EVALUATING EMERGING INFECTIOUS DISEASES (EIDs) FOR TRANSFUSION SAFETY: TRANSCRIPTS

[hidlyn]

It's not looking good that anyone in power is taking XMRV seriously enough in this country to do something about the blood supply. The quote below if from the published transcript of a recent meeting with the FDA.
http://www.fda.gov/downloads/Biolog...ts/WorkshopsMeetingsConferences/UCM214030.pdf


UNITED STATES FOOD AND DRUG ADMINISTRATION CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

EMERGING INFECTIOUS DISEASES: EVALUATION TO IMPLEMENTATION FOR TRANSFUSION AND TRANSPLANTATION SAFETY (DAY 1)

EVALUATING EMERGING INFECTIOUS DISEASES (EIDs) FOR TRANSFUSION SAFETY

The Hilton Washington D.C. North/Gaithersburg 620 Perry Parkway Gaithersburg, Maryland 20877

Tuesday, May 11, 2010


Starting on page 111

Now, Lou Katz (phonetic) said "Gosh, if you remember this you must be old." And Matt's already hinted about this, but there was an interesting movie, and it brings me to the topic of XMRV. Everybody's lips, Xenotropic Murine Leukemia virus-Related Virus. It is a Xenotropic retrovirus, that is one that can no longer actively infect its host organism, the mouse, or apparently the mouse, but can infect other species. It's a cell associated virus with an unknown transmission rate to and between humans, and appears from genetic data to be of Murine origin.
It certainly generates asymptomatic infection, and to date we have not observed or indeed even looked for transmission by transfusion. The assumption is that a virus of this nature should be transfusion transmissible, but we have no data to support this. There's no -- equally, there's no information about its survival in blood products. We would assume that it would survive, but we don't know. And to date we don't have any known causative relationship to disease. And I think that this is an important point.
There are data that suggests the virus is responsive to the usual range of antivirals, and the prevalence of infection in the donor population is unknown, or have been scattered observations suggesting somewhere between zero and three or four percent, depending on populations looked at, tests used, and there may be more data coming down the pike in the nearly -- near future.
The epidemiology of this agent is unknown, but there's considerable media interest, and there's a great deal of interest from a patient affinity group, this is the Chronic Fatigue Syndrome patient group, and there's general regulatory concern about retroviruses, and specifically about this agent. Any intervention that we could conceive of at the moment assuming that the decision was made to develop an intervention would be strictly at the research level would be of unknown value and questionable impact, both in terms of its efficacy in preventing a future downturn or downside, or of its impact on the availability of blood and donors.
The current status is that there's highly controversial literature, there have been inconsistent findings for viral markers of infection with XMRV in various prostate cancer populations, and in patients with chronic fatigue syndrome, and healthy controls. But no causality has been established in these cases.
And there are publications that define such a presence; there are many counter-publications that fail to find these associations. So I think at the moment the jury has to be out on what the significance is of infection with this agent.
As I already commented, transfusion transmission is theoretical; we don't see an obvious intervention to prevent such transmission. And test methods, as Steve already pointed out, are not yet standardized. Now, there's certainly very general concern when HIV is seen as the model of an evil retrovirus, with particular focus on two aspects, species jump, and potential for mutation to become a pathogen. But we have to note that to date, in the
published studies, this agent has had a very stable genomic structure, which suggests that it's not out there mutating furiously. As I already commented, the CFS affinity groups and their surrogates are very interested in this agent. And just yesterday, the CFS advisory committee came up with a recommendation to screen blood donors for CFS by a questioning focus. We'll have to see where that goes.

Just infuriating!!

p. 126

Mr. Dodd: In the context of XMRV, I think that there is an emergency, but it's a perceptual emergency.

Keep reading folks. It just gets better and better.

 

[Robin]

This is annoying but it's really unsurprising. Look at the perception of this illness and the utter lack of funding for research. Most people have no idea how bad it is until they or a loved one gets it. We're not dying in droves like AIDS patients -- and they got brushed off initially.

