Gene Therapy Regulation: The Need for Third Party Fiduciaries

© 2001 Peter Free

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The FDA put all the IHGT's investigational new drug trials on hold. [63]  The University of Pennsylvania withdrew from the business of doing human trials. [64]

            Parallel problems existed in IHGT's animal studies, including the monkey study in which the OTC adenoviral vector was also being tested.  An FDA investigation revealed that

                        (a) IHGT did not have an effective Quality Assurance Unit; [65]

                        (b) researchers deviated from changes made in three protocols; [66]

                        (c) the Study Director did not approve protocol amendments; [67]

(d) some animals did not meet the specified weight ranges: [68]

(e) records were incomplete or inaccurate;   [69]

(f) there was no standard operating procedure for labeling monkey tissue samples; [70]

(g) there was no standardized definition of critical parameters key to the monkey study; [71]

(h) the adenoviral vector used in the monkey study was past expiration, leading the FDA to conclude that it may have provided only 34.4 to 47.8 percent of the dose the protocol called for, potentially causing an underestimation of dose toxicity in humans infused with fresh vector; [72]

(i) the adenovirus used in the monkey study was inconsistently diluted; [73]

(j) virus preparation records failed to list dates of preparation, lot and vial numbers, concentrations, animal identification numbers, dosages, controls, and certificates of analysis; [74]

(k) IHGT had not prepared final audited reports for studies conducted since 1998; [75]

(l) study data was archived on the open shelves of an unused restroom, and no one was identified as being responsible for maintaining the data; [76] and

(m) control and test samples were not retained for the record. [77]

In total, the FDA findings document a lack of appreciation for the scientific method.  The monkey study had implications for the Gelsinger trial.  Had it been conducted and reported according to protocol, Gelsinger might have lived.

Informed Consent Was Not Adequate

            The Institute for Human Gene Therapy withheld information that might have encouraged the Gelsinger family to reconsider their decision to participate in Cohort 6 of the trial. [78]  Jesse's father testified before the Senate Subcommittee on Public Health that his son had been told that the most that could happen to him would be a week of flu-like symptoms.  After his son's death, Paul Gelsinger learned that

(a) the statement to him that one patient had shown a 50 percent improvement in ammonia elimination was not true;

(b) he had not been told of the toxicity previous patients had experienced;

(c) the consent forms he saw did not mention the monkey deaths previous forms had reported; and

(d) researchers withheld information about adverse effects in a similar trial by another company. [79]

As a consequence, Gelsinger sued the research team, an associated bioethicist, the University of Pennsylvania, and Genovo Inc. for negligently, recklessly and fraudulently recruiting and treating his son. [80]  The suit was settled a few weeks later for an undisclosed amount. [81]

Subsequent Criticisms of the Regulatory Process

            Criticism of gene therapy regulation and review was widespread after the Gelsinger death.  The University of Pennsylvania incident focused attention on the sloppy science and deficient patient protection that are common in clinical research. [82]  These inadequacies result from (1) scientific competitiveness aggravated by limited funding, (2) commercialization and conflicts of interest, (3) the anecdotal medical mindset, (4) ordinary human laziness and institutional inefficiency, and (5) inadequate administrative infrastructure and enforcement.

Scientific Competitiveness Aggravated by Limited Funding

Scientific research is highly competitive, funding is short, and the pressure to produce quickly is intense.  Money is often limited to fashionable or already profitable research topics.  Few labs have the luxury of not having capable competitors pursuing similar ideas.  Recognition goes almost entirely to a few lead names, and everyone wants to be one of these.  Given that scientific advancements almost always come from the young, few ambitious people voluntarily pursue apparent dead ends or tedious unrewarding research.  Since accurate documentation and analytical thought take time and discipline, there is a temptation to cut corners in the interests of speed and perceived productivity. [83]  Intelligent people also recognize that protocol parameters are often scientifically arbitrary.  The temptation to modify them to speed up the discovery process is significant.

Commercialization and Conflicts of Interest

            The competitive drive for recognition is aggravated by the drive for wealth.  Biotech has enormous remunerative potential under the protection of intellectual property law.  Academic-affiliated researchers, universities and hospitals own substantial equity in biotech ventures. [84]  Ethical guidelines vary among these, and some are quite strict.  It is unlikely, however, that talented researchers will give up chances to prosper simply to stay in these settings.  Regulatory agencies are staffed with people who also have financial interests in the biotech industry.  Consequently, the urge to slant informed consent, conceal worrisome experimental results, fudge data and plead for proprietary information protection will persist.  In the absence of criminal or substantial civil penalties, there is essentially no downside to the self-interested approach.  Openness works against recruiting volunteers, staying ahead of competitors, and obtaining patent protection.  Therefore, it is likely that third party enforcement of the ethical treatment of trial subjects will be necessary. [85]

The Anecdotal Medical Mindset

Medicine is particularly vulnerable to scientific corner cutting.  At the practitioner's level, it is often based on anecdotes tempered by science, rather than the reverse. [86]  Anecdotes rebel against statistics and free-float above method.  People accustomed to thinking in anecdotal terms do not fully appreciate or abide by the constraints of scientific reasoning and data keeping.

Ordinary Human Laziness and Institutional Inefficiency

            Day to day fallibilities intrude on the best intentions.  Individually speaking, documentation of the humdrum components of a clinical trial is not easy, particularly when the trial subjects are capable of diverting investigators from analytically accurate routines.  Most people recognize the utility of tedious detail only in retrospect.

Institutionally, problems are compounded when busy investigators work on several projects at once or rely on less experienced people to assist them.  Due to high workloads in the medical field generally, one suspects that the names listed on experimental protocols are not consistently the people doing the actual work and data recording.  The average teaching hospital, for example, routinely assembles a disconnected, randomly integrated series of tasks often requiring immediate attention.  People in training do most of the work, and they are frequently thrown into situations for which they are poorly prepared.

 

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