Sylvan Health Pty Ltd and Minister for Health and Ageing - [2009] AATA 814

Administrative Appeals Tribunal

DECISION AND REASONS FOR DECISION [2009] AATA 814

ADMINISTRATIVE APPEALS TRIBUNAL )

) No: 2008/4810

GENERAL ADMINISTRATIVE DIVISION )
ReSylvan Health Pty Ltd

Applicant

And Minister for Health and Ageing

Respondent

DECISION

TribunalMr RP Handley, Deputy President
Professor GAR Johnston AM, Member

Date23 October 2009
PlaceSydney
DecisionThe decision under review is affirmed.
................[sgd]..................
Mr RP Handley
Deputy President

CATCHWORDS

HEALTH AND AGEING – Therapeutic Goods Act 1989 – registration of a complementary medicine – whether safety of the product for the purpose for which it is to be used has been satisfactorily established – complex mixture of ingredients – inclusion in Schedule 4 of the Poisons Standard – further data required – decision under review affirmed

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RELEVANT ACT

Therapeutic Goods Act 1989 (Cth): ss 25, 28, 52A, 52E, 52F, 52G, 60A, 60, 42ZE

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OTHER AUTHORITIES

Australian Regulatory Guidelines for Over-the-Counter Medicines

Australian Regulatory Guidelines for Complementary Medicines

Australian Regulatory Guidelines for Prescription Medicines

European Medicines Agency Guidelines

Guidelines for Levels and Kinds of Evidence to Support Indications and Claims for Non‑Registrable Medicines including Complementary Medicines and Other Listable Medicines

Standard for the Uniform Scheduling of Drugs and Poisons: Schs 2, 3, 4

Therapeutic Goods Regulations 1990: Reg 42ZE

…

REASONS FOR DECISION

23 October 2009

Mr RP Handley, Deputy President

Professor GAR Johnston AM, Member

Sylvan Health Pty Ltd (Sylvan) has applied to the Tribunal for the review of a decision of a delegate of the Minister for Health and Ageing to reject an application made under the Therapeutic Goods Act 1989 (Cth) (the Act) for the registration of a complementary medicine called Cholesen. The issue in dispute is whether the safety of Cholesen for the purpose for which it is to be used has been satisfactorily established.

Background

Cholesen capsules are manufactured from an extract of Red Yeast Rice (RYR), a traditional Asian food and medicine reputedly used for thousands of years. RYR is fermented rice on which the fungus ‘red yeast’ (Monascus purpureus) has been grown. While the composition of RYR may vary considerably, Sylvan has standardised the composition of RYR in Cholesen with respect to key constituents. Nevertheless, Cholesen is a typical complementary medicine in that it is a complex mixture of ingredients. It is relatively atypical in that it contains at least two clearly defined ingredients that have relatively well characterised pharmacological actions, one of which is also a prescription drug.
The major active ingredient of Cholesen is Monacolin K, a prodrug that is activated in the body, for example by an enzyme. This ingredient is chemically identical to Lovastatin, a prescription drug used to lower cholesterol. Lovastatin is one of a family of drugs collectively called statins that are prescribed worldwide to treat hypercholesterolaemia (excessive levels of cholesterol in the blood). Another significant active ingredient in Cholesen is Monacolin KA (Monacolin K Acid), which is found at a level approximately one third of Monacolin K, and, unlike Monacolin K, does not need to be converted into an active form in the body.
The cholesterol-lowering effects of Cholesen are appreciably higher than can be accounted for by the level of Monacolin K in Cholesen. The reason for this is not well understood. It may be due to the presence in Cholesen of the already active Monacolin KA, or the influence of other ingredients in Cholesen that compete with Monacolin K and Monacolin KA for metabolising enzymes in the liver. This could result in slowing the excretion of Monacolin K and Monacolin KA from the body, thus increasing their levels in the blood.
Although statins are generally regarded as very safe drugs, in a small number of cases adverse effects have been recorded, for example, myopathy (muscle wastage) characterised by aches and pains. At a meeting of the National Drugs and Poisons Schedule Committee (NDPSC) held on 16 - 17 June 2009, the NDPSC determined to include statins in Schedule 4 to the ‘Poisons Standard’ except when separately specified in the Schedules, with effect from 1 January 2010. The ‘Poisons Standard’ is the ‘Standard for the Uniform Scheduling of Drugs and Poisons’ published by the Australian Health Ministers' Advisory Council (s 52A of the Act).
The scheduling of substances (poisons) in the Poisons Standard takes into account various factors related principally to their safety and toxicity set out in s 52E of the Act. The NDPSC has also published administrative guidelines setting out criteria relevant to the inclusion of a poison in a particular schedule. Schedule 2 poisons are those which are essentially safe for therapeutic use for minor medical ailments/symptoms not requiring medical diagnosis or management. Schedule 3 poisons are those which are substantially safe in use but require professional advice or counselling by a pharmacist. Schedule 4 poisons are those requiring professional medical, veterinary or dental management or monitoring.
At its meeting on 20 - 21 October 2009, the NDPSC is to consider the scheduling of RYR, including a proposal to include RYR “for therapeutic use when not containing more than 0.425 per cent w/w total monacolins and with a recommended daily dose not more than 10 mg total monacolins, in Schedule 3”.
Sylvan applied to the Therapeutic Goods Administration (TGA) for registration of Cholesen capsules under the Act. On 16 May 2008, a delegate of the Minister refused the application (relying on a decision of the Complementary Medicines Evaluation Committee, referred to below), a decision that was confirmed by another delegate, Richard Pembrey, on 10 October 2008. Mr Pembrey said that the data provided for Cholesen “does not sufficiently address the degree of safety associated with the use of this product as a registered complementary medicine”.
On 15 October 2008, Sylvan applied to the Tribunal for a review of this decision.

