CLINICAL TRIALS IN AUSTRALIA: SUN, BEACHES AND LIFESTYLE ARE NOT THE ONLY REASONS TO GO THERE

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1 CLINICAL TRIALS IN AUSTRALIA: SUN, BEACHES AND LIFESTYLE ARE NOT THE ONLY REASONS TO GO THERE Although the major drug development regions of the world are recognized to be North America, Europe and Japan, continuing growth of the pharmaceutical market into emerging regions is being accompanied by similar growth in clinical trial activity outside the traditional big three markets. This increasing interest in undertaking clinical trials within emerging markets has been reflected in recent editions of Applied Clinical Trials where feature articles have included overviews of Africa and of South Korea. Australia might be considered as laying somewhere between: Australia s market size certainly does not compare to the big three pharma superpowers, nor can it be considered as an emerging market, however despite appearing to be in this no-man s land, in a recent international benchmarking study undertaken by The Economist Intelligence Unit Australia was identified as the number one location to conduct pharmaceutical clinical trials. The Economist Intelligence Unit study, Benchmarking Study of the Australian and International Pharmaceuticals Industries, was commissioned by Australian Government Department of Industry, Tourism and Resources, Invest Australia, and the Victorian Government Department of Innovation, Industry and Regional Development. It compared and benchmarked Australia against the USA, the UK, Germany, Japan, Singapore and India across a range of indicators including clinical trials, the intellectual property system, the regulatory environment, investment and the business environment. Australia ranked second overall, with Singapore ranking first. Australia scored highly for many indicators relating to the pharmaceutical? industry skills pool, practices and regulatory processes but scored below Singapore and India on costs. In relation to clinical trials, Australia ranked first overall (as a weighted aggregate), boosted by low average costs of clinical trials, a relatively large amount of recognised trial sites and a high percentage of clinical trials completed within the allocated time. Of particular interest to overseas sponsors was the observation that Australia does less well on the total amount of clinical trials taking place even on a per capita basis, suggesting there is capacity for further growth within the sector. While being identified as an attractive location for conducting clinical trials is music to the ears of the Australian pharmaceutical and biotechnology industry a AUD$12 billion industry employing 35,000 people, exporting almost AUD$2 billion a year 1 and the second largest contributor among manufactured goods to the Australian economy (more than its wine industry) potential clinical trial sponsors are perhaps more concerned with the realities: will my intellectual property be protected, how do I obtain regulatory approval and how long will it take, how fast can I enroll patients, how do I get my clinical trial material into Australia, will the study be performed according to ICH GCP and will the FDA or the EMEA recognize the quality of the study and accept the Australian data? 1 Australian Biotechnology News maybe ask Maria for source?

2 Perhaps reflecting its historical and constitutional links with Great Britain, Australia s regulatory framework for therapeutic goods is primarily based on that of the European Union. Periodically the Australian Therapeutic Goods Administration (TGA) reviews regulatory guidelines issued by the European Community (EC) and issues statements on whether a specific EC guideline has been endorsed or not. In particularly innovative, controversial or evolving regulatory matters the TGA tends to take a best practice approach, whereby it considers existing overseas guidelines, particularly those issued by the ICH, the EC or the FDA, in the context of the local Australian industry, healthcare and social factors. A good example of this best practice approach is the Therapeutic Goods Administration (TGA) and the National Health and Medical Research Council (NHMRC) jointly established Review of the Australian Arrangements for Clinical Trials and Access to Unapproved Therapeutic Goods (referred hereafter as the Review ) that was commissioned in April 2003 and the report published in February 2005 (see The motivation for commissioning this Review was multifaceted, including: the coming into force of the Clinical Trial Directive 2001/20/EC in the European Union (EU); the goals of ensuring the timely access to safe and efficacious new therapies for the public while ensuring public safety and that the Australian pharmaceutical industry remains internationally competitive; and also the expected formation of the joint Australian and New Zealand Trans Tasman Regulatory Agency in July 2006 (see box?). Public submissions in response to the Review s report closed on 8 July 2005 and are under consideration. The response of the Australia authorities to the Review s recommendations is still the subject of speculation but it seems likely that the EU Clinical Trial Directive 2001/20/EC will not be fully endorsed in Australia and that the existing regulatory framework for clinical trials in Australia, the Clinical Trial Exception (CTX) and Clinical Trial Notification (CTN) schemes (see Box?), will continue albeit with some tweaks here and there; such as additional support for the institutional ethics committees (IEC), especially in the context of advance and high technology investigational products. As highlighted in the Review, there is a lack of publicly available data on the nature and number of clinical studies conducted in Australia, especially in recent years. Data taken from 1990 to 2000 presented in Figure 1 2 below demonstrates that the far majority of clinical trials are conducted under the CTN scheme and that trend has certainly continued. The Review also indicates that during the 1990 s the majority of clinical trial sites were in Victoria and New South Wales (see Figure 2) 3, the Australian States with the greatest population, and the far majority of studies were Phase 3 (see Figure 3) 4. Although the data presented in Figure 2 and 3 is several years old, there is little reason to expect that the predominant locations of the clinical trial sites has changed significantly, despite increasing activity in the biotech industries within Western Australia and 2 Table 2 from Rankin report 3 Table 4 from Rankin 4 Table 5 from Rankin

