31 May 2018 - Authored by:Eveline Van Keymeulen
Yesterday, the European Commission adopted Regulation 2018/781 amending Regulation (EC) No 847/2000 as regards the definition of the concept “similar medicinal product” in the context of the Orphan Medicines Regulation. The Regulation extends the definition of “similar active substance”, by clarifying that “[i]f the principal molecular structural features cannot be fully established, the similarity between two active substances shall be assessed on the basis of the biological and functional characteristics”, and gives detailed guidance on what is meant by “molecular structural features” in relation to chemical medicinal products, biological medicinal products and radiopharmaceutical medicinal products.
The text of the adopted Commission Regulation is largely similar to the draft that was published in the context of the public consultation in late 2017. The most important changes compared to the draft text are set forth below (and you can find a full comparison here):
- The definition of “similar active substance” has been modified slightly, and clarifies that instances in which “the principal molecular structures cannot be fully defined” refer (solely) to ATMPs. The definition now reads as follows:
“Similar active substance” means an identical active substance, or an active substance with the same principal molecular structural features (but not necessarily all of the same molecular structural features) and which acts via the same mechanism. However, in the case of advanced therapy medicinal products, for which the principal molecular structural features cannot be fully defined, the similarity between two active substances shall be assessed on the basis of the biological and functional characteristics. (modifications compared to the draft are underlined)
- In relation to chemical medicinal products, the adopted Commission Regulation provides some further explanation:
The principal molecular structural features are the relevant structural components of an active substance. They can be the whole or part of the molecule. Whether the principal molecular structural features are the same between two or more molecules will be identified by comparison of their structures.
- With respect to advanced therapy medicinal products specifically, we note the following changes in comparison to the draft:
(3.1) Cell-based ATMPs: Two related cell-based medicinal products are not similar if:
there are differences in starting materials or the final composition of the product which have significant impact on the biological characteristics and/or biological activity relevant for the intended therapeutic effect and/or safety attributes of the product. The different source of the starting materials (e.g. as in the case of autologous ATMPs) is not sufficient to support a claim that two products are non-similar, or
there are differences in the manufacturing technology having a significant impact on the biological characteristics and/or biological activity relevant for the intended therapeutic effect and/or safety attributes of the product.
(3.2) Gene therapy medicinal products: Two gene therapy medicinal products shall not be considered similar when there are differences in the therapeutic sequence, viral vector, transfer system, regulatory sequences or manufacturing technology that significantly affect the biological characteristics and/or biological activity relevant for the intended therapeutic effect and/or safety attributes of the product.
Differences in the therapeutic sequence without a significant impact on the intended therapeutic effect are not sufficient to support the claim that two gene therapy medicinal products are non-similar.
The Commission also published a Q&A document to address questions that have been raised by developers of ATMPs regarding the application of the concept of similarity in an ATMP setting. It responds to the following questions:
- Does the route of administration play a role in the assessment of similarity?
- In the case of ATMPs, differences in the manufacturing technology can be relevant to demonstrate non-similarity between two products. What is the meaning of “manufacturing technology”?
- Which safety attributes are relevant for the purposes of assessing similarity between two ATMPs?
- Are all differences in the therapeutic sequence, viral vector, transfer system, or regulatory sequences relevant for the purposes of assessing similarity between two gene therapy medicinal products?
The Q&A document will be updated in light of experience accumulated with the assessment of this type of medicinal products.
This post was co-authored by Eftychia Sideri.