It seems that over the last few months, whenever one reads the papers or watches the sports channel on television in Australia, another story on AOD9604 and doping surfaces. Most recently, Australian-rule football League (AFL) Jobe Watson revealed on television that he believed that AOD9604 was the substance that he was administered.
Watson’s case is interesting because he was in 2012 also awarded AFL’s highest achievement award, the Brownlow Medal. To add further controversy, the deputy CEO of the AFL, Gillon McLachlan, also stated in a separate interview that in his opinion, he is not certain that the substance AOD9604 is banned under the World Anti-Doping Agency (WADA) Code. This thus contradicts the recent public statements made by WADA.
Overall, there seemed to be confusion in the popular media on both the medical science and the anti-doping rules of AOD9604. This situation is also not helped by the Australian Crime Commission’s (ACC) Organised Crime and Drugs in Sport report. According to ACC’s executive director Paul Jevtovic, this report was produced in consultation with the Australian Sports Anti-Doping Authority (ASADA) prior to publication. The ACC report stated categorically that AOD9604 was not a WADA-prohibited substance and not a substance banned under section S2 of the WADA Prohibited List.
WADA Rules
Sports that are signatory to WADA need to comply with all anti-doping rules. Athletes face the bulk of the consequences for most anti-doping rule violations (ADRV) under a strict liability legal standard. This means that ignorance is not an excuse and the ultimate responsibility is on the athlete to ensure at all times whatever is swallowed, injected or applied to the athlete is legal for use in sport.
WADA Code
Under the WADA Code, various substances and methods are assessed by three criteria to determine if it should be banned in sport: potentially unfair performance-enhancing attribute, potentially a threat to human health, or against the spirit of sport.
Under the criteria of performance-enhancement and health, the level of evidence that is relied upon is in the substance’s or method’s ‘potential’. This means that a substance or method can fulfil the criteria regardless of whether the expectation of performance enhancement is realistic, and/or whether a threat to human health has been scientifically proven or otherwise.
The third criterion of “spirit of sport” is the most nebulous concept of the three criteria and many experts continue to disagree with its use in practice and many believe that there is at least a perceived inconsistency in this criterion’s current application towards various substances and methods.
Prohibited List
Once a substance or method has been assessed by WADA and deemed to have fulfilled at least two out of the three criteria, it is then specified as a banned substance or method in the prohibited list. This list is updated at least once a year but the underlying reasons of how or why a substance or method is assessed under the three criteria is not revealed.
The prohibited list includes substances and methods that are banned ‘in-competition’ only, or both ‘in- and out-of-competition’ and this separation have sometime cause considerable angst. Some substances that are banned only ‘in-competition’ may be detected in the athlete during in-competition testing although the substance was only administered out-of-competition. This is because different individuals metabolise substances differently, and substances administered several weeks out-of-competition may persist in the athletes’ system in-competition. Marijuana is one such example. For our purpose here, we will only consider the ‘in and out-of-competition’ category.
Under the prohibited list for ‘in and out-of-competition’, substances are banned under the sections of S0, S1 to S5; methods are banned under M1 to M3.
If a drug is banned under S0 or S1 to S5, WADA does not differentiate how the substance is administered. For example, anabolic steroids are listed in the prohibited list as a banned substance. This means an ADRV occurs whether that substance is applied as a cream, consumed orally, or injected into the athlete’s muscle or vein.
If, however, a substance is not listed as a banned substance under S0 or S1 to S5, an ADRV may still occur as a banned method. One such example is Actovegin. While not listed as a banned substance, ASADA has previously clarified that giving Actovegin by an intravenous infusion and/or injections of more than 50 mL per 6 hour period may result in an ADRV under section M2-2. The rules do not state the concentration of the substance per volume that is given. This means that an intravenous infusion and/or injections of a more concentrated substance that is given in less than the restricted volume threshold of 50ml 6 hourly is not a violation under M2-2.
For our discussion on AOD9604, S2 (subsection 5 for the 2010-2012; subsection 4 for the 2013 lists) and S0 are the two main sections of interest.
Section S2
Prior to WADA’s official announcement regarding AOD9604 on 22 Apr 2013, AOD9604 could have been deemed to be included under S2-4 of the 2013 prohibited list that came into effect on 1 January 2013 or under subsection 5 in the 2010-2012 lists.
Under section S2-4 (2013) and S2-5 (2010-2012), it states:
PEPTIDE HORMONES, GROWTH FACTORS AND RELATED SUBSTANCES
Growth Hormone (GH) … as well as any other growth factor affecting muscle, tendon or ligament protein synthesis/degradation, vascularisation, energy utilization, regenerative capacity or fibre type switching;
Section S2 also has a “catch-all” phrase:
“…and other substances with similar chemical structure or similar biological effect(s)…”
AOD9604 is a synthetic peptide fragment that is modelled after a terminal section of the human growth hormone (HGH) molecule. This means that it would fit the “catch-all” clause of S2.