3 Queensland. Similarly one would not expect the proportion of the study type performed to have changed dramatically, although if the Review s recommendations are endorsed by the Australian authorities the comparative simplicity of the CTN scheme in comparison to the FDA investigational new drug application (IND) or EU clinical trial application (CTA) procedures may become increasingly attractive to time and money sensitive sponsors eager to generate early proof-of-principle clinical trial data. Hence in comparison to the EU or the USA the regulatory framework for clinical trials in Australia is quite attractive for overseas sponsors. Despite this, and the observations that Australia is internationally recognized for its science and highly trained workforce, has an intellectual property (IP) regime that compares favorably to the EU and the USA, and appears to deliver in terms of ICH GCP-standard clinical trials performed in a timely and cost effective manner, the total number of studies conducted is relatively small in comparison to the EU or the USA. The reasons for this are multi-factorial, including the modest size of the local industry and of the local pharmaceutical market. Further, despite a relatively multicultural society, especially on the East coast, the relative size of the potential trial subject pool is modest and perhaps counter-balances the time and cost efficiencies that Australia can offer in terms of trial conduct, particularly for larger trials. An additional complication for overseas drug developers is the need for a local commercial sponsor for an Australian study, and the fact that organizing local insurance for the study can often be problematic. Of course geographical distance and time differences also must be considered, although with strong project management the time differences can be exploited by increasing the overall working day for a particular project. EU and USA-based drug developers must focus their development activities in those regions and it is not doubt preferred by the regulators in those regions. However, in certain circumstance Australia is an attractive option. As discussed above, in many cases early phase or proof-of-concept studies can be conducted without the burden of an EU CTA or USA IND, a significant advantage in these extremely competitive times. With the data generated to ICH GCP standards and subject to stringent IP regimes, it can be used to add substance to fundraising or partnership activities, and to support future clinical trial applications in the EU and USA. For later stage development, given their quality and cost-effectiveness, Australian sites in an international multiple-site clinical trial program can add value, especially in indications that have a high prevalence rate in Australia (such as melanoma or asthma) or that are seasonal (such as rhinitis). Of course with strong project management there is also the possibility of taking some time to soak in the sun and the Australian lifestyle!

