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CMEC 35 Complementary Medicines Evaluation Committee
Extracted Ratified Minutes Thirty Fifth Meeting 14 June 2002
Abbreviations:
ADEC Australian Drug Evaluation Committee ADRAC Adverse Drug Reactions Advisory Committee ADRU Adverse Drug Reactions Unit (of TGA) ANZFA Australia New Zealand Food Authority AQIS Australian Quarantine Inspection Service ARTG Australian Register of Therapeutic Goods ASMI Australian Self Medication Industry BP British Pharmacopoeia BSE Bovine spongiform encephalopathy CHC Complementary Healthcare Council of Australia CK Creatine kinase CPK Creatine phosphokinase CMEC Complementary Medicines Evaluation Committee DSEB Drug Safety and Evaluation Branch ELF Electronic Lodgement Facility EP European Pharmacopoeia GRB Geographical Risk of BSE JHTF Joint TGA/Industry Herbal Task Force MEC Medicines Evaluation Committee NDPSC National Drugs and Poisons Schedule Committee OCM Office of Complementary Medicines PBS Pharmaceutical Benefits Scheme SUSDP Standard for the Uniform Scheduling of Drugs and Poisons TGA Therapeutic Goods Administration TGAL Therapeutic Goods Administration Laboratory Branch TSE Transmissible spongiform encephalopathies The thirty fifth meeting of the Complementary Medicines Evaluation Committee was held at the Kingsford Room, Stamford Hotel Sydney Airport, Sydney between 9:30 am and 3:45 pm on Friday 14 June 2002.
Members of CMEC present were:
Professor Tony Smith (Chair)
Mr Nick Burgess Dr Roberta Chow Dr Colin Duke Dr Joachim Fluhrer Ms Val Johanson Professor Stephen Myers Mr Kevin Ryan Professor Bill Webster Dr Heather Yeatman
Present from the TGA were:
Dr David Briggs Dr John Hall Dr John McEwen Ms Michelle McLaughlin
1. Procedural Matters
1.1 Opening of Meeting
The Chairman opened the meeting at 9:34 am and welcomed members and TGA staff.
1.2 Apologies
Members noted that Dr Fiona Cumming was unable to attend the meeting.
1.3 Conflict of Interest
Members submitted conflict of interest declarations specific to agenda items for this meeting.
2. Confirmation of Minutes of CMEC 34 (3 May 2002)
The minutes of the thirty-fourth meeting of CMEC were accepted unanimously as an accurate record of proceedings, subject to a number of amendments:
CMEC – Extracted Ratified Minutes 2 Members made the following recommendation:
Recommendation 35.1
CMEC confirms that the draft Minutes of its previous meeting (CMEC 34, 3 May 2002), as amended, are a true and accurate record of that previous meeting.
3. Guidelines on levels and kinds of evidence to support claims for therapeutic goods (Guidelines)
3.1 Update
A TGA officer introduced this item and indicated that following a meeting between the CMEC Guidelines Working Party and members of the Complementary Healthcare Council of Australia (CHC) Working Group preparing a sponsor guide to the CMEC Guidelines, CMEC Working Party members were asked to comment on the CHC guide. Comments have now been received from most members of the CMEC Working Party. Some issues arose concerning the interpretation of some of the technical terms that were used in the CMEC Guidelines and clarification of some terminology was suggested. The OCM is collating CMEC Working Party comments on the CHC sponsor guide and will forward these to the CHC working group. In addition, the CMEC Guidelines will be amended to clarify the meaning of some technical terminology.
4. CMEC Working Party on Herbal Medicine Issues
CMEC considered a draft of the Stakeholder Consultation Paper Review of the Regulation of Herbal Medicinal Substances. A TGA Officer introduced this item and explained that the Consultation paper last viewed by Members has undergone a number of changes. A professional editor has reviewed the paper and merged the Background paper into the Context paper so there are now three parts rather than four and this has greatly improved the readability of the document. The TGA Officer explained that the discussion document on the Standardisation of Herbal Ingredients has now been included in the Consultation Paper. The Officer indicated that the key aim of the consultation paper is to explore solutions to the problems that have been identified and, if possible identify alternative workable solutions to those suggested in the paper.
