Considerations for Non-Clinical Studies in the Development of Diagnostic Radiopharmaceuticals — PMDA Early Consideration Summary

In Plain Language

Diagnostic radiopharmaceuticals are drugs used for diagnostic purposes that contain a radioactive component, and their non-clinical development can raise questions about which studies to conduct and when. This document adds PMDA’s considerations to a general guideline, focusing on safety pharmacology, drug-drug interactions, toxicity studies and impurities that can form through radioactive decay. It describes circumstances in which certain study approaches may be considered, including possible omission of some safety pharmacology studies and shorter or differently structured toxicity studies. Those possibilities are conditional: the document points to factors such as the clinical dose, dosing plan, existing safety information, experience in other countries and the properties of the compound. Its purpose is to help developers consider an approach suited to the product and its development, and to encourage PMDA consultation in specified situations.

What This Guidance Covers

The document concerns non-clinical studies in the development of diagnostic radiopharmaceuticals. It explains selected aspects of the broader “Guideline for Clinical Evaluation of Diagnostic Radiopharmaceuticals,” specifically the non-clinical study items and timing that have generated discussion. The stated aim is to provide additional explanation and a current regulatory perspective based on newly issued ICH guidelines. The document also cautions that its considerations reflect currently available knowledge and may change as new findings emerge.

Its scope is focused rather than comprehensive. It addresses safety pharmacology core battery studies; potential drug-drug interactions; repeated-dose toxicity; and the safety evaluation of radiolytic products and other impurities. It does not set out a complete development plan for every diagnostic radiopharmaceutical or reproduce the full clinical evaluation guideline. The text provides no separate list of product types that are excluded from its scope.

The document distinguishes considerations by product and use. For example, it addresses small-molecule compounds and biologics separately when discussing potential interactions, and it specifically flags repeated clinical dosing and compounds with high novelty when considering repeated-dose toxicity. Its discussion of microdose studies is tied to whether the administered or clinically recommended dose is within the dose range for microdose studies; the document does not itself define that range.

Why It Matters

The general guideline describes non-clinical study items and the planning, conduct and evaluation of clinical studies for diagnostic radiopharmaceuticals. PMDA says discussions frequently arise about the non-clinical study items in that guideline and the timing of their implementation. The document responds by elaborating on selected study questions, including how developers might consider the clinical dose and use pattern alongside the available safety evidence.

The central issue is not simply whether a familiar study should be included or omitted. The document describes circumstances where a different approach may be considered, while also identifying situations in which more extensive evaluation is important. For instance, a single clinical administration and a dose within the microdose-study range may inform consideration of study design, but repeated clinical dosing or high novelty can strengthen the importance of repeated-dose studies in multiple animal species. These distinctions make the rationale and context for a proposed study plan important.

Another practical concern is that radiolytic products may be produced in large amounts between production and administration to patients. A safety assessment focused only on the intended drug substance may therefore fail to address impurities that are present in the administered product. The document calls attention to evaluating impurities, including radiolytic products, and notes that a product with decayed radioactivity may be useful for non-clinical assessment.

Key Recommendations

1. Safety pharmacology. The document states that, according to the general guideline, safety pharmacology core battery studies should in principle be conducted before Phase I clinical studies begin. However, this may not apply when the administered dose—the total amount of active ingredients and non-radioactive ingredients—is within the dose range for microdose studies.

   When the clinically recommended dose is within that microdose-study range, the need for safety pharmacology core battery studies, including safety pharmacology evaluations within toxicology studies, should be evaluated case by case based on ICH S7A and S7B. If the absence of an impact on vital-organ functions can be appropriately demonstrated after considering the factors listed in the document, omission of these studies may be considered. Consultation with PMDA on a case-by-case basis is strongly recommended.

