Source: https://www.hhrjournal.org/2013/08/informed-consent-enforcing-pharmaceutical-companies-obligations-abroad/
Timestamp: 2019-04-18 11:45:38+00:00

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The past several years have seen an evolution in the obligations of pharmaceutical companies conducting clinical trials abroad. Key players, such as international human rights organizations, multinational pharmaceutical companies, the United States government and courts, and the media, have played a significant role in defining these obligations. This article examines how such obligations have developed through the lens of past, present, and future recommendations for informed consent protections. In doing so, this article suggests that, no matter how robust obligations appear, they will continue to fall short of providing meaningful protection until they are accompanied by a substantive enforcement mechanism that holds multinational pharmaceutical companies accountable for their conduct. Issues of national sovereignty, particularly in the United States, will continue to prevent meaningful enforcement by an international tribunal or through one universally adopted code of ethics. This article argues that, rather than continuing to pursue an untenable international approach, the Alien Torts Statute (ATS) offers a viable enforcement mechanism, at least for US-based pharmaceutical companies. Recent federal appellate court precedent interpreting the ATS provides the mechanism for granting victims redress and enforcing accountability of sponsors (usually pharmaceutical companies and research and academic institutions) for informed consent misconduct. Substantive human rights protections are vital in order to ensure that every person can realize the “right to health.” This article concludes that by building on the federal appellate court’s ATS analysis, which grants foreign trial participants the right to pursue claims of human rights violations in US courts, a mechanism can be created for enforcing not only substantive informed consent, but also human rights protections.
In 2001, the families of the dead and injured children filed suit against Pfizer under the Alien Tort Statute (ATS) for violating a norm of “customary international law prohibiting medical experimentation on non-consenting human subjects.”26 Specifically, Pfizer was sued for violating the principle of informed consent, refusing to provide the best treatment available when it supplied low doses of the drug approved by the FDA and when it failed to monitor the progress of the children in the study, and for its decision to conduct a trial using a medication that is known to cause liver damage in children.27 What the families soon learned however — and arguably what Pfizer had known all along — is that neither international nor US law provided redress against American companies for human rights violations committed abroad. What follows is a discussion of how this fact is changing.
Medical professionals have for centuries discussed concerns about the treatment of human subjects. Only recently, however, have these rigorously debated ethical notions and legal protections for human subjects been codified. The six guidelines currently regarded as most influential, internationally, include the Nuremberg Code, the Helsinki Declaration, the Council for International Organizations of Medical Sciences (CIOMS) Guidelines, Article 7 of the International Covenant on Civil and Political Rights (ICCPR), the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practices (ICH/GCP), and the recently revised FDA’s “Good Clinical Practices” (GCP) guidelines for foreign clinical trials.28 While the contours of these guidelines vary somewhat, the primacy of informed consent is a constant in every scheme. Furthermore, these documents reveal several universally accepted components of informed consent — including an explanation of the nature and procedure of the trial in a language that participants can understand and a requirement that the researchers obtain informed consent without pressuring subjects, i.e., ensuring that they understand that they are free to choose whether or not to participate.29 Notwithstanding the clarity and general acceptance of requirements, a gap persists between the theoretical ideal of informed consent and the reality of its application in international clinical trials.
In the context of the Trovan clinical trial, an argument could be made, as the plaintiffs’ did, that Pfizer’s conduct violated the Nuremberg Code to the extent that its doctors did not obtain informed consent from the participants. Would the United States legal system recognize, however, violations on international law that are contained in a document it never adopted?
The researcher obligations contained in the Guidelines regarding clinical trials in general and informed consent in particular are exacting. In sharp contrast, there are no sponsor-specific informed consent obligations. There are, however, five shared sponsor/investigator consent responsibilities, including obligations to ensure that intimidation is not used, that consent is renewed if there is a substantial change in trial conditions or procedures, and that, generally speaking, consent is in written form.47 Unlike the detail provided in the investigator obligations, the Guidelines give neither party any guidance regarding the satisfaction of these joint obligations. Similar to the Code and Declaration, the Guidelines are not legally binding.
