INTRODUCTION

In Australia the regulation and registration of medicines is achieved, at least in part, through the agency of the Therapeutic Goods Administration (TGA) and enabling legislation. Society spends money on medicines because of the benefits that accrue through disease treatment and prevention. In order to maximise such benefits, medicines must meet appropriate standards of quality, safety and efficacy; which means in turn that their development, production and distribution must be regulated to ensure compliance with prescribed standards. It is, however, also important that society achieves a balance, on the one hand facilitating an individual’s access to medicines while on the other ensuring that medicines meet appropriate standards of quality, safety and efficacy.

Concern regarding the safety of medicines was heightened in the early 1960s with the thalidomide disaster which resulted in approximately 10000 children, predominantly in Africa and Europe, being born with severe birth defects.^[1] The drug, whose safety had not been adequately assessed before its release, was aggressively promoted as an antiemetic to combat morning sickness in pregnant women. The outcome of the thalidomide experience was a recognition of the need for regulatory authorities to ensure whether the effect of a medicine on humans had been researched adequately prior to marketing. In Australia, clinical trials, which are a critical component of drug regulation, have been subject to a formal process of regulation since the 1970s.^[2]

In regard to an individual’s access to unapproved medicines, therapeutic goods legislation allows such access under the ‘Special Access Scheme’ in certain circumstances such as:

Drug regulation is a component of the public policy framework that restricts or controls private-sector activity to achieve identified social goals. In Australia such goals are given focus by the National Medicines Policy, which has as its core components:

The pharmaceutical industry has flourished since the 1930s and now represents one of the largest globalised industries. Unfortunately, in parallel with this development has been the phenomenon of counterfeit or substandard pharmaceuticals that include toxic, inactive or non-standardised products. Some notable examples of the risks associated with the use of counterfeit pharmaceuticals include:

A survey undertaken by the Welcome Trust in South-East Asia in 1999 also found that 38% of 104 anti-malarial drugs on sale in pharmacies did not contain any active ingredients.^[7]

Counterfeit medicines represent an enormous public health challenge with the risks being greater in those countries where regulatory oversight is weak. The World Health Organization (WHO) noted that the USA-based Center for Medicines in the Public Interest had predicted that the worldwide sales of counterfeit drugs will reach US$75 billion by 2010, an increase of more than 90% on the estimated 2005 figures.^[7]

Before discussing the role of the TGA in regard to the regulation of therapeutic goods it is useful to briefly consider the constitutional complexities that exist in Australia.

AUSTRALIAN CONSTITUTIONAL COMPLEXITIES

As outlined in Chapter 1, Australia is an independent nation with its own constitution and a federal system of democratic government. The federal government came into existence on 1 January 1901 as a result of the Commonwealth of Australia Constitution Act 1900 (UK). The Constitution sets out the parameters under which the state and federal governments operate and the relationships that exist between them. The constitutional complexities following federation arose from the fact that prior to federation Australia was a collection of separate colonies; while after federation (following two constitutional conventions and extensive negotiation between each of the six Australian states and the newly formed Commonwealth Government) each state was governed by its own (existing) constitution and the Commonwealth Constitution.

Each government in the federal system has law-making functions, with the constitution giving the federal government certain enumerated powers, and the states retaining those general powers necessary to provide peace, order and good government. Some of the powers given to the federal government are exclusive and cannot be exercised by the states and territories. For example, section 90 of the Constitution states:

In other cases the Constitution prohibits states from exercising certain powers. For example, section 114 states:

As both the Commonwealth and the state governments have law-making functions, disputes may arise over the exercise of such powers. This potential for conflict is recognised in the Constitution and is addressed by section 109 that provides that where there is an inconsistency between a state law and a Commonwealth law, the inconsistency is resolved in favour of the Commonwealth. Disputes of this nature are decided by the High Court.

The Commonwealth can only pass laws where it believes it has a constitutional head of power to do so. For example, it could be argued that the Therapeutic Goods Act 1989 (Cth) which imposes quality controls for the preparation, packaging and labelling of therapeutic goods imported into Australia is based in part on its quarantine power (section 51(ix)). Likewise, the trade and commerce power (section 51(i)) provides for the control of medicines being imported or exported under the Customs Act 1901 (Cth). Also the external affairs power has considerable potential for being the basis for Commonwealth legislation. Through a series of decisions the High Court has shown that the external affairs powers can be invoked through the mere signing of an international agreement.^[8] It is worthy of note that Australia became a signatory to the WHO in 1947. The terms of the agreement were incorporated into the World Health Organization Act 1947 (Cth) and appear to be able to support considerable Commonwealth health care legislation.