CMEC Members recalled that following endorsement by the CMEC, the Consultation Paper will be referred to the TGA with a view to releasing the paper for public consultation.
Members made the following recommendation to the TGA:
Recommendation 35.2
CMEC recommends to the TGA that the consultation paper Review of the Regulation of Herbal Medicinal Substances, as amended, be approved and referred to the TGA.
5. Action Arising from Previous Meetings
CMEC – Extracted Ratified Minutes 3 5.1 ADRU review of Waller report on kava adverse reactions
In introducing this item, a TGA Officer also tabled a letter published in The Lancet that summarised the international situation in relation to adverse events associated with kava (Piper methysticum) containing medicines.
The CMEC was requested to note a report from the Adverse Drug Reactions Unit (ADRU). In reviewing a paper by Professor Donald P. Waller commissioned on behalf of the American Herbal Products Association, it was noted that the paper draws upon only five case histories of adverse hepatic events, out of a total of 26 case reports associated with the use of kava. While the role of kava in producing hepatotoxicity cannot be excluded in the cases examined, in a large number of cases, other causes may be responsible for liver damage. Members noted the current international situation and confirmed the current regulatory status of kava in Australia which was based on cautionary approach and appropriate practitioner and consumer alerts.
5.2 Folic acid
A TGA Officer advised Members that the TGA is currently in the process of implementing the CMEC recommendation (Recommendation 30.11, CMEC30, October 2001) in relation to the introduction of a dissolution standard for certain folic acid preparations.
Members were asked to recall that following a testing program implemented by the TGA Analytical Laboratories (TGAL) last year, approximately 20% of products in tablet form containing 100 micrograms or more per dosage unit tested failed to meet the USP dissolution test. Following industry consultation seeking to determine the practical implications of implementing dissolution studies, the TGA is currently in the process informing sponsors regarding the requirements to be introduced and when they will come into effect.
Ultimately, the TGA intends to amend Therapeutic Goods Order No. 56 General Standard for Tablets, Pills and Capsules to include a requirement for certain folic acid formulations to comply with the dissolution criteria in USP25. A suitable period after the introduction of the requirement, the TGA proposes to undertake a survey of folic acid preparations to determine the extent of compliance in the marketplace.
The CMEC noted the proposed action by the TGA.
5.4 Regulation of Azadirachta indica (neem)
At CMEC 27 (June 2001), the CMEC recommended to the TGA that cold-pressed neem (Azadirachta indica) seed oil is suitable for use in listable therapeutic goods, provided it is restricted to topical application on the skin only, and that certain other conditions are met. The restriction to topical application and the conditions attached to the recommendation were made having regard to the potential toxicity of neem seed oil. Members had considered that the long history of apparently safe use of the preparation (in this form) overcame the lack of well-documented evidence about dermal absorption of the substance.
CMEC – Extracted Ratified Minutes 4 At its February 2002 meeting, the National Drugs and Poisons Scheduling Committee (NDPSC) recommended inclusion of Azadirachta indica and all its extracts and derivatives, for agricultural and veterinary use in Schedule 7 and in Schedule 5 for extracts containing 5% or less of total limonoids for agricultural use of the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP), on the basis of the NDPSC’s concerns about the potential toxicity of neem. The NDPSC also foreshadowed the inclusion of “Azadirachta indica (neem) or its extracts or its derivatives in preparations for human use” in Appendix C of the SUSDP.
Present Discussion:
Members were advised that a major function of the NDPSC is to give guidance and bring uniformity to the way substances are regulated by the States and Territories. The actual power to control access to poisons and the conduct of practitioners resides with the States and Territories.
