Australian regulation of prescription medical products
May 2007
It is a requirement under the Therapeutic Goods Act 1989 (the Act) that medical products to be imported into, supplied in, or exported from Australia be included in the Australian Register of Therapeutic Goods (ARTG). In order for a product to be included in the ARTG, a sponsoring company is required to make an application which usually consists of a form accompanied by data to support the quality, safety and efficacy of the product for its intended use.
The Therapeutic Goods Administration (TGA) requirements for data are based on the European Union requirements and the TGA accepts data packages in the EU version of the international Common Technical Document <http://www.tga.gov.au/docs/html/eugctd.htm>.
Within the European system, there is a series of guidelines, most of which have been adopted by the TGA, that deal specifically with the issue of data requirements. These guidelines can be accessed from this website <http://www.tga.gov.au/docs/html/euguideh.htm>.
After an application is made, there is an initial short period during which it is assessed on an administrative level to make sure there is compliance with basic guidelines. This is to save time so that applications which are premature or grossly deficient do not end up within the evaluation system, causing delays for themselves and other products. This phase is called the Application Entry Process. At the end of this phase, a decision is made to either accept the application for evaluation or to reject it.
Over 99% of applications are accepted for evaluation at this point but many require questions to be asked to define further the indication being sought or to substantiate that information will either be provided in the future or is not required. At this point, companies are also able to flag with the TGA additional data that, while not actually required to substantiate the role of the product, could enhance the assessment outcome and will be available at a point determined by negotiation. If acceptable to the TGA, these additional data may later be submitted at that agreed time.
Once an application is accepted for evaluation, the different data parts are allocated to the sections that will evaluate them. The chemistry and quality control aspects of products are evaluated by the Pharmaceutical Chemistry Evaluation section and the Therapeutic Goods Administration Laboratories Branch. The pharmacological and toxicological aspects of products are assessed by the Drug Toxicology Evaluation section and the clinical data are assessed by the Clinical Evaluation section which specialises in medicines for that condition. All of these areas may use the advice of experts and contract out aspects or the entire part of the evaluation process. Evaluation reports are prepared independently by the evaluators following guidelines.
Following evaluation, the chemistry and quality control aspects of a product are likely to be referred to the Pharmaceutical Sub-Committee (PSC), which is a sub-committee of the TGA prescription medicine expert advisory committee, the Australian Drug Evaluation Committee (ADEC) <http://www.tga.gov.au/docs/html/adec/adec.htm>. The PSC consists of experts with pharmaceutical manufacturing and other expertise. The PSC reviews the evaluation reports prepared by the quality control evaluators and the questions that are asked of the company and advises on whether these are reasonable or not. The recommendations of the PSC are given to the company, as are the in-process chemistry and quality control evaluation reports.
In all evaluation sections, the evaluators may ask questions to clarify issues during the evaluation process or to request data that have not otherwise been submitted. When evaluation reports are finished, they are examined by a senior officer within the section to ensure that they are complete and are of an adequate quality. Evaluation reports are then sent to the sponsoring company. The company is allowed the opportunity to provide corrections or comments on the views expressed within the evaluation report.
The applicant may also, in the case of the pharmaco-toxicological and clinical evaluation reports, signal to the TGA its wish to submit supplementary data to address points raised in these evaluation reports. This intention must be notified soon after receiving the reports and causes the clock which monitors the time spent on evaluations to stop for an agreed period which has been negotiated between the industry and the TGA. The supplementary data will be submitted and evaluated with a new time frame.
When all the evaluations are complete, a senior medical officer within the TGA prepares a document outlining the key issues on which advice is sought. For new medicines advice will usually be sought from the Australian Drug Evaluation Committee (ADEC). If the product is already marketed and the current application seeks only to extend its use, and there is agreement amongst evaluators, the senior medical officer and the company, then the advice may be sought from the Peer Review Committee. The summary is sent to the sponsoring applicant who is able to submit a response dealing with issues raised in the summary and those not previously addressed in the evaluation report. This response goes direct to the ADEC or Peer Review Meeting and is not edited by the senior officer.
