A taxonomy for analyzing legal and ethical issues arising when conducting human subject research outside the borders of one's own country.

Author:Bard, Jennifer S.
  1. INTRODUCTION II. SCOPE OF THE PROBLEM A. Why Is Taking Human Subject Research and Clinical Drug Trials Overseas a Problem? B. Why Are Companies Taking Human Subject Research Overseas? C. Where Do the Trials Occur? D. Who Conducts Human Subject Research Overseas? III. ETHICAL ISSUES IN INTERNATIONAL COLLABORATIVE RESEARCH A. Lack of Access to Product by Country Where It Is Tested B. Quality Issues IV. TAXONOMY OF THE REASONS FOR LEAVING THE HOME COUNTRY A. Is There a Substantive Issue Directly Related to the Research that Requires It Being Done in Another Country? B. Is the Research Being Conducted Overseas to Lower Costs or for the Convenience of the Researchers? C. Is the Research Being Conducted Overseas to Evade Human Subject Protections of the Home Country or Because It Is Unlikely that Potential Subjects in the Home Country Would Agree to Participate? V. OPTIONS FOR LEGAL REGULATION OF HUMAN SUBJECT RESEARCH A. Law of the Country Where the Research Takes Place B. Law of the Country Where the Research or Company Is Based C. Law of the Country Where the Product Will Be Sold D. International Law VI. CURRENT REGULATORY SCHEME IN THE UNITED STATES A. General Overview B. Regulation of Human Subject Research Supporting an Application to Sell a Drug, Device, or Biologic in the United States C. Regulation of Human Subject Research Funded by the Federal Government D. Gaps in U.S. Legal Protection E. U.S. Law VII. INTERNATIONAL LAW A. A Brief History of HSR Regulation B. Laws of Individual Country Where Research Is Conducted C. Pitfalls and Risks VIII. CONCLUSION The outsourcing of clinical trials to countries where sick people are so poor they are ready to sign up to anything, whether or not they can read what's on the consent form, is now public knowledge.

    --John Le Carre (1)


    Every day, all around the world, doctors and scientists are leaving their home countries to conduct medical experiments intended either to increase knowledge or produce a marketable product using as their subjects people living in countries likely to have less infrastructure to protect their interests. (2) Their reasons for doing this vary from altruism to curiosity to profit, but when something goes wrong, when one of these subjects suffers harm, there is no clear path to legal redress. For example, if a team of French researchers go to Lithuania to test a cholesterol drug that they hope to sell in the United States, there could be as many as four different legal systems: that of the country where the research took place, the home country of the researchers, the country where the product will be sold, and any applicable international law or agreement among any of the parties involved.

    This article brings together a widely scattered literature outlining the current legal and ethical protections available for human beings who are the subjects of medical research conducted by agents of institutions located in countries other than their own. It builds on an existing taxonomy for evaluating the ethics of different reasons for conducting research outside of one's home country and adds to it a structure for applying legal avenues for redress. It gives particular consideration to U.S. law not because U.S. companies are any more involved in the practice of overseas human testing than pharmaceutical companies based elsewhere, but because the United States is the largest and most profitable market for the products that emerge from these tests. Therefore, a change in the legal requirements for selling a drug in the United States would have considerable global effect. (3) It also highlights a decision made by the Food and Drug Administration to apply a different standard of human subject protection for studies occurring overseas than ones taking place in the United States.

    The concerns addressed here do not assume that the United States has the best possible protections for human subjects of research, or even that international standards such as the ICH's Good Clinical Practices are inadequate, rather it is the fact of applying different standards abroad than would be applied at home.


