Biomedical Engineering Reference
In-Depth Information
the IHGT and the FDA agree, in November 1996 the Penn research
group failed to submit Protocol Version 1.0 to the FDA after the proto-
col was reviewed by Penn's Institutional Review Board. According to
the FDA, nine months later, in August 1997, the Penn research group
raised the permissible ammonia level for subjects entering the trial from
fifty to seventy micromolar in Protocol Version 2.0 without listing this
alteration in the summary of changes for the revision that was sent to
the FDA.
10
It would be possible to dismiss these omissions as failures to file
routine paperwork with a regulatory agency. In retrospect, though, the
next instance of miscommunication was potentially more important.
According to the FDA, in October and November 1998, Grade 3 (mod-
erately serious) laboratory toxicities in two subjects at the fourth dose
level were not reported immediately to Penn's Institutional Review Board
or the FDA, and the study was not placed on clinical hold. In response,
the Penn research group agreed with the FDA's assertions, but replied
that it did report these Grade 3 toxicities to the FDA in a January 1999
letter and a March 1999 annual report. The research group also sum-
marized the toxicities in a table prepared for an annual review by the
Penn Institutional Review Board on August 9, 1999.
There was also a breakdown in communication about parallel animal
studies that were being conducted in 1998 by the Penn research group.
From October through December 1998, the group conducted a preclin-
ical study with three monkeys using adenoviral vectors. According to the
FDA, two monkeys had serious reactions to early versions of the vector
and were therefore euthanized; a third had milder symptoms in response
to the third-generation vector that was simultaneously being used in the
OTC deficiency trial. In reviewing the tragic events of September 1999,
the FDA contended that the results of this preclinical study should have
been reported to the agency because they were directly relevant to the
OTC deficiency study. The Penn researchers agreed that the results of
this study should have been communicated to the FDA in the annual
report of March 2000, but argued that the doses of vector in the pre-
clinical study were seventeen times higher than those used in the clinical
trial. The researchers also noted that the response of the monkey that
received the third-generation vector was less severe than that of the
monkeys receiving the earlier-generation vectors.
