Expert committee on OTC medicines strengthened

Senator Tambling, Parliamentary Secretary for Health and Aged Care, has announced the membership of the new Medicines Evaluation Committee (MEC) to advise on the regulation of 'over-the-counter' (OTC) medicines.

"The membership of MEC has now been augmented to include the full range of expertise necessary to accommodate the wide variety of medicines which are sold through pharmacies and other retail outlets. Expertise now includes: medicine, pharmacy, pharmaceutical chemistry, pharmacology, toxicology, law, microbiology and regulatory affairs." Senator Tambling said.

Opening the new committee's first meeting on 6 May 1999, Senator Tambling pointed to the significant place that OTC medicines have in the Australian community.

"It is important that the community continues to have confidence in medicines such as pain killers, cough and cold remedies and other similar products that people can buy over the counter without a doctor's prescription. People need to know these medicines are safe, of high quality and effective. In addition, this is a significant and growing industry sector which provides jobs for over 3000 Australians, with exports and domestic sales in excess of $1.6 billion per annum."

The members of the new Medicines Evaluation Committee are:

Dr Richard Whiting (Chair), Ms Elizabeth Breden, Dr Nicholas Buckley, Ms Bronwyn Capanna, Mr Graham Carnie, Prof Joan Faoagali, Prof Henry Kilham, Mr David Newgreen, Prof Barry Reed, Prof Gillian Shenfield and Prof David Story.

The committee is pictured here with Mr Paul Archer (Secretary) and Ms Allison Rosevear (Executive Secretary). Ms Capanna and Prof Henry Kilham absent.

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International guest lectures TGA staff on new United States cancer risk assessment policy

Dr Bill Chen with Jack Dempsey (TGA)

Cancer is perceived as one of the most dangerous of all diseases, and consequently, maintaining control over carcinogens is a high priority for regulatory agencies responsible for pesticides, drugs, food additives and industrial and consumer chemicals. On 28 April the Chemicals and Non-Prescription Drug Branch of the TGA held a Toxicology Discussion Group meeting dedicated to cancer risk assessment. The meeting featured special guest Dr Bill Chen, Global Risk Assessment Leader of Dow AgroSciences (DAS), and was attended by scientific staff from the TGA, Australia new Zealand Food Authority (ANZFA), and members of the Advisory Committee on Pesticides and Health. Dr Chen presented a lecture titled "Lessons learned in applying the US EPA's proposed new cancer guidelines". There was also a presentation outlining the International Programme on Chemical Safety (IPCS) "Conceptual Framework on Cancer Risk Assessment" by John Dempsey and Mark Jenner, two TGA toxicologists who had participated in the framework's development at a workshop in Lyon in February this year (see "TGA Toxicologists Advise WHO on Cancer Assessment" in TGA News, Issue 29, May 1999).

Dr Chen congratulated TGA on its efforts to encourage international harmonisation in cancer risk assessment. He was highly supportive of TGA's involvement in the IPCS Framework project, and also encouraged Australia to promote the OECD approach to cancer risk assessment, in contrast to the current guidelines used by the US EPA.

Dr Chen discussed use of the new guidelines in analysing the carcinogenic potential of 1,3-dichloropropene (Telone II), a fumigant subjected to a major restriction of use during the 1980s because of its classification as a carcinogen. DAS have changed their original formulation (by eliminating a carcinogenic stabiliser) and performed new rodent carcinogenicity studies.

However, the company was constrained by USEPA policy to use the MTD, which induced late onset benign tumours. Areview by the non-profit organisation TERA (Toxicological Excellence in Risk Assessment) concluded that Telone II acts through direct irritation and not by damaging genetic material, but the USEPAviews it as at least a promoter of carcinogenesis, and has requested DAS to perform more studies. Whichever way the issue is resolved, the outcome may foreshadow future directions in US cancer risk assessment policy and will be of interest to regulators everywhere.

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Towards a national environmental health risk assessment methodology

Participants at the working group

At a state and national level, risk assessments are being undertaken for a wide variety of projects by governments and industry eg. as part of environmental impact statements, cleanup criteria for sites contaminated by chemicals, the public health impact of outbreaks of pathogens, and environmental sources of radiation. Environmental health agencies have to conduct or review such risk assessments and need to be able to appraise their content and approach against a benchmark. A national Health Risk Assessment Methodology document is being drafted to assist the process of regulatory risk assessment, and to enable regulators to appraise risk assessments performed by other parties.

