Australian regulation of clinical trials

Recent legislative changes have identified the need for the TGA to clearly define its roles and responsibilities with regard to clinical trial monitoring and regulation in Australia. In an effort to fully inform stakeholders of the TGA's involvement in clinical trials in Australia, the TGA has released a comprehensive document titled the Regulation of Clinical Trials in Australia.

This draft document is open for public comment until 26 July 2002.

Bioequivalence data for OTC medicines

The Medicines Evaluation Committee, at its meeting in March 2002, recommended that bioequivalence data (or a justification for not providing bioequivalence data), following CPMP guidelines, should be required for applications to register "generic" versions of loratadine and cetirizine solid dose form products. The issue arose following an inquiry from a potential sponsor of products of this nature.

The committee further recommended that the TGA develop a guideline introducing a requirement for data to establish bioequivalence (or a justification for not providing bioequivalence data) to the Australian originator product where that product has been approved by the TGA on the basis of clinical trials and there are no generic products currently on the Australian Register of Therapeutic Goods. This position is consistent with the approach taken by the European agencies and the US FDA for new OTC products.

In accordance with existing practice, the OTC Medicines Evaluation Section will draft the guideline which will then be returned to the MEC for consideration and endorsement. The guideline will then be discussed with relevant stakeholders before being returned to the MEC for final endorsement, followed by publication in AGRD2.

In the meantime, sponsors considering an application to register a "generic" version of an OTC product that has been approved by the TGA on the basis of clinical trials should contact the OTC Medicines Evaluation Section for advice.

Complementary Medicines Evaluation Committee

Professor Tony Smith has been appointed by the Parliamentary Secretary for the Department of Health and Ageing, Ms Trish Worth, as the new Chair of CMEC until April 2005. Professor Smith was Foundation Professor and is now Emeritus Professor of Clinical Pharmacology, University of Newcastle. He was Chair of Pharmaceutical Health and Rational Use of Medicines Committee, Chair of Education Working Group (National Prescribing Service Advisory Group) and member of many State and Commonwealth committees. He has been a member of CMEC since 1999.

The current membership of CMEC and its Panel of Expert Advisers is due to expire soon. New membership is currently under consideration by the Parliamentary Secretary and it is expected that the new appointments will be announced shortly.

In addition to those new complementary medicine substances previously advised this year, the following substances have been recommended to the TGA by CMEC as suitable for use in listed complementary medicines, and are awaiting gazettal: activated charcoal, bovine colostrum powder, bovine colostrum extract, lutein and zeaxanthin.

L-arginine has also been recommended for approval but it will require a change to Schedule 4 of the Therapeutic Goods Regulations to allow its use in listable medicines.

CMEC has expressed concerns about the availability and use of certain colloidal silver products, including the therapeutic claims made for these products. The TGA is actively considering a range of options under therapeutic goods legislation that will address the concerns relating to the use, availability and therapeutic claims made in relation to these products.

European Union guidelines

Since March 2002, nine more European Union guidelines <http://www.tga.gov.au/docs/html/euguideh.htm> have been published as adopted in Australia.

EU Guidelines are generated by the Committee for Proprietary Medicinal Products (CPMP) and International Conference on Harmonisation (ICH) and are to be regarded as part of Volume 1 of the Australian Guidelines for the Registration of Drugs (AGRD).

EU guidelines - launch of "What's Newly Published" Internet page

During the last six months, the EU Guideline pages on the TGA Prescription Medicines Internet site have undergone a dramatic change of format. Following a change of reference from the 1998 volumes of the EudraLex to the current edition, the Adopted Guidelines page was "rejuvenated" with all outdated guidelines removed to a newly created "Replaced & Superseded Guidelines" page.

In May, a "What's newly published <http://www.tga.gov.au/docs/html/euguideh.htm#eugwnp>" page, was introduced to help evaluators and sponsors keep up to date with new additions to the guideline pages. Finally, in June, the Adopted Guidelines page was further modified, by sorting the guidelines into groups, according to headings used in the new European Common Technical Document (CTD).

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Implementation of the Common Technical Document in Australia

In July 2001, the European Commission released an updated version of Volume 2B - the Notice to Applicants - on the "Presentation and Content of the dossier" incorporating the Common Technical Document (CTD). This newly combined document was further revised in May 2002. A portable document format (pdf) copy of the European document can be found on the Pharmacos website http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/index.htm.

Volume 2B is concerned with the presentation of the application dossier. It provides guidance for compilation of dossiers for applications for European marketing authorisations (and by mutual recognition, applications to register prescription medicines in Australia). The combined document takes account of the international agreements on the structure and format of the Common Technical Document (CTD) which was agreed in November 2000 within the International Conference on Harmonisation (ICH) framework. The CTD is an internationally agreed-upon format for the preparation of a well-structured presentation for applications to be submitted to regulatory agencies in the ICH regions.

While the CTD indicates the appropriate organisation of information, it does not indicate what studies are required for a successful application.

The introduction of an internationally agreed format for data submission represents further harmonisation with our overseas counterparts and allows for a simple transition of dossiers submitted to other regulatory agencies.

The CTD is divided into 5 modules:

1. Region specific administrative and prescribing information
2. High level summaries
3. Quality - chemical, pharmaceutical and biological documentation
4. Non-Clinical study reports
5. Clinical study reports

Following consultation with industry, the TGA has drafted an Australian-specific Module 1, details of which are to be published on the TGA's Internet site.

