Changing details to listed medicines

The TGA/Industry Changes Working Party has been working towards finalising a changes document which describes the steps sponsors need to take to implement a change in information, which may have been relevant to the decision to list the medicine in the ARTG. One of the significant initiatives introduced in this document is a notification process that does not require the change to be assessed or a fee to be paid.

Do environmental chemicals disrupt sex hormones? Separating fact from fiction

Workshop and public lecture on endocrine disruptor chemicals held in Canberra in December 1998

The issue of so-called "endocrine disruptor chemicals" first came to public attention in late 1993. Richard Sharpe (UK) and Nils Skakkebaek (Denmark) published a paper in Nature suggesting that a possible decrease in human sperm counts and apparently increasing incidences of testicular cancer and hypospadias could be due to exposure of male children very early in development to certain synthetic chemicals such as pesticides and industrial chemicals which have the ability to interact with the hormone (or endocrine) system. A television program, 'Assault on the Male', transmitted by the BBC in the UK on 31 October 1993, provided the first public airing of the hypothesis linking some environmental chemicals with sensitive effects on the endocrine system.

However, the public debate didn't really get underway to any significant extent until the publication in the USA in 1996 (1997 in Australia) of the book, Our Stolen Future by Theo Colborn, Dianne Dumanoski and John Peterson Myers. This suggested, on the basis of a review of findings in wildlife populations (including alligators, birds, frogs and mammals), that there is a link between a number of man-made chemicals and a range of hormonal and reproductive effects in animals and humans, particularly disruption of sexual reproduction and development of sex organs. The question of whether such chemicals (and particularly polychlorinated biphenyls and the DDT breakdown product, DDE) are the cause of the increasing incidence breast cancer via an endocrine-related mechanism has also been the subject of much research, particularly in the USA.

There is now an ongoing debate about whether the epidemiological observations can be considered proven and about the likelihood that some chemicals in the environment are the causative agents. At this stage, attention has largely focused on the hazard (that is the observation of adverse effects) without much attention being paid to proof of causation and risk (which together provide an assessment of the probability that these effects are due to chemical exposure).

At the same time that concerns about the adverse effects of synthetic chemicals on the endocrine system were being raised, there have been many reports of beneficial effects of naturally-occurring hormonally-active compounds - particularly phytoestrogens from sources such as soya and red clover - on human health. It is puzzling that chemicals with similar oestrogenic activity could be both harmful and beneficial.

In view of the scientific and public debate, and the need to implement appropriate regulatory controls if some of these concerns prove to be justified, action is being taken at the national and international level to expand the scientific understanding of these issues eg. the formation of the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) in the USA and activities undertaken by the World Health Organisation through its International Programme on Chemical Safety (IPCS) and by the Organisation for Economic Cooperation and Development (OECD), through its test guideline program.

As part of this debate, a Workshop on Endocrine Disruptor Chemicals was held in Canberra on Thursday 10th - Friday 11th December 1998. The workshop, sponsored by the National Environmental Health Forum (NEHF) and the National Research Centre for Environmental Toxicology (NRCET), was largely organised by Drs Les Davies (Manager, Chemical Review and International Harmonisation Section, CNPDB, TGA) and Kevin Buckett (Population Health Division), and utilised the expertise of Professor Iain Purchase, an eminent British toxicologist who travelled to Australia in December 1998 as the British Toxicology Society representative to the annual scientific meeting of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists (Hobart, 13th-16th December).

Professor Purchase, OBE, an internationally renowned scientist, has had a long involvement in the risk assessment of chemicals, and has recently been involved in the preparation of a book for the International Union of Toxicology (IUTOX) on the issue of endocrine disruptor chemicals.

In addition to the Workshop, attended by delegates from a number of government departments, from the chemical industry, from academia, and from community groups, Professor Purchase also presented a public lecture at the Australian Academy of Sciences 'Dome' in Acton, Canberra, at which he addressed the topic, "Do Environmental Chemicals Disrupt Sex Hormones? Separating Fact From Fiction".