Members were advised of the important link between the Listing system and NDPSC decisions, such that if the NDPSC changed a schedule, this has the potential to impact upon Listed products. Scheduled substances may not be used in Listed medicines. There is therefore a direct impact on the substances that the CMEC can recommend as eligible for Listing.
With regard to the regulation of Azadirachta indica, consideration of the substance by the NDPSC had occurred following an application to the National Registration Authority for Agricultural and Veterinary Chemicals (NRA) for azadirachtin as an agricultural chemical.
Members were informed that items for consideration by the NDPSC are normally published in the Commonwealth Gazette prior to deliberation, for the purpose of public consultation. Concerned parties are invited to make submissions, which are then considered by the NDPSC before a decision is made. Once a decision has been made, those parties who made an original submission have the opportunity to make second submission before the resolution is confirmed at the following meeting.
When considering the application for azadirachtin at its February meeting, the NDPSC became concerned with regard to the toxicity of neem (Azadirachta indica), and foreshadowed the inclusion of preparations of neem or its extracts or its derivatives in Appendix C of the SUSDP at the next meeting of the NDPSC (scheduled for June 2002).
As a basic principle, CMEC Members considered that for any recommendation regarding a new listable substance, the attention of the sponsor of the substance should be drawn to the fact that if the substance or a constituent of the substance were to be subsequently considered by the NDPSC, the eligibility of the substance for inclusion in listed products may be affected.
In noting that Azadirachta indica (neem) was still under consideration by the NDPSC, the CMEC requested that an addendum be added to the minutes of the previous meeting and of the meeting where neem was first considered (CMEC 27) to indicate that the scheduling of Azadirachta indica, or its extract, or its derivatives, is currently being considered by the National Drugs and Poisons Scheduling Committee (NDPSC) and that the outcome of this
CMEC – Extracted Ratified Minutes 5 deliberation may have implications on the status of cold-pressed Azadirachta indica (neem) seed oil as a potentially listable good.
This recommendation was accepted.
Recommendation 35.3
CMEC recommends to the TGA that an addendum be included with Item 5.1 of the Minutes of CMEC 34 (Regulation of Azadirachta indica (neem)), to indicate that the scheduling of Azadirachta indica, or its extracts, or its derivatives, is still under consideration by the National Drugs and Poisons Scheduling Committee (NDPSC). The TGA will make a decision on CMEC recommendation 27.7 (CMEC27, June 2001) following consideration of scheduling by the NDPSC.
5.3 Red yeast rice
At CMEC 34 (May 2002), Members considered the evaluation of ‘red yeast rice’ as a new listable complementary medicine substance. Members reflected on the discussion held at this previous meeting, and recalled that the substance evaluated was a specific extract of red yeast rice, prepared in a non-traditional manner. This extract appeared to have a much higher level of lovastatin than would be expected in a traditional preparation of red yeast rice. Members agreed that the minutes for Item 6.2 CMEC34, and Recommendation 34.7, should be amended to indicate that the substance evaluated was specifically a red yeast rice extract. This should therefore reflect that the decision did not relate to all red yeast rice substances.
Members confirmed that the possible usage of red yeast rice extract in the treatment of hypercholesterolaemia, did not affect the decision to not permit the substance as a listable substance. The decision not to permit red yeast rice extract for listing was based upon the inadequate data in support of the safety of the particular extract.
6. Evaluation of New Substances
6.1 Emu oil
A TGA Officer introduced this item, which was an application for the use of emu oil as a complementary medicine substance, both orally and topically, in listable medicines.
CMEC Members noted that emu oil is currently registrable as an active for topical application, and is listable as an excipient. Members were advised that there are 14 registered products and 34 listed products containing emu oil included in the Australian Register of Therapeutic Goods (ARTG), primarily in the form of ointments, liniments and creams for topical application. Emu oil is also marketed in the USA and Europe as a dietary supplement and a nutritional food, as well as for topical skincare usage.