Unlike the level of detail provided in other parts of the ICH/GCP, the principle that addresses sponsor obligations is cursory at best. The ICH/GCP limits a sponsor’s obligation to “implementing and maintaining quality assurance,” verifying that “subjects are protected” and ensuring that investigators comply with GCP and regulatory requirements.55 The ICH/GCP allows the sponsor to transfer all trial-related duties to a contract research organization. Thus, sponsors are not required to have any direct involvement in ensuring quality or human rights protections. While the standards create stringent requirements for informed consent, the daily responsibility for ensuring compliance remains with the investigator.56 Accordingly, the majority of sponsor obligations are merely supervisory in nature. In 1997, the FDA adopted these standards as guidance but declined to incorporate them into mandated FDA regulations.
FDA Good Clinical Practice: One step forward, two steps . . .
However, criticism of the FDA’s GCP is its self-admitted “flexibility.” In drafting the GCP, the FDA refused to incorporate the ICH/GCP’s detailed approach with respect to identifying responsibilities of various parties. For instance, the ICH/GCP has specific protocols that must be carried out by particular parties for reporting adverse events and monitoring trials. Instead, the FDA adopted regulations that are sufficiently malleable to permit countries to take one of any number of different approaches to regulate clinical research and obtain informed consent. 66 The extent to which that “flexibility” leaves the door open for continued human rights abuses remains to be seen. These issues and concerns are a reminder that, while advances have been made in the area of informed consent, work is still needed to ensure that meaningful human rights protections exist for all subjects participating in clinical trials.
The evolving obligation — Where to next?
The scope of those responsible for ensuring informed consent protections has evolved since its international inception in 1946. It has been argued that human subject experimentation is one of the few areas of health where the language of “rights” has evolved enough to have practical consequences.67 There is a certain amount of truth in this assertion. For the countries that have adopted them, the ICH/GCP and revised FDA regulations require more specificity and accountability in obtaining informed consent than previous guidelines. In particular, the revised FDA guidelines require sponsors, rather than just researchers, to take active responsibility for ensuring proper informed consent procedures. These developments suggest that the gap between the theoretical ideal and the practical reality of informed consent protections may be closing. Though not entirely found in one document, many of the components of the fully evolved set of obligations for pharmaceutical companies currently exist. Drawing from those sources, Table 1 outlines what that set of obligations might look like.
Description of when and how informed consent was obtained * The FDA requires sponsors to make this disclosure when submitting clinical trial data from outside the United States.
These obligations would require tighter US regulations that ensure more specificity in what information is given to subjects. On an international level, the obligations call for WHO and UN to hold pharmaceutical companies to the same level of accountability as investigators in acquiring informed consent. Finally, on the industry level, they necessitate pharmaceutical companies’ willingness to accept responsibility for adverse incidents and compensation of victims without resorting to protracted litigation. However, for any of these current or proposed measures to have a meaningful effect, adequate enforcement mechanisms are necessary.
The literature on informed consent often includes discussion on how to enforce the human rights protections of trial participants, or in the alternative, how to enforce actions against non-state actors who violate these rights. Many proposals struggle to adequately address the challenges to informed consent requirements created by multinational pharmaceutical companies conducting trials in countries with limited regulatory frameworks and/or inadequate human rights protections. For example, a frequently discussed solution is the creation of an international UN or WHO type tribunal that would have the authority to police international trials.68 Under the terms of this proposal, all countries would recognize this entity, and participation in resolving disputes would be mandatory. Another suggestion has been to use the Agreement on Trade-Related Aspects of International Property Rights (TRIPS) to deny intellectual property protections to pharmaceutical companies that have developed drugs through sponsored trials that violated the rights of trial participants.69 Still others have suggested enforcement of human rights protections for trial participants that requires the universal and mandatory adoption of an ethical guideline like the Nuremberg Code or Helsinki Declaration discussed in this article.70 The flaw in these proposals is their reliance on the creation of an international agency or law that could challenge national sovereignty.
