1 CMEC16 Extracted ratified minutes CMEC 16 Complementary Medicines Evaluation Committee Extracted Ratified Minutes Sixteenth Meeting 21 and 22 October 1999 2 CMEC16 Extracted ratified minutes The sixteenth meeting of the Complementary Medicines Evaluation Committee was held at the Sydney Airport Parkroyal Hotel, on the 21st October, and at the Sydney Airport Sheraton Hotel, on 22nd October 1999. Members of CMEC present were: Professor David Roberts (Chair) Mr Nick Burgess Dr Roberta Chow Dr Colin Duke Dr Joachim Fluhrer Ms Val Johanson Dr Stephen Myers Mr Kevin Ryan Prof Tony Smith (22nd October only) Prof Bill Webster Dr Heather Yeatman Members of the Expert Advisory Panel present for discussion of Item 3 of the agenda (Report of the Working Party on Substantiation of Claims) on 22nd October were: Dr Alan Bensoussan Ms Robyn Minski Mr Robert Santich Present from the TGA were: Mr Terry Slater (21st October only) Dr Fiona Cumming Dr John Hall Dr Judy Cunningham 1. Procedural Matters 1.1 Opening of Meeting Professor Roberts, as Chairman, opened the meeting at 1.45 pm on 21st October and welcomed members. 1.2 Apologies Apologies were received from Prof Tony Smith (21st October only), and Mr John Lumby and Dr Rajen Cooppan of the Expert Advisory Panel. 1.3 Conflict of Interest Members submitted conflict of interest declarations specific to agenda items for this meeting. 3 CMEC16 Extracted ratified minutes 2. Confirmation of Minutes of CMEC 15 (24 September 1999) Members ratified the minutes of CMEC 15. 3. Report of the Working Party on Substantiation of Claims The Chairman welcomed members of the Expert Advisory Panel who were attending for discussion of this major agenda item. Recommendation 16.1 CMEC endorses the amended document Standards for levels and kinds of evidence to support claims for therapeutic goods, noting that during the implementation process CMEC may need to further refine aspects of it. 4. Action Arising from Previous Meetings Members considered the action lists for meetings 1–11 and for meetings 12-15, prepared by the Secretariat, and noted the following: • Members were reminded to provide biographical profiles for the TGA’s website. • In regard to the broader use of evaluation papers, extracts of papers, edited to maintain confidentiality, are sometimes sent to individuals on request and the TGA is investigating means to increase availability without unduly straining resources. • The TGA is preparing a briefing paper for the Chair of the working group on herbal medicine matters, to define the scope of this group’s work. • Draft guidelines on sustained release claims for mineral and vitamin products have been placed on the TGA website. • It was noted that the report Towards a Safer Choice is available on the Victorian Government website. 4.1 CMEC14 Meeting 4.1.1 Guarana (item 4.1.3 of CMEC 14 refers) A TGA officer outlined the implementation process for CMEC’s recommendations at CMEC14 in relation to the labelling of products containing Paullinia cupana (guarana). CMEC had recommended that products should carry a declaration that they contain caffeine and that the quantity of caffeine per unit dosage is to be stated. A number of practical problems had emerged in implementing this recommendation but the TGA and industry had negotiated an outcome that is consistent with the spirit of CMEC’s recommendations and 4 CMEC16 Extracted ratified minutes acceptable to industry. A recall to wholesale level is being undertaken for all existing goods containing guarana, to ensure compliance with the new requirements, and the Therapeutic Goods Regulations are being amended to impose the same requirements on all future products. Discussion: A member queried the process for dealing with recommendations for regulatory action that are sent to the TGA, such as the recommendations of the WA Coroner in relation to guarana. In this case, CMEC had made a recommendation concerning the labelling of guarana- containing products prior to the Coroner's consideration of the matter in relation to a specific adverse event. A TGA representative advised that each case is considered on its merits and referred to CMEC when appropriate. Members supported the actions of TGA in this matter and agreed that a declaration of maximum caffeine content per dose (eg “contains not more than x mg”) is acceptable, as the key priority in this regard is to alert consumers to the maximum level of caffeine likely to be present in a product. The presence of caffeine in range of other herbal substances was discussed and members noted that the TGA intends to investigate whether or not the same labelling requirements should be imposed for these other substances. The need for such statements may not simply depend on the total quantity of caffeine per dose of these other herbs, as factors such as tannins in tea may reduce the bioavailability of caffeine. Further, a product such as guarana is likely to be promoted in a different way to, for example, one containing tea. Guarana products are being promoted largely to youth as a stimulant to increase stamina and endurance. 