Carmen Langley La Rosa Langley Pty Ltd. Sydney, Australia

Transcription

1 Carmen Langley La Rosa Langley Pty Ltd. Sydney, Australia Australia has a well-developed, rigorous and independent system for pre-market evaluation of pharmaceutical products. This system has extended to matters of quality as well as efficacy and safety, much to the consternation of multinational organisations failing to anticipate the depth and extent of scrutiny conducted by the Australian authorities. Since the Australian government took up responsibility for drug evaluation in the 1960s, community expectations of the quality, safety and efficacy of therapeutic goods, and the scientific ability to satisfy those expectations, have advanced considerably. Today there are some 24,000 drugs and 30,000 therapeutic devices on the Australian market. Despite calls to dismantle the local drug evaluation system, Australia has retained its sovereign decision-making capacity. Whilst approvals in selected overseas countries are noted, traditionally they carry little weight with local decision makers. However, there is a careful comparison of information appearing in approved product information (i.e., summary of product characteristics, labelling, data sheets) from Sweden, Canada and the United States with that proposed for use in Australia. In addition, it is a condition of drug registration approval that rejections or withdrawals that occur in the United States or Canada at any time during or after registration in Australia are notified to the Australian authorities, and that detailed reasons for the rejection are submitted. In common with the situation in many countries, the evaluation process in Australia has attracted criticism in the past for being unduly protracted and prescriptive, and for including a requirement for unique local data requirements and format for presentation of the marketing application. However, following recommendations of the 1991 Baume Review (Baume 1991), application and approval processes have been streamlined to a significant degree such that approval times

2 are now comparable with those of key regulatory authorities. In addition, there is an increasing emphasis placed on international harmonisation of regulatory requirements. Nevertheless, as seen in other countries, some unique requirements or differing interpretations of harmonised requirements prevail in Australia, despite moves towards harmonisation. In Australia the term therapeutic good is used to designate medicinal products for human or veterinary use. The term is given a particular meaning in the legislation, and broadly speaking it includes anything used for the prevention, diagnosis or treatment of diseases and other conditions (such as pregnancy). This broad definition encompasses pharmaceutical products (drugs) of chemical and biological origin, as well as devices and any products that, because of their appearance or the way in which they are advertised or presented, are likely to be considered therapeutic. Herbal and homoeopathic remedies, vitamin and mineral supplements and sunscreens also fall within the scope of the definition. Cosmetics are generally excluded unless therapeutic claims are made in connection with the goods. Foods are specifically excluded, although there is considerable activity and plans to increase regulation in the area of the food/therapeutic good interface. COUNTRY DESCRIPTION The Commonwealth of Australia is a federation comprising six states and two selfgoverning territories with a total population of approximately 18 million. The national capital is Canberra in the Australian Capital Territory where the majority of the headquarters of government departments and regulatory authorities are located. The legal practices and traditions of Australia are heavily modelled on the British system and the country has a so-called "Westminster style" of government (i.e., a two-house or bicameral system). Under the Australian Federal system, each of the States and Territories has its own Parliament and most of the State Parliaments are also bicameral. Members of Parliament are democratically elected representatives of the people. Acts of Parliament are known as statutes and are a means by which Parliament makes new law or changes existing law. Regulations support the Act under which they are made and define conditions and mechanisms through which the Act is put into place. Various departments are defined under the Constitution, as are the laws of Parliament that each department is entrusted to administer. Due to the size and complexity of the legislation administered by each department, for ease of administration Parliament has included provisions in most Acts and Regulations to delegate discretionary and other powers that normally vest in the Minister or perhaps the Secretary of the Department, to more subordinate officers.

3 There are three levels of Government in Australia: 1. Municipal or local government, responsible for matters such as water supply, building regulations, sewerage and garbage; 2. State or Territory government which covers areas such as education and hospitals; 3. Commonwealth (Federal or Australian) government which deals with defence, social security, import controls, major forms of taxation, public health insurance (Medicare) and supply of Pharmaceutical Benefits, etc. The professional practice of medicine and pharmacy and the public hospital system are controlled by the respective States and Territories. Other areas of healthcare, including registration of pharmaceutical products and licensing of manufacturers, are the responsibility of the Federal government. The Commonwealth government is also responsible for Medicare which is a public insurance scheme funded from taxation, and it also regulates private health insurance which is complementary to Medicare. Through Medicare, the Federal government also provides access to subsidised pharmaceuticals under the Pharmaceutical Benefits Scheme (PBS). The PBS accounts for 81 percent of total prescription drug sales, with the hospital sector representing 10 percent of sales and the private prescription market accounting for remaining 9 percent (Owens 1996). The Australian pharmaceutical industry represents approximately 1 percent of the world market for pharmaceuticals. It comprises approximately 120 companies and is dominated by subsidiaries of some of the largest multinational companies. The small number of Australian owned companies includes Faulding, Sigma, AMRAD, CSL and Blackmores. In 1994, the Australian industry made up around 1.3 percent of total employment, 1.9 percent of total turnover and 2.1 percent of total value added1 across the manufacturing sector. In the same year, total sales, including exports, were around $3.8 billion, of which the over-thecounter (OTC) component was around 26 percent. The industry employs approximately 12,000 persons (Owens 1996). Approximately 40 companies have manufacturing facilities in Australia, located mostly in Sydney and Melbourne which are the two largest State capital cities. The activities of prescription drug producers are mainly confined to formulation and packaging, with active ingredients being imported (although there is a small amount of niche production of active raw materials). There are roughly 50 companies manufacturing and distributing OTC products. Australia has a significant trade deficit in pharmaceutical products, with the value of imports twice that of exports. Australia's largest export destination is New Zealand, accounting for some 30 percent of export sales (Owens 1996). Other 'Calculated as turnover, plus the increase (or less the decrease) in the value of stocks, less purchases, transfers in and selected expenses.