In many developing countries, this enforcement vacuum creates insurmountable challenges for injured trial participants who are forced to look outside of their own country’s judicial system for relief against US-based clinical sponsors. In these situations, participants quickly learn that there is no internationally binding law; no international forum to assess the validity of a human rights infringement by a non-state actor, much less sanction the violator or compensate the victim; and a multitude of jurisdictional obstacles that threaten their ability to sue in the sponsor’s country.71 The FDA’s revised clinical trial guidelines offer little in the way of penalties for noncompliance and even less in terms of participant redress. For example, according to the GCP, if a sponsor’s conduct violates the informed consent regulations, the trial data is still reviewed; it just cannot be used to market or sell the drug in the United States. If the sponsor’s conduct injured or caused the death of a participant, the regulations do not require the sponsor to administer post-trial care, compensate participants, or in the event of death, compensate the participant’s family.
Even the robust set of obligations proposed in the previous section is, in isolation, inadequate to guarantee a pharmaceutical company’s compliance with informed consent requirements throughout the developing world. However, as illustrated in the Second Circuit Court of Appeals’ ruling in the Trovan case, perhaps the answer to enforcing sponsor obligations and ensuring human rights protections can be found, not through regulatory agencies, but rather through the courts.
In the aftermath of Pfizer’s departure from Nigeria, the victims and family members of victims wanted to file suit against the company. Among their first challenges was to find an appropriate forum. Unlike Anglo-American corporate law, international law generally does not consider corporations as “legal persons.”72 Rather, the focus of international law is on systematic abuses of human rights and state interests and duties. Accordingly, violations of international norms by a corporation are seldom enforceable in an international human rights forum. Given the lack of a viable international forum, the plaintiffs pled their case under the United States’ Alien Tort Statute (ATS).
As a result, the court dismissed the plaintiffs’ claims for failing to provide a predicate for ATS jurisdiction.
In correcting the trials court’s misapplication of Sosa v. Alvarez-Machain, the appellate court clarified that nothing in that opinion suggests that the ATS inquiry be halted “if some of the sources of international law giving rise to the norm are found not to be binding or do not explicitly authorize the cause of action.”83 Thus, after eight years of litigating whether US courts have jurisdiction to hear the case, the US Court of Appeals for the Second Circuit affirmed the plaintiffs’ right to sue Pfizer in the United States. On January 30, 2009, the appellate court remanded the case to the US district court for a trial on these merits. On August 10, 2009, Pfizer filed a writ of certiorari (an appeal) to the Supreme Court to hear its appeal.84 To date, the Court has not ruled.
The significance of the Second Circuit’s decision is twofold. First, it identified “informed consent” as a universally recognized legal norm. Second, it permitted a lawsuit against an American-based pharmaceutical company for human rights violations. In doing so, the court articulated a legally enforceable framework for a foreign country’s nationals to pursue clinical trial violations. This case also builds on the Second Circuit’s application of the ATS to other human rights-related claims. In Khulumani v. Barclay National Bank Ltd., the plaintiffs alleged that the defendants — more than 50 multinational corporations including Bristol-Meyers Squibb and Coca-Cola — actively collaborated with the South African government to perpetuate the repressive system of apartheid.85 In reversing the district court’s dismissal of the plaintiffs’ ATS claims, the court of appeals explicitly extended its jurisdictional reach over international human rights violations.86 These cases signify an important step in the advancement of universal rules of law condemning human rights abuses. By repeatedly affirming foreign victims’ right to proceed with actions to redress wrongs and to hold companies accountable for human rights violations, whether those rights are explicitly codified in US law or not, the Second Circuit has increased the ambit of actionable ATS conduct.87 Together, these holdings serve as persuasive authority in American courts.
