The Australian drug regulatory system

Summary
Before a drug can be marketed in Australia, it must be evaluated by the Therapeutic Goods Administration (TGA). The functions of the TGA were reorganised following the Baume report of 1991. In addition to evaluating the quality, safety and efficacy of drugs, the TGA must also consider their timely availability. New chemical entities and applications which require expert advice are referred to the Australian Drug Evaluation Committee (ADEC). Although the ADEC can make recommendations, the TGA makes the final decision to register a drug for use in Australia. In addition toevaluating prescription drugs, the TGA is also responsible for other medications, including overthecounter medicines, 'alternative medicines' and medical devices.

Introduction
The Therapeutic Goods Administration (TGA), through the Therapeutic Goods Act 1989¹ and the Therapeutic Goods Regulations², is responsible for the quality, safety, efficacy and timely availability of drugs and medical devices in Australia. Prescription drug evaluation is the public image of the TGA, but this is only one of many TGA functions. The TGA also regulates nonprescription drugs, medical devices, and vitamin, nutritional and herbal products.

There are approximately 48 000 products included on the Australian Register of Therapeutic Goods (ARTG). This total includes approximately 21 000 devices and 27 000 drugs, of which only 3500 are registered prescription-only products.

Prescription drug regulation
The drug regulation process is complex and resource intensive. It must be accountable in terms of the quality, safety and efficacy of drugs made available in Australia. This accountability includes an acceptance of a balance between safety and efficacy. There is no such thing as a totally safe drug, and the approval process must recognise the risk/benefit ratio of any particular drug. This requires a detailed evaluation of the data supplied by the company sponsoring an application.

A drug may first come to the attention of the TGA when an application for marketing is received or when an Australian clinical trial is being planned. For clinical trials, the sponsoring company may submit preliminary data for evaluation to the TGA (CTX scheme) or notify the TGA (CTN scheme) that the trial has been approved by an institutional ethics committee.

The drug evaluation process for new chemical entities is illustrated in Table 1. The drug's chemistry, toxicology and clinical use are evaluated using data submitted by the sponsoring company. Most of the evaluations are done within the TGA, but external evaluations can be used. When all the data have been evaluated, the application is considered by the Australian Drug Evaluation Committee (ADEC). This committee is a group of doctors appointed by the Minister to advise on the suitability of drugs for marketing in Australia. The TGA takes into consideration the advice received from the ADEC when making a final recommendation.

Before the Baume report, virtually all applications involving prescription medicines were reviewed by the ADEC. Now only new chemical entities, new routes of administration, new fixed combinations, new therapeutic indications and changes in patient groups are considered by the ADEC because such applications generally involve complex clinical issues. Generic products, new formulations, new strengths and reformulations of existing products are no longer referred to the ADEC, unless the TGA has recommended a rejection of the application, or when there are clinical issues which require the ADEC's advice.

Baume report
In 1991, the timely availability of drugs was emphasised by the Baume report.³ This report was commissioned because of the perceived dissatisfaction with the performance of Australia's drug evaluation system.

The major criticisms of the drug evaluation process at the time were:

• the TGA mission statement made no reference to timely availability
• the TGA did not meet its own performance targets for the various steps of the drug evaluation process
• there needed to be easier access to experimental drugs for individual patients and clinical trials
• there were inefficiencies in the evaluation process
• pharmaceutical companies had to reformat data to suit Australian requirements and also had to meet some unique Australian standards
• the ADEC process was a source of delay
• delays occurred in the approval process following meetings of the ADEC
• there was a confrontational relationship between the TGA and the pharmaceutical industry.