The Relevant Legislation and Guidelines

Section 25(1) of the Act provides that where an application is made for the registration of therapeutic goods (on the Australian Register of Therapeutic Goods), the goods are to be evaluated for registration having regard to:
(d)whether the quality, safety and efficacy of the goods for the purposes for which they are used have been satisfactorily established; …
There is no dispute as to the quality or efficacy of Cholesen. The sole issue therefore is whether the safety of the goods for the purposes for which they are used has been satisfactorily established.
Rights of review in respect of decisions made under the Act are set out in s 60. Pursuant to s 60(8), an application may be made to the Tribunal for the review of a ‘reviewable decision’, meaning a decision made by a delegate of the Minister on a reconsideration of the initial decision. Section 60A provides that if an appellant lodges new information (as defined in s 60A(8)) in support of an application, the Tribunal may remit the matter to an authorised delegate for a fresh determination (s 60A(3)), but must not otherwise consider that new information in making its determination except where the new information “indicates that the quality, safety, or efficacy of the therapeutic goods is unacceptable” (s 60A(5)(d)).
The TGA has compiled guidelines to assist in the process of evaluating medicines. These include, relevantly:
(a)The Australian Regulatory Guidelines for Over-the-Counter Medicines (ARGOM);
(b)The Australian Regulatory Guidelines for Complementary Medicines (ARGCM);
(c)Australian Regulatory Guidelines for Prescription Medicines (ARGPM); and
(d)The Guidelines for Levels and Kinds of Evidence to Support Indications and Claims for Non-Registrable Medicines including Complementary Medicines and Other Listable Medicines (October 2001) (LoE Guidelines).
The European Medicines Agency Guideline (ICH E1), “The Extent of Population Exposure to Assess Clinical Safety for Medicines Intended for Long-Term Treatment of Non-Life-Threatening Conditions” (revised edition June 1995) (EMA Guideline), has also been adopted by the TGA.
The Complementary Medicines Evaluation Committee (CMEC), which was established by s 52G of the Act, has functions prescribed by the Therapeutic Goods Regulations 1990, including evaluating and reporting to the Minister or Secretary on complementary medicines (Reg 42ZE(1)(a)), and including on whether or not a complementary medicine should be included in the Register (Reg 42ZE(2)(b)).
The CMEC considered the evaluation of Cholesen at its meeting on 22 February 2008 and recommended that Cholesen was not suitable for registration on the Australian Register of Therapeutic Goods. The CMEC:
considered that the manipulation of the growth and harvesting conditions (using a specific strain of fungus and unique manufacturing conditions) resulted in a red yeast rice (RYR) preparation that is significantly different in composition to that of traditional RYR preparations, particularly in terms of statin (monacolin K, monacolin K acid) content. CMEC determined that the safety of the Sylvan Health Pty Limited’s RYR preparation could not be assured based on the traditional therapeutic/dietary uses of RYR and, whilst it was acknowledged that a number of modern RYR preparations may in fact have a similar statin content, the emerging safety issues with some of these products were of concern.
The CMEC determined that there was insufficient data to establish a positive benefit‑to‑risk assessment and to recommend that Cholesen was suitable for registration. The CMEC then invited Sylvan to appear before the Committee to make a short presentation of its case. Sylvan declined to do so. The CMEC recommendation that Cholesen was not suitable for registration was subsequently ratified at its meeting on 18 April 2008.

