Maria Sharapova and Meldonium – Consideration of a Therapeutic Use Exemption After a Positive Drug Test

Maria Sharapova – London 2012 – Photo by Oliver Catlin, http://www.bscg.org

The coverage of Maria Sharapova’s announcement of her positive drug test for meldonium, or mildronate, has been astounding. Her case is yet another amazing example of a great champion falling victim to performance-enhancing drugs in one way or another. We wrote an immediate blog post about it an attempt to consider the two potential sides to a doping issue. That post still provides an interesting view of the perspective we were aiming to provide and we stand behind the bulk of the content.

In our haste to give Ms. Sharapova the benefit of the doubt in the situation, however, as we did in our conclusion and in the suggestion that perhaps her therapeutic use would be considered retrospectively, we did not fully consider the realities behind Ms. Sharapova’s claim of therapeutic use. Thankfully our friends in the anti-doping doping community have elegantly expounded on this element of the case.

The expert analysis below on therapeutic use and application in World Anti-Doping Agency (WADA) doping control is important to consider. It corrects the notion that a TUE could be granted retroactively and impact a pending sanction, which would be extremely rare if not completely unique in the field of anti-doping.

The information below was written by Dr. Ken Fitch and distributed by Jim Ferstle, both valued friends and colleagues who care deeply about clean sport and anti-doping and have spent their careers fighting for the cause as we have. The points of primary interest: retroactive TUEs would be unlikely to be considered from a standpoint of sanction relief, and the defined timeframe and clinical guidelines for use of a drug should always be scrutinized when evaluating potential therapeutic use. Thank you, Ken, for providing an insightful explanation of the criteria involved in the consideration of therapeutic use exemptions and the potential application to meldonium.

Dr. Ken Fitch is an Australian doctor and Professor, School of Sports Science, Exercise and Health, Faculty of Life Science University of Western Australia. Dr. Fitch wrote the original rules for TUEs in 1991 for the IOC, chaired the IOC’s TUE Committee for 20 years, chaired WADA’s interim committee (2001-2003) that established the initial International Standard for TUE (2004) and chaired Australia’s national TUE Committee for 22 years.

Maria Sharapova’s lawyer exploring a possible TUE to exempt a sanction
by Ken Fitch, M.D.

The ludicrous suggestion by Sharapova’s lawyer that she might seek a retroactive Therapeutic Use Exemption (TUE) to avoid a sanction for testing positive to meldonium demands a response. Ignoring whether the 2016 World Anti-Doping Code and the 2015 International Standard for TUEs does or does not make a retroactive TUE a possibility in her circumstances, if anybody examines the criteria that must be met to grant a TUE, he/she would understand that no respectable TUE Committee could approve any such application.

WADA states that there are four criteria, all of which must be met to grant a TUE.

1. The drug is necessary to treat an acute or chronic medical condition and the athlete would experience a significant impairment to health if it were to be withheld.
2. The therapeutic use of the prohibited drug is highly unlikely to produce any additional enhancement of performance beyond what might be anticipated by a return to the athlete’s normal state of health following the treatment.
   
3. There is no reasonable therapeutic alternative to the use of the prohibited drug.
4. The necessity to use of the prohibited drug is not a consequence of prior use of a prohibited drug or method.

Would Sharapova’s health be significantly impaired if she was denied a TUE? The Latvian makers of meldonium advise that it should be taken in intermittent courses of 4-6 weeks and for what period of time Sharapova administered meldonium during the past ten years, has yet to be disclosed. As the only acceptable medical indications are for ischemic cardiac and ischemic cerebral conditions, it is unthinkable that Sharapova has either. Hence any claim that should she be denied the right to take meldonium would impair her health is simply fanciful. Any TUE application must fail criterion 1.

The second criterion was introduced because some athletes had an essential need to take a prohibited drug. For example, an insulin dependent diabetic would die if denied insulin which has been prohibited in sport since 1998 and their daily insulin injections that are permitted with a TUE do not enhance performance. Whether meldonium actually enhances performance in humans has yet to be demonstrated. That WADA has advised that in less than two months since it was added to the Prohibited List, 99 athletes have tested positive for meldonium would appear to indicate that many athletes and their advisors believe that it does. No athlete could claim that meldonium was essential to restore their health back to normal levels. To claim that without it, a person’s health would be less than normal is surely fictitious. Fails criterion 2.

There are many drugs that have been demonstrated in scientific trials to be valuable in cardiac ischemia and the vast majority would be far superior to meldonium. The few meldonium studies performed in humans have been on persons who recently had experienced a myocardial infarction or an acute coronary syndrome. That the makers of meldonium recommend that it be administered only in intermittent courses in contrast to most of the widely acceptable, prescribed alternatives that are to be taken daily, is further evidence of the non-essential status of meldonium to treat cardiac ischemia. As the drug is marketed in only ten countries globally and Sharapova has lived in the USA for much of her life where meldonium is not approved for human use, this poses further questions for the tennis player.

Drug therapy for cerebral ischemia is generally ineffective and less frequently used than for cardiac ischemia but those patients on whom meldonium was trialled had had either a recent stroke or evidence of deteriorating brain function. As Sharapova could not possibly demonstrate that she has either of these or indeed significant cardiac or cerebral ischemia, and if she could, alternative permitted drugs are at least as effective if not more so, she fails criterion 3.

Hence Sharapova fails 3/3 and the fourth criterion has no relevance. Finally, should an unscrupulous or ignorant TUE Committee happen to grant Sharapova a retroactive or even a prospective TUE for meldonium, WADA would be certain to appeal to CAS and the decision would be or should be overturned.

