Jesse Gelsinger was diagnosed with ornithine transcarbamylase (OTC) deficiency when he was two years old. OTC deficiency is a metabolic disorder that a body eliminates an enzyme that degrades ammonia in newborns, and the accumulated ammonia in the bloodstream can cause severe damage when travelled to brain (Sibbald, 2001). Most newborns with OTC deficiency become comatose within 72 hours from birth, and half of them die within a month from birth (Sibbald, 2001). Jesse, however, was a unique case where he only had a partial OTC deficiency, and he was able to maintain his health with a low-protein diet and a lot of medicines.
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Jesse was approached by Dr. Randy Heidenreich, his pediatric geneticist, to a gene-therapy trial on a corrective OTC gene encased in an attenuated cold virus, a recombinant adenoviral vector (Sibbald, 2001). The study was run by Dr. Steven Raper and his coinvestigator, Dr. James Wilson, at the Institute of Human Gene Therapy located in the University of Pennsylvania. The clinical trial was to determine if the corrective OTC would help newborns with a fatal from of the disease, thus Jesse would not have benefited from the trial. However, he still was willing to participate for the sake of those babies (Stolberg, 1999). On September 13, 1999, Jesse was infused with the corrective OTC into his hepatic artery. He experienced a severe immune reaction to the vector and died four days after the infusion (Sibbald, 2001). The exact cause of his death was from adult respiratory distress syndrome, which means that his lungs shut down. Before that however, he had a multiple organ system failure that composed of a blood-clotting disorder, kidney failure, and brain death (Stolberg, 1999).
There are many reasons behind why this tragedy happened, and some of them are associated with the clinical staffs’ professional performance and the true intention of Dr. James Wilson and the Institute of Human Gene Therapy behind the study. According to an article written by Barbara Sibbald, Jesse’s family were not aware of the cases where several other patients had experienced serious side effects in the study nor of the cases where three monkeys died from blood clotting disorder and severe liver inflammation from the corrective OTC gene (Sibbald, 2001). The serious side effects that other patients experienced include change in liver function and blood-cell counts, minor strokes, mental confusion, and nausea (Stolberg, 1999). Failing to inform the severe side effect cases to patients participating in the study is against the FDA’s Protection of Human Subjects regulation on informed consent (eCFR, 1980). The investigators must inform every patient participating in the study if adverse events occur and reobtain their informed consent because the patients have the right to discontinue the study when they feel like their health is at risk.
Not getting a complete informed consent is not only against the FDA regulations, but also against the Good Clinical Practice (GCP) guideline made by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Humans (ICH), which both the Food and Drug Administration (FDA) and Health Canada are a part of. In the GCP guideline section 4.8, it states that the investigators must inform every information on the study to patients before they give their informed consent and obtain a new written informed consent “whenever important new information becomes available that may be relevant to the subject’s consent” (ICH, 2016). If this study was done in Canada, their behaviour would be against the Tri-Council Policy Statement 2 (TCPS2) by the Panel on Research Ethics, Government of Canada as well. A Respect for Persons is one of the core principles in TCPS2, and it implies that the research participants should fully understand the risks and the benefits of the study (TCPS2, 2014). Thus, informing every aspects of the study to patients and ensuring that they fully understand them is critical in the clinical trials both in United States and in Canada.
Moreover, there were more reports of death after Jesse’s death yet the investigators from the study did not report them to the Recombinant DNA Advisory Committee (RAC) because they thought the death was not due to the drug but due to their disease (Stolberg, 1999). A part of an investigator’s role is to report detailed progress and safety reports to the sponsor in accordance to Part 312 of Code of Federal Regulation (CFR) by the FDA (eCFR, 1980). In this case, Dr. Raper and Dr. Wilson should have reported the patients’ deaths to the RAC regardless of what they think the cause of the deaths was. They were irresponsible to decide that the information was not important when they should report every little detail to the RAC and to the FDA.
Incomplete reporting to the legal and ethical authorities also goes against the ICH guidelines and TCPS2. The ICH guideline part 4.9 and 4.10 states that accurate and complete Case Report Forms (CRFs) should be filled for any incidence that occur in the study, and the investigators should submit written summaries of the trial to the IRB consistently (ICH, 2016). This of course includes CFRs and reports on the adverse events and deaths that occurred during the study. TCPS2’s Concern for Welfare is all about maintaining (or improving if possible) an individual’s physical, economic and social circumstance during the study (TCPS2, 2014). Dr. Wilson and Dr. Raper made a huge negative impact on Jesse’s welfare and changed both Jesse’s and his family’s lives by causing his death. If the investigators reported to the FDA and to the RAC as soon as possible when patients experienced adverse events, the system of the study might have been improved or an action would have taken by the time Jesse joined, which might have prevented his death.