Performance Enhancing
Although initial drug development of AOD9604 was conducted in the hope that it would have therapeutic uses as an anti-obesity drug by promoting fat metabolism, or recovering from cartilage damage in joints, there is currently no conclusive human evidence to validate this. This means that based on current evidence, AOD9604 is unlikely to have any performance enhancing effects in respect to fat metabolism or tissue repair in humans. However, as discussed above, a substance only needs to have a potential and not the proof of its efficacy under the WADA rules to be deemed illegal.
In personal communications, WADA has indicated that the experts of the List Committee had intentionally chosen not to ban the substance under section S2 but may do so if it becomes approved by a health organisation. This suggests that WADA agrees that section S2 is an appropriate classification for AOD9604 based on its chemical structure and/or potential biological effect(s) but have nevertheless chosen to ban it under section S0 (for reasons undisclosed). In my opinion, because S2 is reliant on a theoretical and potential biological effect and is also robust to any administrative and regulatory changes, it is a much harder legal hurdle to overcome than S0 (see S0 below). Certainly, this is what would have concerned Stephen Dank–the maestro behind Australian football’s current symphony of confusion–as revealed in the alleged email exchanges he had with WADA before his human experiments on athletes began.
Section S0
Section S0 was only included as a category in the Prohibited list in 2011. Under section S0 (2011-2013), the prohibited list states that:
S0. NON-APPROVED SUBSTANCES
Any pharmacological substance which is not addressed by any of the subsequent sections of the List and with no current approval by any governmental regulatory health authority for human therapeutic use (e.g. drugs under pre-clinical or clinical development or discontinued, designer drugs, substances approved only for veterinary use) is prohibited at all times.
What this means is that a substance that does not meet the government therapeutic drug regulatory guidelines for humans of at least one country would fall within this section. What this also means is that if a drug that has been approved by the Food and Drug Administration (FDA) in the US but not by the Therapeutic Goods Administration (TGA) in Australia would presumably fail under S0. The anaesthetic drug of Etomidate is an example that may fit into this situation (although not been reported in sport use). Similarly, the fact that the Romanian Ministry of Health has previously approved the use of Humanofort (containing thymosin beta-4) as a nutritive supplement in humans potentially means that thymosin beta-4 may not qualify under section S0 of the prohibited list.
The section S0 is useful for WADA as a legal “catch-all” category. This is because for many new substances, scientists have yet to fully understand the actual mechanism of action of how the substances work. In my opinion, section S0 thus affords WADA, or any National anti-doping agency, the option of avoiding having to defend an ADRV sanction when it is challenged in the Court of Arbitration of Sports on the grounds of the substance’s true (rather than theoretical) mechanism of action.
Unfortunately, section S0 also has its limitations if applied to “non-therapeutic” and/or “non-pharmaceutical” substances. For example, various traditional therapies and complementary and alternative medicine (CAM) have been used by many indigenous and Eastern cultures for centuries. Western scientists do not as yet understand how some of these compounds act. If no pharmaceutical company decides to apply for approval for its use as a therapeutic drug, then these CAM substances remain “legally” available for use in society but unapproved for use as a therapeutic drug. The lack of governmental approval does not, however, mean that a substance does not have any pharmacological effect. An example of varied governmental approval that is relevant for the matter concerning CAM use and drug regulation is the herbal stimulant of qat (Catha edulis) that is traditionally used by the Somali, Yemeni and Ethiopian communities. This matter is of recent interest in the UK. Closer to Australia, the sedative and muscle-relaxant Kava (Piper methysticum) used by the Fijian, Hawaiian, Samoan and New Guinean people; and the medicinal tonic of Cordyceps (Cordyceps Sinensis) used in the Chinese cultures are also relevant for consideration.
There is also another complexity to S0. If a substance is promoted as a “food addictive” or “supplement” and not as a “therapeutic substance” then it is often not controlled by government regulatory health authorities. In the US, under the FDA Generally Recognized As Safe (GRAS) programme pursuant to sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act, any substance that is intentionally added to food is not subject to the approval by FDA if the substance is generally recognized, among qualified experts, as having been adequately shown to be safe under the conditions of its intended use. Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), the onus is also on manufacturers, marketers and distributors of dietary supplements to be responsible for ensuring that they are marketing a safe product.
It has been postulated that because of the lesser burden under DSHEA as compared to GRAS, some manufacturers may choose to market a functional food as a dietary supplement rather than as a conventional food with added ingredients in order to escape strict FDA regulation of the safety of functional substances. DSHEA makes it more difficult for the FDA to remove an unsafe, or potentially unsafe product from the market. Prior to DSHEA, the FDA would have been able to use its authority to regulate food additives as a method of declaring a supplement ingredient unsafe or inadequately tested and the burden is on the manufacturers to prove otherwise. Under the DSHEA the onus of proof is now shifted to the FDA to prove something is unsafe.
