A Window of Opportunity
by Amy Mayer
June 2007
The cooperative efforts of government agencies, pharmaceutical manufacturers and academic researchers are helping to modernize Japan’s drug development climate.
As the second largest domestic market for pharmaceuticals in the world—after the United States—Japan would seem a naturally attractive place for research and development. But domestic and multinational companies confront barriers that make what should be a promising market for drug development perennially frustrating. A young and relatively inexperienced regulatory agency, an inadequate infrastructure for clinical trials and a national health care system that sets drug prices and adjusts them every two years all contribute to the idiosyncratic nature of the market. Despite these challenges, researchers, regulators and industry representatives are working together to modernize clinical research and ensure a more efficient delivery of medicines.
For more than 15 years, medical oncologist and pharmaceutical researcher Dr. Masanori Fukushima worked on the development of new drugs. But in 2000, he left the Aichi Cancer Center in Nagoya, Japan and moved to Kyoto University Hospital, where he launched the Translational Research Center. As the center’s director of clinical trial design and management, Fukushima desires to see new, innovative medicine reach patients in Japan and elsewhere once manifested itself in the lab, where he earned patents for some of his developments. Today, his mission is to support the work of other researchers by improving the atmosphere for clinical trials in Japan. His efforts, coupled with the work of government officials, industry leaders and the Japanese Pharmaceutical Manufacturer’s Association (JPMA), aim to bring Japan’s market environment in line with the pharmaceutical research and development infrastructures of the United States and Europe.
Regulatory Progress
Fukushima is focused on clinical trials because of their importance in bringing new drugs to market as well as their historical shortcomings in Japan. Despite recent revisions, the Pharmaceutical Affairs Law doesn’t have authority over clinical trials conducted in certain settings. When a medication is developed in a hospital, and clinical trials are conducted on patients in that hospital, the trial doesn’t have to be registered with the government, Fukushima says. As long as the drug’s developers don’t intend to seek market approval, they are not required to register their in-house trial. Although ethical guidelines outline appropriate trial practices, they are difficult to enforce, Fukushima says.
In addition to harboring both registered and unregistered studies, the clinical trials infrastructure in Japan faces criticism for being insufficient and inefficient. “Japan is well known for the unfavorable environment, and three things are frequently cited: high expense, slow pace and low quality associated with clinical trials,” says Shigeki Tsuda, director of the department of scientific affairs and education at the Society of Japanese Pharmacopoeia, and former international affairs division director at the Pharmaceuticals and Medical Devices Agency (PMDA), both in Tokyo, Japan. “Speed and quality are said to be improving.”
Pharmaceutical manufacturers have reported that they don’t always get a timely response to their initial application to conduct a trial, and some have complained that it’s not always clear what data the PMDA requires, Tsuda says. “We are not responding fully to the needs from the sponsors, and we will increase the resources to be able to respond to that. That will surely contribute to a smoother review process.”
Tsuda acknowledges the frustrations companies have expressed about the PMDA. In its Business Policies for Fiscal Year 2006, the JPMA states that in order to encourage improvements at the PMDA, it will work with the agency and the Ministry of Health, Labour and Welfare (MHLW) to assess business operations at the PMDA. “We will also make necessary proposals and cooperate on increasing the transparency of the review standards, reducing the drug screening and review period, and conducting proper management of clinical trial consultations, so that new products can be introduced promptly and patient access can be improved,” the statement reads.
Commitment to Efficiency
The slow review time at the PMDA can be attributed to understaffing, but the agency plans to grow from 319 employees in 2006 to 582 by March 2010, Tsuda says. Most of the new workers will be reviewers. In addition to the current shortage of reviewers, the newness of the PMDA, which began operations in 2004, has meant many of the staff hired to conduct reviews of new drug data don’t have enough experience to operate at top productivity, he says.
“It’s said that reviewers tend to ask more questions because they don’t know very much about that field or issue,” Tsuda says. But the PMDA is committed to getting more training for the reviewers and to sending them to workshops and conferences that will help them gain expertise on par with their European and U.S. counterparts, he says.
The MHLW works closely with the PMDA, which itself is a half-governmental, half-independent agency located about a mile from the MHLW’s Tokyo offices. Toshiyoshi Tominaga, Ph.D., international planning director for pharmaceutical affairs at the MHLW, in Tokyo, Japan, agrees with Tsuda’s assessment and his commitment to improving the efficiency of the review process, but he also defends the reviewers. “Sponsors are always complaining about PMDA reviewers’ questions,” he says. “But [reviewers] shoulder huge responsibility. Sponsors might as well consider how they could best present their data and answer the question.”