4 major export destinations are the United Kingdom, the United States and the Association of South East Asian Nations (ASEAN) group of countries. AN OVERVIEW OF THE REGULATORY ENVIRONMENT Regulation of pharmaceuticals is shared between the governments of the Commonwealth and the state^.^ The Commonwealth (or Federal) government uses direct and indirect means to regulate the quality, safety and efficacy of therapeutic goods supplied in Australia. Direct controls are exercised through constitutional powers over corporations, interstate trade and customs, whereas indirect control is exercised through funding of pharmaceutical benefits under the National Health Act. State governments are responsible for the standard of goods manufactured and supplied by individuals and unincorporated enterprises within their jurisdictions. These controls are exercised, for the most part, through the poisons scheduling systems in each State and through State legislation which is complementary to the Commonwealth Therapeutic Goods Act, Since the introduction of this Federal legislation, there has been greater cooperation between the Commonwealth and State governments so that regulation of therapeutic goods has become more coordinated. A Brief History of Drug Regulation in Australia Historically, responsibility for health and health issues rested with the States and was covered by State legislation. The first State government regulation occurred in 1862 in South Australia with an Act to regulate the supply of medicines. Similar legislation was passed in 1884 by the States New South Wales and Victoria. The Commonwealth government exercised control at a federal level on matters relating to imported goods via the Customs Act, 1901 and the Quarantine Act, The National Health Act, 1953 was the original legislation that empowered the Commonwealth government to have direct responsibility for a number of matters related to the nation's health. This legislation established the National Health Scheme (NHS) across Australia, extensions of which have established Medicare and the PBS in their present form. In more recent times, the Commonwealth Therapeutic Goods Act, 1989 has provided a national system for regulating therapeutic goods. The Present Legislative Controls With few exceptions, therapeutic goods must be included in the Australian Register of Therapeutic Goods (ARTG) before they can be supplied. Persons who import or manufacture therapeutic goods (or have these goods imported or manufactured on their behalf) for supply for human use within Australia, or persons 2uState" refers to State or Territory.

5 who export therapeutic goods from Australia are defined as sponsors under the Therapeutic Goods Act, Further controls are exercised at the State level in relation to distribution and classification of drugs. Registration and Manufacture The Therapeutic Goods Act, 1989 established a single, national system for the control and regulation of therapeutic goods. The objectives of the Act are to safeguard the quality, safety and efficacy and ensure timely availability of therapeutic goods for human use. It also sets standards for the quality of therapeutic goods used in humans and animals. The Therapeutic Goods Administration (TGA) administers the Act in relation to goods for human use.3 The mechanisms used to ensure the quality, safety and efficacy of therapeutic goods are: pre-market assessment manufacturing controls post-market monitoring The major features of the Therapeutic Goods Act, 1989 are: Unless exempt, therapeutic goods for human use that are imported, manufactured in Australia, exported or otherwise supplied within the meaning of the Act must be included in the ARTG in relation to that importer, manufacturer, supplier or exporter. Unless exempt, Australian manufacturers of therapeutic goods for human use must be licensed and comply with principles of good manufacturing practice (GMP). Therapeutic goods supplied for use in humans or animals must comply with relevant standards (e.g., Therapeutic Goods Orders (TGOs) made under the Act, British Pharmacopoeia). The term supply has a broad definition within this legislation. Activities such as supply by way of sale, exchange, gift, sample, advertisement or administration to humans or animals (including testing for safety or efficacy) are encompassed by this definition. Also under the Act, manufacture means to produce the goods or to engage in any part of the process of producing goods, including processing, assembling, labelling, packaging, testing or releasing for sale and component or ingredient of the goods. This interpretation includes certain activities of contractors such as contract sterilising, analytical or microbiological laboratory services and contract packing. Specific licenses are required for individual premises or sites involved in 3Registration of therapeutic goods for animal use is administered by the Department of Primary Industries and Energy (DPIE).

6 these operations. These provisions cover warehousing or storage of the goods as a part of manufacture, but do not include wholesaling from the manufacturing premises (or from other premises), which come under State control. Imported therapeutic goods are also required to meet acceptable standards of manufacture. A distinguishing feature of the ARTG is that it contains two parts, one pertaining to registered goods and the other pertaining to listed goods. Differences in the evaluation processes for registration and listing reflect the varying levels of risk associated with different products. This distinction applies both to pharmaceutical products as well as devices. As a general rule, prescription and some OTC pharmaceuticals are registerable goods and undergo a full evaluation for quality and safety as well as efficacy. These products are identified by an AUST R number on their labels. Unscheduled (or general sale) pharmaceuticals, vitamins and minerals, homoeopathic and herbal preparations are generally classified as listable goods. These are subject to abbreviated assessments with a focus on quality and safety, and are required to carry an AUST L number on their labels. Section 16 (1) of the Therapeutic Goods Act, 1989 describes the characteristics of separate and distinct goods. These characteristics distinguish one registerable or listable product from another for the purposes of the ARTG. If changes are made to any of these aspects, then a new registration is required. Other changes constitute avariation to the registered or listed goods. These defining characteristics are outlined below: a different formulation, composition or design specification a different strength or size (disregarding pack size) a different dosage form or model a different name different indications different directions for use a different type of container (disregarding container size) In addition to ongoing inspection and monitoring of manufacturing plants, the post-marketing monitoring activities of the TGA include sampling of goods on the market and testing for compliance with official standards and agreed specifications, as well as investigation of product complaints by consumers. Adverse reaction reporting is also a large part of the post-marketing surveillance programme. Clinical Trials There is no requirement for clinical trials to be performed in Australia before new or modified products are approved for registration. Also, since 1991, there have been no restrictions to applying for clinical trials in conjunction with applications for registration of a drug. This means that applications for registration of a drug

