Erythropoietin doping in cycling: lack of evidence for efficacy and a negative risk-benefit / J.A. Heuberger, J.M. Cohen Tervaert, F.M. Schepers, A.D. Vliegenthart, J.I. Rotmans, J.M. Daniels, J. Burggraaf, A.F. Cohen. – (British journal of clinical pharmacology (2013) 6 (June) : p. 1406-1421) doi: 10.1111/bcp.12034.

Comment in:

Little soldiers in their cardboard cells / E. van Breda, J. Benders, H. Kuipers. - (British journal of clinical pharmacology (2014) 3 (March) : p. 580-581) doi: 10.1111/bcp.12187.

World-class cyclists on erythropoietin / J.A. Heuberger, A.F. Cohen. - (British journal of clinical pharmacology (2014) 3 (March) : p. 582) doi: 10.1111/bcp.12186.

Content:
- Sport is big business
- Physiology of erythropoietin
• Production and metabolism
• Recombinant erythropoietin in disease
• …and in sport. But does it work?
- Wat is endurance performance?
• Main determining performance?
• VO²max is aprerequisite but not a sole determining factor
• It is more than the VO²max
• Lactate Thresholt (LT)
• Lactate Turn Point (LTP)
• Economy (C)
• Other factors
- Studying the effects of rHuEPO on endurance performace
• Search strategy
• Study population mismatch with professional cyclists
• RHueEPO dosing
• Haematological effects of rHuEPO
• Effects on VO²max
• Does it translate to cycling performance?
• Other endurance performance parameters unstudied
• Alternative mechanism by which EPO works?
• Lack of scientific evidence
• A more scientific approach needed
- rHuEPO adverse effects in athletes
- Cyclists and rHuEPO: a risky choice to what advantage?

Imagine a medicine that is expected to have very limited effects based upon knowledge of its pharmacology and (patho)physiology and that is studied in the wrong population, with low-quality studies that use a surrogate end-point that relates to the clinical end-point in a partial manner at most. Such a medicine would surely not be recommended. The use of recombinant human erythropoietin (rHuEPO) to enhance performance in cycling is very common. A qualitative systematic review of the available literature was performed to examine the evidence for the ergogenic properties of this drug, which is normally used to treat anaemia in chronic renal failure patients. The results of this literature search show that there is no scientific basis from which to conclude that rHuEPO has performance-enhancing properties in elite cyclists. The reported studies have many shortcomings regarding translation of the results to professional cycling endurance performance. Additionally, the possibly harmful side-effects have not been adequately researched for this population but appear to be worrying, at least. The use of rHuEPO in cycling is rife but scientifically unsupported by evidence, and its use in sports is medical malpractice. What its use would have been, if the involved team physicians had been trained in clinical pharmacology and had investigated this properly, remains a matter of speculation. A single well-controlled trial in athletes in real-life circumstances would give a better indication of the real advantages and risk factors of rHuEPO use, but it would be an oversimplification to suggest that this would eradicate its use.

CAS 2012/A/3031 Katusha Management SA v. Union Cycliste Internationale (UCI)

Katusha Management SA (Katusha) is the licence holder of the Russian cycling ProTeam Katusha (the Team) which has competed as a UCI Pro Team.
On 13 September 2012 Katusha applied for a licence with the UCI for the season 2013. On 18 December 2012 The UCI Licence Commission decided to refuse Katusha’s registration for 2013.
The Commission noted that the Team’s financial situation should in any event be subject to periodical audits during the season.
Their ethical (doping) problems constituted a ground for refusing to register the Team because of:
- the doping cases in the team since its formation, namely in this instance two cases that occurred in 2009, one in 2011 and one in 2012;
- the cases of riders hired by the team, who had infringed the anti-doping rules in another team in the past 7 cases in this instance;
- the cases of staff who were team members and had infringed the anti-doping rules in the past, in this instance the cases of Andreï Mikhaylov and Eric Zabel;
- cases of infringing the rules regarding the riders’ whereabouts obligations, namely 8 filing failure and 4 missed tests from 2009 to 2012.

