Guideline for Clinical Evaluation of Diagnostic Radiopharmaceuticals in Japan

1. What the guideline is (and what it is not)

Japan’s Ministry of Health, Labour and Welfare issued PFSB/ELD Notification No. 0611-1 (June 11, 2012) to provide a general framework for the non-clinical items and the planning, conduct, and evaluation methods of clinical studies needed for approval applications of diagnostic radiopharmaceuticals. The guideline states it reflects current scientific knowledge and does not require strict adherence when an applicant has a scientifically rational basis that reflects academic or technological progress.

Primary reference (PDF): Guideline for Clinical Evaluation of Diagnostic Radiopharmaceuticals (PMDA).

2. What makes diagnostic radiopharmaceuticals different

The guideline defines diagnostic radiopharmaceuticals as unsealed radioisotope-containing compounds administered for clinical diagnosis by detecting photons/positrons emitted from radioisotopes. It highlights several distinguishing features that shape evaluation expectations:

• Clinical value comes from target-site accumulation and signal detection, not a pharmacological therapeutic effect.
• The administered mass is often extremely small (trace dosing), so biological effects are usually minimal.
• They are generally single-dose products, and dose selection must consider radiation exposure.

3. Non-clinical package: purpose, content, and timing

3.1 Why non-clinical studies are needed

Non-clinical studies support screening/characterization, pre-human safety evaluation, interaction assessment, and clinical trial design. The guideline expects non-clinical work to align with development stage and relevant international/domestic standards (e.g., ICH, GCP context).

3.2 Key non-clinical components (examples)

The guideline lists documentation and data areas typically reviewed, including:

• Pharmacology (primary, secondary, and safety pharmacology)
• ADME and biodistribution, including human absorbed dose / effective dose estimation based on animal biodistribution (e.g., using the MIRD method) before Phase I
• Toxicology: single-dose and (as applicable) repeated-dose, with microdose-related pathways described (e.g., extended single-dose tox in at least one mammalian species when repeated-dose tox has not been done before Phase I in certain microdose scenarios)

3.3 Practical nuance: dosing is both radioactivity and mass

The guideline emphasizes that dose may be expressed in radioactivity (MBq) and mass (µg), and that radioactivity declines with physical half-life while mass does not—important when interpreting biodistribution and setting clinical administration conditions.

4. Clinical evaluation: proving accuracy and clinical significance

4.1 Two pillars of clinical efficacy

Clinical efficacy for diagnostic radiopharmaceuticals is demonstrated by:

1. accuracy of information obtained from images, and
2. the clinical significance of that information.

4.2 Image evaluation models

The guideline describes multiple approaches, including:

• evaluation from imaging findings,
• investigator (facility) evaluation, and
• blinded third-party evaluation, with attention to readers, randomization, information disclosure, and evaluation methods to manage bias and reliability.

4.3 Standard of truth and statistics

For diagnostic performance assessment, results should be judged against an appropriate standard of truth and analyzed using suitable statistical methods, including reliability and diagnostic performance evaluation and, where relevant, comparison against other diagnostic techniques.

5. Clinical studies across phases: what is typically expected

The guideline lays out Phase I–III expectations:

• Phase I: safety, pharmacokinetics, and absorbed dose (dosimetry) as core elements.
• Phase II (exploratory): establish imaging performance and refine evaluation approach.
• Phase III (confirmatory): validate diagnostic accuracy and clinical significance with robust design, standard of truth, and appropriate statistical analysis.

A practical dose-setting point in the guideline is the tradeoff between imaging time and radiation exposure: increasing radioactive dose can shorten imaging time but increases radiation exposure, so an appropriate dose should be established by Phase III based on both.

6. Key takeaways for developers

• Start planning with the product’s diagnostic nature (trace mass, imaging endpoint, radiation considerations).
• Build a coherent evidence chain: biodistribution → dosimetry → clinical imaging performance and clinically meaningful interpretation.
• Choose image reading and statistics to demonstrate both accuracy and clinical significance, anchored to a defensible standard of truth.
• Use scientific rationale to justify alternative methods when appropriate, consistent with the guideline’s flexibility statement.

References (PDF)

• Guideline for Clinical Evaluation of Diagnostic Radiopharmaceuticals (PFSB/ELD Notification No. 0611-1).