7 may be accepted while a clinical trial for the same drug is underway or that applications for clinical trials may submitted or notified to the TGA whilst an application for registration for the same drug is under review. Unapproved (unregistered) products may be supplied in clinical trials under special provisions in the Therapeutic Goods Act, 1989 which exempt these products from the need for prior registration. There are two mechanisms by which clinical trials may be initiated in Australia: a Clinical Trial Exemption (CTX) where the goods require approval prior to their use in a trial, and a Clinical Trial Notification (CTN) where only a notification is required to the TGA. Export There is no restriction on the export of therapeutic goods if they are in no way modified from those already supplied within Australia and entered on the ARTG. However, in practice, export goods often do differ in some way from those entered on the ARTG, for example by way of specific labels (say in another language or to comply with the regulations of the importing country) or in respect of a distinct product name. In such cases, the goods intended for export are not identical to those supplied in Australia and require a special listing in the ARTG. This distinction arises due to the definition of separate and distinct goods and due to the conditions of supply under the Therapeutic Goods Act, Therapeutic goods for export and not for supply in Australia must be listed on the ARTG before they can be exported, unless they are exempt goods. Exported goods are not required to comply with the statutory requirements for labelling of the goods supplied in Australia nor are they required to comply with advertising regulations. The goods may also be listed with an export only name which differs from the name applicable to the same goods as supplied within Australia. Export only goods are allocated an AUST L number, although there is no requirement for this number to be displayed on the label of those goods. Reimbursement Reimbursement and registration are two separate activities which are governed by different legislative instruments. The steps involved in registration and entry into the ARTG under the Therapeutic Goods Act, 1989 are a prerequisite for applications for reimbursement under the National Health Act, The Pharmaceutical Benefits Branch (PBB) of the Department of Health and Aged Care (DHAC) is responsible for the administration of the PBS of the National Health Act, The TGA, although part of the DHAC, is not involved in any aspect of assessment of applications for reimbursement. The nationally funded PBS ensures access to subsidised pharmaceuticals for patients in the general community. However, public hospitals come under State control. Therefore pharmaceuticals supplied to hospital patients are almost exclusively funded via State tendering mechanisms.

8 Drugs and Poisons Scheduling Australia is unusual in that the scheduling (classification) of therapeutic substances takes place separately from their registration. At present, the Commonwealth Therapeutic Goods Act, 1989 does not deal with the scheduling of drugs and poisons. Under the Australian Constitution, scheduling is a State function. The Commonwealth prepares and publishes the Standard for Uniform Scheduling of Drugs and Poisons (SUSDP) in the interests of promoting uniform scheduling of dangerous substances, including drugs, throughout the country and to promote uniform packaging and labelling requirements. Thus the SUSDP has no legal standing in its own right but serves as a model for the States. The SUSDP is derived from the recommendations of the National Drugs and Poisons Schedule Committee (NDPSC) regarding the classification of drugs and poisons for inclusion into State legislation. The committee is made up of relevant experts as well as representatives from each State and from New Zealand, as well as industry and consumer representatives. The SUSDP is also responsible for the harmonisation of Australian and New Zealand labelling and packaging requirements for drugs and poisons. The States have each developed their own mechanisms for adoption of the SUSDP, and in most cases, classification of individual substances is uniform in all States. Drugs and poisons are included in schedules for the purposes of classification. These schedules reflect different levels of risk or the need for professional advice on the use of products within the classification. The term OTC in Australia (and also New Zealand) has a peculiar meaning in that there are several levels of OTC availability via pharmacies or licensed dealers (for poisons), whereas an unscheduled item may be sold freely in supermarkets and other general sales outlets. The principal schedules relating to human use pharmaceutical products are found in Table 1. Table 1. Principal schedules relating to human use pharmaceutical products. Schedule Pharmacy Medicine Pharmacist-Only Medicine Prescription-Only Medicine Controlled Drug S2 S3 S4 S8 Description OTC medicines sold through pharmacies and advertised to the public. Medicines which can be sold directly by pharmacists without prescription and cannot be advertised to the public. Medicines which are available with the prescription of a doctor, dentist or veterinarian. Advertising to the public is prohibited. Narcotics and drugs of abuse available only with prescription and require other special controls.

