Navigating the New Era of Reform and Revitalization: Japan
Dr. Mary Bareilles • Director Clinical Operations, ICON Clinical Research – Tokyo
With an improved clinical trial infrastructure now a high priority, Japan offers an advantageous development environment for pharmaceutical, biotechnology, and medical device companies. To address a decade-long downward trend in trial applications and a lag in the availability of drugs within the country as compared to other developed nations, Japan's Ministry of Health, Labor and Welfare (MHLW) has ushered in significant changes in recent years. These include bold steps to create a more welcoming and efficient approach to trials while maintaining global standards such as those of the International Conference on Harmonization/ Good Clinical Practice (ICH-GCP).
Revisions to the Pharmaceutical Affairs Law (PAL) of 2005 indicate that indeed the Japanese regulatory review process is in a new era. While the process continues to pose challenges, significant development opportunities now exist for organizations that successfully navigate this transitional terrain.
This article presents an overview of the Japanese population for clinical studies as well as the regulatory environment, with emphasis on how regulations differ from ICH-GCP standards.
The 127 million people of Japan make up a population whose total has remained unchanged for the last 20 years due to a declining birthrate. The population is aging and boasts the world's longest average lifespan at 79.19 years for men and 85.99 years for women, according to the CIA World Factbook, 2009.
Japan is the second largest market worldwide in terms of pharmaceutical sales, behind the US and just ahead of China. According to IMS Health, sales grew 7.6% in 2009 over 2008. This high rate of pharmaceutical consumption is an irony given the fact that many top-selling products globally have not even been made available in Japan due to the lengthy and expensive trial and approval process.
Primary health conditions and treatment needs in Japan are in the areas of: Oncology, Diabetes, Gastroenteritis, Diseases of the Elderly, Respiratory Diseases, Cardiovascular Diseases, Hepatitis, Infectious Diseases, Central Nervous System (CNS) Diseases, Musculoskeletal and Joint Disorders, Immunology, and Vaccines.
National Healthcare Provision
Healthcare services in Japan are provided by national and local governments offering relative equality of access, with fees set by committee. People without insurance from employers can participate in a national program administered by the local government. All elderly are also covered by a government program. Patients may select physicians and facilities of their choice.
A Fresh, Welcoming Environment
With recent amendments to PAL, drug and device developers can now plan and conduct clinical trials in Japan under Clinical Trial Notifications (CTNs), which are reviewed in just 30 days, a turnaround time comparable to that achieved in the US. A grant program subsidized by MHLW is designed to accelerate the development of high-priority drugs and medical devices recommended by the member societies of the Japanese Association of Medical Sciences (JAMS) that are:
- Widely used as standard treatment in the US or Europe but not yet approved in Japan
- Already marketed in Japan and commonly used for off-label indications1
Interest in revitalizing the clinical trials process in Japan is increasingly obvious through improved infrastructure, IT investments, and education of physicians and patients on the need for reform. The Japanese market offers dedicated research teams within national and university hospitals across a variety of therapy areas. Networks such as the National Hospital Organization facilitate reaching into both large- and medium-sized cities with multiinstitutional studies and clinical trials. Such an environment offers direct access to healthcare professionals, including a solid network of primary care physicians.
The Japanese market also can make accessible large groups of aging, recurrent patients in specific therapy areas. And, although a variety of dialects are spoken, the Japanese communicate via one standard language, making communicating with patients and investigators easier.
Japanese investigators participate in international conferences and are ICH-GCP and Japan GCP compliant. As the government wants to maintain and encourage further research within the country, both on-site and centralized Institutional Review Boards (IRBs) convene regularly (as often as once a month) to keep the clinical study process moving. Centralized IRBs that are managed by Site Management Organizations (SMOs) are especially flexible in this regard.
Another advantage is that smaller communities within hospital regions develop strong patient/research links, so patients tend to be compliant, and sites increasingly deliver the predicted patient numbers.
Remaining Hurdles Require In-Country Expertise
Although Japan provides high-density populations in urban areas, patients can be difficult to recruit because of their easy access to healthcare coverage. The lack of an incentive to participate, coupled with little awareness of the need for trials, continues to be problematic and adds to the trial timeline.
What is more, the cost of conducting clinical trials in Japan remains higher than in the West because of the need to use SMOs, which add labor costs. There is no specialized research hospital in Japan, so SMOs, having access to a pool of patients, are essential.
Trials also tend to take longer for a range of reasons – from the lack of patient incentives and lower physician incentives to the still maturing infrastructure.
Due to the complexities of conducting research in Japan, corporate sponsors should ensure that they have ready access to in-country experts.
The Regulatory Landscape
Recent changes to the regulatory system for pharmaceuticals and medical devices have enabled Japan to align its safety measures more closely with those of other developed nations. Since its establishment in 2004, the Pharmaceuticals and Medical Devices Agency (PMDA) has provided comprehensive risk management from pre-clinical research to approval through three functions: review (risk reduction), safety (continuous risk mitigation), and relief (services for adverse health effects).
