Conducting clinical trials in japan chris merriam-leith

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Conducting Clinical Trials in Japan
Written by Chris Merriam-Leith, MS, PMP
1. Overview of Clinical Trials in Japan
The clinical trial process is one of the most critical and necessary steps for the development of all new drugs,
biologics or medical devices. Conducting clinical trials in Japan requires a delicate balancing act between having a
thorough understanding of the Japanese regulatory framework, as well as having an even much better
understanding of how clinical trials must be managed within the nuances and boundaries of the Japanese culture.
In 2008, Japan had the second largest pharmaceutical market in the world, with approximately $82 billion in annual
sales.1
Though despite its large market size and its regulatory sophistication, according to Japan's Pharmaceutical
and Medical Device Agency (PMDA), historically it takes almost 2.5 years longer for a drug to receive market
approval in Japan than it does in the United States.2
In order to successfully navigate Japans complex regulatory
structure, it’s necessary to become familiar with the Ministry of Health, Labor and Welfare (MHLW) and the
Pharmaceutical and Medical Devices Agency (PMDA), the Japanese equivalent of the FDA.
Japan is the 3rd
most efficient producer of new drugs only following behind the United States and the United
Kingdom. But over the years its domestic market size for pharmaceutical products has been decreasing to that of
being only about 10% of the overall world market. Unfortunately, as a result of an MHLW Ordinance that defined
Good Clinical Practice (GCP) that was implemented back in 1997, Japan had experienced a significant decrease in
the number of clinical trial notifications that sponsors were initiating.3
The impact of this new regulatory ordinance
would be felt throughout the industry as a whole, and would be measured in extra time, cost, and an increased
burden of bureaucracy. The time required to perform clinical trials would be longer in Japan than in both Europe
and the U.S., the cost for performing clinical trials would be higher in Japan than in both Europe and the U.S., and
an excess amount of bureaucracy existed in both the management of quality control (QC) and quality assurance
(QA) processes of clinical trial data.4
Japan and the MHLW have historically had a conservative regulatory environment which unfortunately resulted in
the perpetuation of a less than efficient regulatory infrastructure, slowing down the development of new regulatory
policies. In Japan, during the 1990’s and the early part of this decade, the development and implementation of new
regulatory policies would move at a much slower pace than that compared to the U.S. and Europe.5
This practice of
slow policy change created a significant barrier to both domestic and to especially foreign companies who were
trying to initiate and manage their clinical development efforts within Japan. Japans historical slow pace of
regulatory development and the lack of innovation regarding clinical practices forced sponsors to have to utilize
outdated and inefficient business practices, as well as less than ideal data management and reporting methods.

1
Invest Japan Department, Japan External Trade Organization, 2009
2
Pharmaceutical and Medical Device Agency Japan, Annual Report FY 2007
3
"New vision for the pharmaceutical industry." Ministry of Health, Labour and Welfare. (2007): 31. Print.
4
"New vision for the pharmaceutical industry." Ministry of Health, Labour and Welfare. (2007): 31. Print.
5
Brock, Andy, Kevin McNulty, and Maria Sumner. "EDC Acceptance in Japan." Applied Clinical Trials. Nov (2009): 1. Print.