    There is no legal requirement in any country to track, let alone report, human subject research being conducted within its own borders. Equally, there is no requirement to track or report what percentage of that research is being conducted by or on behalf of individuals, institutions, organizations, or entities whose main place of domicile is in a different country. Therefore, all attempts at quantification must come from aggregation of unofficial data. For example, in 2008, reporters Donald L. Barlett and James B. Steele did their study of publically available material submitted by drug companies to the FDA and found that 6,485 of the trials took place outside of the United States. (4) Another source of information comes from Wemos, a Dutch nongovernmental organization that seeks to promote clinical trials overseas in order to advance public health in general. As it explains:

    [p]ublic health is strongly influenced by the effects of globalization, which range from free trade to climate change to population growth. Many of the health challenges facing us today are not simply domestic issues, but transcend national boundaries, meaning we should no longer be focusing on purely domestic solutions. Many health problems still lack supranational policy. Tackling those challenges will require effective cooperation, policy and governance at a global level. (5) However, Wemos has also served as a watchdog and has issued several reports on what it describes as the "Clinical Trials Industry" in Kenya, (6) South Africa, (7) and other non-EU countries.

    Another source of information about how much clinical research is being done overseas comes directly from articles and reports within the research community.

    1. Why Is Taking Human Subject Research and Clinical Drug Trials Overseas a Problem?

      All of us in the United States assume that the prescription drugs we use have been certified as safe and effective by the Food and Drug Administration. That is correct. But we may also assume that the data the drug companies supply to the FDA comes from clinical trials conducted under the same standards of safety for the human beings involved as would apply in the United States. This is not true.

      The FDA does not test drugs itself. Instead, it relies on data supplied by the companies seeking to sell them. (8) When clinical drug trials are conducted in the United States, the FDA requires that the companies follow U.S. laws passed to protect human subjects of research. (9) But when the trials are conducted exclusively outside of the United States, the FDA does not require sponsors to apply for an IND. (10) At one point, there was confusion as to whether sponsors who did not need an IND had to comply with 21 C.F.R. 312 anyway. This was clarified on April 28, 2008 when the FDA issued a final rule modifying 21 C.F.R. 312.120, entitled "Human Subject Protection; Foreign Clinical Studies Not Conducted Under an Investigational New Drug Application." (11)

      Before the 2008 modification, 21 C.F.R. 312 required that studies conform to whichever of the following provides greater protection of the human subjects: (1) the ethical principles contained in the 1983 version of the Declaration of Helsinki; or (2) the laws and regulations of the country in which the research was conducted. (12)

      Also, under 21 CFR 814.15(a) and (b), the FDA will accept a foreign clinical study involving a medical device not conducted under an IDE only if the study conforms to whichever of the following provides greater protection of the human subjects: (1) the ethical principles contained in the 1983 version of the Declaration of Helsinki; or (2) the laws and regulations of the country in which the research was conducted. (13)

      This reference to the "Declaration of Helsinki" refers to a statement by the World Medical Association (WMA) of "Ethical Principles for Medical Research Involving Human Subjects." (14) The first Declaration of Helsinki was adopted by the WMA in 1964 and has been revised nine times since then, with the most recent version adopted at the 64th WMA General Assembly, Fortaleza, Brazil, October 2013. (15) Therefore, the FDA's reference to the 1983 version of the Declaration of Helsinki refers to a version that has been edited and superseded eight times. (16)

      Critics of the FDA's decision not to require sponsors of drugs tested overseas to comply either with the latest version of the Helsinki Doctrine or the regulatory requirements of an IND argue that as a result the protection of human subjects overseas is inadequate. (17) Specifically, clinical trials overseas are allowed to use placebos even when there is an existing effective treatment. This is only permissible in the United States when there is no effective treatment. Others minimize the concerns stating that, in effect, the FDA is complying with international standards in that many countries where drugs are tested follow the guidance of the International Conference on Harmonization--Joint Safety/Efficacy. (18) As a legal matter, the FDA's decision has created the need to analyze the laws of the country where the drug is tested in order to compare it to the Helsinki "ethical principles." This is a "comparing apples to oranges" task because of the inherent differences in a legal system and principles of ethics.

      The volume of human subject research conducted overseas has created the need for a way of first categorizing the legal and ethical issues arising when human subject research is conducted overseas and then identifying the sources of law, and ethics, that can be used to analyze specific situations. This article addresses this need by creating a taxonomy that will assist in identifying the legal issues arising in a specific scenario and then identifying the sources of law available for protecting the people who...

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