'Developing' Japan intent on clinical trial catch-up
lagging behind the rest of the developed world in the availability
of drugs in the country, which ironically is the world's number two
pharma market behind the US.
An English-translated version of new draft guidelines developed as part of proposed reforms was released for the first time at last week's Drug Information Association (DIA) conference in Vienna, Austria, by the Japanese regulatory authority, the Pharmaceuticals and Medical Devices Agency (PMDA). However, while copies were obtainable at the conference, the document will not be available on the internet "for some time yet, perhaps several months," Masaki Fujii from the PMDA told Outsourcing-Pharma.com. The $60bn (€45bn)-a-year Japanese pharmaceutical market has been forever in a state of what is known as "drug-lag" since it takes on average 3.5 years longer for a drug to hit this market than it does in the US and Europe. Japan is the worst of the Asian countries to be affected by the drug-lag curse - in 2004, of the 88 top-selling drug products, 32 (36 per cent) were not available in Japan, with the next most affected countries being Singapore and Chinese Taipei which had 10 and 20 more drugs approved than Japan respectively. "Japan is still a developing country as far as clinical trials are concerned," Noriaki Muraro, representative director of Schwarz Pharma Japan, told delegates during a presentation at the DIA. Because of inter-ethnic differences in dose-response between Japanese and Caucasian populations, in order to get a drug approved in Japan the regulators have insisted that Phase I-III pharmacokinetic (PK) clinical trials must first be carried out on the drug in Japanese populations - a costly and timely process. The Japanese clinical trial environment has typically been less than welcoming, burdened by red tape (sometimes up to 150 essential documents being required as part of good laboratory practice (GLP) paperwork), language barriers, slow patient recruitment and trial duration (often 2-2.5 times longer than in the US and Europe). As a result, many drug companies have been deciding not to make this extra investment in Japan and as such, many much-needed drugs never reach the Japanese market. From a business point of view, Japan is also failing to capture many of the lucrative western clinical trial outsourcing contracts that are flooding into the palms of its neighbouring countries such as Singapore and China. A previous attempt at addressing this lag - the introduction of ICH E5, a bridging strategy introduced in late 1990s allowing a western PK Phase III data to be submitted if Japanese Phase I-II PK data was found to be comparable with the western Phase I-II PK data - has failed, with no new drugs approved within the desired 12 months between 2003-2005. According to Muraro, the current Japanese government, led by Prime Minister Junichiro Koizumi, responded for the first time on a national level to this mounting problem at the end of the 2006 and began to actively promote the Japanese pharmaceutical industry, in which clinical trial reforms were given a central stage with a new budget to match. Four progression paths were laid down by Koizumi: the promotion of clinical trials in Japan, particularly on a global level, and the establishment of a clinical trials issue review committee; a five-year plan for clinical trials; new guidelines for global studies; and improved resources for clinical trial review processes. Included in the reforms are plans to develop new infrastructure, education of both doctors and patients, improve the GCP documentation process and invest in IT. In addition, the PMDA plans to hire an additional 236 clinical trial reviewers over the next two years to more than double the number it currently has. To help fund this they are also increasing their user fees for all regulatory meetings with trial sponsors. "Achieving a cost and speed that is comparable to the US and Europe and running a number of global clinical studies that is comparable to other Asian countries are the primary goals for the Japanese government," said Muraro. "It is hoped that the effects of these reforms will begin to materialise within one to two years." As a reflection of the seriousness of Japan's intentions to catch up with the rest of the developing world in the clinical trial arena, the PMDA made its presence felt at the DIA conference for the first time. The agency released the first English version of the proposed new guidelines for global studies, which offers guidance for trial sponsors wanting to conduct research in the country. A strong emphasis is placed on encouraging Japan's inclusion in global clinical trials from the outset. "To substantially solve the drug-lag problem it is necessary to synchronise drug development timings in Japan with those of other countries," the document states. "It is recommended [to sponsors] to consider the timing beforehand [when designing a global trial] so that Japan can participate in the global clinical development from the earliest possible timing, and at the latest from dose-response studies following the completion of a proof-of-concept study." In principle, the guidelines state that the dosage regimen to be used in the global trial should be confirmed beforehand as to whether it does not have any particular safety problems for the Japanese. "For this purpose, it is appropriate before the start of the global study to first examine single-dose safety and PK in healthy Japanese volunteers, compare the results with those of the non-Japanese, and confirm there is no particular concern regarding increased risk in the Japanese." Ten further points are addressed in the draft document.