The Expert Evidence

At the hearing, the Tribunal had before it reports from seven expert witnesses, six of whom (excluding Dr Wlodarczyk) were called to give evidence. Professors Le Couteur, Nestel, Myers, Colquhoun, and Cohen gave evidence concurrently. The Tribunal had expertise in that Professor Johnston holds the honorary position of Director, Research Programs in the Herbal Medicines Research and Education Centre at the University of Sydney and has considerable experience in the chemical characterisation and pharmacological evaluation of active ingredients from natural sources.
Dr John Wlodarczyk, Medical Statistician and Consultant, was not called to give evidence. In his report dated 11 August 2008, he analysed a study undertaken for Sylvan on the lipid‑lowering effect of Sylvan RYR. He said the results of the study “confirm that compared to placebo, full dose Sylvan red yeast rice is effective in changing LDL-C by -20.09% (se = 4.38) after 12 weeks of treatment”. The half dose Sylvan RYR showed approximately half the treatment effect.
Associate Professor David Leach of the Centre for Phytochemistry and Pharmacology at Southern Cross University (formerly the Director of the Centre, which provided a report to Sylvan under cover of a letter from the Manager of the Analytical Division, Ashley Dowell, dated 24 July 2009) gave evidence about tests carried out for Sylvan at the Centre comparing RYR manufactured and marketed by Sylvan Bioproducts, Inc in the United States (US) with Cholesen made by Sylvan in Australia. The results show the composition of the two products to be very similar with some minor variation between the ratios of the ingredients of the two products “consistent with the natural variation that could be expected with natural fungal substances” (letter from Ashley Dowell to Sylvan dated 24 July 2009).
Professors Le Couteur, Nestel, Myers, Colquhoun and Cohen gave evidence concurrently.
Professor David Le Couteur, Geriatrician, Clinical Pharmacologist and General Physician, Professor of Geriatric Medicine, University of Sydney, Director of the Centre for Education & Research on Ageing of the University of Sydney, affiliated with Concord RG Hospital (reports dated 31 March 2009 and 6 August 2009), said the intended use of Cholesen must be taken into account and the fact that it could be used by a large number of people. He expressed concern about the safety of Cholesen, noting that there have been some reports of adverse reactions in the US affecting muscle tissue and the liver. He said there is inadequate data on how Cholesen interacts with other medicines.
Professor Le Couteur considered the results of the Xuezhikang RYR trial in China as “unhelpful” because the composition of RYR is different from Cholesen and, in any event, he considered the adverse drug reaction rate was “unbelievably low”. In his view, there was a need for:
pharmacokinetic data by equivalence against Lovastatin and looking at the additional metabolites that Paul [Professor Nestel] has mentioned. If additional agents are found that have a lipid‑lowering effect, then the pharmacodynamics of that, or the mode of action of that, would need to be addressed. I’d want some drug interaction data and that could be in vitro, and I think a reasonable attempt at the identification of the structure and toxicology of all the constituents of red yeast rice. None of those are a huge deal. Any Western pharmaceutical industry that’s wanting to get into what is a multi-billion market is able to produce such data.

