TOKYO - Efforts by Japanese regulators to better equip local pharmaceutical companies for the global marketplace could also pay dividends for Western multinationals looking to secure marketing authorization in Japan, according to a recent panel discussion during BIO-Asia in Tokyo.

Panelists concurred that Japan's Pharmaceuticals and Medical Devices Agency is streamlining global clinical trial requirements to accelerate drug approvals for Japanese companies at home and abroad. These changes will also benefit multinationals, according to the Jan. 29 panel.

A Large Moving Ship

A key development related to this new approach was a final notification promulgated by the Ministry of Health, Labor and Welfare Sept. 28, entitled "Basic Principles On Global Clinical Trials." In the notification, MHLW set forth principles for conducting studies through simultaneous development in global trials, as an alternative to the traditional approach of conducting bridging studies after a drug is first approved elsewhere.

For instance, MHLW notes that "to facilitate drug development and reach regulatory approval in Japan at the same time as approvals overseas, it is recommended to include Japanese patients in a dose-finding study to identify inter-ethnic difference[s] in dose-response relationship early in clinical development, and subsequently design a confirmatory study," according to an unofficial translation by PMDA.

However, changes at the agency will take time to fully implement, according to the BIO-Asia panel.

"You must look at the PMDA as a very large ship, and it's moving," KMG Japan Managing Director Kyle Murphy told meeting attendees. "It takes time for it to adjust."

According to Murphy, PMDA is committed to reducing the lag that drugs often face in reaching the Japanese market. After new policy "filters all the way down to the initial reviewers … where they start to have that positive attitude, then it's up to companies to make sure they continue to allow that to grow," Murphy advised.

"The ministry has made clear commitments to be a global player, not only for the ministry itself, but also for its companies," he said. "I imagine they are focusing more on their multinational Japanese companies, as opposed to [Western] multinational companies, but nonetheless it benefits everybody."

Foreign Clinical Data

One area of focus for PMDA is liberalizing its approach to accepting foreign clinical trial data, panelists emphasized.

"PMDA has now accumulated experience in accepting foreign data, and based on their experience they have found some disease areas that ethnic differences will be observed," Bristol-Myers Squibb Japan Regulatory Science Director Eiko Tomita said. "In such areas, they will become conservative for accepting foreign-based data. However, in the other areas they have started accepting foreign data," she told conference attendees.

Diabetes and cardiovascular disease are two areas where PMDA may find ethnic differences related to clinical response, she said. However, if sponsors can demonstrate that no ethnic differences exist for a particular mechanism of action, then PMDA may be willing to accept the foreign clinical data, according to Tomita.

In particular, Phase I data from Korea and other Asian countries could be viewed in a favorable light by PMDA. Discussing an ongoing Phase I oncology study in Korea, Banyu Pharmaceutical Clinical Development Institute Executive Director Tadaaki Taniguchi said that although PMDA had "some concerns" during initial discussions, the agency eventually said it would accept the Korean pharmacokinetic study, and that Banyu is now planning to expand the trial to other areas of Asia.

"Asian PK, at least in the case of oncology, will be accepted by PMDA," the Merck subsidiary exec told meeting attendees. "In the future, what we [will] try thinking is whether we can expand this kind of experience to other therapeutic areas like diabetes or cardiovascular."

PMDA "positions Asian data as very good supporting data for Japanese patients," Tomita agreed. During consultations with sponsors, PMDA "will always ask the question, 'how much Asia data do you have at this time?'"

How Japanese Is Japanese?

Other options also may exist, particularly for smaller U.S or European companies unable to conduct a Phase I dose-ranging study in Japan.

"PMDA has accepted [a] Phase I study in Japanese patients from Brazil and there was a CRO in Hawaii [that] has prequalified Japanese patients to do Phase I studies, and those studies were being accepted by the Japanese government," Murphy said.

However, a key factor to consider is: "What is the definition of a Japanese?" Murphy explained. "Just because you're ethnically Japanese and you've lived overseas, the ministry may not consider you Japanese because of food changes and diets and things of that sort."

Another area where PMDA has adjusted its thinking is related to global studies using an active control drug that is unapproved in Japan, panelists said.

"If you are sure that your comparator drug will be approved soon or may be [approved] at [the time] of approval of your product, you will ask PMDA to use this unapproved comparator drug in your clinical trials and they have started to accept that as a basic concept for international clinical development guidance," Tomita said.

In the end, it is imperative for companies to meet with PMDA to discuss global clinical trial designs, panelists said. Via a point system, the agency currently assigns priority to accepting consultation requests related to global clinical trials, Taniguchi noted.

In its September final notification, MHLW emphasized that for global clinical trials, "It is important that sponsors and PMDA sufficiently discuss the clinical study design and data handling, etc. for individual development programs through the clinical trial consultations."

- Joshua Berlin (j.berlin@elsevier.com)

New Japanese Global Clinical Trial Requirements Could Help MNCs – BIO-Asia Panel

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