They will be unwilling to do anything until there's rock solid evidence (not just from the Science study.)

 

[Patience]

Evidence ? How much more evidence do you need. Red Cross Japan, Germany, WPI, CC, NCI, Abbot Disgnostics, Ila Singh, Bateman, Van Der Meer and his lying team, Jonathon Kerr. Hello???? Canada is the only smart people in this. Oh and the othervquote I love from this paper well we coukd lose a lot of donors !!! Our government is literally out of their head on this one. I for one will be sending this to my representatives explaining to them these are the people you Hire to protect our world from infectious disease. Oh pulezzz if this had been found in MS or Lupus patients you think we'd still be yelling and no one listening . This is the old fashioned Bias of we say we believe CFS is serious but shhh we don't really . How stupid do they really think we are ? Perception Emergency !!!! The NIH will roast them . I cannot wait for the new studies.

 

[Kati]

p118

I think we have to be concerned that there are really two axis that don't interact very well; the axis of public health which is the benefit of an intervention, and the access of public concern, which is basically panic.

They're worried about creating panic. Just like HIV created panic in people because the government didn't want to talk about a gay men disease.

 

[Kati]

p 122

But at this time there is no way of establishing the quantitative or qualitative risks of XMRV to blood safety, and there are no available meaningful interventions. But responsible research would be expected to resolve some key uncertainties. And test implementation and research involve completely different resource pools.

So this is where I end up at the apparent split in the road; Babesia we should seriously consider donor testing, we're in the right position to make that decision. And XMRV, I believe is still subject to research although there are significant public policy and public concern overheads here. Thank you very much. (Applause)

They are trying to decide which bug they should focus on, babesia or XMRV. They're thinking XMRV will cost them a lot of money. Sheesh- They haven't got the disease, so hey, let's flip a coin. Clap clap clap.


p.125, Q &A for Dr Dodd:

MR. DODD: Well, as I say, I think -- as I try think there are two different axis that we need to say, I to consider is, as scientists we need to consider what the data are or are not telling us, and what responsibly could be done in the short timeframe to provide adequate information to really know what's going on or what might be going on.

From a public policy point of view, I think there's a lot of pressure, there's a lot of pressure particularly from people with CFS, which is a disease of considerable concern, and their belief is that if this is -- does have an infectious cause, and that's a very open question, shouldn't we be reducing the risk of transmitting this to other people. But the problem of transmission of XMRV if it is a problem, it's going to be very much bigger than I think CFS alone.

So I don't know what the answer is. I think those we'll probably discuss later. We do need a realistic system, but I don't know how you trade one against the other. But Jay is going to tell us what to do.
summed up
(Laughter)

So are they going to answer the serious threat of XMRV and fund CFS or are they gonna try to shut us up?

 

[usedtobeperkytina]

prophesying and then fulfilling it themselves by the decisions they make.

 

[Kati]

p126 Still Mr Dodd talking:

In the context of XMRV, I think that there is an emergency, but it's a perceptual emergency. And I'm not as well versed in the tools of managing that, but I think that what we need to do is to manage people's reactions rather than people's safety at this point.

So it's where he's at, managing people's reactions. Gag them CFS people, they're making too much noise. :tear: (sarcastic)

Question/comment from a different speaker:

Just a follow-up to the last comment that Roger made that I agree very much, and I think you touched the important point, is that I believe that we are going to confront this type of issues more and more frequently. It became a pattern with for instance, Gulf War syndrome, and all that where affinity groups as you called -- have adopted transfusion as a way of calling more resources to their issues.
And in fairness to them, it's a very serious problem and they haven't gotten enough in attention and support. But I think that we have to be able to deal with the issue because it is going to become more frequent than it is now.
me.
MR. DODD: Thank you. I'm glad you said it, not

No respect for the silent. There is no respect.

