Department of Health and Human Services 

OFFICE OF 

INSPECTOR GENERAL 

JANET REHNQUIST 

Inspector General 

SEPTEMBER 2001 

OEI-01-00-00190 

The Globalization of Clinical Trials 

A Growing Challenge in Protecting Human Subjects 
OFFICE OF INSPECTOR GENERAL 

The mission of the Office of Inspector General (OIG), as mandated by Public Law 95-452, is to 

protect the integrity of the Department of Health and Human Services programs as well as the health 

and welfare of beneficiaries served by them. This statutory mission is carried out through a nationwide 

program of audits, investigations, inspections, sanctions, and fraud alerts. The Inspector General 

informs the Secretary of program and management problems and recommends legislative, regulatory, 

and operational approaches to correct them. 

Office of Evaluation and Inspections 

The Office of Evaluation and Inspections (OEI) is one of several components of the Office of Inspector 

General. It conducts short-term management and program evaluations (called inspections) that focus 

on issues of concern to the Department, the Congress, and the public. The inspection reports provide 

findings and recommendations on the efficiency, vulnerability, and effectiveness of departmental 

programs. 

OEI's Boston regional office prepared this report under the direction of Mark R. Yessian, Ph.D., 

Regional Inspector General and Joyce M. Greenleaf, M.B.A., Assistant Regional Inspector General. 

Principal OEI staff included: 

BOSTON HEADQUARTERS 

Steven P. Keenan, Program Analyst Genevieve Nowolinski, Program Specialist

Aimee K. Golbitz, Program Analyst

China D. Eng, Program Analyst

Nancy L. London, Program Analyst

To obtain copies of this report, please call the Boston Regional Office at 617-565-1050. 

Reports are also available on the World Wide Web at our home page address: 

http://oig.hhs.gov/oei 
EXECUTIVE SUMMARY 

PURPOSE 

To document the growth of non-U.S. clinical drug trials contributing data to New Drug 

Applications for Food and Drug Administration (FDA) approval, and to assess FDA’s capacity 

to assure human subject protections in these trials. 

BACKGROUND 

In our June 2000 report, Recruiting Human Subjects: Pressures in Industry-Sponsored 

Clinical Research (OEI-01-97-00195), we drew attention to the fact that clinical drug trials 

conducted outside the U.S. can be an important source of data in FDA’s determination of the 

safety and efficacy of new drugs. Pharmaceutical companies submit trial data to FDA as part 

of a New Drug Application, the application for FDA approval to market a drug in the U.S. 

Although the majority of foreign clinical drug research that is submitted in New Drug 

Applications is still conducted in countries with a history of clinical drug research, increasingly, 

countries with less experience are emerging as desirable locations for sponsors to conduct this 

research. 

In conducting this inquiry, we analyzed two FDA databases: one of clinical investigators 

conducting drug research and one of clinical investigators conducting drug research who have 

been inspected by FDA. We interviewed FDA officials and industry representatives. We also 

reviewed pertinent FDA documents and related literature. 

FINDINGS 

FDA oversees significantly more foreign research than it did 10 years ago. 

The number of foreign clinical investigators conducting drug research under Investigational New 

Drug Applications increased 16-fold in the past decade. In 1990, 271 of these foreign clinical 

investigators were in FDA’s database. By 1999 the number grew to 4,458. FDA inspections 

of foreign clinical investigators conducting drug research have also increased dramatically, from 

just 22 in 1990 to 64 in 1999. 

Sponsors have expanded research sites into many countries that appear to have 

limited experience in clinical trials. 

The number of countries in which clinical investigators conduct drug research that is tracked by 

FDA increased from 28 in 1990 to 79 in 1999. Among the countries that have experienced the 

largest growth in clinical investigators are Russia and countries in Eastern Europe and Latin 

America. Sponsors explain this growth by pointing to readily 

The Globalization of Clinical Trials i OEI-01-00-00190 
accessible human subjects, potential new markets for approved drugs, and recent international 

agreements that ease FDA acceptance of foreign research data. Contract research 

organizations are also moving into these areas. FDA is also beginning to inspect investigators in 

areas where FDA-regulated research has not previously been conducted. 

FDA cannot assure the same level of human subject protections in foreign trials 

as domestic ones. 

FDA receives minimal information on the performance of foreign institutional review boards. It 

does not inspect these boards, nor does it tend to receive much information from the host 

countries of these boards. It cannot necessarily depend on foreign investigators signing 

attestations that they will uphold human subject protections. It has an inadequate database on 

the people and entities involved in foreign research. 

Key entities overseeing or studying foreign research have raised concerns about 

some foreign institutional review boards. 

The pharmaceutical industry, national regulatory agencies, the National Bioethics Advisory 

Commission, and the World Health Organization have all raised concerns about some of the 

institutional review boards that review research at foreign sites. Their concerns tend to focus on 

the boards’ lack of experience and insufficient monitoring practices. 

RECOMMENDATIONS 

The purpose of these recommendations is to help ensure that the protections provided for 

foreign clinical drug research are at least equivalent to U.S. regulations, not to discourage the 

submission of non-U.S. data. We direct most of our recommendations to FDA, since it has the 

jurisdiction for the commercially funded research that was the focus of our inquiry. We also 

make recommendations to the Office for Human Research Protections, which is in a prime 

position to foster integrated approaches to protecting human subjects across Federal agencies. 

We recognize that FDA has taken many important steps in strengthening human subject 

protections despite the difficulties of limited resources and limited information about foreign 

research. In recommending an increase in human subject protection efforts, we also 

acknowledge that all efforts in this area must be respectful of the sovereignty of other countries 

and compatible with harmonization efforts. Furthermore, we recognize that some of our 

recommendations may require additional resources. 

We recommend that FDA: 

Obtain more information about the performance of foreign institutional 

review boards. By working with the regulatory authorities in foreign countries to 

The Globalization of Clinical Trials ii OEI-01-00-00190 
obtain information about the practices of local institutional review boards, or more directly by 

assisting in inspections, FDA can address its lack of information about the adequacy of foreign 

institutional review boards’ review of human subject protection issues in clinical research 

submitted in New Drug Applications. 

Help foreign boards build capacity. By working with the Office for Human Research 

Protections, the National Institutes of Health, and others, FDA can help newly established 

foreign review boards conduct effective human subject reviews. 

Encourage sponsors to obtain attestations from foreign investigators. By 

encouraging attestations from non-U.S. investigators stating that they will adhere to ethically 

sound principles of research, FDA can promote adherence to ethical guidelines. Foreign 

investigators working under an Investigational New Drug Application should sign attestations, 

as Investigational New Drug Application regulations require. Similarly, foreign investigators 

working under other research guidelines could be encouraged to sign a statement of their 

intention to comply with the guidelines they follow. 

Encourage greater sponsor monitoring. By encouraging more rigorous monitoring of 

foreign research sites by sponsors and their agents, FDA can reinforce their responsibility to 

ensure human subject protections. FDA can work with sponsors to achieve a clearer mutual 

understanding of the roles they can play in that regard. 

Develop a database to track the growth and location of foreign research. 

Given the significant growth occurring in non-U.S. research submitted as part of New Drug 

Applications, it is important for purposes of oversight and resource allocation that FDA have 

more and better information about key elements of that growth. 

Finally, we recommend that the Office for Human Research Protections: 

Exert leadership. By developing strategies to ensure that adequate human subject 

protections are afforded for non-U.S. clinical trials that are funded by the Federal government 

and/or that contribute data in support of a New Drug Application, the Office for Human 

Research Protections can exert leadership. It is already moving in this direction. In its 

leadership role, it can foster integrated approaches that would apply across Federal agencies 

and to federally funded and New Drug Application research conducted at non-U.S. sites. 

Encourage accreditation. Encouraging participation of institutional review boards in a 

voluntary accreditation system is one way to improve the capacity to conduct appropriate 

reviews of human subject protections in proposed research. The Office for Human Research 

Protections, working with FDA, NIH, and others, can help develop such a system 

internationally. 

The Globalization of Clinical Trials iii OEI-01-00-00190 
COMMENTS ON THE DRAFT REPORT 

Within the Department of Health and Human Services, we received comments from the FDA 

and the Office for Human Research Protections (OHRP). The OHRP concurred with the two 

recommendations we directed to it and stressed its readiness to engage in the kind of leadership 

we called for. The FDA supported all of our recommendations except for the one calling for 

better data collection on foreign research. It indicated that the purpose and methods we 

presented concerning the recommendation were not sufficiently clear. In this final report, we 

modified the recommendation to more clearly define the goal for FDA to develop a database to 

track the location and growth of foreign research. Such a data base, we suggest, can be helpful 

in guiding FDA oversight and setting priorities. We also suggested one way to begin gathering 

such data as well as a broader strategy for the future. 

FDA emphasized its lack of resources and its limited authority in foreign countries as constraints 

in carrying out the remaining recommendations. While we agree that these are limiting factors, 

we believe the FDA can use its technical expertise, its influence as the approving authority for 

drugs marketed in the U.S., and its prestige and experience in international circles to promote 

reforms even in foreign countries. 

External to the Department, we solicited comments from the Pharmaceutical Research and 

Manufacturers of America (PhRMA), Public Citizen Health Research Group, Public 

Responsibility in Medicine and Research (PRIM&R), and Applied Research Ethics National 

Association (ARENA). The following is a summary of the comments we received: PRIM&R 

and ARENA urged FDA “require” not as we suggested “encourage” investigator attestations 

for foreign research used in support of New Dug Applications. But in general the two 

organizations supported our recommendations. Public Citizen was more critical, indicating that 

our recommendations were not strong enough in light of the problems we identified. The 

comments of these organizations warrant consideration and reinforce our central concern: that 

FDA cannot assure the same level of protections in foreign trials as domestic ones. 

The Globalization of Clinical Trials iv OEI-01-00-00190 
TABLE OF CONTENTS 

PAGE

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

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

PRIMER ON FDA REGULATION OF FOREIGN DRUG RESEARCH ............... 5

FINDINGS 

Significant Increase in Foreign Research ........................................ 6

Research Sites With Limited Experience ........................................ 8

FDA Limitations in Assuring Protections ....................................... 12

Key Entities Raise Concerns ................................................ 15

RECOMMENDATIONS ...................................................... 17

COMMENTS ON THE DRAFT REPORT ....................................... 22

APPENDICES 

A: Foreign Investigator Inspections .......................................... 24

B: International Research Guidelines ......................................... 26

C: Clinical Investigator Attestation Commitments ................................ 28

D: Comments on the Draft Report ........................................... 29

E: Endnotes ............................................................ 43

The Globalization of Clinical Trials OEI-01-00-00190 
INTRODUCTION 

PURPOSE 

To document the growth of non-U.S. clinical drug trials contributing data to New Drug 

Applications for Food and Drug Administration (FDA) approval, and to assess FDA’s capacity 

to assure human subject protections in these trials. 