However, historically it has not always been straightforward in regard to federal legislative power. In 1944 the Commonwealth Government attempted to set up a national scheme to provide health services including pharmaceutical benefits. The scheme was thwarted by a decision of the High Court where the scheme was held to be unconstitutional.^[9] As a result of a 1946 referendum the Commonwealth Government was given constitutional power to provide a range of services under section 51(xxiiiA). The section states:

While the Therapeutic Goods Act 1989 (Cth) and the National Health Act 1953 (Cth) are the two pieces of federal legislation most likely to affect practising pharmacists, practitioners should also be aware of the Narcotic Drugs Act 1967 (Cth), the Psychotropic Substances Act 1975 (Cth) and the Customs (Prohibited Imports) Regulations 1956 (Cth). The Narcotics Drugs Act 1967 (Cth) is an act to ‘… regulate the manufacture of narcotic drugs in accordance with the United Nations Single Convention on Narcotic Drugs 1961’. The Psychotropic Substances Act 1975 (Cth) is an Act to:

The Customs (Prohibited Imports) Regulation 1956 (Cth) prohibits the import of a wide range of goods including drugs, unless the person importing the drug holds the appropriate licence. Exceptions include where a person is a passenger on a ship or plane and where the drug was prescribed by a medical practitioner for the purposes of treatment.

THERAPEUTIC GOODS ADMINISTRATION (TGA)

The TGA, a division of the Department of Health and Ageing, conducts a range of assessment and monitoring activities which ensure therapeutic goods available in Australia are of an acceptable standard, and that therapeutic advances are made available to the Australian community within a reasonable time. The overall control of therapeutic goods is maintained predominantly through five processes. These can be characterised as:

Therapeutic goods are defined within the Therapeutic Goods Act 1989 (Cth) (s3) as goods:

The Therapeutic Goods Act 1989 also defines (s3) ‘therapeutic use’ as use in or in connection with:

The definition of therapeutic goods does not include those goods declared not to be therapeutic goods under an order in force under section 7 of the Act, or goods for which there is a prescribed standard in the Australia New Zealand Food Standards Code as defined in subsection 3(1) of the Australian New Zealand Food Authority Act 1991, or goods which have a tradition of use in Australia and/or New Zealand as foods for humans in the form in which they are presented. The differences between a ‘medicine’ and a ‘cosmetic’ should be noted. The main determining factors are the claims made about the product. For example, moisturisers containing sunscreens and therefore having a stated therapeutic purpose are classified as medicines, whereas moisturises without a specific therapeutic ingredient are classified as cosmetics. When a product is classified the ingredients, route of administration and therapeutic claims are taken into consideration.

The regulation of therapeutic goods in Australia is based ‘… on a risk management approach designed to ensure public health and safety, while at the same time freeing industry from any unnecessary regulatory burden’.^[10] The risk management process identifies, assesses and evaluates the risks posed by a therapeutic good, applies any measure necessary for treating the risks posed, and monitors and reviews the risks over time. The Act also sets out the legal requirements for the import, export, manufacture and supply of medicines in Australia. The TGA further states:

From 1 July 1998, the TGA has been required by the government to fully recover its operating costs for all activities that fall within the scope of the Act, including regulation of the industry and the TGA’s public health responsibilities.

In terms of the Therapeutic Goods Regulations 1990, Regulation 9A, a sponsor must supply written information for consumers as specified in Schedule 12 or 13 for all prescription products and Pharmacist Only medicines. This written information is referred to as Consumer Medicine Information (CMI) and can be in various formats; for example, electronic, pads, and package inserts.

In is also worthy of note that a Trans-Tasman Harmonisation Agreement was signed between Australia and New Zealand to implement a joint regulatory scheme for therapeutic products. However this process has been deferred indefinitely due to New Zealand not passing enabling legislation.

