ABA Health eSource
October 2008 Volume 5 Number 2

FDA Requires Foreign Clinical Studies be in Accordance with Good Clinical Practice to Better Protect Human Subjects
by W. Thomas Smith, University of Florida, Gainesville, FL

W. Thomas SmithNews reports in recent years have raised concerns of unethical use of human subjects in clinical drug trials sponsored by US companies but conducted in undeveloped countries. 1 According to an article in the Boston Globe, as the number of foreign drug trials increases, ethical concerns, such as the exploitation of research participants, are raised. 2 An article in the New York Times reported that pharmaceutical companies conducting research overseas often recruit the poor and illiterate for drug testing, fail to report adverse test results, and even conduct unauthorized clinical trials. 3

FDA Responds to Concerns Over Foreign Clinical Trials

In response to concerns about the conduct of clinical trials in foreign countries, in June 2004, the Food and Drug Administration (FDA) published a proposed rule that would revise the agency's earlier regulations involving the conditions under which it would accept the results of foreign clinical studies not conducted under an investigational new drug (IND) application. A final rule (Final Rule) was published in April 2008 and will take effect on October 27, 2008. 4

Means by which the FDA Accepts Clinical Trial Data for Review

Under current FDA guidelines, there are two routes by which clinical drug trial data are accepted for review. With the first route, researchers may file an IND, which is necessary to introduce the study drug into interstate commerce. 5 Before an investigational drug is approved, it will undergo three clinical trial phases in the US in order to study the safety and efficacy of the drug. In taking this first route, the researchers must comply with all federal research regulations. 6 With the second route, researchers may choose to conduct the three premarketing clinical trial phases outside the US, which allows researchers to steer clear of direct FDA regulation. Once researchers complete the three premarketing phases, they apply for a new drug application (NDA) in the US. 7 During FDA review of the NDA, the agency determines whether the studies used to support the researchers' NDA satisfies either the guidelines expressed in the Declaration of Helsinki (Declaration) 8 or the regulations of the country where the research was conducted, whichever represents the greater protection for the individual. 9

The Globalization of Clinical Trials

Ten years ago, only 14% of all clinical drug trials were performed outside the US. 10 Today, however, an increasing number of pharmaceutical companies recruit more and more human subjects for clinical drug trials in Eastern Europe, Latin America, Africa, and Asia. 11 Within the next three years, it is projected that the top pharmaceutical companies will conduct up to 65% of clinical drug trials outside the US, up from 43% today, due to economic advantages and ready access to large numbers of treatment-naive patients. 12 The most significant costs of research and development of drugs are incurred in the three premarketing phases. By outsourcing these phases to countries where R & D can be conducted less expensively, pharmaceutical companies can save hundreds of millions of dollars. 13 Additionally, US companies prefer to enroll foreign patients because they are not as likely as Americans to be enrolled in a competing clinical trial or to be under treatment with other medications. 14

Ethical Issues

A major concern with clinical trials conducted abroad is that pharmaceutical companies may take advantage of vulnerable citizens. For many foreign research subjects, especially in underdeveloped countries, the only way to receive needed drugs is through participation in clinical trials. Also, in some countries where citizens are less educated than in the US, research participants may not understand their individual rights in a clinical trial and may be more inclined to follow the researchers' recommendations. 15 Furthermore, according to a December 2000 investigative report by the Washington Post, human subjects in trials conducted in foreign countries were exposed to inappropriate risks when researchers deviated from protocols, when adverse findings were not reported, when the risks of participation were not explained to potential subjects, and when enrolled subjects whose conditions worsened were not moved from experimental to standard treatments. 16 Few regulatory safeguards exist to protect human research subjects in many of the countries where premarketing clinical trials are being conducted.

FDA Amends Regulations

As a means to protect human subjects and to help ensure the quality and integrity of data obtained from foreign clinical trials not conducted under an IND, the FDA Final Rule revises the regulations in Section 312.120 (21 CFR part 312) by requiring that these studies be conducted in accordance with good clinical practice (GCP) rather than in accordance with the ethical principles expressed in the Declaration or the regulations of the country where the research was conducted. 17 The FDA will only accept a study as support for an IND or an application for marketing approval if standards of GCP are met. 18 The FDA will, however, examine data from a noncompliant study because the data may have a bearing on the safety of the drug. 19