Professor Paul Nestel, Consultant Physician, of Alfred Hospital and the Baker Heart and Diabetes Institute, Melbourne (reports dated 22 March 2009 and 31 July 2009), expressed concern at the lack of evidence about the synergistic effect of the constituents of Cholesen other than Monacolin K and how they affect the concentration of Monacolin K in the bloodstream. Australia has a large vulnerable population, many of whom will require statins and for whom this product will be very attractive. In particular, he noted the higher levels of statins in elderly people and that the Asian population do not metabolise statins as rapidly as Caucasians. However, with adequate patient information and monitoring by a medical practitioner, it should be possible to identify high levels of statins in the bloodstream and any adverse effects will resolve.
Professor Stephen Myers, Principal Investigator and Research Fellow of the Australian Centre for Complementary Medicine Education and Research, a joint venture of the University of Queensland and Southern Cross University (reports dated 29 August 2006, and February 2007), sought to distinguish between complementary medicines, which may have been used for thousands of years, and pharmaceutical medicines, which are mostly new chemical products that undergo a process of study and evaluation. While noting that “I don’t disagree with my learned colleagues that more data is preferable”, he questioned whether it was necessary. He pointed to 96 clinical trials done on RYR, including the Xuezhikang trial, which demonstrate that RYR is “a relatively safe preparation”. No major safety concerns have emerged from these trials. In addition, there is the evidence of its contemporary use in the US, Canada and the United Kingdom (UK) and its long history of traditional use.
In Professor Myers’ view, there is enough safety data to put Cholesen on the market. However, the product should have a warning statement to the effect that if a person experiences unusual muscle pain they should consult their prescriber and that Cholesen should not be taken with other prescription drugs without supervision by a medical practitioner. Further, there is a need for post-marketing surveillance, including a “pharmaco-vigilant study”, to demonstrate the longer term wider public safety of the preparation.
Associate Professor David Colquhoun, Consultant Cardiologist, of the University of Queensland and Medical Director of the CORE Research Group (reports dated 5 August 2008 and 23 December 2008), said it is important that patients take therapy that works. If adherence with the use of a complementary medicine is better than with a pharmaceutical medicine, then patients should be able to use such a medicine. The use of statins and similar products has been a huge benefit for cardiovascular disease and has resulted in a significant reduction in mortality among the elderly who are most risk at risk.
Professor Colquhoun said the risk of adverse effects is very small; 90 percent occur within the first few weeks of use and he had no specific safety concerns in relation to Cholesen beyond those with ordinary statin therapy, noting that because of the inclusion of statins in Schedule 4, Cholesen will only be used under medical supervision. He considered Cholesen “a very good, useful addition” to available medications and said he would monitor the use of Cholesen exactly as he would with other lipid-lowering therapy.
Professor Marc Cohen, of RMIT University (report dated 27 January 2009), acknowledged that there are concerns over adverse reactions to the use of Cholesen but only of the same kind that one would expect generally with statins, which are considered a very safe class of drugs. Those concerns “can be mitigated through appropriate product information, consumer information, warnings on the packet and the appropriate supervision, whether it’s by a pharmacist or by the general practitioner”. Cholesen’s long term safety can only be finally established through post-marketing surveillance.

Is Cholesen safe for the purpose for which it is to be used?

As stated above, the issue to be determined is whether the safety of Cholesen for the purpose for which it is to be used has been satisfactorily established, as required by s 25(1)(d) of the Act.
The Minister contends that there are a number of safety issues in respect of Cholesen. Summarising these, first, Cholesen contains clinically significant levels of Monacolin K, which is known to cause adverse reactions in some people and, because of this, its use should be supervised by a clinician. Second, there is a lack of data as to the long‑term safety of the use of RYR (which has also caused adverse effects), and, in particular, on its effect in the presence of other common prescription medicines. Cholesen differs from traditional RYR in ways that increase rather than decrease the safety risk. Third, there is a lack of pharmacokinetic studies, particularly given the possible synergistic effects of other components of Cholesen, and also a lack of pharmacodynamic studies.
Sylvan contends that statins are the most closely studied, most therapeutically successful and most widely used medications in modern medical practice, and also among the safest. It proposes that Cholesen be used for the reduction of cholesterol and for assistance in maintaining healthy blood/cholesterol concentration, and has told the TGA that it is prepared to negotiate over the indication/claim to be made in respect of Cholesen attached to the product. Sylvan asserts that RYR and Cholesen have been shown to be safe in both clinical trials and real-world usage, and relies on the following evidence:
(a)traditional use of RYR in China and by Chinese communities around the world;
(b)the Xuezhikang RYR trial in China;
(c)US adverse reaction data;
(d)the Lismore trial (this was a study undertaken for Sylvan by the Australian Centre for Complementary Medicine in Lismore on the efficacy and safety of Cholesen); and
(e)UK data from the use of Simvastatin, a close analogue of Lovastatin, available as a pharmacist‑only medicine in the UK in its 10 mg dose form.
Dr Bennett noted that Professors Myers, Colquhoun and Cohen stated that in their view Cholesen is safe for use, although all agreed that some professional guidance and label warning statements should be included with the product. In his report dated 31 July 2009, Professor Nestel stated that if Cholesen was included in Schedule 4 (as a prescription only medicine), he would withdraw his original objections to the product being available for sale because, being available only on prescription, it could “be expected that a patient would be advised about the possible adverse effects of statins, most particularly about the risk of serious muscle damage known as myopathy which in extremely unusual circumstances can be fatal”.