Compositionally, emu oil is essentially 100% triglycerides, with a species-specific fatty acid profile. It is approximately 70% unsaturated fatty acids, with approximately 50% oleic acid as the major fatty acid. Members noted that emu oil is similar in composition to some other fats and oils that are commonly used as foods. Emu oil is well characterised, and a draft compositional guideline has been developed. However Members were advised that variation
CMEC – Extracted Ratified Minutes 6 in the composition of emu oil does occur, and appears to be a result of differences in the source of the product, the farming method and the type of rendering process used.
The oil is processed from emu fat using standard manufacturing techniques used in the commercial oil industry. Australian Aboriginals and early explorers and bushmen are reported to have used emu oil, often in the form of emu fat, for healing and for treating pain.
The pharmacokinetics of emu oil is typical of other triglycerides and the available data indicated that emu oil would undergo emulsification, enzymatic transformation, absorption and metabolism similarly to other edible fats and oils.
Members noted the limited toxicological data for emu oil. Most studies undertaken on emu oil relating to its pharmacology and toxicology, were studies of its efficacy rather than directly of its safety. Members were informed that the OCM evaluated these studies from a safety perspective in so far as was possible since evaluation for efficacy is not considered for Listable substance applications.
No toxicity was observed in rats after a single oral administration of 2g, and the individual fatty acids found in emu oil appeared to have low oral toxicity when administered separately to rodent species. No dermal irritancy was observed in limited animal and human studies, and one rabbit skin test suggested that emu oil does not appear to induce acne. There was no data available on the toxicity, genotoxicity, carcinogenicity or the reproductive toxicity of emu oil.
Only one of two adverse reaction reports to the Australian Adverse Drug Reactions database appears possibly associated with emu oil, and this was a case of scalp seborrhoeic dermatitis. There are no reports to the FDA recording system for products containing emu oil and there are no other known cases of adverse reactions recorded for emu oil used topically or orally. According to the product’s Material Safety Data sheet, emu oil is classified as non-irritant to mucous membranes for most skin types.
Members were provided with a copy of the sponsor’s response on the Evaluation Report.
Current discussion:
A member commented on the triglyceride profile of emu oil primarily put forward in the draft compositional guideline. It was noted that all the fatty acids listed in emu oil are well known in vegetable oils and/or as animal fats. The Member noted that emu oil has a relatively high palmitic acid content of 22%, and commented that palmitic acid is associated with raising LDL cholesterol levels, thus is therefore not considered to be a ‘healthy’ fatty acid. Other fatty acids were noted to have either neutral or slightly beneficial status in relation to cardiovascular health, although emu oil does contain 15% linoleic acid, an essential fatty acid. There is also approximately 1% linolenic acid, however, as this is in the alpha form, it is not considered to be an essential fatty acid.
No data were provided to indicate the amount of cholesterol in the oil, which is referred to as ‘low cholesterol’, and Members also noted that comparing the health benefits of emu oil to coconut oil (with a palmitic acid content of approximately 91%), was not appropriate.
CMEC – Extracted Ratified Minutes 7 Members commented on the fact that no definitive evidence was provided on the toxicity emu oil. Members agreed that the components of emu oil are all part of a normal diet, thus despite an absence of animal toxicology data, there would seem to be sufficient evidence in humans that these types of fatty acids may be consumed with no obvious adverse effects, other than the fact that some of these fatty acids might not be considered to be ‘healthy’. Members briefly considered requesting a specific toxicological search for each constituent of emu oil. It was agreed that in the absence of direct evidence, the accepted safety of comparable dietary food-stuffs could provide underlying evidence of safety for emu oil.
Members noted that there could be some as-yet undetected minor constituents in emu oil, commenting that judgement of the suitability of a substance is based upon the presumption that this data is complete.
A CMEC Member observed that under the heading of traditional use, there are three references to the use of emu fat by aborigines for healing and pain control. The Member commented that it would be useful for more details on such references, particularly when there is a need to rely on traditional use.
Members noted that there is a difference from the emu fat traditionally used and the refined oil that is the subject of this evaluation.