2. Potential drug-drug interactions. Information about interactions is valuable for appropriate use even for diagnostic radiopharmaceuticals. Assessments should therefore be conducted stepwise, taking the stage of development into account. For in vitro evaluation of whether an investigational drug could be an object (affected drug) or a precipitant (interacting drug), the study methods and timing should follow ICH M12.

   The document gives a qualification for induction studies: if the drug is administered as a single dose in clinical use and is rapidly eliminated from the body, in vitro studies to assess its potential to induce drug-metabolizing enzymes are not necessarily required.

   For biologics such as monoclonal antibodies used as diagnostic radiopharmaceuticals, the risk of pharmacokinetic interactions is generally considered lower than for small-molecule compounds. Because in vitro methods designed for chemical substances are not generally applicable to biologics, the assessment should take account of the biologic’s pharmacological action, its clearance, and concomitant medications commonly used in the patient population. The document says potential interaction mechanisms should be carefully evaluated with these factors in mind.

3. Repeated-dose toxicity. According to the general guideline, even when clinical use involves a single dose and the clinically recommended dose is within the microdose-study range, a four-week repeated-dose toxicity study in two animal species—one rodent and one non-rodent—is generally required before submitting a marketing authorization application.

   Considering the relevant factors, it may be acceptable instead to conduct a shorter-duration repeated-dose toxicity study or an extended single-dose toxicity study in one species, typically rodents. The factors identified are whether existing non-clinical safety and clinical study results show unexpected safety concerns; clinical usage experience in other countries; and safety information on related compounds, if extrapolation is judged appropriate based on structural similarity, such as compounds labelled with different radionuclides.

   The document emphasizes a counterpoint: when repeated clinical dosing is planned, or when the compound has high novelty and off-target effects require careful consideration, evaluation using repeated-dose studies in multiple animal species is crucial. If toxicity is evaluated without following the repeated-dose toxicity studies recommended in the general guideline, consultation with PMDA before conducting the study is strongly recommended to help ensure the validity of the study plan.

4. Radiolytic products and other impurities. Radiolytic products may form in large amounts between production and administration to patients. The safety of impurities, including these products, should be evaluated in accordance with the principles outlined in ICH Q3A, Q3B and M7. Non-clinical studies using a product with decayed radioactivity may be useful for assessing impurity safety.

Practical Implications

Interpretation: The document encourages development teams to connect each proposed study decision to the product’s properties and intended clinical use, rather than treating a possible alternative as a general exemption. For example, the discussion of safety pharmacology relates specifically to a clinically recommended dose within the microdose-study range and to an appropriate demonstration that vital-organ functions are not affected. The factors listed should be considered together when making that case.

For a study plan, teams can organize the relevant evidence around the questions PMDA identifies: What is known about the investigational drug’s pharmacology, including on-target and off-target effects? What do existing non-clinical and clinical findings show? Is there relevant clinical-use experience in other countries? Can safety information from structurally similar compounds be extrapolated appropriately? For repeated-dose toxicity, also clarify whether clinical use will involve repeat dosing and whether the compound’s novelty makes off-target evaluation a particular concern.

For interaction assessments, the document points to a stepwise process that reflects the development stage. Teams should distinguish whether they are assessing the investigational drug as an affected drug or as an interacting drug, and follow the methods and timing specified by ICH M12 for in vitro work. When the product is a biologic, the document’s factors—pharmacological action, clearance and commonly used concomitant medications—provide the stated basis for carefully evaluating possible mechanisms rather than assuming chemical-substance in vitro methods apply.

For product and quality teams, the radiolytic-product discussion highlights the time between production and administration as relevant to impurity safety. The document identifies evaluation in line with ICH Q3A, Q3B and M7 principles and notes a possible use for material with decayed radioactivity in non-clinical studies. The exact assessment and evidence remain product-specific; the document does not give a universal study protocol.