BACKGROUND 

In our June 2000 report, Recruiting Human Subjects: Pressures in Industry-Sponsored 

Clinical Research (OEI-01-97-00195), we drew attention to the fact that clinical drug trials 

conducted outside the United States can be an important source of data in FDA’s 

determination of the safety and effectiveness of new drugs. Pharmaceutical companies 

conducting these trials submit data to FDA as part of a New Drug Application, the application 

for FDA approval to market a drug in the U.S. for specified use(s).1 Although the majority of 

foreign clinical drug research that is submitted in New Drug Applications is still conducted in 

countries with a history of clinical drug research, increasingly, countries in Eastern Europe, Latin 

America, and East Asia are emerging as desirable locations for sponsors to conduct this 

research. 

In this report we seek to determine the extent to which this overseas research has been 

increasing and to assess FDA’s oversight of such research as it relates to human subject 

protections. The importance of such oversight is underscored by a December 2000 

Washington Post series focusing on the adequacy of protections afforded in international 

clinical drug trials.2 

FDA Oversight of New Drug Research 

This report refers often to two applications that FDA uses to oversee and evaluate new drug 

research. The first application is the Investigational New Drug Application (IND). Sponsors of 

drug research submit an IND to FDA prior to the start of research that will be conducted under 

FDA regulations. The second application is the New Drug Application (NDA). After research 

is complete, sponsors submit an NDA to obtain FDA approval to market a new drug. 

FDA approves an NDA after determining that a drug is safe and effective for its intended 

use(s). The application contains the clinical and other data FDA needs to evaluate risks and 

benefits. The drug sponsor, usually a pharmaceutical company, demonstrates that a drug is safe 

and effective by conducting clinical trials on human subjects. A sponsor must test a drug on 

many subjects—often several thousand—to produce data that reliably predict the drug’s 

effects. Sponsors generally contract with many clinical investigators, 

The Globalization of Clinical Trials 1 OEI-01-00-00190 
who conduct this research simultaneously at multiple research sites. Although these research 

sites were based almost exclusively in the U.S. in the past, they are increasingly based in foreign 

countries. 

NDAs can contain research conducted at U.S. and foreign sites. Although all U.S. clinical drug 

research must be conducted under an IND, foreign clinical drug research may be conducted 

either under an IND or other international guidelines. If foreign research is not conducted under 

an IND, then FDA requires it to have been conducted under the standards of the 1989 version 

of the Declaration of Helsinki or other guidelines, if they provide a higher level of human subject 

protections. (See Primer on p. 5 for application information, and appendix B for international 

guidelines.) FDA accepts NDAs containing three types of research data: (1) U.S. research, (2) 

foreign research conducted under an IND, and (3) foreign research conducted under other 

guidelines. A single NDA can contain any combination of these three types of data (see table 1 

below). 

Table 1 

Possible Combinations of U.S. Research Data and Two Types of 

Foreign Research Data in a Single FDA New Drug Application

Possible 

combinations 

of data 

U.S. research 

conducted under an 

IND 

Foreign research 

conducted under an 

IND 

Foreign research Not 

conducted under an 

IND 

Combination 1 V

Combination 2 V V

Combination 3 V V

Combination 4 V V V

Combination 5 V V

Combination 6 V

Combination 7 V

Source: OIG analysis of FDA information. 

Mechanisms for Assuring Human Subject Protections in Foreign Trials 

FDA’s investigational new drug regulations define institutional review boards as the oversight 

bodies “designated by an institution to review, to approve the initiation of, and to conduct 

periodic review of, biomedical research involving human subjects. The primary purpose of 

such review is to assure the protection of the rights and welfare of the human subjects.”3 

Institutional review boards are intended to protect human subjects in clinical trials, in part, by 

independently reviewing proposed research before investigators can enroll subjects in trials. 

The Globalization of Clinical Trials 2 OEI-01-00-00190 
According to FDA regulations, foreign boards must adhere to international ethical standards, 

whether the standards are set by FDA, the Declaration of Helsinki, or the International 

Conference on Harmonization, as well as any regulations of their respective countries’ 

regulatory agencies.4 Although these ethics boards go by several names, in this report we will 

refer to them all as institutional review boards. 

In addition to foreign institutional review boards, other entities play roles in overseeing foreign 

drug trials that contribute data to NDAs. FDA oversees the protection of subjects in foreign 

clinical trials through its regulation of the clinical investigator (see Primer p. 5). The sponsor, 

under an IND, is also responsible for monitoring the investigator. Finally, the regulatory agency 

of the country hosting the research, analogous to FDA in the U.S., may play an oversight role. 

Another entity that plays a role in the oversight of human subject protections is the Office for 

Human Research Protections, in the Office of the Secretary of the Department of Health and 

Human Services, previously known as the Office for Protection from Research Risks in the 

National Institutes of Health. This office is primarily responsible for overseeing research funded 

through the Department of Health and Human Services, but also serves an important leadership 

role within the Department, and in the Federal government as a whole. 

International Harmonization of Research 

FDA has played an important role in efforts to create international standards for clinical 

research that facilitate the acceptance of well conducted international research. The 

International Conference on Harmonization was established in 1990 to create international 

standards for ensuring and assessing the quality, safety, and efficacy of drugs, including Good 

Clinical Practice guidelines for investigators, institutional review boards, and sponsors. Its 

members include FDA, the regulatory agencies of the European Union and Japan, and the 

pharmaceutical industry trade groups from these three regions. In May 1997, FDA published 

the International Conference on Harmonization guidelines in the Federal Register, as official 

U.S. guidance. These guidelines are very similar to FDA regulations.5 An increasing amount of 

international research is being conducted under these voluntary guidelines. 

This Inquiry 

In this report we seek to document the extent of the growth of non-U.S. research that is 

submitted to FDA as part of an NDA and to assess FDA’s oversight of this research. We 

focus primarily on FDA’s capacity to ensure human subject protections in this foreign research. 

Our aim is not to examine or judge the merits of the ethical decisions made by foreign 

institutional review boards. Rather, we intend to assess FDA’s capacity, regulatory or 

otherwise, to adequately ensure human subject protections in this subset of foreign clinical 

research. In the past we have raised concerns about the oversight of 

The Globalization of Clinical Trials 3 OEI-01-00-00190 
clinical research within the U.S.6 We do not expect these foreign trials to meet a higher (or 

lower) standard than those conducted domestically. 

This inquiry primarily focuses on FDA’s oversight of clinical drug trials that sponsors monitor 

and submit in an NDA. Of all the foreign clinical trials that FDA oversees, including drugs, 

medical devices, and biologics, drug trials constitute the largest number of non-U.S. trials and 

have occurred over the longest period of time, making these trials the most informative area to 

examine. This report does not focus on international research that is funded by the U.S. 

government or by non-profit organizations. However, some of the same concerns raised here 

may apply to this sphere of research as well. 

Methodology 

We analyzed FDA’s database on foreign clinical investigators who are conducting drug 

research under INDs. Investigator information in this database is taken primarily from FDA 

Form 1572, which we will refer to as “attestations.” We also analyzed the FDA’s database of 

the results of both foreign and domestic inspections of clinical investigators conducting drug 

research. In addition, we interviewed key FDA officials involved in overseeing and harmonizing 

international drug research, including five who have inspected foreign sites. We also 

interviewed sponsor representatives. Finally, we reviewed pertinent FDA documents and 

related literature. 

We conducted this inspection in accordance with the Quality Standards for Inspections 

issued by the President’s Council on Integrity and Efficiency. 

The Globalization of Clinical Trials 4 OEI-01-00-00190 
Primer on FDA Oversight of 

U.S. and Foreign Drug Research 

This Primer applies to FDA’s regulation of clinical drug research. The distinction between U.S. 

and foreign research is based on the location where the research is conducted, not on 

characteristics of sponsors or investigators. After completing their research, sponsors submit 

research data in a New Drug Application (NDA). A single NDA can contain combinations of 

data from research conducted under an Investigational New Drug Application (IND) and data 

from research conducted under other research guidelines. All investigators whose research is 

submitted in an NDA are subject to inspection by FDA. 7 

Research conducted at U.S. Sites 

Sponsors intending to conduct U.S. based clinical studies must submit an IND to FDA before 

beginning research.8 FDA then has an opportunity to review the study design and procedures and 

suggest changes. Sponsors are also required to obtain a signed attestation (1572 form) from each 

of their clinical investigators, stating that they will conduct research in an ethical manner and 

according to FDA regulations. (See appendix C for specific commitments.) During the study, 

sponsors submit annual reports and other information to FDA. 

Research conducted at foreign sites 

In contrast to U.S. research, FDA does not require sponsors of foreign-based research to 

conduct research under an IND, although these sponsors can choose to do so. 

Foreign research conducted under an Investigational New Drug Application. Sponsors of 

foreign-based research who choose to submit an IND to FDA must also conduct research 

according to FDA regulations. However, FDA has less information about this research than it 

does for U.S. based research because it does not track investigators through a comprehensive 

database of signed attestations. 

Foreign research not conducted under an Investigational New Drug Application. If 

sponsors submit an NDA containing foreign research that was not conducted under an IND, that 

research must adhere to FDA regulations for foreign clinical studies not conducted under an 

IND.9 This type of foreign clinical research must be conducted according to the ethical principles 

of the Declaration of Helsinki, or the countries’ own regulations, whichever offers the greater 

protection to the human subject.10 Many countries have adopted the Good Clinical Practice 

guidelines from the International Conference on Harmonization as their regulatory standard.11 

(See appendix B for a description of international guidelines.) Sponsors are not required to obtain 

attestations for investigators conducting research under these guidelines. 

The Globalization of Clinical Trials 5 OEI-01-00-00190 
FINDINGS 

FDA oversees significantly more foreign research than it did 

10 years ago. 

Until recently, almost all of the clinical drug research submitted in support of NDAs was 

conducted at sites within the U.S. Increasingly, sponsors are conducting this research at sites 

outside of the U.S. Determining the precise growth of this particular subset of foreign research 

is difficult, however, because FDA’s current data system does not track NDA information by 

the location where research was conducted. As a result, FDA’s existing databases cannot 

provide information on the growth of NDAs that contain data from foreign clinical trials. 

FDA’s database for tracking clinical investigators who conduct drug research is based upon 

INDs, not NDAs. It therefore does not include foreign investigators whose research was not 

conducted under an IND, but was submitted in an NDA.12 Thus, we use this database as just 

one source of information to support our finding of growth in foreign research that is submitted 

in NDAs. 

The number of foreign clinical investigators conducting drug research under 

Investigational New Drug Applications increased 16-fold in the past decade. 

In 1980, just 41 foreign clinical investigators conducted drug research under an IND. By 1990,

that number grew to 271, and by 1999, to 4,458. The growth of these foreign clinical

investigators has been particularly sharp in recent years (see figure 1). As mentioned

previously, although FDA’s database does not capture the growth of foreign investigators who

have submitted data in NDAs, the number of foreign clinical investigators FDA tracks under

INDs has

increased

sharply.

The Globalization of Clinical Trials 6 OEI-01-00-00190 
The number of FDA investigator inspections at foreign sites increased 

dramatically. 

