Roadmap to determine non-clinical safety program for radiopharmaceuticals

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Non-clinical study for radiopharmaceuticals

For the complete radiopharmaceutical, and in almost all scenarios, you will need a biodistribution study with the radiolabeled compound. From this study, you can obtain data on tissue distribution and elimination and use dosimetry calculations to calculate exposure to radiation. TRACER conducts such studies, and, as a radiopharmaceutical CRO, we can conduct the subsequent clinical trials. The biggest advantages of this are the time saved with parallel clinical trial preparation and reusing the parts of the chemistry manufacturing and controls (CMC) work already conducted for preclinical studies.

Radiopharmaceuticals based on a known or unknown non-radioactive part

The first thing to know is that a complete non-clinical safety program for radiopharmaceuticals may be waived if the non-radioactive part is known or minimally changed. In the following situations, an abbreviated or reduced preclinical program may suffice.

Scenario 1: You’re changing the radionuclide in an existing radiopharmaceutical.
Action: Provide the non-clinical testing data of the unchanged non-radioactive part.

Scenario 2: You’re adding a radionuclide to a known non-radiopharmaceutical.
Action: Provide information that radiolabeling or replacement of an existing non-radioactive atom does not alter pharmacology.

Scenario 3: You’ve performed minor changes to the non-radioactive part.
Action: Bridge existing non-clinical data and address possible changes in pharmacology and safety.

Using existing non-clinical data in your application

Using existing non-clinical data is possible when changing the radionuclide in an existing radiopharmaceutical. The same applies to labeling an existing drug with a radionuclide, or replacing an existing non-radioactive atom. For known compounds or biologics, you can use existing data from previous applications (your own, or with permission), or existing public literature. Of course, relevancy should be justified and a gap analysis may be needed to identify which studies are still required.

TRACER can assist you in both, finding the gaps and filling the voids so your preclinical package is ready for approval. Contact us to learn more.

Preclinical studies for new radiopharmaceuticals

When your non-radioactive part is new, you will need to perform non-clinical studies. The necessary preclinical studies for radiopharmaceuticals depend on the dose and dosing regimen.

The guidelines on the non-clinical requirements for radiopharmaceuticals by the EMA depend on exposure levels and risk-benefit considerations. To help you, we’ve derived five clear categories based on the EMA guideline.

Non-clinical contents on pharmacology, pharmacokinetics, toxicology, and genotoxicity

Between the categories, the non-clinical contents on pharmacology, pharmacokinetics, toxicology, and genotoxicity may differ. The focus of the non-clinical program lies on the non-radioactive part of the radiopharmaceutical. For radiotherapeutics, the damaging effect is intended, and for radiodiagnostics, the aim is to have no harmful effect at all. For both, the targeting agent should ideally have no pharmacologic effect, and the studies below should provide evidence of its absence or inform on its activity.

Table with non-clinical studies for new radiopharmaceuticals

In the table below, you can easily find the non-clinical studies required for your radiopharmaceutical.

Things to keep in mind:

• ICH S9 may apply to oncological radiotherapeutics; ICH S6 to biotechnology-derived products.
• Reproductive toxicity and carcinogenicity studies may be waived, but can be required when there is concern about the non-radioactive part due to the duration of the treatment, while the radiation emission is low.
• Regulations may vary between regions and countries and is known to lack harmonization.

Complete package for clinical trial application

The complete package for your clinical trial application will consist of detailed characteristics and quality of the drug product, the in this article already described non-clinical safety program on the non-radioactive part, and preclinical studies with the complete radiopharmaceutical. Data from in vitro testing and in vivo animal studies, including dosimetry studies, are required.

In vitro testing for radiopharmaceuticals

Your in vitro testing should inform your in vivo studies to work efficiently and according to the 3Rs in animal research (Replacement, Reduction, and Refinement). Typically, this includes:

• Serum stability
• Protein binding (for example to plasma proteins)
• Receptor ocupancy
• Interaction with target and non-target tissue and cells
• Functional effects (agonistic and antagonistic, signaling, internalisation, etc.)
• Lipophilicity

The exact contents of in vitro studies for a radiopharmaceutical depend on its purpose. You can supplement with literature on basic pharmacology of the same class of radiopharmaceutical, differently labeled or unlabeled non-radioactive component. Provide, if applicable, comparative data from literature of a known compound or data from a comparative affinity study.

In vivo animal studies for radiopharmaceuticals

For animal testing with radiopharmaceuticals, regulators emphasize the 3Rs in animal research. Studies other than those on rodents should be conducted only when specifically suitable. That being said, the following studies may be required:

• Biodistribution
• Dose escalation
• Dosimetry studies
• Pharmacokintics
• Pharmacodynamics
• Blocking studies
• Toxicology

Include also ex vivo analysis in animal studies.

Recommended review on non-clinical studies and clinical translation for radiopharmaceuticals

In addition to the EMA Non-clinical requirements for radiopharmaceuticals – Scientific guideline [1], we would recommend reading the following review paper: Practical considerations for navigating the regulatory landscape of non-clinical studies for clinical translation of radiopharmaceuticals [2]. As the title suggests, this paper provides further, in-depth information on this topic. It also includes references to other relevant (regulatory) documents.

For a quick answer to questions regarding your radiopharmaceutical development, feel free to contact TRACER.

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