Gene Therapy Regulation: The Need for Third Party Fiduciaries

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Supervision of the full scope of detail by more experienced staff is habitually inadequate, given that the workload is sufficient to tax everyone. Significantly, few people in the training hierarchy, comprised mainly of interns, residents, and the occasional attending physician or surgeon are actually selected on the basis of their ability to teach. This is also true of PhD researchers whose main focus is their work and not their ability to interact with others in the capacity of teacher or mentor. Consequently, a good deal of what is done by trainees is done without a full understanding of the nuances of the big picture. This is worrisome in settings where the scientific method and its attention to seemingly trivial detail is key. [87]

Given that these institutional settings magnify the likelihood of error, it would be wise to create an administrative system that improves the chances of detecting and rectifying lapses. Yet this is exactly where the current system fails. It does not pay sufficient attention to the mechanisms required for effective first-line supervision.

Inadequate Administrative Infrastructures

The FDA and NIH are overburdened when institutional compliance with clinical trial regulations is inadequate. The FDA is the only agency that may approve or terminate Investigational New Drug (IND) trials. [88] As of May 2000, FDA was responsible for 206 gene therapy INDs, including 900 protocol changes arriving each year. [89] The load is expanded by the fact that a single new drug application may involve multiple protocols conducted at multiple test sites. [90] The FDA's supervisory contact is primarily with the trial sponsor (a step removed from research level), although it contacts the investigator during inspections. [91] The FDA's Biological Response Modifiers Advisory Committee advises the agency on policy, including recommendations on proposed gene therapy products and clinical trials. [92]

NIH's Office of Biotechnology Activities supervises federal money invested in clinical trials and has authority to approve and terminate federal funding to institutions that violate its guidelines. [93] It does not have legal authority to terminate or hold clinical trials, [94] and its contact is with the trial investigator rather than the sponsor. [95] The Recombinant DNA Advisory Committee (RAC) regularly reviews selected studies before they are allowed to proceed. [96] Review is public and treats ethical, safety, and scientific issues. [97] Currently, the majority of gene transfer protocols are subject to the NIH approval. [98]

The supervisory burden on both federal agencies is theoretically reduced by the requirement that an applicant have an Institutional Review Board (IRB) approve and continuously review each new drug trial. [99] The burden on the applicant is increased, because NIH adds requirements. NIH's Office of Biotechnology Activities requires that each applicant for recombinant DNA funding establish an Institutional Biosafety Committee (IBC) to ensure the study's compliance with NIH Guidelines. [100] If the applicant institution engages in large-scale research/production of this type, it is required to appoint a Biological Safety Officer. [101] NIH Guidelines explicitly regulate the level of preliminary approval required for protocols of different types. This varies from combined approval from the IBC, RAC, and NIH Director for "major actions" to simple IBC go-aheads for more ordinary research. [102]

The FDA/NIH overlap means that government funded protocols must at minimum get FDA, IRB, and IBC approvals and, at maximum, add approvals from RAC, OBA and NIH Director. Neither federal agency, however, is equipped to confidently assure itself that required reports at any level are timely, accurate, or even being submitted. [103]

Built into the regulatory system is a disincentive for reporting to NIH. The agency is permitted to make public nonproprietary information it receives in regard clinical trials. This is routinely done by the RAC. The FDA, on the other hand, is prohibited from releasing any information about the existence of an application for an IND unless the application has been previously disclosed or acknowledged. [104] As a consequence, research institutions believe the FDA better protects their privacy, and they report accordingly. [105]

Inadequate finances, expertise, and staffing plague this cumbersome system; consequently, it does not work as advertised. [106] On the ground, too much is left to self-reporting by investigators and sponsors with interests harmed by disclosure. Despite these shortcomings, administrative law in place at the time of the Gelsinger protocol would have been adequate to prevent his death had the resources for sufficient oversight and enforcement been available. Flimsy oversight was an error of motivation, not shortsightedness. The regulations in place at the time indicated that everyone realized bad things could and would happen if laissez faire medical science were permitted.

Subsequent Proposals for Improvements in Regulatory System

About ten months after Gelsinger's death, an NIH working group came up with some proposals for mending the NIH Guidelines. [107]

(1) Institutional biosafety committees (IBC) should not approve a protocol until the RAC has reviewed it. [108] Specifically,

(a) If the RAC judged the protocol to be novel, the IBC could not approve it until the RAC has completely reviewed it.

(b) If the RAC found the protocol not novel, the IBC could approve it.

(2) NIH should clarify serious adverse event reporting.

(a) "Serious adverse events" should be defined.

(b) A time frame for such reporting should be explicit.

The working group failed to reach accord on the problem posed by differing FDA and NIH confidentiality requirements. A majority believed that rules should be consistent as to criteria and timeliness.

The FDA proposed significant changes to the Code of Federal Regulations bearing on gene therapy trials in January 2001. The suggested rules were intended to:

(1) Improve access to information relevant to informed consent. [109]

(2) Inform public discussion on gene therapy and xenotransplantation. [110]

(3) Publicize the existence of clinical trials that might be of interest to patients. [111]

(4) Address long-term needs for gene therapy surveillance, post-mortem analysis, and analysis of infectious disease risks to patients and their contacts. [112]

To accomplish these ends, the FDA proposed adding a new 21 C.F.R. 601.52. [113] The new regulation would:

(1) Disclose generally:

(a) the trial sponsor's name and address;

(b) clinical indications to be studied;

1. scientific and lay abstracts;

2. a statement of the study's purpose, objectives, and rationale;

3. the name and address of each investigator;

4. the name and address of representatives of the local IRB/IBC;

5. criteria for patient selection/exclusion;

6. the number of patients to participate; and

7. a description of treatment, procedures, and tests.

(2) Identify particularly:

(a) vector name and type;

(b) gene insert;

(d) intended target cells;

(e) source organs/tissues/cells and methods of preparation;

(f) vector production methods;

(g) cell purity;

(h) delivery system;

(i) ancillary products;

(h) source animal health maintenance/surveillance records; and

(j) source animal material to be archived.

(3) Provide safety reports, including:

(a) IND safety reports, including adverse event reports;

(b) sponsors' annual FDA reports, including:

1. evidence for gene transfer, expression, and activity;

2. observed immune response;

3. biodistribution;

4. significant preclinical and clinical toxicities;

5. evidence of infection;

6. adverse experiences;

7. patient deaths (personal identifiers to be withheld), including:

(i) cause of death,

(ii) status of autopsy requests,

(iii) postmortem evidence of gene transfer, gonadal and general biodistribution

(4) Disclose the status of and dates/reasons for regulatory investigations.

(5) Provide sample informed consent forms.

(6) Permit the Director of the Center for Biologics Evaluation and Research to release other information necessary for the appropriate consideration of public health and scientific issues.

To protect patient and sponsor confidentiality, the FDA suggested adding 21

C.F.R. 601.53. [114] This new regulation would require IND sponsors to submit information required by the IND process and 601.52 disclosure in two forms. One form would fully disclose required data, and the other would be an edited version protecting proprietary and patient confidentiality. The FDA could then release the censored version under the new 601.52 disclosure requirements. The agency estimated that average annual cost per sponsor of providing this redacted data would be $847. [115]

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Gene Therapy Regulation: The Need for Third Party Fiduciaries