Japan is the world’s second-largest single-country pharmaceutical market, accounting for approximately 10 percent of global drug sales and expanding quickly.

Top foreign pharmaceutical companies operating in Japan enjoy annual growth rates from 12 to 31 percent, rivaling the expansion observed in emerging markets. This growth spurt has been largely attributed to the Japanese government’s multi-year focus on transforming the way drugs are approved, regulated, and reimbursed in their country. [1]

Due to many factors, including market size and clear regulatory guidelines, there is always an interest in conducting clinical trials in Japan. This also calls for adequate awareness about the regulatory process required for starting clinical trials in Japan.

Click here to learn about various regulatory incentives and financial benefits provided by Japan regulatory in orphan drug development

Regulatory Authority

Pharmaceuticals and Medical Devices Agency (PMDA) is the regulatory agency within the Ministry of Health, Labor, and Welfare (MHLW). 

MHLW conducts scientific reviews of marketing authorization and clinical trial applications of pharmaceuticals and medical devices, monitoring of their post-marketing safety, and providing relief compensation for sufferers from adverse drug reactions and infections by pharmaceuticals or biological products.

Clinical Trial Approvals

  • Clinical trials are regulated under the Pharmaceutical Affairs Law.
  • In accordance with Article 15 of the Good Clinical Practices, foreign sponsors must appoint an in-country representative.
  • The process of approval for clinical trials is sequential.

Ethics Committee

  • To obtain IRB/IEC approval in Japan, it generally takes 4-8 weeks. Japan also operates a local IRB/IEC process and has a Japanese GCP (JGCP) guideline.
  • JGCP is harmonized with the ICH-GCP guideline, although there are some considerations specific to JGCP.
  • It is preferred that each site uses its own IRB/IEC, but it is possible to get external IRB/IEC approval.
  • As per JGCP requirements, the site director would need to ask IRB whether the trial is feasible and the head of each trial location must take responsibility for signing any contracts and overseeing the trial. [3]

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Clinical Trial Notification (CTN)

  • Sponsors of clinical trials must conduct the following standards specified in the Ministry of Health, Labour and Welfare (MHLW) Ordinance.
  • Sponsors of clinical trials must submit the clinical trial protocol to Pharmaceuticals and Medical Devices Agency (PMDA).
  • Persons submitting protocols, shall not sponsor the clinical trial until after 30 days have passed from the submission date. In such cases, the Minister shall undertake a review of the clinical trial protocol to prevent jeopardizing public health and hygiene.

Category of Drugs that come under CTN

  • Drugs with active ingredients differing from that of approved drugs.
  • Drugs with active ingredients that are the same but the route of admission differing from approved drugs.
  • Drugs differing from combination ratio of active ingredients, or indications or dosage and administration of approved drugs.
  • Drugs with active ingredients that are the same ingredient that had approved as a new molecular entity, but that reexamination period has not expired.
  • Drugs expected to be biological products.
  • Drugs manufactured using recombinant technology.

Documents required for Clinical Trial Notification

  • Statement regarding the reason why the sponsoring of the proposed clinical trial is scientifically justified.
  • A protocol of the proposed clinical trial
  • An explanation document used for informed consent and consent form
  • A Sample of Case Report Form
  • Current investigator’s brochure all the documents in Japanese. [5]

Time for submission of CTN

  • The first notifications regarding trial drugs must be submitted at least more than 31 days before the day of planning on contract with the medical institutions.
  • Notifications other than those specified above shall be submitted at least around 2 weeks before the day of planning on contract with the medical institutions.

Approval Process

  • The sponsor before entering any contract for the conduct of a clinical trial must send in an initial notification and the study protocol to the PMDA.
  • Submission requirements are similar to other countries (protocol, informed consent form, names of all investigators, and ethical approvals.
  • PMDA assesses whether a proposed study complies with the requirements for regulatory submission, taking into consideration the science, proposed data collection and analysis techniques, patient safety, and ethics and implements the “Clinical trial consultation system” where the PMDA gives guidance and advice concerning study protocols.
  • Clients may choose whether or not to request a consultation before submitting a CTN however PMDA strongly encourages sponsors to utilize the consulting system as a system that decreases the time an application review.
  • In cases where local trials are being conducted purely to register the drug in Japan, PMDA input on population, efficacy and safety endpoints, and the sample size is likely to be invaluable and speed the time to approval.
  • Clients planning multinational trials with some sites in Japan may choose to skip the pre-CTN consultation but request a session before the NDA is filed to confirm that their trial data is adequate. The time from request to the consultation is approximately two months.
  • PMDA ensures that the same reviewers will be assigned to a study throughout its lifecycle thus eliminating the need to acquaint a new reviewer with the study.
  • Different offices within PMDA are responsible for different categories of clinical trials and the number of consultations normally required will also vary by therapeutic category.
  • Approval is by default; if the client does not receive any queries from PMDA in the specified period, the trial may commence. [1][2][4]

 

Timelines

  • The consultation process of PMDA takes about 3 months
  • Notifications for drugs with new active ingredients or new routes of administration and new combination drugs must be submitted at least 31 days before the planned start date of the trial stated in the contract with the medical institution performing the clinical study.
  • For other categories of drugs other than above must be submitted at least 2 weeks before the planned date of the trial.

Challenges for conducting Clinical Trials in Japan

While Japan’s clinical trial infrastructure is growing, there are still several unique challenges to address

Standards for Good Clinical Practice: Clinical trials in Japan are governed by Japan – Good Clinical Practice (J-GCP) which is harmonized with the international standard (ICH-GCP), is more comprehensive and include additional requirements that often slow the development process

Language barrier: Although most Japanese physicians can understand clinical trial-related documents written in English, other site-level personnel (e.g., clinical research coordinators, pharmacists, and administrative assistants) may not have the same level of fluency.

Limited availability of investigators: With increases in health care expenditures, and a rapidly aging population, the Japanese government has been forced to limit spending on health care. There is a shortage of clinicians at all levels, and few physicians have time to devote to clinical research

Limited incentives for Investigators & Patients: Unfortunately, the issue of limited availability of Japanese investigators is exacerbated by the lack of incentives for participation and since every Japanese patient has full medical coverage, enrollment in clinical trials does not provide a means to access a higher level of care. [1]

Still have some questions?

Japan offers a lot to all kinds of drug / medical device / biotech companies in terms of market expansion. It’s always interesting to consider Japan in your global strategy.

Having reviewed the regulatory process and considering benefits / challenges in Japan, if you have more questions, feel free to ask us.

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Reference

  1. https://www.ppdi.com/~/media/Files/PPDI%20Files/Expert%20Community/Whitepapers/Clinical-Trials-Japan-PPD-White-Paper.ashx
  2. https://www.nihcollaboratory.org/sites/CbyC/Pages/CSIGovAg.aspx?Country=Japan
  3. https://www.georgeclinical.com/resources/research/regulatory-timelines-asia-pacific
  4. https://www.lexology.com/library/detail.aspx?g=da567e4d-0506-4402-975c-f89527171e51
  5. https://www.pmda.go.jp/files/000152326.pdf

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