European Union: Europe—The Draft New Definition Of "Similarity" For Orphan Products Is Out For Public Consultation Again

The European Commission (EC) has finally published the draft amendment to Commission Regulation No 847/2000 regarding the concept of "similar medicinal product" (Draft Amendment). Comments are due within four weeks (by November 27, 2017).

The concept of similarity sets the limit of orphan exclusivity ("market exclusivity" in the European Union) and, as such, is key for orphan medicinal products. The 10-year orphan exclusivity afforded by Regulation No 141/2000 on Orphan Medicinal Products (Orphan Regulation) prevents health regulators from accepting an application for authorization, or granting an authorization, "for the same therapeutic indication, in respect of a similar medicinal product." Commission Regulation No 847/2000 defines, among other concepts, the concept of "similar medicinal product" and gives examples of products that would be considered similar.

Last year, the EC launched a public consultation on the concept of similarity, which was long overdue for an update given the scientific and technical progress that had taken place over more than 15 years.

The Draft Amendment does not change the definition of "similar active substance":

However, the Draft Amendment specifies that if the principal molecular structural features cannot be fully established, similarity is to be assessed on the basis of the biological and functional characteristics.

It then further explains the concept of "principal molecular structural features" in relation to chemical products, biological products, advanced therapy medicinal products (ATMPs) and radiopharmaceutical products respectively, thereby acknowledging that ATMPs should be approached differently from other biological products. The concept of similarity is especially important to define for ATMPs given their composition and manufacturing process and the fact that many are in companies' pipelines and target rare diseases. The Draft Amendment specifies, for example, that with regard to cell-based products, 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 that with regard to gene therapy medicinal products, they should not be considered similar in cases of differences in the therapeutic sequence, viral vector, transfer system or regulatory sequences that significantly affect the biological characteristics and/or activity relevant for the intended therapeutic effect of the product.

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.

The following substances are considered similar:

• Isomers, mixture of isomers, complexes, esters, ethers, salts and derivatives of the original active substance.
• 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.
• Synthetic polynucleotide substances (single- or double-stranded) consisting of two or more distinct nucleotides where either of the following apply:
  
  
  • The difference in the nucleotide sequence of the purine and pyrimidine bases or their derivatives is not major. Therefore, for antisense or interfering nucleotide substances, addition, substitution or deletion of a nucleotide not significantly affecting the kinetics of hybridization to the target shall normally be considered similar.
  • The difference in structure is related to modifications of the ribose or deoxyribose backbone sugars or to the replacement of the backbone sugars by synthetic analogues. For antisense or interfering nucleotide substances, changes in the (deoxy-)ribose not significantly affecting the kinetics of hybridization to the target would normally be considered similar.

Biological medicinal products (other than ATMPs):

The principal molecular structural features are the structural components of an active substance that are relevant for the functional characteristics of that substance. These 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 using similar methods of modification or conjugation technology shall normally result in similar substances.

The following substances are considered similar:

• Biological active substances that differ from the original biological substance only with respect to minor changes in the molecular structure shall be considered similar.
• Proteinaceous substances where:
  
  
  • the difference in structure between the two substances is due to post-translational events (such as different glycosylation patterns). However, exceptionally, some post-translation modifications may result in a non-similar substance if this significantly affects the functional characteristics of the substance;
  • there is no major difference in the amino acid sequence. Therefore, two pharmacologically related protein substances of the same group (having differences related to, for example, 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; or
  • monoclonal antibodies bind to the same target epitope. However, two monoclonal antibody conjugates or fusion proteins could be determined to be non-similar if either the complementarity-determining region sequences of the antibody or the additional structural element of the conjugated monoclonal antibody were different.
• Polysaccharide substances such as:
  
  
  • substances with identical saccharide repeating units, even if the number of units varies; and
  • Conjugated vaccines derived from the same antigen and using similar methods of modification or conjugation technology. However, a conjugated polysaccharide vaccine compared to a non-conjugated polysaccharide vaccine containing the same antigen is considered a non-similar substance.

ATMPs:

• Cell-based ATMPs: Two related cell-based medicinal products are not considered similar if they have either of the following:
  
  
  • Differences in starting materials or the final composition of the product that have significant impact on the biological characteristics and/or activity relevant for the intended therapeutic effect of the product. However, 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
  • Differences in the manufacturing technology that have a significant impact on the biological characteristics and/or activity relevant for the intended therapeutic effect of the product.
• 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 or regulatory sequences that significantly affect the biological characteristics and/or activity relevant for the intended therapeutic effect of the product. However, 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.
• Genetically modified cells. The considerations above apply.

Radiopharmaceutical medicinal products:

Products are considered similar if either of the following apply:

• They have the same radiopharmaceutical active substance.
• The radiopharmaceutical active substance differs in radionuclide, ligand, site of labeling or molecule-radionuclide coupling mechanism linking the molecule and radionuclide but acts via the same mechanism.

Originally published 31 October 2017

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