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.
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.
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in the Asia-Pacific Region
The Asia-Pacific region is becoming increasingly attractive for global clinical development activities. There are numerous factors driving this trend, including a shortage of trial volunteers in Europe and North America, the sophisticated healthcare systems in many Asian countries, and the availability of highly trained medical professionals in the region. Equally important, Asia is the fastest growing pharmaceutical market in the world, providing significant opportunities for drug development and marketing.
At the same time, the Asia-Pacific region presents a major challenge: a complex and continually evolving regulatory environment. This complicated regulatory landscape can be a barrier to success for foreign companies that don’t have the experience or resources that are essential to overcome the obstacles in countries such as China, Japan, Korea, and Taiwan.
China
China’s growing economic strength and population of more than a billion people hold tremendous potential for global pharmaceutical companies – both as a location for clinical trials and a market for novel therapies. That potential is tempered by the daunting regulatory requirements for pharmaceutical products in China – requirements that have only recently begun to improve.
One of the major drawbacks is the time it takes to receive regulatory approval for a clinical trial: an average of 9-12 months, plus 1-2 months for Independent Review Board (IRB) approval. In October 2007, China’s State Food and Drug Administration (SFDA) issued a new guidance that established timetables for some parts of the review process – a change that has reduced the average review time by 1-2 months. However, this improvement has been offset in the short term by changes in the personnel assigned to review applications for clinical trials. These new reviewers will eventually help speed up the process, but their training requirements have created a temporary slowdown in reviews.
Another important change involves China’s requirements for locally generated Certificates of Analysis (COA) for ingredients in drugs to be tested in the country. For multinational trials that include Chinese patients, the COA requirement can now be waived if a chemical-based product is not going to be registered for sale in China. For global pharmaceutical companies, this change means that Chinese patients can now be more easily included in multinational trials – an important benefit at a time when patient recruitment in other parts of the world is becoming more difficult. However, a local COA is still required for drugs targeting the Chinese market, and for any biological product.
The SFDA regulations covering the requirements for Chinese patients participating in clinical trials have also been eased. For products that will be registered in China, local pharmacokinetic (PK) studies must be conducted in Chinese patients. In addition, a specified minimum number of Chinese patients must be included in multinational Phase III trials for products that will be sold in China. This is a major change from past practice, when separate Phase III trials in China were required – a change that should encourage global pharmaceutical companies to include Chinese patients in multinational trials so they can bring their products to the Chinese marketplace more quickly.
The export of whole blood and tissue samples remains a significant challenge in China. A sponsor must apply for an export permit for each shipment – a process that can take weeks. These restrictions have been eased somewhat in recent months, but the process remains difficult. Given the growing importance of centralized laboratories for patient sample analysis, this burdensome export process poses a substantial drawback for clinical trial programs in China.
Japan
The challenging regulatory environment in Japan has improved substantially in the last decade. The adoption of the International Conference on Harmonisation (ICH) “Guideline on Ethnic Factors in the Acceptability of Foreign Clinical Data” (E5) in 1998, and the approval by Japan’s Pharmaceutical and Medical Devices Agency (PMDA) of a new guideline called “Basic Concepts for International Joint Clinical Trials” in 2007, have eased the country’s strict restrictions on accepting clinical data from non-Japanese patients. These changes resulted from public health concerns about the “drug-lag” challenge facing Japan, where new biopharmaceutical products typically enter the market more than four years after their approval in the U.S. or Europe because of the difficulty of conducting trials in Japan.
The regulatory changes signal Japan’s awareness that its policies must be more flexible in the area of non-Japanese clinical data if the drug-lag issue is to be addressed. However, the regulations continue to require sponsors to account for ethnic differences when gathering and submitting data for drugs intended for sale in Japan. The PMDA guideline strongly recommends early pharmacodynamic (PD) and PK studies involving healthy Japanese volunteers to assess patient safety and ethnic factors. While the amount of non-Japanese data accepted by the PMDA is limited, it is possible that the Agency may allow larger percentages of data from non-Japanese patients – especially from ethnically similar populations – as they gain confidence in trial data from other countries.