Submissions in the CTD format have already been accepted by the TGA and dossiers in both the "old EU" and new CTD formats will be accepted during the Australian "transition period" of three years (which began in April 2002). During this period, the TGA will also accept mixed applications, but only as per the guidelines in Europe, that is, with no mixture of formats within modules or from expert documentation in Module 2 to subsequent modules.

Further information on the implementation of the CTD in Australian can be obtained by phoning 02 6232 8127.

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Orphan drugs program review

Orphan drug products are drugs, vaccines or in vivo diagnostic agents which physicians use to treat, prevent or diagnose rare diseases. Usually the drugs are not commercially viable. Pharmaceutical companies often do not develop and market such products because the financial return is small compared with the costs of developing and marketing. When no pharmaceutical sponsor has previously submitted an application for registration of a product for this reason, it is known as an "orphan drug".

The TGA initiated the Australian Orphan Drug Program in January 1998 to facilitate the Australian community's access to orphan drugs by providing positive incentives for sponsors to register such products and to remove barriers which may be acting as disincentives to registration.

Following a high-level review of listing arrangements for the Pharmaceutical Benefits Scheme (PBS), Senator the Hon Grant Tambling announced in February 2000 that one of the outcomes was that further discussions on a mechanism encouraging applications for PBS listing of orphan drugs should occur. In order to do this, Tom Hayes AO, consultant, was commissioned to:

1. examine the working of the Australian Orphan Drug Program
2. examine the experience of Australian Orphan Drugs in obtaining access to public funding programs including PBS listing
3. identify options for further consideration that would improve the community's access to effective drugs for rare diseases.

Tom Hayes' report, titled The Orphan Drug Program and Improving Community Access to Effective Drugs for Rare Diseases, was published on the TGA Orphan Drugs Internet page in April 2002, for public comment. The deadline for comment is 28 June 2002.

As a result, the TGA Orphan Drug Program booklet (published in January 1998) is also under review. The booklet has been removed from the TGA website, pending the release of the updated document.

• List of drugs designated as orphan drugs in Australia <http://www.tga.gov.au/docs/html/orphand2.htm>

Policy for the export of medicines from Australia

Following extensive consultation with the peak industry associations, the document Policy for the Export of Medicines from Australia <http://www.tga.gov.au/docs/html/export/exppol.htm> was released on 31 May 2002 on the TGA website. This publication outlines the overarching legislative and policy framework that underpins TGA export-related processes. One of the key aims of this policy document is to provide greater transparency in relation to the decision-making criteria for export medicines, in accordance with the recommendations of the 1998 report Review of the Regulatory Regime for the Export of Therapeutic Goods.

The most significant elements in the policy document are:

• The introduction of the Export Advisory Procedure for communicating information to relevant overseas authorities
• Clarification on the responsibility of sponsors in relation to label warning statements, indications and presentation of medicines for export
• Greater certainty for sponsors in anticipating under what circumstances overseas authorities would be contacted under the Safety Approval Process
• A stronger role for the TGA in acting as a liaison point between exporters and other national or overseas agencies on regulatory matters
• Confirmation on the scope of documents able to be certified by the TGA as part of export certification.

An operational guideline has also been drafted which describes in more detail the administrative processes that support these legislative requirements and policies. This guideline is intended to address commonly asked export questions and to clarify certain requirements and practices which are frequently misunderstood. The guideline is currently with the peak industry associations for comment.

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Updated guidelines for sponsors of OTC medicines

Five chapters of the Australian Guidelines for the Registration of Drugs, Volume 2 (AGRD2) have now been updated following consultation with stakeholders. These chapters are:

• Chapter 2 "Manufacture"
• Chapter 3 "Formulation"
• Chapter 4 "Chemistry and quality control"
• Chapter 5 "Stability testing"
• Chapter 15 "Changes to drug products"

The new guidelines have been published as Supplement 2 (Changes to OTC medicines) and Supplement 3 (Pharmaceutical aspects and quality of OTC medicines) to the AGRD2.

The guidelines have been updated to reflect current evaluation practice as recommended by the Medicines Evaluation Committee while remaining consistent with existing guidelines for prescription medicines. As the revision of the AGRD2 proceeds, further supplements will be published.

The next chapters to be revised will be "Safety" (Chapter 9) and "Efficacy" (Chapter 10). The final document will be published on the TGA website and will also be available for purchase in hard copy as Australian Guidelines for the Registration of OTC Medicines (AGRM). Until this document is published sponsors should continue to refer to AGRD2 in conjunction with Supplements 1 to 3.

WSMI Regulators' Forum 2002 - Tokyo

In 2000, the TGA convened a Regulators" Forum in association with the World Self Medication Industry (WSMI) and the Australian Self Medication Industry (ASMI) 4th WSMI/Asia Pacific Regional Conference in Sydney. The forum brought together regulators from fourteen countries in the Asia Pacific Region. An outcome of the forum was the development of a "Declaration" by participating countries, known as the "Sydney 2000 Declaration".

The forum was well received, and following on from its success, a second regulators' forum will be held at the WSMI 14th General Assembly / 5th Asia Pacific Regional Conference, in Tokyo on 16 November 2002. The "Sydney 2000 Declaration" will be revisited and developed further, to strengthen regional understandings and foster closer cooperation in the regulation of therapeutic goods in the region.

Mr Graham Peachey, Executive Head, Trans Tasman Group, has been appointed as a member of the planning committee for the Tokyo forum. The Committee has met a number of times to develop the program for the Tokyo forum with the TGA playing a prominent role in the development of the program.