8 мин.

The Sharapova drug story: What’s the evidence? Part 3

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David Nunan, Senior Research Fellow

Вторая часть можете найти здесь:

http://www.sports.ru/tribuna/blogs/dennytenn/936513.html

This is the third in a series of blogs where I’ve looked at the evidence behind the banned drug Meldonium, for which Maria Sharapova has admitted taking since the age of 17. My first blog focused on the evidence for its use in treating ECG abnormalities, familial history of diabetes and magnesium deficiency in a 17-year-old female.

The second looked at the evidence for its performance-enhancing effects as one of the reasons why it was placed on WADA’s prohibited substances list.

Before starting out I knew very little of the way in which WADA determines what and why a substance should be banned. During my investigations it became apparent that there were some important and worrying issues in relation to the methods used by WADA for populating its Prohibited List. These were eye-opening and left me with a number of concerns, enough in fact to warrant an additional blog.

Why Meldonium was banned – a quick recap

One of the most frustrating things has been trying to obtain details of WADA’s methods for obtaining and reviewing evidence on a substance it is investigating.

This was very much the case for Meldonium.

Some details of the process are provided by WADA in the form of a recent “Notice” to stakeholders which states that between 2011 – 2015, the WADA List Committee conducted:

“A literature review of the scientific information”

“Generation of specific data (in particular via the 2015 Monitoring Program, which revealed a high prevalence of the use of Meldonium by athletes and teams of athletes)”

It appears the review looked specifically at research on the mechanism of action of Meldonium. Notwithstanding the documented limitations when inferring from mechanisms, as well as the potential biases of their literature review process, I’ve been unable to find any publication of the review findings.

I found this blog by jakeshelly claiming (unfortunately no reference is given but I think I found it) that “the literature review showed that Meldonium is an effective anti-ischemic drug with further applications in immunomodulation and in the treatment of neurodegenerative disorders and brochopulmonary diseases.” No mention of performance enhancement here.

Results from the “specific data” generation have been published. One study entailed development of a new mass spectrometry test specifically for Meldonium whereby some 8,320 random doping control urine samples were analysed. 182 (2.2%) positive Meldonium samples in a concentration range between 0.1 and 1428 μg/ml were returned. This study would appear the source of the unreferenced claims above and was discussed extensively in Part 2 of this series.

A second study (published 25th March 2016) looked specifically at the prevalence of Meldonium in samples taken from athletes competing at the Baku 2015 European (Athletic) Games. Whilst only 23 out of 663 (3.5%) athletes declared personal use of Meldonium (including 13 competition winners), 66 of 762 (8.7%) urine samples analysed during the Games and during precompetition tested positive.

Taken together, the above “evidence” ultimately led the List Committee to conclude that “meldonium met two of the three criteria listed in Article 4.3.1 of the World Anti-Doping Code (Code). In particular, claims of performance enhancement had been made by various authors, including the manufacturer of meldonium.” [sic] (I’ll come back to the obvious problems of the last sentence later.)

But at least now we have two out of three inclusion criteria WADA considered as having been met; namely violation of the spirit of sport and evidence of a performance-enhancing effect – well, the manufacturer says so.

The situation is far from clear. WADA’s recent Notice (and accompanying statement) was released on the back of “lack of clear scientific information on excretion times [for Meldonium]” which may give grounds for “no fault or negligence on the part of athletes”. Sharapova may well be exonerated after all!

“These statements and positions are odd (at least to me). The first two go completely against transparency in science, something being fought hard for (at least in the medical community) by campaigns and initiatives the likes of AllTrials and OpenTrials.”

Notwithstanding the embarrassment, more importantly it again calls it to question the methods used by WADA to determine what should and should not be banned. Indeed, Sharapova’s racquet manufacturer Head even waded in, stating, “[T]his highlights a wholly flawed decision-making process by Wada whereby the ban on meldonium has no justification”.

A statement worthy of follow-up.

How does WADA decide if a substance should be banned or not?

Unlike other aspects, WADA’s website is more transparent on the processes for updating the List. In summary a substance gets on to the Prohibited List if it meets two of the following criteria:

Potential to enhance or enhances sports performance

An actual or potential health risk to the athlete

Use violates the spirit of sport (outlined in the Code)

Evidence as to whether a substance meets any of these criteria is considered by the List Expert Group on an annual basis via a process of stakeholder consultation and comment. In the words of WADA, the List Expert Group is “a panel of scientists chosen for their international expertise” and makes decisions on the contents and revisions of the list.

