Gene Therapy Regulation: The Need for Third Party Fiduciaries

Thesis

Appropriate regulation of gene therapy trials requires an enforced balancing of patient autonomy/confidentiality, proprietary confidentiality, and informed public oversight that does not unnecessarily impede medical research. The current regulatory system fails on three counts. It is not adequately enforced. It is biased too far in favor of preserving proprietary and research confidentiality. And it imposes administratively burdensome, duplicative approval procedures on researchers.

Introduction

Jessie Gelsinger's death [1] at the University of Pennsylvania's Institute for Human Gene Therapy (IHGT) in 1999 demonstrated these flaws. His death could have been avoided had regulations existing at the time been followed, or had he and his family been given information to which they were ethically entitled. Though the Food and Drug Administration (FDA) recently proposed regulatory changes [2] that would allow it to release information necessary to informed consent and public oversight, these changes do nothing to put teeth into a deficient first-line enforcement system. Nor do they overtly address the administrative overlap between the FDA and the National Institutes of Health (NIH).

Four regulatory corrections need to be made:

(1) The FDA must release arguably confidential commercial information, in order to

(a) give patients a legitimate shot at informed consent, and

(b) ensure that the public has enough data to discuss and direct the implications of genetic research.

(2) Institutional review boards (IRB) and institutional biosafety committees (IBC), currently charged with first-line oversight of gene therapy trials, must be adequately staffed and funded.

(3) Given that conflicts of interest permeate research and regulatory bodies, patients should be guaranteed access to third party fiduciaries who have access to information pertinent to informed consent.

(4) FDA and NIH must reduce duplicative processes that administratively burden research and commercial institutions,

The Basic Problem: Mutually Incompatible Interests in Gene Therapy Research

At the outset, gene therapy regulation requires a clear look at what interests at stake, and which ones of these require protection. Simplistically, gene therapy has implications for

(a) subjects already involved in trials who are hoping benefit will outweigh cost;

(b) patients who are considering becoming test subjects and need information;

(d) the families of all three;

(e) segments of the general and specifically educated public interested in science, ethics, and a decent society;

(f) research investigators concerned with fulfilling their personal potential for discovery, helping, and wealth;

(g) trial sponsors with corporate or quasi-corporate goals; and

(h) regulatory body staff members wanting to sort it all out in a lawful manner.

One cannot completely protect the aspirations of all these groups. Taken together, their interests are mutually exclusive, and the resulting mess cannot be successfully picked apart.

Nevertheless, the clearest distinctions form a triad with current and about-to-be patients at one apex, sponsors at another, and the general public at the third. Patients, while guarding against the revelation of personal information, want to know everything there is to know about experimental treatments that might help or hurt them. Sponsors want to protect proprietary information, revealing only enough to entice subjects into volunteering for projects that will advance the research and remunerative effort. The public, individually and collectively, wants (a) to access the advancements that unrestricted research will bring; (b) to protect the future patient group that it might, as individuals, someday join; and (c) to protect society and environment from reckless experimentation. The public therefore incorporates the interests of the other two groups and goes one further. Consequently, the problem becomes one in which the interests of patients must be balanced against the interests of sponsors, and the public must be satisfied that the compromise satisfies the societal need for the adequate oversight of this ethically problematic area of medicine.

Jessie Gelsinger's Disease and the Reasons for Gene Therapy

Jessie Gelsinger died under circumstances that rudely illustrated the wisdom of fears about how gene therapy research is being performed under the current regulatory system. He suffered from the partial form of ornithine transcarbamylase deficiency (OTC), [3] an incurable X-linked metabolic disorder of the urea cycle leading to ammonia buildup in the blood and consequent neurological damage. Most males [4] do not survive the neonatal period. The majority of those who do survive have cerebral palsy, metal retardation and developmental disabilities. [5] Even for late-onset disease, mortality is 10 percent. [6] Disease prevalence is 1 in forty to eighty thousand. [7]

Partial ornithine transcarbamylase deficiency is customarily treated with drugs and diet restrictions. [8] Exacerbations are common and require treatment by tertiary care centers equipped to handle hyperammonemia with drugs or renal dialysis. [9] If qualified emergency care is not available, significant neurological damage is likely. [10]

Liver transplantation is used for some OTC patients, [11] but the procedure has serious drawbacks. Organ availability, surgical mortality/morbidity, and post-operative drug-induced suppression of the patient's immune system (necessary to prevent rejection of the alien organ) present significant problems. [12] Immune system suppression leaves the patient chronically vulnerable to sometimes life-threatening infections. [13]

Gene therapy has been proposed as a partial solution to the problems inherent in transplantation. [14] IHGT was exploring this avenue, using an adenovirus delivery vector, when Gelsinger unexpectedly died under its experimental protocol. Questions have been subsequently raised about the Institute's compliance with FDA and NIH requirements, about the adequacy of the requirements themselves, and about the foreseeability [15] of the immune system response that killed the eighteen year old.

Adenovirus as a Gene Therapy Vector

Understanding the import of these questions requires an understanding of the adenovirus delivery method. [16] Since no vector is ideal, [17] compromises must be made in balancing safety and efficacy. These depend upon the fit between the parameters of the disease and the characteristics of the vector. For example, perceptible improvement in OTC deficiency requires that one put the missing gene into at least 10 to 30 percent of liver cells. [18] A useful delivery vector would therefore target the liver and infect a significant proportion of its cells without straying into the host's other tissues. [19] It would be easy to produce and easy to modify.

Adenovirus does all this. In rodent and primate studies, 95 to 98 percent of administered adenovirus was found in the liver after intravenous administration. [20] It can be produced in large quantities according to the FDA's Good Manufacturing Guidelines, [21] and its ability to replicate its disease-causing components can be significantly reduced by deleting its E1, E2, and E3 genes. [22] The virus does not integrate into the host cell genome, and it infects dividing and non-dividing cells, [23] thereby increasing dispersal of the hoped for effect.

On the negative side, adenovirus provokes a significant immune response. [24] This prevents effective re-administration of this form of gene therapy, because the host system learns to recognize and eliminate the virus at the first infusion. This characteristic may pose a significant problem for gene therapy based on vectors that do not integrate into the host chromosome. [25]

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Gene Therapy Regulation: The Need for Third Party Fiduciaries