Medscape - Blood Products Advisory Committee Mulls XMRV Information

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http://www.medscape.com/viewarticle/725820

July 27, 2010 The US Food and Drug Administration (FDA) Blood Products Advisory Committee yesterday heard briefings from a number of public health agencies and other experts on whether the recently discovered human retrovirus xenotropic murine leukemia virusrelated virus (XMRV) poses a threat to the nation's blood supply.

The committee also heard how laboratories from the National Cancer Institute (NCI), the Centers for Disease Control and Prevention (CDC), the Blood Systems Research Institute, and the FDA are working to develop state-of-the-art assays to speed recognition of the virus and facilitate screening of potential blood donors.

The panel was treated to a rehash of conflicting studies some showing an association with XMRV and prostate cancer and chronic fatigue syndrome (CFS), and others showing zero association between the gammaretrovirus and these diseases.

Indira Hewlett, PhD, from the FDA's Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research and Review, briefed the panel on the conflicting studies that linked or did not link XMRV with prostate cancer and CFS.

In one study, XMRV was detected in 7 of 11 prostate cancer patients with a genetic predisposition for prostate cancer; in another, 6% of 334 prostate cancer patients were found to be positive for XMRV by polymerase chain reaction (PCR), and 23% were found to be positive for XMRV by immunohistochemistry. "Taken together, these findings suggest an association of XMRV with prostate cancer," Dr. Hewlett said.

In CFS, one study (Science. 2009;326:585-589) showed that XMRV could be detected in 67% of patients with CFS vs 3.7% of healthy control patients, using PCR and serology testing.

Horns of a Dilemma

However, other studies have yielded negative results for both prostate cancer and CFS, and these have placed researchers and policy makers on the horns of a dilemma.

The possibility of potential transfusion transmission of XMRV comes from experiments with rhesus macaque monkeys intravenous inoculation showed disseminated infection and low but detectable transient viremia between 4 and 14 days, Dr. Hewlett told the committee. Seroconversion occurred between 11 and 14 days, with titers peaking around day 95. In addition, XMRV was isolated from lymphoid cells, reproductive tissue, and a number of organs.

"These findings lend support to potential transfusion transmission of XMRV and suggests that there is a need for additional studies using well-standardized assays," Dr. Hewlett said.

Because of the potential for transmission of XMRV during blood transfusions, the Canadian government has decided to err on the side of caution by mandating that all patients with CFS refrain from donating blood, Peter Ganz, MD, from Health Canada, Ottawa, told the panel.

Caution in Canada

The Canadians have been ultracautious ever since the "tainted blood" scandal of the mid-1980s, which saw a number of people become infected with HIV through blood transfusions, Dr. Ganz said.

Blood from donors with CFS who were asymptomatic was accepted in Canada until April 2010, but now 90% of these would-be donors are indefinitely referred. The remaining 10% are from the province of Quebec, which still allows donors to give blood as long as they feel well.

"In Canada, one of our overarching guiding principles with regard to blood safety is the precautionary principle, which means that authorities must act, even if there is only a theoretical risk of harm," he said.

Robert Silverman, PhD, who was part of the team that first reported the potential link between XMRV and prostate cancer and CFS, presented those data again and also told the panel about possible ways that the virus infects humans.

Dr. Silverman told the panel that XMRV is found in semen and that its infectivity is enhanced by androgen and inhibited by antiandrogens.

Evidence Mixed for Disease Links

Of the 12 studies on XMRV and prostate cancer, 9 found evidence of the virus at some level. In CFS, the evidence has been less: Only 1 study of the 5 that have been done found a link between XMRV and this debilitating disease.

Dr. Silverman suggested that laboratory contamination, geographical distribution, sequence variants, clinical criteria for patient selection (particularly with CFS), and lack of standardized screening methods and positive control human participants are factors that could be responsible for large differences in the detection rate.

"XMRV is associated with prostate cancer and CSF in humans in some, but not all, studies. All individuals are at risk, regardless of the RNA cell genotype. XMRV establishes both acute and chronic persistent disseminated infection in primates the prostate epithelium is an early target, the stroma a late target, CD4 and other blood cell types are infected," he told the panel.