Dr Bennett recognised that Sylvan should address the concerns expressed by Professor Le Couteur. Professor Le Couteur stated that 15 percent of the population have hyperlipidaemia and that because the claim made for Cholesen is a high level claim a high standard of safety is required. (According to the LoE Guidelines, p 5, high level indications/claims are those that relate to serious diseases or disorders or which relate to treatment, cure, management or prevention of any disease, disorder or condition or the treatment of a specific named vitamin or mineral deficiency diseases.) Yet the LoE Guidelines, to which reference is made, are stated to apply to listable rather than to registrable medicines. In any event, Dr Bennett questioned whether a claim that Cholesen reduces cholesterol is a high‑level claim.
Dr Bennett noted that Professor Le Couteur referred to concern over unsupervised use of Cholesen. Yet, statins are now included in Schedule 4, involving supervision by a medical practitioner, and even if RYR is subsequently included in Schedule 3 (after the NDPSC meeting on 20 - 21 October 2009 – referred to in paragraph 7 above), its use will still be supervised by a pharmacist. Professor Le Couteur also expressed concern for those people who become acutely ill with, for example, pneumonia, renal failure or stroke while taking a statin. However, Dr Bennett noted that in such a case the person would already be under medical supervision, and that Professor Le Couteur seems to be overly concerned with process.
Dr Bennett referred to Professor Le Couteur’s comment that because traditional RYR is different from Cholesen, the results of the Xuezhikang study are not directly relevant. However, Professor Myers said that the average Chinese consumes more RYR per day than that contained in the Cholesen preparation. (The Tribunal notes that whether they thereby consumed more statins was not established.)
Professor Le Couteur referred to reports of adverse reactions to the muscles and liver in the US and said that these adverse reactions may be caused by unknown substances in RYR. Dr Bennett noted that even with the enhanced reporting system in the US (after 22 December 2007), the percentage of those experiencing adverse reactions to RYR is miniscule. Professor Leach’s evidence is that the composition of RYR is largely known. To suggest that it is necessary to know the possible clinical effect of every minor ingredient in isolation is to take an extreme position. However, Professor Le Couteur acknowledges that in terms of additional tests, “it would not require too much more effort to achieve satisfaction”.
With regard to other matters, Dr Bennett noted that there has to be a weighing of the risk with the benefits of such medicines. No product is entirely safe for all people and most adverse reactions are dose related. He noted that all the experts agreed that there is better patient compliance with complementary medicines. One of the serious potential side effects of statin use – rhabdomyolysis (the rapid breakdown of skeletal muscle) – is so rare as to be virtually irrelevant. Moreover, while myopathy (muscle wastage) is a possible side effect of all statins, it is of a relatively minor nature resulting in aches and pains which disappear once treatment ceases. Generally, statins are considered very safe. However, there was general agreement among the five experts who gave evidence concurrently that potential adverse effects could be mitigated by product information for patients and warning labels on the product. Ultimately, post-marketing surveillance is the best real-world evidence of safety.
Mr Anforth submitted that the Tribunal, like the TGA, has power, pursuant to s 28(1) of the Act, to impose conditions on the registration of a medicine and could, therefore, determine to impose conditions on the registration of Cholesen such as product warnings, post-marketing surveillance etc. He also noted that the Act draws a distinction between complementary and other medicines, addressing complementary medicines in Part 6-4, where complementary medicines are defined in s 52F, including by reference to ‘traditional use’ (with the example given of Chinese traditional medicine). With regard to the EMA Guidelines, he submitted these apply in respect of ‘new use’ drugs. Cholesen is not such a drug, RYR having been used widely for many years.