AUSTRALIAN REGISTER OF THERAPEUTIC GOODS (ARTG)

All medicines marketed in Australia must be included in the Australian Register of Therapeutic Goods (ARTG) unless they are specifically exempt or excluded. The ARTG, established under Part 3 of the Act, is divided into two parts; the first part is for ‘Listed Goods’, the second part for ‘Registered Goods’. Some goods otherwise captured by the Act are classified as ‘Exempt Goods’ and include homoeopathic preparations, extemporaneously prepared medicines, dandruff shampoos, fluoride toothpastes and antiperspirants. It is important to note that although Listed Goods appear in the ARTG (a ‘register’) they are not ‘registered’ as such.

It is intended that Listed Goods contain ingredients that are generally considered to be safe. Such ingredients are usually characterised as being well known, established, and with a long history of use. Examples include most complementary and alternative medicines, vitamin and mineral products, and sunscreens. Prior to listing they are assessed for quality and safety, with the manufacturer being required to comply with the Code of Good Manufacturing Practice and to be licensed by the TGA. However, and this goes to the core of concerns that have been raised about Listed Goods, they are neither independently assessed for efficacy nor stability. Listed Goods are denoted by the symbol ‘AUST L’ followed by an identifying number. They do not contain substances scheduled in the Standards for the Uniform Scheduling of Drugs and Poisons (SUSDP) unless the products are for export only and not marketed in Australia.

There has been recent criticism by Harvey et al of the AUST L scheme with concerns being expressed over inadequacies and abuses of the listing mechanism as well as complicated and ineffectual complaint processes.^[11] Particular attention has been drawn to weak controls on the supply and promotion of complementary medicines in Australia (using weight-loss products as an example) and the fact that Listed Goods were not independently evaluated for efficacy; for example, companies sponsoring products only have to certify it held substantiating evidence in support of claims made. It is worthy of note that when the ARTG was first introduced a sponsor was not required to have any evidence in support of claims made about a product. It was only after concerns were raised regarding the improbable and extravagant claims made for some complementary and alternative medicines that, in 1999, a requirement was introduced that sponsors hold substantiating evidence in support of such claims.^[12] At the present time 80% of Listed Goods do not undergo any assessment for compliance with TGA requirements. Harvey et al further state:

Medicines assessed as having a higher level of risk must be ‘registered’ as opposed to being ‘listed’. Registered medicines are denoted by the symbol AUST R followed by an identifying number. The degree of assessment and regulation is rigorous and detailed with sponsors being required to provide comprehensive safety, quality and efficacy data. The evaluation is usually undertaken through one of the TGA’s expert advisory committees. Such committees include the Australian Drug Evaluation Committee (ADEC), the Medicines Evaluation Committee (MEC) and the Complementary Medicines Evaluation Committee (CMEC).

Registered medicines are evaluated as either ‘low risk’ or ‘high risk’. Low-risk medicines do not contain ingredients included in Schedule 4, Schedule 8 or Schedule 9 of the SUSDP and are available without a doctor’s prescription. Low-risk medicines are those found in S2 and S3 of the SUSDP and include mild analgesics, cough and cold preparations, and antifungal creams. High-risk medicines usually include ingredients included in Schedule 4, Schedule 8 or Schedule 9 of the SUSDP and are only available on a doctor’s prescription or through other approval mechanisms.

NATIONAL DRUGS AND POISONS SCHEDULE COMMITTEE

Australia has a uniform process for the scheduling of medicines and poisons through the agency of the National Drugs and Poisons Schedule Committee (NDPSC). The NDPSC is a statutory committee established under the Therapeutic Goods Act 1989 and the Therapeutic Goods Regulations 1990 (as amended). Membership includes representatives from the Commonwealth, states and territories, the TGA, the Australian Pesticides and Veterinary Medicines Authority (APVMA), Medsafe and the Environmental Risk Management Authority in New Zealand, experts in a range of disciplines and representatives from industry, consumers and practising pharmacists. The current membership of the NDPSC and the secretariat contact details may be found at the NDPSC website www.tga.gov.au/ndpsc.