 

[Kati]

p 144-146 Dr Susan Stramer, American Blood Bank

We have created a fact sheet just to touch on what we're doing for XMRV. We do not have a donor specific question. There is not one in use. We don't believe one is feasible because we cannot identify risk factors with any certainty. There are only experimental tests that have not been validated. It's difficult or impossible to ask a sensitive or specific question for CFS. If the studies have already been published of up to four percent donors is the reality, we would be losing many, many donors.

The specificity of XMRV infection in that four percent is unknown, and if we ask a CFS question, the sensitivity of that is also unknown if we're basing this on medically confirmed chronic fatigue syndrome because over 85 percent of CFS cases are unconfirmed and undiagnosed. And then lastly, do we do -- we haven't done anything yet for a donor deferral period that may change.

But this is currently what's in the fact sheet, that there is no FDA guidance or AABB standard. Current practice for FDA guidance and AABB standards is to accept donors who are healthy at the time of donation. Both CFS advocacy groups and the NCI have historically discouraged blood donation by CFS patients not only for their own health but also to protect the safety of recipients since the number of etiologic agents have been linked to CFS but none proven.

And then last thing we said blood collection facilities should follow their SOPs with respect to cancer, that is the link with prostate cancer. So I leave you with two slides to ponder. We have human RNA tumor viruses or called "rumor viruses" and in the introduction of this paper and Roger has already made reference to this.

In humans, estimates from the genome sequencing project suggest that indigenous retroviruses now comprise some eight percent of our DNA. So we are walking retrovirus factories representing around 4,000 pro-viruses and 1,000 more solitary long terminal repeats.

And if you look at that paper just to show you the number of retroviruses many or all of these for which except for HTLV -- no HTLV is not on this table -- but we do not test this list this long -- and has been associated with cancer, neurological diseases, and autoimmune diseases. So with that, I thank you for your attention.
(Applause)

So now they're trying to find excuses not to test for yet another retroviruses.

 

[Kati]

p 341-343, Discussion

Here if I can just use an example I think that you know the XMRV is an excellent model. And I think that what we've done so far with XMRV has been very deliberate. You know the literature came out a couple of years ago with XMRV and in prostrate cancer. And then most recently in October of last year it was the XMRV and relationship with individuals with chronic fatigue syndrome. So what we've done right now is very deliberate
341
process of trying to standardize the procedures along the way. We've identified that there are things that we have to tweak such as sample preparation, the time for preparation.
And so now I think that what we've laid out even this morning was the idea that there are repositories, okay. So we don't know whether it causes disease in man. We do know about the trigger that really got us thinking was that it has the potential of being transmitted in the blood. It is associated with white cells. There are certain amount of the viruses in the plasma. So because it has the potential for being transfused -- transmitted then that really got us going. That was one of the triggers.
Now the deliberate process that we have is that we have to be able identify it in a standardized way and then also to see does it cause disease. Now as Harvey mentioned because it's unclear there's no clear-cut scientific then the societal issues are weighing in the pressure is then what are you doing about this. how much risk would the society be willing to take. think that maybe, we have an opportune time here to take XMRV as the model process and really work our way through on how do we handle these for the future.

Maybe there is hope?

 

[V99]

It's the reactions of the general population they should be worried about. CFS patients are already sick, and less likely to panic. Can't catch something you already have.

As for the causal issue, well no ones has got to that stage yet, so why would you know. Everyone is too busy trying to see if there is an association.

In the meantime they need to stop stalling, or is it their fear/panic that we may gain more resources to the CFS issue?

 

[Mithriel]

Blood products are a very tricky area as without them people die, simple as that. They can't be stored so there is no next month's operations depend on this month's donations. If they stop everyone donating who has ever felt fatigued there will not be enough blood available.

The dodgy definition of CFS which mean just being tired makes you qualify is confusing the issue. Until there is a validated test so blood can be screened how much blood do you reject on the off chance it is infected?

