Learning from Loss: The Gelsinger Case and Reforming Gene Therapy Research

This is a post of one of my graduate school assignments where I'm currently pursuing my Master of Science degree in Regulatory Affairs.

Seventeen-year-old Jesse Gelsinger had a genetic disease called ornithine transcarbamylase (OTC) deficiency. OTC deficiency prevents the body from breaking down ammonia, a metabolic waste product. In patients with this disease, the excessive buildup of ammonia often causes death soon after birth unless the patient's diet is immediately adjusted and monitored throughout their entire life. Gelsinger lived on a strict non-protein diet and controlled his OTC reasonably well.

Gelsinger volunteered for a gene therapy experiment designed to test possible treatments; he thought volunteering could help newborns afflicted with OTC. He enrolled as a subject in a gene therapy experiment in which a vector carrying a normal OTC gene was injected into his liver. The vector used to deliver the OTC gene was adenovirus, a modified version of the virus that causes the common cold.

Gelsinger was informed that previous subjects had received adenovirus without serious complications. But he had an adverse reaction to the injection, and four days later, on September 17, 1999, he died. [1 &2]

Several ethical issues have emerged from gene therapy research, particularly the Gelsinger case. Many of these issues are expected in experiments involving human volunteers; some are unique to gene therapy. Here are three specific to this case: [3-5]

a.?Approval of the design of the experiment:?An ethical question raised in the Gelsinger case was whether relatively healthy adult volunteers with OTC (such as Gelsinger) should have been used as subjects. At first, it was suggested that babies born with OTC be utilized in the experiment with their parents' consent. If infants were to be used, their parents would have to give informed consent first. A concern was raised as to whether parents with very ill newborns could understand that gene therapy experiments were complex and probably would not help their babies.

In contrast, adults with the condition could understand the risks and weigh them against the experiment's potential benefits. Adults were chosen because they could better comprehend the dangers of the investigation and provide informed consent. The risks in this study were significant; they were life-threatening. The potential benefits to the participants were nonexistent. Such an experiment violated the Nuremberg Code, the Declaration of Helsinki, and any conceivable ethical norm governing science and medicine.

b.?Informed Consent:?Everyone has the right to determine whether they want medical treatment or decide to participate in an experiment. The notion that people should be fully informed and able to consent to participation in a research trial freely is accepted as a minimum requirement for the use of human subjects in an experiment.

At first, it was thought that the vector that caused Gelsinger's death was relatively safe and that the deadly reaction was random and unforeseeable. However, as the investigation into Gelsinger's death continued, reports began to emerge that past research subjects and experimental animals had become sick from the vector. This revelation raised ethical concerns since these previous problems were not communicated to Gelsinger and the other volunteers. Gelsinger's family said they were never adequately informed of these past cases. As a result, they claimed Gelsinger believed the risks were lower than they were.

c.?Conflict of Interest:?A conflict of interest that involved the lead scientist, Dr. James Wilson, was identified. Dr. Wilson was financially interested in developing the adenovirus vector used in the OTC gene therapy trial. If his gene therapy vector worked correctly and was successful, he could make a lot of money by using it to treat people or selling it to other researchers. This conflict of interest may have influenced the decisions made by Dr. Wilson as he continued with his experiments.?

No, adequate informed consent was missing from this case. As per the essential elements of informed consent mentioned in 45 CFR 41.116 part (a), [6]

• A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any experimental processes;
• A description of any reasonably foreseeable risks or discomforts to the subject;

In uncovering the truth of what happened to Jesse, some significant problems in the informed-consent process were found. The researchers did not adequately fulfill the above basic principles in this case. The over-enthusiasm of the clinical investigators led Jesse and his father to paint a misleading picture of safety and efficacy. That enthusiasm closed their eyes to the ill effects that the researchers were witnessing. They did not communicate those effects to them or those responsible for overseeing their work, notably Penn's research ethics board and the FDA. Some of that blindness appears to have been deliberate. Following Jesse's death, Penn continued misinforming Jesse and his father about what they knew, telling them only what would keep them on their side. [7]

After examining this case, as a Human experimentation course student, there are a few things I would have done differently in this scenario:

1. Capacity to Consent: There were also questions about whether Jesse Gelsinger, who was just 18 years old then, could fully understand the risks and implications of participating in the trial. Ensuring that individuals have the cognitive capacity to provide informed consent is crucial to upholding the ethical principle of respect for autonomy.
2. Disclosure of all the risks and complications related to the study:?As a participant in any clinical trial or study, a volunteer and their guardian/family member must be told about all the risks and complications at every trial stage. Disclosing the risks can help the volunteer make a sound and aware decision to participate in the trial. The FDA and the IRB should also be immediately aware of every complication that happens during any trial stage by the investigator. An adequately informed consent document should be made as per 45 CFR 41.116, covering all the parts in this CFR efficiently.?
3. Disclosure of any conflict of interest:?The investigators must disclose any conflict of interest to the IRB, the FDA, and every clinical trial volunteer. This will help ensure transparency and trust among every party involved.
4. Approval with IRB on every step:?The IRB must determine the importance of the knowledge gained by the result and the likelihood of achieving that knowledge by the experiment. The IRB must also ensure the investigation is based on competent animal studies and generally accepted scientific principles. The IRB must understand the risk-benefit calculus of the protocol and determine that the risks have been minimized. The IRB must evaluate the competence of the investigator. Those performing human studies should be at the top of their profession. In addition, the IRB must make certain clinically competent medical personnel are available for supervision and support. The IRB must review the informed consent document to determine if it describes the design and purpose of the trial, the procedures to be performed, the risks, the benefits, and the alternative treatments available.

References:

1. Wilson, R. F. (2010). The Death of Jesse Gelsinger: New Evidence of the Influence of Money and Prestige in Human Research.?American Journal of Law & Medicine,?36(2–3), 295–325. https://doi.org/10.1177/009885881003600202
2. Liang, B. A., & MacKey, T. (2010). Confronting Conflict: Addressing Institutional Conflicts of Interest in Academic Medical Centers.?American Journal of Law & Medicine,?36(1), 136–187. https://doi.org/10.1177/009885881003600103
3. NYU Langone's High School Bioethics Project. (n.d.).?Gene therapy research & the case of Jesse Gelsinger. NYU Langone Health. https://med.nyu.edu/departments-institutes/population-health/divisions-sections-centers/medical-ethics/education/high-school-bioethics-project/learning-scenarios/jesse-gelsinger-case
4. Cross, R. (2019, September 12).?The redemption of James Wilson, gene therapy pioneer. Chemical and Engineering News. https://cen.acs.org/business/The-redemption-of-James-Wilson-gene-therapy-pioneer/97/i36
5. Stolberg, S. G. (1999, November 28).?The Biotech Death of Jesse Gelsinger. The New York Times. https://www.nytimes.com/1999/11/28/magazine/the-biotech-death-of-jesse-gelsinger.html
6. Office for Human Research Protections. (n.d.).?Informed Consent FAQs. U.S. Department of Health and Human Services. https://www.hhs.gov/ohrp/regulations-and-policy/guidance/faq/informed-consent/index.html#:~:text=The%20informed%20consent%20process%20involves,to%20participate%20in%20the%20research.
7. GELSINGER, P. L. (2006). Uninformed Consent: The Case of Jesse Gelsinger. In T. LEMMENS & D. R. WARING (Eds.),?Law and Ethics in Biomedical Research: Regulation, Conflict of Interest and Liability?(pp. 12–32). University of Toronto Press. https://www.jstor.org/stable/10.3138/9781442676596.5