4.2 CMEC13 Meeting 4.2.1 Hydroxycitric acid (item 5.1 of CMEC 13 refers) Members were reminded that at an earlier CMEC meeting they had recommended that hydroxycitric acid and its sodium, potassium and calcium salts as active ingredients be approved for use in listable therapeutic goods. The Regulations are now being amended to permit the use of these substances but in the meantime it has become apparent that magnesium hydroxycitrate has now become available in the US. It is also likely that zinc hydroxycitrate will become available in future. Members were asked to consider the type of information they would need to be able to recommend a broadening of the current permission to encompass the zinc and magnesium salts of hydroxycitric acid. On a broader level, the TGA is examining ways to increase its efficiencies and is therefore seeking ways in which evaluations could be conducted with broadly applicable outcomes or so that subsequent consideration of similar or related substances could be facilitated. Discussion: The parameters that CMEC may need to consider to broaden its existing recommendation relating to hydroxycitrates were discussed. On the one hand, the limited human studies that are available for hydroxycitrates were not conducted with either the magnesium or zinc salts. 5 CMEC16 Extracted ratified minutes On the other hand, zinc and magnesium salts of ascorbic acid and citric acid are permitted as listable actives. If a salt dissociates rapidly in the stomach, then any safety evaluation should primarily consider the anions and cations separately. If both the anions and cations are then approved in the form of other salts (eg zinc in zinc ascorbate and hydroxycitrate in calcium hydroxycitrate) then a recommendation to allow the use of, in this case zinc hydroxycitrate, could be considered. Therefore one aspect that should be considered in a broader evaluation is the rate of dissociation of a salt. Information on the rate of disassociation is generally readily available in reference books. However even if a salt dissociates rapidly, it would still be important to know which ionic form is the therapeutically active one and to know whether or not the other ion interferes with, or is otherwise involved in, any metabolic pathways relating to the active ionic form. Also, some cations may destabilise certain anions, as is the case with iron and ascorbate. Members discussed briefly the general safety of zinc salts. While some Australians consume high levels of zinc, others have inadequate dietary intakes. The effect of taking supplemental zinc on top of diet-derived zinc is difficult to assess. While acute human toxicity has been reported for zinc, chronic toxic levels are not clearly established. The SUSDP requires certain warning statements if a zinc product provides more than 25 mg zinc per daily dose, but consumers of multiple, lower dose zinc products would not receive such advice although they may consume in excess of 25 mg supplemental zinc per day. Members noted that all active ingredients must be declared in the labels of therapeutic goods and therefore if a consumer wished to avoid a particular cation (eg. zinc) they would be able to readily identify whether or not such an ion was present in a product. Recommendation 16.2 Members agreed on the following general principles, in addition to existing requirements, to assist the TGA in the safety evaluation of a group of related salts: • Provided that there is evidence that the anion and cation of a salt dissociate rapidly, the safety evaluation can focus on the anion and cation separately. • A review of the current literature should be conducted to establish what involvement, if any, the cation has in the metabolic pathway of the anion. 5. Evaluation of new substances 5.1 Colloidal silica The TGA evaluator introduced this item and explained that the evaluation had been conducted because an application had been received to use colloidal silica as an active ingredient in a listable good. Although colloidal silica is widely used as an excipient in therapeutic goods, and is also present in some grandfathered, registered goods as an active, its use as an active in listable goods is not permitted under Schedule 4 of the Regulations. 