The balance of risk is very hard to decide and if some people get infected in the meanwhile they won't die immediately and there may be a treatment soon anyway. If people are terrified to get a transfusion they could die.

Also, legally, there is no liability if you get an infection from a transfusion unless the services had a test available but didn't use it. And there will always be someone who will sue if they refused a transfusion, got sicker and it turned out that XMRV did not pass on in blood.

Mithriel

 

[V99]

Another interesting quote on pages 115/6

What are the scenarios for the future with respect to XMRV? I would submit that at this time they're completely unknown and essentially unpredictable. And again, in my opinion, range from the completely irrelevant, to a doomsday scenario. The irrelevant situation is that this is a phenomenon reflecting contamination, cross-reactivity, or even normal viral flora.

And in the latter case, there is certainly some models where we have viruses that are widespread, that are transfusion transmissible but which do not appear to cause any negative outcomes either to donors or recipients. The TTV/SEN-V complex, HGV/GBV-C, and even simian foamy virus have all been discussed in this context. And we appear to be relatively comfortable at this time, paying no further attention to them.

The doomsday scenario of course is the one that provokes a lot of concern that the virus causes a dread disease or diseases. That it has an extended incubation period, that it spreads rapidly by common routes, that it's already widespread. And perhaps there has been or there will be a viral mutation event. This is -- this I think is something that has to concern us.

 

[VillageLife]

And perhaps there has been or there will be a viral mutation event

what does that mean?

 

[bullybeef]

I just been having this debate with my cousin. He seems to think I am of the opinion that XMRV may become like 'I am Legend'!

I actually replied XMRV may not be proven a life ending disease, like HIV, but more like a life sentence disease. The problem there is, if a disease kills everyone, there's no one to pick up the bill, and it costs the countries of the world nothing.

But if XMRV goes on to be proven to infect vast numbers of people, costing millions in job cuts, debilitating the welfare, disability, health and insurance systems, who's going to pay for all that? Therefore, XMRV may be a global economical disaster, rather than a doomsday scenario.

Global economical collapse could probably be worse than everyone dropping dead. With the paranoia surrounding global warming (however true that maybe), the fact weve already coming out of a global recession, and the lack of natural resources, would this mean the human race could be on the brink of returning to the dark ages?

 

[kit]

"The doomsday scenario of course is the one that provokes a lot of concern that the virus causes a dread disease or diseases. That it has an extended incubation period, that it spreads rapidly by common routes, that it's already widespread. And perhaps there has been or there will be a viral mutation event. This is -- this I think is something that has to concern us."

You bet your @ss it is something to concern you. "A dread disease. . . that is already widespread." Congratulations, Roger Y. Dodd, you're getting warmer. Hi patience, welcome to the forum!

 

[VillageLife]

Some quotes from the meeting, which was attended by:

C.D. ATREYA - Associate Director for Research

HIRA NAKHASI Director, DETTD, CBER

CAROLYN WILSON Associate Director for Research CBER

JAY EPSTEIN Director Office of Blood Research and Review CBER

JAMES HUGHES Professor of Medicine and Public Health Emory University

MATTHEW KUEHNERT Director Office of Blood, Organ, and other Tissue Safety CDC

MARTA GWINN Medical Epidemiologist Office of Public Health Genomics CDC

STEVEN KLEINMAN Senior Medical Advisor, AABB Clinical Professor of Pathology University of British Columbia

Roger Y. Dodd Vice President, Research and Development Holland Laboratory American Red Cross

SUSAN L. STRAMER Executive Scientific Officer Biomedical Services American Red Cross

PETER R. GANZ Director Center for Biologics Evaluation Health Canada

MARK WALDERHAUG Associate Office Director for Risk Assessment Office of Biostatistics and Epidemiology CBER

JERRY A. HOLMBERG Senior Advisor for Blood Policy HHS Office of the Secretary

HARVEY ALTER Chief of Clinical Studies Associate Director for Research Department of Transfusion Medicine NIH