Furthermore, Dr. Wilson, the University of Pennsylvania, and the Genovo Inc. had a financial interest from the clinical trial. Dr. Wilson was the founder of Genovo Inc. where he held patents related to the vectors used for gene transfers that were derived from the adenovirus (Steinbrook, 2008). Dr. Wilson (and his immediate family) and the Institute of Gene Therapy located in the University of Pennsylvania had 30% and 3.2% nonvoting equity stake in Genovo Inc. respectively (Hensley, 2000). Thus, the more adenovirus-derived vectors are marketed for use, the stock for Genovo Inc. will increase, and the more money Dr. Wilson and the institute will earn. This financial interest was stated in the informed consent of the corrective OTC study as follows: “Please be aware that the University of Pennsylvania, Dr. James M. Wilson (the Director of the Institute for Human Gene Therapy), and Genovo, Inc. (a gene therapy company in which Dr. Wilson holds an interest), have a financial interest in a successful outcome from the research involved in this study” (Batshaw, et al., 1999).
Investigators having a financial interest is not a problem. However, the FDA must evaluate the disclosure statement, effect of the financial interest on a study design, and monitor the clinical trial to ensure there is no bias introduced in the obtained data (eCFR, 1980). The Penn’s Center for Technology Transfer requested the Conflict of Interest Standing Committee (CISC) to evaluate Dr. Wilson’s and the university’s behaviours at the study (Steinbrook, 2008). On the minutes from the February 6, 1995 meeting, the members of the CISC were concerned that Dr. Wilson’s multiple roles would lead to conflicts between his responsibilities at each role, which may include allocating resources or implementing ethical and academic policies at the University of Pennsylvania (Steinbrook, 2008). Members were also concerned that Dr. Wilson will make unethical decisions on the corrective OTC study for his financial gain in the future (Steinbrook, 2008). It seemed that Dr. Wilson and the University of Pennsylvania purposely did not report patient adverse events and deaths to the RAC so that they could continue with the study. This kind of behaviour goes against the ethical regulations that protect human subjects.
The GCP guidelines do not actually specify a guideline when an investigator has a financial intention on the study, but it states that they should be conducting with the best interest of improving patients’ health and wellbeing not for other reasons, such as financial benefits they will be receiving (ICH, 2016). The Canadian ethical guideline, the TCPS2, mentions that researchers should not financially benefit from any type of sponsors because “financial incentives have the potential to distort researchers’ judgment in ensuring the design and conduct of the trial is ethical” (TCPS2, 2014). Thus, the corrective OTC study would not be approved to be initiated in Canada unless Dr. Wilson removes himself as an investigator because he has a financial incentive.
Lastly, it was Dr. Raper’s responsibility as a Primary Investigator to report anything and everything to the RAC that he suspects unethical. It is not known the exact story on Dr. Raper’s side (whether he also had a financial intention or not), but he might have wanted to report adverse events and deaths that occurred during the clinical trial to the RAC. He might have realized that what Dr. Wilson consistently went against the GCP guidelines, but maybe he was threatened by the university of his career or they gave him a compensation for keeping him quiet. If that was the case, he should have reported to the RAC sooner and included the threats and/or the compensation details to protect the patients involved in the study.
In conclusion, the clinical team on the corrective OTC clinical trial at the University of Pennsylvania was not compliant with the protocol and did not follow the GCP guidelines. They were more interested in marketing the gene therapy by forcing to obtain “good results” from patients in order to make money. Following the regulations and guidelines are very important when using humans as research subjects because clinical trials are conducted to protect human rights and improve their health not to do the opposite. Canadian and United State governments have policies and revise those policies when needed to best protect their citizens from researchers who do not have the best intention on.
References
Electronic Code of Federal Regulations. (1980, May 30). Regulations: Good Clinical Practice and Clinical Trials. The Food and Drug Administration. Retrieved from https://www.ecfr.gov/cgi-bin/text-idx?SID=31042205817afb0b7dcd59f9bbab69c4&mc=true&node=pt21.1.50&rgn=div5
Hensley S. (2000, August 10). Targeted Genetics’ Genovo deal leads to windfall for researcher. The Wall Street Journal. Retrieved from https://www.wsj.com/articles/SB965865382866163400
Batshaw, M. L., Wilson, J.M., Raper, S.E., Yudkoff, M., Robinson, M. B. (1999, Septbember 20). Recombinant Adenovirus Gene Transfer in Adults with Partial Ornithine Transcarbamylase Deficiency (OTCD). Hum Gene Ther, 10(14): pp.2419–2439.
Sibbald, B. (2001, May 29). Death but one unintended consequence of gene-therapy trial. CMAJ, 164(11), 1612. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC81135/
Steinbrook, R. (2008). The Gelsinger Case. The Oxford Textbook of Clinical Research Ethics. Oxford University Press. Retrieved from https://www.uab.edu/ccts/images/steinbrook_Gelsinger_-_Oxford_Textbook_08_3.pdf
Strolberg, S. G. (1999, November 28). The Biotech Death of Jesse Gelsinger. The New York Times Magazine, p. 6006137. Retrieved from https://www.nytimes.com/1999/11/28/magazine/the-biotech-death-of-jesse-gelsinger.html
Tri-Council Policy Statement 2. (2014). Ethical Conduct for Research Involving Humans. Government of Canada. Retrieved from http://www.pre.ethics.gc.ca/pdf/eng/tcps2-2014/TCPS_2_FINAL_Web.pdf
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