Hereafter, On 14 January 2013, the UCI granted Katusha the registration as a Professional Continental Team for the season 2013 under the condition to fulfil and put into practice a number of financial and anti-doping measures.
On 20 December 2012 Katusha appealed this UCI decision with CAS.

After hearing the positions of the parties the CAS Panel finds that the adoption of measures marks a quite important step made by Katusha along the lines indicated by the UCI, also in the License, in order to build an anti-doping environment within the Team. In order to keep the License and obtain the registration for the following season(s) Katusha should confirm during the entire 2013 season that it is actively implementing the measures adopted, in accordance with the Regulations. In that respect, Katusha is to be reminded of the power of the UCI to withdraw the License, if the information taken into account in granting the registration has changed so that the registration conditions are no longer satisfied.

The Panel concludes that the appeal brought by Katusha against the Decision is to be upheld, and that the Decision is to be set aside. At the same time, the Panel wishes to underline that this conclusion is not to be intended to constitute a backwards step in the fight against doping. This Panel is indeed mindful of the fact that the fight against doping requires a tough stance against anybody who tries to undermine it, and does not underestimate its importance. A coherent, reasonable and proportionate approach is however an indefectible part of such fight.

Therefore the Court of Arbitration for Sport rules that:

1.) The appeal filed by Katusha Management SA on 20 December 2012 against the decision taken by the License Commission of the Union Cycliste Internationale (UCI) on 7 December 2012 is upheld.
2.) The decision taken by the License Commission of the Union Cycliste Internationale (UCI) on 7 December 2012 is set aside.
3.) The application of Katusha Management SA to be registered as a UCI ProTeam for the season 2013 is accepted, and registration is granted to Katusha Management SA for the season 2013.
4.) (...)
5.) (...)
6.) All other prayers for relief are dismissed.

Gene Doping: Gene delivery for Olympic victory / David Gould. - (British Journal of Clinical Pharmacology 76 (2013) 2 : p. 292-298)

With one recently recommended gene therapy in Europe and a number of other gene therapy treatments now proving effective in clinical trials it is feasible that the same technologies will soon be adopted in the world of sport by unscrupulous athletes and their trainers in so called ‘gene doping’. In this article an overview of the successful gene therapy clinical trials is provided and the potential targets for gene doping are highlighted. Depending on whether a doping gene product is secreted from the engineered cells or is retained locally to, or inside engineered cells will, to some extent, determine the likelihood of detection. It is clear that effective gene delivery technologies now exist and it is important that detection and prevention plans are in place.

The 2014 Prohibited List International Standard : The World Anti-Doping Code / World Anti-Doping Agency (WADA). - Montreal : WADA, 2013.

- The official text of the Prohibited List shall be maintained by WADA and shall be published in English and French. In the event of any conflict between the English and French versions, the English version shall prevail.
- This List shall come into effect on 1 January 2014

Gene Transfer and Athletics : An Impending Problem / Theodore Friedmann, Johann Olav Koss. - (Molecular Therapy 3 (2001) 6 (June) : p. 819-820)

Is it possible to imagine athletes, trainers, and sports associations irresponsible enough to use the currently highly experimental and imperfect techniques of gene transfer for athletic use? Sadly, yes.
As imperfect and immature as they may be, as little as we know about their long-term dangers, current gene transfer methods may prove to be irresistible to the sports world.
It is hoped that other bodies, including athletic associations, the gene therapy community, and review and regulatory agencies, take the
issue seriously and begin to plan how they might prevent or respond to premature gene transfer attempts in athletes.