9 In general, all new chemical entities or compounds not previously available in Australia are first classified as prescription-only medicines. In the light of experience and depending on their use, they may be made available as OTC medicines with gradually decreasing levels of controls. Procedures for switch submissions will be discussed later in this chapter. Distribution of pharmaceuticals is also controlled by State-based licensing arrangements for wholesalers, hawkers and community pharmacies. Many of these licenses are issued under State Drugs and Poisons scheduling legislation. It is possible that the Commonwealth Therapeutic Goods Act, 1989 could be replaced by a new Therapeutic Goods and Poisons Act which would contain a new part dealing with the control and scheduling of drugs and poisons. This would integrate drug registration and classification activities and further streamline regulatory controls. REGULATORY AUTHORITIES Department of Health and Aged Care (DHAC) The Department of Health and Aged Care (DHAC) is a large Federal department which is responsible for many areas of legislation that have a direct and indirect effect on the pharmaceutical industry. The department is headed by the Minister for Health and Aged Care who is supported by Minister for Aged Care, a Parliamentary Secretary and an Executive. The Executive is comprised of a Secretariat, a Principal Medical Officer and Deputy Secretaries. There are a number of divisions which make up the DHAC, including the TGA and the Health Access and Financing Division (See below). The divisions of the DHAC report to the Minister through the office of the Secretary to the Department. For administration, evaluation and reporting purposes, the services provided by the Health and Aged Care portfolio are delivered through a variety of programmes. The Health Advancement Programme includes the services of the TGA. Therapeutic Goods Administration (TGA) Drug evaluation has been conducted in Australia for many decades, however, these services were formerly ascribed directly to the Department of Health. In 1990 the TGA was established as the national therapeutic goods control authority. The TGA is the key division of the DHAC concerned with the actual registration process. The TGA has an objective to ensure the safety, quality and efficacy of therapeutic goods available in Australia at a standard equal to that of comparable countries, and that pre-market assessment of therapeutic goods is conducted within a reasonable time. The TGA adopts the following strategies to meet these objectives: Regulatory reform Pre-market assessment procedures that ensure a balance between product safety and timely availability

10 International harmonisation of regulatory procedures and requirements Manufacturing standards enforced through licensing of all manufacturers and suppliers of therapeutic goods Comprehensive post-market monitoring systems Effective communication and consultation with public health, industry and consumer organisations Systems for the international sharing of regulatory information Cost recovery linked to improved service levels The TGA is made up of six branches: Drug Safety and Evaluation Chemicals and Non-Prescription Drug Conformity Assessment TGA Laboratories TGA International Services Business and Services It is important to note that separate branches of the TGA are responsible for prescription drug evaluation, OTC drug evaluation, regulation of therapeutic devices and compliance issues. There are approximately 350 staff involved in TGA operations. The offices and the laboratories are located at Syrnonston in Canberra. Some evaluation work is contracted to external organisations, such as academic and teaching institutions. The Therapeutic Goods Act, 1989 defines which classes of goods are to be evaluated by the Drug Safety and Evaluation Branch (DSEB) by means of Schedule 10 (Part 1) of the Regulations to the Act. The scope of this authority extends beyond a simple distinction of prescription or OTC status, and includes high technology products and specialised dosage forms, regardless of the classification of the drug in the dose form. The drug products that are currently evaluated by the DSEB are outlined below: therapeutic goods containing a substance mentioned in Schedule 4,8 or 9 to the SUSDP (and new substances meeting the criteria for inclusion in these schedules) medical gases all injectable drug dosage forms vaccines and allergens (other than allergens for skin patch testing on unbroken skin)

11 biotechnology products blood products (unless coated on a therapeutic device) and immunoglobulins radiopharmaceutical and radio contrast agents (other than barium sulphate preparations for radiological use) peritoneal dialysis and haemodialysis solutions irrigation solutions special dosage forms such as transdermal systems and osmotic pumps; therapeutic devices that depend on release of a substance for some or all of its action products referred to the DSEB by another branch of the TGA Non-prescription goods (and those meeting the criteria for OTC status) are handled by the Chemical and Non-Prescription Drug Branch (CNPDB). Applications to register new OTC medicines are handled by the Scheduling and Over-the- Counter Section, whereas applications for listable goods and those for new complementary medicines are handled by other sections within the same branch. Further details on specific products or substances are provided in Parts 2 and 3 of Schedule 10 of the Regulations. Health Access and Financing Division The Health Access and Financing Division of the DHAC includes the PBB which is responsible for the administration of the PBS. The objective of the PBS is to enable access to necessary therapeutic substances at the lowest cost to government and consumers consistent with reliable supply. The scheme is subject to the following strategies: A positive list of cost-effective, necessary medicines Controls over the unit costs of benefits Use of community pharmacies as the main distribution system Improving the quality use of medicines Ensuring prescribing decisions involve cost considerations (general practice reforms)

12 Advisory Committees The activities of the DHAC in general and those of the TGA and Health Access and Financing Division in particular are complemented by a number of advisory committees. The following discussion gives a brief introduction to some of the key advisory committees with more direct involvement with registration, reimbursement and scheduling matters. Most of these committees have a statutory basis (they are constituted under an Act of Parliament). Australian Drug Evaluation Committee (ADEC) The Australian Drug Evaluation Advisory Committee (ADEC) is a statutory committee originally established in the 1960s and also under Regulations to the Therapeutic Goods Act, The functions of the committee are to make medical and scientific evaluations of any drugs referred to it by the Minister or the Secretary and to evaluate any drug that the Committee considers necessary in the interests of public health. In practice, following the evaluation of new drugs by the DSEB of the TGA, ADEC receives summaries on the quality, safety and efficacy of the drug. ADEC then makes a recommendation in the form of advice to the Delegate of the Secretary, who is a senior medical officer within the DSEB. It is the Delegate who has the final responsibility of approving or rejecting the application, and of determining the conditions and indications for the approved use of the drug. Following approval (which is called and approval to register), the drug can be entered on the ARTG. ADEC has 6 or 7 core members and between 10 and 20 associate members, all of whom are appointed by the Minister. Of the core members, at least 3 must be eminent medical practitioners and at least 1 must be a specialist in clinical medicine. In addition, at least 1 core member must be a pharmacologist or a specialist in pharmaceutical science. Associate members complement the skills and expertise of the core members. ADEC has established key subcommittees and a number of specialist working parties to assist in the work of the committee. Each consists of one or more ADEC members and other relevant experts. The functions of several of these committees will be discussed below. Adverse Drug Reactions Advisory Committee (ADRAC). This committee is serviced by the Adverse Drug Reactions section of the DSEB of the TGA. ADRAC encourages healthcare professionals and companies to report all suspected adverse drug reactions. Reports are made directly to the TGA on specified forms or to companies who in turn, as a condition of registration, must advise the TGA in accordance with local requirements. ADRAC publishes and widely circulates clinical details of adverse reports in the Adverse Drug Reaction Bulletin. Detection of serious problems can lead to drug recalls, to cancellation of registration, amendments to the approved product information or other regulatory measures.

