CLINICAL TRIALS………… JAPAN

Clinical trials

Clinical trials, also known as clinical studies, are scientific studies of drugs, medical devices or other treatments in humans. These studies are most often conducted for the following reasons:

  • To verify the safety and effectiveness of potential drugs, medical devices or other treatments,
  • To compare trial-treatments against existing treatments,
  • To determine better ways to use treatments to make them more effective, easier to use, or to decrease side effects,
  • To determine how best to use a treatment in a specific population. For example, in children or in a particular ethnic group.

Clinical trials for new drug development

There are three main stages in clinical trials for drug development: Phases I, II and III. Phase I clinical trials are conducted with 50~200 healthy participants and involve incremental dose increases of investigational drug within a predefined dose range to evaluate tolerability and safety, monitor food and drug interaction, as well as gather information about what the drug does to the body (pharmacodynamics1(PD)) and what the body does to the drug (pharmacokinetics2 (PK)).

1 Pharmacodynamics (PD) is the study of a drug’s biological and physiological effects on the body. Examples of physiological effects include changes in heart rate, blood pressure or blood glucose level.

2 Pharmacokinetics (PK) is the study of the mechanisms and rates of drug absorption, distribution, metabolism and excretion after administration of a drug.

This information is vital in understanding how safe a drug is, how it works, potential as a treatment, and appropriate dosage levels for safe and effective usage. A series of phase I trials typically take about 1 year to complete. If successful, these would lead to Phase II patient trials incorporating 100~400 participants to assess drug efficacy, provide further information about safety, and establish proper dosage. This process can take about 2 years to complete, after which, larger scale Phase III patient trials can begin with as many as 1,000~5,000 participants enrolled under the wider supervision of general physicians, hospitals and clinics. These studies take about 3 years to complete before, if successful, the data is submitted to the relevant regulatory authorities to obtain marketing authorization for the new drug. After review and approval by regulatory authorities the drug can be made available to the general public.

Caucasian inclusive clinical trials in Japan

In Japan, clinical trials for drug development are called chiken (治験). Generally speaking chiken focus on Japanese subjects only, but in cases where international drug development entails consideration of multi-ethnic studies, or where pharmaceutical companies wish to submit Caucasian Phase II ~ III data from overseas for drug approval here in Japan, multi-ethnic comparative PK studies may be required. In such cases, carrying out these studies in Japan can be a viable option for sponsoring pharmaceutical companies.

Introduction to Caucasian clinical trials in Japan

These multi-ethnic comparative PK studies are generally Phase I trials as described earlier. In these studies Japanese and Caucasians, and/or other ethnic groups, participate as separate groups in a single trial at a single site. Each group is given the same investigational drug at the same doses, with the same diet and the same routine. The significance of this is the achievement of excellent comparability through standardization of operating procedures and equipment, and reduced variation in human technique and judgement. Collectively this results in higher quality and more robust data about the drug being studied.

Clinical trial organisers

InCROM (International Clinical Research Organisation for Medicine Ltd) is the Site Management / Clinical Research Organisation responsible for the management of clinical trials conducted at its affiliate medical facilities. In the case of Caucasian inclusive studies, these facilities are Koganeibashi Sakura Clinic in Tokyo and Osaka Pharmacology Clinical Research Hospital (OPHAC) in Osaka. Clinical trials are typically commissioned by a sponsoring pharmaceutical company, which outsources its research and development to clinical research specialists such as InCROM, that have the experience, knowledge, staff and facilities to carry out these studies safely and smoothly.

InCROM Volunteer Centre is a major source of recruits for InCROM trials, with a Japanese database of about 40,000 registered members and a growing database of Caucasian volunteers.

With a strong international presence, more than 400 dedicated staff and over 60 affiliated medical facilities engaged in Phase I through to Phase III and post-marketing trials, InCROM Group is a recognised leader in the clinical research field. InCROM Group has conducted over 1,100 Phase I clinical trials and more than 400 Phase II or later phase trials (including overseas trials) and we are proud to count all of the major global pharmaceutical companies amongst our client base.

Clinical trial organisers

For more information please see the InCROM Group website.

Your safety

In Japan, as in Western countries, the conduct of clinical trials is strictly legislated and administered by government regulatory authorities. Here in Japan, those authorities are theMinistry of Health, Labour and Welfare (MHLW) and the Pharmaceutical and Medical Devices Agency (PMDA). Clinical trials are conducted in accordance with Japanese standards for Good Clinical Practice (Japanese GCP), which are based upon International standards for Good Clinical Practice (ICH-GCP). These standards include a requirement for independent review of each trial protocol (the detailed trial plan) by a qualified clinical trial review board. This committee, referred to as an Institutional Review Board (IRB), consists of a team of impartial medical professionals, medical institution representatives and regular citizens. To ensure the rights, safety and well-being of clinical trial participants, it is the duty of the IRB to review trial protocols and procedures and the materials to be used in obtaining and documenting informed consent (see below).