Discussion session at the Workshop on Endocrine Disruptor Chemicals (10th-11th December 1998). Professor Iain Purchase is pictured explaining a point during the workshop. Left to Right: Dr Les Davies (one of the workshop organisers); Professor Purchase; Dr Brian Priestly (Scientific Director, Chemicals and Non-Prescription Drugs Branch, TGA).

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New administrative arrangements for minor errors identified during the eligibility review of listed medicines

Industry and TGA have recognised that a new approach is required for dealing with minor errors or omissions identified during the eligibility review of listed medicines. Under the current arrangements, notices proposing to cancel products under Section 30 of the Therapeutic Goods Act 1989 are issued for all incorrect applications, irrespective of the nature of the error.

In certain circumstances, the Listing Unit will now be advising sponsors either by telephone or in writing that information is either missing or incorrect in their applications. Sponsors will then be given an opportunity to submit replacement data or variations, prior to a Section 30 notice being issued.

While administrative rather than legislative action is now possible to resolve certain types of inaccuracies, the overriding goals of the current listing process have not changed. These goals are to ensure the eligibility of the product for listing and accuracy of information in the ARTG.

Under these new arrangements it is expected that the number of Section 30 notices proposing to cancel a listed medicine will be substantially reduced. However, where safety concerns are identified, either a Section 30 notice or actual cancellation will continue to be issued. Guidelines for correcting minor errors and omissions are being prepared in consultation with industry interest groups. They should be finalised in the very near future.

Registration of non-prescription medicines - hints from the evaluators

Sponsors of OTC medicines often work within tight timeframes, particularly with seasonal products such as cough and cold preparations. In these circumstances, delays in the registration process can be frustrating and expensive. This article sets out some suggestions from the OTC Medicines Evaluation Unit as to how these delays can be minimised.

• Pay the correct application and evaluation fees (a schedule of fees and charges is available from the Publications Office)
• Make sure you are familiar with all requirements in the Australian Guidelines for the Registration of Drugs Volume 2 (AGRD2) - especially relating to stability
• Provide a covering letter outlining the context of the application - eg. the reason for a reformulation, the relationship of the product to similar products in the range - and any special features of the application which are not covered elsewhere
• Provide a summary of any data and an explanation of their relevance to the application
• Provide starting material specifications for each ingredient and finished product specifications with details of tests and test methods at release and expiry
• Provide details of stability test methods and validation data supporting these methods including at least accuracy, precision, linearity and specificity. Where relevant, the actual chromatograms and tabulated raw data should be provided
• Provide results of stability testing on at least 2 batches of the formulation proposed for registration together with a summary of the data and an explanation of any unusual results or trends
• If trial batches are used for the stability trials, indicate the size of the batches and the relationship between the method of manufacture of the trial batches and production batches
• If the product contains water, provide results of preservative efficacy testing on at least 2 batches at the end of the stability testing period even if the formulation is self-preserving and does not contain a preservative
• Provide details of microbial content testing at the end of the test period on at least 2 batches showing compliance with TGAL's guidelines (Appendix 3 to AGRD2)
• Make sure your label complies with all regulatory requirements (see the check list at the back of the application form) and that any CMI or PI documents are grammatically correct and consistent with the label and requested indications
• For "variation" applications, highlight differences between the "old" and "new" labels and PI and CMI if they are present. Make sure you include all the assurances specified in the Changes table (Chapter 15 AGRD2)
• Phone an OTC medicines evaluator if you are unsure about any aspect of the application.

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TGA toxicologists advise WHO on cancer assessment

Maintaining adequate controls over carcinogens is a major issue faced by agencies responsible for regulating the availability of pesticides, drugs, food additives and industrial and consumer chemicals. The World Health Organisation, through its International Programme on Chemical Safety (IPCS), plays a lead role in coordinating the international approach to assessing the carcinogenic potential of chemicals.