13 Pharmaceutical Subcommittee (PSC). The PSC reviews the chemical and pharmaceutical issues, including bioavailability and bioequivalence for each application before consideration by the full committee of ADEC. In effect, it is the PSC which makes recommendations on behalf of the ADEC in relation to pharmaceutical aspects of applications being proposed for registration. The PSC also advises ADEC on matters of policy in the pharmaceutical area and acts as arbitrator between the TGA and an applicant who objects to a TGA request for bioequivalence data in certain types of abridged applications. Medicines in Pregnancy Working Party. This is an ad-hoc group whose principal function is to generate a national guide on the categorisation of drugs used in pregnancy. The booklet, entitled Medicines in Pregnancy-An Australian categorisation of risk of drug use in pregnancy, was first published in The third edition was issued in 1996 and a new edition was anticipated at the time of writing (mid 1999). Medicines Evaluation Committee (MEC). In simple terms, the MEC can be considered the equivalent of the ADEC in terms of applications for OTC medicines which are evaluated by the CNPDB of the TGA. The MEC consists of medical and pharmaceutical experts and includes industry representation. Until mid 1997, the MEC operated through a contractual arrangement with the Victorian Department of Human Services. The committee has had a long historical connection with drug registration and regulation in Australia through the former Victorian system of registration of proprietary medicines which operated in that State since the 1950s. The TGA has since assumed full responsibility for evaluation of OTC products, including the activities of the MEC. The CNPDB now includes an OTC Drug Evaluation Unit. A new MEC is to be established by the Minister as a statutory committee under the Therapeutic Goods Act, 1989 and until this legislation is in place, there will be a transitional committee advising the TGA. Complementary Medicines Evaluation Committee (CMEC). The CMEC was established in 1997; a Traditional Medicines Evaluation Committee (TMEC) had been established by the Minister to provide expertise for the evaluation of non-prescription traditional medicines and advice on their registration. Whereas ADEC and MEC had a long history prior to the enactment of the Therapeutic Goods Act, 1989, there was no committee to handle traditional and alternative medicines which. came under regulation for the first time with this Act. Although the TMEC was not a statutory committee, its role was to advise on quality and manufacture of traditional and alternative medicines, their pharmacognosy and toxicology and their clinical use. In practice, the committee formed a broad advisory role rather than a substance-by-substance evaluation role. In recognition of the potentially greater role of this committee and following recommendations of a review of the TGA (KPMG 1997), the Government directed that the TMEC be disbanded and replaced by a new committee, the CMEC. This new body held its first meeting in December, 1997, and after more than 12 months

14 of operation, in March 1999 the CMEC became established as a statutory committee under the Therapeutic Goods Act, CMEC has met regularly since its first meeting in The committee's membership is wider than that of the TMEC and includes experts in nutrition, complementary and traditional medicine, orthodox medicine, toxicology and chemistry, as well as people with experience in consumer issues and the regulation of foods and drugs. CMEC's function is to provide advice to TGA on matters pertaining to safety of new complementary medicines and substances, and to provide postmarket reviews of certain products and substances. The CMEC now works in conjunction with the ADEC and the MEC, thereby ensuring independent expert advice across the range of medicinal products. This committee is supported by the Complementary Medicines Section within the CNPDB of the TGA. Therapeutic Devices Evaluation Committee WEC). TDEC is a statutory committee established under the Regulations to the Therapeutic Goods Act, Its functions are to advise on registration of medical devices. This committee advises on policies and priorities rather than the registration of individual devices. Individual device registration is handled within the Medical Devices Section of the Conformity Assessment Branch (CAB) of the TGA. However, unusual or controversial matters are referred to the TDEC. The membership of TDEC reflects the wide range and diversity of therapeutic devices. The committee establishes subcommittees and advisory panels to address particular matters of interest. Therapeutic Goods Committee VGC). The TGC is a statutory committee established under the Therapeutic Goods Act, 1989 to advise the Minister on standards for therapeutic goods. The committee also establishes standards for labelling, packaging and manufacturing practices. After consideration, the committee advises the Minister whether the standards, known as TGOs should be adopted. Membership of the TGC includes representatives of the prescription, non-prescription and alternative medicines industries, the medical device industry, consumers and a range of clinical, pharmaceutical and biological scientists. Pharmaceutical Benefits Advisory Committee (PBAC). This committee was established in the 1950s under the National Health Act, 1953 to advise the Minister on the listing of products eligible for subsidy as pharmaceutical benefits under the PBS. Like the ADEC, it is a statutory committee and consists of six medical practitioners, a pharmacist, a clinical pharmacologist and a DHAC pharmacist, each of whom is appointed by the Minister. In general the committee will not recommend listing of products in the PBS other than those registered. In making its recommendations on the suitability of drug products for subsidy, the PBAC considers the clinical effectiveness, cost effectiveness and clinical place of a product compared to other products already listed in the PBS for the same or similar indications. Where there is no listed alternative, the comparisons are made with standard medical care or the committee examines the benefits for patients that the new product will provide compared to the cost of achieving those