The Scientific Director of the Chemicals and Non-Prescription Drug Branch of the TGA, Brian Priestly and Senior Toxicologist, Jack Dempsey, of the Chemical Review and International Harmonisation (CRIH) Section recently took part in a working group tasked with drafting a Health Risk Assessment Methodology document. The meeting was hosted by the SA Public & Environmental Health Service, with the support of the Environmental Health Unit of the Department of Health and Aged Care, and was held from 31 May to 2 June 1999 in Adelaide. Invitations were provided to a range of risk assessors from regulatory agencies in Australia and overseas, and representatives of industry and the community.

The draft methodology document presents a general health risk assessment methodology that can be applied to a range of environmental health hazards. This first draft of the document had a focus on chemical hazards, but the core methodology can also be applied to physical (eg. radiation) and microbiological hazards, and the methodology document will eventually incorporate specialised 'modules'. The links of risk assessment to risk management and community consultation/risk communication were clearly identified in the first draft.

A preliminary draft document was reviewed by the working group during the three-day meeting, with many discussions helping to clarify contentious issues. The participants included representatives from Greenpeace (Darryl Luscombe) and the National Toxics Network (Marian Lloyd-Smith), who made significant contributions especially to the sections of the document dealing with risk communication, while Deborah Read (ERMA, NZ), Professor Steve Hrudey (University of Alberta) and Dr Hugh Davis (Health Canada) contributed an invaluable international perspective. The working group acknowledged the expertise provided by the Chemicals Unit of the TGA and requested that the CRIH section take the lead in redrafting the entire section of the draft document that deals with hazard and toxicology assessment and its role in environmental health risk assessment. The redrafted methodology document is due out in mid 1999.

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Office of Complementary Medicines news

First meeting of the Complementary Healthcare Consultative Forum

The Complementary Healthcare Consultative Forum (CHCF) held its inaugural meeting on 1 July 1999 at Parliament House, Canberra. The Forum is a Federal Government initiative and, along with the launch of the Office of Complementary Medicines in April, the revamping of the Complementary Medicines Evaluation Committee and the review of the Therapeutic Goods Advertising Code, forms another central component of the package of reforms in the complementary healthcare sector.

Senator Tambling, who chaired the Forum, underlined that its role was to facilitate consultation between government and the complementary healthcare sector.

In opening the Forum Senator Tambling said that the Forum provided members with an opportunity to exchange information and views on broad policy, regulatory performance and other related issues. "This can only serve to facilitate even further the already well grounded consultation between the Government and the complementary healthcare sector," he said.

Membership of the Forum includes representatives from the following areas: complementary healthcare practitioners, consumers, complementary healthcare research, the Complementary Healthcare Council, the Proprietary Medicines Association of Australia, complementary healthcare marketing and advertising, the Australian Medical Association, State and Territory Governments, the Australian Pharmaceutical Advisory Council, the Complementary Medicines Evaluation Committee, the Department of Industry, Science and Resources, the Australia New Zealand Food Authority and the TGA. Two New Zealand observers were also in attendance.

The agenda for the Forum included a wide range of topics relevant to the regulation and operation of the complementary healthcare sector. There was considerable interest in the issue of strategies to stimulate research in the complementary healthcare fields and the role such research can play in promoting greater recognition and acceptance of complementary healthcare modalities in the array of healthcare choices available to consumers. Other issues on the agenda included the review of the therapeutic goods advertising code and the potential benefits of the review for the complementary healthcare sector, and the Government's work towards a National Medicines Policy. With the increased emphasis of the reform package on mechanisms for postmarketing surveillance there was examination of the challenges of enhancing the existing system for monitoring adverse reactions to be more accessible for complementary medicines, given that they are normally considered to be 'low risk' products.

Each of the issues which came before the Forum is to be the subject of further discussion and will include the opportunity for broad community input. The Forum will meet approximately twice a year. A more detailed account of the outcomes of the Forum will be featured on the TGA website in the near future.

Forum participants in discussion at Parliament House

Consumer representative, Lila Notley (centre), from the Northern Territory contributes to the discussions at the Forum. On the right is Iggy Soosay a medical practitioner involved with teaching complementary medicine to practitioners of orthodox medicine and at left is Janne Graham who has served on both the Consumer' Health Forum and the National Health and Medical Research Council.

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Herbal Ingredient Names Committee (HINC) news

Since the December 1998 edition of the TGA News, the following Herbal Component Names (HCNs) have been approved by the Herbal Ingredient Names Committee (HINC):

• resveratrol (of Vitis vinifera)
• tetracyclic oxindole alkaloids (of Uncaria tomentosa)
• pentacyclic oxindole alkaloids (of Uncaria tomentosa)
• furostanol saponins calculated as protodioscin (of Tribulus terrestris)
• flavonoids calculated as baicalin (of Scutellaria baicalensis)
• naphthaquinones calculated as lapachol (of Tabebuia avellanedae)
• kavalactones (of Piper methysticum)
• forskolin (of Coleus forskolii)
• hyperforin (of Hypericum perforatum)

There has also been one new plant part-AAN approved:

• "style and stigma"

Sponsors are reminded to select those herbal component names to be entered into the ELF application form from the drop down menu. If a new (but approved) HCN has not yet been added to the ELF code tables, the HCN should be entered complete, as expressed in the letter of approval: eg "hyperforin (of Hypericum perforatum)"

1999 Edition of the TGA Approved Terminology for Medicines

The 1999 edition of the TGA Approved Terminology for Medicines <http://www.tga.gov.au/docs/html/aan.htm> was released at the end of July. As well as being available in printed form, this reference is also available on CD.

