Wednesday, July 23, 2008

Fallout 24

News
Sydney Morning Herald says Ricco was caught in part because of a marker molecule Roche put into CERA specifically for this purpose.

Yet, there is still no word on any of Piepoli's tests. Curious, that, eh?

IHT reports that Roche did NOT plant a marker in Micera, contrary to the claim above, where Fahey seems to have left the wrong impression, as it were.

Roche Holding, which makes a version of a stamina-building drug illegally used by some athletes, said it didn't plant a molecule in the substance to help identify it in doping tests, spokeswoman Martina Rupp said, Bloomberg News reported on Wednesday.

[...]

John Fahey, the president of the World Anti-Doping Agency, said in an interview with the Australian Broadcasting Corp. that Roche planted a molecule in its red-cell boosting product CERA, or Continuous Erythropoietin Receptor Activator, during its manufacture to help anti-doping authorities detect its illegal use. Roche sells the drug as Mircera.

"The information that a special molecule has been added to Mircera is wrong," Rupp said in an e-mail.

WADA issued a statement Wednesday saying that Fahey's remarks had been misinterpreted. The agency said the drug can be detected because Roche and accredited sport-doping laboratories worked with the agency early.

"WADA received the molecule well in advance and was able to develop ways to detect it, including through the current EPO detection method," the agency said in the statement.

The last is interestring, because it says there are multiple independant methods of detecting Micera.

But still no report on Piepoli's tests.

Bicycling
has a long report on Slipstream, and the proof that Vande Velde is clean, doggonit, by getting data on him and Millar from the ACE and UCI passport programs. It was reviewed by Ashendon. He doesn't look much at hematocrit, but reticulates and OFF score, and marches through data saying everything looks basically OK. It also highlights some variability issues with equipment and transport that make looking at raw numbers problematic:
Lab quality control counts for a lot as well. On one extreme example, Millar was tested late in the Giro d'Italia on the same day by both ACE and the UCI. The UCI results showed a reticulocyte count of 1.15; the ACE test showed only .8; OFF-Scores were 86 and 96, respectively. The test is an object lesson in the perils of relying on hematocrit, as Millar pegged a 49 percent rating on the ACE test, but only 44.4 on the UCI test. According to ACE, his average readings are .86 (retic) 91.82 (OFF-Score) and 44.16 (Hct).

While a hematocrit rising to 49 at the end of a three-week stage race would be a clear cause for concern, Vaughters explained that the ACE test that day had been processed by a partner lab in Italy that had clearly had sample transport issues (causing the red cells to swell and throw off the hematocrit reading). He pointed out that David's reticulocyte count, hemoglobin and OFF-Score that day were within normal ranges and the UCI scores were similarly unremarkable. Finally, he said that he'd be concerned if David had been showing fantastic form at the same time, but noted Millar lost 10 minutes that day and 31 the next. The culprit, then? The lab. "We will not be using that lab again," he said.

Landis got whacked on this issue when some of his raw numbers from 2006 came out.

NBCOlympics reports a A + B positive for stimulants on US Olympic Swim Team member Jessica Hardy. Landis-slammer Abrahamson takes the neutral position on this case, not calling her a dirty, guilty doper cheat. Why do you suppose that would be?

Blogs
Steroid Report discusses biosimilar EPO agents and the BBC report, and has a list of over 40 that are available. Then he lays into WADA's public posturing:

I think the science director of WADA could be considered delusional in his claim that WADA is catching all users of recombinant EPO.

Dr Olivier Rabin is WADAs science director. Is he happy that the test is catching all the drug cheats?

I am reasonably confident, yes, he told the BBC. Now, it would be very presumptuous on my part to say that we are absolutely 100% sure we are going to get everyone. But I can assure you that if you were to take recombinant EPO and that would be in your urine - then, yes, we would detect it.

Maybe the public will buy it, but the athletes already know better.

Mesomorphosis notes a so-far-unsuccessful attempt to void domain name registrations for sites that sell steroids as violations of the registrar's terms-of-service.

Flahute has a theory why Amgen doesn't have markers in its EPO:

In the United States, it would be nearly impossible to insert a marker into a drug after the fact, as it would have to go through the entire testing and approval process from the FDA all over again, which is why Epogen and Aranesp (Amgens EPO drugs) have taken so long to become detectable; they werent designed with the markers already built in, so the drug-testers had to devise another way.

But Micera (the brand-name for CERA) was developed with the marker already built in; a fact that surely would have been disclosed to the approvers, and obviously to WADA, but not widely spread, especially to the athletes. And what better way to catch the cheaters than to not tell them HOW youre going to catch them.

This is the right way to catch drug cheats; not witch hunts.

Adding:

Yeah, Floyd Landis likely doped. He still got screwed by a system which admits no wrong and the system still has a lot of other problems. Now that Dick Pound is no longer pounding his dick at WADA, their organizational issues should get better. Its too bad hes now a part of the Court of Arbitration for Sport, but one step at a time and well clean up both the sport and the governing bodies.

27 comments:

sugaken said...
This comment has been removed by the author.
("Eightzero") said...

The Roche drug referred to in both the Sydney Morning Herald and the Velonew article is "MIRCERA."

Here's the FDA label for this commercial drug:

http://www.fda.gov/cder/foi/label/2007/125164lbl.pdf

Note on page 20, line 29 the disclosure of "ethoxy polyethylene glycol-epoetin beta." I am told by people that know far more about this (Mrs. 80 is a doctor) that this makes the molecule a "a PEGylated product" and thus easily distinguishable from chemicals secreted by one's own organism.

It seems to me that any doctor that actually read the labelling would know this. What would they disclose to their cycling "patients?"

I am highly doubtful of the claim this was designed in cooperation with WADA specifically for purposes of doping detection. And that this was somehow kept secret is patently (!) false. The FDA label is dated November 2007.

m said...

80

"I am highly doubtful of the claim this was designed in cooperation with WADA specifically for purposes of doping detection."

I believe WADA. They and Roche have no reason to lie about inserting a special marker molecule into MICERA for detection purposes.

Nothing you quote from the FDA label is inconsistent with that. The polyethlene glycol molecule is used in a number of drugs to delay the excretion of the drug, including this synthetic EPO. Look up peglylated on wikipedia. This doesn't mean that some other molecule wasn't inserted, or this molecule was marked, in such a way so as to aid identification.

The FDA makes it clear that this was "synthetic" EPO. No one is claiming this was "secret".

Larry said...

"M" -

Do you figure that the MICERA marker molecule was small, so that it would easily pass into a rider's urine, and that it would pass separately from the large MICERA molecule that stimulates the production of red blood cells?

Any idea how you create such a marker molecule that would be sufficiently distinct so that it could come from no other source except MICERA?

Do you envision the day when the government will scan the urine of senior citizens for marker molecules, to make sure that they're not buying their prescription drugs from Canada? ;^)

m said...

Larry,

I wouldn't be surprised if Roche didn't insert this marker molecule to help it police pirated knock-offs in the market.

In general I'm for a weaker regime of intellectual property protection. So yes I could see this as a nefarious "plot" by monopoly drug makers to help control the market!

m said...

Ps. Larry

I cruised over to Rant and happened to read you mention of L'As du Falafel. Love that place. Sometimes the simple foods are best. Still have memories of the peche melba's and wood fired pizza's in Provence lo these many years ago.

And I have no idea about the science of marker molecules. Have to ask OMJ about that.

Larry said...

M, I have very fond memories of pizza (with tuna and olives) in Provence.

All kidding aside, the placement of marker molecules in pharmaceuticals has disturbing implications with regard to medical privacy. It will also tend to push dopers to use unregulated products from unconventional sources (like the many varieties of EPO that appear to be available from Chinese sources), which may not only be more dangerous for the dopers but also make it harder (not easier) to do doping testing.

On the topic of doping in China, there's also this story about gene doping in China.

("Eightzero") said...

m, I simply believe that the PEGylation was done for reasons wholly unrelated to WADA detection. WADA may have discussed the implication with Roche, but I seriously doubt the product was designed with a "detection feature." WADA has many, many reasons to act deceptively when telling athletes about its capabilities.

The Velonews article reported that Roche developed the drug with this structure "so that ...[it]... was always going to be able to be detected once a test was taken." I simply doubt a drug manufacturer would do this. Where is the value in it to Roche? Unless this is a preemptive attempt to label their drug for a known mis-use, anticipating a lawsuit from a non-doping teammate? Wow.

OTOH, I *can* see a drug manufacturer developing a proprietary drug with detection features along with a patented method for detecting its use. *That* they could sell/license to others, like ACE, WADA, et.al. However, mass spec and detection of the PEGylated structure is surely prior art, so I'm not sure how that could be patented or protected. As a method patent maybe....

I am told by Smart Scientific People that there could be a deuterium molecule strategically inserted into a drug to make it show up unmistakably on mass spec. (And no, it doesn't make it radioactive.) While it is possible this was done with MIRCERA, it is also very unlikely this would not be disclosed on the labeling document. But, in fairness, this label doesn't have the usual molecular representation. I'm told this is unusual, but not suspicious.

The manufacturer has no economic incentive to do what WADA is claiming happened, and many, many reasons not to do so.

But we'll never know, will we? WADA operates in secret, and drug companies aren't known for their openness.

dailbob said...

Because this form of EPO was specifically designed to stay in your system longer, I'm guessing that Roche needed a way to determine its rate of excretion, and that the molecule was inserted for this reason. If this were the case, then WADA saying that they worked with Roche to insert a molecule is bluff to keep athletes inclined to dope guessing.

m said...

80,

"m, I simply believe that the PEGylation was done for reasons wholly unrelated to WADA detection."

Of course. I agree. PEGylation and the resultant large molecule is what gives this drug it's special persistent effect. But this doesn't mean that some other molecule wasn't inserted for identification purposes, or that the PEGylated (?) molecule wasn't modified in some additional way to aid identification.

In any case, we can agree that Roche "cooperated" with WADA in providing the know how and knowledge to enable identification.

("Eightzero") said...
This comment has been removed by the author.
("Eightzero") said...

m, I do agree. I just think that cooperation was simply disclosure to WADA by Roche of the molecule the latter inteded to manufacture and market. I do not believe Roche changed their drug to make illicit use of it more easily detectible.

But, I have been wrong about many, many things.

Larry said...

Cycling News says no secret molecule in MICERA.

m said...

"Cycling News says no secret molecule in MICERA."

You mean there is no nefarious plot by Roche to prevent Chinese knockoffs, take away our rights to medical privacy, and aid the worldwide WADA conspiracy? Does this the mean drug monopolists are benevolent after all.

("Eightzero") said...

"You mean there is no nefarious plot by Roche..."

By Roche, no.

whareagle said...

The latest comment on the fallout board, showing the VARIABILITY issues with the tests, really pisses me off. This is exactly what Hamilton dealt with when he was on Phonak in the months coming up to the Olympics and the Vuelta, and by God it covers some of the same issues we covered here in months past with Floyd's data.

One more indicator that standards are anything but in this detection business.

MMan said...

One more indicator that standards are anything but in this detection business.

Millar's a reformed anti-doping poster boy, so he's got to be "clean" no matter what any test says.

Reminds me of something I saw on a political blog: "If standards are good, double standards are twice as good!"

Thomas A. Fine said...

"... he'd be concerned if David had been showing fantastic form at the same time, but noted Millar lost 10 minutes that day and 31 the next."

Does Vaughters really believe in magic?

If a high crit was a guarantee of good form, then those with naturally high crits would never lose ,(or at least, never drop below their baseline performance level). Doping with EPO or anything else is not a guarantee that you won't have bad days.

Anyone actually involved in anti-doping should understand this.

tom

whareagle said...

Tom,
Look back in some of the older records - Vaughters was one of those 'naturally high' HCT guys, and honestly, he never was that great of a performer. Maybe he was too cerebral, maybe he was juiced to the gills, and he was good, but he was never 'great'.

Larry said...

Um ... I don't understand the commotion here about the Millar test. Vaughters and ACE looked at the Millar hematocrit measurement from the ACE test, and DISCARDED it. It was inconsistent with other measurements, it looked like the lab screwed up, so they DISCARDED it.

Y'know, DISCARD a screwed-up lab result? Like many of us WISH they'd done for Landis?

This is the way the world is SUPPOSED to work.

Thomas A. Fine said...

Oh, I don't disagree with how they handled it.

And I certainly commend Vaughters for doing a lot more than most people to deal with doping problems.

And I didn't mean to distract from the primary point as I see it, which is that lab results can vary quite a bit, especially if the lab is a mess. I whole-heartedly agree with this.

I'm just curious about the statement he made regarding hematocrit and performance, which I just consider naive.

tom

Thomas A. Fine said...

And let me add a bit more.

I think it bothers me because I think the current doping mythology leads to a lot of the problems we have now.

There's a widespread belief that doping products are magic pills that push your performance through the roof in an instant, and I just think that's a load of crap. With anything short term, I think most of the effect that athletes see is placebo. I'd love to see a good study try to separate real performance enhnacement from placebo effect.

tom

Cheryl from Maryland said...

I emphatically agree with Tom. There are several chronically ill people in my family, and they daily cope with new health problems caused by medications -- they only take the meds as the disease is worse than the cure. Even the simplist things such as increased drowiness or headaches can pull you down everyday.

Larry said...

Tom, here's a report on a test performed to show the effects of EPO on cycling, where a group taking EPO was compared to a group taking a placebo. It's not a double-blind study - apparently, you can't ethically do a double-blind study with a drug like EPO - so the group taking EPO knew they were taking EPO, and the group taking the placebo were told that they might be taking EPO.

As a general matter, I've been impressed by the quality of information and analysis on the Science of Sport web site.

I'm not a scientist, but I'm pretty much persuaded that in a lab at least, EPO has a pronounced performance-enhancing effect.

Thomas A. Fine said...

That's a four week test, and I was discussing short-term (like today and tomorrow) results. And it isn't even completely single-blind, let alone double blind. There's a big difference between "maybe you are and maybe you aren't" and "You got the stuff!".

The everyday placebo effect is presumed to be related to a decrease in stress hormones, or an increase in "happy" hormones. Confidence even increases testosterone production. At any rate, I think that for PEDs, there's an additional placebo effect, which is this: "I paid the money, I'm risking my health, I'd damn-well better get my fat ass off the couch and train and see what it'll do for me".

There's all kinds of things that I don't get about EPO usage. There's a 50% crit cap in cycling. Your typical rider can only hope for a few points of improvement from EPO. A similar improvement is available from living at altitude or using an altitude chamber for sleeping. And on top of all that, plenty of riders with crits in the low 40s have won major races. These are the reasons I don't think EPO (or anything) is a magic pill for winning races.

tom

Larry said...

Tom -

First of all, I'm no scientist. Chances are that your science knowledge tops mine. All I'm doing here is sharing what I've learned.

No question, the information out there on the effects of EPO is not 100% conclusive. Of course, EPO was not designed to help world-class athletes improve their times up mountains, so you can't expect that this would be the focus of a lot of study. But the studies they've done (including part 1 of the study where they sent the urine samples to the 2 labs as part 2) all show pretty considerable performance gains.

Very true, this is not a magic pill. EPO seems to be used in two different ways. First, it allows for more intense training, and second, it appears to improve the system's ability to process oxygen during performance. The guys at the Science of Sport site stress that a doping athlete still has to bust his butt in training to achieve a world-class result at the time of performance.

The evidence on altitude training appears to be kind of shaky, depending on who you listen to. There appear to be positive effects from the Live High Train Low method. The guys at the Science of Sport web site think that these effects are modest, but that may be because they're only looking at the hematocrit percentage gains. It may well be the case that Live High Train Low improves the ability of the system to handle oxygen without focusing solely on hematocrit levels. I'm FAR from understanding this stuff in any depth, but there appears to be much more to the biochemistry of blood and oxygen than the hematocrit count.

I don't know if EPO drugs HAVE the kind of short-term effect you're mentioning. Again, what I don't know about this topic dwarfs anything I do know ... but even if EPO worked overnight, what EPO creates first are reticulocytes -- baby red blood cells. This is why the ACE-Damsgaard programs look at reticulocytes, because if someone has started taking EPO, this is where you'll see it first. Wikipedia says that reticulocytes develop in bone marrow and circulate for about a day in the blood before becoming a mature red blood cell. So, I don't think an athlete could take EPO today and see an effect tomorrow.

I'm not sure what to say about the 50% crit cap. Yeah, I guess that if someone is naturally at a 49% hematocrit level, there's not a lot that EPO can do for him. However, I think that a level in the low-to-mid 40s is more usual. Also, reportedly hematocrit levels will normally drop during the course of a Tour, even for people naturally at a high level, so EPO might allow a 49% guy to stay at 49%.

There's also a big difference between the lab and the road. It may well be that what looks like a big EPO effect in the lab becomes smaller in competition, when so many other factors (strategy and tactics, bike handling skill, teamwork, etc.) come into play. I've argued this at RYHO: the strongest guy does not win every boxing fight, the guy with the highest vertical leap does not always lead the NBA in rebounding, and so forth. Dope is not going to help Denis Menchov descend faster or keep John Augustyn (and more importantly, his bicycle!) from sliding down the mountain.

We've discussed here the fact that there's little to no evidence that exogenous testosterone would do a cyclist any good. Can't say the same about EPO. The evidence is, that stuff is effective.

We can dive into the specific studies if you want to do so.

Thomas A. Fine said...

I don't doubt that EPO is effective. I just think it's use in competition is marginal. If not for the 50% cap, I think we'd see quite a few cyclists with crits in the mid-50s, at which point the boost is more significant.

As far as reticulocytes, I've always been skeptical. There's a presumption of steady production, but how well does that really apply to an elite athlete in competition? Fluctuations due to altitude, effort, insufficient diet, and other factors seems inevitable.

If you're an athlete in the middle of the TdF, it seems to me that your body wants to grow new blood cells quite badly, but simply can't keep up with demand. Having the right meal in the evening could make the difference in whether or not your body generates a bunch of new blood cells.

tom