Checklist for 30-day Clinical Trial Notification (CTN) Review in Japan: Initial CTN for Oncology Drugs

PMDA published an English “early consideration” checklist dated December 10, 2024 to help sponsors understand what should be clearly described in an initial Clinical Trial Notification (CTN) package for oncology drugs and its attachments.

Reference (PDF): Check List for 30-day-Clinical Trial Notification Review on an Initial Clinical Trial Notification (Oncology Drugs).

How to use this checklist

Use it as a pre-submission quality gate: map each checkbox item to (1) a CTN field and/or (2) a specific section of the protocol, IB, ICF, or quality dossier, then confirm the information is explicit, internally consistent, and Japan-relevant (e.g., unapproved indications/devices are clearly disclosed).

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I. General matters: site–sponsor communication and trial infrastructure

1) Safety information contact system and reporting timelines

The checklist expects the CTN/attachments to specify the contact system and reporting deadlines:

• site → sponsor (or Clinical Trial In-country Representative, CTIR),
• sponsor/CTIR → other sites, and
• sponsor/CTIR → Japanese sites for overseas safety information, including how after-hours emergency contractors relay information back to the sponsor/CTIR.

2) Medical devices/equipment used in the trial

If trial procedures use a device/equipment that is already certified/approved in Japan, the certification/approval number should be stated in the CTN remarks. If not certified/approved, the checklist asks the sponsor to describe actions consistent with relevant notifications and to ensure the use of such devices/equipment is reflected in the protocol/IB and informed consent materials for transparency.

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II. Clinical safety: Phase 1 ethics, dosing rationale, DLT/tolerability, and informed consent completeness

1) Phase 1 participants: ethical selection and “standard therapy” considerations

For dose escalation, the checklist emphasizes selecting patients with malignant tumors unlikely to respond to standard therapy or lacking standard options. If enrolling patients who could still benefit from standard therapy after recommended dose selection, the sponsor should explain why the investigational treatment is expected to be comparable or better, and provide the scientific/ethical rationale for combinations with established therapy. It also highlights communicating in consent documents that standard therapy may become unavailable if DLT/SAE occurs.

2) Starting dose and administration plan

The package should explain how the human starting dose was determined from non-clinical pharmacology/PK/toxicology, or—if Japan is joining after overseas initiation—how starting dose/dosage was set using overseas DLT onset and intrinsic/extrinsic ethnic factors. For competitively enrolled MRCTs, the presumed Japanese starting dose/dosage should be clearly stated once sufficient safety information exists.

3) First-in-human safeguards

The checklist looks for a defined sentinel interval between dosing the first and second participants (and rationale). It also asks for justification if repeated-dose administration starts without a prior single-dose study.

4) Concomitant administration and combination therapy safety logic

If combination dosing is planned, the attachments should explain why overlapping toxicity profiles are unlikely to cause unacceptable risk and why the planned combination dose levels are tolerable based on monotherapy/overseas experience.

5) Safety during tolerability evaluation period (e.g., Cycle 1)

The checklist expects a clear plan: either hospitalize participants during the tolerability evaluation period, or—if outpatient monitoring is planned—describe what qualifies for outpatient management, emergency hospital readiness, and concrete measures ensuring patient safety.

6) Inclusion/exclusion criteria: anticipating known oncology risks

Examples explicitly called out include:

• criteria aligned with expected AEs from MoA/tox/similar drugs,
• HBV screening/monitoring measures when immunosuppression is plausible,
• excluding ILD history or significant pulmonary comorbidity if ILD risk exists,
• excluding hypersensitivity history to drug substances.

7) Tolerability evaluation and DLT definition (including modern dose-escalation designs)

The checklist expects:

• an objective DLT definition,
• how tolerability is handled when dose is reduced/interrupted/postponed,
• safeguards to avoid underestimating DLT (e.g., interruptions/reductions and hematologic toxicity management),
• and, for MRCTs, how tolerability is evaluated for Japanese participants at recommended dose. If a statistically driven escalation design is used, the sponsor should document simulation-based operating characteristics and key rules (escalation rules, MTD definition, stopping rules, and simulation outputs).

8) AE management rules and resumption criteria

Criteria for resuming the investigational drug and the dose at resumption should be pre-defined.

9) Concomitant drugs and interaction-related restrictions

The checklist asks sponsors to state whether concomitant anti-cancer drugs are allowed, disclose when a concomitant drug’s indication is not approved in Japan, specify restrictions on drugs/foods/supplements affecting PK, and instruct participants (in consent) to consult investigators before taking other drugs/supplements.

10) Contraception, pregnancy, and breastfeeding requirements

Expect explicit definitions of who requires contraception, the required contraception period, contraceptive methods and whether the methods/devices are certified/approved in Japan, pregnancy testing and exclusion of pregnant patients, what to do if participant/partner becomes pregnant, and breastfeeding exclusion (including conditions/timing if breastfeeding is suspended).

11) Sufficiency of non-clinical package before clinical exposure

The checklist calls for confirmation that non-clinical studies are sufficient for trial initiation, referencing relevant non-clinical guidance (e.g., ICH S9/S6/M3 context).

12) Anticipated adverse events: monitoring plans and transparency about limited data

Sponsors should align test items/schedules with anticipated risks from non-clinical and overseas data (including early detection testing if ILD is a concern) and describe anticipated side effects in an understandable way in the informed consent. It also highlights disclosing when safety information is limited (e.g., long-term dosing before long-term tox completion, or dosing women before reproductive tox completion).

13–15) Genomics/pharmacogenomics and consent completeness

The checklist includes detailed expectations for:

• sample collection purpose/timing, privacy protection, storage/disposal, and disclosure policy for genetic results,
• disclosures when genetic testing uses unapproved diagnostics/devices (risk of false positives/negatives) and secondary development use,
• and additional consent items such as missed-dose handling, emergency contacts, and instructing participants to inform non-trial physicians about trial participation.

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III. Attached documents: completeness and Japan-specific disclosures

1) CTN entries for special trial types

If applicable, the CTN should contain appropriate descriptions for situations such as MRCTs, genomic testing, Cartagena Act-regulated products, biologics designation expectations, microdose trials, trials involving devices/equipment, companion diagnostics, and combination products, in line with relevant notifications.

2) Protocol / Investigator’s Brochure language control

If both Japanese and English versions are provided to Japanese sites, the sponsor should state which version prevails; if English prevails, the sponsor should ensure Japanese and English content are identical.

3) Quality information attachment (notably for non–low-molecular products)

For formulations other than low-molecular-weight compounds, the checklist notes that a quality document prepared per the cited Q&A should be attached to the CTN.

Practical takeaway

This checklist is essentially a “what reviewers will look for in 30 days” map: it pushes sponsors to make safety reporting workflows unambiguous, align Phase 1 ethics with oncology realities, justify dosing and escalation decisions transparently, and ensure informed consent and attachments anticipate Japan-specific disclosure and documentation expectations.

Reference (PDF)

• Check List for 30-day-Clinical Trial Notification Review on an Initial Clinical Trial Notification (Oncology Drugs).