Good Clinical Practice

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), in its document E6 Good Clinical Practice: Consolidated Guidance (ICH E6), defines GCP as an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. 20 Compliance with this standard provides public assurance that the rights, safety, and wellbeing of trial subjects are protected and that the clinical trial data and reported results are credible. 21 Under the Final Rule, GCP is defined as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials in a way that provides assurance that the data and reported results are credible and accurate and the rights, safety, and wellbeing of trial subjects are protected. 22 GCP specifically includes review and approval by an independent ethics committee (IEC) 23 before initiating the study as well as continuing IEC review of ongoing studies. The Final Rule also requires that researchers obtain and document the freely-given informed consent of study subjects. 24

Why the FDA Amended Its Regulations

The FDA stated that the change in requirements for non-IND foreign clinical trials was due to three primary reasons: a) evolution of the standards for protecting human subjects, b) a desire to provide greater assurance of the quality of the data obtained from these studies, and c) a need to head off potential confusion that may result from future revisions of the Declaration. 25 First, in 1997, the FDA adopted the ICH E6 standard of GCP as a guidance for the industry. 26 The FDA believes that the standard of GCP in the Final Rule is consistent with that in ICH E6; however, the Final Rule is more flexible. 27 This flexibility allows the agency to adapt to differences in how countries regulate the conduct of clinical research and obtain informed consent, which will enable it to better protect human subjects. 28 Next, the Final Rule, unlike the Declaration, provides guidance on how to ensure proper conduct of clinical trials by specifying that GCP includes providing assurance that the data collected is credible and accurate, and requiring that researchers submit information on study monitoring and conformance with protocols. 29 Last, the final rule codifies ethical guidelines that are consistent with the Declaration without referencing the Declaration in the rule. The FDA made this change because of concern that the Declaration is subject to change independent of FDA authority and could thereby be modified to contain provisions that are inconsistent with US laws and regulations. 30

Potential Implications of the Final Rule

By mandating independent review of clinical research by an IEC, the Final Rule attempts to assure society that pharmaceutical companies and the American people will not benefit from abuse of subjects. However, it may be too soon to predict whether the Final Rule will indeed diminish the harms that befall foreign research participants. The Final Rule mandates that a qualified and experienced IEC take responsibility for ensuring the protection of the rights, safety, and wellbeing of the research participants. An independent review board (IRB) 31 is one type of IEC. 32 Historically, foreign IRBs have had difficulty understanding clinical trial standards, perhaps because these IRBs are located in remote areas with limited access to information. 33 In addition, empirical evidence suggests that researchers often fail to meet ethical standards in foreign clinical trials. 34 Furthermore, if the FDA chooses to conduct any oversight of foreign testing, the oversight usually occurs after the trials are complete. 35 The Final Rule allows the FDA to validate foreign clinical trial data through onsite inspection although the rule does not require that the FDA visit the site of every foreign trial. 36 Consequently, it may still be possible even under the Final Rule that the FDA will be unaware of researcher impropriety until long after the studied drug is on the market. Finally, it is highly unlikely that pharmaceutical manufacturers will be deterred from conducting clinical trials abroad since the ability to game the system still exists, as does their desire to conduct clinical trials quickly and inexpensively.