RAYMOND P. GOODRICH Chief Science Officer CaridianBCT Biotechnologies

CLARK TIBBETTS Executive Vice President TessArae, LLC

DAVID ASHER Chief, Laboratory of Bacterial, Parasitic, and Unconventional Agents OBRR, CBER

PAUL A. MIED Deputy Director Division of Emerging and Transfusion Transmitted Diseases OBRR, CBER

I spent a little time considering whether there are any precedents from things that we've done since the appearance of AIDS. And I find really not a lot; HTLV, we took rapid action because after all, it was a retrovirus.

XMRV, I honestly don't know where one might put this. And after I put this slide together, I thought, well maybe this isn't even the right shape, maybe we need something that's much more irregular and doesn't have a clear position anywhere on this matrix because my sense at the moment is probably the public concern access is higher than the science and epidemiology. But we really don't know.

But at this time there is no way of establishing the quantitative or qualitative risks of XMRV to blood safety, and there are no available meaningful interventions. But responsible research would be expected to resolve some key uncertainties. And test implementation and research involve completely different resource pools.

And XMRV, I believe is still subject to research although there are significant public policy and public concern overheads here.

From a public policy point of view, I think there's a lot of pressure, there's a lot of pressure particularly from people with CFS, which is a disease of considerable concern, and their belief is that if this is -- does have an infectious cause, and that's a very open question, shouldn't we be reducing the risk of transmitting this to other people. But the problem of transmission of XMRV if it is a problem, it's going to be very much bigger than I think CFS alone.

think that what we need to do is to manage people's reactions rather than people's safety at this point.

we've had over seven queries now for XMRV in which transfusion-transmission hasn't been proven, clinical disease association haven't been unequivocally demonstrated.

It's difficult or impossible to ask a sensitive or specific question for CFS. If the studies have already been published of up to four percent donors is the reality, we would be losing many, many donors.

the fact that decisions were made in Canada to defer individuals with chronic fatigue and obviously there are global implications and why did we do it, on what basis did we do it? And so there would be -- it would be helpful to have clarity around how that decision was taken and what it means for other jurisdictions.

you're having a blood products advisory committee on XMRV coming up in July.

But if you had a formula and you took XMRV we know a rough donor prevalence that we'd be okay there but we haven't yet proven it's blood transmissible. That information should probably be coming out soon. But we don't have a disease. So I think -- so that would turn your formula right now to zero but -- so that puts it into a very low priority based on science. That's where maybe perception would come in and then the perception would say well, maybe we should do something but something mild. You know, maybe ask a question or give more information to the donors. Those are mild interventions which are commensurate with the risk. If it turns out that it really causes chronic fatigue syndrome that it moves up the ladder on your priority list.

mean we do have a plan with XMRV now and that is to try to fill in some of the missing pieces, right. So at some point your intervention is to make that agent a research priority which I think was done very early on by HHS and you know we even came up with some money to fund some studies which unfortunately have been slow to get underway but at least recognize that this agent because of public concern and because of scientific reports was deserve -- at least made the radar screen to be deserving a further work. So I mean is that an intervention? I guess intervention is a wrong word because we haven't mitigated risk yet but we've put it on a priority list to take some actions that we wouldn't have taken otherwise

Now the deliberate process that we have is that we have to be able to identify it in a standardized way and then also to see does it cause disease. Now as Harvey mentioned because it's unclear there's no clear-cut scientific then the societal issues are weighing in and the pressure is then what are you doing about this. And how much risk would the society be willing to take. So I think that maybe, we have an opportune time here to take XMRV as the model process and really work our way through on how do we handle these for the future.

if their public perceptions getting stronger and stronger what do we do in that. So that's the discussion we're having that we are having a deliberate process. We are doing systematic way and then at the same time, you know, we have a public perception and public pressure from certain affinity groups as was pointed out how do we react to that. I think that's the key.

here we are now with XMRV is where we were in 1999 when West Nile virus first hit New York. And I think that's where we have to go back to and it was five years before the test was in place. So once we had the proof it moved very fast. But from the first recognition of the virus as -- and looking at that epidemic that suggests that it might be transfusion transmitted. So in one respect we did great but the other respect we were late. And maybe if we had a more active model about that time we would have done better.

when you think about XMRV we started to really give it attention when the science article came out about the association with chronic fatigue not when it was associated with prostrate cancer.

