, MD 20993 

DATE: 

TO: 

FROM: 

SUBJECT: 

April 23, 2010 

inspector General 

Principal Deputy Commissioner ofFood and Drugs 

FDA's Response to OIG's Draft Report Entitled, Chall

Ahilily 10 Monilor and fnspecl Foreign Clinical Trials 

mges 10 FDA '.\' 

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 

OEI·01·0e·00510 CHALLENGES TO FDA's ABILITY To MONITOR AND INSPECT FOREIGN CLINICAL TRIALS 34 
 

 

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APPENDIX~E 
 

 

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APPENDIX~E 
 

 

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APPENDIX~E 
 

 

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APPENDIX~E 
 

 

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APPENDIX~E 
 

 

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APPENDIX~E 
 

 

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APPENDIX~E 
 

 

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APPENDIX~E 
 

 

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APPENDIX~E ACKNOWLEDGMENTS 

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. 
 

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 OIG’s 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. 

Office of Counsel to the Inspector General 

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 Investigations 

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 Evaluation and Inspections 

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 Audit Services 

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: