All About Salbutamol

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What will the verdict in Froome's salbutamol case?

  • He will be cleared

    Votes: 43 34.1%
  • 3 month ban

    Votes: 4 3.2%
  • 6 month ban

    Votes: 15 11.9%
  • 9 month ban

    Votes: 24 19.0%
  • 1 year ban

    Votes: 16 12.7%
  • 2 year ban

    Votes: 21 16.7%
  • 4 year ban

    Votes: 3 2.4%

  • Total voters
    126
Pantani posted this in the Froome thread, deserves posting here as well:

Pantani_lives said:
USADA head Travis Tygart says Froome's salbutamol case is a blow to WADA's credibility:
https://www.bbc.com/sport/cycling/44924435
Seems to be a conflict:

Tygart said in nearly 75,000 drug tests conducted by Usada since the salbutamol rule was updated in 2011, the organisation did not find "a single athlete" in any sport that exceeded the maximum permitted amount.
vs.

In response, a Wada spokesperson told BBC Sport: "Wada has publicly set out the reasoning for its position on the case of Mr Froome. Mr Tygart's assessment appears uninformed, is unconstructive, and, quite frankly is surprising given that Usada has itself previously taken the decision to close a salbutamol case where the athlete exceeded the threshold without a controlled pharmacokinetic study being conducted.
Maybe that was before 2011? In any case, we just have more trust-us-we-know-what-we’re-doing-and-aren’t-going-to-be-transparent. "Setting out the reasoning" is obviously not sufficient lacking details. Remember how Froome said, right after the announcement that he had been cleared, that the full report would be made public in a a few days? If he said he wanted it released, I don't know how UCI could prevent it, but even if they could, Froome in that event could publicly state that he wanted it released, but UCI wasn't allowing it. Just like this UCI vs. WADA on who initially reached the final decision, no one on either side has the balls to be open and honest about what happened. Maybe now that the TDF is over, someone will be more forthcoming, but I doubt it.

I have critiqued the decision based on the little we know about it here:

https://www.dopeology.org/incidents/Froome-adverse-analytical-finding/
 
Jan 11, 2018
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ClassicomanoLuigi said:
So, not only did he get away with it, by escaping sanction... in addition, framing the narrative as a debate about asthma was very successful as distraction from the proper, substantial doping. With salbutamol being one of the metabolic tools in the Sky arsenal. Was that fact ever made clear in the mass media, or even in sporting journalism? I don't think so...
I don't think it was. Firstly because Sky, even after everything that has gone down, can still be very good at controlling the narrative, and secondly because for any mainstream journalist or publication to actually claim or insinuate that Froome was really taking salbutamol orally or by injection would be considered slanderous without evidence. It's quite simple to join the logical dots and determine that this is indeed what he was doing, but there's no actual direct evidence of it either from the data or any personal statements. So no-one was prepared to push that line for fear of recriminations from Sky. Guys like Kimmage alluded to it on podcasts or blogs, but not in print or in front of a camera.
 
ClassicomanoLuigi said:
Mamil said:
I don't think it was. Firstly because Sky, even after everything that has gone down, can still be very good at controlling the narrative, and secondly because for any mainstream journalist or publication to actually claim or insinuate that Froome was really taking salbutamol orally or by injection would be considered slanderous without evidence. It's quite simple to join the logical dots and determine that this is indeed what he was doing, but there's no actual direct evidence of it either from the data or any personal statements. So no-one was prepared to push that line for fear of recriminations from Sky. Guys like Kimmage alluded to it on podcasts or blogs, but not in print or in front of a camera.
You're right about that, probably true. Evidence, but not proof. But as you know, I think a lot of people just missed the point, and I don't blame them, because it's not at all intuitive that oral salbutamol is being used in that way in sports doping. Seth Davidson is an attorney himself (and a MAMIL) and thus one of the few examples where someone got the salbutamol case right, by thinking independently. Seth 'goes there' explicitly, in this piece from the very beginning, last December... "no doubt at all that this is what Chris Froome has been doing"
https://pvcycling.wordpress.com/2017/12/16/the-truth-behind-chris-froomes-doping/

A bit contrived in its pseudo-legalistic reasoning and writing style, but otherwise I thought that was a good article. Can't remember any other good examples of that specific subject having been exposed. (From the legal standpoint, about a possible claim of libel it probably makes not much difference that Seth wrote that on a personal blog, versus publishing it in print media)

Anyway, MerckxIndex and others succeeded in the original medico-legal intent of this "All About Salbutamol", the thread turned out to be quite extensive
This part is a bit nonsensical if you consider Froome's performance in 2013 compared to 2017 or now:

If you have any doubt at all that this is what Chris Froome has been doing, take a look first at this photo of his legs from 2013. Then compare it with 2017. In four short years he has put on a visible amount of muscle and lost weight. Not a lot of muscle, and not a lot of weight. Just a marginal gain … and not coincidentally one that has gone hand-in-glove with his very public announcement of a lifelong asthma condition that requires constant use of Salbutamol.

i.e. he was more dominant in 2013 than later, when he is supposedly using salbutamol for weight loss/muscle gain.
 
I wasn’t going to revisit this topic, but when the biggest debate in the Clinic is over Froome’s nationality, it seems like a good time to summarize what I’ve learned about his salbutamol case since he was exonerated.

After I wrote a summary/critique of the Froome case, several months ago, Daren Austin, the GLAXO researcher who convinced WADA/UCI that Froome’s urinary salbutamol level could have occurred without taking more than the maximum allowed amount, got in touch with me, and discussed some general aspects of his work. He asked that I not share his personal communications, and he would not discuss the specifics of Froome’s case, including his salbutamol levels during other stages of the 2017 Vuelta, which I really wanted to know. However, he did make a couple of very general points about salbutamol, which I believe I can share here without violating the spirit of my agreement.

First, he noted that most scientists assumed, incorrectly, that drug concentrations in the urine follow a Gaussian or normal distribution. That is, if you give a group of subjects a fixed dose of salbutamol—or if one subject takes the same dose at different times—the urinary levels at some time after the dose will be distributed as a typical Bell curve. From such a distribution, one can determine a mean and standard deviation, and from these values, one can estimate the probability of any particular urinary level occurring by chance.

For reasons I won’t get into here, usually the distribution is not normal, but log normal. That is, it’s the logarithms of the values that are normally distributed. This is critical to Froome’s case, because in a lognormal distribution, the actual values—as opposed to their logarithms—are skewed to the right. This means that the probability of very high values is considerably greater than one would estimate based on a normal distribution.

The second key point is that there are different kinds of inhalers; in particular, there’s a distinction between the MDI, measured dose inhaler, and the Diskus, in which dry powder is inhaled. A study that was published about a year ago showed that the amount of salbutamol getting into the circulation was 50-100% greater when the MDI was used than when the Diskus was used, despite the fact that the nominal dose inhaled was the same. This is also critical to Froome’s case, because while he used the MDI, some of the studies on which WADA based its criterion used the Diskus. In other words, while Froome may have inhaled no more than the maximum allowed dose of 800 ug, as determined by the MDI, that dose could have been equivalent to much more than the 800 ug dose used by WADA in its Diskus studies.

Austin’s argument was that when these two factors—and several others that I will not get into here—are taken into account, Froome’s salbutamol level had a reasonable probability of occurring despite his not taking more than the maximum allowed dose. Since he didn’t specify what this probability was, and I’m not privy to Froome’s other values, I can’t judge how valid this conclusion is. I did go back and re-evaluate all the published WADA studies assuming a lognormal distribution. I was able to show that their values generally did follow this distribution, in agreement with Austin, but I also established that for most of these studies, the actual mean and SD values, based on a lognormal distribution, still indicated that the probability of Froome’s value was quite low. In 7/8 studies, the probability was < 3%, and the weighted mean of all the studies was about 1.5%.

This probability would be a problem for a test applied to a large number of subjects, as the risk of a false positive would be relatively high, and no doubt this is why WADA has suggested it will lower the maximum amount allowed to be inhaled. Probably the only reason there haven’t been more salbutamol positives in the past is because athletes generally have not taken the full allowed dose. However, as applied only to Froome, this probability indicates that his value—based simply on the lognormal argument, nothing else-- would be quite unlikely to result from an allowed dose. I'll also add that i personally never emphasized the standard deviation argument, anyway, but just noted that out of nearly 200 published samples, none exceeded Froome's value, assuming the correction for urine specific gravity was allowed. This point holds regardless of the nature of the distribution.

As for the inhaler effect, while it’s true that some WADA studies used the Diskus, other studies used the MDI, so their results should be relevant to Froome’s level. In fact, comparison of the results of studies using the two types of inhalers generally does not support the conclusion that the amount of salbutamol getting into the system with the MDI is much greater than with the Diskus. That is, there are studies using the MDI at a given dose which result in urinary levels very similar to those observed when the Diskus was used to inhale the same dose. These studies directly contradict the result of the study that Austin pointed out to me. I don’t know how to resolve this discrepancy, except to note that the latter study only measured amounts of salbutamol in the blood, not in the urine. This shouldn’t matter, but FWIW, there’s no study I’m aware of that compares urinary levels of salbutamol following inhalation with MDI vs. Diskus.

Though Austin didn’t say so, I suspect that one reason WDA/UCI did not publish the report is because it was embarrassing to them. They should have known about the lognormal distribution—I should have known this, too, and that is mea culpa,though again, it doesn't really affect the argument I was making—and they should have known about the difference between the inhalers, though that study was only published shortly before the 2017 Vuelta. They have not come out of this looking good.

Another important factor, noted by UCI when it announced its decision, was the effect of dehydration. Several studies suggest that dehydration can increase urinary levels, not simply because the urine was more concentrated, but even taking into account correction for this concentration. However, a crucial question becomes, how dehydrated was Froome on the day of his positive test? While we don’t know—and I don’t think he himself or his legal/scientific team knows--we do know what his urinary specific gravity (USG) was, and I found a couple of studies that relate USG to body mass. Based on these studies, it appears that Froome had a maximal body fluid loss of 3%. This is in agreement with other studies, discussed earlier in this thread, that indicate that greater loss of body fluid is associated with performance deficits. In fact, most evidence indicates that performance deficits occur at losses of > 1.5- 2.0%, so I would think it unlikely that Froome’s loss exceeded this. When Petacchi tested positive for salbutamol, he had an even greater USG, suggesting an even greater fluid loss. This is quite difficult for me to understand, given he not only won the stage, but on a flat sprint, where the power loss would not at least be partially compensated for by a lower body weight, as in the case of the climbing finish that Froome faced. In any case, it seems that dehydration would have a limited effect on Froome’s levels. One of the studies being touted as relevant to Froome’s levels used a body fluid loss of 5%, and that almost certainly was far more than Froome’s loss.

Austen told me that he was publishing a couple of papers relevant to the salbutamol criterion, though as far as I know, they haven’t appeared yet. Absent the actual report, which apparently will never be released despite promises from various parties, it’s not possible to judge how strong the case was for letting Froome off. But based on what data I’ve seen, I’m pretty sure that the probability of his level occurring without taking more than the allowed amount was still fairly low. When Austin’s role was first announced in the media, a figure of 10% was mentioned, which sounds shockingly high, but which still indicates that he would more likely than not have taken more than the allowed amount. I suspect that what probably carried the day was the argument that he would never intentionally dope with salbutamol during a race when he knew he would be tested. So even a relatively low probability would be higher than the probability of the alternative.
 
Re:

TourOfSardinia said:
MI nice work
but
how come it's CF the hits a high log-normal score and nobody else?
That’s a good question. We don’t know the actual values in all salbutamol positives, but almost all that have been published were lower than Froome’s. I wish all the values were published, so we could find out exactly where Froome stands relative to prior cases. Clearly a major point made by his defense is that very few athletes have ever inhaled the maximum allowed dose. If they did, regularly, then we would expect to see more values over the limit, and maybe some values higher than Froome's. But as with so many other aspects of the case, there is so much we don’t know.

Robert5091 said:
Thanks for the post MI - did Daren Austin have access to Froome's other samples from the Vuelta?
He had access to the urinary concentrations of those samples, yes. They were essential to his argument. The actual samples, I doubt, but he didn't need them.
 
Austin suggesting Froome could have ingested 1600ugs instead of the allowable 800
Wow...no wonder Froome overdosed

You might also be interested to know that the MDI (blue puffer) delivers about double the systemic salbutamol level of the dry powder inhaler (DPI) for the same lung effect. So if you are using an MDI at the highest allowed dose, you will be more likely to have higher urine levels. The studies previously looking at dehydration used DPI not MDI. -djaustin
http://www.timetriallingforum.co.uk/index.php?/topic/128395-froome-cleared/&page=5
 
70kmph said:
Austen suggesting Froome could have injested 1600ugs instead of the allowable 800
Wow...no wonder Froome overdosed

You might also be interested to know that the MDI (blue puffer) delivers about double the systemic salbutamol level of the dry powder inhaler (DPI) for the same lung effect. So if you are using an MDI at the highest allowed dose, you will be more likely to have higher urine levels. The studies previously looking at dehydration used DPI not MDI. -djaustin
http://www.timetriallingforum.co.uk/index.php?/topic/128395-froome-cleared/&page=5
Yes, I covered that in my post above. It's true that there has been a study comparing the two types of inhalers, and that when the same nominal doses are taken, the blood concentrations of salbutamol are 60-100% greater following the MDI. Also, a few of the salbutamol anti-doping studies provided serum data which support this. But as I noted above, there have been studies using the MDI that found much lower levels than the usually cited study by Haase using 1600 ug.

I hadn't seen that forum before. Since Austin posted on it, anything he says there can of course be discussed. I noticed he mentioned Petacchi's data, which he discussed a little in his private communications with me. He noted that Petacchi should have gotten off, but that was obvious anyway, because if the USG correction has been applied, his salbutamol level would have been well below the threshold. What's especially interesting about Petacchi's data, though, is that they indicate a much lower variability than is reported in inter-subject studies. This is what one would expect in data from a single subject, but if Froome's variability were similar, then it would make it more difficult for a model like Austin's to predict that he could exceed the threshold or decision limit very often. I would really like to see Froome's data, but of course WADA is too chicken-sh!t to publish them.
 
Re: Re:

gillan1969 said:
samhocking said:
Dr Daren Austin was a speaker at American Conference on Pharmacometrics regarding his work clearing Froome last week. Might be possible to get his slides perhaps MI?
or.......how not doing a pharmokinetic study helped Froome retain....... ;)
WADA RMP clearly shows pharmokinetic study is required once the AAF is confirmed. WADA would not confirm the AAF after the athlete explanation phase and so then the UCI entered into an ad-hoc procedural agreement to continue via tribunal instead, so the AAF remained presumptive only.

Following notification of the presumptive AAF in September 2017, the UCI and Mr. Froome, on 28 December 2017, entered into an ad-hoc procedural agreement (WADA was not involved in any fashion in the process leading to this procedural agreement). The UCI and Mr. Froome agreed that Mr. Froome’s evidentiary requests would be decided by the UCI Anti-Doping Tribunal. The requests were ultimately determined by the tribunal in mid-March 2018 after substantial submissions by Mr. Froome and the UCI.
So basically, UCI & Froome agreed an ad-hoc tribunal agreement outside WADA RMP and this tribunal was being used as the AAF Confirmation Procedure, not the Pharmokinetic Study. This is probably because Salbutomol would have been written in each anti-doping control form by Froome I assume?

3.4.2.2 Glucocorticosteroids and Beta-2 Agonists

For these substances, some Laboratories report a Presumptive Adverse Analytical
Finding
to the Testing Authority and enquire if a Confirmation Procedure is required.
The Testing Authority(or RMA, if a different ADO) then checks if a TUE has been
granted, and/or contacts the Athlete to enquire about the route of administration

 
Re: Re:

samhocking said:
gillan1969 said:
samhocking said:
Dr Daren Austin was a speaker at American Conference on Pharmacometrics regarding his work clearing Froome last week. Might be possible to get his slides perhaps MI?
or.......how not doing a pharmokinetic study helped Froome retain....... ;)
WADA RMP clearly shows pharmokinetic study is required once the AAF is confirmed. WADA would not confirm the AAF after the athlete explanation phase and so then the UCI entered into an ad-hoc procedural agreement to continue via tribunal instead, so the AAF remained presumptive only.

Following notification of the presumptive AAF in September 2017, the UCI and Mr. Froome, on 28 December 2017, entered into an ad-hoc procedural agreement (WADA was not involved in any fashion in the process leading to this procedural agreement). The UCI and Mr. Froome agreed that Mr. Froome’s evidentiary requests would be decided by the UCI Anti-Doping Tribunal. The requests were ultimately determined by the tribunal in mid-March 2018 after substantial submissions by Mr. Froome and the UCI.
So basically, UCI & Froome agreed an ad-hoc tribunal agreement outside WADA RMP and this tribunal was being used as the AAF Confirmation Procedure, not the Pharmokinetic Study. This is probably because Salbutomol would have been written in each anti-doping control form by Froome I assume?

3.4.2.2 Glucocorticosteroids and Beta-2 Agonists

For these substances, some Laboratories report a Presumptive Adverse Analytical
Finding
to the Testing Authority and enquire if a Confirmation Procedure is required.
The Testing Authority(or RMA, if a different ADO) then checks if a TUE has been
granted, and/or contacts the Athlete to enquire about the route of administration

the bolded

looks like you are trying to rewrite the WADA rules...to be fair they rewrote themselves so fair play ;)

you are of course 100% wrong...the rules state

The presence in urine of salbutamol in excess of 1000 ng/mL
or formoterol in excess of 40 ng/mL is not consistent with
therapeutic use of the substance and will be considered as an
Adverse Analytical Finding (AAF) unless the Athlete proves,
through a controlled pharmacokinetic study, that the
abnormal result was the consequence of a therapeutic dose
(by inhalation) up to the maximum dose indicated above.

the study comes before the confirmation...it should be part of your defence......well, it would be if it gave you a defence ;) ;)
 
gillan1969, you are stating the rules that apply to a confirmed AAF.
70kph. Glucocorticosteroids and Beta-2 Agonists report a Presumptive Adverse Analytical That has nothing to do with B confirming A. Exclusively for Glucocorticosteroids and Beta-2 Agonists the rules clearly state the RMA, should verify the route of administration used as part of its Initial Review before prosecuting a case as an AAF. That is the part of the rules Froome's AAF got to. If UCI had begun prosecuting as an AAF, then Froome would have had to have take the pharmo test. This is the same as Ullissi exactly.
 
Re:

samhocking said:
gillan1969, you are stating the rules that apply to a confirmed AAF.
70kph. Glucocorticosteroids and Beta-2 Agonists report a Presumptive Adverse Analytical That has nothing to do with B confirming A. Exclusively for Glucocorticosteroids and Beta-2 Agonists the rules clearly state the RMA, should verify the route of administration used as part of its Initial Review before prosecuting a case as an AAF. That is the part of the rules Froome's AAF got to. If UCI had begun prosecuting as an AAF, then Froome would have had to have take the pharmo test. This is the same as Ullissi exactly.
that's the rules...there's no ambiguity...they are as quoted...and the reading's an AAF unless you do the test...and he didn't do the test

I know some ambigiuty has been introduced (that's what lawyers are for) but the rules themselves allow for none...if the reading is over a certain amount, the way around that is to undertake the study.......and he....er.....didn't undertake the study

there's only so many way to say that

I presume you'd like our hapless hero to release his own readings?...that way we could all see if his metabolism tended to act in the manner that might present a false postive?
 
Whats the cut off point for any fresh doping revelations coming out of the 2018 season.... The Clinic is in desperate need of something to see us through the off season; surely we cant survive a full winter still poring over the scraps of last years news :sad:
 
Re: Re:

gillan1969 said:
samhocking said:
gillan1969, you are stating the rules that apply to a confirmed AAF.
70kph. Glucocorticosteroids and Beta-2 Agonists report a Presumptive Adverse Analytical That has nothing to do with B confirming A. Exclusively for Glucocorticosteroids and Beta-2 Agonists the rules clearly state the RMA, should verify the route of administration used as part of its Initial Review before prosecuting a case as an AAF. That is the part of the rules Froome's AAF got to. If UCI had begun prosecuting as an AAF, then Froome would have had to have take the pharmo test. This is the same as Ullissi exactly.
that's the rules...there's no ambiguity...they are as quoted...and the reading's an AAF unless you do the test...and he didn't do the test

I know some ambigiuty has been introduced (that's what lawyers are for) but the rules themselves allow for none...if the reading is over a certain amount, the way around that is to undertake the study.......and he....er.....didn't undertake the study

there's only so many way to say that

I presume you'd like our hapless hero to release his own readings?...that way we could all see if his metabolism tended to act in the manner that might present a false postive?

That's not ambiguity, that is how WADA stated Froome's AAF as 'presumed' not me, because that is how the lab reports it and WADA guidelines describe it too until confirmed. The lab doesn't know if it's theraputic via route of allowed administration. Also 20% of other above threshold salubutomol cases from 2013 to 2015 resulted in aquittal too, so hardly unique to Froome, other than Froome's circumstances it seems?

Anywya we went round and round in circles at the time. I'm happy the rules were followed, you are not convinced they were, so not much we can do about that.
 
brownbobby said:
Whats the cut off point for any fresh doping revelations coming out of the 2018 season.... The Clinic is in desperate need of something to see us through the off season; surely we cant survive a full winter still poring over the scraps of last years news :sad:
It is a bit telling how dull the clinic is once anti-doping is not about Sky anymore. Says a lot about people's real motivations to fight the good fight and rider preferences lol!
 

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