The SUSDP and its amendments give effect to the decisions of the NDPSC regarding the classification of drugs and poisons into schedules for inclusion in the relevant legislation of the states and territories. For the purposes of the SUSDP a poison means ‘any substance or preparation included in a Schedule in this Standard’, while a drug means ‘a poison intended for human or animal therapeutic use’. The SUSDP also includes model provisions about containers and labels, a list of products recommended to be exempt from those provisions, and recommendations about other controls on drugs and poisons. The SUSDP promotes uniform scheduling of substances and uniform labelling and packaging requirements throughout Australia. The decisions of NDPSC have no force in Commonwealth law but are recommended for incorporation into state and territory legislation. This has been achieved in all states and territories.

The amendments to the SUSDP (of which three are issued each year) include recent decisions of the NDPSC and must be read in conjunction with the SUSDP, not as stand-alone documents. The SUSDP and its three amendments are consolidated annually and available for purchase as an annual subscription. The SUSDP is also now available electronically.^[13]

The SUSDP Introduction discusses the classification of drugs and poisons and the principles of scheduling. Part 1, Interpretation, provides dictionary definitions for terms appearing in the SUSDP. Part 2, Labels and Containers, includes general requirements for: labels (including the immediate wrapper, primary packs and immediate container, statements on quantity, proportion or strength, and exceptions); and containers (including approved containers, child-resistant closures, exemption and prohibitions). Part 3 provides for Miscellaneous Regulations (advertising; sale or supply; prohibition on sale, prescribing and possession; storage; and dispensed medicines). Part 4 covers the schedules and provides a range of definitions for each of the schedules. (See Chapter 11.) In general terms the scheduling of poisons depends on a number of factors, which include: toxicity; purpose of use; potential for abuse; and other safety concerns. Poisons for therapeutic use (drugs or medicines) are included in Schedules 2, 3, 4, and 8, with Schedule 2 being the least controlling and Schedule 8 having the strictest controls. Agricultural, domestic and industrial poisons are included in Schedules 5, 6 and 7, which once again demonstrate increasingly strict controls when progressing through the schedules. Schedule 9 includes those substances usually only available for medical and scientific research.

The following appendices are included in the SUSDP:

There is a trend in Australia towards the down-scheduling of certain categories of medicines as they progressively prove to have a relatively safe profile. The increasing tendency to down-schedule not only provides pharmacists with an expanded range of medicines available as over-the-counter therapies but also increases the professional responsibility and professional liability risk. Down-scheduling requests are submitted periodically by pharmaceutical manufacturers as part of the normal lifecycle of products. As new products enter the market, manufacturers prefer to focus their marketing efforts on the prescribers of newer products, encouraging the down-scheduling so established therapies become available without prescription.

The trend to down-schedule medicines is also evident in other countries. As an example, there were approximately 50 changes to the legal status of medicines in the UK between 1992 and 2002 which facilitated easier access to those medicines by patients. In a document, ‘Building the Best’, the UK government committed to doubling the rate of conversions from prescription medicines to pharmacy medicines from 5 to 10 per year.^[14]

Medicines that have been recently down-scheduled by the NDPSC from Prescription (S4) to Pharmacist Only (S3) have included the oral preparation for vaginal thrush Diflucan (fluconazole); the emergency post-coital contraceptive Postinor-2 (levonorgestrel); and the weight management product Xenical (orlistat). The importance of pharmacists exercising appropriate professional judgment in relation to the supplying of any of these products prompted the PSA to develop protocols that could be adapted by the pharmacist.[15, 16, 17] These scheduling changes clearly demonstrate the increasing need for vigilance by pharmacists and regulatory authorities.

ADVERTISING

The advertising of therapeutic goods in Australia is governed by the Therapeutic Goods Act 1989 (Cth) through the Therapeutic Goods Advertising Code 2007. Advertising in this context includes any statement, pictorial representation or design, however made, that is intended, whether directly or indirectly, to promote the use or supply of the goods. Section 22(5) of Act specifies that an advertisement can only refer to indications in the ARTG. The Therapeutic Goods Advertising Code 2007 revokes and replaces previous codes. It has as its objective:

The code includes the World Health Organization: Ethical Criteria for Medical Drug Promotion 1988, which states:

The Therapeutic Goods Advertising Code Council (TGACC) is established under the regulations to the Therapeutic Goods Act 1989. The council is a broad representative body that considers the requirements for the advertising of therapeutic goods, any proposed changes to the code, accepts submissions, and advises the Minister for Health where appropriate.