In January 1998, TGA toxicologist John Dempsey (Chemical Review and International Harmonisation Section, CNPD Branch) participated in a workshop in Hannover, Germany, under the auspices of an IPCS project on the Harmonisation of Approaches to the Assessment of Risk from Exposure to Chemicals. The Harmonisation Project was instituted in 1993 following a recommendation at the United Nations Conference on Environment and Development (UNCED) in 1992. The objective of this project is to improve understanding of the assessment methods and practices used by various countries and organisations so as to develop confidence in, and acceptance of, assessments that use different approaches (convergence being the long term goal). The Hannover workshop recommended the development of an agreed conceptual framework for evaluating the mode of action by which exposure to chemicals results in the formation of cancer. The framework's principal aim is to assist in the analysis of carcinogenicity data obtained in toxicology studies on chemicals.

The Harmonisation Project hosted a workshop on the framework during 16th-18th February 1999, at the International Association for Research on Cancer, Lyon, France. John and his toxicologist colleague Mark Jenner were among an inter-disciplinary group of 30 scientists, who were invited to trial and critique the proposed conceptual framework, and give advice as to its suitability for use by toxicologists working in regulatory agencies. John was a presenter and member of the working group which had planned the workshop, while Mark participated in a "breakout group" that applied the framework to 5 case studies of carcinogenic chemicals and then provided feedback to the plenary session.

Workshop participants suggested a number of improvements to the draft framework, and expressed enthusiasm for trialing the revised version within their national agencies and international fora, including the Joint WHO/IPCS Meeting on Pesticide Residues, Joint WHO/IPCS Expert Committee on Food Additives, the EU (for pesticides), the US Environmental Protection Agency and the Canadian Pest Management Regulatory Agency. Publication of the framework by the WHO/IPCS is envisaged, once sufficient experience has been gained within different organisations.

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Complementary medicines news

Changes to the regulatory status of goods containing selenium

The National Drugs & Poisons Schedule Committee has made a series of recommendations relating to the status of selenium for human therapeutic use. On 18 June 1999 the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP) will be amended to exempt goods containing selenium at a daily dose of 26 µg or less from scheduling requirements. Goods containing more than 26 µg and up to 100 µg selenium per daily dose will become schedule 3 poisons. Goods with more than 100 µg selenium per daily dose will remain as schedule 4 poisons. Later in 1999, another amendment to the SUSDP is expected that will deschedule goods containing up to 52 µg selenium per daily dose when the selenium is in inorganic form.

Once the scheduling status of selenium changes, the Therapeutic Goods Regulations will be amended to allow sodium selenite, selenomethionine and selenocysteine as active ingredients in Listable therapeutic goods, up to a daily dose of 26 µµg. Both Listed and Registered nonprescription medicines containing selenium must carry the following label statements when presented for oral consumption:

In conjunction with these regulatory changes, the TGA also intends to issue declarations under section 7 of the Therapeutic Goods Act 1989 that the following classes of goods are therapeutic goods:

1. Goods for oral consumption consisting of isolated selenium or selenium compounds.
2. Goods for oral consumption containing added selenium or selenium compounds other than those standardised in the Food Standards Code and enteral foods, very low energy diets, medical foods, and special infant formula.
3. Yeast which contains more than 1 milligram selenium per kilogram.

These declarations will take effect from the date of gazettal, expected to be in June 1999.

Colloidal silver is a health risk

Colloidal silver is becoming a significant public health problem because of the proliferation of products and marketing avenues, while in fact, no such products are included in the Australian Register of Therapeutic Goods (ARTG). These products are promoted as containing a special form of silver for use against a large variety of infections and conditions. The colloidal form is claimed to be safer and more effective.

The Complementary Medicines Evaluation Committee found, however, that there is no evidence that colloidal silver behaves differently in the body compared to other silver preparations and little evidence to support therapeutic claims. The silver taken orally is likely to be converted to poorly soluble silver chloride. Long term excessive intake results in agyria (irreversible discolouration of the skin). Silver ions in the blood react with small molecules such as glutathione, inducing metabolic effects such as oxidative stress.

There is no legitimate therapeutic use for colloidal silver when the potential for toxicity is taken into account. Any anti-microbial properties of silver ions, as shown in in vitro studies, have to be put in perspective. Modern antibiotics are more effective and microbes can develop resistance to silver ions just as to antibiotics. The risk to consumers outweighs any value in trying an unsubstantiated treatment.

On the current evidence, colloidal silver products are not eligible for inclusion in the ARTG.