4 BOX X REGULATION OF CLINICAL TRIALS IN AUSTRALIA THE CTN & CTX SCHEMES Clinical trials of medicines and medical devices in Australia are subject to national government regulations administered by the Therapeutic Goods Administration (TGA). There are two schemes under which clinical trials involving therapeutic goods may be conducted, the Clinical Trial Exemption (CTX) scheme and the Clinical Trial Notification (CTN) scheme. Either a CTX application or a CTN notification is required to conduct a clinical investigation of a product where that use involves: o Any product not entered on the Australian Register of Therapeutic Goods, including any new formulation or new route of administration of an existing product, or in the case of a medical device, new technology, new material or new treatment modality, or o Use of a product beyond the conditions of its marketing approval, including new indications and the extension of doses or duration of treatments outside the approved range. The CTN Scheme All the material relating to the proposed trial, including the protocol, is submitted directly to the Institutional Ethics Committee (IEC) by the principle investigator at the request of the Sponsor. The IEC assesses the scientific validity of the trial design, the protocol, the safety and efficacy of the investigational therapeutic good, and the ethical acceptability of the trial. When satisfied the IEC, the Approving Authority, gives the approval for the study to be initiated at the site that it has jurisdiction over. The IEC signs the CTN form and the sponsor sends the form to the TGA, who logs it in their database but does not conduct a formal review of the study. Although it is not legally required some sponsors prefer to wait for the TGA s acknowledgement before commencing the study at that site. Timelines: varies according to the IEC, who typically meet monthly, and the specific issues that might arise. A complete submission could expect to be approved within 2-3 months from the date of receipt of the submission, which consists of a study protocol, Investigator s Brochure and a Patient Informed Consent Form. Cost: Each IEC have modest individual fee structures, ranging from a few hundred to a few thousand Australian dollars. The TGA notification fee is AUD$240/site for a medicinal product and AUD$260/site for a medical device. The CTX Scheme Under the CTX Scheme a sponsor submits an application to conduct clinical trials to the TGA for evaluation and comment. The TGA reviews the information provided by the sponsor, including the proposed Usage Guidelines for the investigational product. If an objection is raised the clinical trial cannot commence until it is addressed to the TGA s satisfaction. A CTX applies to all clinical trials conducted under the specified Usage

5 Guidelines; however the sponsor must obtain subsequent IEC approval for each clinical trial performed. The CTX and IEC applications can be made concurrently but the IEC must be kept informed of the TGA s comments and recommendations relating to the CTX. Once the CTX and IEC approval is obtained, the sponsor must notify the TGA within 28 days of commencing to supply the goods at each individual site. Timelines: the TGA s review time is 30 days if the application contains data only relating to chemical, pharmaceutical and biological issues, and 50 days if the application also includes pharmacotoxicological and clinical data. Cost: for medicinal products the TGA fees are AUD$1,240 for a 30 day evaluation and AUD$15,300 for a 50 day evaluation. The comparable fees for devices is AUD$1,850 and AUD$12,300. The IEC fees are the same as for a CTN (see above). CTN vs CTX The choice of whether to follow the CTN or the CTX scheme lies with the sponsor and then with the IEC. For the sponsor the CTX is an opportunity to interact and obtain advice from the TGA on the development of the product, which can be useful in the early phase of development, particularly for local industry. For the IEC, the determining factor is whether it has access to appropriate scientific and technical expertise in order to assess the safety of the product and approve the clinical trial under the CTN scheme; if the IEC deems that is does not then they can request that a CTX be lodged with the TGA. The far majority of clinical trials conducted in Australia are performed under the CTN scheme. Gene Therapy and Related Therapies It is important to note that clinical trials involving gene therapy or related therapies require approval from both the IEC and the Gene and Related Therapies Research Advisory Panel (GTRAP), an expert committee established by the Australian National Health and Medical Research Council (NHMRC). Importation of Clinical Trial Material Being an island Australia is quite protective of its borders. Typically a specific import permit is not required for clinical trial material, however some clinical trial materials may be subject to additional restrictions and separate approvals may be required (for example products containing substances that are listed as prohibited imports, and materials of biological origin).

6 BOX X The Pros and Cons of Conducting Clinical Trials in Australia PROS - Most studies conducted without a clinical trial application to the competent authority (CTN) - Highly skilled clinical trial staff trained in ICH GCP - Cost-effective in comparison to EU and USA - High percentage of clinical trials completed on time - Multicultural population - Prevalence of some medical conditions (such as melanoma, asthma) - Possibility of continuing seasonal studies in Australia during off-season in the Northern Hemisphere CONS - Geographical distance and time differences - More expensive than many emerging markets, such as India and Singapore - Modest population and therefore pharmaceutical industry size - Requirement for local commercial sponsorship and insurance - Need for multiple ethics committee submissions for multi-site studies in Australia - Rigorous review gene-therapy and related therapy studies