All trials conducted by InCROM are reviewed thoroughly before and throughout conduct, by this qualified Institutional Review Board. All medical facilities are government approved and highly competent medical and clinical professionals supervise all trials. When you are invited to apply to participate for a specific study, you will be provided with information about the trial purpose, the trial drug, time frames, procedures, your rights, compensation, etc. It is only with a full understanding of the above that you will be permitted to register to participate in a trial.

Many people express concern about the potential side effects of investigational drugs. The first thing to note however is that all drugs, including the ones we take for common colds and headaches, produce side effects. Side effects are the secondary effects of taking a drug – that is, any effect other than the intended therapeutic effect that lessens or stops the symptoms of a disease or condition. These secondary effects may be unnoticeable, could include cold-like symptoms, dry throat, stomach cramps or drowsiness, and in rare cases, could include symptoms of a more serious nature.

In Japan based Caucasian studies planned by InCROM, safety data about the drug has already been collected and suitability for trial continuation has been established.

Your safety

Trial time frames

The time frames for every trial are different, but as a rough guide, our studies will typically require a hospital stay of several nights to several weeks. During this time you will need to stay in the hospital, eat the prescribed diet and refrain from overexertion. You will need to cooperate for ongoing blood and urine sampling, temperature, blood pressure and other vital sign checks. After hospital discharge there may also be several non-stay follow-up visits required.

Course of events for a clinical trial (example only)

* Regular checks’ includes blood and urine sampling

Compensation for participation

As a healthy volunteer participating in a clinical trial, it is unlikely you will derive any direct health benefits from participation. This being the case, to compensate you for your time and any discomfort experienced during the trials, an honorarium is provided. The amount of compensation may vary according to the study, but in general this is based upon the number of hospital visits and the length of the hospital stay. Specific details about compensation are provided in the informed consent form for each study, however you may contact us at anytime for generic details..

Enrolling to take part

To take part in a clinical trial, you need to fill in an online or post-out registration form to become a member of our volunteer panel.

This registration allows us to match upcoming trial requirements with your profile and then to contact you with basic details about studies you may be interested in participating in. If you are interested, we then invite you to a more detailed trial briefing. This will cover the purpose, duration, procedures, your rights, any potential risks associated with participation in the trial, compensation, and confidentiality requirements etc. This also provides a face-to-face opportunity for you to ask questions.

Following on from the briefing, before you are enrolled (or participate) for a trial, it is a requirement that you give ‘Informed Consent’3. This is essentially the same form of consent required of patients undertaking any serious treatment or medication provided by a doctor. Detailed information will be provided to you both verbally and in writing. You will also be given time to consider, consult with those you trust, and to contact us with any further questions you may have before, should you wish to, signing and returning the completed Informed Consent form.

3‘Informed Consent’ is a legal condition whereby a person can be said to have given consent, based upon a clear appreciation and understanding of the facts, implications and future consequences of their actions – in this case participation in a clinical trial.

This document verifies that you participate out of your own free will, and with full understanding about the nature and implications of your participation. Note that even once you have given Informed Consent, you may withdraw from a trial at anytime without explanation.

Once your Informed Consent is received you will receive a medical check and an interview to confirm that you are in good health and that you meet the conditions for participation.

Enrolment restrictions

Restrictions vary by trial, but in general the main things that would prevent you from participating in a trial are:

  • Insufficient time lapse between participating in studies: Usually, a 3-month break between periods of participation is required.
  • Participating in more than one trial for the same drug: Regardless of time frames this is not allowed.
  • Recreational drug use (marijuana etc.): Recreational drug users are not allowed to participate in clinical trials.
  • Smoking: There are many instances where smokers cannot participate or you will be asked to refrain completely while participating in the trial. If you are a smoker please keep this in mind if you intend to register to participate.
  • In the days preceding a trial you may also be asked to avoid products containing caffeine, alcohol and grapefruit, as these substances can significantly alter drug action and absorption, and negatively affect the results of the study.
  • While a working visa is not a requirement of participation please note that tourist visa holders are bit eligible for participation.
  • In some cases it will be necessary to hold follow-up checks or interviews. For this reason we ask that participants intend to remain in Japan for at least several months from the completion of the trial.