In her closing submissions, Ms Allars dealt with four specific issues. The first is clinical evidence of safety. She noted the Xuezhikang trial was for RYR, which differs in composition from Cholesen, and, in any event, Professor Le Couteur considered the adverse drug reaction rate to be “unbelievably low”. The experts agreed that US reporting of adverse events was inaccurate. Because US Sylvan RYR was regarded as a dietary supplement until 22 December 2007, the system did not require the reporting of adverse events. Professor Le Couteur noted, nevertheless, that there had been a number of reported cases of adverse effects with statins including problems with muscles and the liver.
Ms Allars rejected the distinction that Professor Myers sought to draw between pharmaceutical medicines and complementary medicines. This is not a distinction drawn by the Act, which applies in respect of therapeutic goods and devices and applies the same standards of evidence to complementary medicines as other therapeutic goods. Ms Allars said Cholesen has a higher level of Monacolin K than traditional RYR, and contains ‘active’ monacolins, unlike much RYR. Cholesen should not be treated like other complementary medicines which seek listing and not registration, do not make higher level claims and which are not included in Schedule 4 of the Poisons Standard. The Tribunal should apply the relevant policies and, in particular, the LoE, ARGCM, ARGPM and EMA Guidelines.
Secondly, with regard to mechanisms for safety, Ms Allars contended that safety is not established because there is an absence of pharmacokinetic data for Cholesen. She referred to Professor Le Couteur’s and Professor Nestel’s evidence about this and, in particular, to their comment about the need for further drug interaction studies. Cholesen is unlike Lovastatin (a pharmaceutical medicine), because it is a more complex product with a greater potential for interaction with other substances. Ms Allars rejected Professor Myers’ evidence that safety concerns should be mitigated by the long‑term traditional use of RYR, because the composition of traditional RYR is likely to vary significantly from one batch to another and the level of monacolins in such preparations is generally of a lower concentration. Moreover, as both Professors Le Couteur and Nestel recognised, there is a need for further evidence about the pharmacology and toxicology of Cholesen so that its efficacy, when compared to Lovastatin, is better understood.
Thirdly, with regard to the nature of the data required but not yet provided to satisfactorily establish safety, the Minister contends that since Sylvan makes a higher level indication/claim in respect of Cholesen and seeks its registration, the data required to establish safety should be appropriate for a Schedule 4 medicine, and meet a level guided by the LoE and EMA Guidelines. The data required should also include pharmacokinetic data drawing a comparison with Lovastatin and identifying additional metabolites, and data on the pharmacodynamics of the different components of Cholesen, on the interaction of Cholesen with other drugs and on the structure and toxicology of the principal active ingredients of Cholesen. Ms Allars said such information is required in order to properly fulfil the objects of the Act of providing “for the establishment and maintenance of a national system of controls relating to the quality, safety, efficacy and timely availability of therapeutic goods” (s 4).
Fourthly, Ms Allars referred to the role of consumer information, and comments by several experts that concerns about safety could be met by providing product information for consumers, warning labels on the product and post‑marketing surveillance. She submitted that the use of warnings cannot satisfactorily establish the safety of Cholesen for the purposes of s 25(1)(d) of the Act. Rather it is a question of whether the product is safe for its intended purpose. Ms Allars rejected comparisons with Simvastatin, which has been available over the counter in the UK for five years. Professor Le Couteur noted that Australia has a different regulatory system that has determined, currently, that all statins are treated as Schedule 4 poisons. Moreover, as Professor Nestel pointed out, there are differences between Simvastatin and Cholesen that must be taken into account, and, in particular, a different composition and lower concentration of statins.