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This had a very strong negative impact on the Japanese pharmaceutical industry both from an efficiency
perspective as well as from a competitiveness perspective.
Although ICH practices and GCP standards have been in place in Japan since 1997, the country has been very
slow to adopt global clinical processes, infrastructure, and methodologies to increase efficiency. This combined with
many cultural complexities, has led many pharmaceutical companies to bypass Japan when selecting global trial
site locations. This has further led to a performance gap between Japanese sites and other global clinical trial
destinations.6
The above trend was very troubling to both Japanese regulators and the industry as a whole. This regulatory
bottlenecking was identified and considered as being one of the primary causes for the 2.5 year time difference that
was required in order to take a drug to market in Japan. It was also feared that the dramatic decrease of clinical
research activities would have even greater repercussion beyond just a decrease in drug development. The MHLW
feared that other effects would include, patients experiencing delays or not being able to participate in clinical trials
or being able to gain access to the most current treatments and / or the latest new drugs. Furthermore, they feared
that this could have a very serious impact on the Japanese pharmaceutical industries ability to be able to compete
in the global market place.7
In an effort to resolve the deficiencies the Ministry of Health, Labor and Welfare (MHLW) in 2003 / 2004 developed
a new plan named “The 5 Year Clinical Trial Activation Plan” that was targeted at correcting some of the problems.
The plan included resources for the creation of “The Massive Network for Clinical Trials Project” a nationwide
network of clinical trial sites. It also included the development of a standard set of forms such as contracts, and
enrollment applications to help reduce the paperwork involved with clinical trials. It recommended new policy
guidelines to streamline regulations and to help reduce the amount of regulatory bureaucracy that existed regarding
excessive GCP inspections, quality control (QC) and quality assurance (QA) processes.8
The MHLW also
developed incentives to encourage clinical research institutions to invest more time and resources in the training
and development of clinical development staffs. Institutions began by providing specialized training and developing
new career paths for physicians and CRC. As a result of these efforts, the MHLW was able to see significant
improvements by 2007 as was indicated in the increased numbers of clinical trial notifications over previous years.

6
7
"New vision for the pharmaceutical industry." Ministry of Health, Labor and Welfare. (2007): 4. Print.
8
Japan Medical Association Website; http://www.jmacct.med.or.jp/english/whatwedo/5yearplan.html

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2. Clinical Trial Improvements over the Last 5 Years
Japanese clinical research regulations have experienced some dramatic improvements over the last 5 years.
Starting back in 2004, some of the specific problems that were identified as contributing to the causes for the
decline of clinical research in Japan, included the following, 1) there were very few economic incentives for doctors,
patients and institutions to perform or participate in clinical trials, 2) clinical research was very expensive on a per
subject basis, 3) the number of subjects available to participate in clinical research was very low and the process of
recruitment was over burdensome for those institutions who engage in research, 4) there was a serious deficiency
and lack of institutional development of clinical research experts, such as Primary Investigators (PI), and Clinical
Research Coordinators (CRC), and 5) there was no significant investment support from industry or government
agencies.9
The Japanese government and the Ministry of Health, Labor and Welfare recognized that they needed to develop a
longer term strategy in order to correct the systemic problems that were identified within the system, therefore in
April 2007; the Japanese government introduced an integrated package called the “5-Year Strategy for the Creation
of Innovative Pharmaceuticals and Medical Devices”. The plan called for a concentrated effort of financing of R&D
activities, the development of venture businesses, actions for improving the environment for clinical trials, policy
recommendations for increasing partnerships with other Asian countries, improvements to regulations in order to
speed up quality reviews, and also an appropriate recognition of new innovative products.10
Over the last several years, the Japanese government, in conjunction with its national pharmaceutical industry, has
embarked upon an even more ambitious program to update the country's clinical development procedures and to
bring them in line with global best practices. Japan has been rapidly updating its clinical trial practices with great
success. Over the past few years, Japan has outpaced all other Asian countries in increasing the rate of new
clinical trial starts, and according to a 2008 CenterWatch report and FDA analysis. Drug development in 2007,
exploded 600% over the previous 2006 year rates and was expected to continue to grow.11
As a part of the five-year strategy, the Japanese government created an action program aimed at reducing lag
times for new product approvals. The plan includes a focused effort by industry to speed the development and
delivery of globally superior drugs, devices, and other technologies to the market. The strategy lays a solid
foundation to create an environment that allows for joint product development with the United States, Europe and
other countries.12
In recent years, the government of Japan has considered it to be very important to form
partnerships with other Asian countries in the research and development activities of new pharmaceutical products.
They agreed to a new forward looking concept of cooperation between Japan and China. In April 2007, in a
meeting between the Secretaries of Health from Japan, China and South Korea, the Japanese government signed
a “Memorandum of Understanding” in which the parties agreed to cooperate on the collaboration of clinical data in
the development of new pharmaceutical products within the 3 countries. The benefits of strengthening cooperative
ties with other Asian nations is expected to result in the streamlining of the clinical research processes as well as
speeding up clinical trials within all of the Asian countries.13

99
"New vision for the pharmaceutical industry." Ministry of Health, Labor and Welfare. (2007): 31. Print.
10
11
Applied Clinical Trials Website; http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/article/articleDetail.jsp?id=640460&sk=&date=&&pageID=1
12
13
New vision for the pharmaceutical industry." Ministry of Health, Labour and Welfare. (2007): 15. Print.