15 benefits. Matters of pricing are determined by the Pharmaceutical Benefits Pricing Authority (PBPA) which, after taking advice from the PBAC, recommends to the Minister the prices of pharmaceuticals listed on the PBS. The PBAC is assisted by subcommittees such as the Drug Utilisation Subcommittee (DUSC) and the Economics Subcommittee (ESC). DUSC monitors the patterns and trends of drug use and makes such utilisation data publicly available. The ESC advises on cost-effectiveness aspects of submissions to the PBAC. National Drugs and Poisons Schedule Committee (NDPSC). For many years the NDPSC has been a Standing Committee of the Australian Health Ministers Advisory Council (AHMAC) and its membership is appointed by AHMAC. More recently, this committee was established as a statutory committee under the provisions of the Therapeutic Goods Act, The structure and functions of this committee were outlined in the previous section. REGULATORY REQUIREMENTS AND PROCEDURES The following section will outline the procedures and data requirements for registration of pharmaceutical products in Australia. The requirements for device registration will not be covered. It should be noted that Australia has entered into a Mutual Recognition Agreement (MRA) with the European Union (EU), and the requirements and procedures for registration of devices are undergoing a great deal of change. Applications via Drug Safety and Evaluation Branch (DSEB) The Drug Safety and Evaluation Branch (DSEB) evaluates applications for initial registration and for variations in relation to products listed in Part 1 of Schedule 10 to the Regulations of the Therapeutic Goods Act, This schedule includes prescription products and certain classes of non-prescription products considered to carry a higher level of adequate risk than other non-prescription drugs. Data requirements and presentation details are given in the Australian Guidelines for Registration of Drugs, Volume 1 (AGRD1). The evaluations are carried out under legislated timelines, with the evaluation fees paid by the sponsor (i.e., applicant). Applications fall within one of three categories based on the type of information submitted for evaluation. Category 1 This category includes applications for new products or variations to existing products. They are required to be: accepted or rejected for evaluation within 40 working days of receipt evaluated in 255 working days

16 Applications which do not meet the criteria for one of the other two types of applications are by default Category 1 applications. Category 2 This category includes applications for new products or variations to existing products which relate to goods having recent evaluation reports from 'acceptable' countries (e.g., Canada, United States, United Kingdom, Sweden, Netherlands) that have independently evaluated and approved the identical product. They are required to be: Category 3 accepted or rejected for evaluation within 20 working days of receipt evaluated in 175 working days This category includes applications to vary the information on an existing product, relating only to minor changes in pharmaceutical data and which, in the opinion of the Secretary, do not need to be supported by clinical, preclinical or bioequivalence data. There is a single processing period which begins on the day of lodgement (provided the correct fees have been paid) and the application must be decided within 45 working days. If the TGA raises an objection, the application must be decided within 30 days of the applicant's response to the reasons for the objection. In addition to variations which fall into the classification of Category 3 applications, the DSEB has established a mechanism for self assessment, with or without notification, for changes to some aspects of pharmaceutical data in a variety of circumstances. Provided certain specified conditions are met, such as the generation of experimental validation data, then certain changes may be implemented without prior approval. These permitted changes and their relevant conditions are outlined in appendices to the AGRD1. There is also a mechanism established under the Therapeutic Goods Act, 1989 for notification of changes to approved Product Information (PI) when the changes are safety related. In the case of Category 1 and 2 applications, the sponsor pays 75 percent of the total evaluation fees at the time of lodgement, although in some cases the fee may be paid after the application has been accepted for evaluation. If the TGA meets the legislated time frame, the remaining 25 percent is paid by the sponsor upon completion of the evaluation. However, if the TGA exceeds the legislated time frame, the sponsor is not required to pay the balance. If the TGA does not accept the application for evaluation, or it is withdrawn before acceptance for evaluation, part of the evaluation fee is retained by TGA to cover the cost of screening the application. This screening fee is set at 10 percent of the evaluation fee to a maximum of Australian $5,000. In the case of Category 3 applications, 100 percent of the applicable fee is payable at the time of lodgement.