Where a team proposes an approach other than the repeated-dose toxicity studies recommended in the general guideline, the document strongly recommends consulting PMDA before the study. It also strongly recommends case-by-case consultation about possible omission of safety pharmacology studies in the described microdose context. In practice, this means study-plan discussions are most useful when they explain the product-specific evidence and reasoning behind the proposed design.

Technical Details

The document uses several conditions that should be kept distinct:

• Administered dose: for the safety pharmacology discussion, this is expressly the total amount of active ingredients and non-radioactive ingredients. The possible non-application of the general expectation is linked to this dose being within the dose range for microdose studies.
• Clinically recommended dose: the case-by-case consideration of safety pharmacology necessity is described when this dose is within the microdose-study range. The document does not supply a numerical boundary for that range.
• Single-dose use: for interaction assessment, single-dose clinical administration must occur together with rapid elimination for in vitro enzyme-induction studies to be not necessarily required. For repeated-dose toxicity, single-dose clinical use and a dose in the microdose range are part of the situation in which the general guideline still describes a four-week study as generally required.

For safety pharmacology, the document’s considerations include pharmacological properties such as binding specificity and affinity to receptors, channels, transporters and enzymes, including on-target and off-target effects. The other stated evidence categories are existing non-clinical safety and clinical study results, clinical usage experience in other countries, and safety information on related compounds where extrapolation based on structural similarity is appropriate. The possible outcome is that omission may be considered if absence of impact on vital-organ functions is appropriately demonstrated; it is not presented as an automatic consequence of meeting the dose condition.

For toxicity study design, the general approach described is a four-week repeated-dose study in two species, one rodent and one non-rodent, before a marketing authorization application. The alternatives described are either a shorter-duration repeated-dose study or an extended single-dose study in one species, typically rodents. These are framed as potentially acceptable in light of the listed factors, not as universally interchangeable study designs. Multiple-species repeated-dose evaluation is highlighted as crucial when repeat clinical dosing is planned or high novelty calls for careful consideration of off-target effects.

For potential interactions, the terms object and precipitant are explained in the document as affected drug and interacting drug, respectively. The document says in vitro methods and timing should follow ICH M12 for evaluating these roles. For biologics, the stated limitation is that chemical-substance in vitro testing methods are not generally applicable; the assessment should instead consider the biologic’s pharmacological action, clearance and commonly used concomitant medications in the patient population.

Finally, the impurity section concerns radiolytic products that may arise before patient administration. It says impurity safety should be evaluated according to principles outlined in ICH Q3A, Q3B and M7, and identifies studies using a product with decayed radioactivity as potentially useful. The document does not specify a particular assay, acceptance threshold or testing schedule for that purpose.

Who Should Read It

This document is relevant to non-clinical safety scientists, pharmacologists, toxicologists, pharmacokinetic and drug-interaction specialists, radiopharmaceutical scientists, and regulatory affairs professionals supporting diagnostic radiopharmaceutical development. It may also help project teams planning first-in-human and later development studies, teams assessing a proposed alternative to the general repeated-dose toxicity approach, and quality or analytical colleagues considering radiolytic products and other impurities. Investigators and clinical operations staff may find the clinical-use conditions useful context when study plans depend on single versus repeated administration.

Official PMDA Source

• Official title: Considerations for Non-Clinical Studies in the Development of Diagnostic Radiopharmaceuticals (Early Consideration)
• Issuing body: Pharmaceuticals and Medical Devices Agency, Office of New Drug II
• Date on the cover: March 26, 2025
• PMDA PDF: Official document PDF
• PMDA list page: PMDA Early Consideration documents

Source: Pharmaceuticals and Medical Devices Agency (PMDA) website, PMDA Early Consideration documents. This page was created by editing and summarising the PMDA document.

Consult the official document for the full text; this summary does not replace it. PMDA provides the English version for reference, and if it differs from the Japanese original, the Japanese original prevails. PMDA describes Early Consideration documents as reference information reflecting the Agency’s views at the time of publication; those views may change as scientific knowledge develops.

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