Adoption of best project management and drug development practices have driven significant changes within clinical trials in Asia and Eastern Europe Eric Morfin director of PMO at Chiron Corporation discusses the many opportunities now available in these new and growing areas
The area of global clinical trials has seen some exciting changes in the recent years. Not only have project management best practices greatly influenced the development and management of global clinical trials within GCP guidelines and FDA regulations, but these practices have also enabled project managers/leaders and clinical trial specialists to face the challenges encountered when conducting trials outside the USA with more success (specifically language and cultural differences, and medical practices). These practices have become critical for the successful implementation of clinical trials in what can be called the new and emerging areas of clinical trial opportunity - India, China, South Korea and Eastern Europe.
Across all these countries, there are common issues to watch for. For example: the lack of intellectual property. India has started to enforce new intellectual property laws this year and it should go along way toward addressing some of the issues encountered in past years. Protection in Eastern Europe is still patchy; it depends very much on what country you are dealing with. In China, there is no protection, however the status of favoured nation is placing additional pressure on China to comply.
Another common area to watch for is the implementation of GCP and ethical standards. India accepts ICH GCP and has produced FDA-approved NDA studies for Pfizer, Lilly and Aventis. Clinical studies in India are mandatory for approval in India. Eastern Europe again differs depending on the countries. The Baltic States (Estonia, Latvia and Lithuania) have high standards for GCP and follow the EU Directive. Hungary and Poland have also high standards for GCP and are EU Directive compliant.
Russia has in many areas high-quality medicine, but lacks the trained resources. The political situation is rather fluid. If planning a trial in an ex-USSR nations, it is recommended that specialist CROs be used. China follows its own rules to some extent. Approval in China requires the enrollment of 300 national Chinese patients in the study. Diet, herbal medications and acupuncture are often concurrent to drugs and this is regularly the source of confusion. Overall, China accepts the general principles of ICH GCP. In terms of patient recruitment, India, Eastern Europe and China all have a large patient population that facilitates rapid recruitment. These countries also have untreated virgin diseases. India has the advantage of having investigators who are western trained. Study and site logistics can sometimes be a problem.
Japan is the most established Asian pharmaceutical market, but cost containment measures implemented by the government to slow healthcare spending have proved unpopular with the international pharmaceutical industry, and many companies have begun to look to additional national markets in the region.
China has received the most interest in the media, largely due to the fact that its economy is growing at a tremendous rate and foreign firms in a variety of sectors, including pharmaceuticals, have invested heavily there.
South Korea is another Asian country that has attracted the attention of pharmaceutical companies, and the increasing popularity of the country for foreign businesses has largely gone unreported by the media. From a pharmaceutical company perspective, the South Korean government's renewed focus on healthcare and demand from the population for new medicines is providing a long-term incentive for pharmaceutical companies to invest in the country.
In terms of clinical trials,major reasons cited for carrying out clinical trials in South Korea include providing local physicians with experience of the product and generating additional data from post-marketing surveillance work.
Interestingly, some companies expressed that the requirement for them to carry out additional local clinical trials at the pre-submission stage acted as a major barrier to the rapid registration of their product in South Korea. Barriers are also a feature of other Asian markets such as China, India, and Malaysia, but these factors were not deterring companies from making further investments in South Korea.
The major attraction for pharmaceutical companies has been the separation of medical prescribing and dispensing, which represents a key part of South Korea's landscape. Since the prescribing changes were finally introduced, multinationals have expanded their share of the total South Korean pharmaceutical market from 23 per cent in 2000 to 26 per cent in 2001, and to 29 per cent in 2002.There were predictions that by the end of 2003, multinationals would achieve a 31 per cent pharmaceutical market share, and a more recent assessment has suggested a market share of 70 per cent by 2005.
There have been frequent complaints by foreign pharmaceutical companies about inadequate data protection measures, excessive requirements in the area of clinical trials for their products, and the lack of transparency of the South Korean pharmaceutical pricing system, as they believe that current procedures favor domestic companies.
In 2000, the Korean Food & Drug Administration (KFDA) registered 34 clinical trials on its database, of which 29 were defined as local trials and five as multinational. By 2002, this number had increased to 55 clinical trials, of which 38 were registered as local trials and 17 as multinational clinical trials. In 2003, the KFDA recorded 107 clinical trials on its database, of which 67 were local and 30 multinational. Potential improvements I would be more f ocus on the technical expertise available in these regions to carry out studies to international standards, and more focus on the existence of an ethics system that ensures subjects are well cared for and that they participate in studies of their own free will.
Some significant changes took place over the last few years. In the 1980s, a number of IRBs were set up and in 1995 their importance was confirmed when Korean Good Clinical Practice (KGCP) guidelines, which stated that clinical trials had to abide by IRB regulations, were introduced. In 2001, the government revised KGCP in line with ICH-GCP and in 2002, the Korean Association of Institutional Review Boards conducted a survey of IRBs operating in the country. Out of 74 IRBs approached, 63 responded to the survey.
Around 80 per cent of the respondent IRBs confined the scope of their evaluation to the clinical evaluation of drugs or medical devices. The IRBs appeared to limit their work to those areas that they were legally obliged to review rather than extending them to cover other areas of research involving human participants.
There is also a growing interest in stem cell research. Today, IRBs are still considered a new concept. There is a worry that given the volume of biomedical research being carried out in South Korea, the IRBs are not yet ideally structured nor experienced enough to handle the increase in workload.
The KFDA is the regulatory agency for food, drug, and other cosmetic products in South Korea and instigates guidelines and procedures concerning medicinal products, medical devices, cosmetics and biological products. The KFDA is also involved in ensuring the safety and effectiveness of medicines, regulating controlled drugs, and approving manufactured and imported medical devices. In terms of submission, an initial consultation is recommended by the agency, which can vary in terms of time and content depending on the type of product under investigation. Following consultation, the sponsor then submits the application dossier, which should include essential documents such as the protocol, investigators brochure, CMC section and preclinical data. The KFDA has shortened regulatory approval timelines to bring them more on a par with those in North America and Europe, and consequently, sponsors can now expect authorisation within 30 days of receipt of the clinical trial application.
The overall approval procedure in South Korea is further expedited due to the possibility of making parallel submissions to both the ethics committees and the competent authorities, with the import permit issued along with regulatory approval. Nevertheless, time must be allocated to ensure that the full CTA dossier is fully translated into Korean prior to the submissions. Once the application is received by the KFDA, assessors in the appropriate departments review the dossier. This assessment is normally done within the Pharmaceutical Safety Bureau, which reviews all data associated with the CTA in compliance with national standards. At present, the KFDA is poised to make further changes to their pharmaceutical regulations and an effort is currently being made to publish an English version of their present legislation on the KFDA website.
For marketing authorisation applications, in contrast to the competent authorities in the USA and the EU, the KFDA has historically required repetition of clinical trials already performed outside of South Korea for products that have been developed within a reasonably short time frame. For the sponsor, this has inevitably resulted in increased overheads and caused unwanted delays in the registration process. The KFDA, however, is making imminent plans to amend the existing requirements and bring them more in line with ICH guidelines. Timelines for marketing authorisations vary depending on the product in question, but on average authorisation takes approximately 70 days.
Overall, there are significant opportunities in these new and growing areas of clinical trials. There has been huge changes in these countries recently, many of which are driven by the adoption of best project management and drug development practices. While South Korea certainly holds much promise, the coming changes in China will also be of great interest.