Proving Causation in Clinical Research Negligence

*Many thanks to Professor Shepherd for her guidance and many helpful comments. I am grateful for the time and work of the members of the Editorial Board of the Virginia Law Review and, in particular, for the careful attention of Megan Ong. Any mistakes remain, of course, my own.Show More

Investigators conducting clinical research create a risk of harm to their human subjects. The common law recognizes a variety of duties that these investigators owe to their subjects. When they breach these duties, such as by negligently designing the study or failing to obtain informed consent, subjects who experience a negative outcome relative to not having participated in the study should be able to maintain a cause of action for negligence against the investigators.

Yet when researchers are negligent, it will often be impossible to show whether the study caused any individual subject’s injuries. The infamous SUPPORT study, in which researchers should have reasonably foreseen that they were exposing randomly selected infants to a higher risk of death, is one example. As the subsequent litigation over that study showed, traditional principles of causation operate to make it difficult or impossible for research subjects to pursue such claims against investigators. This is because the factual circumstances of most clinical research preclude individual plaintiffs from being able to show that their injuries were more-likely-than-not caused by their participation in the study.

The loss of chance doctrine developed in medical malpractice suits provides one potential solution for overcoming this causation problem. An even better solution, which provides optimal deterrence and as-good-as-possible compensation for injured subjects, would be for courts to adopt a theory of “marginal causation,” which permits proof of causation by the aggregate marginal damages suffered by plaintiffs as a group, as an extension of the existing doctrines of loss of chance and alternative liability.

Introduction

Human-subjects research is vital for advancing scientific and medical knowledge. In particular, the development of new drugs relies on studies carried out on human volunteers. The COVID-19 pandemic and the corresponding race to develop a vaccine have placed the risks and rewards of medical research in the spotlight.¹ 1.See, e.g., Carl Zimmer, Jonathan Corum & Sui-Lee Wee, Coronavirus Vaccine Tracker, N.Y. Times, https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.​html[https://perma.cc/MTG4-6P9H] (last visited Oct. 20, 2020).Show More While there is much concern about the safety of potential vaccines for the public,² 2.Katie Thomas, Experts Tell FDA It Should Gather More Safety Data on Covid-19 Vaccines, N.Y. Times (Nov. 9, 2020), https://www.nytimes.com/2020/10/22/health/covid-vaccine-fda-advisory-committee.html [https://perma.cc/A8AY-SFJE].Show More scant attention has been placed on the risks to participants in the preclinical trials, which include tens of thousands of volunteers.³ 3.William A. Haseltine, The Risks of Rushing a COVID-19 Vaccine, Sci. Am. (June 22, 2020), https://www.scientificamerican.com/article/the-risks-of-rushing-a-covid-19-vaccine/ [https://perma.cc/QG6D-P26G].Show More Indeed, three COVID-19-vaccine clinical trials were halted due to safety concerns.⁴ 4.Carl Zimmer, 3 Covid-19 Trials Have Been Paused for Safety. That’s a Good Thing., N.Y. Times (Nov. 23, 2020), https://www.nytimes.com/2020/10/14/health/covid-clinical-trials.htm​l [https://perma.cc/J377-L62Z].Show More Although nothing suggests that these studies have deviated from appropriate ethical standards,⁵ 5.Id. Monitoring and reacting appropriately to adverse events are part of routine clinical research. SeeFDA, Guidance for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting to IRBs—Improving Human Subject Protection 3–6 (2009), https://www.fda.gov/​media/72267/download [https://perma.cc/AE2L-ANDA].Show More the demand for a speedy solution and the prospect of financial reward create complicated ethical pressures.⁶ 6.U.S. Dep’t Health & Hum. Servs., Explaining Operational Warp Speed (2020), https://www.nihb.org/covid-19/wp-content/uploads/2020/08/Fact-sheet-operation-warp-spee​d.pdf [https://perma.cc/94NK-MVJL]; Emily A. Wang, Jonathan Zenilman & Lauren Brinkley-Rubinstein, Ethical Considerations for COVID-19 Vaccine Trials in Correctional Facilities, 324 JAMA 1031 (2020); Euzebiusz Jamrozik & Michael J. Selgelid, COVID-19 Human Challenge Studies: Ethical Issues, 20 Lancet Infectious Diseases e198, e199–e202 (2020).Show More Besides these highly publicized Phase 3 trials, the National Institutes of Health (“NIH”) reports that there are currently 947 studies conducting human-subjects research on COVID-19.⁷ 7.ClinicalTrials.gov, https://clinicaltrials.gov/ct2/results?cntry=US&Search=Apply&recrs=‌a&recrs=f&recrs=d&age%20_v=&gndr=&type=&rslt= [https://perma.cc/RC4E-CTK8] (last visited Oct. 1, 2021) (selecting “COVID-19” for “Condition or disease,” “United States” for “Country” and “Recruiting,” “Enrolling by invitation,” and “Active, not recruiting” from “Status”).Show More

