Blood Products Advisory Committee Meeting Announcement (BPAC) December 14-15, 2010

[Deatheye]

Phase IIb - more structured to overcome limitations of Phase IIa. Interesting that one patients started ARV therapy about the time the first study started.

I thought the this is the end of phase 2? But now they are talking about phase IIa and IIb? Are they both closed or is this just the end of phase IIa?

 

[Jemal]

But the monkeys only had XMRV for a few months before they were killed, if memory serves - I thought the working model for CFS was that you get XMRV and then viruses that you catch later cause the fatigue.

Yes, I don't think XMRV is causing fatigue that quickly. Also most animals need to be really sick, before they display it openly. They don't want to show weakness, because of possible predators.

 

[Cort]

Antibodies! The test Judy is really focused on...CDC negative while WPI finds some positives...this is good - they are finally getting down to brass tacks here.

Some not very good news; both Alter/Lo and WPI report that the negative control is positive!

Some more not very good news; both NCI and WPI find positives but in different samples - not good at all but then Judy says

Judy - Complete concordance between Ruscetti's and WPI results by serology. WPI doesn't do direct PCR, were asked to by this study.

Judy appears to be saying that yes, the PCR results were off but the antibody tests identified the same samples at the WPI and NCI with XMRV. She states the WPI doesn't do direct PCR (I imagine they do only culture) - (so they're not surprised they would off here.) (They did do direct PCR for the first study- but they have apparently dropped it.?)

That's it for now! Back after a break.

Processing/Storage

No evidence that not processing a sample quickly makes any difference

Serology results:

CDC all negative.
NCI/Ruscetti - found some positives.

Conclusions slide - already posted above, I think.

Will continue with collection of Phase III panel. Need to include serology concurrently w/other tests.

Question: Same subjects in IIa and IIb. Yes.
To Stoye: No experience w/delayed processing.

CDC researcher -- biological plausibility. Have no longitudinal data for any of these methods. Don't know if transient responses or maintained.

Phase IIa study - only WPI and Lo labs reported positive signals in negative control.

Serology in IIb from WPI and NCI - absolutely no concordance between results.

Coffin - No retrovirology evidence that delayed processing increases detectability. But aware that delayed processing improves detectability of some viruses (not sure who this is, but will speak later) in other labs.
Coffin - free RNA doesn't survive in plasma more than a few seconds, so would have to be in a protected

Judy - Complete concordance between Ruscetti's and WPI results by serology. WPI doesn't do direct PCR, were asked to by this study.

 

[Cort]

I don't see many real conclusions......I don't even see that much testing, honestly....We'll have to wait for the CAA webinar I guess to really figure out what happened. It always seems like underwhelm with these guys...

 

[Esther12]

I thought the this is the end of phase 2? But now they are talking about phase IIa and IIb? Are they both closed or is this just the end of phase IIa?

It could be that because II came up with such difficult to interpret results they've now added in IIb before moving on.

I don't know what to think about all this. It all seems so incredible.

I think I'm marginally more pessimistic than before we got the BWG results, but still arround 50/50 on it. The new WPI UK paper sounded solid though.

 

[urbantravels]

Phase II inconclusive, but they're not giving up - they're adding a Phase IIb.

I'm confused by most of this but hopefully will become more clear as more info gets out.

 

[Otis]

Small sample sizes is one issue here.

 

[Esther12]

Actually, I do now want to take back my patronising 'how hard can it be to run some blinded tests and clear this up' whinging about XMRV. It does seem like it's pretty darn hard to work out what's going on.

I wish they'd got on with something like the BWG a year ago though. I can't believe we're still not going to know if it's just a contaminant or not this year.

 

[Esther12]

Small sample sizes is one issue here.

Yeah. It makes it difficult to say anything with any confidence.

Stange that the day the sample was taken could make such a difference too.... yet the wPI seems to be getting such clear results for the Science paper and their new UK one.

 

[Jemal]

So... can I call it disappointing so far? It kinda looks like we moved only a few inches since october last year. Like Cort said, I can't really find any conclusions so far.