Members concluded that Emu oil was suitable for use as an active ingredient in Listable medicines and made the following recommendation:
Recommendation 35.5
CMEC recommends to the TGA that emu oil is suitable for use as an active ingredient in listable therapeutic goods.
7. Safety or Efficacy Reviews
No matters were considered under this agenda item.
8. Registration Applications
No matters were considered under this agenda item.
9. Variation to a Registered Product
No matters were considered under this agenda item.
CMEC – Extracted Ratified Minutes 8 10. Matters referred from within the TGA
10.1 ADRAC Report
Members noted the Report from the 260th meeting of the Adverse Drug Reactions Advisory Committee (ADRAC) on recent considerations of adverse reactions associated with the use of complementary medicines. Members noted several adverse reaction reports.
10.4 Kava
A TGA Officer updated the CMEC as to a testing program that was recommended be undertaken in relation to the presence of a synthetic form of the kavalactone, kavain. The processing of samples has begun.
Members were advised that the TGAL has developed a method for resolving +/- kavain into its enantiomers using chiral chromatography. Kavalactone profiles have been generated for the crude material and these can be used to estimate the quantities per dosage form. Members noted that the question has been raised in the past as to whether the hepatotoxicity observed in relation to kava could be associated with the ‘d’ (synthetic) form of kavain.
11. Recommendation record
CMEC members adopted the following as a summary of the recommendations made at its meeting:
Item 2 Minutes of CMEC’s 34th Meeting
Recommendation 35.1
CMEC confirms that the draft Minutes of its previous meeting (CMEC 34, 3 May 2002), as amended, are a true and accurate record of that previous meeting.
Item 4.1 Working Party on Herbal Medicine Issues
Recommendation 35.2
CMEC recommends to the TGA that the consultation paper Review of the Regulation of Herbal Medicinal Substances, as amended, be approved and referred to the TGA.
Item 5.4 Regulation of Azadirachta indica (neem)
Recommendation 35.3
CMEC recommends to the TGA that an addendum be included with Item 5.1 of the Minutes of CMEC34 (Regulation of Azadirachta indica (neem)), to indicate that the scheduling of Azadirachta indica, or its extracts, or its derivatives, is under consideration by the National Drugs and Poisons Scheduling Committee (NDPSC). The TGA will make a decision on
CMEC – Extracted Ratified Minutes 9 CMEC recommendation 27.7 (CMEC27, June 2001) following consideration of scheduling by the NDPSC.
Item 6.1 Emu Oil
Recommendation 35.5
CMEC recommends to the TGA that emu oil is suitable for use as an active ingredient in listable therapeutic goods.
12. For Information
12.2 Chlorella and Spirulina
Chlorella pyrenoidosa and Spirulina maxima, are currently eligible for inclusion only as non- active components in medicines.
The OCM was requested to amend the excipient status of these two herbs to a listable medicine. Chlorella and spirulina are currently included in approximately 170 products in the Australian Register of Therapeutic Goods (ARTG). Members examined information relating to data on the world spirulina production and consumption and usage data from Australian manufacturers and major contract managers. There is currently limited reviewed safety data, although a search of the ADRAC Adverse Drug Reactions database revealed only one reported adverse reaction to spirulina. A ‘possible’ rating was assigned to this report.
The OCM has recommended that, subject to confirmation of compliance with the definition of ‘designated active ingredient’, and provision of a recent literature search on spirulina and chlorella designed to elicit any adverse effects (or possible safety data), the use of these two herbs in Listed medicines be extended for use as active ingredients in listed medicines.
Members noted from the Health Canada Report that microcystin levels have been tested for spirulina. Members also noted that the amounts of chlorella and spirulina included as excipients in therapeutic goods are at amounts similar to that when they are included as active ingredients.
CMEC noted the OCM recommendation.
13. Other business
There was no other business.
The meeting closed at 3.45 pm on Friday 14 June 2002. The next meeting is to be held on Friday 26 July 2002.
CMEC – Extracted Ratified Minutes 10