Beyond COVID-19, NIH reports that there are 34,907 studies involving human subjects that are recruiting, enrolling, or active in the United States.⁸ 8.ClinicalTrials.gov, https://clinicaltrials.gov/ct2/results?cntry=US&Search=Apply&recrs=‌a&recrs=f&recrs=d&age%20_v=&gndr=&type=&rslt= [https://perma.cc/XR6G-GPFA] (last visited Oct. 1, 2021) (selecting “United States” for “Country” and “Recruiting,” “Enrolling by invitation,” and “Active, not recruiting” from “Status”).Show More If carried out correctly, these studies, on COVID-19 or otherwise, will advance the collective knowledge of society, increase the quality of medical treatment, and save lives. But these studies also risk treating their human subjects as merely a means to a scientific end.⁹ 9.Immanuel Kant, Groundwork for the Metaphysics of Morals 46–47 (Allen W. Wood ed. & trans., Yale Univ. Press 2002) (1785) (“The practical imperative will thus be the following: Act so that you use humanity, as much in your own person as in the person of every other, always at the same time as end and never merely as means.”).Show More An ethical violation of this nature is particularly insidious in the context of medical research, where subjects often place their trust in medical professionals. Yet clinical research differs from medical treatment because medical professionals conducting research are not acting for the benefit of any specific patient, but rather are attempting to generate scientific knowledge. Any benefit to a specific subject is incidental.¹⁰ 10.See infraSection II.A.Show More

The history of medical research in the United States, including the forty-year failure of the Tuskegee Syphilis Study to obtain consent from, inform, or treat nearly 400 Black men infected with syphilis¹¹ 11.CDC, The Tuskegee Timeline, https://www.cdc.gov/tuskegee/timeline.htm [https://perm​a.cc/422Y-SUUX] (last visited Nov. 19, 2019).Show More shows that investigators in this country are capable of reprehensible research.¹² 12.Frederick Adams, ForewordtoVivien Spitz, Doctors from Hell: The Horrific Account of Nazi Experiments on Humans, at xv, xv–xxvii (2005).Show More Tort law ought to provide a safeguard against such ethical failures. But it fails to do so because satisfying the traditional requirements of causation is impossible for most clinical research. The loss of chance doctrine, familiar in the medical malpractice context, should be accepted as a means of satisfying causation in clinical research cases. The best way for tort law to address clinical research harms is to extend the canonical Summers v. Tice doctrine of alternative liability to loss of chance.¹³ 13.33 Cal. 2d 80 (1948).Show More This Note calls this proposed approach “marginal causation.”

In Part I, this Note discusses the Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial Study (“SUPPORT study”), which is a salient instance of possible clinical research negligence. There are good reasons to believe that this study was negligent in its informed consent process and in its design. Yet institutional review boards approved the study and investigators conducted it. While negligence for the research was litigated in Looney v. Moore, the application of Alabama’s traditional causation doctrine by the trial and appellate courts prevented the plaintiff-subjects from even reaching a jury.¹⁴ 14.18 F. Supp. 3d 1338 (N.D. Ala. 2014), aff’d, 886 F.3d 1058 (11th Cir. 2018).Show More

As Part II describes, there is a sufficient foundation existing in the common law for the courts of most jurisdictions to find that legal duties exist between investigators and subjects in clinical research and that their breach is legally cognizable. Nonetheless, the particular factual circumstances of clinical research preclude subjects from proving causation under traditional negligence doctrine. Investigators’ conduct itself shields them from liability when they negligently conduct their research on human subjects.