Once agreed, the List Expert Group recommends the new List to the Health, Medical and Research Committee, which in turn make recommendations to the Executive Committee.

All fairly straightforward then. That is until you start to ask questions about the methods utilised by the List Expert Group and the resultant “evidence” produced by it. The most detail I can find on the evidence considered for the three criteria appears in WADA’s Code itself, whereby: “A substance or method shall be considered for inclusion on the Prohibited List if WADA, in its sole discretion, determines that the substance or method meets any two of the following three criteria:

4.3.1.1 Medical or other scientific evidence, pharmacological effect or experience that the substance or method, alone or in combination with other methods, has the potential to enhance or enhances sport performance;

4.3.1.2 Medical or other scientific evidence, pharmacological effect or experience that the Use of the substance or method represents an actual or potential health risk to the Athlete;

4.3.1.3 WADA ’s determination that the Use of the substance or method violates the spirit of sport described in the introduction to the Code.”

There’s much ambiguity here – e.g. what constitutes ‘other scientific evidence’? Whose ‘experience’ is considered? How is the experience established? How much or how little experience is required? Etc.

It would be helpful then to see some of this “scientific (and other) evidence” and the decision processes used to determine its validity. But then you see this statement from WADA’s Chief Operating Officer, Olivier Niggli: “We have experts who look at it, they have three criteria. It has to meet two of the three and we never disclose nor discuss the specifics of a substance because otherwise, every time you have a positive case, there would be a challenge.” No point in an FOI here then!

Equally worrying is that WADA has previously argued that it doesn’t have to scientifically justify why a substance is on the Prohibited List. “That’s specifically the way that the Code’s wording has been put so that we would not have to justify why a substance is on the list.” states Niggli.

“This is not how science works. Science is an iterative process, ever evolving and building upon prior knowledge. Things change.”

The Code also states: “WADA’s determination of the Prohibated Substances and Prohibited Methods that will be included on the Prohibited List is final and shall not be subject to challenge by an Athlete or other Person based on an argument that the substance or method was not a masking agent or did not have the potential to enhance performance, represent a health risk or violate the spirit of sport.”

These statements and positions are odd (at least to me). The first two go completely against transparency in science, something being fought hard for (at least in the medical community) by campaigns and initiatives the likes of AllTrials and OpenTrials.

The latter is equally bizarre – if it were a research publication it would be tantamount to saying “Our conclusion is final and we will ignore any research or evidence to the contrary, so na na ne na na [rasping noise with tongue]!”

This is not how science works. Science is an iterative process, ever evolving and building upon prior knowledge. Things change. We only need to look at Vioxx, rosiglitozone, flecainide or SIDS as examples where new knowledge challenged common practice that was unwittingly harming people. If we apply the WADA criterion, these drugs and practices would be left unchallenged to continue harming millions.

Moreover, it appears that evidence considered by WADA doesn’t even need to be scientific nor does it need to be justified. The likes of Nightingale, Bradford-Hill, Kelsey, Sackett, heck any scientist worth their salt, would be turning!

WADA appears not to want, nor allow, any challenge to its processes for populating its Prohibited List. I’m no expert but I’m not sure how this would stand up in a court of law? We may yet find out.

Summing up

My investigations over the past month or so have led me to conclude that the evidence to support a 17 year-old female taking Meldonium (Mildronate) for mild ECG anomalies, risk factors for diabetes or magnesium deficiency is extremely weak.

However, equally weak and unconvincing is the evidence used (from what I can gather) by WADA as ‘proof’ Meldonium causes (or has potential to cause) an enhanced sporting/athletic performance.

I’ve also concluded there is much inconsistency in the way WADA applies it’s own criteria, with huge potential for bias and agenda influence over the List. Equally worrying is WADA’s lack of transparency as to its processes for obtaining and reviewing evidence and its own self-imposed ban on challenging their “evidence-based” decisions.

I feel I have only scratched (maybe scoured) the surface here. Perhaps this will inspire someone else to take up where I have left off?

http://www.cebm.net/sharapova-drug-story-whats-evidence-part-3/

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