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Global clinical development activities will be vitally important to the long term success of Japanese pharmaceutical
companies in the 21st century. Globalization increases the speed to market, by opening up diverse new
populations for recruitment, including the treatment of naïve patients, while it lowers the overall cost of conducting
clinical trials. Until recently, Japan had been very resistant to allowing clinical data generated entirely outside the
country to be included in any regulatory submissions.14
With the rapid increase in market growth over the last few
years, and the dramatic transformation of the regulatory system, this old attitude has changed. As a result, Japan’s
pharmaceutical and medical device companies are now very well positioned, to offer a much brighter and friendlier
R&D future, to both foreign and domestic companies, who may choose to perform their clinical research within the
country of Japan.15
3. Barriers and Impediments to Conducting Clinical Trials in Japan
When conducting clinical trials in Japan a sponsor needs to be aware of some of the more challenging issues that
they may face. Japan still has a ways to go before it will achieve regulatory parity with the United States or Europe,
and there are still many differences between the countries. The following are some of the important difference:16
 Because of inter-ethnic differences in dose-response between Japanese and Caucasian populations, in
order to get a drug approved in Japan, the regulators have insisted that Phase I-III pharmacokinetic (PK)
clinical trials must first be carried out on the drug in Japanese populations - a costly and timely process.17
 The Japanese clinical trial environment has typically been less than welcoming, burdened by red tape and
bureaucracy, sometimes up to 150 essential documents may be required as part of the good laboratory
practice (GLP) paperwork.
 Language barriers may slow the patient recruitment process and / or prolong the trial duration often 2-2.5
times longer than in the U.S. and Europe.
 Differences in cultural values, specifically around collaboration and hierarchy, play a role in the degree of
cross-functional involvement in developing protocols and staffing quality assurance teams. In general,
individual and department roles may be more specifically defined and more senior people may be involved
than in comparable organizations in the United States.
 Cultural differences may influence the interpretation and standards applied to regulatory compliance, which
can affect the project’s target standards. The Japanese, for example, may tend to set standards of quality
assurance so high that U.S. partners fear they are unachievable.
 There are still substantial international differences in regulations on the interpretations of Suspected or
Unexpected, Serious Adverse Events (SAE’s). The rules on reporting to regulatory agencies are not fully
harmonized, and different regions have different expectations on the timing and amount of information
provided to investigators and regulators. For example, in the definition of "serious," all hospitalizations are
considered "serious" in the ICH E2A document and in the U.S. and the EU regulations. However, in Japan
only hospitalizations or extension of hospitalization "for treatment" qualify as serious.18

14
15
16
Outsourcing Pharma Website; http://www.outsourcing-pharma.com/Clinical-Development/Developing-Japan-intent-on-clinical-trial-catch-up
17
Pharma Focus Asia Website, http://www.pharmafocusasia.com/clinical_trials/japan_clinical_studies.htm
18
Applied Clinical Trials Website; http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/article/articleDetail.jsp?id=154249&sk=&date=&pageID=2