Within the context of informed consent, the Trovan decision is instructive in terms of the gap that still exists between domestic and foreign trial participant protections. The court’s holding suggests that sponsor conduct that violates protections afforded to trial participants in the United States or countries governed by the ICH/GPS but not prohibited by the GCP could be actionable under the ATS.88 It is this potential for US pharmaceutical companies to face liability for human rights violations committed abroad, more than the change in regulations or international standards, that may hasten informed consent measures that offer true protection to clinical trial participants regardless of nationality.
I would like to thank Professors Chester Chambers, Maqbool Dada, and my mentor, Laura Hartman, for their invaluable comments and assistance in editing this article.
Stacey B. Lee, JD is a lecturer of business law and ethics in the Johns Hopkins Carey Business School, Baltimore, Maryland, USA.
Please address correspondence to the author at Johns Hopkins University Carey Business School, 100 North Charles Street, Baltimore, Maryland, 21201, email: staceyb.lee@jhu.edu.
1. Throughout this article, the term “developing countries” refers to countries with relatively low standards of living and underdeveloped infrastructures. US Department of State, “The language of trade: Glossary” (Washington, DC: US Department of State, n.d.). Available at http://www.4uth.gov.ua/usa/english/trade/language/glossdi.htm#devgco. Recent articles have highlighted the lure of locating clinical trials in developing countries. Because of their impoverished governments’ inability to provide medical treatment to their citizens, host countries (in Africa in particular) have little to no legislative protections for human subjects. As a result, the value proposition of developing countries to pharmaceutical companies is the ability to conduct clinical trials with minimal interference from regulatory bodies. The tacit agreement is that if the host country enacts laws or enforces international protections the pharmaceutical company dislikes, the company could simply move its resources to a less burdensome host country. M. Flaherty, “Testing tidal wave hits overseas,” Washington Post (December 18, 2000).
2. F. Kelleher, “The pharmaceutical industry’s responsibility for protecting human subjects of clinical trials in developing nations,” Columbia Journal of Law and Social Problems 38/67 (2004), pp. 67–106.
3. According to the CIOMS Guidelines, the sponsor is often a pharmaceutical company that initiates, funds, organizes, and oversees the conduct of the clinical trial. The need to address sponsor conduct is a relatively recent concern born out of the emergence of for-profit organizations conducting clinical research in developing countries. Relocating trials to developing countries began after the 1980 FDA ruling that allowed data from foreign trials to be used in support of new drug applications. Flaherty (see note 1). This global expansion has brought with it a set of new unknowns related to sponsor conduct and possible exploitation of foreign subjects.
4. This article examines one of the many issues surrounding global clinical trials. This single focus does not suggest that inadequate informed consent protections are the most pervasive or egregious threats facing research participants. However, beyond the scope of this article, inadequate placebo controls, denials of standards of care, and lack of compensation for direct injury pose serious harm to the lives and safety of trial participants.
5. International Covenant on Economic, Social and Cultural Rights (ICESCR), G.A. Res. 2200A (XXI) (1966). Available at http://www2.ohchr.org/english/law/cescr.htm.
6. The United States Court of Appeals for the Second Circuit is one of the thirteen United States Courts of Appeals. Its territory comprises the states of Connecticut, New York, and Vermont. It has appellate jurisdiction over the district courts in those regions. Available at http://www.uscourts.gov/court_locator/CourtMapDetails.aspx?state=NY.
7. Multinational companies are difficult to regulate. By using multiple facilities around the globe, corporations can strategically avoid state power and certain national regulatory schemes. For example, many of the FDA requirements regarding clinical trials do not apply outside of the United States. Moreover, to the extent that foreign trials must adhere to some FDA requirements, the agency lacks the resources to ensure compliance. Kelleher (see note 2), p. 84.
