SCHEDULE 4 Insertion of new Schedule 9A
Regulation 54
1 After Schedule 9, insert—

“SCHEDULE 9A Meaning of terms used in the orphan criteria and in regulation 58D
Regulation 50G(4)

1 Prevalence of a condition in the United Kingdom
(1) The following provisions apply for the purposes of establishing, pursuant to regulation 50G(2)(a) and (b)(i), that a medicinal product is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting not more than five in 10,000 persons in the United Kingdom.
(2) The material provided pursuant to regulation 50G(3) must include—
(a) material which demonstrates that the disease or condition for which the medicinal product would be authorised affects not more than five in 10,000 persons in the United Kingdom at the time at which the application for an orphan marketing authorisation is submitted, where this is available;
(b) details of the condition intended to be treated and a justification of the life-threatening or chronically debilitating nature of the condition, supported by scientific or medical references; and
(c) copies of, or references to, relevant scientific literature, as well as copies of information from relevant databases in the United Kingdom, where available.
(3) If there are no databases as referred to in paragraph (2)(c), information from relevant databases in other countries may be supplied, provided appropriate extrapolations are made.

2 Potential for return on investment
(1) The following provisions apply for the purposes of establishing, pursuant to regulation 50G(2)(a) and (b)(ii), that a medicinal product is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition in the United Kingdom and that the medicinal product is unlikely, when marketed, to generate sufficient financial return to justify the necessary investment.
(2) The material provided pursuant to regulation 50G(3) must include—
(a) details of the condition intended to be treated and a justification of the life-threatening or chronically debilitating nature of the condition, supported by scientific or medical references;
(b) details of the costs incurred in connection with the development of the medicinal product;
(c) details of any grants, tax incentives or other cost recovery provisions received in the United Kingdom or any other country in relation to the development of the medicinal product;
(d) where the medicinal product is already authorised in the United Kingdom for any indication, or where the product is under investigation for one or more other indications, an explanation of, and justification for, the method that is used to apportion the development costs among the various indications;
(e) a statement of and justification for all development costs that the applicant expects to incur after the submission of the application for a UK marketing authorisation;
(f) a statement of and justification for all production and marketing costs that the applicant has incurred in the past and expects to incur in the first ten years that the medicinal product is authorised;
(g) an estimate of and justification for the expected revenues from sales of the medicinal product in the United Kingdom and elsewhere during the first ten years that the medicinal product is authorised; and
(h) information on the prevalence and incidence in the United Kingdom of the condition for which the medicinal product would be authorised at the time at which the application for an orphan marketing authorisation application is submitted.
(3) The information concerning costs and revenue referred to in sub-paragraph (2) must be determined in accordance with generally accepted accounting principles and must be certified by a person who is a member of a body of accountants which is established in the United Kingdom and which is approved by the licensing authority for the purposes of this paragraph.

3 Existence of other methods of diagnosis, prevention or treatment
(1) The following provisions apply for the purposes of establishing, pursuant to regulation 50G(2)(c), that there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorised in the United Kingdom, or if such method exists, that the medicinal product will be of significant benefit to those affected by the condition.
(2) The material provided pursuant to regulation 50G(3) must include—
(a) details of any existing methods of diagnosis, prevention or treatment of the condition in question that have been authorised in the United Kingdom, making reference to scientific or medical literature or other relevant information, including information relating to authorised medicinal products, medical devices or other methods of diagnosis, prevention or treatment which are used in the United Kingdom; and
(b) a justification as to why either—
(i) the methods referred to in paragraph (a) are not considered satisfactory; or
(ii) the medicinal product for which an orphan marketing authorisation is sought will be of significant benefit to those affected by the condition.
(3) In this paragraph, “significant benefit” means a clinically relevant advantage or a major contribution to patient care.