Consideration by the Tribunal

As stated above, the sole issue for the Tribunal is whether the safety of Cholesen for the purposes for which it is used has been satisfactorily established. The evidence indicates and there appears to be general agreement that the cholesterol‑lowering effects of Cholesen are appreciably higher than can be accounted for by the levels of Monacolin K in Cholesen. Cholesen is more than simply a preparation of Monacolin K (or its prescription drug equivalent Lovastatin), containing Monacolin KA, other minor monacolins, and various other ingredients whose properties, in conjunction with the other ingredients of Cholesen, are not yet well understood.
The Tribunal notes that the LoE Guidelines are stated to apply to Listable and not to Registrable medicines and state that high level indications/claims can only be made for Registrable medicines. The claims made in respect of Cholesen relate to “the treatment, cure, management or prevention” of a serious disease (p 5 of the LoE Guidelines), namely cardiovascular disease, and should therefore be characterised as high‑level claims. Ms Allars also referred the Tribunal to the EMA Guidelines. These provide guidance on the evaluation of studies of medicinal products. The Tribunal, in making its decision in relation to Cholesen, has relied principally on the evidence of the expert witnesses.
In seeking to establish the safety of Cholesen, Sylvan relied on the widespread consumption of RYR in its various forms and thus the widespread ingestion of Monacolin K and other monacolins, particularly in China, without adverse effects. There is, however, a lack of reliable information about the actual levels of monacolins in RYR used in China with reports cited by the Minister even claiming that RYR contained no detectable monacolins: T14 p181; T86 p858. Further, Professor Le Couteur considered the Xuezhikang RYR trial results to be “unbelievably low”. It is reasonable to conclude that traditional preparations of RYR contain highly variable amounts of monacolins. Cholesen, on the other hand, is a quality controlled RYR preparation in which the concentration of the principal ingredients has been standardised. In particular, the level of Monacolin K and Monacolin KA is appreciably higher than in most preparations of traditional RYR.
With regard to the use of similar products in other countries, we note that according to Professor Nestel (transcript 30 September 2009, pp81 and 113), the Simvastatin available and widely used in the UK as an over-the-counter medicine contains significantly lower levels of statins than Cholesen and data on the use of RYR products similar to Cholesen but used as a dietary supplement in the US until 22 December 2007 have, as a result, not been considered reliable in terms of comprehensive reporting of adverse effects. According to Professor Le Couteur, there have nevertheless been some recent reports of adverse reactions affecting the muscles and liver.
Cholesen differs in some important respects from traditional RYR. It is more than simply a preparation of the prodrug Monacolin K and its active metabolite Monacolin KA, possessing as yet unaccounted for cholesterol-lowering properties. We accept the expert evidence, for example that of Professor Cohen, that statins are generally considered a very safe class of drugs and we note his evidence that statins “are currently the most heavily subsidised drug class” in Australia under the Pharmaceutical Benefits Scheme (PBS). However, unlike with pharmaceutical medicines such as Lovastatin, it is the unaccounted for properties of Cholesen that give rise to concerns regarding the long‑term safety of its use, particularly in relation to myopathy (muscle wastage) and, ultimately, in a serious case, possible liver and kidney damage and even rhabdomyolysis (rapid breakdown of skeletal muscle), albeit that this is likely to be extremely rare.
It is not unusual for complementary medicines to have unaccounted for properties. Such medicines often have a long history of widespread traditional use. While traditional preparations of RYR are widely used and readily available, Cholesen is clearly different from these traditional preparations and does not have a history of long‑term use or adequate reporting of any adverse effects.
The enhanced cholesterol‑lowering properties of Cholesen over and above its known Monacolin K content raise significant concerns regarding interactions with other drugs and other ingested products. Professor Le Couteur gave the example of grapefruit juice, the consumption of which can increase the level of prescription Lovastatin (ie Monacolin K) in the blood by 10 to 15 fold. This is the result of components of grapefruit juice slowing the metabolism of Monacolin K in the liver thus increasing the concentration of Monacolin K in the blood. A similar mechanism may be at work with the Cholesen preparation given the various components in this preparation that may influence liver metabolism, particularly by inhibiting the enzyme CYP3A4. Cholesen is reported to include substances that inhibit CYP3A4 and/or the transporter P-glycoprotein, such as sapogenins, citrinin and various coloured polyketide pigments: T 86, p 800; T21, p 185; Professor Le Couteur’s evidence – transcript 30 September 2009, p60.
