Metrics: Trials by the Numbers
Asian countries continue to be increasingly important locations for today's clinical trials. In a study of clinical investigators signing on to conduct new clinical trials in 2007, PAREXEL found the following:
Hans van Bronswijk, M.D., Ph.D. VP, European Drug Development Practice, PAREXEL Consulting
Dr. Van Bronswijk is an internationally recognized drug development authority, with a unique combination of global regulatory, medical, scientific, and pharmaceutical industry experience.
Best Practices: Ethnobridging
and the Japanese Pharmaceutical Market
The process for developing and introducing new biopharmaceutical products for the Japanese market has evolved significantly over the past decade. In the past, Japanese regulators required that clinical trials be conducted in Japan for any potential new pharmaceutical product to be approved for sale in that country – even if successful trials and regulatory approvals had already taken place in other parts of the world. As a result of these policies and the high cost of conducting trials in Japan, many novel therapies are unavailable to Japanese patients, or become available long after they reach the market in other regions. Because of serious public health concern about this time lag, Japan’s Pharmaceutical and Medical Devices Agency (PMDA) is demonstrating increasing flexibility in accepting some foreign clinical trial data in an effort to speed up drug development in Japan.
The first major change came in 1998 with the adoption of the International Conference on Harmonisation (ICH) “Guideline on Ethnic Factors in the Acceptability of Foreign Clinical Data” (E5), which established procedures under which clinical trial data gathered in one region could be used to fulfill certain regulatory requirements in other regions. Another important change occurred in 2007, when the PMDA approved a new guideline entitled “Basic Concepts for International Joint Clinical Trials.” This guideline expands Japan’s criteria for accepting clinical data from non-Japanese patients, and encourages Japanese pharmaceutical companies to participate in joint international trials that would bring new products to Japan more quickly.
For sponsors seeking to expand their presence in Japan – which is the world’s second largest pharmaceutical market, after the U.S. – these changes offer significant new opportunities to generate clinical data from outside Japan to meet Japanese regulatory requirements. At the same time, Japanese regulators continue to be sensitive about ethnic differences between various populations that could impact the safety and efficacy of new products for Japanese patients.
To take advantage of these opportunities to utilize foreign clinical data, sponsors must be able to demonstrate a scientifically relevant link between patient data obtained outside Japan and Japanese patients – a concept called ethnobridging. These bridging studies fall into two major categories: those that support Phase I trials, and those supporting Phase II/III trials.
Phase I Ethnobridging
The new PMDA guideline strongly recommends that sponsors conduct early Phase I studies involving healthy Japanese volunteers to obtain vital pharmacokinetic (PK), pharmacodynamic (PD), and safety data. Although these studies typically have taken place in Japan (and thus do not require bridging), the high cost of conducting trials in Japan – combined with a shortage of available volunteers – has fostered an alternative approach: conducting the studies on Japanese citizens temporarily living outside of Japan. This alternative allows pharmaceutical companies to more efficiently conduct the early-phase studies utilizing volunteers recruited from the concentration of Japanese nationals in areas such as Los Angeles. In addition to reducing Phase I trial costs by as much as 30-40 percent, this approach provides more reliable results by enabling greater consistency of medical practices and data collection. It also allows the Phase I process to be completed more quickly.
However, these studies – and the volunteers – must meet strict “bridging” criteria in order to be accepted by Japan’s regulatory authorities as representing the Japanese population. The volunteers must be natives of Japan and must have been away from Japan for a relatively brief time – usually no more than five years. In addition, their lifestyle in the U.S. must not have changed significantly since relocating, especially in terms of diet and other health-related factors. This requirement typically means that the volunteers must live in areas with large Japanese communities where they can more readily maintain their native lifestyle. The companies providing these services maintain ongoing relationships with Japanese regulators to ensure that their data will meet the bridging requirements.
Phase II/III Ethnobridging
While Japanese regulators still require that most pivotal Phase II/III trials be conducted in Japan, the ICH and PMDA guidelines allow for the possibility of including some clinical data from other populations if their equivalency to the Japanese population can be scientifically demonstrated by bridging studies. This flexibility offers the possibility that the growing inclusion of Asian-Pacific countries in global clinical trials could provide valuable data to support new drug applications in Japan. Countries that are considered ethnically similar to Japan – such as China and Korea – could play an increasingly important role providing a portion of Phase II/III data for Japanese regulatory filings, but the equivalency of that data for the Japanese population must be clearly established.
Perhaps most important, the recent PMDA guideline states that the Agency will evaluate proposals for joint trials and the inclusion of foreign data on a case-by-case basis, which could allow additional flexibility for orphan drugs or therapies that address serious unmet medical needs. This trend should continue to grow in the years ahead as Japan’s regulatory authorities gain experience – and confidence – with trial data from other populations.
Speeding up development in Japan
Both the pharmaceutical industry and the Japanese government have a vital interest in speeding up and expanding the marketing of novel therapies in Japan. With the improving regulatory environment, more companies are including Japan in their global development plans. The key success factors for faster product development in Japan are:
- Including Japanese and other Asian populations at the earliest stages of development to support efficient global registration and marketing
- Establishing a broad ethnic base of patient data and design studies that can bridge the data between countries and regions
- Performing PK, PD, and other Phase I testing with multiple populations as early as possible to reduce the chances of ethnicity-based safety issues
- Working with Japanese regulators to ensure that study designs, protocols, analytical methods, and bridging strategies will meet their requirements
- Ensuring that all participating nations and institutions conduct trials under Good Clinical Practices regulations as defined by ICH
As the regulatory environment in Japan continues to evolve, the challenge for the global pharmaceutical industry is to find the right resources and best practices to take advantage of this new regulatory flexibility, while understanding the differences that continue to characterize the drug approval process in Japan. With the right approach, global companies can generate an increasing percentage of clinical data from outside Japan over the next few years that should help them reach the goal of bringing innovative therapies to Japanese patients at the same time as patients in other global markets.
The author of this article, Stanford Jhee, Pharm.D., is the Senior Director of Research for PAREXEL/California Clinical Trials.
To contact Stanford Jhee about "Ethnobridging and the Japanese Pharmaceutical Market," CLICK HERE.