Part III explores a potential solution to the failure of traditional doctrine to address clinical research harms in the doctrine of loss of chance, which courts have developed in the face of similar challenges for plaintiffs in medical malpractice actions. It also discusses how the law of mass exposure torts provides a parallel for clinical research negligence. This Part concludes by suggesting that the factual circumstances of clinical research are best met through an extension of the canonical Summers v. Tice doctrine of alternative liability from defendants to plaintiffs. The theory, which this Note terms “marginal causation,” proposes that when a class of vulnerable plaintiffs can show that it collectively suffered a marginal aggregate injury because of a defendant’s conduct, common law courts should permit individual injured plaintiffs to recover for the likelihood that their injuries were actually caused by the defendant’s conduct.

1. See, e.g., Carl Zimmer, Jonathan Corum & Sui-Lee Wee, Coronavirus Vaccine Tracker, N.Y. Times, https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.​html
   

   [

   https://perma.cc/MTG4-6P9H] (last visited Oct. 20, 2020). ↑

2. Katie Thomas, Experts Tell FDA It Should Gather More Safety Data on Covid-19 Vaccines, N.Y. Times (Nov. 9, 2020), https://www.nytimes.com/2020/10/22/health/covid-vaccine-fda-advisory-committee.html [https://perma.cc/A8AY-SFJE]. ↑
3. William A. Haseltine, The Risks of Rushing a COVID-19 Vaccine, Sci. Am
   

   .

   (June 22, 2020), https://www.scientificamerican.com/article/the-risks-of-rushing-a-covid-19-vaccine/ [https://perma.cc/QG6D-P26G]. ↑

4. Carl Zimmer, 3 Covid-19 Trials Have Been Paused for Safety. That’s a Good Thing., N.Y. Times (Nov. 23, 2020), https://www.nytimes.com/2020/10/14/health/covid-clinical-trials.htm​l [https://perma.cc/J377-L62Z]. ↑
5. Id. Monitoring and reacting appropriately to adverse events are part of routine clinical research. See FDA, Guidance for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting to IRBs—Improving Human Subject Protection 3–6 (2009), https://www.fda.gov/​media/72267/download [https://perma.cc/AE2L-ANDA]. ↑
6. U.S. Dep’t Health & Hum. Servs., Explaining Operational Warp Speed (2020), https://www.nihb.org/covid-19/wp-content/uploads/2020/08/Fact-sheet-operation-warp-spee​d.pdf [https://perma.cc/94NK-MVJL]; Emily A. Wang, Jonathan Zenilman & Lauren Brinkley-Rubinstein, Ethical Considerations for COVID-19 Vaccine Trials in Correctional Facilities, 324
   

   JAMA 1031

   (2020); Euzebiusz Jamrozik & Michael J. Selgelid, COVID-19 Human Challenge Studies: Ethical Issues, 20 Lancet Infectious Diseases e198, e199–e202 (2020). ↑

7. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/results?cntry=US&Search=Apply&recrs=‌a&recrs=f&recrs=d&age%20_v=&gndr=&type=&rslt= [https://perma.cc/RC4E-CTK8] (last visited Oct. 1, 2021) (selecting “COVID-19” for “Condition or disease,” “United States” for “Country” and “Recruiting,” “Enrolling by invitation,” and “Active, not recruiting” from “Status”). ↑
8. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/results?cntry=US&Search=Apply&recrs=‌a&recrs=f&recrs=d&age%20_v=&gndr=&type=&rslt= [https://perma.cc/XR6G-GPFA] (last visited Oct. 1, 2021) (selecting “United States” for “Country” and “Recruiting,” “Enrolling by invitation,” and “Active, not recruiting” from “Status”). ↑
9. Immanuel Kant, Groundwork for the Metaphysics of Morals 46–47 (Allen W. Wood ed. & trans., Yale Univ. Press 2002) (1785) (“The practical imperative will thus be the following: Act so that you use humanity, as much in your own person as in the person of every other, always at the same time as end and never merely as means.”). ↑
10. See infra Section II.A. ↑
11.  CDC, The Tuskegee Timeline, https://www.cdc.gov/tuskegee/timeline.htm [https://perm​a.cc/422Y-SUUX] (last visited Nov. 19, 2019). ↑
12. Frederick Adams, Foreword to Vivien Spitz, Doctors from Hell: The Horrific Account of Nazi Experiments on Humans, at xv, xv–xxvii (2005). ↑
13. 33 Cal. 2d 80 (1948). ↑

14. 18 F. Supp. 3d 1338 (N.D. Ala. 2014), aff’d, 886 F.3d 1058 (11th Cir. 2018). ↑