Coumarin

Products containing coumarin from Melilotis officinalis have been affected recently by a statement from the TGA that sponsors must certify that the level of coumarin is below the general cut-off of 10 mg/kg. Coumarin has anti-coagulant activity. The TGA will, however, ask the CMEC for advice about the safety of coumarin and Melilotis officinalis and any other herbs which may contain coumarin. If appropriate, the CMEC will make a submission to the NDPSC as it did for harmala alkaloids.

Scheduled substances cannot be ingredients in Listed goods and thus when a scheduled substance occurs in an herb, that herb is not Listable. The difficulties in administering this legal situation include the uncertainty about the occurrence in herbs and herbal preparations and to what level.

Further, consistent with a risk based approach, exclusion of scheduled substances from the Listed category should not exclude substances which are in fact low risk when present in herbal preparations. Investigation and research is required to determine the actual level of risk of some Listed herbs, which theoretically contain scheduled components.

Echinacea

Over recent months there has been some media attention focussed on Echinacea. There is to be no change to the regulatory requirements for the thousand or more Echinacea products included in the Australian Register of Therapeutic Goods (ARTG). As a result of the recent review of Echinacea by the Complementary Medicines Evaluation Committee, the potential of plant material such as Echinacea to be allergenic is recognised, but additional information is required before action could be taken.

There is insufficient evidence to implicate all Echinacea products in the allergic reactions reported so far. There is insufficient information to uncover a specific cause in the alleged problem products and adverse reports have not always named a specific suspected product.

Echinacea is one of the most widely used and long established herbal preparations in the world. There is currently no clear reason for the emergence of a handful of reported allergic reactions among the widespread uneventful use of Echinacea.

The TGA will maintain an interest in the potential for adverse reactions to Echinacea and allergic reactions in particular.

Harmala alkaloids

Until now, harmine and harmaline have been included in Schedule 9 of the Standard for the Uniform Scheduling of Drugs and Poisons, which meant that any herbs containing these components were not only Registrable, but were prohibited imports also. After a submission from the Complementary Medicines Evaluation Committee, NDPSC deleted this entry and replaced it with the Scheduling of HARMALA ALKALOIDS except in herbs, or preparations, for therapeutic use:

1. containing 0.1 per cent or less of harmala alkaloids; or
2. in divided preparations containing 2 mg or less of harmala alkaloids per recommended daily dose.

This amendment came into effect 19 March 1999 but this date does not affect the Listing of products with herbs possibly containing the alkaloids at this stage. The descheduling of harmala alkaloids provides greater confidence that products are eligible for Listing, which is good news for sponsors.

Products that may contain harmala alkaloids will not be affected until such time as the TGA determines which herbs most likely contain these alkaloids and what will be an acceptable approach to verification that the amounts of harmala alkaloids are below the cutoff levels. The issue of harmine and harmaline as prohibited imports also needs to be addressed.

Herbs containing scheduled substances

The TGA is working on the issues surrounding the possible presence of scheduled components in Listed herbal preparations. The Complementary Medicines Evaluation Committee achieved a descheduling of harmala alkaloids in herbs as described below and will be making further submissions to the National Drugs and Poisons Scheduling Committee (NDPSC) about other herbal components.

Kavalactones

As of 1 January 1999, it is a requirement of Therapeutic Goods Regulations (Schedule 4, Part 5) that the maximum recommended daily dose of Piper methysticum in a product be limited to 250mg of kavalactones. If a product contains Piper methysticum in tablet or capsule form, there is a maximum of 125mg of kavalactones allowed per capsule or tablet, and where P. methysticum is included in teabags, there should be a maximum of 3g dried rhizome per tea bag.

Any product that exceeds the above limits, is no longer eligible for Listing, and must be Registered in the ARTG.

When submitting an application for Listing of a product containing Piper methysticum, sponsors should be aware that it is mandatory to express the equivalent amount of kavalactones for all ingredients from which kavalactones may be derived.

The herbal component name (HCN) "kavalactones (of Piper methysticum)" has been created specifically to be used in this circumstance. In later versions of the ELF it will be possible to select this HCN from the drop down menu. However, until such an update, it will be necessary for sponsors to over-ride the system.

