Gene Therapy Regulation: The Need for Third Party Fiduciaries

© 2001 Peter Free

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Would the NIH/FDA Proposals Work to Protect Patients and Sponsors?

The NIH/FDA proposals are a start in the right direction.  They do a good job of rebalancing information disclosure to better protect patients and public oversight, but they do not go far enough in providing the enforcement mechanisms necessary to protect against future gene therapy mishaps.  The proposals also do not address streamlining NIH and FDA procedures to reduce burdensome administrative costs on medical research.  In terms of the four corrections suggested in the introduction to this article, the analysis proceeds as follows:

Boosting Informed Consent and Public Oversight

In rebalancing the patient-sponsor-public triad of competing interests, the FDA proposes to release what are arguably trade secrets and confidential commercial information [116] in order to better protect the informed consent and public health.  [117]  The suggested regulations, however, dig so deeply into protocol details–even down to gene sequences, vector production, and targets–that industry cannot help but feel commercially threatened. [118]  Even so apparently desirable a thing as adverse event reporting is controversial.  From the business perspective, these reports depress stock values and give competitors access to potentially damaging progress information.  In the face of business and research opposition, it is likely that a meaningful change in FDA procedures is going to require Congressional statutory intervention or a string of case-specific court battles.  Where those compromises end up is anyone's guess.

The Need for Genuine Enforcement by Review Boards and Biosafety Committees

            Assuming that the FDA proposals go into effect, they will not immediately prevent the sort of carelessness that killed Jesse Gelsinger.  Regulations existing at the time, had they been followed, would have prevented his death.  The FDA would likely have held or terminated the study upon receiving notice of elevated liver enzymes in two patients and the death of one or two monkeys.  Paul Gelsinger has reported that had he been afforded the opportunity for genuine informed consent, he would not have done granted it.  The fact was that neither the FDA nor NIH knew what was going on at IHGT, because Institute researchers failed to document and report what they were supposed to.

            The ultimate problem in the gene therapy field is enforcement, and enforcement requires people and funding.  Institutional Review Boards and Institutional Biosafety Committees are not adequately staffed (and sometimes not motivated) to do what the current system has assigned them to do.  If the warning letters to IHGT are examples, people were caught out by a higher-level review only after Mr. Gelsinger died and only then by blank spaces and contradictions on the face of submitted documents and some falsehoods given in answer to the FDA's subsequent critique. [119]  These are the sorts of errors that first-line supervision should be picking up.  Additionally, most of the investigation appears to have depended on what the miscreants themselves had to say.  This is not good law enforcement practice, [120] and there is no reason why it should be good practice in a setting particularly rife with self-interest and self-protection.

Successful regulatory enforcement comes from the first-hand observation of details.  This is particularly true where the enforcement is proactive.  In the case of gene therapy, the enforcement of approved protocols should come before, not after, someone is harmed.  Consequently, some provision must be made for seeing to it that there are people on the ground to do detail-oriented enforcement.

This is, however, unlikely to happen except among the most motivated of institutions.  Systemic conflicts of interests and inadequate funding are otherwise too pervasive.  Consequently, a limited overlay designed specifically to benefit patients is required.

The Need for Third Party Fiduciaries

Fiduciaries with access to the information the FDA proposes releasing could see to it that patients and families are provided the information required for genuine informed consent.  These intermediaries should be somewhat conversant with medical science, and they should have regular and unimpeded access to all pertinent data.  For conflict of interest reasons, they should probably not come from the staff of the research institution or business entity involved.  Nor should they be part of a regulatory agency.

By law, funding would come from the institution doing the research.  The fiduciaries would have the power to generate complaints requiring investigative action from IRBs, IBCs, and the FDA and NIH.  In this manner, there would be some motivated patient-oriented oversight at the ground level.  Also by law, these fiduciaries would be required to divest themselves of any potential conflict of interest before taking on their advisory/intermediary role.

Significantly, such a group could be sworn to patient and proprietary confidentiality when operating outside the directly fiduciary context.  If the FDA loses in its quest to release what has been heretofore-confidential proprietary data, the fiduciary system would permit patients to receive such data without unduly endangering the commercial venture.  Though this would slight the public oversight aspect of gene therapy research, it might provide a livable compromise.

The Case for Streamlining Redundant Procedures

With a view toward lightening the burden on the research sector, there is a case to be made for informally streamlining duplicative interagency procedures.  The FDA's proposed regulatory changes bring it into closer harmony with the practices of NIH's OBA and RAC.  To the degree that conceptual streamlining is a good thing, the proposals are welcome.  Presidential or Congressional intervention might encourage these turf-protective agencies to speed up progress in the rational integration of interagency gene therapy administration.  There is no reason why medical research should suffer because it is burdened with parallel procedures in areas where FDA and NIH interests are virtually identical.

Conclusion

            Informed consent in the gene therapy sector requires the revelation of information researchers and sponsors want to conceal for proprietary reasons.  Because social inertia, money and political power all pull in the direction of continuing relaxed oversight, comparatively powerless patients [121] should be protected by third party fiduciaries who have access to the information the FDA hopes to release under its proposed 21 C.F.R. § 601.52.  These same fiduciaries would have the clout to prompt FDA and NIH investigation of questionable research practices without necessarily revealing the proprietary and research secrets that lie at the heart of the opposition to openness.  Absent such a compromise, much enhanced first-line supervision of gene therapy trials by institutional review boards and biosafety committees is necessary if we are to build upon Jessie Gelsinger's sacrifice.

 

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