For the medical and hospital stay

  • You will need to show your Alien Registration Card and passport when you visit the hospital for the medical check and trial admission. We will keep a photocopy on file.
  • For hospital stays the hospital will provide towels, pyjamas, soap, toothbrush and toothpaste, shampoo and conditioner, disposable razors and slippers.
  • You will need to bring sufficient underwear and any other personal items you may need.
  • Televisions, DVDs Internet access at our computer room will be made available.
  • Do not bring food or drink to the hospital. During a trial all meals are set and provided according to a study plan and any variation from this is likely to negatively impact the study.

Things to bring to the medical check and hospital stay

Other points to note

  • Your full cooperation will be expected at all times.
  • We ask that you are considerate and courteous to staff and other volunteers.

I’d like to know more…

  • Personal Information Protection Policy

    As a company engaged in clinical trials, InCROM considers the protection of personal information to be a serious social responsibility. When handling personal information in our business activities the protection of this information is one of our highest priorities. To ensure personal information protection, the following policies have been established:

    (In accordance with these policies, all InCROM employees will make every endeavour to ensure appropriate handling and administration of both internal and external personal information. These policies are made public on the Company’s homepage and in other publications (in Japanese only)).

    1. Personal Information Administration
      1. A personal information protection system shall be prescribed and information shall be handled accordingly.
      2. The following positions shall be appointed to carry out the stipulated responsibilities of personal information handling: A Personal Information Manager, a Manager for education on personal information handling, a person responsible for grievances and consultation and a person responsible for internal auditing.
      3. All employees shall be made fully aware of the requirements for personal information handling and the need for extreme care to avoid any leakage of information to any outside parties.
    2. Acquisition, Utilisation and Transfer of Personal Information
      1. When InCROM accepts an individual’s personal information, the individual’s consent to use the information shall also be obtained after providing a clear explanation of its intended use, and the nature and scale of InCROM’s business activities. Further, where an individual’s personal information is to be provided to or handled by a third party, that individual’s consent must be obtained.
      2. Disclosure, correction or deletion of an individual’s personal information will be allowed within reason, at the request of that individual or that individual’s legal representative(s).
      3. Special consideration shall be given to the handling of personal information of persons under the age of 20. Consent from the legal guardian shall also be required.
    3. Personal Information Security
      1. The person(s) responsible for the handling of personal information shall be specified and the number of people given access to this information limited. InCROM will make every endeavour to ensure the prevention and correction of unauthorised access to personal information, leakage, loss or damage etc of personal information, and to ensure that security of personal information is maintained.
      2. Where the handling of personal information is outsourced to a third party, the third party selected shall be a Privacy Mark approved company or acknowledged as meeting comparable standards for personal information protection. Further, where a third party is contracted for the handling of personal information the requirements for handling will be stipulated by contract and every endeavour made to ensure the information’s security.
    4. Regulatory Compliance
      1. With respect to personal information handling, all laws, national policies and applicable standards shall be complied with.
      2. In addition to setting company rules for personal information handling in accordance with relevant laws, national policies and JISQ15001, rules shall be reviewed and improvements made on an ongoing basis.
    5. Continuous revision
      • The implementation of Policies 1~4 (listed above) will be assessed regularly by audit and every endeavour will be made to ensure the ongoing improvement of the Personal Information Management System.
      • If you have any questions or opinions you wish to share in regards to personal information handling, please contact us at the details below:
    Grievances and Consultation Contact
    InCROM Group
    SMO Division, Volunteer Recruitment Department
    Tel: 0120-1966-94 (Mon ~ Fri 9:00~17:00)
    Email: kojinjoho-info@incrom.com

Handling of Personal Information

Personal information shall be handled in accordance with standard agreements between InCROM and its partner medical institution(s).

Personal information shall include

  • Address, Name, Phone number and other information specific to an individual
  • Medical information including medical history, laboratory/physical test data etc
  • Clinical trial participation status (history)

Provision of the above information is not mandatory, however, where necessary information has not been provided, volunteer registration may not be accepted.

InCROM promises to handle personal information in accordance with laws and regulations for the protection of personal information, to review internal rules and handling systems as necessary, and to ensure strict and careful administration of personal information.

Use of personal information

InCROM will only use personal information for the following purposes:
Clinical trials
Correspondence between InCROM and individual volunteers

(Personal information will not be used for other uses without the owner’s permission).

Requesting changes to personal information

InCROM shall respect individual’s rights with respect to their personal information. Should an individual request viewing, correction, addition, deletion, discontinuation of use, or refuse to allow provision of personal information to a third party, these wishes will be followed in accordance with standard agreements between InCROM and partner medical institution(s).

To request any changes to your personal information or its handling please see the notes below. Also, to ensure that your personal information is kept accurate and up to date please notify us of any changes to your address, name, place of work or education, email address etc.

Who can make requests?

