EMA offers insights on when biologics qualify as new active substances

The European Medicines Agency (EMA) is looking for feedback on a draft reflection paper that lays out its criteria for determining whether biological substances are considered new active substances (NAS). The document walks sponsors through the factors to consider when determining whether a NAS claim meets regulatory requirements.

On 18 November, European regulators asked stakeholders for comments on its recently published reflection paper on NAS. Generally, for “well-characterized and highly purified active substances” the main component tends to serve as the basis for the substantiation of a NAS claim. In such cases, it is normally sufficient to compare the substance’s basic structural element to substantiate the claim.

However, in cases where the claim depends on less well-characterized proteins, complex mixtures of biological active substances or certain classes of biologicals, regulators may need additional information. With that in mind, EMA and other key stakeholders, including the Biologics Working Party (BWP) of the Committee for Medicinal Products for Human Use (CHMP), the Committee for Advanced Therapies (CAT), and the Co-ordination Group for Mutual Recognition and Decentralized Procedures-Human (CMDh), published the reflection paper on how NAS claims may be substantiated in marketing authorization applications (MAA).

“This document intends to clarify the elements that may be considered in support of a NAS claim for a biological active substance,” EMA states. “It does not cover every possible scenario, and therefore applicants are invited to seek scientific advice on the evidence that may be appropriate to substantiate a NAS claim, especially for scenarios not covered in this reflection paper.”

“It is the responsibility of the Applicant to provide a satisfactory scientific and robust substantiation for a NAS claim,” the agency added. “This document discusses tools which may be used to support such a claim. An Applicant is not required to address each and every aspect that this reflection paper presents. If one ‘tool’ suffices to support the NAS claim, then other tools are not considered necessary.”

The tools presented in the reflection paper include breaking down the definition of new active substance in Annex I of Chapter 1 of Volume 2A of the Notice to Applicants (NtA). EMA points to two elements of the annex that define what constitutes a new chemical, biological or radiopharmaceutical active substance.

The first element defines active substances as a chemical, biological or radiopharmaceutical substance not previously authorized in a medicinal product for human use in the European Union. The agency notes that the annex addresses the structure of the active substance without considering the need to provide evidence for differences in safety and efficacy.

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

The second element of the annex that applies in this situation is the definition of such substances as a “biological substance previously authorized in a medicinal product for human use in the European Union, but differing significantly in properties with regard to safety and/or efficacy which is due to differences in one or a combination of the following: in molecular structure, nature of the source material or manufacturing process.”

EMA noted that a biological substance can still be considered as a NAS even when structural differences are insufficient for a NAS claim.

“In such cases, the therapeutic moiety has the same basic structural element(s) but other differences in variability are present and have an impact on safety and efficacy,” the agency said.

In such circumstances, the sponsor should use a two-step justification process according to the reflection paper. The first step includes defining the active substance and its difference from previously authorized active substances. Next, the sponsor needs to demonstrate that due to those differences, the active substance has a significantly different safety and efficacy profile compared to active substances authorized in the EU.

EMA offers insights on when biologics qualify as new active substances

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