17 Under Section 31 of the Therapeutic Goods Act, 1989, the TGA may make requests to sponsors for provision of additional information or seek clarification of information provided. Such requests are referred to as Section 31 requests or S31s. For applications in each of Category 1, 2 or 3, the time taken by sponsors to respond to the requests is excluded from the processing time; in other words, the clock is stopped until the S31 is answered in full. The TGA also gives sponsors fixed times in which to respond to S31 requests, usually between 1 week and 2 months, depending on the complexity of the questions. In general terms, additional data may not be submitted once an application has been accepted for evaluation, unless specifically asked to do so on a Section 31 request. However, in some instances there is an opportunity to submit additional data that is identified at the time of the initial application, or at a pre-submission meeting. In such cases, the TGA has the discretion to accept this additional data for evaluation and it is possible that an extended evaluation time may be applied. There are also limited opportunities to submit supplementary data, at the initiation of the sponsor, to address deficiencies that may have been identified in the TGA's assessment of the dossier. In these cases, mutual agreement to stop the clock is essential, and further evaluation fees may also be levied. The data requirements have been closely aligned with those of the EU, in the interests of international harmonisation, and are submitted in accordance with EU requirements for format. However, all administrative particulars are unique to Australia, including designation of all active and inactive ingredients in accordance with Australian Approved Names (AAN) and adherence to approved Australian terminology for dose forms, route of administration, container types and units of expression. There is also a requirement for generation of specific documents such as PI for health professionals and Consumer Medicine Information (CMI) for consumers. These documents must be presented in the prescribed format. Full details are given in the AGRD1. Another important area of difference for Australian submissions is the requirement to provide a duplicate set of bioavailability and bioequivalence studies in each of Part I1 and Part IV. These studies are evaluated by both the pharmaceutical chemistry and the clinical evaluation sections of the TGA. A diagrammatic representation of the evaluation and approval process is shown in Figure 1. This figure depicts the process applicable to new chemical entities and other submissions which are referred to the Australian Drug Evaluation Committee (ADEC) for advice. For example, applications for generic drug products are handled by the DSEB and are only referred to ADEC in cases of intended rejection by the TGA. A key part of the evaluation process is the opportunity for input from sponsors at the pre-adec stage. This is in fact the only opportunity available to sponsors to address ADEC directly. The format of the response is one of written comment only and is limited to six pages. No new data may be introduced during the pre-adec consultation. Personal appearance before ADEC is not generally possible. Figure 1 also shows the first level of appeal which is available under the Therapeutic Goods Act, 1989, the Ministerial Appeal under Section 60. In Section 60 appeals, the matter is reconsidered by another delegate who was not involved

18 Figure 1. Evaluation and approval process for applications via the drug safety and evaluation branch. 40 working days while questions outstanding Evaluations sent to Sponsor for review I Application accepted 1 I / Evaluation starts I Clock stops while questions Evaluations sent to Sponsor for review. 255 working days Delegate's summary & recommendations sent to Sponsor and to ADEC while questions outstanding Evaluations sent to Sponsor for review. ADEC consideration Delegate's Decision Appeal to Minister Entry into ARTG & Registration Certificate Issued Appeal to AAT I Rejection /

19 with the initial decision. In rare cases, the matter may be referred once more to the ADEC for further advice. This delegate may confirm or revoke the initial decision or substitute a new decision. There is also recourse for a higher level of appeal to the Administrative Appeals Tribunal (AAT) and these proceedings are handled in a court-like fashion. In addition to these formal appeal mechanisms under the Act, there are informal avenues of appeal which sponsors are encouraged to pursue before initiating formal appeal proceedings. Applications via the Chemicals and Non-Prescription Drug Branch Registera ble Drug Products If a therapeutic good is not listable on the Australian Register of Therapeutic Goods (ARTG) or exempt, then it is by default registerable. Most registerable OTC products are handled by the CNPDB. Evaluations of applications to register or vary registerable OTC products via the CNPDB are carried out at a less rigorous level compared to applications via the DSEB. This is because they do not involve new chemical entities and involve compounds which have been evaluated previously and are well understood. In addition, the products can have only limited approved uses which have evolved through experience in use, or have a history of traditional use. Data requirements are outlined in the Australian Guidelines for Registration of Drugs, Volume 2 (AGRD2). As with the AGRD1, there is provision for notification of certain minor variations, subject to certain conditions. The format for presentation of applications is not currently specified in the AGRD2 and data requirements concentrate on matters of formulation, stability and good manufacturing practice (GMP). Product labels and associated literature are carefully examined to ensure that proposed claims are in accordance with accepted practice and that they are not prohibited representations within the meaning of the Therapeutic Goods Act, In rare cases, safety and/or efficacy (including bioavailability) data may be required. Applications may be referred to one of two expert committees for evaluation and approval. The structure and function of these committees, the Medicines Evaluation Committee (MEC) and the Complementary Medicines Evaluation Committee (CMEC), was discussed in the previous sections. There are no legislated time frames for registration applications via the CNPDB, unlike applications via DSEB. However, the AGRD2 has established target evaluation times which take account of evaluation and committee processing time. Time taken for sponsors to respond to questions raised during the course of an evaluation are additional to these target times. The target times for various applications are listed in Table 2. Lista ble Drug Products Goods required to be listed in ARTG are defined in Schedule 4 of the Regulations to the Therapeutic Goods Act, Broadly speaking, the group includes herbal

20 products, vitamins, minerals and amino acids, sunscreens, homoeopathic medicines, medicated throat lozenges and medicated syrups as well as export-only goods that are not already registered or listed in the ARTG. Listable products are not given a comprehensive evaluation, however, they must comply with all relevant statutory standards, meet all labelling requirements and must be manufactured under GMP conditions. Australian manufacturers must be licensed under the Therapeutic Goods Act, Listable products can make only very limited label claims and can only be used for self-limiting conditions. The application, evaluation and listing process for listable goods is conducted through an Electronic Lodgement Facility (ELF) which was established by Section 26A of the Therapeutic Goods Act, In the ELF system the pre-market assessment of products is conducted by sponsors in an electronic process which checks input against precise guidelines. If the guidelines have been followed, the product application will be computer verified and a listing certificate will be generated. The target times for processing ELF applications for listing is 10 working days. The ELF system has been described in detail in special publications entitled TGA Accelerated Drug Listing Bulletin Numbers 1,2 and 3. Software and directions are available from the TGA and manual applications under Section 26 of the Act can still be made by using the TGA publication Application to List a New Drug or to Vary the Particulars of a Listed Drug for Supply in Australia. Switching from Prescription to Non-Prescription Status Various advisory committees (usually the ADEC) will refer a new substance to the NDPSC for inclusion in the SUSDP and thereafter into State poisons legislation. New chemical entities are almost always classified as prescription only, although there have been some notable exceptions (e.g., fexofenadine). Some time after local marketing experience, applications for rescheduling are lodged to the NDPSC by sponsoring companies or other interested parties. The NDPSC will normally initiate rescheduling actions only in cases of public health concern, where reclassification to a higher schedule and/or requirements for special label warnings are the usual outcome. However, there is a government-led programme of harmonisation of poisons classification with New Zealand, which is resulting in a Table 2. Target times for various applications. Application Type Target Time (Working Days) New application via MEC 70 New application via CMEC 90 Variation via MEC 70 Variation via TGA (not referred to either MEC or TMEC) 30 Notification of variation-acceptance and acknowledgment 22

