Japan clinical trial notification (CTN): who files, 30 days

The CTN is a notification, but the first one waits 30 days

Japan has no trial approval. A sponsor files a notification, and only the first one for a drug new to Japan makes it wait.

The rule is PMD Act Article 80-2. A company that intends to ask hospitals to run a trial, or a physician who intends to run one personally, must notify the Minister of Health, Labour and Welfare in advance. Article 80-3 lets the Minister hand the investigation to PMDA, and then the notification goes to PMDA instead. PMDA's own page puts the point plainly: it accepts notifications whose documents are formally in order, and it does not grant permission. In a genuine emergency, the notification may follow within 30 days after the trial starts.

Not every drug trial needs a CTN. Article 268 of the Enforcement Regulations lists the cases. They include a new active ingredient, a known ingredient given by a new route, or a known ingredient with a new combination ratio, indication or dosage. Drugs expected to become biological products and drugs made with recombinant DNA technology are also on the list. Bioequivalence studies are excluded for most of these categories.

The wait is in Article 80-2, paragraph 3. Whoever files the first notification for a given drug may not ask hospitals to run the trial, or run it, until 30 days have passed from the filing date. MHLW investigates the plan in that time to prevent harm. MHLW's notice on CTN handling, in the version revised on March 29, 2024, says which plans this covers. They are trials in which the investigational drug is given to humans in Japan for the first time and is a new active ingredient, a known ingredient by a new route, or a new combination ratio. A phase 1 already run in the US does not take a Japanese trial out of the 30-day investigation.

Treat the first CTN as the gate on your Japanese timeline, because the 30 days run from the filing date whatever has already happened in trials abroad.

When can you file, and when can you sign the site contract?

The notice ties the filing date to the site contract. That turns the 30 days into a contracting deadline.

For a plan subject to the 30-day investigation, the notice says to file at least 30 days before the planned date of the contract with the trial site. It then says the contract may not be signed until 30 days have passed from the filing. A microdose study is filed about 30 days ahead, and the first notification after it is the one that gets the 30-day investigation. Every other CTN goes in about 2 weeks before the planned contract date. If one of those covers a phase 1 or similar trial, the notice recommends consulting PMDA about timing in advance.

PMDA reads a full package in those 30 days. The notice lists a document giving the reasons the sponsor judged the trial scientifically justified, the protocol and the informed consent forms. It adds a sample case report form, unless the protocol already shows its items, and the latest investigator's brochure. Documents on the other drugs used in the trial come with it. Where relevant, the sponsor adds an assessment of mutagenic impurities and quality data for proteins made in cell lines. PMDA's review departments send inquiries during the investigation, and since August 21, 2023 the answers and replacement documents for 30-day cases can be filed online.

Each protocol gets its own notification, however many investigational drugs it uses. Filing has been possible online through PMDA's application e-data system since January 11, 2023, or on CD-R or DVD-R at the counter or by post. After filing, the sponsor must also register the trial in jRCT, Japan's clinical trial registry.

Changes have their own clock. Most must be notified before they take effect. Adding a drug that falls under the 30-day investigation needs 30 days' notice before the revised protocol is used. Adding another investigational drug, or changing the purpose or target disease, needs about 2 weeks. A list of minor items, such as changes to the CRO or the foreign manufacturer's corporate name, may be gathered and notified about every 6 months.

Set your first site contract date at least 30 days after the planned filing date, and for a later notification that covers a phase 1, ask PMDA about timing first.

Who files: the company, the physician, or the caretaker

The filer depends on who runs the trial. Japan has two kinds of trial, and both are notified.

In a company-sponsored trial, the company that asks hospitals to conduct it is the sponsor and files. In a physician-led trial, the physician who conducts the trial personally files. PMDA's page names both: sponsors such as drug companies, and physicians or dentists who conduct trials themselves.

The notification's contents are set by Enforcement Regulations Article 269. It names the investigational drugs with their ingredients and quantities, the manufacturing method, and the expected indication and dosage. It gives the purpose, content and period of the trial, every site and its review board, and the principal investigators and sub-investigators. Planned drug quantities and subject numbers are given per site. Any CRO is named with the scope of its work.

Two items concern a company abroad. If the sponsor has no address in Japan, the notification gives the name and address of its caretaker. In a physician-led trial, the notification also names whoever supplies the investigational drugs, with an address. MHLW's notice asks for the overseas sponsor's and the foreign manufacturer's names and addresses in both Japanese and English.

If a Japanese physician will run a trial with your drug, expect your company to be named in that physician's notification as the drug supplier, and agree in the supply contract who answers PMDA's questions about the drug.

A sponsor abroad acts through its in-country clinical caretaker

A foreign company can sponsor a trial in Japan without a Japanese entity. It cannot do so without a caretaker.

