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Focus on Regulation


On 17 December 2015, the European Medicines Agency (“EMA”) published a Reflection Paper on the chemical structure and properties criteria to be considered for evaluation of new active substance (“NAS”) status of chemical substances (hereafter “Reference Paper“).

Scope of the Reflection Paper

This reflection paper is intended to echo the current experience of the Quality Working Party (QWP) of the Committee for Medicinal Products for Human Use (CHMP) and the Co-ordination Group for Mutual Recognition and Decentralised Procedures-Human (CMDh) concerning the definition of a NAS in the context of preparation of dossiers and submissions for marketing authorisation applications.

The Reflection Paper would apply to applications for marketing authorisation of medicinal products through the centralised procedures, the mutual recognition procedure, decentralised procedure and purely national procedures.

This Reflection Paper should be read in conjunction with the “Reflection paper on considerations given to designation of a single stereo isomeric form (enantiomer), a complex, a derivative, or a different salt or ester as new active substance in relation to the relevant reference active substance” . This second document provides further clarification concerning the non-clinical and clinical evidence that must be presented to support the claim that the NAS differs significantly in features regarding safety and/or efficacy, from those already approved in the EU.


The Reflection Paper defines a NAS as follows:

“a chemical active substance that is not previously authorised in a medicinal product for human use in the European Union and that is from a chemical structure point of view not related to any other authorised substances should be considered as a NAS. Such substance is considered to be new in itself when the administration of the applied active substance would not expose patients to the same therapeutic moiety as already authorised active substance(s) in the European Union.”

The Reflection Paper recommends that this claim be substantiated by comparison of structural substance/features which can be obtained using established databases and discussion on the therapeutic moieties for any structurally related already authorised substances in relation to the therapeutic moiety of the claimed NAS. Results of such investigations should be provided within the dossier.

The Reflection Paper further provides that if the chemical active substance is structurally related as a salt, ester, ether, isomer, mixture of isomers, complex or derivative of an already approved active substance(s) in the EU, the relevant competent authority should assess whether the chemical active substance shares:

“The same therapeutic moiety at the site of the biological activity as the already approved active substance and if so whether it differs significantly in properties with regard to safety and/or efficacy.”

The documentation needed for such a claim will be dependent on the specific case and applicants are, therefore, advised to apply for a scientific advice.