In addition, the PMDA still requires most of the pivotal Phase II/III studies to be conducted in Japan. This requirement will continue to cause delays in conducting trials and submitting regulatory filings in Japan because of the high cost of conducting trials and the shortage of available volunteers.
Another regulatory challenge in Japan is the relatively slow review and approval process, which takes an average of 2.5 years longer than in the U.S. Part of that delay is the result of a shortage of reviewers. In 2005, Japan had just 197 reviewers for drug applications, compared with 693 in the UK, 942 in France, and 2,200 in the U.S. In June 2007, the PMDA announced that it was increasing the number of reviewers by 236 over the next three years to help speed up the process.
Korea
Until a few years ago, obtaining approval to import a foreign investigatory new drug (IND) into Korea was very difficult. In most cases, an IND could be submitted only after a drug had received market approval in the U.S. or Europe. Since 2002, however, companies conducting multinational studies have been allowed to include Korean patients in clinical trials at the same study stage as trials being conducted elsewhere. This change has greatly improved the regulatory climate in Korea, and is paving the way for Korean patients to have access to novel therapies much more quickly than in the past. It has also provided new opportunities for global pharmaceutical companies looking to expand their multinational trials.
Officials in the Korea Food and Drug Administration (KFDA) continue to be sensitive to ethnic equivalence in safety and efficacy data gathered from foreign patients. However, sponsors can utilize the provisions of the ICH E5 guideline on ethnic factors to demonstrate the applicability of foreign trial data to patients in Korea.
Other significant changes in the regulatory environment in Korea include:
- Implementation of GCP standards at major health centers across the country
- Changes in KFDA regulations that now require INDs to be approved within 30 working days (if no additional information or clarifications are necessary)
- Significant reductions in the requirements for translating regulatory documents into Korean
Taiwan
Like other countries in the Asia-Pacific region, Taiwan has implemented a number of changes in recent years to improve the regulatory environment for clinical trials involving foreign pharmaceutical companies. The Department of Health and its Center for Drug Evaluation are working closely with the FDA to share knowledge and opinions aimed at bringing Taiwan’s regulations more closely in alignment with those of the U.S. and Europe. Taiwan has also established a program that allows its regulatory reviewers to receive training from FDA officials on best practices and procedures for reviewing IND and NDA submissions.
Additional changes to improve the regulatory process in Taiwan include:
- Shorter timelines for regulatory reviews and approvals
- New procedural regulations that are bringing greater transparency to Taiwan’s regulatory processes
- Increased emphasis on strong scientific data in regulatory submissions and official reviews
Meeting the Challenges
The Asia-Pacific region is one of the most vibrant and rapidly growing areas in the world. China is expected to become the fifth largest global pharmaceutical marketplace within the next few years. The environment surrounding the regulation of pharmaceutical products has shown steady improvement since the beginning of the new century, with significant changes over the last five years. These changes have brought greater transparency and professionalism to the regulatory arena, and increased the opportunities for the pharmaceutical industry to conduct clinical trials and introduce novel therapies. In fact, health officials in the region have made it clear that they want to play a greater role in the global drug development process and offer their citizens the latest therapies at the same time they are available in Europe and North America.
However, major regulatory challenges remain for pharmaceutical companies looking to expand their clinical trial programs into this region. Equally important, the challenges are different for each country. The Asia-Pacific region cannot be treated as a single market, but must be approached with an abundance of local knowledge. Success is contingent upon understanding the regulatory – as well as medical and social – nuances that characterize each country.
With the right combination of local knowledge, perseverance, and flexibility, sponsors can overcome most of the challenges and take advantage of the opportunities to expand their clinical development programs in this dynamic part of the world.
The author of this article, Albert Liou, is the Corporate Vice President and General Manager for PAREXEL APEX International.
To contact Albert Liou about "Regulatory Challenges in the Asia-Pacific Region," CLICK HERE.