Increased safety or effectiveness and clinical superiority
4 (1) The following provisions apply for the purposes of establishing, pursuant to regulation 58D(6)(c), that a second medicinal product is similar to a medicinal product to which an orphan marketing authorisation relates or is safer or more effective than, or clinically superior to, that product.
(2) The following definitions apply for the purposes of this paragraph—
“clinically superior”, in relation to a medicinal product, means that it is shown to provide a significant therapeutic or diagnostic advantage over and above that provided by an authorised orphan medicinal product in one or more of the following ways—
(a) greater efficacy;
(b) greater safety in a substantial portion of the target population, as evidenced where appropriate through comparative clinical trials; or
(c) in exceptional cases, where neither greater safety nor greater efficacy has been shown, a demonstration that the medicinal product otherwise makes a major contribution to diagnosis or to patient care;
“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 is to be assessed on the basis of the biological and functional characteristics;
“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.
(3) For the purposes of the definition of “clinically superior” in relation to a medicinal product which shows that superiority by means of greater efficacy, this is to be assessed by the effect on a clinically meaningful endpoint in adequate and well controlled clinical trials, representing the same kind of evidence needed to support a comparative efficacy claim for two different medicinal products.
(4) The clinical trials referred to in paragraph (3) should be direct comparative clinical trials, unless comparisons based on other endpoints, including surrogate endpoints, can be justified.
(5) Paragraphs 5 to 8 make further provision about the definition of “similar active substance” in relation to certain types of product.
5 (1) This paragraph applies for the purposes of the definition of “similar active substance” in relation to chemical medicinal products.
(2) The principal molecular structural features are the relevant structural components of an active substance, which may be the whole or part of the molecule.
(3) Whether the principal molecular structural features are the same between two or more molecules will be identified by comparison of their structures.
(4) Isomers, mixtures 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, are to be considered similar.
(5) Synthetic polynucleotide substances, single or double stranded, consisting of two or more distinct nucleotides where—
(a) the difference in the nucleotide sequence of the purine and pyrimidine bases or their derivatives is not major, are to 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 are usually to be considered similar; and
(b) 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 usually result in substances being considered similar, and for antisense or interfering nucleotide substances, changes in the ribose or deoxyribose backbone sugars not significantly affecting the kinetics of hybridisation to the target are usually to be considered similar.
6 (1) This paragraph applies for the purposes of the definition of “similar active substance” in relation to biological medicinal products other than advanced therapy medicinal products.
(2) The principal molecular structural features are the structural components of an active substance that are relevant for the functional characteristics of that substance.
(3) The principal molecular structural features may be composed of a therapeutic moiety or a therapeutic moiety in combination with an additional structural element significantly contributing to the functional characteristics of the active substance.
(4) An additional structural element as described in paragraph (3) may be conjugated, fused or linked by other means to the therapeutic moiety or may be an extension of the therapeutic moiety protein backbone by additional amino acids.
(5) Substances with structural elements for which similar methods of modification or conjugation technology are used usually result in similar substances.
(6) Biological active substances which differ from the original biological substance only with respect to minor changes in the molecular structure are to be considered similar.
(7) In relation to proteinaceous substances—
(a) if the difference in structure between them is due to post-translational events, such as different glycosylation patterns, substances are usually to 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;
(b) if the difference in the amino acid sequence is not major, substances are usually to be considered similar; therefore two pharmacologically related protein substances of the same group, for example, having differences related to N-terminal methionine, naturally extracted as opposed to recombinant nucleic acid-derived proteins or other minor variants, are usually to be considered similar; however, the addition of a structural element may result in substances not being considered similar if this significantly affects the functional characteristics of the substance;
(c) monoclonal antibodies binding to the same target epitope are usually to be considered similar; however, two monocloncal antibody conjugates or fusion proteins may be considered not to be similar if either the Complementary Determining Region sequences of the antibody or the additional structural element of the conjugated monoclonal antibody is different.
(8) In relation to polysaccharide substances—
(a) if the substances have identical saccharide repeating units, even if the number of units varies, the substances are usually to be considered similar; and
(b) a conjugated polysaccharide vaccine compared to a non-conjugated polysaccharide vaccine containing the same antigen is considered not to be similar.
7 (1) This paragraph applies for the purposes of the definition of “similar active substance” in relation to advanced therapy medicinal products.
(2) In relation to cell-based advanced therapy medicinal products, these are not to be considered similar if—
(a) there are differences in starting materials or the final composition of the product which have a significant impact on the biological characteristics or biological activity relevant for the intended therapeutic effect or safety attributes of the product, and the different source of the starting materials, such as in the case of autologous advanced therapy medicinal products, is not sufficient to support a claim that two products are not similar; or
(b) there are differences in the manufacturing technology having a significant impact on the biological characteristics or the biological activity relevant for the intended therapeutic effect or safety attributes of the product.
(3) In relation to gene therapy medicinal products—
(a) two gene therapy medicinal products are not to be considered similar when there are differences in the therapeutic sequence, viral vector, transfer system, regulatory sequences or manufacturing technology which significantly affect the biological characteristics or biological activity relevant for the intended therapeutic effect or safety attributes of the product; and
(b) differences in the therapeutic sequence with a significant impact on the intended therapeutic effect are not sufficient to support a claim that two gene therapy medicinal products are not similar.
(4) The considerations in paragraphs (2) and (3) also apply in relation to genetically modified cells.
8 (1) This paragraph applies for the purposes of the definition of “similar active substance” in relation to radiopharmaceuticals.
(2) 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 which acts via the same mechanism, are to be considered similar substances.”

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