On 18 November 2022, the European Medicines Agency (EMA) published a draft reflection paper (Paper) for public consultation on the criteria for the evaluation of new active substance (NAS) status for biological substances. The Paper provides guidance for applicants on the elements required for a successful NAS claim, including practical examples and a Q&A. This is an area of significant practical importance for pharmaceutical companies and the Paper is a key element to consider during the development of regulatory strategies for biological, biotechnology-derived and advanced therapy medicinal products (ATMPs).

Chemical active substances are excluded from the scope of the Paper, given they are already addressed in two previous reflection papers. The Paper builds on these reflection papers and provides guidance to applicants based on the EMA’s experience with biological products to date, and the current scientific thinking.

The public consultation on the Paper is open until 31 May 2023.

Definition of NAS

There is no definition of NAS in the EU legislation. However, the dedicated regulatory guidance and case law on this element is crucial for the determination of the applicable regulatory data protection (RDP) period for a medicinal product and ultimately its successful commercialisation.

The concept of NAS in the context of biological substances is defined in Annex I of Chapter 1 of Volume 2A of the Notice to Applicants (NtA), according to which a new biological active substance includes a biological substance:

  • “not previously authorised in a medicinal product for human use in the European Union” (the “first indent”) or
  • “previously authorised 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” (the “third indent”).

The Paper is structured around and builds upon these two criteria, and provides guidance on how to apply them to biotechnology-derived medicinal products and ATMPs.

The Paper states that for ‘well-characterised’ and highly purified active substances, the main component serves as the basis for the substantiation of an NAS claim, and it is normally sufficient to compare its basic structural elements. However, for less ‘well-characterised’ proteins, complex mixtures of biological active substances, or certain classes of biologicals (for example, vaccines and plasma-derived products), assessment of differences in the basic structural elements may require additional considerations. These active substances contain several molecular species that are all related to the intended molecular entity. As such, as well as the main molecular entity, other active structurally related entities or isoforms (product related substances) may be present and may be relevant to the determination of NAS.

The Paper notes that it is the responsibility of the applicant to provide a satisfactory, scientific and robust substantiation for an NAS claim. While the Paper discusses tools that may be used to support such a claim, the applicant is not required to address each and every criteria for NAS status: if one ‘tool’ is enough to support the NAS claim, other tools are not necessary. Given that the Paper does not cover every possible scenario, applicants are invited to seek scientific advice on the evidence that may be appropriate to substantiate an NAS claim.

Active substances derived by recombinant or non-recombinant systems 

  • First indent – If a biological active substance has not been previously authorised in a medicinal product in the EU and is not, from a structural point of view, related to any other authorised substance, it should be considered as an NAS. According to the Paper, such substance is considered an NAS if it would not expose patients to the same therapeutic moiety as already authorised active substances. The therapeutic moiety comprises one or more basic structural elements. The Paper sets out the structural elements that make up a therapeutic moiety, along with specific examples to assist applicants apply these principles to their products.
  • Third indent – A biological substance can be considered as an NAS if, even though the therapeutic moiety has the same basic structural elements as an already authorised product, it presents differences having an impact on safety and efficacy of the medicinal product. The Paper notes that, despite the fact that the guidance in previous reflection papers is not generally applicable to biological medicinal products, it nevertheless offers guidance on the type of evidence required to show differences in safety and/or efficacy compared to the active substances contained in medicinal products already authorised in the EU, as well as on what might constitute a significant difference in safety and/or efficacy to justify the designation of the active substance as NAS.

Advanced Therapy Medicinal Products (ATMPs)

The Paper sets out specific guidance in relation to ATMPs and notes that an adapted approach should be applied, having regard to the specific characteristics of these products. In particular, the Paper notes that:

  • First indent – The consideration of whether an active substance constitutes an NAS could be based on its biological characteristics and/or biological activity, rather than focusing on structural elements. The Paper discusses the assessment of cell-based and tissue engineered products (including a non-exhaustive list of examples to justify an NAS claim such as a different cell type or different cell source) and in vivo gene therapy. The claim of substantial differences in the biological characteristics and/or biological activity and/or in basic structural element, of the active substance should be based on analytical data or plausible scientific grounds.
  • Third indent – Differences in properties with regard to safety and/or efficacy could be due to differences in molecular structure, nature of the source material or the manufacturing process. Again, this justification should be based on plausible scientific grounds.


The Paper includes a Q&A section with some practical examples in the context of NAS applications for biological substances. These seek to address some of the examples that have been before the EMA and in recently approved products. For example, it sets out a question on whether a different amino acid sequence for biological active substances derived by recombinant DNA technology could substantiate a new active substance claim, and whether a pegylated version of an existing active substance could be considered a new active biological substance.

Next steps

The EMA is requesting that comments to the draft Paper are submitted using a specified template before the deadline on 31 May 2023. The completed template form should be sent to BWPsecretariat@ema.europa.eu.