EMA publishes Concept Paper on Guidance Development on non-clinical Evaluation of Radiopharmaceuticals

Radiodiagnostics as well as radiotherapeutics agents are regulated by the Directive 12 2001/83/EC for medicinal products for human use, which covers development as well as marketing authorisation. Amongst the general non-clinical  requirements described in ICH M3(R2), ICH S9 and ICH S6(R1), there is no detailed guidance available specifically addressing non-clinical testing of radiopharmaceuticals. Therefore the following problem statement can be found in the current concept paper:

"ICH M3(R2) provides general guidance on the nonclinical safety studies recommended to support human clinical trials. However, since the replacement of "Note for Guidance on Radiopharmaceuticals"  (3AQ20a) with the "Guideline on Radiopharmaceuticals"  (EMEA/CHMP/QWP/306970/2007), no guidance is available to specifically support non-clinical development of this type of medicinal products. Radiation is an inherent – and intended – property of this class of compounds and, from this perspective, safety is considered to be appropriately addressed by dosimetry. Therefore, it is not anticipated to discuss the non-clinical safety assessment of the radionuclide in detail in the new guidance. However, due to the conjugated design of radiopharmaceuticals (i.e. radionuclide linked to a cold ligand, possibly with a linker in between them and/or chelators) the safety of each individual “cold” part needs to be evaluated. The cold moiety may be an already known/ characterised part of the construct or a new chemical or biological requiring a complete characterisation. In addition, radiopharmaceuticals developed in recent years show a large variety of clinical uses ranging from single to multiple administrations. The aspects outlined above give rise to specific considerations regarding the extent and type of the non-clinical data package to support clinical use and marketing authorisation of radiopharmaceuticals. Specific approaches will avoid the unnecessary use of animals, allowing an optimal use of resources and, ultimately, facilitate the progression of these medicinal products into clinical use."

The scientific development and new innovations which enables today the small-scale manufacturing of pharmaceuticals with highly-targeted ligands have led to a lot of products which are not intended to receive a marketing authorisation (e.g. PET tracers). Therefore, for such products or for products, mainly radiodiagnostics, where a single application as well as very short clinical trial duration can be anticipated, additional guidance will be necessary. The new guidance document will provide basic considerations for a 50 non-clinical data package taking into account the specific features of radiopharmaceuticals. The following aspects will be highlighted in this new document:

• Extent of pharmacological activity of the cold part (in vitro and in vivo); whether the cold part of 54 the radiopharmaceutical is a known substance or not
• Outcome of biodistribution/ADME studies for the cold part(s) of the radiopharmaceutical including 56 extent of off-target binding where appropriate
• Types of clinical settings for the radiopharmaceutical such as:
  - First-in-human clinical trial
  -  Dosing frequency, microdose use (in the case of radiodiagnostics) 
• Marketing authorisation intended
• GLP requirements

More details about the background and intention of the proposed new document van be found in the "Concept paper on the development of guidance on the non-clinical evaluation of radiopharmaceuticals".