Apart from updating the various AAN lists (Herbal Substances, Plant Parts, Plant Preparations and Herbal Component Names) and the application forms, there have been some changes to the format of the document.

Firstly, all botanical names (AHNs) with the status of "RN" or "registerable new" in the July 1995 Edition) have been removed from the Herbal Substances AAN list. The aim is to avoid confusion about herbal substances which are Listable and herbal substances which may be listable but have not yet been evaluated for safety. Prior to the establishment of the CMEC, unevaluated herbs and herbal substances were regarded as Registrable, at least in the first instance.

Secondly, the introduction to the Plant Parts AAN List and the Plant Preparations AAN List, has been expanded to include some of the background information currently included in the Guidelines to the Expression of Herbal Ingredients in ARTG Applications and on Labels.

Comments and queries should be directed to the Herbal Names Coordinator, Office of Complementary Medicines. Phone: 02 6232 8476 Fax: 02 6232 8577.

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Information survey work of the Office

Other work of the Office of Complementary Medicines includes surveying the available literature on various topics:

• the canavanine content of different parts of Medicago sativa (alfalfa)(L-canavanine has been associated with auto-immune disease in humans);
• the determination of the occurrence of scheduled constituents such as coumarin, melatonin, harmala alkaloids and saffrole in different herbs;
• phytooestrogens in herbs;
• the safety of products called No Tobacco cigarettes; and
• the pharmacology and physiology of caffeine, within and separately from guarana, in humans.

This survey work is as much about verifying the safety of products as identifying potential hazards.

Irresponsible promotion of excess vitamin A consumption

The TGA has recently become aware of some media promotion of mega doses of vitamin A, for example for the prevention or treatment of colds. Daily doses of up to 50,000 IU have been promoted without reference to the teratogenicity and toxicity of vitamin A at high doses. The TGA is calling for a responsible approach from those giving advice to consumers about vitamin intake.

Limits on the amount of vitamin A that can be used in listable goods are imposed through the Standard for the Uniform Scheduling of Drugs and Poisons. Listed goods for internal use may not contain more than 5,000 IU vitamin A per recommended daily dose and must carry the following warnings if they contain more than 100 IU vitamin A per dosage unit:

Whenever vitamin A is recommended to consumers, practitioners and other promoters of complementary medicines should remind patients of the risk of birth defects. The minimum teratogenic dose of vitamin A (as retinol and its derivatives) is not clearly known. Carotenoids, which act as precursors of vitamin A in the body, do not appear to have teratogenic potential. Children may be at greater risk of vitamin A toxicity than adults.

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Introduction of new edition of sunscreen standard

A new edition of the joint Australian/New Zealand sunscreen standard (AS/NZS 2604:1998) has now been published.

The TGA is making arrangements to amend the Therapeutic Goods Regulations to clarify the status of the new edition. However, sponsors may start to market products taking into account the new standard provided they first apply to amend the Australian Register of Therapeutic Goods to accurately reflect the product to be supplied, and the register has been amended accordingly.

Sponsors of sunscreen products already on the Australian market before the publication date (5 October 1998) of the 1998 edition of AS/NZS 2604 are being allowed two years (from October 1998) to amend their products, when necessary, to comply with this latest edition.

The changes to the 1998 edition of the Standard are outlined in detail in the Preface and Foreword to the Standard and can be summarised as follows:

• a revision of the category descriptions, and the inclusion in the Foreword of an explanation of the sun protection factor (SPF) rating system; and
• the term 'sunblock' is referred to in the foreword of the Australian/New Zealand AS/NZS 2604:1998 Sunscreen Standard as a misnomer.

Matters for open consultation

The Office of Complementary Medicines often invites comment from stakeholders on matters being researched or on matters for which the impact on stakeholders should be considered. A stakeholder list is held by the Office and used to send individual invitations. The list includes industry associations and professional bodies. Anyone may ask to be included on the list.

Comments have been sought on matters such as section 7 declarations at the food/medicine interface and reviews of safety of Listable herbal preparations.