1 Sonia Shah, Body Hunting: The Outsourcing of Drug Trials, The Globalist. January 31, 2007, available at http://www.theglobalist.com/DBWeb/StoryId.aspx?StoryId=5637 (last visited Sept. 16, 2008).
2 Christopher Rowland, Clinical Trials seen Shifting Overseas: Tufts Study Cites Lack of US Subjects, Study Finds Clinical Trials Shifting Out of US, The Boston Globe. July 11, 2003 Third Edition, at C1.
3 Saritha Rai, Drug Companies Cut Costs with Foreign Clinical Trials, The New York Times. February 24, 2005, available at http://www.nytimes.com/2005/02/24/business/24clinic.html(article link truncated) , (last visited Sept. 25, 2008).
4 Federal Register Vol. 73, No. 82, Monday April 28, 2008 (21 CFR 312) (Rules & Regulations) page 22800.
5 Code of Federal Regulations, Title 21(Food & Drugs) Volume 5 Section 312.1 (a), Revised April 1, 2003.
6 Fazal Kahn, Article, The Human Factor: Globalizing Ethical Standards in Drug Trials Through Market Exclusion, 57 DePaul L. Rev. 877, 888 (2008).
7 The Food & Drug Administration, http://www.fda.gov/cder/regulatory/applications/nda.htm, (last visited Sept. 16, 2008). For decades, the regulation and control of new drugs in the United States has been based on the New Drug Application (NDA). Since 1938, every new drug has been the subject of an approved NDA before U.S. commercialization. The NDA application is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S. The data gathered during the animal studies and human clinical trials of an Investigational New Drug become part of the NDA.
8 The World Medical Association, http://www.wma.net/e/policy/b3.htm, (last visited Sept. 16, 2008). The World Medical Association developed the Declaration of Helsinki as a statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects.
9 Kahn, supra note vi, at 888.
10 Gregory Lopes, Drug Makers Look East for Testing; Lower Costs, More Patients in Asia to Help Speed Approval, The Washington Times. December 8, 2007 Saturday, at A01.
11 Rowland, supra note ii at C1. Lopes note viii at A01. Robert Gatter, Article, Conflicts of Interest in International Human Drug Research and the Insufficiency of International Protections, 32 Am. J. L. and Med 351, 352 (2006).
12 Tufts Center for the Study of Drug Development, Outlook 2008, available at http://csdd.tufts.edu/InfoServices/OutlookPDFs/Outlook2008.pdf, (last visited Sept. 16, 2008).
13 Drug Industry Daily, Clinical Trials in Low-Cost Countries Offer Big Savings, GSK Says, August 4, 2004. http://www.fdanews.com/newsletter/article?issueId=6850&articleId=65622 (last visited Sept. 16, 2008).
14 Rowland, supra note ii, at C1.
15 Id.
16 Gatter, supra note xi, at 353, citing Joe Stephens, The Body Hunters: Exporting Human Experiments (pt 1), WASH POST. Dec. 17, 2000, at A1.
17 Fed. Reg., supra note iv, at 22800.
18 Id at 22801, 22805.
19 Id. at 2201.
20 US Department of Health & Human Services, Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance. April 1996, http://www.fda.gov/cder/guidance/959fnl.pdf, (last visited Sept. 16, 2008).
21 Id.
22 Fed. Reg., supra note iv, at 22806.
23 Id. at 2209. As a means to document the adequacy of an IEC, the FDA requires that there be adequate documentation of the IEC composition; this includes submitting the names and qualifications of the members of the IEC to the trial sponsor or applicant. Alternatively, the FDA requires submission of the name and address of the IEC that reviewed a particular study and a statement that the IEC meets the definition of an IEC in 21 CFR ยง312.3. Furthermore, the trial sponsor or applicant must maintain records supporting the statement, including records of the names and qualifications of the IEC members, and make these records available to the FDA for review upon request.
24 Id at 22801.
25 Id.
2 6 Id.
27 Id.
28 Id.
29 Fed. Reg., supra note iv, at 22801.
30 Id.
31 FDA, Information Sheet Guidances Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors, available at http://www.fda.gov/oc/ohrt/irbs/ (last visited Sept. 25, 2008). Under FDA regulations, an IRB is an appropriately constituted group that has been formally designated to review and monitor biomedical research involving human subjects. Typically institutions (hospitals and universities) have created their own IRBS; however, an institution may hire an independent IRB if it is without one. In accordance with FDA regulations, an IRB has the authority to approve, require modifications in (to secure approval), or disapprove research. This group review serves an important role in the protection of the rights and welfare of human research subjects. The purpose of IRB review is to assure, both in advance and by periodic review, that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in the research. To accomplish this purpose, IRBs use a group process to review research protocols and related materials (e.g., informed consent documents and investigator brochures) to ensure protection of the rights and welfare of human subjects of research. See generally, Grimes v Kennedy Krieger Institute, Inc. 366 Md. 29; 782 A.2d 807 (2001). Functions of IRBs are to assess the protocols of the project to determine: whether the project itself is appropriate, whether the consent procedures are adequate, whether the methods to be employed meet proper standards, whether reporting requirements are sufficient, and the assessment of various other aspects of a research project. Thus, the overarching function of an IRB is to protect human research subjects from coercion and unreasonable risk.
32 Fed. Reg., supra note iv, at 22805.
33 Food and Drug Administration, NIH Sees More Ethical Problems with Foreign IRBs; Steps up Training, FDA Week. Vol. 12 No. 11. March 17, 2006.
34 Kahn, supra note vi, at 891, citing David M. Kent et al., Clinical Trials in Sub-Saharan Africa and Established Standards of Care: A Systematic Review of HIV, Tuberculosis, and Malaria Trials, 292 JAMA 237, 239 (2004). A study that focused on compliance with the "best current" therapeutic efforts standard of the Declaration in sub-Saharan African clinical trials found that only 16% of studies satisfied the requirement.
35 Kahn, supra note vi, at 891.
36 Fed. Reg., supra note iv, at 22802.

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