8. National Center for Infectious Diseases, “Meningitis.” Available at http://www.cdc.gov/meningitis/index.html.
9. J. Stephens, “Where profit and lives hang in balance,” Washington Post (December 17, 2000). The intravenous form of chloramphenicol used by MSF was recommended by WHO as the first line treatment for bacterial meningitis in low-income countries. World Health Organization, Meningiococcal meningitis, Fact sheet 141 (February 2010). Available at http://www.who.int/mediacentre/factsheets/fs141/en/. At the time, however, ceftriaxone, was regarded in the industry as standard of care for bacterial meningitis. Federal Ministry of Health of Nigeria, Report of the investigation committee on the clinical trial of trovafloxacin (Trovan) by Pfizer, Kano, 1996 (Kano, Nigeria: Federal Ministry of Health, 2001). Available at http://www.circare.org/info/trovan_clinicaltrialreport.pdf. In the use of ceftriaxone in its trial, Pfizer wanted to show that Trovan outperformed the FDA-approved industry standard, but the choice of ceftriaxone also demonstrates Pfizer’s compliance with the rules governing human subjects research to provide standard of care.
10. J. Stephens (see note 9).
14. Abdullahi v. Pfizer, Inc. (2009), 562 F. 3d 163 (2d. Cir), pp. 3–7.
26. Ibid, pp. 4–5. The ATS grants US courts jurisdiction over claims brought by foreigners that constitute a violation of international law, as defined by Statutes of the International Court of Justice, art. 38 (1), June 26, 1945, 59 Stat. 1055, 1060, T.S. No. 993.
28. These sources are located respectively at (1) United States v. Brandt, Trials of War Criminals Before the Nuremberg Military Tribunals Under Control Council Law No. 10, (Washington, DC: US Government Printing Office, 1949), vol. 2, p. 181–182 [hereinafter Nuremberg Code]. Available at http://www.hhs.gov/ohrp/references/nurcode.htm; (2) World Medical Association, Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects, art. 20, 22, G.A. Res. (adopted 1964, amended 1975, 1983, 1989, 1996, and 2000). Available at http://www.wma.net/e/policy/pdf/17c.pdf [hereinafter Declaration of Helsinki]; (3) Council for International Organizations of Medical Services [CIOMS], International Ethical Guidelines for Biomedical Research Involving Human Subjects, guideline 4 (3rd ed. 2002), superseding the 1993 second edition at guideline 1; (4) International Covenant on Civil and Political Rights, art. 7, Dec. 19, 1966, 999 U.N.T.S. 171 [hereinafter ICCPR]; International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline for Good Clinical Practice (ICH-GCP) Federal Register 62/90 (May 9, 1997) pp. 25692–25702; and Department of Health and Human Services, Food and Drug Administration, “Human Subject Protection; Foreign Clinical Studies Not Conducted Under an Investigational New Drug Application 21 CFR 312 [hereinafter GCP], Federal Register 73/82 (April 28, 2008), pp. 22800–22816. Available at http://www.regulations.gov/search/Regs/home.html#documentDetail?R=0900006480537f08.
29. Kelleher (see note 2).
30. H. Freyhofer, The Nuremberg medical trial: The Holocaust and the origin of the Nuremberg medical code (New York: Peter Lang, 2004), pp. 103–104.
31. The Nuremberg Code (see ref. 28).
34. A. Laughton, “Somewhere to run, somewhere to hide? International regulation of human subject experimentation,” Duke Journal of Comparative & International Law 18/181 (2007), pp. 118–212.
35. World Medical Association, Declaration of Helsinki. Available at http://www.wma.net/en/30publications/10policies/b3/index.html. The other revisions occurred in 1975, 1983, 1989, 1996, and 2000, with notes of clarification added in 2002 and 2004.
36. For further discussion, see B. Meier, “International protection of persons undergoing medical experimentation: Protecting the right of informed consent,” Berkeley Journal of International Law 20/513 (2002), especially pp. 526–529.
38. 21 C.F.R. §312.120 (c) (1).
39. Abdullahi v. Pfizer, Inc. (see note 14), pp. 37–39.
43. Council of International Organization of Medical Societies, International Ethical Guidelines for Research Involving Human Subjects at General Ethical Principles. Available at http://www.cioms.ch/?frameguidelinesnov202.htm.