 

[Bob]

I'm confused... One sentence says that there's no concordance between WPI and NCI by serology, and then another says that there's complete concordance... Can anyone work out what's actually going on there?

And do we have any info about the actual detection rates by the WPI and NCI in Phase IIb? Have I missed anything about that?

Do we have any helpful conclusions from Phase IIb, or was it a complete mess?

Have they now finished Phase II or are they continuing with Phase IIb or starting a Phase IIc? Questions, Questions, Questions!

 

[Ernie]

I doubt much is going to be accomplished at this meeting.

 

[Jemal]

Picked up these two tweets:

No direct evidence of transmission or with a transfusion transmitted disease, so FDA has not established donor policy specific to MLV/XMRV.

http://twitter.com/xmrvbug

And:

#BWG proposes a #XMRV study but it ain't funded. No blood safety until after study, no study until $, so demand the $ now!

http://twitter.com/CreekFeet

 

[Esther12]

I'm not really clear on the results either. It would be nice to have them concisely laid out somewhere. From the sounds of it, they're deeply ambiguous.

 

[Cort]

One thing I get is that they really do realize how hard it is to find this virus....but where are the conclusions....They certainly weren't spelled out in the posts. Hopefully during the webinar we'll be able to address the members and get something definitive.....

 

[Riley]

I don't mean to be vulgar, but this sounds like a real clusterf***. Also, whose bright idea was it to only use 4 samples?

 

[Jemal]

I doubt much is going to be accomplished at this meeting.

At the moment I think this might be an understatement

Well, I guess it's not that easy, like Esther already said. If it was easy we would already have a cure...

 

[Cort]

Coffin - All sequences must have fairly recently come out of mice. Local outbreaks linked to a single mouse could be identified. Need to be careful not to think of this like HIV. Must put that to one side, e.g. genetic variation, epidemiology. Unwarranted until have agreement on positive samples.

He's saying this, I think, because XMRV is not that different sequence wise from those found in mice. The longer XMRV remains out of mice - the more it should diverge.

 

[urbantravels]

They could still, very easily, decide to defer (not just discourage) diagnosed CFS donors at ALL blood banks on the precautionary principle until more is known. Why they haven't done that already is kind of a mystery to me.

It looks like they can't possibly call for donor blood screening yet since the assay question is still so far up in the air.

 

[Cort]

He's saying this, I think, because XMRV is not that different sequence wise from those found in mice. The longer XMRV remains out of mice - the more it should diverge.

Discussion of issues to be resolved to qualify the antigens for use in the sero-assays.
Need positive subjects in normal donor population.
Need known pos and neg samples.
Don't know levels of antibodies in XMRV pos subjects.

Need an assay to devel clinical control. Need clinical control to validate assay.

Limitation of assay:
Calculated from small sample number.
Assumption of sesro-status (assume most donors are neg, if pos by other test, assume they'll be sero-pos)
Immune profile after infection unknown.
Another one I missed.

Obtained "training set" of samples
77 donors from NCI Frederick RDP
donor plasma from 1990s
39 XMRV pos subjects

Assay to XMRV antigens
Used stat analyses to determine utility of antigens in assay.

Looking for sensitivity, specificity, of course. (ROC curves).

IN and RT curves bad.
CA, TM and SU a bit better. SU curve is encouraging but based on only 1 lot, couldn't replicate with others. Found production error, going back now.

Training sets aren't blinded. 10/39 had reactivity for CA, TM and SU above "noise"
Found 1 non-pt donor pos on all three.

Donor samples from Dr. Alter, assayed for CA, TM and SU, concordance between CA and TM about 5.5% (raw, uncalibrated data, no SU available).

Some subjects are reactive to p12, MA and NC (including donor controls)

Inclusion of antigens reactive in human sera into a positivity algorithm. Maybe 2/3 or 3/3 of CA, TM and SU?

Still working.

Secondary assays: WB, NA tests

Trying to identify pedigreed clinical controls.

Also need samples from experimentally infected animal models.

It looks like they have a long, long way to go......