Meeting 32, May 10, 2002
Questions for Committee Discussion
- If vector sequences
are detected in the motile sperm fraction of clinical trial subjects, the
FDA’s current approach is to suspend accrual to the study pending
additional data regarding the persistence of the vector.
Enrollment has been allowed to proceed when there are data to show
that the vector does not persist (three consecutive samples test negative).
- Does the committee
agree that a clinical hold is warranted when motile sperm tests positive
for vector sequence, or should enrollment be allowed to continue with
appropriate modification made to consent documents?
- Please discuss the
implications of detecting vector sequences due to the presence of
contaminating transduced PBMC or vector (either free or on the surface of
a sperm) in the motile sperm fraction.
- There are technical
limitations in the ability to monitor women and certain men for evidence of
germline alterations. One
approach to monitoring subjects for germline alteration would be to restrict
early clinical development of certain gene transfer products to subjects who
have been shown to be capable of repetitively supplying adequate semen
samples for analysis in order to collect data regarding distribution of the
vector to germline tissues and the persistence of vector.
Depending on the amount of data required, much of the early clinical
experience with the vector might be limited to this restricted population.
A development program requiring extensive characterization of
distribution to germline cells and germline alterations might substantially
delay acquisition of adequate safety and efficacy data in other populations
discuss those situations in which clinical development of a gene transfer agent
might proceed in the absence of the ability to monitor semen for evidence of
germline alterations or the presence of vector gene sequences.
- Given a situation
where vector sequences are persistently, not transiently, detected in the
motile sperm fraction of clinical trial subjects please discuss what
regulatory actions would be appropriate for the FDA to take.
Should these trials proceed with appropriate modifications made to
consent documents? Should further studies be limited to subject populations
that are unable to reproduce?