On 10 November 2022, the European Medicines Agency (EMA) published a drafted document, Reflection paper on the criteria to be considered for the evaluation of new active substance (NAS) status of biological substances.
The paper provides an insight to the EMA’s likely approach in assessing evidence supporting an application for new active substance status, for biological active substances, as part of the marketing authorisation application process.
Under the provisions of Directive 2001/83/EC, a generic manufacturer making an application for a marketing authorisation to sell a generic medicine cannot, for a certain time period, rely on pre-clinical and clinical data produced for the authorisation of an earlier ‘reference’ product in support of the generic’s application.
This period of ‘data exclusivity’ for the reference product applies for eight years, with a further two years of market exclusivity. Any subsequent variations or line extensions to the reference product, including changes to strength, pharmaceutical form or route of administration, are considered to fall within this same period of data and market exclusivity, under the concept of the ‘global marketing authorisation’.
Substances which are granted NAS status do not fall within the global marketing authorisation of any earlier products and are entitled to their own period of data and market exclusivity. NAS status is therefore very valuable to pharmaceutical companies as it protects a product from generic competition for many years.
There is no definition of an NAS in EU legislation. However, annex 1 of chapter 1 of volume 2A of the European Commission’s Notice to Applicants (NtA), on the procedures for marketing authorisation, defines a new chemical, biological or radiopharmaceutical active substance as including:
In the reflection paper, the EMA notes that, for the purpose of a assessing an NAS claim, substances falling within the ‘first indent’ do not require evidence of their safety or efficacy profile to be submitted.
The paper discusses a variety of ‘tools’ which may be used by an applicant to support an NAS claim for a biologic. If the NAS claim is supported by one ‘tool’, for example by providing evidence of a new amino acid sequence, then evidence obtained using other tools is not required.
According to the reflection paper, in order to substantiate an NAS claim for well-characterised and highly purified active substances, it is normally sufficient to compare the ‘basic structural elements’ with those of other authorised substances.
The ‘basic structural element’ is defined as ‘the core structure of the active substance without added functional molecular structures or other structures that are added, for example, due to post-translation modifications’. Product or process related impurities and extraneous agents will not be considered when assessing an NAS claim.
The position taken by the EMA is that biological substances which were not previously authorised in a medicinal product for human use in the EU and which ‘from a structure point of view’ are unrelated to any other authorised substance should be considered an NAS. Such a substance would be considered an NAS under the first indent of the NtA.
For proteins, the amino acid sequence would be considered as the basic structural element, and the difference in the protein sequence when compared with other substances should be ‘substantial’ and result in different activity (for example, a change in one amino acid might not be enough).
An example provided by the EMA is that a monoclonal antibody containing mutations which did not result in different binding characteristics or activity different to another known antibody would be unlikely to be an NAS. A substance would not be considered new if its administration would expose patients to ‘the same therapeutic moiety’ as that of a medicinal substance which had already been authorised in the EU.
Where the product is more difficult to characterise, for example because it contains a complex mixture of biological active substances, more information may need to be submitted to the regulator. For example, some classes of biological medicinal products comprise a group of related molecules which have heterogeneous basic structural features (for example, heparin). In this circumstance, changes to the range of hetereogeneous basic structure would need to be shown.
In cases where a molecular structure has the same basic structural element but has additional post-translational modifications, the molecule would not be considered to be an NAS unless it can be shown that the modifications have ‘significant clinical impact’ in terms of safety and/or efficacy.
The EMA’s position is that a biological substance can still be considered as an NAS even when structural differences are insufficient for an NAS claim under the first indent of the NtA, if there are other differences which ‘have an impact on safety and efficacy’.
The EMA describes a ‘two-step justification process’ for this type of NAS claim:
What evidence is needed for step two? The reflection paper refers to earlier EMA guidance on when enantiomers, complexes, derivatives or different salts or esters of an existing active substance should be considered as an NAS. According to this earlier guidance, the evidence preferred by the EMA is head-to-head clinical studies demonstrating clinically relevant differences in safety and/or efficacy compared with the earlier active substance.
However, in some cases, compelling evidence from pre-clinical and/or other clinical data, such as pharmacologic or pharmacodynamic studies, animal models, or toxicological studies, may also be acceptable. Ultimately, applications will be considered on a case-by-case basis.
The paper contains a number of practical examples of biologics which are likely to be considered NASs, together with a set of informative questions and answers.
The deadline for comments on the draft is 31 May 2023.