21 considerable level of reclassification, usually to the lowest schedule. All scheduling and rescheduling applications are accompanied by several opportunities for public consultation with all proposals published in the Commonwealth Government Gazette both before and after formal adoption by the Committee. The NDPSC has issued a document to assist intending applicants in preparing applications for rescheduling. The document is entitled Guidelines for National Drugs and Poisons Schedule Committee and was issued in August of Applications may be referred to an external expert with recognised and relevant expertise. In late 1996 the secretariat of the NDPSC was brought within the TGA's responsibility, and in 1999 the committee was established as a statutory committee under the Therapeutic Goods Act, 1989 and further administrative changes to application requirements are anticipated. In general terms, applications for rescheduling should focus on the public health risks and benefits of the proposal rather than with matters such as drug quality, efficacy or safety. The NDPSC usually requires at least two years of local marketing experience before giving consideration to the rescheduling of a prescription drug. The reclassifications usually go step-wise from Prescription Only status (S4) to Pharmacist Only status (S3) and then to Pharmacy Only status (S2), if appropriate. However, there are precedents for rescheduling directly from S4 to S2. Reclassifications from S2 to unscheduled status are rare, and are usually restricted to small pack sizes (for example, small packs of simple analgesics). There are no legislated time frames for consideration of rescheduling applications. In general terms, from the date of lodgement of an application to the date in which it will take effect in the SUSDP is approximately 12 months. This period allows for adoption of the change into State legislation. In cases where public safety is at risk, expedited mechanisms can be set in train. Applications for Reimbursement After products are included in the ARTG, they may be eligible for listing on the Pharmaceutical Benefits Scheme (PBS). The scheme is designed to meet community needs and covers prescribing by community medical practitioners and dispensing by community pharmacists. Such applications are made under Section 85 of the National Health Act, Under special funding arrangements in Section 100 of the Act, the Commonwealth also pays for some highcost drugs which can only be supplied from hospitals to outpatients. Products are listed in the PBS on the recommendation of the PBAC (See previous section). The PBAC receives requests from both health professionals and pharmaceutical companies for drugs to be subsidised by the PBS. Ultimately, it is the sponsor of the product who must provide the necessary data to substantiate applications for PBS listing. The Government relies heavily on the advice of the PBAC, however, its final decision to subsidise a drug may also reflect other considerations such as whether assistance is already provided or is more appropriate through other programmes such as State public health programmes. For drugs considered appropriate for

22 PBS listing on medical grounds, economic factors including cost-effectiveness are taken into account, as required by the National Health Act, Fixed combination products are seldom considered suitable for inclusion in the PBS. Notable exceptions to this norm are oral contraceptives and combination hormone replacement therapies. Any new listing which has the potential to cost the PBS more than $10 million in the first full year of reimbursement must be approved by the Federal Cabinet. Otherwise, applications are approved by the Health Minister. Application guidelines are detailed in a comprehensive series of publications, including Guidelines for the Pharmaceutical Industry on Preparation of Submissions to the Pharmaceutical Benefits Advisory Committee. In almost all cases, applications must be accompanied by economic evaluations and data to demonstrate the effectiveness of the drug in the wider setting of general usage. Successful applications are listed in the PBS approximately 9 months after lodgement. ORPHAN DRUGS An Orphan Drug Programme was introduced in 1998 to encourage the registration of products that would not normally be commercially viable. The programme, which is based on that of the US FDA, covers drugs, vaccines and in vitro diagnostics. The Australian programme stipulates a disease prevalence of 2,000 affected individuals, or less. Designated orphan drugs are published in the Australian Gouernment Gazette and details are also posted on the TGA's website. In contrast to the US programme, there is no financial support for research and development of orphan drugs. However, the TGA waives the initial evaluation fees and offers market exclusivity for designated orphan drugs (unless clinical superiority can be proven). In addition, the TGA aims to conduct accelerated approval for designated orphan drugs, although the applications are technically treated as a Category 1 application for TGA tracking purposes. Full details on the operation of the Australian Orphan Drug Programme may be found in the TGA publication of the same name. FUTURE TRENDS The Industry Commission report on the Pharmaceutical Industry (Owens 1996) encapsulates the future direction of drug regulation in Australia in one of its recommendations, namely: The Commission recommends that Australia, through the Therapeutic Goods Administration attempt the following: continues to pursue harmonisation of standards and data requirements pursue further agreements to exchange evaluation reports and to undertake joint evaluations At the time of writing, the market exclusivity provisions of the Orphan Drug Programme were not fully operational.