  • Requests can be made by the individual to which the personal information pertains or the legal/nominated representative of that person.
  • Where requests are made, verification of identity will be required.
  • Where a legal/nominated representative makes a request on an individuals behalf proof of right to act on that individuals behalf (proxy) will also be required in the form of an official document (or its copy).

Requests cannot be accepted in the following instances

  • Where the request form is filled out incorrectly or incompletely
  • Where identity cannot be confirmed
  • Where the right to act on behalf of an individual cannot be confirmed
  • Where the subject of the request form does not match the information disclosed
  • Where law prevents the execution of the request
  • Where the request will cause significant damage to, or risk of damage to, InCROM’s business

Please understand that your personal information will be shared between InCROM and the medical institution(s) with whom InCROM has contracted to for the conduct of clinical trials. Your personal information will not be provided to any other third party without your permission.

Further to the above, personal information will be handled in accordance with law (Law No.57 30 May 2003).

Enquiries

For enquiries regarding personal information handling, please contactmakoto.tsunoda@incrom.com or phone 0120-72-8343(Makoto Tsunoda).

The Procedure for Manufacturing Drugs in Mie Prefecture, Japan.

 

The Procedure for Manufacturing Drugs in Mie Prefecture, Japan.

The following details the necessary procedure for the commencement of manufacture (or importing) of drugs in Mie Prefecture, Japan.
Note: The procedures described below are applicable in Mie Prefecture, Japan, as of April 2002. Due to future amendments and the disparities of laws in different prefectures, it is necessary to be informed as to the correct application procedures directly by the relevant prefecture.

1. For Manufacture (or Importing) of Drugs

Approval for the manufacture (importing) of each item, and a manufacturing (importing) license are required for the manufacture (or importing) of drugs.

Drug Manufacture Approval The quality, effectiveness and safety of the drug under application must pass the examination. However, drugs listed on the Pharmacopoeia of Japan do not require approval.
License The structural conditions (building and facilities) and human resource requirements (e.g. Administrators) of the drug manufacturing facilities must pass the examination to acquire a business license.

2. Standard Period for the Administrative Process

There is a standard period for the administrative process of the approval and licensing examinations. Unless there are irregularities in the application or supplied data, the examinations are generally completed within the time specified.

(Example)

*Approval Ethical Drugs (new drugs) 1 year
(branded generic drugs) 1 year
(modification) 1 year
Non-prescription drugs 10 months
IVD (in vitro diagnostic) 6 months
(approval for modification of storage conditions and period of effectiveness: 3 months)
*Mie Prefectural License
(for manufacture or importing)
Drugs, quasi-drugs, cosmetics, or new medical devices 56 days

Note:
(1) The above periods for approval and licensing are applicable only in Mie Prefecture. Be aware that the standard periods for the administration process may differ in other prefectures. Further, the above period may be extended where a replacement of the application documents is required.
(2) Please feel free to contact us if you have any further questions.

3. Drug Approval Inspection

Apart from those drugs which do not require approval, most drugs are approved by the Minister of Health, Labor and Welfare, and some are approved by the Governor. However, approval and receipt of applications based on both national and prefectural standards will occur at the prefectural government. The drug approval process is detailed below.
Quasi-drugs, and medical devices are approved under the same process as drugs. As for cosmetics, those which contain ingredients that are not displayed, require approval.

4. License for Drug Manufacture (or Importing)

Below is a flowchart illustrating the license application process in Mie Prefecture. Applications are accepted by the Mie Prefectural Government.

At present, provided that there are no problems found at the site inspection, licensing will take 2 weeks. If you require licensing within 2 weeks due to your production schedule, with advance notice, we may give you special consideration and shorten the duration of the licensing process.
The license is valid for 5 years, and must be renewed after 5 years. In addition, the application process for the business license for manufacturers (and importers) of quasi-drugs, cosmetics, and medical devices is the same as for a drug manufacturer (or importer).

Pharmaceutical Affairs Food Team, Mie Prefectural Government
13 Komei-cho,Tsu City,Mie Prefecture 514-8570 Japan
TEL +81-59-224-2330 or 2331/FAX +81-59-224-2344/E-mail yakumus@pref.mie.jp

WHAT IS MIE PERFECTURE..SEE………http://en.wikipedia.org/wiki/Mie_Prefecture

 

 

 

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.

Market Characteristics

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

navigating fig 1

navigating fig 2

NDA Review Process

PMDA frequently performs a team review with experts in quality, nonclinical, and clinical trials, biostatistics, and other fields.

navigating fig 3

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.

Conclusion

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.

References

1. http://www.jmacct.med.or.jp/english/publications.html

ICC Responsibilities

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)

……………….