Considerations for Non-Clinical Studies in the Development of Diagnostic Radiopharmaceuticals in Japan (PMDA)

Why this document matters

PMDA issued an Early Consideration (March 26, 2025) to add practical clarification on what non-clinical studies are expected for diagnostic radiopharmaceuticals and when they should be conducted, building on Japan’s existing guideline for diagnostic radiopharmaceuticals and reflecting newer ICH thinking.

Core idea: tailor the non-clinical package to “diagnostic” use

Diagnostic radiopharmaceuticals often involve single administration and, in many cases, microdose-level total mass (including non-radioactive ingredients). PMDA’s key message is that requirements should be assessed case by case, with early PMDA consultation encouraged for agreement on the study plan.

1) Safety pharmacology: when microdose may change expectations

PMDA reiterates that, in principle, core battery safety pharmacology is expected before first-in-human studies, consistent with ICH safety pharmacology concepts. However, where the clinically recommended dose is within the microdose range, PMDA indicates the need for core battery studies (including safety pharmacology embedded in tox studies) should be evaluated case by case, and may be omitted if a convincing rationale demonstrates no meaningful impact on vital organ functions.

PMDA lists examples of information that can support the case-by-case decision:

• Pharmacological properties (on-/off-target, binding specificity/affinity, etc.)
• Existing non-clinical and clinical safety information
• Overseas clinical use experience
• Safety information from structurally related compounds (including different radionuclide labels)

2) ADME and drug–drug interactions: stepwise and proportionate

Even for diagnostic products, PMDA notes DDI information can be valuable for appropriate clinical use. The document points to a stepwise approach aligned with ICH DDI principles and timing expectations.

Key practical nuance from PMDA:

• If clinical use is single-dose and the product is rapidly eliminated, in vitro evaluation of enzyme induction potential is not necessarily required.
• For biologics used as diagnostic radiopharmaceuticals (e.g., radiolabeled monoclonal antibodies), PMDA highlights generally lower PK-DDI risk than small molecules and recommends evaluating interaction potential using factors such as pharmacological action, clearance, and likely concomitant medications (since standard in vitro methods for chemicals may not apply).

3) Toxicology: repeated-dose expectations, plus accepted alternatives

PMDA notes that, per the underlying guideline, a 4-week repeated-dose toxicity study in two species (rodent + non-rodent) is generally expected before a marketing authorization application—even if clinical use is single-dose and the mass is in the microdose range.

However, PMDA also describes scenarios where alternatives may be acceptable, such as:

• A shorter-duration repeated-dose study, or
• An extended single-dose toxicity study in one species (typically rodents),

when justified by evidence such as the absence of unexpected safety signals, overseas use experience, and relevant data on related compounds.

PMDA cautions that if repeated clinical dosing is planned, or if the compound is highly novel with off-target concerns, repeated-dose evaluation across multiple species becomes particularly important—and consultation with PMDA before finalizing a non-standard tox plan is strongly recommended.

4) Radiolytic products and impurities: apply ICH impurity principles

Radiolytic products may form between production and administration. PMDA states impurity safety (including radiolytic products) should be evaluated consistent with ICH impurity principles (e.g., Q3A/Q3B and M7), and mentions that non-clinical studies using a product with decayed radioactivity may be useful for assessing impurity safety.

Practical takeaways for developers

1. Start with the diagnostic context (single use, microdose mass, rapid clearance) and build a proportionate plan.
2. Justify omissions with structured evidence (pharmacology, prior data, overseas experience, related compounds).
3. Use a stepwise DDI strategy, especially where clinical use or clearance profile suggests limited interaction potential.
4. Treat radiolysis/impurities as a core CMC–nonclinical interface topic early, not an afterthought.
5. Engage PMDA early to align on any streamlined package before committing to studies.

References (PDF)

• PMDA Early Consideration: Considerations for Non-Clinical Studies in the Development of Diagnostic Radiopharmaceuticals (March 26, 2025)
• PMDA: Radiopharmaceuticals – Guidelines and Guidance (includes the above PDF)