After receiving an NDA, FDA inspects clinical investigators at some of the key—sometimes 

referred to as “pivotal”—sites contributing data to the application. Pivotal sites are generally 

those that have enrolled the most subjects, and therefore contribute the most data to an NDA. 

High enrollment is not FDA’s only criterion for selecting investigators to inspect, but it is the 

main one.13 The number of FDA clinical investigator inspections that occurred at sites outside 

the U.S. increased sharply over the past decade—from 22 in 1990 to 64 in 1999 (see figure 

2). The rising number of investigator inspections occurring outside the U.S. does not fully 

reflect the growth of applications that contain some foreign data.14 However, dramatic growth 

in the number of foreign investigator inspections indicates the increasing role of foreign clinical 

drug research under FDA oversight. 

The Globalization of Clinical Trials 7 OEI-01-00-00190 
Sponsors have expanded research sites into many countries 

that appear to have limited experience in clinical trials. 

Although the majority of foreign research contained in NDAs is still conducted in countries with 

a history of hosting this research, such as the United Kingdom, Germany, and Canada, 

countries in regions such as Eastern Europe, Latin America, and East Asia are emerging as 

desirable locations for sponsors to conduct research. For the purposes of this report, we will 

be referring to regions that are experiencing a vast growth in this research and that lack a 

history of hosting research as “emerging sites.” 

Once again, no definitive source of data exists on the amount of research occurring in each 

country that is intended for or is included in NDAs. Yet the pharmaceutical industry and FDA 

agree that this research is expanding into many new areas. Several sources of evidence 

demonstrate the regions and countries experiencing the most rapid growth. 

Sponsors attest to this growth. 

An industry source reports that, in 1992, 61 premarket clinical research protocols were 

approved in Hungary; by 1998, that number almost tripled to 178 approved protocols.15 

Another industry source reports that the number of multi-site trial protocols in Russia grew from 

38 in 1996 to 99 in 1999.16 

Access to subjects. Sponsors report using emerging sites for their research to gain access to 

large numbers of subjects with a particular disease, especially those that are “naive subjects” 

(i.e., have not been treated for the disease being studied), and to obtain data on different racial 

or ethnic groups.17 Sponsors also report that these sites allow them to recruit subjects quickly 

and, therefore, bring their drugs to market faster. Sponsors report being able to recruit 

subjects more quickly in certain countries, particularly Russia and those in Eastern Europe, than 

in Western sites. For example, an organization specializing in managing clinical trials in Eastern 

Europe cited a study conducted in Poland where “the recruitment was so fast that 40 extra 

patients were enrolled at the sponsor’s request before some of the Western countries, still 

awaiting Ethics Committee’s approvals, had even started.”18 Another organization, specializing 

in Russian trials, states that, on average, any Russian site recruits twice as many subjects as any 

site in Western Europe, and some Russian sites have recruited up to 300 percent more than 

other sites.19 

Market development. Another reason why sponsors are conducting drug research in these 

emerging sites is to develop a market for the study drug in the event that it is approved by the 

FDA.20 Many of these emerging sites are in regions of the world that are gaining purchasing 

power. 

The Globalization of Clinical Trials 8 OEI-01-00-00190 
Regulatory standardization. The recent growth in this research is also likely related to the 

international regulatory harmonization efforts of the past decade. During this period, the 

International Conference on Harmonization standardized procedures of trial design, institutional 

review board review, and research conduct. As a result, FDA has become increasingly willing 

to accept data from foreign research as part of an NDA. In fact, FDA has the authority to 

approve applications that contain data exclusively from foreign sites, although such approvals 

are rare. 

Contract Research Organizations are beginning to expand into these countries. 

Contract research organizations are entities with whom drug sponsors often contract to manage 

trials in foreign countries, particularly those in which sponsors have no offices.21 An analysis of 

industry trends cited a “global presence” as one of the main qualities that will make these 

organizations competitive in the future.22,23 The expansion of these organizations into more 

countries suggests that these countries are emerging as places where sponsors are currently 

conducting research or plan to in the future. In July 2000, the world’s largest contract research 

organization, which is currently located in 38 countries, opened offices in 7 new countries: 

Chile, Czech Republic, Greece, Norway, the Philippines, Romania, and Thailand.24 The 

second and third largest organizations, located in 29 and 17 different countries respectively, 

also recently opened offices in emerging sites.25 In 2000, another large organization expanded 

its clinical monitoring services into Asia and the Pacific Rim, claiming “the opportunity for the 

conduct of clinical trials in Asia, let alone prosperous drug sales, provides potentially limitless 

pharmaceutical business possibilities—especially in China.”26 

In addition, contract research organizations and site management organizations that specialize in 

managing and conducting clinical trials in these emerging areas have recently been established. 

For example, a contract research organization specializing in organizing clinical trials in Eastern 

Europe was established in 1994 and, in 1999, began applying this experience to trials in Latin 

America.27 A site management organization entirely focused on Russian clinical trials was 

established in 1999.28 Another organization began specializing in Baltic countries in 1998.29 

The Globalization of Clinical Trials 9 OEI-01-00-00190 
FDA tracked investigators working under 

Investigational New Drug Applications in 

28 foreign countries in 1990 and 79 

countries in 1999. 

We have noted the limitations of FDA’s 

database of investigators conducting research 

under an IND for quantifying the growth of 

non-U.S. clinical research that is submitted in 

NDAs. Yet the fact that these investigators 

are conducting research in so many new 

countries over the past 10 years seems to 

indicate that sponsors are conducting their 

research in support of NDAs in areas not 

used extensively for this type of research in 

the past. The largest growth appears to be 

occurring in Eastern Europe, Latin America, 

and Russia (see table 2). 

Table 2 

Clinical Investigators Working Under IND 

Regulations in Selected Countries. 

Fiscal Year 1991 to 1999 

Source: OIG analysis of FDA data 

Country 91-93 94-96 97-99 

Argentina 6 122 271 

Brazil 16 52 187 

Hungary 9 35 161 

Mexico 29 48 187 

Poland 4 100 190 

Russia 0 5 170 

Thailand 1 2 24 

FDA is beginning to inspect investigators in emerging regions. 

FDA inspections of investigators can provide evidence of the growth of clinical

research conducted outside of the U.S. as well as the areas where the research is taking place

(see figure 3). Although FDA databases can not provide precise aggregate or specific

information on the location of research contributing data to NDAs, the increasing number of

countries experiencing their first investigator inspection demonstrates the growth of this research

in emerging countries. FDA may choose to inspect investigators in certain countries, even if the

site has not enrolled a large number of subjects, because these countries have not hosted

research for NDAs before. In this case, FDA may use the investigator inspection as an

opportunity to learn about the research conducted at a particular site and the conduct of clinical

research in that country generally.

The Globalization of Clinical Trials 10 OEI-01-00-00190 
Countries experiencing their first FDA investigator inspection between 1996-1999 (19) 

Figure 3. Emerging Sites 

Brazil (1996), Costa Rica (1996), Peru (1996), Russia (1996), Austria (1997), Nigeria (1997), Panama (1997), Philippines (1997), 

Czechoslovakia (1998), Slovenia (1998), Hungary (1998), Romania (1998), Norway (1998), Hong Kong (1998), China (1998), 

Gabon (1998), Ireland (1998), Kenya (1998), Portugal (1998). 

Source: OEI analysis of FDA data. 

The Globalization of Clinical Trials 11 OEI-01-00-00190 
FDA cannot assure the same level of human subject 

protections in foreign trials as domestic ones. 

FDA has minimal information on the performance of foreign institutional review 

boards. 

Institutional review boards play a critical role in ensuring that proper protections are afforded to 

human subjects. They are responsible for carrying out this role at the outset, before the 

research is initiated, and on a continuing basis thereafter. These institutional review board 

reviews provide a valuable complement to FDA’s own reviews of IND applications. 

To help ensure that domestic institutional review boards perform their responsibilities in accord 

with FDA regulations, FDA conducts on-site inspections; in 2000, it carried out nearly 250 

such inspections. In contrast, FDA does not inspect foreign institutional review boards. Given 

the emphasis on international agreements, the sensitivities associated with national sovereignty, 

and the resource implications of international inspections, it is understandable why FDA may be 

reluctant to inspect foreign institutional review boards. But as the amount of foreign research 

contained in NDAs continues to grow, particularly in areas where boards may have little 

experience, FDA’s lack of information about the review of human subject protections in this 

subset of international research becomes increasingly problematic. 

FDA draws on more indirect means of assessing the performance of foreign institutional review 

boards, but these are quite limited in scope. When conducting investigations of foreign clinical 

investigators FDA can get some indication of how thoroughly the institutional review board is 

carrying out its review responsibilities by examining the investigator’s records of 

correspondence with the board.30 Also, when reviewing NDAs, it gets some basic information 

on the institutional review board reviews conducted.31 But neither of these processes provides 

the degree of information that can emerge from an on-site review of the board itself. FDA 

cannot depend on the regulatory bodies of the host countries to provide this information 

either.32 

Not all foreign investigators who conduct research that is submitted in New Drug 

Applications sign an attestation that they will uphold human subject protections. 

An attestation is a means of holding an individual investigator clearly and directly accountable 

for conducting research ethically. For foreign research conducted outside of an IND and 

subsequently used in support of an NDA, FDA does not require the sponsor to obtain a signed 

attestation from the foreign investigator; nor do the Declaration of Helsinki or the International 

Conference on Harmonization have any similar guidelines directed to the individual investigator. 

For research conducted under an IND, whether foreign or domestic, FDA does require 

sponsors to obtain a signed attestation from an investigator before the investigator begins 

The Globalization of Clinical Trials 12 OEI-01-00-00190 
research. The great majority of research The Attestation submitted to FDA in support of NDAs is 

carried out by investigators working FDA requires that clinical investigators working 

under INDs. FDA does not have data on under an IND sign an attestation. Following are 

how many of these investigators actually some of the commitments they make in signing that 

sign attestations. But through our 

inquiries in FDA, we learned that C To adhere to the study protocol. 

sponsors of foreign research conducted 

under INDs may not always be obtaining 

written attestations from foreign 

C

C

C

To personally conduct the research. 

To inform subjects that the drugs are being 

used for investigational purposes. 

To ensure that FDA regulations of informed 

investigators, even though, as we have consent and IRB review are met. 

indicated, they are required to by FDA.33 C To report adverse events. 

C To report to the IRB any changes in the 

document: 

Thus, for research submitted to FDA in study protocol or any unexpected problems. 

support of an NDA, there is reason to Source: FDA Form 1572

believe that the potential of an investigator

attestation as a means of fostering human

subject protections is not being fully realized.

FDA experiences challenges inspecting investigators at foreign sites. 