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4. Nuances to Conducting Clinical Trials and Japan
When conducting clinical trials in Japan a sponsor may want to be sensitive to some of the cultural and regulatory
nuances that might be encountered. Some of these differences can make things easier, while others may cause
potential reporting issues.19
 Subject Compliance - Subjects in some countries are very compliant and eager to attend all study visits.
They tend to listen to their doctors and follow orders unequivocally. In Japan, for example, a “culture of
compliance” dictates that patients follow doctors’ orders explicitly. This tradition presents a benefit to
sponsors since enrollments tend to be quicker and retention is higher.
 Informed Consent - The “culture of compliance” may also create difficulties in documenting informed
consent. Japanese subjects and their families traditionally prefer the attitude of “I put myself in your hands,
doctor.” A “full informative discussion of risks” requires investigators to break the pattern of treating patients
without sharing with them the sometimes frightening details of their illness.
 Reporting Adverse Events - One consequence to this “culture of compliance” is that subjects in Japan, for
example may not readily report adverse events. They may not complain, because they don’t want to
jeopardize their status as a participant or lose access to medical treatment. Investigators may need training
to actively solicit adverse events from subjects.
 When conducting a global clinical trial that will include Japan, because of inter-ethnic differences in dose-
response between Japanese and Caucasian populations, it would be important that the dosage regimen be
confirmed, that it does not have any particular safety problems for the Japanese, beforehand. For this
purpose, it is appropriate before the start of the global study to first examine single-dose safety and PK in
healthy Japanese volunteers, compare the results with those of the non-Japanese, and confirm there is no
particular concern regarding increased risks.
 The consensus-driven nature of the Japanese business climate seeks approval from all stakeholders
before any major new initiative is implemented, which can prolong the decision making process. It is
important to have patience, and to take this cultural nuance into consideration when negotiating or
establishing clinical development teams.
 In Japan, clinical trial sites differ from U.S. markets in that deep values within the culture favor the
community over the individual. Social status is revered, as are behaviors geared toward building long term
relationships. This is a very important aspect of the Japanese culture and must be taken into consideration
by the sponsor.20
5. Managing Global Clinical Trials in Multiple Countries
Conducting global clinical trials across multiple countries is not an easy task. There are many challenges to be
faced and many difficulties to be overcome. A sponsor needs to be aware of the many complexities that will be
involved when conducting clinical trials especially across multiple countries. The first thing to recognize is that even
though there have been significant efforts made to harmonize regulatory standards across regions; there are still
many significant differences. Second, cultural and language difference will also represent a significant challenge

19
20
Multinational Clinical Trials, Breaking Language and Cultural Barriers, Mary Strober, Applied Clinical Trials, Sept 2003

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that will require extra time and resources to smooth out. Below are some of the more important challenges that a
sponsor might face;
Regulatory challenges – The Asia-Pacific region presents some special regulatory challenges because of a
complex and continually evolving regulatory environment. This complicated regulatory landscape can be a barrier
to success for foreign sponsors that don’t have the experience or resources that are essential to overcome the
obstacles in countries such as China, Japan, Korea, and Taiwan.21
 For example, China has requirements for a locally generated Certificates of Analysis (COA) for ingredients
in drugs to be tested in the country. For multinational trials that include Chinese patients, the COA
requirement can now be waived if a chemical-based product is not going to be registered for sale in China.
For global pharmaceutical companies, this change means that Chinese patients can now be more easily
included in multinational trials – an important benefit at a time when patient recruitment in other parts of the
world is becoming more difficult. However, a local COA is still required for drugs targeting the Chinese
market, and for any biological product.22
Infrastructure – As clinical research spreads into nontraditional sites, such as some 3rd
world countries, the sponsor
may need to think about infrastructure requirements. Infrastructure needs at nontraditional sites may require
sponsor to build clinics and to supply special technologies such as computers and refrigeration systems. Some
countries have sophisticated infrastructures such as, power-grid, telecommunications, and internet access, (i.e.
U.S. Europe, Japan) while other countries may have limited infrastructures or limited access to technologies (i.e.
Africa, Latin America) or filtered access to the internet (i.e. China).23
Language differences – There are many unanticipated issues that can arise when a sponsor starts to expand
clinical trials across language boundaries. Sponsors tend to rely on English as the global language for clinical trials,
but often English will not be the primary spoken language of the host country. It is important to keep in mind the
logistical complexities of translating protocols, informed consent forms, questionnaires, adverse event reports and
other data sources back and forth between English and the host language. Potential costs associated with
translation errors can be significant.24
Investigator recruiting - Investigators may be participating in a clinical trial because it increases their status in the
community, a powerful incentive in relationship-based cultures (i.e. India and Latin America). Sponsors may solidify
investigator dedication by including key regional investigators in scientific publications and presentations at
conferences and symposia.25
As clinical research continues to expand around the globe, it will only become much more important for a Sponsor
to understand all of the unique implications that may exist from country to country. With the right combination of
knowledge, patience, and flexibility, sponsors can navigate even the most challenging environment and take
advantage of the opportunities that exist to expand their clinical development programs on a global scale.