GCP Ministerial Ordinance Article 15 sets the rule. A sponsor with no address in Japan must appoint, from people with an address in Japan, someone who can request the trial on its behalf. A Japanese office of a foreign corporation qualifies through its representative. The ordinance gives the reason: so that the caretaker can take the measures needed to prevent or limit harm from the investigational drugs. The sponsor must have the caretaker carry out the procedures for requesting the trial.

The caretaker then becomes the filer. Enforcement Regulations Article 271 says that for a sponsor abroad, the caretaker handles the procedures for the notification and for every later change, discontinuation or completion notice. The notification form has a field for whether the filer is the sponsor or the caretaker. A change of caretaker must itself be notified under Article 270.

The record duty is easy to miss. GCP Article 16 makes the sponsor keep records of each investigational drug's manufacturing date, method and quantity, its stability and other quality tests, its delivery to and collection from each site, and its disposal. Article 26 says a sponsor abroad must have its caretaker keep those records. The retention period runs until marketing approval or 3 years after the trial ends or is discontinued, whichever is later.

Article 15 asks only for an address in Japan. It does not ask the caretaker or the sponsor to hold a marketing authorization holder license, which only becomes necessary when you sell. The MAH guide covers that later step. The caretaker for a Master File is a different role under different rules, described in the Master File guide.

Choose a caretaker that can take PMDA's inquiries during the 30 days and hold your investigational drug records for the full retention period, and write both duties into the contract.

What the drug must carry when it ships to Japan

GCP sets the label and the source of the drug. Customs then checks the notification.

Article 16 requires the container or package of the investigational drug to state in Japanese that it is for clinical trial use. The label also carries the sponsor's name and address. For a sponsor abroad, it shows the sponsor's name and the country of its address, plus the caretaker's name and address. Then come the chemical name or code, the lot number, and storage conditions and expiry where needed. The label, package and any insert may not show the planned brand name, indication or dosage, except in open-label and expanded access trials. The drug must be packed to prevent contamination and deterioration in transport and storage.

Article 17 says the sponsor must deliver drugs made at a site that has the facilities needed to ensure quality and uses appropriate manufacturing and quality control. That is the point where a CDMO's documents meet the trial.

Import follows the notification. With a CTN on file, the regional bureau's guidance lets the sponsor of a company-sponsored trial import trial drugs without a separate import certificate, as the Yakkan Shomei guide explains. A notification filed online comes back without PMDA's receipt stamp. MHLW's November 16, 2022 notice says customs will accept PMDA's acceptance email together with a copy of the notification instead.

Label the investigational drug in Japanese with the caretaker's name and address before it leaves your site, and make sure the importer holds PMDA's acceptance email and the notification copy for customs.

After the 30 days: changes, safety reports and the end of the trial

The notification stays live for the whole trial. Reports and updates follow it.

Safety reporting runs on fixed clocks in Enforcement Regulations Article 273. Unexpected deaths and life-threatening cases suspected to be caused by an investigational drug, in the trial or in clinical studies abroad, are reported within 7 days. Other serious unexpected cases and the other events listed are reported within 15 days. A line listing for each investigational drug is due every year, within 2 months after each one-year period counted from the first notification. Under PMD Act Article 80-2 the Minister may order a trial suspended or changed to prevent harm.

The end is notified too. A discontinued trial is notified without delay. A completion notice follows once every site has reported completion and the investigational drugs have been collected. If you decide to stop developing the drug, a development discontinuation notice goes to PMDA without delay, with specific reasons.

Agree before the first CTN who in Japan will send the 7-day and 15-day safety reports, because Article 273 sets those clocks for the sponsor and the caretaker rule in Article 271 covers only the notifications.

Steps before your first trial in Japan

Take these in order. Steps 1 to 3 come before the 30-day clock starts.

1. Check against Enforcement Regulations Article 268 whether the trial needs a CTN, and whether the drug has ever been given to humans in Japan. If it has not, plan for the 30-day investigation.
2. Appoint an in-country clinical caretaker with an address in Japan under GCP Article 15. Put into the contract the notifications, PMDA inquiries, the retention of investigational drug records under Article 26, and who sends safety reports.
3. Prepare the package: the scientific justification, protocol, consent forms, CRF sample, latest investigator's brochure and documents on the other drugs, plus impurity and cell-line protein data where relevant. Give the caretaker your company's and the foreign manufacturer's names and addresses in English for the form.
4. Have the caretaker file with PMDA at least 30 days before the planned contract date, and register the trial in jRCT. A later notification goes in about 2 weeks ahead, after a timing consultation with PMDA if it covers a phase 1.
5. Label the investigational drug in Japanese under GCP Article 16, ship it from a site meeting Article 17, and give the importer PMDA's acceptance email and the notification copy for customs.
6. Sign site contracts only after the 30 days have passed. Then notify changes before they take effect, report serious unexpected reactions within 7 or 15 days, and file the annual line listing within 2 months after each year.

For the Japanese terms on PMDA forms, see the side box and the glossary.