FDA’s main mechanism for overseeing clinical research outside of the U.S. is its inspections of 

clinical investigators. It inspects investigators after research has been conducted, after an NDA 

has been submitted but before an approval decision. When FDA inspects clinical investigators, 

it focuses primarily on ensuring the integrity of the data submitted as part of the NDA. It also 

examines the adequacy of human subject protections by collecting from the investigator 

documentation of institutional review board approvals and modifications, subjects’ records, and 

informed consent documents.34 These inspections are a particularly useful oversight tool for 

FDA when inspecting clinical investigators who did not conduct research under an IND, since 

FDA is generally uninformed of these investigators’ activities throughout the entire research 

process, in contrast to investigators conducting research under an IND (see Primer on p. 5). 

FDA has faced some challenges in inspecting foreign sites: 

Logistics. FDA inspectors must give advance notice to the State department and obtain visas 

for the host countries. FDA schedules multiple foreign inspections in order to maximize 

resources. Domestic inspections, in contrast, are generally within driving distance of the district 

office. Another problem mentioned by one FDA official is that sometimes just before an FDA 

inspector is scheduled to inspect a foreign site, the site will contact them and inform them that 

they are missing source documents or other relevant documents at the site.35 

Diplomacy. FDA officials must ensure the safety and integrity of clinical trials without 

offending the host country. This can require making arrangements through diplomatic 

The Globalization of Clinical Trials 13 OEI-01-00-00190 
channels, such as parliaments or departments of health, commerce, or trade, which further 

complicates arranging foreign inspections. In addition, FDA inspectors must undergo additional 

training regarding cultural differences before conducting foreign inspections. 

Expense. Foreign inspections are more expensive than domestic inspections. Airfare alone to 

some countries exceeds the entire FDA estimate of $2500 per investigator per inspection.36 

Foreign inspections are also more expensive than domestic ones because FDA must pay food 

and lodging expenses of its employees.37 

FDA has limited information on the people and entities involved in foreign 

research. 

During the course of research, FDA has little or no information about the sites, investigators, 

institutional review boards, and human subjects involved in research that is not conducted under 

an IND. It only obtains this information when a sponsor submits the NDA after completing all 

research. FDA’s only database that aggregates data across projects is restricted to data from 

IND submissions. Presently, FDA is unable to generate data from a database, or set of 

relational databases, that could answer the following questions about institutional review 

boards, investigators, sites, and human research subjects: 

Institutional review boards. How many are there? Where are they? How many protocols 

have they reviewed that ultimately led to NDAs? 

Investigators. How many are there outside of the U.S.? In which countries are they 

conducting their research? Is this changing? How many are working under an IND? 

Sites. How many are there? In which countries? How many research subjects are enrolled at 

each site? 

Human research subjects. How many have participated in NDA research? Which countries 

contribute the most subjects? Is this changing over time? 

Lacking this information, FDA is unable to systematically target its limited resources either for 

inspections or for educational purposes. It is also hard pressed to provide guidance or plan 

educational programs in regions experiencing rapid growth in clinical trials. 

FDA typically does not review or discuss with sponsors the study designs and 

monitoring plans of New Drug Application research that was not conducted under 

an Investigational New Drug Application. 

Sponsors are required by both FDA regulation and International Conference on Harmonization 

guidelines to monitor the progress of clinical trials.38 But only under IND regulations is the 

sponsor required to submit its study design and monitoring plan prior to 

The Globalization of Clinical Trials 14 OEI-01-00-00190 
conducting research. FDA is at liberty to reject the trial data when the NDA is submitted if it 

believes that the study was improperly designed or unethical. But, by the time a sponsor 

submits a New Drug Application, the trial is already completed. Thus, the study subjects would 

have already been placed at risk, or possibly harmed. 

The critical time for FDA to provide advice to sponsors on trial design and oversight is when 

the sponsor submits an IND, before any research subjects are enrolled in the trial. FDA 

engages in dialogue with sponsors during IND submissions. FDA evaluates the study design to 

determine whether the study is designed in such a way that it can achieve its intended 

objectives. At the time of an IND submission, FDA may also recommend to sponsors what 

would be an appropriate level and type of monitoring for that particular study. In order to 

determine the proper extent and nature of the monitoring, FDA conducts a clinical review of 

data from the study’s animal trials or earlier human trials to assess the potential risk of the trial. 

Key entities overseeing or studying foreign research raise 

concerns about some foreign institutional review boards. 

FDA has no direct regular contact with foreign institutional review boards, but other entities that 

have worked with or studied foreign institutional review boards have raised concerns about 

those boards that are inexperienced in conducting ethical reviews. 

The pharmaceutical industry. Sponsors have raised concerns regarding the capacity of the 

institutional review boards in some of the emerging sites to adequately review research 

according to Good Clinical Practice guidelines, under the International Conference on 

Harmonization or FDA standards. In one article, a pharmaceutical company representative 

stated, “...investing in Latin America, as in other emerging markets, presents some challenges 

not necessarily encountered in countries traditionally included in global clinical development 

programs,” including verifying the adequacy of institutional review boards used.39 A medical 

director of a U.S. pharmaceutical company based in China stated that it is difficult to obtain 

memberships, meeting schedules, and minutes of Chinese institutional review boards.40 One 

representative of a contract research organization noted that the protocol-approval process of 

Malaysian institutional review boards is poorly defined.41 An employee of a Russian-based 

contract research organization reported that she had frequently encountered problems with lack 

of full disclosure to potential subjects about the side effects of the study drug.42 In fact, one 

large pharmaceutical company was concerned enough about the adequacy of ethics boards in 

some of these regions to contract a U.S. institutional review board to train members of the 

foreign institutional review boards reviewing its research. 

Regulatory agencies in the countries hosting research. When the Korean regulatory 

agency for clinical research inspected its sites, it found such deficiencies as: institutional review 

boards unaware of departures from protocol, institutional review boards not being informed of 

protocol changes, inappropriate review board operations, inadequate 

The Globalization of Clinical Trials 15 OEI-01-00-00190 
composition of review boards, inadequate informed consent, and lack of continuous trial review 

by review boards.43 In another recent case, South Africa’s health ministry forced companies to 

withdraw profitable clinical trials, stating that half the protocols seeking approval were 

substandard, both scientifically and ethically, including inadequate handling of informed consent 

of human subjects.44 

National Bioethics Advisory Commission. A recently commissioned report, Attitudes and 

Experiences of U.S. and Developing Country Investigators Regarding U.S. Human 

Subjects Regulations, found that institutional review board shortcomings may be particularly 

common in the developing world.45 It contained a survey of clinical investigators conducting 

research, mostly in Africa, Asia, and Latin America. The surveyed investigators raised 

concerns that some institutional review boards were improperly trained, were conducting 

primarily a scientific and budgetary review rather than an ethical one, and were not properly 

monitoring research.46 The Nuffield Council on Bioethics, a British council with a similar 

mission to the National Bioethics Advisory Commission in the U.S., also expressed concerns 

about some institutional review boards.47 

World Health Organization. In 1999, The World Health Organization’s Tropical Disease 

Research group conducted two seminars analyzing the status of ethical review in Asia, Africa, 

and the Western Pacific. These 

seminars revealed several weaknesses 

in the ethical review systems of these 

countries (see box at right).48 As a result 

of the seminars, the World Health 

Organization developed Operational 

Guidelines for Ethics Committees 

that Review Biomedical Research, a 

document which provides guidance to 

countries and institutions for creating 

and operating their own research ethics 

committees.49 It also established the 

Forum on Ethics Committees in Asia 

and the Western Pacific, a network for 

mobilizing resources, exchanging 

Some Weaknesses in Ethical Review 

Systems in Asia, Western Pacific, and Africa 

1. Lack of procedures for reviewing the protocol 

and informed consent forms 

2. Lack of trained institutional review board 

members 

3. Insufficient resources 

4. Lack of monitoring systems 

5. Lack of quorum requirements for institutional 

review board meetings 

6. Lack of independence 

Source: World Health Organization 

information and coordinating activities relating to institutional review boards. Among other 

activities, this forum facilitates training and education of members of ethics committees.50 

The Globalization of Clinical Trials 16 OEI-01-00-00190 
RECOMMENDATIONS 

The evidence we have gathered indicates that the current situation is a serious one warranting 

further attention by the FDA and by the U.S. Department of Health and Human Services as a 

whole. The significant growth in foreign research that is submitted in New Drug Applications 

presents challenges to the Department’s ability to assure human subject protections.51 

We recognize that FDA has taken many important steps in strengthening human subject 

protections in foreign research, despite the difficulties associated with limited resources and 

limited information. We also recognize that all efforts in this area must respect the sovereignty 

of other countries and occur within the collaborative system governing international research. 

The National Bioethics Advisory Commission recently indicated the importance of achieving 

human subject protections, regardless of trial location.52 

In many countries hosting drug trials that generate data for NDAs, a well-established set of 

rules and enforcement mechanisms exist to protect human subjects. But in some emerging sites, 

where a significant growth in NDA research is occurring—and is likely to continue to 

expand—current conditions may not allow for a level of protection comparable to that in U.S. 

sites.53 

Some of our recommendations may require additional regulations or additional resources on the 

part of FDA, the Office for Human Research Protections, regulatory agencies in foreign 

countries, and sponsors. 

We lead with five recommendations to FDA, which has the explicit jurisdiction for the 

commercially funded research that has been the focus of our inquiry, and close with two 

recommendations to the Office for Human Research Protections. 

We recommend that FDA: 

Examine ways in which it can obtain more information about the 

performance of non-U.S. institutional review boards reviewing 

clinical trials that provide data in support of New Drug Applications. 

We recognize that this is a complex matter that raises difficult questions about international 

relationships and the use of scarce resources. But our review provides an early warning signal 

that FDA does not have adequate assurance of human subject protections in a growing 

proportion of the research submitted in support of NDAs. In foreign, no less than in U.S. sites, 

institutional review boards must play a key role in ensuring such protections. 

The Globalization of Clinical Trials 17 OEI-01-00-00190 
FDA’s informational void concerning the performance of foreign institutional review boards is 

of particular concern for emerging sites with little experience in conducting clinical research for 

NDAs and in providing human subject protections. One way in which FDA could help fill this 

void is to work with the host countries, encouraging them to oversee their institutional review 

boards and to share with FDA any information they have about the performance of those 

boards, particularly in cases where they review a substantial amount of research to be used in 

support of an NDA. 

Another more direct approach is to selectively conduct some reviews of institutional review 

boards at sites where such research is occurring and where FDA has minimal information about 

board review. With the participation of the host countries, FDA could conduct reviews with a 

focus on providing assistance to enhance review board performance. To conserve resources, it 

could also consider conducting these reviews in tandem with non-U.S. clinical investigator 

inspections. 

Help inexperienced non-U.S. institutional review boards build their 

capacity. 

As we have noted, various parties involved in clinical research have raised concerns about 

inexperienced institutional review boards, particularly when these boards are reviewing research 

not conducted under an IND. In recommending this capacity-building, we echo a similar 

recommendation made by the National Bioethics Advisory Commission in its recent report, 

Ethical and Policy Issues in International Research. The Commission found that “although 

ethics review committees are widely used throughout the international research community to 

ensure the protection of human participants, differences still remain in the level and quality of 

review.”54 It found that, in general, “ethics review committees in developing countries were less 

likely to raise either procedural or substantive issues for a given study, compared to U.S. 

boards.”55 

. 