Anti-Dope Testing in Sport : The History and the Science / Larry D. Bowers. - (FASEB Journa l 26 (2012) 10 (October) : p. 3933-3936)

Brief history about developments in doping tests, starting from the 1900s till the XXX modern Olympic Games and de XIV Paralympic Games in London. Also how the Anti-Doping Agencies originate starting from concerns regarding the effects of anabolic steroids on athletes in the U.S. congressional hearings in 1988. Programs for testing where developed, but athletes altered their drug abuse behaviors to avoid detection. This resulted in more innovation for test methods and strategies and expanded the scientific disciplines. More collaboration in research enhances the rate of discovery of innovative approaches to solve doping problems.
There are numerous opportunities for members of the scientific community to assist in the fight against the use of performance-enhancing drugs and cheating.

CAS 2012/A/2997 Nationale Anti-Doping Agentur (NADA) v. Y.

In 2008 the 16 year old cyclist Y. was treated by Dr. Andreas Franke with the UV blood treatment at the training center run by the German Olympic Sports Confederation in Erfurt.
In January 2012 admitted cyclist Y. to the German National Anti-Doping Agency (NADA) that he had received these UV blood treatments in 2008. Hereafter in June 2012 the German National Anti-Doping Agency opened proceedings against cyclist Y., charging that the UV blood treatments were blood doping.
The German sports court ruled on 2 November 2012 that the method of removing blood, treating it with ultraviolet light and then re-infusing it, did not violate rules in effect at the time, as it has been specifically banned only since January, 2012. Therefore the German Sports Court cleared cyclist Y. of wrongdoing. The NADA appealed the decision to the CAS on 26 November 2012.

On 19 July 2013 The Court of Arbitration for Sport rules that cyclist Y. has not committed an anti-doping rule violation when he received UV blood treatment in 2008, because the procedure took place before being banned by the World Anti-Doping Agency on Jan. 1, 2011.
According to the CAS Panel, the WADA forbids blood manipulation only when it serves to increase oxygen transfer, an effect which is not proven in this case, and therefore does not meet the requirements for a forbidden method.
The CAS also ruled that the athlete involved did not act negligently or deliberately.

Gerhard P. Baumann
Endocrine Reviews, April 2012, vol. 33, iss. 2: pp. 155–186

GH is believed to be widely employed in sports as a performance-enhancing substance. It's use in athletic competition is banned by the World Anti-Doping Agency, and athletes are required to submit to testing for GH exposure. Detection of GH doping is challenging for several reasons including identity/similarity of exogenous to endogenous GH, short half-life, complex and fluctuating secretory dynamics of GH, and a very low urinary excretion rate. The detection test currently in use (GH isoform test) exploits the difference between recombinant GH (pure 22K-GH) and the heterogeneous nature of endogenous GH (several isoforms). Its main limitation is the short window of opportunity for detection (12–24 h after the last GH dose). A second test to be implemented soon (the biomarker test) is based on stimulation of IGF-I and collagen III synthesis by GH. It has a longer window of opportunity (1–2 wk) but is less specific and presents a variety of technical challenges. GH doping in a larger sense also includes doping with GH secretagogues and IGF-I and its analogs. The scientific evidence for the ergogenicity of GH is weak, a fact that is not widely appreciated in athletic circles or by the general public. Also insufficiently appreciated is the risk of serious health consequences associated with high-dose, prolonged GH use. This review discusses the GH biology relevant to GH doping; the virtues and limitations of detection tests in blood, urine, and saliva; secretagogue efficacy; IGF-I doping; and information about the effectiveness of GH as a performance-enhancing agent.

CAS 2012/A/2986 World Anti-Doping Agency (WADA) v. Riley Salmon & Fédération Internationale de Volleyball (FIVB)

Volleyball
Doping (methylhexaneamine (dimethylpentylamine))
CAS jurisdiction (notion of appealable decision)
Condition to benefit from a reduced sanction for the presence of a Specified Substance
Sanction for a second anti-doping rule violation
Absence of reduction of the sanction in case of retirement of an athlete

1. CAS has jurisdiction to hear an appeal against a doping-related decision where the rules of a federation clearly provide for the jurisdiction of the CAS against decisions rendered by a federation with regards to anti-doping issues. In this regard, a document called “Acceptance of Sanction”, although not signed by the federation but prepared according to the provisions of the federation’s medical regulations which can be considered to contain a unilateral ruling tending to affect the legal situation of an athlete therefore constitutes a “reasoned decision” appealable before the CAS.