In addition, "XMRV growth is fueled by androgen, which is a possible oncogenic mechanism, XMRV might be transmitted by blood transfusion, and there is now donor deferral for people with CFS in 3 countries," he said.

Knowledge Still Emerging

In spite of these observations, Dr. Silverman cautioned that knowledge about the infectious nature of XMRV is still emerging. "We need to let science do its work. Any causal link to human disease remains to be established."

R. Michael Hendry, DSC, from the CDC in Atlanta, Georgia, followed Dr. Silverman's presentation. He told the panel that, in direct and complete contrast to Dr. Silverman's experience, the CDC was unable to find any evidence of infection with XMRV in their population of CFS patients by any means, including using Western blot or ultrasensitive PCR assays.

"Many people have alluded to differences in patient population, complexities of defining [CFS], lab methods, and strain differences, to explain the contrasting results; however, our results do not support an association of XMRV with the majority of [CFS] patients," he said.

Stuart Le Grice, PhD, from the NCI Frederick Laboratory, Frederick, Maryland, described how he and his colleagues have been working to develop a single-copy assay for XMRV DNA, RNA, and serology, based on the assay that was developed for HIV.

"The HIV single copy that was developed at the NCI is regarded as the gold standard assay. We now believe that we have an equivalent assay for XMRV."

Dr. Le Grice and his team have also developed a cell line, dubbed the Derse cell line, which can detect XMRV in as little as 3 days.

He said that the XMRV assay that his lab has developed has been transferred to labs in Sweden, Australia, Vietnam, and South Africa to prove its utility. "Developing an assay is one thing, but transferring it to a laboratory where it can be reproduced is clearly important when we are talking about single copy assay. Contamination is a huge problem, and the ability to transfer these reagents is very important," he noted.

Dr. Le Grice added that the aim of the NCI is to make sure that the assays they have developed are as valid as possible. "Our goal is to develop a series of assays that we feel confident in and to test those head to head with other assays. I think that is really important at the moment. We should start with 6 assays in house, and if we have a problem, I think it is important to sit amongst ourselves and try to understand where those problems are before we disagree with anybody else's assay."
 

paddygirl

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Did I read that right, a 'gold standard assay' for XMRV from the NCI? The CDC is looking increasingly like the little boy who didn't do his homework.
 
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You're embarrassing me :Retro redface:

I liked this bit:
R. Michael Hendry, DSC, from the CDC in Atlanta, Georgia, followed Dr. Silverman's presentation. He told the panel that, in direct and complete contrast to Dr. Silverman's experience, the CDC was unable to find any evidence of infection with XMRV in their population of CFS patients by any means, including using Western blot or ultrasensitive PCR assays.
Yes, they are not only disagreeing with the WPI.
 

OverTheHills

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I was very interested in Mr Hendry's use of a particular word, some might call it a Weasel-word.

"Many people have alluded to differences in patient population, complexities of defining [CFS], lab methods, and strain differences, to explain the contrasting results; however, our results do not support an association of XMRV with the majority of [CFS] patients," he said.

More evidence of CDC trying to split CCC ME/XMRV+ from Reeves disease? I suppose things are past claiming 1000% confidence that there is no association between XMRV and 'CFS'.

OTH
 

muffin

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Sorry V99, just think you are way cool! No more GME comments!! Promise! But thanks for catching stuff like this. It fills in the blanks big time.
 
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Hopefully we will get the NIH/FDA study soon. That will occupy us for months. GME right back at ya.:victory:
 

SOC

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I was very interested in Mr Hendry's use of a particular word, some might call it a Weasel-word.

"Many people have alluded to differences in patient population, complexities of defining [CFS], lab methods, and strain differences, to explain the contrasting results; however, our results do not support an association of XMRV with the majority of [CFS] patients," he said.

More evidence of CDC trying to split CCC ME/XMRV+ from Reeves disease? I suppose things are past claiming 1000% confidence that there is no association between XMRV and 'CFS'.

OTH
Good catch! I sure does sound like their CYA tactics.

It's a shame that the writer of this article didn't point out that the CDC not only didn't find XMRV in their CFS patients, but they didn't find it at all.
 

anciendaze

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CYA

For those who have watched hierarchical organizations in action, the signs of CYA began long ago. The maneuver of allowing Reeves to complete negative research before reassigning him without an immediate replacement is a classic.