Many possible mechanisms exist for building the capacity of foreign boards. For example, 

FDA staff currently use travel outside of the U.S. for conferences or other reasons as an 

opportunity to conduct outreach to institutional review boards. It should continue these 

educational efforts but should expand them to provide technical assistance to these boards. It 

could also provide technical assistance to foreign ministries of health, which in turn could assist 

FDA in ensuring that boards are operating according to FDA or other research guidelines. 

Other entities that are currently helping FDA in these capacity-building efforts should continue 

to do so. The National Institute of Health’s Fogarty International Center recently awarded 

grants to U.S. and foreign academic institutions to extend existing U.S. bioethics curricula to the 

international arena and to assist developing nations in creating their own ethics education.56 In 

addition, international bodies, such as the World Health Organization, have played key roles in 

this area. 

The Globalization of Clinical Trials 18 OEI-01-00-00190 
Finally, sponsors should take steps to educate the non-U.S. boards that they use, particularly 

those that lack experience reviewing FDA-regulated research. One way that they could do this 

is by contracting with experienced U.S. boards to help train the foreign boards. 

Encourage sponsors to ensure that all non-U.S. investigators 

participating in research for New Drug Applications sign 

attestations indicating that they will uphold human subject 

protections. 

FDA can take two steps toward this end. The first is to make certain that the attestations that 

are required of foreign investigators working under an IND are, in fact, signed. We received 

some indications that this has sometimes not been the case. We suggest that FDA reinforce to 

sponsors their obligations to obtain attestations from all investigators (foreign and domestic) 

conducting research as part of INDs. 

The second step concerns those foreign investigators who are not working under an IND, but 

are conducting research to be included in an NDA. In these instances, where there is no FDA 

requirement for an attestation, FDA could encourage sponsors to obtain an attestation from all 

participating investigators. The attestation could indicate readiness to comply with FDA 

requirements, the Declaration of Helsinki, the International Conference on Harmonization Good 

Clinical Practice standards, or with other local standards. Securing commitments from all 

investigators prior to the start of research, that they will follow an established set of clinical and 

ethical practices, can promote greater accountability among investigators and sponsors for 

protecting human subjects. 

Encourage more rigorous monitoring of foreign research sites by 

sponsors. 

Sponsor monitors can play an important role in overseeing all clinical trials because monitors 

are present at the research site with some regularity. Sponsor monitoring of research is 

required under FDA regulations and under International Conference on Harmonization 

guidelines. This is particularly important in non-U.S. sites because of the gaps in monitoring by 

other oversight entities. 

FDA could review all sponsor monitoring plans for research conducted at foreign sites to verify 

that those plans include provisions for ensuring that human subject protections are upheld. For 

example, in regions that are new to conducting research under FDA standards, FDA could 

encourage sponsors to occasionally observe the informed consent process or an institutional 

review board meeting. In doing this, FDA would be encouraging sponsors to shoulder 

additional review board oversight responsibilities. Currently, FDA often engages in an informal 

dialogue with sponsors about their monitoring plans. However, we suggest that FDA formalize 

this dialogue, as it has done recently for certain types of clinical trials. For example, FDA 

requires sponsors of gene transfer research to submit their monitoring plans for review prior to 

conducting research.57 

The Globalization of Clinical Trials 19 OEI-01-00-00190 
Develop a database to track the growth and location of foreign 

research. 

Currently, FDA databases lack important information on the extent of foreign research. They 

do not track the number of sites where NDA research is being conducted or the number of 

investigators or subjects involved in this research. Nor do they distinguish between sites that 

are operating under an IND and sites that are not. 

FDA should explore ways to track information about NDAs, including the investigators 

involved in NDA research, not just those who are working under INDs, who are currently 

tracked. It could enter this information into the investigator database retrospectively after NDA 

submissions, which contain this information. Although retrospective data would not improve 

oversight during these trials, it would allow FDA to analyze trends in the growth and location of 

research. 

FDA is now in the process of designing two other databases that relate to clinical trials. One 

will include a registry of all U.S. IRBs; the other will track demographic information on clinical 

trial subjects. As FDA designs these databases, it should consider ways in which it could 

develop them to facilitate the tracking of information on foreign research. 

Such data would enable FDA to improve its planning of oversight activities. For example, 

FDA could analyze this data to determine which regions of the world are hosting FDAregulated clinical research for the first time or which regions are experiencing rapid growth in 

clinical research and then could target educational programs accordingly. FDA could use 

investigators’ and review boards’ names and contact information to disseminate relevant 

guidance and training materials. 

Finally, we recommend that the Office for Human Research 

Protections: 

Exert leadership in developing strategies to ensure that adequate 

human subject protections are afforded for non-U.S. clinical trials 

that are funded by the Federal government and/or that contribute 

data to New Drug Applications. 

The Office for Human Research Protections has already started moving in this direction through 

its stated intention to establish an office that will focus on international affairs. Because of its 

location in the Office of the Secretary, its recently established National Human Research 

Protection Advisory Committee, and its role (through the office director) as chair of Human 

Subjects Research Subcommittee of the White House Office of Science Technology and 

Policy, it is in a prime position to provide leadership on how to foster protections in non-U.S. 

sites where research is submitted in NDAs and/or is funded by the U.S. government. 

The Globalization of Clinical Trials 20 OEI-01-00-00190 
As part of its leadership, we suggest that it work with FDA and the National Institutes of Health 

to determine specific steps that could be taken to assure proper protections for subjects 

participating in overseas trials. To the maximum extent possible, the Department of Health and 

Human Services should pursue developing an integrated approach that ensures proper 

protections regardless of whether the research is government funded or commercially funded as 

part of an NDA. 

In this context, it could be particularly helpful for the Office for Human Research Protections to 

address how the Department can better assess whether other nations’ laws and practices afford 

equivalent protections to those that apply to human subjects participating in clinical trials in the 

U.S. We recognize the sensitivities and complexities associated with such guidance, but the 

matter appears to warrant serious consideration. 

We also suggest that the Office for Human Research Protections use its position on the White 

House Human Subjects Research Committee, composed of 17 Federal agencies that have 

adopted the Common Rule for human subject protections, to stimulate integrated approaches 

across Federal agencies.58 The Common Rule has served such an integrating function for 

domestic research funded by the member agencies. Perhaps a new section of the rule could be 

added spelling out a similar integrated strategy directed specifically to government funded and 

NDA research at non-U.S. sites. 

Encourage the development of a voluntary accreditation system for 

human subject research programs. 

One way of helping inexperienced institutional review boards and research sites to improve 

their capacity to provide human subject protection is to encourage their participation in a 

voluntary accreditation system. While voluntary accreditation should not preclude additional 

FDA oversight, it can serve as a vital means of enhancing performance through collegial 

interaction and minimized reliance on the use of regulatory mechanisms. The Office for Human 

Research Protection has already contracted with the Institute of Medicine to develop a 

program and the Department of Veterans Affairs’ Office of Research Compliance and 

Assurance has contracted with the National Committee for Quality Assurance to develop and 

conduct a program. The Office for Human Research Protections should work with FDA, the 

National Institutes of Health, and international partners to foster effective accreditation practices 

throughout the world that are supported by the research community. 

The Globalization of Clinical Trials 21 OEI-01-00-00190 
COMMENTS ON THE DRAFT REPORT 

Within the Department of Health and Human Services, we received comments on the draft report from 

the Food and Drug Administration (FDA) and the Office for Human Research Protections (OHRP). 

External to the Department, we solicited comments from the Pharmaceutical Research and 

Manufacturers of America (PhRMA), Public Citizen Health Research Group, Public Responsibility in 

Medicine and Research (PRIM&R), and Applied Research Ethics National Association (ARENA). 

We received comments from Public Citizen and joint comments from PRIM&R and ARENA, two 

organizations that reflect the perspectives of many engaged in ensuring and/or studying human subject 

protections. Based on the comments we received, we made some clarifications that are reflected in the 

final report. Below we briefly summarize their comments and offer our responses in italics. Appendix 

D contains the full text of each set of comments. 

Food and Drug Administration 

The FDA disagreed with our draft recommendation calling for it to improve the collection of data about 

the location and oversight of research submit in New Drug Applications. It elaborated that neither the 

purpose nor method of data collection we proposed were clear enough to warrant a commitment of 

scarce resources. In this final report, we modified our recommendation to more clearly call for 

FDA to develop a database to track the location and growth of foreign research, (and suggested 

at least one way to do so.) With the significant growth taking place in foreign research that is 

submitted as part of New Drug Applications, we regard such an information base as an 

important means to help guide FDA oversight. FDA is developing other data bases to track 

IRBs and demographic information on clinical trials. As it works on these other databases, it 

might explore ways in which they could be developed to facilitate the tracking of information on 

foreign research 

At a general level, FDA agreed with our remaining recommendations. It did not elaborate on the 

specifics of how it would carry them out. It emphasized the importance of capacity building efforts in 

dealing with foreign IRBs and the minimal resources FDA now has to support such efforts. It also 

underscored its concern that it not discourage the submission of important, ethically conducted foreign 

research and thereby slow the approval of products that could benefit the American public. And it 

noted its limited authority in foreign countries as a constraint in carrying out the remaining 

recommendations. We recognize the importance of capacity-building to address the concerns we 

raise in our report and of drawing on available, relevant data in support of New Drug 

Applications. At the same time, we urge FDA to recognize that our review presents a significant 

warning signal that it does not have sufficient assurances of human subject protections in a 

growing proportion of the research submitted to support New Drug Applications. Within the 

limits of its resources, it is important that FDA do all it can to draw attention to this situation 

and to foster corrective actions. Its relationships with sponsors can be particularly valuable in 

this regard. Finally, while we agree that resources and authority are limiting factors, we believe 

the FDA can use its technical expertise, its influence as the 

The Globalization of Clinical Trials 22 OEI-01-00-00190 
approving authority for drugs marketed in the U.S., and its prestige and experience in 

international circles to promote reforms, even in foreign countries. 

Office for Human Research Protections 

The Office concurred with the two recommendations we directed to it. It referenced its establishment 

of a new component office on international activities and underscored its readiness to engage in the kind 

of leadership we urged and to foster voluntary accreditation as a means of enhancing human subject 

protections. We are pleased with the Office’s positive response. Through its educational 

activities, its own oversight efforts, and its leadership position among Federal agencies, it has a 

major opportunity to help foster human subject protections in the emerging sites where so much 

research is now being done in support of New Drug Applications. 

