(a)

deleted;

(b)

“similar medicinal product” means a medicinal product containing a similar active substance or substances as contained in a currently authorised orphan medicinal product, and which is intended for the same therapeutic indication;

(c)

“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.

For the purpose of application of point (c) above, the following applies for:

(1)   Chemical medicinal products

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.

(1.1)   Isomers, mixture of isomers, complexes, esters, ethers, salts, and derivatives of the original active substance, or an active substance that differs from the original active substance only with respect to minor changes in the molecular structure, such as a structural analogue, shall be considered similar.

(1.2)   Synthetic polynucleotide substances, single or double stranded, consisting of two or more distinct nucleotides where:

(2)   Biological medicinal products (other than advanced therapy medicinal products)

The principal molecular structural features are the structural components of an active substance that are relevant for the functional characteristics of that substance. The principal molecular structural features may be composed of a therapeutic moiety or a therapeutic moiety in combination with an additional structural element(s) significantly contributing to the functional characteristics of the active substance.

Such an additional structural element(s) can be conjugated, fused or linked by other means to the therapeutic moiety or can be an extension of the therapeutic moiety protein backbone by additional amino acids. Substances with structural elements for which similar methods of modification or conjugation technology are used shall normally result in similar substances.

Biological active substances that differ from the original biological substance only with respect to minor changes in the molecular structure shall be considered similar.

(2.1)   Proteinaceous substances:

(2.2)   Polysaccharide substances:

(3)   Advanced Therapy Medicinal Products (ATMPs)

(3.1)   Cell-based ATMPs: Two related cell-based medicinal products are not similar if:

(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.

(3.3)   Genetically modified cells. The considerations under (3.1) and (3.2) apply.

(4)   Radiopharmaceutical medicinal products

The same radiopharmaceutical active substance, or one differing from the original in radionuclide, ligand, site of labelling or molecule-radionuclide coupling mechanism linking the molecule and radionuclide provided that it acts via the same mechanism shall be considered similar substances.’