Here's how this covers all bases.

First, should the XMRV research be confirmed, the CFS group is now loosely under the infectious diseases hierarchy. All that is necessary is to reorganize a bit and you will be able to show the CDC was on top of things back in February. No fundamental change is necessary because the organization has already been purged.

Second, should the XMRV connection be refuted, all you need do is finally get around to that delayed appointment of Reeves replacement, and things can tick along as in the past. The Science paper was merely a blip on the radar, and administrators never took those spurious results seriously. They were on top of the situation last October.

Third, if the XMRV research has some validity, you are now in a position to fight a delaying action under the rubric of scientific integrity. You have pointed out weaknesses in the initial research, and by the time all loose ends are nailed down, you may be able to portray your organization as holding the true scientists, while meeting policy goals of suppressing public panic, and buying time to implement necessary public health measures.

Anyone calling this excessively cynical must lack personal experience in close-combat hierarchiology.
 

ixchelkali

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Good article. It actually sounds like Medscape is treating this seriously, with well-balanced reporting (something they haven't always done with ME/CFS in the past). The line "The panel was treated to a rehash of conflicting studies" made me laugh.

I agree with Dr Silverman that we need to let science do its work, yet I like the Canadian principle with regard to blood safety, that authorities must act, even if there is only a theoretical risk of harm. Especially in a case like this where defering patients isn't likely to seriously diminish the blood supply.

Dr Le Grice's part was the most promising sounding to me, that they think they've developed a good valid assay and have sent it around the world for confirmation testing. "...if we have a problem, I think it is important to sit amongst ourselves and try to understand where those problems are before we disagree with anybody else's assay." Could that have been a subtle dig at another federal health agency, do you think? ;)
 

ixchelkali

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No more GME comments!! Promise!
GME right back at ya.:victory:
Okay, I give up. I even checked Acronym Geek, but none of them seemed to fit:
Goat's Milk Esbilac? Naw.
Glucocorticoid Modulatory Element? Not likely.
Genomes Medicine and the Environment? I don't think so.
Gelatine Manufacturers of Europe? Naw.
Google Mashup Editor? I hope not.
Grizzly Mountain Engineering? I give. Uncle.

What is GME, please?
 

ixchelkali

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They are digging more deeply than anyone- NIAID is completely out of the ballgame. It would be worth it just to get the egg on that Institutes face. How lovely that would be!
Why, Cort, you sounded downright...human there. :Retro wink::Retro tongue: Nice to know you're not completely impartial and objective. :innocent1:
 

muffin

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FYI FROM FDA: Access to the transcripts if anyone wants them - from email to FDA:

Thank you for your recent inquiry to the Center for Biologics Evaluation and Research (CBER) regarding Blood Products Advisory Committee (BPAC) Meetings. CBER, one of seven centers within the FDA, is responsible for the regulation of many biologically-derived products, including blood intended for transfusion, blood components and derivatives, vaccines and allergenic extracts, and cell, tissue and gene therapy products.

I apologize for the delay in response. The Center makes every attempt to respond in a timely fashion.
Detailed information regarding the July 26-27, 2010 BPAC meeting is available on CBER's website at http://www.fda.gov/AdvisoryCommitte.../BloodProductsAdvisoryCommittee/ucm205013.htm. You may also obtain up-to-date information by calling the Advisory Committee Information Line at 1-800-741-8138. You may also access meeting materials, including transcripts of BPAC meetings at the following website: http://www.fda.gov/AdvisoryCommitte...cs/BloodProductsAdvisoryCommittee/default.htm.
Additionally, you can sign up to receive updates on advisory committee meetings by clicking the link Sign up for updates on advisory committee meetings found on FDAs website at the following link: http://www.fda.gov/AdvisoryCommittees/Calendar/default.htm. We hope this information is helpful.
Sincerely,
H.A.
Consumer Safety Officer
Consumer Affairs Branch
Division of Communication and Consumer Affairs
Center for Biologics Evaluation and Research
US Food and Drug Administration

This communication is consistent with 21 CFR 10.85 (k) and constitutes an informal communication that represents my best judgment at this time but does not constitute an advisory opinion, does not necessarily represent the formal position of FDA, and does not bind or otherwise obligate or commit the agency to the views expressed.