External Comments 

PRIM&R and ARENA expressed support for our assessments and recommendations. They 

emphasized the importance of fostering mechanisms for locally driven education, using approaches such 

as those that PRIM&R and ARENA have used in the United States. They strongly endorsed our 

recommendation for improved data collection and urged that FDA not just encourage, but in fact 

require attestations from all investigators conducting research to be used in support of New Drug 

Applications. The educational approaches that PRIM&R and ARENA have taken over the years 

do serve as a good model for locally driven education efforts in emerging sites. We urge both 

FDA and OHRP to draw upon them as they proceed with their own efforts. We recognize 

PRIM&R and ARENA’s sense of urgency about attestations for all research. Before any such 

requirement, we think it is important for FDA to try to use existing points of leverage to 

promote the wider use of attestations. 

Public Citizen was more critical, noting in particular that our recommendations were not strong enough 

in light of the serious problems we identified. It also noted that we failed to draw adequately on prior 

research and to give sufficient attention to deficiencies in the data collected by FDA. Public Citizen 

underscored the significance of our central finding that FDA can not assure the same level of 

protections in foreign trials as domestic ones. Public Citizen’s impatience with the current situation 

reflects that of other advocates we spoke with in the course of our inquiry and warrants 

consideration. We did draw on considerable prior research, much of it cited in the 65 endnotes 

in the report. What we did not do is cite specific incidents wherein human subject protections 

were compromised in foreign sites. Our aim in this report was to provide a systematic review of 

existing oversight, not to assess the adequacy of protections in foreign sites. 

The Globalization of Clinical Trials 23 OEI-01-00-00190 
APPENDIX A 

Foreign Investigator Inspections 

Between 1981, when FDA first began inspecting foreign sites where clinical investigators 

conduct NDA research, and 1999, FDA conducted 352 inspections in 41 foreign countries. 

Our analysis of the results of FDA clinical investigator inspections found that the outcomes of 

these inspections, based on FDA’s classifications — FDA’s overall evaluation of clinical 

investigator’s compliance — were very similar to those given to domestic inspections.59 For 

example, in both fiscal years 1998 and 1999, FDA found serious problems in about 3 percent 

of foreign and domestic inspections. (See table 1) 

Table 1. Classifications of Foreign and Domestic Investigator Inspections 

Fiscal 

Year 

Location Number of 

Inspections 

Percent 

“Official 

Action 

Indicated” 

(OAI) 

Percent 

“Voluntary 

Action 

Indicated” 

(VAI) 

Percent 

“No Action 

Indicated” 

(NAI) 

Percent 

Pending 

1998 

foreign 60 3 53 43 0 

domestic 286 5 54 41 0 

Source: FDA data 

1999 

foreign 64 3 55 42 0 

domestic 242 2 52 45 1 

OAI= FDA takes official action against investigator (e.g., sends warning letter outlining 

violations and requesting response or, for more serious violations, refuses to accept data). 

VAI= FDA asks investigator to make voluntary changes. 

NAI= Inspection reveals no objectionable conditions or practices; clinical investigator not 

required to make any changes. 

In addition to classifying the investigator inspection overall, FDA can cite clinical investigators 

for specific deficiencies, based on observations made during investigator inspections. Our 

analysis found that, as with overall classifications, the deficiency codes given to foreign 

inspections have not been significantly different from those of domestic inspections (see table 2 

on next page). 

The Globalization of Clinical Trials 24 OEI-01-00-00190 
APPENDIX A 

Table 2. A Comparison of Deficiency Code Distributions for Foreign and Domestic 

Investigator Inspections (1995-99) 

Deficiency Code 

Percent of Foreign 

Deficiencies 

(n=362) 

Percent of Domestic 

Deficiencies 

(n=1781) 

Problems with records availability <1 <1 

Failure to obtain patient consent 1 <1 

Inadequate patient consent form 12 18 

Inadequate drug accountability 12 10 

Failure to adhere to protocol 30 27 

Inadequate and inaccurate records 26 21 

Unapproved concomitant therapy – <1 

Inappropriate payment to volunteers – – 

Inappropriate delegation of authority – <1 

Failure to obtain or document IRB approval – <1 

Source: FDA data 

Failure to notify IRB of changes, failure to submit 

reports, etc. 

– 1 

Failure to report adverse reactions 9 10 

Submission of false information – <1 

The Globalization of Clinical Trials 25 OEI-01-00-00190 
APPENDIX B 

International Research Guidelines

The Declaration of Helsinki.60 Established in 1964 by the World Medical Association, 

these were the first somewhat detailed set of ethical guidelines for international clinical research. 

They are ethical principles directed at clinical investigators. Although the Declaration is not 

prescriptive about the oversight of investigators conducting human subjects research, the 

October 2000 revision does state that investigators should be aware of the ethical, legal, and 

regulatory requirements for research on human subjects in their own countries and 

internationally. Moreover, it states that investigators should submit the research protocol to an 

independent ethics committee for review prior to conducting the research. In terms of 

conducting research in other countries, the Declaration states that 

Medical research involving human subjects is only justified if there is a reasonable 

likelihood that the populations in which the research is carried out stand to benefit 

from the results of the research. 

International Ethical Guidelines for Biomedical Research Involving Human Subjects.61 

These guidelines were developed in 1982 by the Council for International Organizations of 

Medical Sciences, in collaboration with the World Heath Organization. The purpose of these 

guidelines was to aid developing countries in applying the principles of the Declaration of 

Helsinki. 

These guidelines do contain provisions for ensuring that ethical principles are adhered to, giving 

special attention to preventing exploitation of human subjects in developing countries. For 

example, the commentary for “Research involving subjects in underdeveloped communities,” 

indicates the need for review by an ethical board: 

To guard against exploitation of individuals and families in socially and economically 

exploitable communities, sponsors and investigators who wish to conduct in such 

communities research that could be carried out reasonably well in developed 

communities must satisfy their national or local ethical review committees, and in the 

case of externally sponsored research the appropriate ethical review committee in the 

host country, that the research would not be exploitative. The reason for choosing an 

underdeveloped community should be made explicit.

62 [Italics added] 

“Obligations of sponsoring and host countries,” suggests another oversight provision—that an 

objective entity in the sponsoring country review the protocol: 

When externally sponsored research is initiated and financed by an industrial 

sponsor such as a pharmaceutical company, it is in the interest of the host 

country to require that the research proposal be submitted with the comments of 

a responsible authority of the initiating country, such as a health administration, 

research council, or academy of medicine or science.63 

The Globalization of Clinical Trials 26 OEI-01-00-00190 
APPENDIX B 

International Conference on Harmonization Good Clinical Practice Guidelines.64 The 

International Conference on Harmonization, a collaboration between the United States, the 

European Union, and Japan, was established in 1990 to create international standards for the 

quality, safety, and efficacy of drugs to facilitate international trade. The Good Clinical Practice 

Guidelines include standards for overseeing human subject protections. Mostly, the guidelines 

hold sponsors accountable for ensuring these protections. Among other responsibilities, the 

guidelines state that the sponsor should verify that the investigator has adequate qualifications, 

has written informed consent before each subject’s participation in the trial, and is only enrolling 

eligible subjects. The sponsor must also confirm that the protocol was adequately reviewed by 

the appropriate institutional review board. 

There are also guidelines for institutional review boards. These spell out the institutional review 

board’s responsibilities. For example, the institutional review board is responsible for reviewing 

recruitment advertisements, the informed consent document, and the amount of compensation 

to be given to research subjects. Other institutional review board responsibilities laid out in 

International Conference on Harmonization guidelines include reviewing the qualifications of the 

investigator who will be conducting the study and conducting continuing review of the trial. In 

addition to specifying review board responsibilities, it lays out guidelines for board composition, 

function, operations, and procedures. 

Operational Guidelines for Ethics Committees that Review Biomedical Research.65 

This document, developed by the Tropical Disease Research group of the World Health 

Organization, provides guidance to countries and institutions for creating and operating their 

own research ethics committees. The group developed these guidelines because investigators 

in developing countries were conducting increasingly more research, but few people in these 

countries had experience setting up and running ethics committees. The existing international 

research ethics documents focused on ethical issues, not on how the ethical review committee 

should be staffed, organized, or operated. 

The Globalization of Clinical Trials 27 OEI-01-00-00190 
APPENDIX C 

Commitments in Clinical Investigator Attestation 

1. I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will only 

make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, 

rights, or welfare of subjects. 

2. I agree to personally conduct or supervise the described investigation(s). 

3. I agree to inform any patients, or any persons used as controls, that the drugs are being used for 

investigational purposes and I will ensure that the requirements relating to obtaining informed consent in 

21 CFR Part 50 and institutional review board (IRB) review and approval in 21 CFR Part 56 are met. 

4. I agree to report to the sponsor adverse experiences that occur in the course of the investigation(s) in 

accordance with 21 CFR 312.64. 

5. I have read and understand the information in the investigator’s brochure, including the potential risks 

and side effects of the drug. 

6. I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the 

study(ies) are informed about their obligations in meeting the above commitments. 

7. I agree to maintain adequate and accurate records in accordance with 21 CFR 312.62 and to make 

those records available for inspection in accordance with 21 CFR 312.68. 

8. I will ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible 

for the initial and continuing review and approval of the clinical investigation. I also agree to promptly 

report to the IRB all changes in the research activity and all unanticipated problems involving risks to 

human subjects or others. Additionally, I will not make any changes in the research without IRB 

approval, except where necessary to eliminate apparent immediate hazards to human subjects. 

9. I agree to comply with all other requirements regarding the obligations of clinical investigators and all 

other pertinent requirements in 21 CFR Part 312. 

The Globalization of Clinical Trials 28 OEI-01-00-00190 
APPENDIX D 

The Globalization of Clinical Trials 29 OEI-01-00-00190 
APPENDIX D 

The Globalization of Clinical Trials 30 OEI-01-00-00190 
APPENDIX D 

The Globalization of Clinical Trials 31 OEI-01-00-00190 
APPENDIX D 

The Globalization of Clinical Trials 32 OEI-01-00-00190 
APPENDIX D 

The Globalization of Clinical Trials 33 OEI-01-00-00190 
APPENDIX D 

The Globalization of Clinical Trials 34 OEI-01-00-00190 
APPENDIX D 

The Globalization of Clinical Trials 35 OEI-01-00-00190 
APPENDIX D 

The Globalization of Clinical Trials 36 OEI-01-00-00190 
APPENDIX D 

The Globalization of Clinical Trials 37 OEI-01-00-00190 
APPENDIX D 

The Globalization of Clinical Trials 38 OEI-01-00-00190 
APPENDIX D 

The Globalization of Clinical Trials 39 OEI-01-00-00190 
APPENDIX D 

The Globalization of Clinical Trials 40 OEI-01-00-00190 
APPENDIX D 

The Globalization of Clinical Trials 41 OEI-01-00-00190 
APPENDIX D 

The Globalization of Clinical Trials 42 OEI-01-00-00190 
APPENDIX E 

Endnotes

1. This report focuses on those non-U.S. trials that are submitted to FDA in New Drug Applications. 

Many drug studies are conducted outside the U.S. that do not result in these submissions. 

2. Joe Stephens, Mary Pat Flaherty, Deborah Nelson, “The Body Hunters: Testing Drugs on the 

World,” The Washington Post, Sunday, 17 December, 2000, through Friday, 22 December, 2000. 