47. Ibid., Guidelines 1, 4–6.
48. ICH-GCP (see note 28).
51. Kelleher (see note 2), p. 76.
52. ICH-GCP (see note 28), p. 25698.
56. Kelleher (see note 2), p. 77–78.
57. Food and Drug Administration, “Human subject protection: Foreign clinical studies not conducted under an investigational new drug application,” Federal Register 73/82 (April 28, 2008). Available at http://edocket.access.gpo.gov/2008/pdf/E8-9200.pdf.
66. Federal Register (see note 57), p. 22810.
67. D. Otto, “Linking health and human rights: A critical legal perspective” Health and Human Rights: An International Journal 1/3 (1995), pp. 272–281.
68. See, for example, R. Yearby, “Good enough to use for research, but not good enough to benefit from the results of that research: Are clinical HIV vaccine trials in Africa unjust?” DePaul Law Review 53 (2004), pp. 1127–1154.
69. F. Khan, “The human factor: Globalizing ethical standards in drug trials through market exclusion,” DePaul Law Review 57 (2008), pp. 877–915.
70. R. Drinan, “The Nuremberg principles in international law,” in G. Annas and M. Grodin (eds), The Nazi doctors and the Nuremberg Code: Human rights in human experimentation (NY: Oxford University Press, 1992), pp. 174–182.
71. J. Ford and G. Tomossy, “Clinical trials in developing countries: The plaintiff’s challenge,” Law, Social Justice & Global Development (2004/1), pp. 3–17. Available at http://www2.warwick.ac.uk/fac/soc/law/elj/lgd/2004_1/ford/.
73. Abdullahi v. Pfizer, Inc. (see note 14) pp. 14–15.
74. Filartiga v. Pena-Irala (1980), 630 F.2d 876 (2d Cir.).
75. Sosa v. Alvarez-Machain (2004), 542 U.S. 692, 732.
77. Abdullahi v. Pfizer, Inc. 2005 U.S. Dist. LEXIS 16126 (S.D.N.Y. Aug. 9, 2005), p. 26.
80. Abdullahi v. Pfizer, Inc. (see note 14), pp. 24–25.
84. Pfizer Inc., v. Abdullahi, writ of certiorari file to the Supreme Court of the United States, Docket No. 09–301 filed August 10, 2009. In a related matter, in May 2007, the state of Kano filed civil and criminal charges against Pfizer for the deaths in the Trovan case. After two years of negotiations, in April 2009, Pfizer agreed to pay the US$30 million to the state, US$35 million to the families and US$10 million in attorney fees. In a separate action, in June 2007, the Nigerian federal government filed suit against Pfizer, its CEO and several of its employees seeking nearly US$7 billion in damages for the deaths of children involved in the Trovan drug trial. In January 2009, the Nigerian federal government and Pfizer agreed to settle out of court. J. Stephens, “Pfizer Reaches Settlement in Nigeria Drug-Trial Case,” Washington Post (April 4, 2009).
85. Khulumani v. Barclay National Bank, Ltd. (2007), 504 F.3d 254 (2d Cir).
87. The ATS only provides an avenue for foreign victim redress in circumstances involving conduct that violates universally accepted international norms. In the area of human subject experimentation by nonstate actors, the necessity of informed consent is the only norm held to meet that standard. To that end, informed consent protections take on a “gatekeeper” type function. Neither the proposed sponsor obligations set forth in this paper, nor much Pfizer’s conduct in the Trovan case, void of an informed consent violation, could serve as a basis for filing suit under the ATS. The trend of future law, however, is unclear. Currently, the Trovan case is on appeal before the Supreme Court. I am hopeful that the Court will further expand the Second Circuit’s interpretation of ATS applicability in human rights cases to include redress in situations where valid consent exists but other abuses occurred.
88. Abdullahi v. Pfizer, Inc. (see note 14).

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