The Rise of Litigation in Human Subjects Research

There is a growing perception that the regulation of research involving human subjects has been inadequate and must change (1). Spurred by deaths of research subjects at leading academic institutions (2, 3), federal legislators are considering sweeping changes in the laws governing human research (4). In the meantime, the Office for Human Research Protections (OHRP) has assumed an activist posture and induced most institutions to bolster their human subjects oversight (5). By all appearances, human subjects research is moving from a very flexible form of self-regulation to a more bureaucratically oriented system of oversight. The federal government's regulations (6), issued three decades ago in the wake of shocking revelations surrounding the Tuskegee Syphilis Experiment (7), devolve responsibility for reviewing and monitoring human studies to institutional review boards (IRBs). The review calculus prescribed by federal law consists of a rough utilitarian weighing of the risks and benefits of the study and an evaluation of subjects' ability to give meaningful informed consent to participation. In practice, the informed consent inquiry tends to focus heavily on the wording of the consent form (8). Recent revelations suggest that IRBs have often miscalculated the riskbenefit ratios and failed to ensure the integrity of the consent process. Moreover, evidence indicates that IRBs have been systematically underestimating the importance of a range of factors that bear on the ethical inquiry, from the vulnerability of subjects to the pressures created by financial conflicts of interest (1, 8, 9). These findings have served as the impetus for closer federal monitoring of human studies. What many involved in research today may not appreciate is that stricter government regulation is not the law's only response to harms from research. Our society also relies on private litigation to deter poor practices and compensate persons injured by substandard conduct. Historically, personal injury lawsuits by research subjects against researchers have been rare. However, both the frequency and stakes of these lawsuits are on the rise, and the lawsuits are now beginning to implicate IRBs. In this report, we trace the evolution of this litigation and explain why we expect to see more of it. In considering its implications, we conclude that while the litigation may help compensate injured subjects, it has potentially undesirable ramifications for research oversight because it is likely to drive IRBs toward a more legalistic, mechanistic approach to ethical review that does not further the interests of human subjects or scientific progress. The Evolution of Litigation in Human Subjects Research Informed Consent Claims Litigation over injuries to research subjects is not new. For at least two decades, occasional cases alleging a failure to obtain informed consent have been brought against various defendants. The doctrine of informed consent dates to the 1914 case of Schloendorff v. New York Hospital (10), in which New York's highest court articulated a patient's right to full information before undergoing treatment. Informed consent litigation relating to medical treatment blossomed in the 1960s and 1970s (11), when courts in many jurisdictions decided to replace a profession-based disclosure standard with a patient-based standard. In other words, jurors were asked to judge claims not according to what information physicians thought a patient reasonably should be given but rather according to what the patient might reasonably expect to be told (11). Claims alleging a negligent failure to obtain informed consent continue today as a fairly common species of medical malpractice litigation. These claims have been easily transplanted to the research context. The typical allegation is that the research subject was not given sufficient information to permit meaningful consent to research participation. For example, in Berman v. Fred Hutchinson Cancer Center (12), brought by the husband of a patient with breast cancer who died in a chemotherapy trial, the plaintiff alleged that his wife would not have agreed to participate in the trial if she had known that a drug intended to prevent lethal side effects from the chemotherapy was not available in intravenous form. Contrary to what doctors allegedly told her, the drug was available only in tablet form, and she died after vomiting the pills. In August 2002, the trial court ruled for the plaintiff on this claim (13). In recent years, three important innovations have occurred in litigation over research-related injuries. First, the types of legal claims have diversified. Second, as a result the number and types of defendants named in these lawsuits have increased. Finally, plaintiffs' attorneys are increasingly using class action techniques to bring claims on behalf of large groups of research subjects. These developments individually and collectively may have significant implications for the future of human subjects research. We explore these developments in the context of several of the dozen or so high-profile cases filed in the last few years. The New Legal Claims Enterprising plaintiffs' attorneys have turned to a daunting array of legal doctrines in framing lawsuits against those who perform and oversee research. A lawsuit that 20 years ago would have been brought as a routine informed consent claim may today include allegations of defective products, fraud, negligent conduct and monitoring of the research, intentional infliction of emotional distress, breach of patients' rights protected by state law, violation of federal regulations, and violation of constitutional rights. This diversification in legal causes of action is not unique to research-related litigationit is also visible in other tort litigation such as suits brought by health maintenance organization enrollees against health plans that deny them coverage for services (14). However, it is especially pronounced in the human subjects area. A popular approach in lawsuits alleging injuries in pharmaceutical trials is to combine the traditional informed consent claim with product liability claims against the drug manufacturer (15). For example, the mother of an infant who died in a trial of the heartburn drug Propulsid recently filed suit against the Children's Hospital of Pittsburgh and Janssen Pharmaceuticals, alleging that she was not informed of risks and adverse events associated with Propulsid and that the drug was defectively designed (16). This legal tactic recycles one used in some of the earliest human subjects litigation, claims brought by women whose infants were injured by diethylstilbestrol (17, 18). Three other recent cases illustrate even greater legal creativity in the drafting of claims. The case of Gelsinger v. University of Pennsylvania Hospital arose from the death of 18-year-old Jesse Gelsinger in a phase I gene therapy trial (19). The Gelsinger family coupled the usual informed consent claim with a product liability claim, and then went further: They alleged that the investigators had committed fraud by not revealing that previous subjects enrolled in the protocol had died and that the principal investigator had a financial relationship with the sponsoring biotechnology company (20). The parties reached a confidential settlement in November 2000. Robertson v. Oklahoma, a state court case that grew out of a federal suit dismissed for lack of jurisdiction (21), involved injuries to subjects in a phase I/II melanoma vaccine trial at the University of Oklahoma Health Sciences Center at Tulsa. The plaintiffs made three main allegations. First, they alleged a lack of informed consent based on the investigators' failure to reveal that the vaccine had not been subjected to animal studies, their failure to disclose all the relevant risks, and their misrepresentation of the vaccine as a potential cure for cancer. Second, they claimed that the trial itself was negligently runessentially a claim of investigator malpractice in the conduct of researchbecause the investigators enrolled ineligible patients and failed to monitor the subjects' health appropriately. Third, they alleged that investigators fraudulently misrepresented the purpose, risks, and benefits of the study. Some of the defendants reached a settlement with the plaintiffs in July 2002 (22). The case of Wright v. Fred Hutchinson Cancer Center is another interesting cocktail of legal claims; it incorporates the kind of research malpractice and fraud claims used in Robertson, includes conflict of interest allegations like those in Gelsinger, and adds several new theories (23). In this case, subjects in a trial to prevent graft failure in patients undergoing bone marrow transplantation alleged that the investigators used misleading consent materials and failed to disclose various conflicts of interest. The plaintiffs also claimed that the investigators failed to report deaths appropriately to the IRB and failed to update consent forms as required by the IRB, in essence alleging negligent conduct of the trial. In addition, the plaintiffs in Wright posited a breach of the right to be treated with dignity under the due process clause of the 14th Amendment to the U.S. Constitution, arguing that international conventions such as the Nuremburg Code and the Declaration of Helsinki substantiated this right. The same group of attorneys have taken these groundbreaking constitutional and international law claims even further in other cases (12, 24), although it is too early to judge their legal sway. The trial court in Wright recently dismissed the constitutional and international law claims made in that case (13), while a New York district court allowed similar claims to proceed in a case involving a drug trial in Nigeria (25). The fraud claims in cases like Wright are of particular interest because they give the plaintiffs' attorney significant leverage in court. An allegati