3. 21 CFR sec. 56.102 (b)(21)(g). 

4. FDA’s Investigational New Drug regulations at 21 CFR sec. 312.120 (c) state, in part, that “foreign 

clinical research is required to have been conducted in accordance with the ethical principles stated in 

the Declaration of Helsinki” and that “for each foreign clinical study submitted under this section, the 

sponsor shall explain how the research conformed to the ethical principles contained in the Declaration 

of Helsinki or the foreign country’s standards, whichever were used. If the foreign country’s standards 

were used, the sponsor shall explain in detail how those standards differ from the Declaration of 

Helsinki and how they offer greater protection.” 

5. One difference between FDA regulations and International Conference on Harmonization Good 

Clinical Practice standards is that FDA is slightly more explicit in its institutional review board 

requirements, matters such as membership and quorum. In a few areas, the International Conference 

on Harmonization is stronger. For example, it requires the person obtaining consent to be identified 

through signature on the informed consent statement. 

6. Department of Health and Human Services, Office of Inspector General, Institutional Review 

Boards: A Time for Reform, OEI-01-97-00193, June 1998. 

7. FDA can reject the data in a New Drug Application if an investigator refuses to allow an inspection. 

8. 21 CFR sec. 312. 

9. 21 CFR sec. 312.120. “Foreign clinical studies not conducted under an IND.” These state, in part, 

that “[i]n general, FDA accepts such studies provided they are well designed, well conducted, 

performed by qualified investigators, and conducted in accordance with ethical principles acceptable to 

the world community.” They must also be conducted under the principles of the Declaration of 

Helsinki, or the local country’s standards, if they offer greater human subject protections: 

(a) Introduction. This section describes the criteria for acceptance by FDA of foreign clinical studies 

not conducted under an IND. In general, FDA accepts such studies provided they are well designed, 

well conducted, performed by qualified investigators, and conducted in accordance with ethical 

The Globalization of Clinical Trials 43 OEI-01-00-00190 
APPENDIX E 

principles acceptable to the world community. Studies meeting these criteria may be utilized to support 

clinical investigations in the United States and/or marketing approval. Marketing approval of a new 

drug based solely on foreign clinical data is governed by Sec. 314.106. 

(b) Data submissions. A sponsor who wishes to rely on a foreign clinical study to support an IND or 

to support an application for marketing approval shall submit to FDA the following information: 

(1) A description of the investigator's qualifications; 

(2) A description of the research facilities; 

(3) A detailed summary of the protocol and results of the study, and, should FDA request, case 

records maintained by the investigator or additional background data such as hospital or other 

institutional records; 

(4) A description of the drug substance and drug product used in the study, including a description of 

components, formulation, specifications, and bioavailability of the specific drug product used in the 

clinical study, if available; and 

(5) If the study is intended to support the effectiveness of a drug product, information showing that 

the study is adequate and well controlled under Sec. 314.126. 

(c) Conformance with ethical principles. (1) Foreign clinical research is required to have been 

conducted in accordance with the ethical principles stated in the “Declaration of Helsinki” (see 

paragraph (c)(4) of this section) or the laws and regulations of the country in which the research was 

conducted, whichever represents the greater protection of the individual. 

(2) For each foreign clinical study submitted under this section, the sponsor shall explain how the 

research conformed to the ethical principles contained in the “Declaration of Helsinki” or the foreign 

country's standards, whichever were used. If the foreign country's standards were used, the sponsor 

shall explain in detail how those standards differ from the “Declaration of Helsinki” and how they offer 

greater protection. 

(3) When the research has been approved by an independent review committee, the sponsor shall 

submit to FDA documentation of such review and approval, including the names and qualifications of 

the members of the committee. In this regard, a “review committee” means a committee composed of 

scientists and, where practicable, individuals who are otherwise qualified (e.g., other health 

professionals or laymen). The investigator may not vote on any aspect of the review of his or her 

protocol by a review committee. 

10. The Declaration of Helsinki is an international guideline for conducting human subjects research. It 

was first issued by the World Medical Association in 1964 and most recently revised in October of 

2000. The October 2000 revision was a cooperative effort of medical representatives from 45 

countries. For this updated version, see http://www.wma.net/e/policy/17-c_e.html, accessed October, 2000. 

11. Because these guidelines are more explicit than the Declaration of Helsinki, they meet FDA’s 

criteria of being the higher standard for protecting subjects. 

The Globalization of Clinical Trials 44 OEI-01-00-00190 
APPENDIX E 

12. In addition, FDA’s database for tracking for tracking clinical investigators who conduct drug 

research does not accurately represent the number of foreign investigators working under an IND who 

have signed attestations that they will follow FDA regulations, because not all foreign investigators are 

required to submit them, and not all of those who are required to submit them may be doing so. 

The clinical investigator database contains investigator information including name, site, address, and 

degree, based on information contained in the sponsor’s IND submission (Form FDA 1571). This 

form requires sponsors to provide investigator information either by submitting the attestation form 

signed by the investigators (Form FDA 1572) or by providing information described in 21 CFR sec. 

312.23(a)(6)(iii)(b), which includes “[t]he name and address and a statement of the qualifications 

(curriculum vitae or other statement of qualifications) of each investigator, and the name of each 

subinvestigator (e.g., research fellow, resident) working under the supervision of the investigator; the 

name and address of the research facilities to be used; and the name and address of each reviewing 

Institutional Review Board.” The majority of information in the database does come from attestations. 

However, because sponsors are not required to submit attestations and because the database does not 

identify the source of the investigator information, the database can not be used to determine how 

many foreign investigators have signed attestations. According to 21 CFR sec. 312.53 (c), sponsors of 

research conducted under an IND must obtain a signed attestation from an investigator “before 

permitting an investigator to begin participation in an investigation.” 

13. Department of Health and Human Services, Office of Inspector General, FDA Oversight of 

Clinical Investigators, OEI-05-99-00350, June 2000. 

14. Figure 2 does not fully reflect the growth of clinical investigator inspections where the NDA 

contains foreign data because FDA tracks investigator inspections by the site at which the investigation 

occurs, not by the content of the data contained in the NDA. As a result, even clinical investigator 

inspections that occur in the U.S., which are not reflected in Figure 2, may be part of an NDA that 

contains data from foreign research that goes uninspected. 

15. This includes phase 1, 2, and 3 trials. B.L. Natorff, “Clinical Trials in Central and Eastern 

Europe,” Presentation at the 36th Annual Meeting of the Drug Information Association, San 

Diego, CA, 12 June 2000. 

16. The number of approvals includes trials that, despite approval, may have never been launched or 

may have stopped prior to completion. W. Allen, “Russian Market Meets its First SMO,” 

Centerwatch 7 (February 2000) 2:4. 

17. K. Kaitlin, “Global Drug Development and International Harmonization: the Emergence of China 

as a World Pharmaceutical Player,” Drug Information Journal 32 (1998): 1187S; S. Wanless, 

The Globalization of Clinical Trials 45 OEI-01-00-00190 
APPENDIX E 

“Ethical and Policy Issues in the Oversight of Human Subjects: Private Sector Roundtable,” 

Presentation at the 39th meeting of the National Bioethics Advisory Commission, Washington, DC, 7 

April 2000; C. Statuch, “Clinical Trials is Russia: Are They Really as Good as They Sound?” 

Presentation at the 36th Annual Meeting of the Drug Information Association,” San Diego, CA, 13 June 

2000; 

and J. DeSilva, “Site Selection for Clinical Trials,” Drug Information Journal 32 (1998): 1257S. 

18. B.L. Natorff, “Experiences of a CRO Operating in Central and Eastern Europe,” EPC

International.

19. P. Loveday, “Clinical Trials in Russia: Are They Really as Good as They Sound?,” Presentation at

the 36th Annual Meeting of the Drug Information Association,” San Diego, CA, 14 June 2000.

20. S. Wanless, “Ethical and Policy Issues in the Oversight of Human Subjects: Private Sector

Roundtable,” Presentation at the 39th Meeting of the National Bioethics Advisory Commission,

Washington, DC, 7 April 2000.

.

R.J. Taylor and F. Knox, “A Clinical and Regulatory Perspective on Conducting Clinical Trials in Latin

America,” Applied Clinical Trials, 1999. http://actmagazine.com/articles/act.taylor.cfm, accessed May,

2000; P. Loveday, “Clinical Trials is Russia: Are They Really as Good as They Sound?” Presentation at

the 36th Annual Meeting of the Drug Information Association,” San Diego, CA, 13 June 2000.

21. L.R. Ptak, “The Globalization of Clinical Research,” Journal of Pharmacy Practice 9

(December 1996) 6: 418.

22. K.L. Miller and S.L. Pryce, “Better, Faster, Worldwide Too— Update on Pharmaceutical

Contract Support Organizations,” Hambrecht & Quist, L.L.C., Industry Report (4 January 1999): 1. 

23. Association of Clinical Research Professionals, ACRP’s White Paper on Future Trends: Faster 

Time to Market (1998): 7. 

24. S. Engel, “Holding On,” R&D Directions 6 (September 2000) 8: 109. 

25. The three largest contract research organizations are Quintiles, Paraxel, and Covance. The 

number of countries where contract research organizations are located is constantly changing. 

Quintiles: “Quintiles Signs Letter of Intent to Acquire Pharmacia’s Clinical Development Unit in 

Stockholm,” 30 November 2000, 

http://www.quintiles.com/press/press_releases/press_release/1,1286,723,00.html, accessed December, 2000; 

Covance Inc.,“Corporate Information,” http://www.covance.com/aboutcvd/index.html, accessed December, 

The Globalization of Clinical Trials 46 OEI-01-00-00190 
APPENDIX E 

2000;

Paraxel International Corporation, “Parexel And Acadia Collaborate to Incorporate

Pharmacogenomics Into Neuropsychiatric Drug Development,” 28 November 2000

http://www.parexel.com/main.htm, accessed December 2000

26. Kendle International Inc., “Clinical Development in Asia,” http://www.kendle.com/asia.html, accessed 

December, 2000. Information on its plans for global expansion in 1999 Annual Report. 

27. Pharm-Olam International, Inc. From DataEdge “CRO Capability Assessment Service,” 

http://www.dataedge.com/crop.html, accessed December 2000 

http://www.norma.dk/htm/exp100.htm 

28. W. Allen, “Russian Market Meets its First SMO,” Centerwatch 7 (February 2000) 2:4. 

29. NORMA ApS, “Development,” http://www.norma.dk/htm/con100.htm, accessed December, 2000 

30. If during the investigator inspection FDA finds evidence of an ethical violation (e.g., lack of 

institutional review board approval of the protocol prior to conducting the research), it can refuse to 

accept that investigator’s data in the NDA. 

31. This is the only information that FDA receives about the board review of research conducted at 

sites not under an IND application that FDA does not inspect. According to the FDA medical officers 

that receive these submissions, this is generally very basic information, such as the name and address of 

the review board and a statement that the board reviewed and approved the protocol. 