6 CMEC16 Extracted ratified minutes The evaluator indicated that colloidal silica appeared to be of very low risk when consumed orally, although there is little clinical evidence of safety other than the long history of use of colloidal silica as an excipient ingredient and in food processing. However two areas of potential safety concern were identified: the potential for silicosis from inadvertent inhalation of colloidal silica if it were to be presented in the form of a loose powder, and a theoretical potential for drug binding when colloidal silica is consumed in conjunction with other medications. Discussion: Colloidal silica is generally supplied as a very fine particulate, of varying particle size. It was noted that the qualifier 'colloidal' does not mean that the silica is necessarily presented in the form of a fluid colloid; 'colloidal' implies that the substance is capable of forming a colloid. The term 'colloidal silica' encompasses two substances for which specifications exist in the British Pharmacopoeia, colloidal anhydrous silica and colloidal hydrated silica, which has the Australian Approved Name silicon dioxide. Members noted that Australians already have an extensive exposure to silica through dust in the air and through the diet. The safety of silica will depend on the form in which it is presented. Colloidal silica is used extensively as a pharmaceutical excipient and in laboratory procedures. Although it appears to be of low risk when consumed orally, extensive precautions are taken to prevent inhalation in the industrial/laboratory environment. Nevertheless colloidal silica, which is partially soluble in aqueous environments, probably presents a lower risk of silicosis than do the crystalline forms of silica to which miners, for example, are exposed. Members agreed that there do not appear, based on current evidence, to be any significant safety concerns with the oral use of colloidal silica, provided products are not presented in a form (such as a loose powder) where the silica could be accidentally inhaled. Encapsulated powdered silica would be considered to be an acceptable presentation, as the use of a capsule would minimise the risk of inhalation of the powdered contents. If products are not presented in the form of a loose powder then there is no need for any label statements about inhalation risk. As oral toxicity of colloidal silica appears to be very low, members considered that there is no need for any restriction on daily dose or dose size. The potential for binding of pharmaceutical drugs to the surface of silica particles was discussed. A member advised that colloidal silica is used in chromatography in conjunction with non-polar solvents to bind polar compounds. However in an aqueous environment such as the intestines, binding of polar drugs is unlikely to occur. Therefore there did not appear to be a need for a label statement about possible interaction with pharmaceutical preparations. Members agreed on the following recommendation: Recommendation 16.3 CMEC recommends to the TGA that colloidal anhydrous silica and silicon dioxide (otherwise known as colloidal hydrated silica) are suitable for use as active ingredients in listable therapeutic goods, other than in goods where the dosage form is a powder. 7 CMEC16 Extracted ratified minutes 6. Safety reviews 6.1 Fish oils The TGA evaluator introduced this item and outlined the current regulatory framework for fish oils. The evaluator noted that the regulation of fish oils is anomalous compared to other listable active substances, as the Regulations only permit fish oils to be used as active ingredients if: • they are a source of vitamins; or • they are a source of omega-3 marine triglycerides and provided they are accompanied by a statement that the recommended daily intake of omega-3 marine triglycerides is less than 1g. These restrictions are causing a number of implementation problems for the sponsors and TGA, such as: • claims about other components of fish oils (eg squalene) are restricted by the wording of the Regulations; • measurement of triglyceride content of oils is not routine, fatty acids being the most commonly measured component; • there is no Australian recommended daily intake for omega-3 marine triglycerides, and the 1 g per day maximum quoted is no more than would be supplied by a 100 g serve of many fresh fish. Further, the absence of a compositional specification for fish oils has led to problems in interpreting the range of substances that are covered by permission to use fish oil. A few oils have monographs within the British Pharmacopoeia (eg cod liver oil), but most do not. The TGA has therefore developed a draft compositional specification for fish oils and is seeking CMEC comment on it. The focus of the draft specification is on identifying factors that control the safety of these oils, and in defining the sorts of substances that are included under the term 'fish oil'. Discussion: Members agreed that, based on current evidence, interference with blood clotting by omega-3 polyunsaturated fatty acids does not appear to be a significant safety issue. Recorded adverse events do not appear to relate to bleeding disorders. Members agreed that there was no evidence available to suggest that a statement of maximum daily intake of omega-3 triglycerides should be retained, and further that there is no reason why use of fish oils should be restricted to their role as sources of vitamins or