The presence of a substance in a supplement or food under the auspices of DSHEA or GRAS does not automatically mean that the substance does not have pharmacological or potential health effects. One such example is DMAA (1,3 Dimethylamylamine). DMAA was previously readily available in various over-the-counter (OTC) supplements such as Jack3D. DMAA/Jack 3D has also been implicated in several recent ADRV in sports.
The FDA issued strict warning on April 27, 2012 against the inclusion of DMAA in supplements and stated that synthetically produced DMAA is not a “dietary ingredient” and, therefore, is not eligible to be used as an active ingredient in a dietary supplement. The FDA further clarified that under the DSHEA: a dietary ingredient is a vitamin, mineral, amino acid, herb or other botanical; a dietary substance for use by man to supplement the diet; or a concentrate, metabolite, constituent, extract, or combination of these substances. In Australia, the TGA also banned the inclusion of DMAA in supplements on 8 August 2012.
According to the global licence holder for AOD9604, Metabolic Pharmaceuticals Pty Ltd (“Metabolic”), the company stated that it had achieved a self-affirmed GRAS status for OTC, which allowed the marketing of AOD9604 into the US market and legally added to foods, drinks, nutraceuticals and dietary supplements. Given the reasoned decision of the FDA on DMAA, one questions if the synthetically produced AOD9604 should be considered a “dietary ingredient” and if suitable under GRAS or DSHEA?
In addition, Metabolic has also indicated that AOD9604 is already available in cosmetics sold as a cream throughout Australia in Myer stores, David Jones, Pulse Pharmacies, Priceline, and Terry White Chemists and in Asia through the A.S. Watson Group and distribution networks in South Korea and northern Asia. As indicated previously, in the context of the WADA rules, how a substance is applied to the body is not relevant if a substance is banned under S0 or S1 to S5.
Health Effects
Leaving aside the issue of the classification of AOD9604 within the prohibited list, let us consider next if the substance is able to fulfil the criterion of potential adverse health effects as described in the WADA Code.
According to a scientific paper published in April 2013, the authors stated that AOD9604 displayed a very good safety and tolerability profile indistinguishable from placebo and that AOD9604 did not result in any of the adverse effects associated with HGH treatment. The paper listed six human trials that were conducted where AOD9604 was either administered intravenously or as a capsule/tablet. It should be noted that the authors of the paper included the CEO of Metabolic and two other co-authors who had direct and indirect financial interests related to Metabolic. All six human trials were also sponsored by Metabolic.
In reviewing the details of the published paper, it was noted that a total of 893 participants were involved in the six human trials between 2001-2006. While many adverse effects were reported, the authors have classified most as mild or moderate. In one adverse event of a participant complaining of a feeling of chest tightness in one of the Phase IIa trial, it was determined by the authors that the adverse effect was potentially related to AOD9604. While this event was determined as of severe in intensity it was not classified as a “serious adverse event” under the research protocol.
There were several participants in the trials that reported “serious adverse events” according to the research protocol: In another Phase IIa trial, one participant had diarrhoea and this was deemed “possibly related” to AOD9604; another participant had pneumonia and this was deemed to be “unrelated” to AOD9604. Five participants who separately reported to have developed basal cell carcinoma, moderate lipoma, squamous cell carcinoma, malignant melanoma and breast cancer were all not considered by the authors to be “possibly, probably or definitely” related to AOD9604. The rationale given for this judgment was that none of the cancer forms occurred in the highest dosage group and therefore a dose effect can be excluded. The authors also further stated that the participants that had cancers had neglected their personal medical care for a long period of time, and the authors assert that the higher incidence of cancer may well have occurred due to the natural incidence rate of cancer events in the population and not due to AOD9604.
Based on the presented material, it is not possible to judge (to have proof) or to conclude from an evidence-based statistical perspective if AOD9604 has any significant adverse health effects. Certainly, from a statistical perspective, the authors’ dismissal of serious adverse events as unrelated to AOD9604 seems problematic on prima facie without further statistical and clinical information. However, if one goes by the lower WADA-evidentiary threshold of potential and relying only on the human trial reports, then there are at least some adverse health effects and AOD9604 would thus appear to qualify under the health criterion.
Abusus Non Tollit Usum
We should note that just because something is misused does not mean it cannot be used correctly. No medication that is approved by any governmental regulatory health authority is without some adverse effects. Similarly, as stated by Paracelsus;
All things are poison, and nothing is without poison; only the dose permits something not to be poisonous.
If Watson’s admission is true and that AOD9604 has indeed been administered to athletes, it is not revealed at this time how the substance was administered, and how much of it was dispensed.
If the dose of AOD9604 that were allegedly given were in quantities (either orally or intravenously) that far exceeds that assessed in the reported human trials, then any human safety profile as positioned by Metabolic in those trials cannot be relied upon. In addition, beyond the issues of ADRV, as employees of the clubs, athletes should in my opinion at least be owed a duty of care from an occupational, health and safety perspective. Besides, one wonders if it can be construed as an informed consent when all the relevant facts were not provided to athletes.
Image: theconversation.com