32. Foreign regulatory agencies, analogous to FDA in this country, may inspect the institutional review 

boards within their countries. However, FDA officials were unaware of any foreign regulatory agencies 

that did so. For example, the European Medicines Evaluation Agency, the regulatory agency that 

oversees all clinical research in the European Union, inspects many different entities involved in clinical 

trials, but does not inspect institutional review boards. Some regulatory agencies' investigator 

inspections involve reviewing certain aspects of the institutional review board. FDA does not routinely 

collect or maintain information on the way different countries’ regulatory agencies oversee institutional 

review boards. Because the extent and type of clinical research inspections conducted by regulatory 

agencies varies significantly by country, FDA cannot rely on this oversight mechanism to protect human 

subjects in non-U.S. trials. 

33. See endnote 11. 

34. According to FDA’s protocol for clinical investigator inspections, the FDA inspector should: 

obtain copies of the protocol and all approvals and modifications; determine whether the protocol 

changed and whether these changes were approved by the institutional review board before 

The Globalization of Clinical Trials 47 OEI-01-00-00190 
APPENDIX E 

implementation; obtain consent forms and determine whether consent was sought prior to the subject’s 

entry into the study; determine whether the consent form is compliant with FDA or International 

Conference on Harmonization -Good Clinical Practice standards; obtain the name, address, and chair 

of the institutional review board; and determine whether the investigator maintains copies of all 

correspondence with the institutional review board and whether the investigator reports all deaths, 

adverse events, and unanticipated problems to the institutional review board. Food and Drug 

Administration, “Bioresearch Monitoring for Clinical Investigators: FDA Compliance Program 

7348.811,” 1 October 1997. http://www.fda.gov/ora/compliance_ref/bimo/7348_811/default.html, accessed 

October 2000 

35. Antoine El-Hage, “Preparing for FDA Visits,” Presentation at FDA’s Clinical Trials 2000 

Conference. Rockville, MD, October 6, 2000. 

36. For example, an FDA official mentioned a flight to South Africa that cost about $5,000. 

37. In some locations, such as parts of Japan and Brazil, lodging alone can be exorbitantly expensive. 

The listed maximum Federal employee travel rates for certain foreign cities with high costs of living fail 

to reflect the actual cost of lodging in these cities. Because no hotels are available for U.S. government 

rates, FDA officials state that they sometimes must exceed maximum rates by up to 300 percent. For 

Federal per diem allowances see: U.S. State Department, “Maximum Travel Per Diem Allowances 

for Foreign Areas,” Section 925, a Supplement to the Standard Regulations (Government Civilians, 

Foreign Areas). http://www.state.gov/www.perdiems/2000/0004bperdiems.html, accessed April, 2000. 

38. According to FDA guidance, sponsors are responsible for: the selection of adequately qualified 

and trained monitors; written monitoring procedures; preinvestigation visits to ensure that investigators 

understand the protocol and understand their obligation to obtain IRB approval prior to conducting the 

study, as well as to obtain informed consent from each study subject prior to enrollment in the trial; 

periodic visits to the site throughout the trial, which are to be documented in writing; and a review of 

subjects’ records to ensure that they are accurate and complete. FDA guidance states, "proper 

monitoring is necessary to assure adequate protection of the rights or human subjects and the safety of 

all subject involved in clinical investigations and the quality and integrity of the resulting data submitted 

to the FDA." Food and Drug Administration Office of Regulatory Affairs, "Guideline for the Monitoring 

of Clinical Investigations," January 1988. http://www.fda.gov/ora/compliance_ref/bimo/clinguid.html accessed 

October 2000. See also 21 CFR 312.53 “Selecting investigators and monitors.” 

If a sponsor brings questions to FDA about a non-U.S. non-IND study, FDA will very likely give input 

and comments, even though such a submission is not required. 

39. R.J. Taylor and F. Knox, “A Clinical and Regulatory Perspective on Conducting Clinical Trials in 

Latin America,” Applied Clinical Trials, 1999. http://actmagazine.com/articles/act.taylor.cfm, accessed 

The Globalization of Clinical Trials 48 OEI-01-00-00190 
APPENDIX E 

May, 2000. 

40. J. Lee, “Clinical Research in China,” Drug Information Journal 32 (1998): 1271S. 

41. S. Puri, Covance Asia, as cited in CC. Lang, “The Current Status of Clinical Trials in Malaysia,” 

Drug Information Journal 32, (1998): 1245S. 

42. “Russian Market Meets its First SMO,” Centerwatch 7 (February 2000) 2:4. 

43. S. Shin, “The Current Status of Clinical Trials in the Republic of Korea,” Drug Information 

Journal 32 (1998): 1220S. 

44. P. Sidley, “Drug Firms in Bind Over Clinical Trials” Business Day, 28 August 2000. 

http://allafrica.com/stories/200008280121.html, accessed October, 2000. 

45. N. Kass and A. Hyder, (Draft) “Attitudes and Experiences of U.S. and Developing Country 

Investigators Regarding U.S. Human Subjects Regulations,” A Commissioned Paper for the National 

Bioethics Advisory Commission, (15 June 2000): 25. 

46. Ibid., 13, 78, 93, 167-8. 

47. Nuffield Council on Bioethics, The Ethics of Clinical Research in Developing Countries, 

October, 2000. 

48. World Health Organization’s Division of Tropical Disease Research, “Developing the Ethical 

Review Process,” TDRnews 61 (February 2000). 

http://www.who.int/tdr/publications/tdrnews/news61/ethical.htm, accessed November, 2000. 

49. World Health Organization, Operational Guidelines for Ethics Committees That Review 

Biomedical Research, Geneva, 2000. 

50. World Health Organization’s Division of Tropical Disease Research, “The Ethics of Biomedical 

Research: Sustainable Activities Begin in Asia and the Western Pacific,” TDRnews 63 (October 2000). 

http://www.who.int/tdr/publications/tdrnews/news63/ethics.htm, accessed November, 2000. 

51. In prior reports, we raised concerns about how well such protections are being met in clinical trials 

in the U.S. and have made recommendations to FDA and other Department of Health and Human 

Services components. Many Department efforts are currently underway to improve human subject 

protections in the U.S. 

52. National Bioethics Advisory Commission, Ethical and Policy Issues in International Research: 

Clinical Trials in Developing Countries. April 2001. 

The Globalization of Clinical Trials 49 OEI-01-00-00190 
APPENDIX E 

53. Our interviews, review of the literature, and attendance at conferences suggest that to varying 

degrees those conditions can be described as follows: 

(a) A fragile foundation for independent review: Foreign institutional review boards may lack 

the support to conduct a review that is sufficiently independent of the research interests. For 

host countries and their research institutions, participation in clinical trials conducted by 

international pharmaceutical companies can bring money, prestige, and the opportunity to 

develop a local research industry. For physicians, clinical trials can present an opportunity to 

participate in cutting edge research on a multinational scale, and may substantially enhance the 

income they receive for patient care. For potential subjects, clinical trials can represent the only 

opportunity to access medications that might help their medical conditions. 

(b) A political and cultural environment that may not accord sufficient emphasis to individual 

autonomy: Human subject protections are based on the principle of individual autonomy. In 

some environments it can be difficult to ensure the kind of substantive and procedural 

protections regarded as essential in FDA and international research guidelines. 

(c) A limited base of experience in providing human subject protections: The expertise that 

develops with experience in conducting ethical reviews of clinical trials is lacking in areas where 

research has not been conducted extensively. Countries with little experience hosting such trials 

are unlikely to have much of a knowledge base to tap in handling the various aspects of the 

ethical review process. 

54. National Bioethics Advisory Commission, Ethical and Policy Issues in International Research: 

Clinical Trials in Developing Countries. Chapter 5: “Ensuring the Protection of Research Participants in 

International Clinical Trials” April 2001: 82. 

55. Ibid. 

56. The director of the Fogarty International Center identified bioethics training for researchers in 

developing nations a priority initiative for the center when he assumed the center’s leadership in 1999. 

The Center awarded grants for training investigators from developing countries to Johns Hopkins 

University School of Public Health, Albert Einstein College of Medicine, Harvard School of Public 

Health, Case Western Reserve University, and the University of Toronto. The Center awarded 

planning grants to University of Cape Town, University of Chile, and University of Pretoria School of 

Health Systems. “FIC International Bioethics Grants May Support IRB Improvement,” The Blue 

Sheet 43 (October 18, 2000) 42: 15. 

57. National Institutes of Health, “New Initiatives to Protect Participants in Gene Therapy Trials,” 7 

March 2000. http://www.nih.gov/news/pr/mar2000/od-07.htm, accessed 5/00. FDA requires sponsors of gene 

The Globalization of Clinical Trials 50 OEI-01-00-00190 
APPENDIX E 

transfer research to submit their monitoring plans for review prior to conducting research; “FDA 

Inspecting All NME Applications for Appropriate Clinical Trial Monitoring,” The Pink Sheet 62 

(October 16, 2000) 42: 24. FDA has recently expanded its compliance inspections of sponsor 

monitors to include examining all new molecular entity applications to ensure appropriate clinical trial 

monitoring. 

58. 45 CFR sec. 86. 

59. Outcomes of foreign and domestic clinical inspections, in terms of corrective actions, are 

comparable (see appendix A). However, FDA officials have stated that they usually detect some 

problems when they visit areas of the world where clinical investigators are inexperienced in conducting 

research under FDA or International Conference on Harmonization - Good Clinical Practice guidelines. 

Each year FDA inspects more countries that it have not previously inspected. One FDA official noted 

that when inspectors go into new regions they “usually find some kind of problem there that 

recapitulates historically what [they] have seen first in the United States when [they] started in the ‘60's 

and then in the European Union in the ‘70's and ‘80's.” That is, clinical investigators experience a 

learning curve in properly conducting these trials. (See D. Lepay, “Ethical Issues in International 

Research: Overview of FDA,” Presentation to 

the National Bioethics Advisory Commission, 

Baltimore, MD, 2 December 1999. 

60. World Medical Association, World Medical Association Declaration of Helsinki: Ethical 

Principles for Medical Research Involving Human Subjects, adopted by the 18th World Medical 

Assembly, Helsinki, Finland, June 1964, and most recently revised October, 2000. 

http://www.wma.net/e/policy/17-c_e.html, accessed October, 2000. These guidelines have been revised five 

times since their original adoption: in 1975, 1983, 1989, 1996, and 2000. 

61. Council for International Organizations of Medical Sciences, International Ethical Guidelines for 

Biomedical Research Involving Human Subjects (1993): 9. 

62. Ibid., 25. 

63. Ibid., 44. 

64. International Conference on Harmonization, Consolidated GCP Guideline, finalized May 1996; 

in implementation phase. http://www.ifpma.org/ich5e.html#GCP, accessed May, 2000. 

65. World Health Organization, Operational Guidelines for Ethics Committees That Review 

Biomedical Research, Geneva, 2000. 

The Globalization of Clinical Trials 51 OEI-01-00-00190