Biomedical Engineering Reference
In-Depth Information
In September 1999, patient 019, Gelsinger, was infused with the vector
and the inserted gene even though his ammonia level was ninety-one
micromolar on the day before he received the infusion. (The permissible
level was either fifty or seventy micromolar, depending on the version of
the protocol.) The Penn researchers replied that Gelsinger's ammonia
levels were within the stated range when he was screened for possible
participation in the trial in June 1999, that he was given a drug to reduce
his ammonia levels, and that they had made a clinical judgment that an
ammonia level of ninety-one would not be harmful to the subject.
In addition to the foregoing questions at the local level, the tragic
history of the Penn OTC deficiency protocol revealed serious problems
in the national oversight system for human gene transfer research. As
noted above, there was a long period of uncertainty that stretched from
May 1996 to October 1997, at least. During this time, there were mul-
tiple proposals about the role and the very existence of RAC. There were
also multiple versions of the NIH guidelines. Researchers received
quite clear signals from the NIH: “You in the research community
will be dealing primarily with the FDA from now on.” The net effect
of these developments was confusion and an undermining of RAC's
authority.
Perhaps the most important system problem was the failure of most
gene transfer researchers to report serious adverse events to the NIH and
RAC in a timely fashion. A December 21, 1999, letter from NIH direc-
tor Varmus to Congressman Henry Waxman contains this sobering con-
cession: “Of the 691 serious adverse events reported [in trials using
adenoviral vectors], 39 had been previously reported as required by the
NIH Guidelines
.”
11
Thirty-nine out of 691 is 5.6 percent.
The great unknown at the national level is how the FDA was
exercising its oversight responsibilities for the Penn OTC deficiency pro-
tocol and other human gene transfer protocols between 1996 and 1999.
One would like to know the answers to honest questions such as the
following:
•
How many FDA medical officers and reviewers were involved in over-
seeing the OTC deficiency protocol?
•
How carefully did they read correspondence and annual reports on
this and other Investigational New Drug applications?
•
What types of database capabilities did they have?
