From the Editor: Japan Globalizes, But Won’t Compromise on Core Values

Japan has embraced ICH, but doesn’t yet have any official “mutual recognition” policy with FDA regarding GMP inspections. The nation also maintains a unique position on clinical trials, which influences many drug manufacturing decisions. Can genomics resolve a highly politicized issue? MIT scholar Dr. Wen-Hua Kuo shares his insights.

By Agnes Shanley, Editor in Chief

This month, we look at a topic that hasn’t been covered much lately: developments within Japan’s pharmaceutical industry.

Japan accepted GMPs when it adopted the International Council on Harmonization (ICH) standards, but has not yet formally established mutual agreements for GMP inspections with FDA, as it has with the EU.

And, as you may know, Japan has some of the most stringent quality standards in the world, such as defect rates of one cracked film-coated tablet per million, according to Globepharm Consultants (Deerfield, Ill.). Perhaps some of you have already had, or heard about, run-ins with some of Japan’s more “perfectionistic” inspectors?

But the world’s second largest drug market is removing barriers, including obstacles to outsourcing, that have kept many of your employers from doing business within its borders in the past.

More importantly, Japan’s drug manufacturers lead the world in applying new aseptic methods and automation to drug manufacturing. It was Japan, after all, that pioneered the use of “pipeless batch plants,” as well as the automated guided vehicles (AGVs) and machine vision that more of your facilities are using today.

In this issue, we offer some best aseptic drug manufacturing practices from Japan. We also peek behind the closed doors of Japan’s regulatory agencies, which, like our own FDA, are striving to bring more science and risk analysis to bear in regulatory decisions.

The story of how Japan is adapting to ICH and to the “globalization” of pharmaceutical regulations is a fascinating one. In our cover story, ICH founder, Dr. Osamu Doi, outlines some of the challenges ahead.

While desiring harmony with FDA and EMEA, Japan is adamant about maintaining its own identity and values. And Japan’s identity is inextricably tied up with race, says MIT scholar Dr. Wen-Hua Kuo, a native of Taiwan who has studied these issues extensively.

Consider Japan’s practices regarding clinical trials. For many years, Japan required that any foreign drug manufacturer who wanted to sell product in Japan had to duplicate Phase I through III trials within Japan, with Japanese subjects. Officials argued that the Japanese race was distinct enough to warrant this extra, and extremely expensive, precaution. Western companies accused Japan of protectionism; for some, the emphasis on racial separatism raised the ghost of Emperor Hirohito.

In 1986, Japan signed an agreement with the U.S. that it would not require unnecessary clinical trial duplication, but Japan’s regulators appeared to ignore it for 16 years.

Then along came ICH, with its E-5 guideline, designed to eliminate redundant clinical trials. E-5 allows drugs to be approved without Japanese clinical trials. It calls for the use of “bridging” studies when a drug is suspected of having different interactions within Japanese patient populations — for example, when pharmacokinetics or dose-response curves are different between Japanese and non-Japanese subjects, explains Dr. Kuo. For companies outside of Japan, this is a pragmatic step, but many Japanese regulators consider it a compromise, and even a case of “regional discrimination.” Japan hasn’t warmly embraced the idea, advanced by some ICH experts, of accepting “pan-Asian” clinical trial data from other Asian countries, either.

Ironically, E-5 may have created more problems than it has solved, says Dr. Kuo, but science may settle questions of race. Former FDA reviewer, Takeuchi Masahiro, now with Kitasato University, has suggested that future global trials be undertaken using genomic statistics and information. This idea, though interesting, requires new methodologies and creates new problems. Whether genomics can provide the ultimate answer to the age-old controversy over race, Dr. Kuo says, remains in question.

Some U.S. pharma companies are assuming that the situation won’t change for a while. Wyeth, for example, which recently acquired 80% of its joint venture with Takeda, is moving ahead with clinical trials in Japan, but running them in parallel with trials in the U.S. and Europe. This “parallelism” already shows progress toward harmonization. Whether you participate in it, compete with it, or both, Japanese pharma promises to be very interesting to follow over the next few years.

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