Recently, comments were invited on the issue of labelling of listed goods containing squalene, necessary to ensure squalene in medicinal products is low risk. While generally considering squalene to present a low risk to consumers, the Complementary Medicines Evaluation Committee (CMEC) identified two major areas of concern - squalene's potential to affect cholesterol metabolism in humans and the potential for consumers to believe that it can be taken to reduce cholesterol levels. Squalene is an intermediate compound in the conversion of mevalonate to cholesterol. Feeding large amounts of squalene to animals does not generally alter total serum cholesterol levels.

In humans, conflicting results have been obtained. Human cholesterol metabolism is complex and the effects of taking supplemental squalene on cholesterol levels cannot be predicted. In one study, squalene supplementation resulted in a statistically significant reduction in serum total cholesterol and serum LDLcholesterol levels among elderly patients with elevated cholesterol levels. Another study supports the opposite effect.

The relationship between cholesterol and health outcomes is also complex. Elevated serum total and LDL-cholesterol levels have been implicated as risk factors in coronary artery disease. Conversely, very low serum cholesterol levels may also present a health risk to consumers.

Because of the need for consumers of squalene products to be alerted to the potential for effects on serum cholesterol levels, CMEC recommended that some form of advisory statement be used on the label of therapeutic goods containing isolated squalene. CMEC also recommended that the TGA seek comment on this statement prior to squalene being accepted as a listable active substance. The following words were suggested for discussion purposes:

The deadline for comments on squalene was in July 1999.

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New listable substances

Eight new active substances can now be used in listable therapeutic goods following gazettal of an amendment to the Therapeutic Goods Regulations - four forms of selenium, three forms of HMB and a probiotic bacterium.

Sodium selenite, selenomethionine, selenocysteine and high selenium yeast are the four forms of selenium now able to be used, following a recent amendment to the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP). Under the SUSDP, listable goods cannot contain more than 26 micrograms selenium per recommended daily dose. On 19 September 1999, the SUSDP will change again to allow a maximum daily selenium dose of 52 micrograms in listable goods, provided that the selenium is present in an inorganic form (ie as sodium selenite). The 26 microgram limit will remain for organic forms of selenium. Goods containing selenium must carry label statements warning:

• that selenium is toxic in high doses.
• that selenium from dietary supplements should not exceed a daily dose of 100 micrograms.
• that goods containing selenium are not suitable for use by children under the age of 15 years.

Beta-hydroxy-beta-methylbutyric acid ("HMB") and its sodium and calcium salts, are now permitted as active ingredients in listable goods. No specific requirements are associated with the use of these substances. While the Complementary Medicines Evaluation Committee (CMEC) review process established that HMB was of low risk, a corollary to that decision was CMEC's conclusion that current evidence does not support any therapeutic claims for HMB associated with lean muscle mass increase. Potential sponsors who wish to make claims about HMB products are reminded that the Therapeutic Goods Act currently requires applicants to hold efficacy data for listed products.

Bifidobacterium longum strain BB536 is a probiotic bacterium. No specific restrictions are associated with its use in listable goods.

Specification development

Another process involving open consultation to be managed by the Office of Complementary Medicines is specifications development. Where there is no applicable standard in the British Pharmacopoeia it is proposed that a compositional specification be developped jointly by industry and the TGA and approved by CMEC. Specifications are necessary in order to specify exactly what the substance is that has been accepted as low risk. Specifications are required at present for royal jelly, shark cartilage, chitosan, honey and squalene.

The Office in conjunction with industry is also developing a draft specification for hydroxycitric acid at the request of the CMEC, which is concerned about the proportion of a sample present as the lactone. Once a draft specification is developed for hydroxycitric acid, the CMEC will consider its eligibility for use as a Listable substance. The issue of an appropriate specification will now be routinely considered in evaluating the safety of potential new Listable substances.

Submissions relevant to the development of the abovementioned six specifications will be greatly appreciated. Technical information, and other information appropriate for the Office to assess the regulatory impact of any specification, are encouraged and should be sent to Office of Complementary Medicines, PO Box 100 Woden ACT 2606.

The Complementary Healthcare Council has been working on a draft specification for royal jelly, which will shortly be available for wider comment.

These draft compositional specifications will be prepared for consideration and endorsement by the CMEC.

Verification required for the listing of sustained release products

In December 1998 the Complementary Medicines Evaluation Committee (CMEC) recommended that all intending sponsors of listed sustained release products must submit supporting evidence to verify their products release claims. In response to inquiries from Industry on the technical requirements of the required supporting data, the TGA has prepared a draft policy document which outlines how supporting dissolution data should be constructed to confirm the sustained release characteristics of product. CMEC14 will be requested to consider the draft policy in their August meeting and if endorsed by CMEC the document will be circulated for stakeholder comment.