And a donor question is not a simple thing to do, I mean, it has to be developed, procedures have to be written, training has to occur, we've got to make sure we're doing it effectively. We have to determine what needs to be asked.
I mean is it a medically diagnosed case of XMRV? If we say that then we're missing 85 -- I mean of CFS. If we're doing that then we're missing 85 percent of undiagnosed CFS cases. If 4 percent of the donor population carries XMRV and doesn't have CFS even if we put a CFS question in, I mean, what benefit will it have?

XMRV we don't have a transfusion transmitted disease that we can identify. We need to be sure we're chasing a disease. For XMRV we don't have that. If it causes chronic fatigue syndrome then it moves up the ladder. So that has been made a research priority, XMRV. So really it's on the priority list for action already.

 

[bluebell]

Gag them CFS people, they're making too much noise. :tear: (sarcastic)

And this is how loud we are with absolutely no energy. I can imagine they are really scared that some of us might become well again. Hell hath no fury like millions of people scorned for decades...

 

[Robyn]

xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx

 

[usedtobeperkytina]

Without a test, there is no danger of losing 4% of population of donors. When test for XMRV is available at local doctor's office, then a ban on XMRV positive people might make you lose a lot of donors. But honestly, why would a healthy person ask to be tested, well, if they have a relative who has CFS and tested positive.

Either way, I agree that such a question and deferment of CFS patients will not do a whole lot to protect blood supply from XMRV. Most people who have CFS would answer no to the question since they haven't been diagnosed. If you are severely ill, then you likely have the diagnosis but you also won't answer yes to the question of "are you feeling well now?" And the question will do nothing to stop the 4% of healthy people with the virus from donating.

Still, I think a very quiet change to asking the question and deferring CFS patients is the way to do. I disagree that there has to be a lot of red tape to this. Simply put out some new forms that add the question, "Have you ever been diagnosed with chronic fatigue syndrome?" Heck, you can print it out on some labels and have the people attach them right as people come to fill out the form.

Why do that if it won't make a huge difference in XMRV level in blood supply and it isn't known for sure if it causes disease?

Because, while the evidence is not conclusive at this time, there is enough evidence that there is a strong possibility people with CFS are infected with XMRV, a retrovirus that has been shown to infect immune system cells.

If it turns out to be a bust, throw the labels away and go back to previous policy. No harm done. No big announcement.

Even if the news media asks, you can say, "The evidence is not clear on XMRV, but we value the safety of our blood supply, so we are taking this step at this time to protect blood transfusion recipients based on the knowledge we have now. We want the public to trust that every day we do all we can to ensure the safety of blood transfusions."

And if it does turn out to cause CFS, or cancer, and you know that you had reason to believe it could cause the illness but you did nothing, can you look in the mirror and say, "But I didn't know for sure"?

Sometimes we have to take safety measures based on probabilities. It's a risk / effort / consequences of action and consequences of no action assessment. Do you really want to wait until the hurricane hits before you measure the probability of damage coming to your house? When your neighbors are evacuating and you see storm clouds overhead and the wind is blowing and the weather man reports there is a 67% chance of the hurricane hitting your house? Will you just play in your band in your house until you know for sure?

The hurricane of which I speak of is not just the possibility of more people being infected and it leading to disease, but the public outcry that you did nothing when you should have been proactive, putting safety first.

Tina

 

[Rrrr]

what a great thread. deserves to be bumped up!