Dismantling the Gray Maze

A bureaucratic drug regulatory system — once referred to as a “gray maze” — has long isolated the world’s second largest pharmaceutical market from the rest of the world. Japan’s regulators are moving toward an international, science-based framework. Can they move fast enough? Agnes Shanley interviews ICH founder Dr. Osamu Doi and experts in regulatory affairs, for their views on what the future holds.

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By Agnes Shanley, Editor in Chief

Japan’s pharmaceutical market may be the world’s second largest, but, until recently, only the most persistent of optimists hoped to do much business there. Drug approval requirements, among the most stringent in the world, drove many foreign drug manufacturers away, leading some to focus their efforts elsewhere in Asia. As a result, the supply of pharmaceuticals approved for sale in Japan still lags several generations behind what’s available in the U.S.

If the term “risk averse” sums up the U.S. drug industry, it’s even more applicable to Japan. Lawsuits may be unheard of, but any Japanese citizen can launch a product recall or bring a drug company to its knees, simply by going to the press with a complaint about a serious adverse reaction, which they assume to be linked to a drug.

Dismantling the Gray Maze - Opening page artRegulators are extremely concerned about safety, a concern that intensified during the 1980s and 1990s, when a scandal involving HIV-tainted blood rocked Japan’s top drug-regulating body, the Ministry of Health, Labor and Welfare (MHLW). The result was a closed, bureaucratic approach to drug regulation — a “gray maze,” as Mark Colby and Michael Birt called it in a 1997 book by that name.

In this closed environment, it could be very difficult for foreign companies to understand the context behind feedback they would receive from MHLW, or to grasp the basis for regulatory hurdles, says Sue James, vice president of worldwide regulatory affairs, compliance and quality for GlaxoSmithKline in Parsippany, N.J. There was an unwillingness to challenge the existing paradigms, she says.

Cultural issues

Of course, cultural challenges compounded the difficulties, as well as the subtlety of the Japanese language. An interesting example is the concept of “elegance,” so pervasive in Japanese culture, which has led some Japanese reviewers to reject up to 40% of foreign made materials. Even a microscopically small speck on a tablet that has passed all quality and safety tests in the U.S. and Europe may be deemed unacceptable in Japan, says Dr. Ulrich Taglieber, an independent expert on Japanese pharmaceutical regulatory affairs, and former VP of international regulatory affairs for Merck.

This attitude can extend to inspections and documentation, too. “Six minor typos or errors in a 50-page document can lead some Japanese officials to describe the document as ‘seriously flawed’,” he says. “Japan would like to assume 100% inspection of everything, and achieving that final 4% of perfection can take as much effort as the initial 96% did.”

Within the past few years, the U.S. FDA has, at least, articulated a more scientific and risk-based framework for drug regulation. Experts say that Japan could benefit from such an approach. However, they agree that Japan has already made tremendous progress in a very short time, opening up what had been a closed and highly protected industry.

A black box

To appreciate the changes that have taken place within Japan, one must go back to the 1980s and 1990s, Dr. Taglieber says, when Japan was “running on its own separate rail.” Foreign drug companies hoping to sell pharmaceuticals in Japan had to duplicate all Phase I through III data in Japan, on Japanese subjects.

“At that time, the consultation process was essentially a black box,” Taglieber says. “You threw a new Japan-specific drug application file into the system, and, a year and a half later, you received an oral pronouncement attributed to the Agency’s expert reviewers, all in Japanese. You’d have to get a stenographer to take down the pronouncements, literally, at an expert’s door. Sometimes you interpreted them correctly. Sometimes you didn’t.”

The conduct of clinical trials in Japan was another issue. The trials themselves were often dominated by investigators rather than by the scientific focus of the sponsors. Often they were poorly organized and inefficient, so that the output was quite unpredictable, Taglieber says. “You could have as many as 150 or more investigators for a single trial, each covering one or two patients.”

This situation changed dramatically in the 1990s (see Graph below), a decade that saw the establishment of the International Conference on Harmonization (ICH), whose goal is to standardize and coordinate efforts between regulatory bodies in the world’s three largest drug markets: the U.S., Europe and Japan.

Dismantling the Gray Maze: Clinical Phase and Approval Times

In 1997, Japan established new guidelines for Good Clinical Practice (GCP), based on ICH standards, which brought “structure, science and rules” to the process, Taglieber says, setting guidelines for informed patient consent and monitoring. A year later, it adopted ICH’s E-5 standards, designed to reduce the unnecessary duplication of clinical test data. Guidelines for E-5 are a bit vague, however, and the acceptance of foreign data continues to be a major point of contention (see CLINICAL TRIALS AND E-5, below). Nevertheless, from this point on, Japan no longer required that all trial data be duplicated. For many foreign firms, this was a major step forward, and earnest discussions with sponsors began to take place.

In 2002, another turning point came when the Ministry issued a “pharmaceutical vision statement,” acknowledging the need for the Japanese regulatory environment to change and for the Japanese industry to become more competitive, internally and globally.

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