Welfare and Dignity of the Subject Fundamental in Clinical Research

By Claire Castles, J.D., LL.M. candidate

“In research on man, the interest of science and society should never take precedence over considerations related to the well being of the subject; …in any medical study, every patient…including those of a control group…should be assured of the best proven diagnostic and therapeutic method.”
-Declaration of Helskinki of the World Heath Organization
The fundamental ethical precept of research on humans is that the subject’s welfare and dignity is paramount to the pursuit of science.  Clinical research must not fall into the temptation of tunnel vision and focus solely on the importance of the scientific study and the benefits to future patients.   Pursuant to 45 C.F.R. § 46.116, all clinical research must secure informed consent from research participants.  A participant’s consent must include  “any reasonably foreseeable risks or discomforts to the subject,” as well as informed consent regarding the existence of alternative treatments.  45 C.F.R § 46.116(a)(2), (a)(4).  Yet, adequacy of informed consent may not sufficiently protect the subjects’ welfare where there exists an “asymmetry in knowledge and authority between researchers and their subjects.  See Angell, Marcia The Ethics of Clinical Research in the Third World, 337 N. Eng. J. of Med. 847, 847 (1997).

The aforementioned asymmetrical relationship is perhaps never so obvious as in clinical research in developing and Third World countries.  Societies ravaged by epidemics, political unrest, corruption, and inadequate medical facilities have become opportunities for private sponsors of research to escape the regulatory overlap of the United States and sponsor research that could not be conducted under our regulatory scheme.  Generally, the authority and jurisdiction of United States courts foreclose opportunity to foreign subjects aggrieved by the unethical business practices of American companies.  However, under the Alien Tort Claims Act, 28 U.S.C.A. § 1350, a foreign plaintiff may recover damages for violation of a customary international law against a private American corporation as a de facto state actor.  In light of Abdullahi v. Pfizer, Inc., 2003 WL 22317923 (2nd Cir. (N.Y.)), sponsors of clinical research in developing countries must now factor in the liability and risk of civil actions brought by foreign plaintiffs.

As discussed in Abdullahi v. Pfizer, Inc., 2002 WL 31082956 (S.D.N.Y.), Pfizer developed an antibiotic Trovaflozacin Mesylate, Trovan®, and began aggressively conducting clinical research in 1996.  Following epidemics of bacterial meningitis, measles and cholera in Kano, Nigeria, Pfizer sent a medical team to Kano’s Infectious Disease Hospital to establish a treatment center and began treating afflicted pediatric patients.  Id.  Plaintiffs allege that Pfizer exploited the epidemic as an opportunity to research Trovin® a “new, untested and unproven” antibiotic.  Id. at 2.  Plaintiffs plead that Pfizer “purposefully ‘low-dosed’” the control group with “one third of ceftriaxone’s recommended dosage” an FDA-approved drug for meningitis in an effort to exaggerate Troven®’s effectiveness.  Id.

Plaintiffs allege that Pfizer did not disclose to the children’s parents that the drug was experimental, the potential risks of serious joint and liver damage, their right of refusal, or that other organizations offered more conventional treatments at the same site free of charge.  Id.  Additionally, plaintiffs contend that Pfizer repeatedly failed to conform to its own protocol by failing to analyze blood samples and provide follow-up evaluations.  Id.

The significance of Abdullahi v. Pfizer is twofold.  First, the District Court found that the plaintiffs successfully alleged Pfizer as de facto state actor for jurisdictional purposes of the Alien Torts Claims Act pursuant to 42 U.S.C. § 1982 analysis to determine color of law or official action.  Secondly, the appellate court expressly addresses the fact that the underlying decision did not address the threshold issue of whether the plaintiffs’ grievances were a violation of customary international law.

The Restatement (Third) of Foreign Relations Law § 702(1987) identifies violations that are actionable when committed by the state.  See Abdullahi v. Pfizer, 2002 WL 31082946 (S.D.N.Y.).  As discussed this list is illustrative of actions that violate the “law of nations,” but it is not presumed to be exhaustive.  Id.  The District Court used the §1983 standard as first suggested in Kadic v. Karadzic, 70 F. 3d 232, 245 (2d Cir. 1995).  In Kadic, the Court suggests the § 1983 standard as “a relevant guide.”  Id.  In Abdullahi, the District Court found state action was sufficiently alleged by the plaintiffs, and Pfizer and the Nigerian government were joint participants in the clinical trial.  It is essential to note that the court did cite Doe v. Unocal, 176 F.R.D. at 345 remarking that state action inquiries are better suited for summary judgment rather than in a motion to dismiss where the facts must be construed in light most favorable to the plaintiff.

Sponsors of clinical trials in developing countries must be aware of the facts the plaintiffs plead to sufficiently allege state action for jurisdiction under the Alien Claims Tort Act.  The District Court found that Pfizer demonstrated joint participation by the following actions: the Nigerian government sent a letter to the FDA requesting export of Trovan® for use in the study; the Nigerian government arranged for accommodations at the hospital; the Nigerian government assigned government physicians to assist Pfizer; the Nigerian government back-dated an “approval letter that international protocol was satisfied; the Nigerian government silenced Nigerians critical of Pfizer’s clinical trial.  Id. at *6.

As this case develops procedurally, the crucial issue will be whether medical experimentation can give rise to a violation of customary international law.  This issue has yet to be addressed by either the district or the appellate court.  The plaintiffs hinge their complaint on article 7 of the ICCPR, the Nuremberg Code, the Declaration of Helsinki, FDA regulations as evidence of customary international law.  Despite repeated questioning by the District Court in oral argument, Pfizer has not responded nor has the court ruled on whether the alleged conduct violates customary international law.  Id. footnote 4 at *3 (app).

The history of informed consent is rooted in the international concern voiced in response to the Nazi experiments conducted in World War II.  See Esther Chang, Fitting a Square Peg into a Round Hole?: Imposing Informed Consent and Post-Trial Obligations on United States Sponsored Clinical Trials in Developing Countries, 11 S. Cal Interdisc. L.J. 339, 345 (2002).  Although the documents referenced by the plaintiffs in Abdullahi have played an influential role in the development of regulations and policies within the United States, it is unclear that they could be considered “law of nations” since they are not “collectively adopted by the international community.”  Id. at 346 supra footnote 56.
 
Private sponsors are under great pressure to expedite research and limit associated costs.  Regardless of the importance of the science and the potential for life-saving treatments of millions of future patients, the dignity and welfare of the human subject must be always be the first and foremost concern.

12/23/03