The code does not apply to advertisements directed at health professionals mentioned in Appendix 2 of the code, including pharmacists, medical practitioners, nurses and dentists. Neither does the code apply to information or advice being provided directly to a patient by a health professional.

Appendix 6 of the code defines prohibited, restricted and permissible representations of therapeutic goods. For example, the code specifically prohibits any advertising regarding abortifacient action or any representation involving the treatment, cure or prevention of neoplastic disease, sexually transmitted diseases, HIV, AIDS and/or HCV, and mental illness. However, it is noteworthy that the prevention of skin cancer through the use of sunscreens, devices used for contraceptive purposes or in the prevention or transmission of diseases are able to be advertised under the restricted representation. Restricted representation enables reference in advertising for therapeutic goods for diseases, conditions, ailments or defects listed in Table 1 of Appendix 6, provided prior approval is obtained. The conditions included in Table 1 are generally accepted as not diagnosable or treatable without consultation with a suitably qualified health professional, or being beyond the ability of the average consumer to evaluate accurately and treat safely. All such applications for advertising approval must be referred to the TGACC who will make a recommendation to the secretary. The TGACC must take into account: consumer’s vulnerability when faced with disease; whether the reference would be likely to result in consumers not seeking timely professional advice; whether such reference would have a negative effect on public health; and other aspects of the public interest that may be appropriate. However, these public-interest criteria must be balanced against the benefits of self-medication, which arguably can help prevent and treat symptoms and ailments that:

Unlike the United States of America and New Zealand, direct-to-consumer advertising (DTCA) in Australia is not permitted, other than advertising or representation permitted under the code. DTCA has been a controversial development in the area of medicine promotion, with its proponents claiming that advertisements to consumers educate them about health in general, inform them about new treatments and encourage improved communication between patients and their doctors. Opponents however argue that advertisements simply promote expensive new drugs even when less expensive and often safer treatments, or even no treatment at all, would suffice.^[18]

One form of advertising that is permitted in Australia is that which provides the general public with information about the price of prescription medicines and certain ‘Pharmacist Only’ medicines. Such advertising is regulated through the TGA’s Price Information Code of Practice (the code). Price information, as defined by the code, can only be provided by retail pharmacists, or agents acting on their behalf (including marketing groups), or dispensing doctors. Price information may not be provided by medicine manufacturers, distributors or sponsors. Price information may be distributed by methods including newspapers, magazines, leaflets and the internet; however, those utilising radio or television transmission or displays including posters (e.g., on public transport or billboards) are specifically precluded.

The code prohibits the promotion of a product as part of the provision of price information. For example, no medicine should be given prominence over any other medicine referred to in the information provided. In addition, any price information ‘… must include a sufficient number of medicines, from three or more sponsors, so that no promotional emphasis is given to any medicine referred to in the price information…’. Medicines must be described using the brand name and strength of the active ingredient(s), and any medicines subsidised under the Pharmaceutical Benefits Scheme must be identified and the total purchase price specified as the general or concessional price.

CLINICAL TRIALS

Clinical trials represent a critical component of drug regulation and are usually conducted with ‘unapproved therapeutic goods’. However, it should not be assumed that clinical trials are restricted solely to new drugs. A clinical trial may also be undertaken using a previously marketed medicine to evaluate a possible new approved indication. One example is the compound thalidomide, which was first marketed in Europe in the late 1950s for the treatment of morning sickness during pregnancy. It was later withdrawn from sale when it was recognised that there was a causal relationship between its administration to pregnant women and birth defects. Subsequent research involving a number of clinical trials demonstrated its effectiveness in the treatment of multiple myeloma (where combined with dexamethasone it is standard therapy) and erythema nodosum leprosum. There is also ongoing research into its anti-inflammatory effects and its inhibition of new blood vessels.

The therapeutic goods legislation provides a number of avenues whereby such unapproved goods may be supplied, including use in clinical trials, personal importation, the Special Access Scheme and through an authorised prescriber.^[19] For the purpose of clinical trials, the avenues for access are the Clinical Trial Notification (CTN) and the Clinical Trial Exemption (CTX) schemes.

