Radiopharmaceuticals - Draft Guideline on non-clinical Requirements

Recommendation

7/8 May 2024

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Regulatory Requirements and Practical Implementation

At the end of 2018, the EMA published the long-awaited draft guideline for non-clinical radiopharmaceuticals. This guideline deals with the data that must be submitted in the context of marketing authorization applications or clinical studies in connection with the non-radioactive part of radiopharmaceuticals. The demand on guidelines focusing specifically on the non-clinical testing requirements for radiopharmaceuticals had increased significantly as there were no detailed guidelines to date but an increasing number of radiopharmaceuticals. Therefore, in addition to the general non-clinical requirements described, for example, in the documents of ICH M3(R2), ICH S9 and ICH S6(R1), this Directive lays down the principles for non-clinical data generation in support of the specific clinical use of radiopharmaceuticals.

The new paper covers both radiodiagnostics and radiotherapy and provides guidance for a targeted approach to assessing the pharmacology and safety of the non-radioactive part of a radiopharmaceutical. The principles set out relate to non-clinical evaluation as a prerequisite for the authorisation of a clinical trial and for the application for authorisation. According to the existing categorisation in the "Radiopharmaceuticals Directive" (EMEA/CHMP/QWP/306970/2007 , Radiopharmaceuticals), the so-called "ready-to-use" radiopharmaceuticals are covered. However, a number of the principles laid down there could also be applied to the non-radioactive component of so-called "kits" and non-radioactive chemical precursors.

The current possibilities to produce highly specific ligands have led to a large number of different radiopharmaceuticals for a variety of clinical applications. They are used as radiodiagnostics, e.g. in scintigraphy, for measuring biodistribution or as radiation therapeutics, which are administered to humans only once or, with a small frequency of multiple doses, with no measurable pharmacological effect. What almost all have in common is that these radiopharmaceuticals are produced in small quantities, e.g. for exploratory studies, which are usually not completely developed with the aim of marketing approval.

However, the same principles of safety assessment should apply as for other medicinal products before radiopharmaceuticals are used in human clinical trials and for regulatory purposes. Therefore, a non-clinical risk assessment in accordance with the relevant legislation is required before a radiopharmaceutical is first administered to humans and then clinically developed. The risk assessment is generally dealt with in the non-clinical programme and is reflected in the protocol of the clinical trial's risk reduction plan.

Due to their conjugated design and radio labelling, radiopharmaceuticals are a special class of drugs. They consist of a "cold" part (non-radioactive) and a radionuclide linked to the "cold" part by a linker and/or chelator.

In the event that data and results on the affected product or its components are already available, the new document states:
"In many cases, however, there is already knowledge about the non-clinical characteristics and clinical experience for the non-radioactive part. As with any other submission, the existence of published or clinical data may eliminate the need to conduct the entire non-clinical program in accordance with ICH M3(R2). This would also contribute to a reduction in animal consumption in line with the principles of the 3Rs. Important factors are the degree of evidence on the pharmacological and toxicological properties of the non-radioactive part, the expected mass dose of the radiopharmaceutical in the clinical trial or for the approval and duration of treatment.
It is important to avoid physiological distribution studies that only serve the quality assurance of the investigational product. These should be made obsolete by characterising the product parameters using state-of-the-art methods".

For further details, please refer directly to the new draft directive "Directive on non-clinical requirements for radiopharmaceuticals".