The ADEC is an expert advisory group appointed by the Minister. The Committee meets every two months and examines applications referred to it by all the TGA. It also provides advice on matters to do with drug regulation and specifically, on whether new chemical entities should be approved for marketing in Australia and whether products already approved should have their indications varied. The Committee receives full copies of the clinical evaluation report, the toxicology/pharmacology report, a summary of the pharmaceutical chemistry evaluation report and the minutes and resolutions of the PSC if relevant. Its resolutions are provided to sponsor companies after five working days.
The Peer Review Committee is a group of senior medical officers from all area of Prescription Medicine Regulation that meet to consider non-contentious applications for other than new medicines. All senior medical officers within DSEB and ADRAC are requested to attend peer review meetings. These include officers from other streams, experimental drugs and the adverse reactions area.
A delegate within the TGA is the decision-maker who takes into account the advice of the ADEC or Peer Review Committee in reaching a decision to approve or reject a product. Approvals may have conditions associated with them.
Strengths of the system are the independent checking of the quality of the review process at all levels and the inbuilt transparency. This ensures a fair process for all parties involved.
At times there is confusion about the availability of medicines in Australia. It is a requirement under the Act that a sponsor initiate an application. It is not possible for the TGA to require a potential sponsor to submit an application. There may be a number of factors that will influence whether a company will apply to have a product registered in Australia. For example, the product may be registered overseas but a local company does not have a licence agreement. There may also be delays because dossiers may be submitted at different times throughout the world.
It is also possible that a product is approved, but the sponsor company may choose not to supply the product or not to launch it for some time after approval is given. The TGA is aware of examples where products have been launched one to two years after TGA approval was actually given.
The time taken to approve a product can vary considerably. This time consists of time spent by TGA evaluating the product and time spent with the company clarifying questions raised by the TGA. The TGA and industry work together to reduce the total evaluation time. The total time is heavily dependent on the quality of the submission as initially received and on the preparedness of the sponsor to work with the TGA. For example, the approval of the anti-cancer drug Glivec, or imatinib, was achieved within five calendar months. It was a very short time and was a result of the company's preparedness to work with the TGA and to provide information quickly to the TGA during the evaluation process.
An international research institute, CMR International, has published some comparisons of the approval times for new chemical agents from different regulatory agencies. It concluded that Australia's performance was similar to those of comparable international agencies, including the US and Europe.
The TGA has a system of priority evaluation for products that meet certain criteria: the product should be a new chemical entity (that is, it is not otherwise available on the market as an approved product); and, the product is for the treatment of a serious, life-threatening illness for which other therapies are either ineffective or not available (that is, that the product should offer a significant therapeutic advance). The allocation of a priority review is limited to these circumstances as it is very resource-intensive.
The European Guidelines referred to above, which have been adopted by Australia, allow for the approval of products for certain serious conditions, such as cancer or HIV, based on Phase 2 trials. For example, in the case of serious cancer for which there is no available treatment, approval may be based upon Phase II date. There is no requirement for a trial for every medicine to be conducted in Australia before a product can be approved. There are, however, requirements that trials be conducted in accordance with international good clinical practice and ethical standards, and requirements regarding the minimum quality of trial data.
There are some legal exemptions to the requirement for a product to be registered by the TGA. These are implemented through the clinical trials systems <http://www.tga.gov.au/ct/index.htm> (CTX and CTN) and the Special Access Scheme (SAS) <http://www.tga.gov.au/hp/sas.htm>.
The TGA has a multi-faceted program for monitoring approved products that are on the market. There is a problem reporting system, a recall unit, and reporting of adverse drug reactions is encouraged by the Australian Drug Reactions Advisory Committee <http://www.tga.gov.au/adr/adrac.htm>. This Committee publishes a regular bulletin (Australian Adverse Drug Reactions Bulletin) <http://www.tga.gov.au/adr/aadrb.htm> for doctors, dentists and pharmacists. The TGA Laboratories undertake random and targeted sampling of approved products. Sponsoring companies are also required to provide regular post-market reports on approved products and to inform the TGA of any international concerns related to the safety or effectiveness of a product.