Under the CTN scheme all material relating to a proposed trial is submitted to a Human Research Ethics Committee (HREC), usually operating in the facility where the trial is being undertaken. The HREC is responsible for assessing all aspects of the trial including the validity of the trial design, the safety and efficacy of the medicine and the ethical acceptability of the process. There is no TGA review of the trial proposal. After review by the HREC, the CTN form is signed by the sponsor, the principal investigator, and the Chairperson of the HREC before it is submitted to the TGA.

Under the CTX scheme the application to conduct a clinical trial is submitted by the sponsor to the TGA for evaluation in regard to the safety of the product utilising its overseas status, a pharmaceutical data sheet and a summary of any clinical or pre-clinical data. While an HREC is responsible for considering the scientific and ethical aspects of a particular trial under the CTX scheme, it is not involved in the original application to conduct the trial, compared to the CTN scheme where it is a co-signatory on the application.

Clinical trials are designed to assess the efficacy, safety and effects of a medicine without exposing the persons involved as subjects in the trial to unnecessary risks. The responsibility for the conduct of the trial and the monitoring of results rests jointly with the sponsor, the institution conducting the trial (through the agency of its HREC), and the person nominated as the investigator. Clinical trials are usually classified according to the phase of the medicines development. While there is sometimes an overlap in individual phases the following definitions are generally accepted.

The primary ethical guideline for researchers conducting clinical trials in Australia is the National Statement on Ethical Conduct in Human Research, developed jointly by the National Health and Medical Research Council, the Australian Research Council and the Australian Vice-Chancellors’ Committee. The TGA also provides the document Access to Unapproved Therapeutic Goods — Clinical Trials in Australia to further inform.

PRODUCT RECALLS

The TGA is not only responsible for issuing alerts and advisories regarding all medicines but also for facilitating product recalls. Recalls may involve specific batches of a registered product where particular problems have been identified in the manufacturing process, or cancellation of registration when serious but previously unidentified effects have been associated with the clinical use of a medicine. Recalls are classified as:

The TGA was involved in the world’s largest recall of medicines when it suspended the licence of Pan Pharmaceuticals Ltd on 28 April 2003. The TGA stated:

This resulted in the recall of 219 products manufactured and supplied in Australia by the company. Concurrently, there was a larger recall of products manufactured under contract by Pan Pharmaceuticals Ltd for some 147 other sponsors.^[23] Pan Pharmaceuticals Ltd subsequently pleaded guilty to 44 charges of dealing with counterfeit therapeutic goods and nine charges of knowingly using a false document. These charges related to employees using false certificates and altering the ingredients of therapeutic medicine products it exported to Vietnam. The company was fined $10 million. (As a footnote: after bitter conflict between employees, pharmacists and creditors, Pan Pharmaceutical Ltd was placed into liquidation on 23 September 2003. A number of court actions are ongoing.)

The following three examples illustrate Australian recall procedures as applicable to individual products:

CODE OF GOOD MANUFACTURING PRACTICE

Internationally, codes of good manufacturing practice are designed to remove barriers to trade in medicinal products, promote uniformity in licensing decisions and ensure the maintenance of high standards of quality assurance. The Australian rules parallel the European Union Guide to Good Manufacturing Practice for Medicinal Products and its annexures.

The Australian Code of Good Manufacturing Practice for Medicinal Products provides manufacturing standards applicable to medicines and similar products intended for human use and serves as a basis for manufacturers in developing specific rules adapted to their individual needs. However, the code recognises that there may be acceptable methods, other than those described in the code, that are capable of achieving similar outcomes. It is noted that the code is not intended:

Manufacturing is defined as producing goods; that is, to engage in any part of a process of bringing the goods to their final state. This includes processing, assembling, packing, labelling, storage, sterilising, testing or releasing for supply.

The code provides a number of principles that underpin the following aspects of the manufacturing process:

As an example, the underlying principle relating to premises and equipment states:

This principle is then further expanded by a number of statements relating to various aspects of premises and equipment including: the general environment; maintenance; lighting, temperature, humidity and ventilation; protection against insects and other animals; and prevention of entry of unauthorised people. There are further detailed statements relating to the production area. The possible impact of the code on extemporaneous dispensing by pharmacists is discussed in Chapter 4.