In Article 3(3) of Regulation (EC) No 847/2000, the introductory sentence and points (a), (b) and (c) are replaced by the following:
‘For the purposes of the application of Article 8 of Regulation (EC) No 141/2000 on orphan medicinal products, the following definitions shall apply:
(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:
—
the difference in the nucleotide sequence of the purine and pyrimidine bases or their derivatives is not major, shall be considered similar. Therefore for antisense or interfering nucleotide substances, addition, substitution or deletion of a nucleotide not significantly affecting the kinetics of hybridisation to the target shall normally be considered similar,
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the difference in structure related to modifications of the ribose or deoxyribose backbone sugars or to the replacement of the backbone sugars by synthetic analogues shall normally result in substances being considered similar. For antisense or interfering nucleotide substances, changes in the (deoxy-)ribose not significantly affecting the kinetics of hybridisation to the target would normally be considered similar.
(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:
If the difference in structure between them is due to post-translational events (such as different glycosylation patterns) substances shall normally be considered similar. However, exceptionally some post-translational modifications may result in a non-similar substance, if there is significant effect on the functional characteristics of the substance.
If the difference in the amino acid sequence is not major, substances shall normally be considered similar. Therefore, two pharmacologically related protein substances of the same group (for example, having differences related to e.g. N-terminal methionine, naturally extracted versus rDNA-derived proteins or other minor variants) shall normally be considered similar. However, the addition of a structural element may result in substances being considered non-similar if this significantly affects the functional characteristics of the substance.
Monoclonal antibodies binding to the same target epitope shall normally be considered similar. However, two monoclonal antibody conjugates or fusion proteins could be determined to be non-similar if either the Complementary Determining Region sequences of the antibody or the additional structural element of the conjugated monoclonal antibody were different.
(2.2) Polysaccharide substances:
If the substances have identical saccharide repeating units, even if the number of units varies, they shall normally be considered similar.
A conjugated polysaccharide vaccine compared to a non-conjugated polysaccharide vaccine containing the same antigen is considered a non-similar substance.
(3) Advanced Therapy Medicinal Products (ATMPs)
(3.1) Cell-based ATMPs: Two related cell-based medicinal products are not similar if:
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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
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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.
(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.’