2. Based on the applicable regulations, an athlete failing to give any explanation on how a prohibited substance came to be present in his body and to prove that his level of negligence was not significant will not be able to benefit from a reduced sanction.

3. Based on the applicable regulations, a second anti-doping rule violation committed by an athlete shall be sanctioned by a period of ineligibility between 4 to 6 years.

4. The purpose and intention of WADA is, inter alia , to make the fight against doping more effective by harmonising the legal framework and to provide uniform sanctions to be applied in all sports. These rules, for instance, do not distinguish between amateur or professional athletes, old or young athletes or individual sport or team sport. Considering the scope of the applicable rules, being active or retired should not allow an athlete to claim a different treatment and therefore justify a reduction of a sanction.

In 2009 the Fédération Internationale de Volleyball (FIVB), the International Federation of Volleyball, has reported an anti-doping rule violation against Ridley Salmon (the Player) after his sample tested positive for the prohibited substance hydrochlorothiazide. The Player was taking an approved medication by the FIVB for hypertension, however the drug’s replacement medication contained the banned substance hydrochlorothiazide. The FIVB decided to impose a 4 month period of ineligibility on the Player, starting on 27 May 2009.

In August 2012 the FIVB has reported again an anti-doping rule violation against the Player after his A and B samples tested positive for the prohibited substance methylhexaneamine (dimethylpentylamine).
On 27 September 2012 the Player signed a retirement form from the FIVB and accepted a 1 year period of ineligibility for his second anti-doping rule violation.

In November WADA appealed the FIVB sanction with CAS.
Without Player’s reply the CAS Panel has no explanation on how the prohibited substance came to be present in Player’s body, neither did he prove that his level of negligence was not significant.

The Court of Arbitration for Sport decides on 30 May 2013 that:

1.) The appeal filed by the World Anti-Doping Agency against the decision of the International Volleyball Federation dated 27 September 2012 is upheld.
2.) The decision rendered on 27 September 2012 by the FIVB is overturned.
3.) Riley Salmon is ineligible to compete for a period of 4 years starting from 27 September 2012. Any period of ineligibility already served by Mr Riley Salmon shall be credited against the total period of ineligibility imposed.
4.) The arbitration costs of the present procedure, to be determined and served by the CAS Court Office, shall be supported by the International Volleyball Federation.
5.) The International Volleyball Federation is ordered to pay CHF 2,000.- (two thousand Swiss Francs) to the World Anti-Doping Agency as a contribution towards the latter’s legal costs and all other expenses incurred in this arbitration.
6.) All other or further claims are dismissed.

CAS 2012/A/2959 World Anti-Doping Agency (WADA) v. Ali Nilforushan & Fédéderation Equestre Internationale (FEI)

Equestrian
Doping (phentermine; hydrochlorothiazide; carboxy-THC)
Admissibility of submissions by a body that did not exercise its right to appeal
CAS power of review
Lack of anti-doping education as a mitigating factor?
Reliance on a doctor as a mitigating factor?
Legitimate therapeutic use as a mitigating factor?
Effect on the sporting career as a mitigating factor?
Lack of intention as a mitigating factor?
Commencement of the period of ineligibility

1. Even if an international federation that has the right to appeal the decision from the first instance tribunal did not exercise that right, it is allowed in an answer to make submissions that the first instance tribunal ruled in error. If such answer does not seek any further relief than that claimed in WADA’s appeal, it does not constitute a counterclaim no longer allowed by the CAS Code.

