PMDA Clinical Trial Notification (CTN)

The Clinical Trial Notification (CTN) is the filing that starts the regulatory clock for conducting a clinical trial in Japan. Rather than requiring a sponsor to obtain affirmative pre-approval before dosing the first subject, Japan’s system is built around notification plus a fixed review-and-objection window: a sponsor notifies Japan’s Ministry of Health, Labour and Welfare (MHLW) of its intent to conduct the trial, the Pharmaceuticals and Medical Devices Agency (PMDA) reviews the filing on MHLW’s behalf, and if PMDA does not raise an objection within the applicable review period, the trial may proceed.

Legal basis

The CTN requirement is established under Japan’s PMD Act (the Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices, formerly the Pharmaceutical Affairs Law) together with Japan’s Good Clinical Practice (GCP) ministerial ordinance, which governs how the trial itself must be conducted once it is underway. A trial run in Japan without a cleared CTN, or conducted out of compliance with the GCP ordinance, is not a compliant basis for a subsequent Japan New Drug Application (J-NDA).

The 30-day review window

For an initial CTN — the first notification for a given investigational product in Japan — PMDA applies a 30-day review period from receipt. During that window, PMDA may raise questions about the protocol, the investigational product, nonclinical data, or the qualifications of participating investigators and institutions; if concerns are raised, the sponsor must resolve them before proceeding. If PMDA raises no objection within the 30 days, the sponsor may begin the trial once the window closes. PMDA publishes review checklists for specific initial-CTN categories (for example, initial oncology drug trials) that lay out exactly what the 30-day review looks for.

Subsequent notifications — amendments to an already-cleared protocol, or CTNs for later trials of the same product — are also filed with MHLW/PMDA, though the scope and handling of review can differ from the initial filing depending on what is being changed. Sponsors should not assume every amendment triggers a full fresh 30-day hold; the applicable requirement depends on the nature of the change and current PMDA guidance at the time of filing.

What a CTN submission contains

• Trial protocol. The full clinical trial protocol, including objectives, design, dosing, and endpoints.
• Investigational product information. Chemistry/manufacturing data and nonclinical (and, where available, prior clinical) safety data supporting first use in the proposed population.
• Investigator and institution details. The qualifications of the investigators and the institutions where the trial will be conducted in Japan.

Who files a CTN

The trial sponsor files the CTN. A foreign sponsor without a physical presence in Japan generally cannot file directly and instead conducts the trial through a Japan-based sponsor entity or an in-country caretaker arrangement — a structural requirement distinct from, but related to, the CTN filing itself, and one that should be planned for well before the notification is prepared.

How CTN compares to a US IND

Sponsors moving between the US and Japan often map the CTN onto the FDA’s Investigational New Drug (IND) application because both gate the start of human trials, but the mechanics differ: an IND is subject to a 30-calendar-day FDA review during which the agency can place the trial on clinical hold, and the trial may proceed automatically once that period lapses without a hold — structurally similar in shape to the CTN’s notify-then-wait design, though the two operate under separate statutes (the US Federal Food, Drug, and Cosmetic Act versus Japan’s PMD Act) and separate agencies, and the specific data package and checklist items PMDA expects for a CTN are not identical to what FDA expects for an IND. Neither filing substitutes for the other; a multi-regional trial that includes Japanese sites needs its own cleared CTN regardless of IND status elsewhere.

Worked examples

• First-in-Japan trial of a new molecular entity. A sponsor with no prior Japan clinical experience for a compound files an initial CTN with MHLW/PMDA, including the protocol and nonclinical safety package, and waits out the 30-day review period before enrolling the first subject at a Japanese site.
• New indication for an already-approved drug. A company seeking to study an approved drug in a new indication or patient population in Japan files a fresh CTN specific to that new protocol, even though the drug itself is already marketed in Japan for a different use.

Counter-example

A retrospective chart-review study, or a purely observational study that does not administer an investigational drug or use an approved drug outside its labeled conditions, does not require a CTN — the CTN requirement attaches specifically to interventional trials of unapproved products or unapproved uses under the PMD Act, not to observational research generally. Similarly, a trial conducted entirely at non-Japanese sites, with no Japanese subjects or investigators, has no CTN obligation even if its sponsor is a Japanese company.

Related terms

See also ICH GCP (Good Clinical Practice), which PMDA applies alongside its own GCP ordinance; ICH E6(R2) Section 5 sponsor obligations; Clinical Trial Protocol; ICH M11, the harmonized protocol template increasingly referenced in CTN and IND submissions alike; and IND Annual Report for the closest US equivalent’s ongoing reporting obligation.