Maria Sharapova and Meldonium – Consideration of a Positive Drug Test

Maria Sharapova – 2012 London Olympic Games – Photo by Oliver Catlin, www.bscg.org

Before jumping to conclusions and lambasting Maria Sharapova as a deliberate doper over recent revelations, we should attempt to educate ourselves and arrive at an informed decision based on the circumstances at hand. There is much to consider when reviewing Ms. Sharapova’s recent positive drug test at the Australian Open for the drug Meldonium.

First, we start with the drug, Meldonium, also known as Mildronate. You can review the pubchem listing for mildronate if you are interested. Other synonyms for the drug include “Quaterin; 76144-81-5; Kvaterin.” The long IUPAC chemical name is 3-[(trimethylazaniumyl)amino]propanoate.

In medicine, Meldonium is used to treat cardiac conditions like angina and vascular disease. It was developed by a Latvian company Grindeks and is approved in the Russian Federation and other countries but not in the Unites States. The description on Drugs.com describes it in two therapeutic categories; “treatment of cardiac disorders” and “inhibitor of carnitine synthesis.” Drugs.com includes 11 brand names across the Russian Federation, Latvia, Georgia and Lithuania: “Cardionate, Meldonium Olainfarm, Meldonium-MIK, Mildronat, Mildronat Grindeks, Mildronats, Mildroxyn, Vazomag, Midromax, Mildronate, Milkor.” There are 189 publications to explore via PubMed if you want to want to spend the time perusing them.

It appears Ms. Sharapova tested positive for the drug in an ITF (International Tennis Federation) drug test on Jan. 26 at the Australian Open. This information comes from her own accounts and the various media summaries of her case, including one from the New York Times that includes a video of her press conference in which she disclosed the positive test results. She explains the details saying, “I was legally taking the drug for the last ten years. I was getting sick very often, I had a deficiency in magnesium. I had irregular EKG results, and I had a family history of diabetes.” She added she had used the drug since 2006 based on treatment advice from her doctor.

Meldonium was added to the World Anti-Doping Agency (WADA) Prohibited List for 2016 under the category ‘S4. Hormone and Metabolic Modulators’. Prior to 2016, Meldonium was on WADA’s monitoring program list, meaning they were watching to see if it was being abused by athletes. The notes from WADA’s 2016 Prohibited List – Summary of Major Modifications and Explanatory Notes that came out on September 16, 2015, says that “Meldonium (Mildronate) was added because of evidence of its use by athletes with the intention of enhancing performance.”

More specifically, an abstract from a publication on Meldonium in Drug Testing and Analysis from December 2015 mentions, “the anti-ischemic drug Mildronate demonstrates an increase in endurance performance of athletes, improved rehabilitation after exercise, protection against stress, and enhanced activations of central nervous system (CNS) functions.” A good explanation on the logic and research leading WADA to prohibit of Meldonium is included in a blog from March 3, 2016, noting the positive drug tests of runners Abebe Aregawi and Endeshaw Negesse, who also recently tested positive for Meldonium.

According to a Roidadvisor.com article, “Performance-enhancing Drugs Used by Athletes That Are Surprisingly Common,” (Oct. 17, 2015),“Meldonium has generally been used by athletes in various sports for its mild stimulant-like properties.” The piece goes on to say, “Of interest to athletes is the finding that it consistently and significantly improves exercise tolerance. Some pharmaceutical companies have recently marketed it explicitly as a performance-enhancing drug. It’s also used as a ‘smart drug’ by non-athletes. Athletes have been using it for over 5 years.” Of additional concern, the article mentions other similar drugs “telmisartan (Micardis) and T3 liothyronine (Cytomel) – are currently being used by numerous elite athletes particularly in endurance sports.”

So, on the one hand there appears to be a plausible and legitimate medical reason for Ms. Sharapova to have used Meldonium. It could have simply been a mistake that she continued to use it in 2016 without realizing it had become prohibited or seeking a therapeutic-use exemption for the drug, which presumably she could have and still might receive if her account holds true. It’s possible that will be evaluated retrospectively. It would appear there was enough time to consider the potential concern as Meldonium was on the WADA monitoring program list since January 1, 2015 and notification of it being added to the Prohibited List came out more than three months before the start of the year. It is not known if the ITF provided any notification to its players in addition to the information WADA provided.

Now, the cynics will probably look at the message board information and say it appears clear that athletes have known about the doping potential of drugs like Meldonium for years now. They may conclude that Ms. Sharapova has come up with a convenient explanation of what happened after the fact. Sadly, that explanation is also plausible.

This issue is the perfect example of a primary challenge we face when confronting the need to conduct anti-doping testing to keep sport clean. All we have is the test results that indicate a positive or negative finding in a urine sample. The results do not speak to the motivations or intentions of the athlete. In situations like this one, or in cases that involve dietary supplement use, it is hard to know whether the athlete is being truthful in their explanation or if they have developed a convenient explanation for their use of the substance involved.

We will see how things conclude in this case. Given what we know about the character of Ms. Sharapova, we have to think this is accidental doping. Of course one can never be certain and the rules of strict liability still apply as they always do in the anti-doping realm, and as she herself notes in her statement. Sadly, she is now subject to a possible two years of sanctions and has had a pall pulled over the culmination of a fabulous career. Tennis will miss her and her the game. This case is the perfect illustration of the need for drug tested athletes to take it upon themselves at the end of each year to be vigilant and review changes in the WADA Prohibited List to ensure their medications and dietary supplements are compliant with the drug testing rules for the next year.

By Oliver Catlin, President, Banned Substances Control Group, www.bscg.org