At its meeting on 22 February 2008 (T 100), the CMEC recommended to the TGA that there was insufficient data to establish a positive benefit‑to‑risk assessment and therefore could not recommend to the TGA that Cholesen was suitable for registration in the Australian Register of Therapeutic Goods. The membership of the CMEC included people with acknowledged expertise in the evaluation of complementary medicines. Nevertheless, the considerable work that Sylvan had undertaken in these studies was recognised. The CMEC noted that “while the sponsor had performed a clinical trial (and addressed some of the deficiencies identified in the earlier application for Listing), the resulting data, on balance, were inadequate to provide an assurance of long-term safety”.
The Tribunal notes that given Cholesen’s intended purpose of lowering cholesterol, and the view expressed by the experts that the community is now often more inclined to take complementary rather than pharmaceutical medicines because of general disillusion with the large pharmaceutical companies, it is likely that, once registered, Cholesen will prove an attractive alternative to pharmaceutical medicines and be used by a large number of people.
We note that all five experts who gave concurrent evidence agreed that Cholesen should have a product warning label to the effect that it should not be taken with other prescription medicines except under supervision. Four of the five experts considered this supervision should be by a medical practitioner while Professor Myers considered supervision by a pharmacist was sufficient. The experts also agreed that the product should include patient information advising that if on taking Cholesen a person experienced muscle pain, the person should immediately consult a medical practitioner. In the Tribunal’s view, warning labels and product information are insufficient to meet the safety concerns relating to Cholesen.
We accept that no medicine will ever be entirely safe and that it is a matter of having regard to the potential adverse effects of a particular medicine for consumers and the community in the context of its intended use and potential benefits. Professor Colquhoun commented on the significant benefits of cholesterol‑lowering drugs for cardiovascular disease, particularly among the elderly who are most at risk. He said that if patients’ adherence to the use of complementary medicines is better than that with pharmaceutical medicines, then the use of such complementary medicines should be open to them.
However, we also note Professor Le Couteur’s opinion that the additional testing required prior to registration is not a ‘huge deal’ and that any company wanting to enter the multi-billion dollar pharmaceutical market should be able to produce such data. In our view, post-marketing surveillance and studies, referred to, for example, by Professor Myers, and to which Sylvan has committed itself once Colesen is registered, while important in providing evidence about widespread use of a medicine over the longer term, are not, at this stage, sufficient to allay safety concerns.
The Tribunal notes that, if registered, Cholesen, because it contains statins, would be classified as a Schedule 4 poison, meaning that it would only be available on prescription by a medical practitioner. However, we note that, at its meeting on 20-21 October 2009, the NDPSC is to consider including RYR in Schedule 3.
While Sylvan has produced a significant amount of data and addressed many relevant issues concerning the composition and use of Cholesen, on the balance of evidence before the Tribunal, we accept the Minister’s submission that further data is required to satisfactorily establish the safety of Cholesen for the purpose for which it is to be used. What is required prior to registration is further data on the composition of Cholesen, the synergistic effects of its ingredients, and the interaction of its ingredients with other substances, in particular:
(a)pharmacokinetic data on Cholesen by equivalence against Lovastatin and the identification of additional metabolites;
(b)the pharmacodynamics of components of Cholesen, in particular in vivo studies of the bioavailability of Monacolin K and Monacolin KA, including whether Monacolin KA has synergistic effects with Monacolin K increasing the retention time of Monacolin K in the bloodstream;
(c)data on interactions of Cholesen with other substances; and
(d)toxicology of known active ingredients of Cholesen.
Thus, the Tribunal has determined that the decision under review should be affirmed.

I certify that the 59 preceding paragraphs are a true copy of the reasons for the decision herein of Mr RP Handley, Deputy President and Professor GAR Johnston AM, Member.

Signed: .................[sgd]..........................................................
A Veness, Associate

Dates of Hearing:  29, 30 September and 2 October 2009
Date of Decision:  23 October 2009
Applicant counsel:  Dr D Bennett with Mr A Anforth
Respondent representative:              Mr M Will
Respondent counsel:  Ms M Allars