The creation of the PMDA itself reflected a commitment to improving the situation and promoting faster reviews, Tominaga says. “At first it did, but probably not to the satisfaction of industry.” Although the improvements were significant, “there was not a quantum leap,” he says.
Improvement Initiatives
The challenging environment for clinical trials contributes to the “drug lag” with which Japan often is associated. “The launch of the new drug in Japan is very late compared to the United States or European countries, or even other Asian countries,” Tsuda says.
The PMDA’s proposal to increase staffing levels and raise reviewers’ knowledge base should decrease that lag eventually, says Nicole Melcher, director of the U.S. Commerce Department’s Office of Japan, in Washington, D.C., USA. “This step forward is likely to help,” she says. “But it doesn’t solve the problem.”
In addition to enlarging its staff, the PMDA also is reviewing its policies regarding foreign clinical trial data, particularly as more Asian data becomes available, Tsuda says. “Other Asian countries have improved their clinical trial infrastructure, and the big sponsors are gaining data from such countries,” he says. A combination of improvements in the domestic system and greater acceptance of foreign data could foster change. Until now the PMDA hasn’t made a clear statement on which trial designs it will accept from multi-country development or trials, Tsuda says. But as its willingness and ability to review foreign data grows, the PMDA will make its expectations more clear, he says. “In order to allow that, the PMDA and the MHLW are now developing a guidance called Basic Policy on International Collaborative Clinical Trials,” he says. A draft of the new policy began circulating for public comment in April 2007.
One possible outcome of the new policy could be smaller trials in Japan for certain drugs. But industry also must confront the Japanese public’s perception of pharmaceuticals, Tsuda says. “It is said that [in clinical trials] the risk is stressed more than the benefit of drugs,” he says. “Some people say that the Japanese people pay more attention to safety than to efficacy.”
The public’s desire for safety assurances could stymie efforts to speed up the approval process if the public perceives a rush to integrate with an international system as potentially leading to less stringent or less ethnically specific testing protocols. On the other hand, if Japanese researchers start participating in more international clinical trials, it could result in many more of the world’s approved drugs getting to Japanese patients faster, because trial data on Japanese subjects would be available at the same time as data on other ethnic groups. That would likely lead to more timely approvals, Tsuda says.
Although the Japanese government has stated an interest in joining global trials, it can’t happen quite yet, Melcher says. “They need to improve the clinical trial environment in Japan if they want that to happen,” she says. “The good news is that they’re interested in improving their environment.”
Closing the Gap
The Office of Japan is actively engaged in discussions between industry, government and others affected by market hurdles in Japan. Pharmaceuticals and medical devices fall under two trade-talk umbrellas—the Market-Oriented, Sector-Selective agreement and the Regulatory Reform Initiative. In addition to clinical trials, one of industry’s leading complaints is the drug pricing system, Melcher says.
Unlike the free market economy of the United States, Japan’s government-run National Health Insurance system determines the price of pharmaceuticals. Representatives from industry as well as the U.S. government have been asking Japan to change its reimbursement pricing system so innovative medicines may receive pricing that reflects the benefits they bring to Japan, Melcher says. “We’ve been encouraging Japan to reward innovation through its pricing system,” she says. “We think this will increase the number of innovative drugs in the Japanese market, which ultimately will lead to shorter hospital stays, for example,” she says. The average hospital stay in Japan is 21 days, compared with six in the United States.
In the current round of annual government-to-government recommendations, U.S. officials asked Japanese officials to “consider the budgetary and health benefits of pricing systems that reward development of innovative products.” It’s a years-old issue, but some progress has been made, Melcher says. “There’s a part of the pricing process where an organization called the Drug Pricing Organization (DPO) meets to determine the pricing of a product,” she says. In the past, companies had no participation in that process. But in 2005, after about five years of effort, the Office of Japan helped persuade Japan’s Health Ministry to agree to allow pharmaceutical companies to make presentations on their products at initial DPO meetings. “That was a big step forward,” she says. “Increased access to regulators is something that has been a long time coming.”
From his perspective at Kyoto University Hospital’s Translational Research Center, Fukushima sees the need to seek more cost-effective treatment development, he says. “We need more inexpensive drugs and inexpensive medical technology,” he says. Once the clinical trials infrastructure improves and the PMDA really gets up to speed, Japan’s role in global drug development will expand, Fukushima says. “I believe Japan is a good competitor or good collaborator or good partner of the United States or the European Union,” he says.
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