the leukemogenesis occurrence in the gene therapy stem cell trials, until the event happened, it was sort of thought about and kept on the back burner, and then when the event happened it transformed the whole field.  The FDA took the leadership role and provided careful instruction.  Everybody redefined the approach that led to the guidance documents which we all live by.  So I think it's a progressive process.

            DR. TAYLOR:   I think you may an excellent point though, that the leukemogenesis was unanticipated.  And one of the things that concerns me here is we're all talking about teratomas as if that's the only adverse event we're likely to see with these cells.  And I think we need to recognize that this is an even newer field than adult cell therapy, and that there is a likelihood for unanticipated events that, by nature, we can't predict.  So I wonder what kind of guidance we need to discuss about monitoring that would make allowance for unanticipated event.

            Specifically, I think about delivering cells in some of these locations that we know are potentially vulnerable, and whether or not the increased incidence of negative outcomes, that are not necessarily related to teratoma formation, are going to be seen.

            DR. SALOMON:  I just wanted to set the record a little straighter on the gene therapy thing.  The creation of leukemias in the children in the French stem cell trial was absolutely predicted and incorporated into FDA guidances long before that trial even began.  Of course that trial was in France and wasn't covered by FDA guidances anyway.

            But the point was is that it wasn't unexpected, it wasn't exactly expected that it would occur at two to three years after the administration, but that was a learning experience and there was adjustments then made.  But everyone should be clear, that that was expected, it was included, and that kind of monitoring was appropriate, and we talked about long term retroviral monitoring.  So I think that should be taken rather as an example of being comfortable that these kind of guidances from experts like us can be incorporated ahead of time.

            CHAIR URBA:  Anybody what to address the migration issue that Dr. Snyder brought up?   No?  Any other comments about questions?  Dr. Bauer, how does the FDA stand?

            DR. BAUER:  Thank you for this discussion.  It's been quite informative.

            I just want to make the comment that we generally don't take a one size fits all approach, and the most important issues that we consider are the nature of the disease, the indication, the severity of the disease, the demographics of the population, and so on.  We hope that, obviously these trials with all cell therapies are not like phase 1 drug trials in terms of their design or their size, and also in terms of the people that are involved, and these are patients of course with the disease not healthy volunteers.  And we expect that if patients will be exposed to some risk, that we hope they will derive some benefit from the trial.

            I'd also like to emphasize the need to gain knowledge from these trials in terms not just of efficacy, but of understanding or documenting some specific pharmacodynamic action which may take biomarkers, if not surrogates.  But that's quite important as well.

            And so, obviously, we need more science, we need greater development of imaging techniques as we've heard which will help this along.  But we thank you.

            DR. SNYDER:  I guess I should bring up just one last issue that I often get asked and maybe we can dismiss this fairly quickly.

            I'm often asked by people whether, before going into clinical trials, there needs to be specified that the cells are grown in a particular fashion.  Can they be grown on feeder layers?  Must it be a biologics-free, feeder-free culture environment before we ever move into a clinical trial?  So probably it'd be useful to the people out there to at least come up with a statement in that regard.  Maybe it's simply as long as it's safe and meets all the safety requirements, it doesn't matter how you grow the cells and we're not going to demand biologics-free medium beforehand.

            CHAIR URBA:  Need for summary?

            DR. WEIR:  No.  I thought this was a very, very nice discussion with so many good contributions.  And, you know, it seems to me that in a way we weren't very specific, but on the other hand I think there were general principles that hopefully will be helpful and obviously the specter of teratoma has been thoroughly aired.  But I think that Bruce's point about how each trial is going to require really incredible detail and each one's going to be different.

            CHAIR URBA:  Thank you.  Dr. Whitten, do you have any comments for us?

            DR. WHITTEN:  I just would like to thank the committee and the guests who came to join us today to join us SGEs and also the guest speakers and the FDA planning committee, and Gail and Bill for making this a useful discussion for all of us.

            CHAIR URBA:  Okay.  Thank you.  I add my thanks to Dr. Whitten for everybody's help today and our guest speakers.  It was a very interesting day.

            Gail, do you have some?

            MS. DAPOLITO:  No.  I just want to  remind the committee that's back here tomorrow that we start at 8:00 tomorrow, not 9:00.  And I know some of the committee are here until tomorrow and if they wanted to go to dinner as a group, see Danielle out in the hallway and she can arrange that.  Thanks.

            CHAIR URBA:  So we stand adjourned.  Thank you.

            (Whereupon, the above-mentioned meeting was adjourned at 5:11 p.m.)