2. As is the case with Article R57 of the Code, where rules or legislation confer on an appellate body full power to review the facts and the law, no deference to the tribunal below is required beyond the customary caution appropriate where the tribunal had a particular advantage, such as technical expertise or the opportunity to assess the credibility of witnesses. This is not, of course to say that the independence, expertise and quality of the first instance tribunal or the quality of its decision will be irrelevant to the CAS panel. The more cogent and well-reasoned the decision itself, the less likely a CAS panel would be to overrule it; nor will a CAS panel concern itself in its appellate capacity with the periphery rather than the core of such a decision. However, the fact that a CAS panel might not lightly interfere with such a tribunal’s decision, would not mean that there is in principle any inhibition on its power to do so.

3. In the absence of other mitigating factors such as exceptional youth or inexperience which in given circumstances may have a bearing, the lack of anti-doping education alone is not sufficiently exceptional to justify a reduction of the ineligibility period.

4. There must be more than simply reliance on a doctor for a reduction based on no significant fault or negligence. An athlete must cross check assurances given by a doctor, even where such a doctor is a sports specialist.

5. It is irrelevant to the determination of fault that the consumption of the prohibited substance was allegedly for a legitimate therapeutic use. This among others ensures a level playing field and is why the possibility, and the process, of applying for a TUE exists.

6. The effect that any ban could have on the athlete’s sporting career is not a relevant factor on the evaluation of an athlete’s degree of negligence.

7. Combined with a number of truly exceptional circumstances (the assessment requires viewing the “totality of the circumstances”), the absence of intention may form part of a matrix of facts which are sufficient to justify a reduction of the ineligibility period. However, lack of intention is a necessary but by no means sufficient condition alone for justifying a reduction of the ineligibility period.

8. A tribunal has discretion to back-date the commencement of the ineligibility period to the date of sample collection in case of early admission by the athlete of the charge of a doping offence. The request of documentation relating to the testing of the sample does not negate early admission, as it is a necessary aspect of an athlete’s rights of defence. Also, it is not required that no positive case in mitigation is advanced. Moreover, the athlete’s candour (or lack thereof) is not necessarily a relevant consideration.

In April 2012 the Equestrian Federation of Islamic Republic of Iran and the United States Equestrian Federation have reported an anti-doping rule violation against Mr. Nilfomshan (the Rider) after his sample tested positive for the prohibited substances Phenermine, Hydrocholorothiazide and Carboxy-THC (Cannabis). After the notification a provisional suspension was ordered. The Rider filed a statement in his defence and he was heard for the FEI Tribunal in June 2012.

The Rider explained he suffered from depression and insomnia and had gained a lot of weight for which he used prescribed medication.
On 3 September the FEI Tribunal decided to impose a 1000 CHF fine and a 1 year period of ineligibility on the Rider starting on the date of the sample collection, i.e. on 3 March 2012.

In October 2012 WADA appealed the FEI Tribunal decision with CAS. Considering the case the CAS Panel finds that the Rider was highly negligent, he did not exercise utmost caution and had no intention to enhance performance.

Therefore the Court of Arbitration for Sport Panel decides on 30 April 2013 that:

1.) The appeal filed by the World Anti-Doping Association on 19 October 2012 is partially upheld.
2.) The sanction imposed at paragraph 8.1.1 of the decision of the Federation Equestre Internationale dated 3 September 2012 (namely that Mr. Nilfomshan be suspended for a period of 12 months commencing on 3 March 2012) is amended as follows:
Mr. Nilfomshan is suspended for a period of 2 years, commencing 3 March 2012.
3.) All competitive individual results obtained by Mr. Nilfomshan from 3 March 2012 through the period of ineligibility shall he annulled.
4.) The award is pronounced without costs, except for the Court Office fee of 1.000 CHF paid by the World Anti-Doping Association, which shall be retained by CAS.
5.) Each party shall bear its costs incurred in connection with these arbitration proceedings.
6.) All further and other claims for relief are dismissed.