omega-3 triglycerides. They therefore agreed that the current restrictions within the Therapeutic Goods Regulations on fish oils in listable goods should be removed. The quantities of omega-3 polyunsaturated fatty acids in a range of fish oils were discussed. All fish oils, including oils from farmed and from freshwater fish, appear to contain high 8 CMEC16 Extracted ratified minutes levels of omega-3 polyunsaturates. Some members highlighted the importance of reliable information on the quantity of omega-3 polyunsaturates in an oil, so that the correct dose can be prescribed. While it is important for efficacy purposes to know the minimum level present, it is the maximum level of omega-3 polyunsaturates that is likely to be important in terms of the safety of fish oils. Members noted that there are a number of production methods for fish oils that can be used to increase the proportion of omega-3 polyunsaturates in the oil. Some of these methods are simple and, in a sense, traditional, such as cold storage of oils to allow saturated fatty acids to solidify and precipitate. Others may involve complex methods of fractionation. While fractionation procedures may be acceptable within the scope of the meaning of the term "fish oil", addition of extra, isolated fatty acids may not be acceptable. Specific industry comment should be sought on the question of "fortification" of fish oils. The draft compositional specifications for fish oils were then discussed. Members identified the following issues as ones that should be addressed in the specifications: • The specification should make clear that the term 'fish oil' refers to oil derived from finfish and does not include oil derived from shellfish. • As fish oils are highly unsaturated they are subject to oxidative rancidity and therefore a specification that relates to degradation should be included, such as a limit on peroxide value. • The limits on vitamin A limits, established via the Standard for the Uniform Scheduling of Drugs and Poisons, should be highlighted. • Comment could be sought on an appropriate maximum level for total omega-3 polyunsaturated fatty acid content. • Comment could be sought on whether a limit should be placed on trans fatty acids, which can be formed during oil processing. • Separate specifications should exist for flesh and liver oils. • Members noted that the draft specification included limits for heavy metals based on those for whole fish contained in the Food Standards Code and that these limits may not be appropriate for oils. Comment should be sought on the need, if any, for heavy metal specifications. • Details on manufacturing process, especially for fortified oils, should be sought. • (Comment should be sought on the need to include any limits on C22:1 fatty acids). • Members queried whether or not the current Food Standards Code pesticide limits, proposed for inclusion in the draft specification, are applicable to fish from shallow marine waters, or to freshwater fish. Comment should be sought on this matter. • Members suggested that the specification indicate which antioxidants are approved for use in fish oils. Members adopted the following recommendation to the TGA: 9 CMEC16 Extracted ratified minutes Recommendation 16.4 CMEC recommends to the TGA that the existing permission within the Therapeutic Goods Regulations to use fish oils as active ingredients in therapeutic goods be amended to remove the requirement that the fish oils can only be used if they are sources of either vitamins or omega-3 marine triglycerides. CMEC also recommends that no daily dose limits or specific label advisory statements be required when fish oils are used in listable therapeutic goods. However, prior to the implementation of these recommendations, CMEC further recommends that the TGA develops compositional specifications for fish oils that are not already covered by pharmacopoeial monographs, and seeks broad comment on these specifications. 9 Matters referred from within the TGA 9.1 Draft compositional specification for royal jelly Members noted a draft compositional specification for royal jelly, prepared by the Complementary Healthcare Council of Australia (CHC), and thanked the CHC for preparing this specification. A member noted the problems for new CMEC members when matters arising from meetings of the former committee were discussed. A request for new members to be provided with copies of earlier CMEC agenda papers was reiterated. A TGA officer advised that progress is being made in making committee papers available electronically. 9.2 Novelty presentation A TGA officer outlined the history of TGA action in regard to presentations of goods in forms that are likely to appeal to young children. Members noted a letter that is to be sent to TGA stakeholders, seeking comments about this matter. The meeting closed at 4.30 pm on Friday 22 October 1999.
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