Please note that the ELF already includes the HCN "kawapyrones (of Piper methysticum)" on the drop-down menu. It is not appropriate to use this HCN unless you have a product that contains an ingredient standardised to this specific group of components (details held by the Complementary Medicines Section). In such a case, you will be required to also express the total amount of kavalactones in the product.

Eg:

Piper methysticum rhizome ext. liq. conc. stand.
(10:1 in x% E:W)	amg
EQUIV. Piper methysticum rhizome dry	bmg
EQUIV. kawapyrones (of Piper methysticum)	cmg
EQUIV. kavalactones (of Piper methysticum)	dmg

In addition to the above restrictions, products containing Piper methysticum are required to include the following two label warning statements:

Kava (Piper methysticum), meeting the restriction and carrying these warnings, has been regarded as not requiring inclusion in a schedule of the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP).

New substances recommended by CMEC

Honey and ubidecarenone (coenzyme Q10) will soon be able to be used as active ingredients in Listable therapeutic goods, following recommendations from CMEC.

Honey is to be permitted as a Listable substance without restriction on dose size or total daily dose. However, when presented for oral consumption, goods containing honey must carry a label statement that they are unsuitable for use by infants under the age of 12 months, or words to that effect. This statement is intended to minimise the risk of the rare but serious condition of infant botulism.

Ubidecarenone, commonly known as coenzyme Q10, will be permitted with a maximum daily dose of 150 mg. Following consideration of reports of ubidecarenone interacting with warfarin, CMEC recommended that the following warning statement be placed on the label of all therapeutic goods containing ubidecarenone:

"Do not take while on warfarin therapy without medical advice."

All Listed goods containing ubidecarenone must carry this statement. The TGA is currently consulting with industry groups on issues relating to the adoption of this statement on Grandfathered Registered goods containing ubidecarenone.

Products to be regulated only as therapeutic goods

The following proposals have been prepared under section 7 of the Therapeutic Goods Act 1989 and were advertised for comment in the last TGA News:

• goods containing extracted squalene or labelled or promoted as containing squalene, unless packed or labelled for cosmetic use;
• goods containing the fruit of Garcinia species in tincture, powder, capsule, tablet or pill form;
• goods containing extracted or synthesised hydroxycitric acid or hydroxycitrate, or labelled or promoted as containing hydroxycitric acid or hydroxycitrate;
• goods for oral consumption containing isolated creatine or creatine salts which are not standardised under Standard R10- Formulated Supplementary Sports Foods, of the Food Standards Code; and
• goods containing propolis unless packed and labelled for (external) cosmetic use.

TGA is aware that amendments to the regulations to permit substances to be included in listable products will be sought before declarations are made. The Office of Complementary Medicines conducts safety evaluations of substances involved in proposals with the appropriate input from sponsors.

The following four Section 7 declarations have been made:

• fibre in capsule, tablet or pill form was declared to be a therapeutic good on 24 February 1999. Order No.1 of 1999, gazette GN8 refers;
• goods labelled and promoted for cosmetic purposes when presented for oral consumption packed and labelled for cosmetic use were declared to be therapeutic goods on 1 March 1999 Order No.2 of 1999, gazette S88 refers; and
• shark cartilage, when presented in the form of capsules, pills, tablets or powder, other than as a wholesale product in powdered form for use as an ingredient in food was declared to be a therapeutic good on 14 April 1999. Order No. 3, gazette GN15 refers.
• goods containing, or promoted as containing, isolated HMB (including ß-hydroxy-ß-methy butyric acid) on its salts, when presented in the forms of powders, tablets, capsules or pills were declared to be therapeutic goods on 14 April 1999. Order no. 4 of 1999, gazette GN15 refers.

Amendments were made to Schedule 4 of the Therapeutic Goods Regulations with effect from 1 January 1999 to provide for products containing these substances (except for HMB) to be Listed on the Australian Register of Therapeutic Goods.

In addition the product "Cellasene" and any products containing "Cellasene" were declared to be therapeutic goods on 3 December 1998. Order No. 1 of gazette no S568 of 3 December 1998 refers.