Improving the infrastructure for clinical trials has been a primary focus in Japan. The Center for Clinical Trials of the JMA (JMACCT) was also established in 2004 to promptly provide the public with medically necessary or new pharmaceutical products and medical devices, organize multiple medical institutions into a network, and conduct model clinical trials.
The current regulatory environment in Japan encompasses:
Procedures for Drug Approval Applications (NDAs)
- The application is made after completion of nonclinical and clinical trials
- Required GCP, GLP, and GMP surveys should be applied for immediately after the NDA submission
- The manufacturer and/or distributor must be authorized and, if a manufacturing plant is overseas, the appropriate accreditation must be obtained
- Information must include the origin or background of discovery, characteristics and efficacy, records of consultation with PMDA, a list of drugs of the same type/indication, conditions of use in other countries, and package inserts
NDA Review Process
PMDA frequently performs a team review with experts in quality, nonclinical, and clinical trials, biostatistics, and other fields.
Notification of Clinical Trial Plan
The Minister in charge of Clinical Trial Protocols must be notified in advance of trials for drugs with new active ingredients, new routes of administration, new combination drugs, new indications, new dosages, and biologics.
Scope of Reporting
When performing a clinical trial, the following information must be reported:
- Unexpected death or cases of adverse experiences potentially leading to death
- Other unexpected serious events, adverse experiences requiring hospitalization, disability, adverse experiences leading to disability, congenital disease or abnormality in a subsequent generation
- Measures taken in foreign countries to prevent the occurrence or spread of risk to public health and hygiene (including discontinuation of manufacturing, import, or marketing or withdrawal or disposal of an item with ingredients equivalent to those of test products; also including revision of the precautions, accompanied by a letter to the distributing doctor)
- Research reports indicating the possibility of the drug causing cancer or any other serious disease due to adverse reactions or showing a lack of anticipated efficacy or clinical benefit
While the precise wording differs, the reporting requirements in Japan reflect the spirit of those in Western markets. The EU, for example, requires that sponsors report untoward medical occurrences from any dose that result in death, are life threatening, require or prolong hospitalization, lead to persistent or significant disability, or a congenital anomaly or birth defect.
Differences Between Japan's GCP and ICH-GCP
Japanese regulatory authorities are particularly eager to avoid any misconduct related to clinical trials, such as past deficiencies in case report forms (CRFs), informed consent, institutional review board practices, and protocol deviations. Transparency is a primary goal for the revised process.
Japan's GCP places greater responsibility on the institute and its head such that:
- The contract is between the sponsor and the institute, not between the sponsor and the investigator
- Items covered in the contract must be defined
- Each institute must have an IRB
- The sponsor must prepare a policy for compensating trial participants for any injuries during the trial prior to submitting documents to the IRB. This policy must be included while obtaining informed consent. In the case of injury, "the subject should be adequately compensated regardless of whether or not the injury is due to negligence. The subject is not burdened with providing a causal relationship."
- A sponsor that does not have an address in Japan must select an In-Country Caretaker (ICC). A CRO in Japan can act as the ICC on behalf of the sponsor. (See sidebar on ICC Responsibilities.)
- Product labels must be in Japanese.
Safety information must be reported periodically (such as every six months) after submission of the initial Clinical Trial Notification (CTN) and within two months after the study is completed.
According to the ICH guidelines, (sections, 5.16.1/2 and 5.17) sponsors are to promptly notify all concerned investigators, institutions, and authorities of findings that could adversely affect subjects' safety or the course of the trial. Suspected, unexpected serious adverse reactions require expedited reporting, while all other safety information can be included in an annual safety report.
While many of the provisions are similar, any differences between Japan's GCP and ICH-GCP must be understood and acted upon. The sponsor should be certain that a regulatory expert is engaged and available for consultation during the clinical trial process.
In the realm of clinical trials, Japan may still be a "developing" country, but is certainly one focused on revitalization and global harmonization. Increased demand and resources for pharmaceutical and medical device research have spurred a new era of reform with the budgets and resources required. Not all the challenges have been addressed, but a more stable and effective infrastructure, network, and standards are now in place. In planning for global studies, sponsors can now be assured that Japan is ready to participate from the outset and is governed by regulations that are tracked closely with the International Conference on Harmonization standards.
The In-Country Caretaker (ICC) is responsible for the progress of clinical trials and must be the primary contact for any regulatory interaction on behalf of the sponsor company. The ICC oversees:
- All clinical development work on behalf of the sponsor
- Submission of a Clinical Trial Notification (CTN) to the PMDA
- Replies to questions raised by the PMDA
- Supply of the investigational drug, including customs clearance, requests made to the drug depot or the contract manufacturing organization (CMO), and the checking of manufacturing records and QC tests
- Monitoring of the clinical trial and preparation of the Clinical Study Report (CSR)
- Collection and reporting of information on adverse reactions, including from overseas
- Translation of documents and data (English to Japanese / Japanese to English)