21
PAREXEL Website; Regulatory Challenges in the Asia-Pacific Region
22
PAREXEL Website; Regulatory Challenges in the Asia-Pacific Region
23
24
25

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Regulatory Pathway for the Japanese Pharmaceutical and Medical
Devices Agency
What is the regulatory process that a potential new drug sponsor must follow in order to initiate a clinical
study of a potential new drug product.
The Pharmaceutical and Medical Devices Agency (PMDA), the Japanese equivalent of the FDA, is responsible for
reviewing Clinical Trial Notifications (CTN) and Manufacturing Approval Applications. The clinical trial process is
one of the most critical and necessary steps for the development of all new drugs, biologics or medical devices.
The process is described below:
 The notification process for clinical trial submissions for manufacturing and distribution application
approvals are defined by Article 80(2) and the reliability and compliance review of application of a dossier
are defined by Article 14 of the Pharmaceutical Affairs Law. The procedures for implementing the
Pharmaceutical Affairs Law rules are the enforcement regulations of Ministerial Ordinance No. 1 issued in
1961.
 The Ministry of Health, Labor and Welfare (MHLW) is the agency that has the authority to approve drugs,
while the PMDA has the responsibilities for license authority and for the approving of clinical trials, and
approval reviews.
The process of conducting a clinical trial starts with the sponsor requesting a clinical trial consultation under the
interview advice, or face to face advice system. The consultation system in Japan allows sponsors to discuss
matters related to clinical trials and approval applications with the PMDA. There are a predefined range of topics
that the PMDA is prepared to discuss in the consultation process, but any topic can be discussed.
The specific requirements for a clinical trial notification are defined in Ordinance No. 28 issued in 1997, titled “The
Standards for the Conduct of Clinical Trials of Pharmaceutical Products”. The below steps define the process:
1. A Clinical Trial Notification (CTN) should be submitted to the PMDA using electronic media.
2. A contract with the investigational sites participating in the first trial must be made at least 30 days after the
PMDA has received the CTN. This allows 30 days for interactions between the sponsors and PMDA.
3. The following items must be submitted to the investigational sites:
 Protocol
 Sample Case Report Form

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 Informed Consent
 Document explaining compensation to the subjects in the event of trial related injuries
 Document of clinical trial cost estimates, including document for payments made to study subjects
 Contract agreement, if available or exists
 Summary of the protocol and study drug
 Standard operating procedures for drug control
 Check list for use at hearing to confirm study design or procedures with the sponsor
4. When study trial is completed, the report must be prepared according to the ICH E3 guideline.
Other process requirements
The Clinical Trial Notification (CTN) for the second and all subsequent studies for a given drug are submitted to the
PMDA, 2 weeks before the estimated date of each contract with the investigative site using Form 9 and including
supporting data.
Data showing that the clinical trial is scientifically appropriate, including all study results and any other new
information obtained after the previous CTN.
 Protocol