The recommendations of the Baume report aimed to improve the evaluation process for prescription drugs while maintaining appropriate public protection. The major changes resulting from the report were:

• a new mission statement, in the form of a goal and objective, was set for the TGA (see box)
• new performance targets for drug evaluation and approval were set and are included in the Regulations²
• the Special Access Scheme for unregistered drugs was introduced and the procedures for approving clinical trials were reviewed
• a streamlined acceptance system for applications was established, greater use of overseas reports was encouraged, and a new approach to the evaluation of clinical data based on summary reports was introduced
• the application format used in the European Union became mandatory in Australia and new guidelines⁴ based on the European guidelines were published. International standards were adopted where appropriate
• changes were made in the composition of the ADEC, and its secretariat became independent of the TGA's Drug Safety and Evaluation Branch. New terms of reference reduced the number of applications referred to the ADEC
• the ADEC focused its activities on being a committee of advice rather than a part of the evaluation process. Appeals which previously went to the ADEC became the subject of new appeal mechanisms. These can involve appeals to the Minister and to the Administrative Appeals Tribunal
• improved communication between the TGA, sponsors and peak industry organisations has improved cooperation

To implement the Baume recommendations, many detailed changes were made to the legislation and to the guidelines and operating procedures of the TGA. These changes were not restricted to the drug evaluation process and have had a big impact on the overall performance of the TGA.

TGA performance
The performance of the TGA is monitored in quarterly performance reports which are reviewed by the Industry/Government Consultative Committee. This committee has membership from the TGA, the Department of Finance, the Department of Industry, Science and Technology, and the peak industry organisations representing the manufacturers of prescription drugs, nonprescription drugs, medical devices and herbal and nutritional products.

The numbers of major drug evaluation applications considered by the ADEC are listed in Table 2. The increased workload in 1988/89 reflects the announcement that evaluation fees would be charged from 1990. This may have encouraged sponsor companies to submit applications before the introduction of fees.

The drop in numbers in 1991/92, with the subsequent increase in 1992/93, could reflect the introduction of Baume timelines in 1992. Companies could have held back applications until the introduction of the new legislation, which limited the amount of time the TGA could spend on evaluations.

The increased number of approvals in 1992/93 and 1993/94 reflect the work of a special task force and the deliberate efforts of the Drug Safety and Evaluation Branch to clear the backlog of work which had built up pre Baume and which was not subject to any timelines.

Table2 ADEC statistics (1987/94)

Timelines
While the workload is an important factor in performance, some would see time as more important. Following the Baume implementation program, the performance report on evaluation times is being carefully monitored. The targets for all types of applications are now set in legislation. If the TGA does not meet the statutory timelines, then it forgoes 25% of the evaluation fee as a penalty. The sponsor concerned can also consider the outcome as a 'deemed refusal' and appeal to the Administrative Appeals Tribunal for a resolution. For variations to the registration of a drug, the TGA must raise an objection within 45 working days, otherwise the application is deemed to be approved.

The timelines for the evaluation of new chemical entities are shown in Table 3.

International cooperation
The Baume report saw great promise in a system which would allow applications to be assessed rapidly if evaluation reports were available from two acceptable overseas regulatory authorities (U.K., U.S.A., Canada, Sweden, Holland). That promise has not eventuated because many applications are filed simultaneously in Australia and in other countries, so overseas evaluation reports are not available. Another problem is confidentiality. A company, or the regulatory authority, may not wish to release the evaluation reports to the TGA.

Other TGA functions
The evaluation process relates to pre marketing activity, but the TGA is also responsible for drugs after they are marketed.

Other activities under the control of the TGA include:

• maintenance of the Australian Register of Therapeutic Goods for the registration and listing of products
• control of drug and device exports from Australia
• inspection and licensing of manufacturing premises (in 1993, 24% of the overseas manufacturers that were inspected failed to meet acceptable standards)
• post marketing surveillance
• adverse drug reaction monitoring (in 1993/94, 8370
• reports were received by the Adverse Drug Reactions Advisory Committee)
• medical device complaint reporting
• drug and device recalls
• laboratory testing, sample testing (in 1993, 20% of the products that were inspected failed to meet acceptable standards)
• complaint reporting and follow up
• drug and device advertising controls

Conclusion
If a new drug is registered for marketing in Australia, prescribers can be assured that its safety and efficacy have been evaluated by the TGA with advice from the ADEC. The price of a drug does not influence the decision to allow the drug to be registered. By 1997, half the costs of the TGA will be met by the pharmaceutical industry. This requires the TGA to be accountable for its performance, with an increased emphasis on the timely availability of new drugs. Unregistered drugs may be available through clinical trials or the Special Access Scheme which are also part of the TGA's function.