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 Written patient information and consent form
 Sample case report form
 Latest version of the Investigator Brochure (IB)
Protocol Modifications
The PMDA must be notified of every modification using a CTN, either before or after implementation. For any
changes made to the study objectives, or to the target disease, then notification with a new CTN is required.
The PMDA must be notified of changes at a minimum of six months before implementation of the following types of
changes:
 Deletion or changes of the name of medical institution(s), coordinating investigator, and any members of
the study coordinating committee.
 Changes regarding any sub-investigator, and changes in the title of investigators, coordinating investigator
and members of the study coordinating committee.
 Changes in the amount of clinical sample to be delivered to investigational sites and planned size of study
populations.
 Any changes in the study period due to differences in contract dates among institutions.
 Changes in the name of medical institutions, participating hospital department, and contact information of
the institution.
 Changes in person who is responsible for trial conduct / management at the institution.
Adverse Event Reporting
Any adverse reactions to an investigations drug and any investigations occurring during the clinical trial are
required to be promptly reported the Minister of MHLW according to the procedures of reporting specified in Article
273 of ER-PAL
 Reporting of AE’s and infections is mandatory after termination of the trial and throughout the review period
of the approval application.
 The reporting system must comply with the ICH guidelines.
 The reporting procedures are defined in regulations
 Clinical Safety Data Management – Notification No. 227, of the Pharmaceuticals and Cosmetics
Division, PAB March 1995.
 Reporting Adverse Reactions to the PMDA – Notification No. 0330001 of PFSB March 2004.
 Points to Consider for Approval Application Data for New Drugs – Notification No. 0331022, and
0331009, of the Safety Division, PFSB March 2006
 Points to Consider in Reporting Adverse Reactions – Notifications No. 0426001 of the Evaluation
and Licensing Division, PFSB April 2006
 Questions and Answers on Adverse Reactions Reporting – Office Communication May 2006.
 Electronic reporting procedures must be based on the ICH E2B – Data Elements and Interchange Formats
for Transmission of Individual Case Safety Reports – Notifications No. 344 of the Evaluation and Licensing

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Division and No. 39 of the Safety Division, PFSB May 2000, and the Q and A on Adverse Reaction
Reporting – Office Communication May 2006
Special Considerations when Conducting Clinical Trials in Japan
When conducting clinical trials in Japan a sponsor needs to be aware of some of the more challenging issues that
they may face. Japan still has a ways to go before it will achieve regulatory parity with the United States or Europe,
and there are still many differences between the countries.
Although ICH practices and GCP standards have been in place in Japan since 1997, the country has been very
slow to adopt global clinical processes, infrastructure, and methodologies to increase efficiency.
The following are some of the important difference:26
 Because of inter-ethnic differences in dose-response between Japanese and Caucasian populations, in
order to get a drug approved in Japan, the regulators have insisted that Phase I-III pharmacokinetic (PK)
clinical trials must first be carried out on the drug in Japanese populations - a costly and timely process.27
 The Japanese clinical trial environment has typically been less than welcoming, burdened by red tape and
bureaucracy, sometimes up to 150 essential documents may be required as part of the good laboratory
practice (GLP) paperwork.
 There are still substantial international differences in regulations on the interpretations of Suspected or
Unexpected, Serious Adverse Events (SAE’s). The rules on reporting to regulatory agencies are not fully

26
27

11

harmonized, and different regions have different expectations on the timing and amount of information
provided to investigators and regulators. For example, in the definition of "serious," all hospitalizations are
considered "serious" in the ICH E2A document and in the U.S. and the EU regulations. However, in Japan
only hospitalizations or extension of hospitalization "for treatment" qualify as serious.28
What regulations or standards must the sponsor and its clinical
investigators comply with when conducting studies to support a
regulatory approval submission?
The PMDA recommends that the sponsor request a pre-application consultation after or near the completion of the
clinical research phase to obtain guidance and advice on the preparation of the manufacturing / marketing approval
(MMA) application package, the adequacy of the data to be contained in the package, and the acceptability of the
interpretation of the clinical data.
Marketing Approval Application Dossier Regulations
PAL Article 14-(1) – Requires a sponsor that intends to market a drug to obtain marketing approval of the Minister,
and PAL Article 14(3) requires the sponsor to include data related to the results of clinical trials and other pertinent
data as specified by the ER-PAL.
 Application Form 22(1) is used for manufacturing / marketing approval applications.
 Data to be submitted to the PMDA for approval review are specified in Article 40 of the ER-PAL – Section
A, Origin and Background of the Discovery as Well as the Conditions of Use in Foreign Countries.
Application data are specified in the, Data Required for Applications for Prescription Drugs - Notification
No. 0331015 of the PMDA March 2005.
 Origin and Background of the discovery as well as the conditions of use in foreign countries
 Manufacturing methods, specifications and test methods
 Stability
 Pharmacology
 Absorption, distribution, metabolism, and excretion
 Acute / sub-acute / chronic toxicity, teratogenicity, and other toxicity
 Clinical studies
New Drug Submission Standards
Notification No. 899 of PMSB June 2001 and No. 0701004 of PFSB July 2003, and Office communication October
2003, are all used for new drug submissions to the PMDA. The product overview document for the application is
prepared according to Module 2 of the ICH M4 guideline and includes the following Japan region specific
components:

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 Table of contents
 Approval application
 Certificates – declarations of those who are responsible for collection and compilation of data for approval
applications, GLP and GCP related data, contracts for co-development.
 Patent Status
 Background or origin, discovery, and development
 Data related to conditions of use in foreign countries
 List of related products
 Package Insert
 Documents concerning nonproprietary name
 Data for review of designation as poisons, and deleterious substances
 Draft of basic protocol for post-marketing surveillance
 List of attached documentation
 Other
Submission of Application Requirements
Drug approval reviews are normally processed in the order that the application forms are received, but drugs that
are designated as orphan drugs as well as other medically important drugs, can request priority review designation
based on the evaluation of the seriousness of the targeted disease and the clinical usefulness of the drug,
Notification No. 0227016 of the Evaluation and Licensing Division, PFSB February 2004. The application and data
is submitted to the PMDA, below are the steps of the process.
1. Application
a. Begins the PMDS review process
2. Initial meeting
a. This will be a briefing on the drug from the applicant and will include characteristics of the drug,
history of development and structure of the application dossier. Review Report I – Summary of
application data and outline of review, should be prepared after the meeting.
3. Expert Meeting I
a. Experts will review the application dossier together with the Review Report 1, and discuss any
problems. Results are summarized as Review Report II, and when all problems are resolved the
Final Review Report is prepared, attaching Review Reports I, and II.
4. Committees on new drugs
a. Expert meeting II – review reports from the agency, applications forms, a draft package insert,
Module 2 documents, a list of attached documents and Expert Meeting Reports. Members of these
committees are not staff of the PMDA.
5. Pharmaceutical Affairs Committee
a. Experts in medical and pharmaceutical sciences examine and review important pharmaceutical
matters based on review report from the Committees on New Drugs, review reports from the
Agency, draft package inserts, and a list of participating medical institutions.

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6. Approval
a. Approval refers to governmental permission to market a drug that has demonstrated quality,
efficacy, and safety or to market a drug that is manufactured by a method in compliance with
manufacturing control and quality control standards based on an appropriate quality and safety
management system. Approval allows the drug to be marketed, and generally distributed, and used
for healthcare in Japan
7. Listing in the National Reimbursement List
Post-Marketing Surveillance Standards
 The sponsor must submit a Draft of Basic Protocol for Post-marketing Surveillance at the time of the
submission to agree that all processes will be taken to ensure the efficacy and safety of drugs after they
are marketed. The post-marketing surveillance consists of three systems:
 Adverse drug reaction reporting system
 Good Post-marketing Surveillance Practices (GPSP) requires compliance by
manufacturers / distributors when performing post-marketing surveillance or studies and
also provides compliance criteria for the preparation of data for re-examination and re-
evaluation applications.
 Re-examination system
 This system is aimed at reconfiguration of the clinical usefulness of drugs by collecting
information on efficacy and safety under various clinical settings during a specified duration
after approval. This duration can range between 4 to 10 years.
 Re-evaluations system
 This system is a system for the efficacy and safety both proprietary and nonproprietary
drugs are re-evaluated on the basis of the current status of medical and pharmaceutical
sciences.
References:
Fossati, Linda, and MaryAnn Foote. Targeted regulatory writing techniques: clinical documents for drugs and biologics. Birkhauser, 2009. Print.
Pharmaceutical Medical Devices Agency, Japan, Profile of Services Fiscal Year 2010

Conducting clinical trials in japan chris merriam-leith

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