The Human Medicines (Amendment etc.) (EU Exit) Regulations 2019

(27A) Where an application is made to the licensing authority for the renewal of a marketing authorisation in the case of a product for sale or supply in Great Britain and the application for renewal— (a) relates to a medicinal product which, at the time the marketing authorisation was granted, contained a new active ingredient; and (b) is the first renewal in relation to that product, the fee payable by the applicant is the fee prescribed in Part 6 of Schedule 2.

Omission of Part 8 (Capital Fees for Regulatory Assistance Given by the United Kingdom Acting as Reference Member State Relating to the Assessment of Applications for the Renewal of Specified Marketing Authorisations)

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Omit Part 8.

Amendment of Schedule 1 (general interpretation provisions)

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In Schedule 1—

• (a) in paragraph 1—

• (ai) in the definition of “marketing authorisation”, in paragraph (a) after “Human Medicines Regulations” insert “(and a reference to a UKMA(GB), UKMA(NI) or UKMA(UK) should be construed in accordance with those Regulations)”;

• (i) in the definition of “medicinal product”, for “includes any medicinal product for human use to which the 2001 Directive applies and” substitute “ has the meaning given by regulation 2 of the Human Medicines Regulations and includes ”,

• (ii) for the definition of “orphan medicinal product” substitute—

“orphan marketing authorisation” has the meaning given by regulation 8(1) of the Human Medicines Regulations;

• (iii) in the definition of “variation”, for “Article 2(1) of Commission Regulation (EC) No 1234/2008” substitute “ regulation 8(1) of the Human Medicines Regulations ”, and

• (iv) at the appropriate places insert—

“Annex I to the 2001 Directive” has the meaning given by regulation 8(1) of the Human Medicines Regulations;

“biological medicinal product” has the meaning given in paragraph 3.2.1.1.(b) of Part I of Annex I to the 2001 Directive;

“the Committee for Medicinal Products for Human Use” means the committee established under Article 5(1) of Regulation (EC) No 726/2004;

“the EMA” means the European Medicines Agency established by Regulation (EC) No 726/2004;

“under the unfettered access route” has the meaning given by regulation 8(1) of the Human Medicines Regulations;

; and

• (b) after paragraph 4 insert—

(5) (1) For the purpose of these Regulations, a company is a medium company if, for the financial year before that in which the application is made, the total value of products it has sold or supplied for the financial year is not more than the amount for the time being specified in item 1 in section 465(3) of the Companies Act 2006 (qualification of company as medium) and the conditions in sub-paragraph (2) are met. (2) The conditions for the purposes of sub-paragraph (1) are— (a) the company's balance sheet total as defined in section 465(5) of the Companies Act 2006 is not more than the amount for the time being specified in item 2 in section 465(3) of that Act; or (b) the average number of persons employed by the company in the financial year before that in which the application is made (determined on a weekly basis) does not exceed the number for the time being specified in item 3 in section 465(3) of that Act. (3) In this paragraph “financial year” is to be construed in accordance with section 390 of the Companies Act 2006.

Amendment of Schedule 2 (capital fees for applications for, and variations to, marketing authorisations, licences, registrations and certificates)

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• (1) Schedule 2 is amended as follows.

• (2) For paragraph 4(a) substitute—

(a) for an extension of a marketing authorisation— (i) in the case of a UKMA(NI) or UKMA(UK), within the meaning of Article 2(4) of Commission Regulation (EC) No 1234/2008; or (ii) in the case of a UKMA(GB), within the meaning given in paragraph 1 of Schedule 10A to the Human Medicines Regulations; and

• (3) In paragraph 22—

• (a) in sub-paragraph (1), for “Article 2(5) of Commission Regulation (EC) No 1234/2008” substitute

• (a) in the case of a UKMA(NI) or UKMA(UK), Article 2(5) of Commission Regulation (EC) No 1234/2008;

• (b) in the case of a UKMA(GB), paragraph 1 of Schedule 10A to the Human Medicines Regulations;

• (b) in sub-paragraph (2)(f), for “Article 2(4) of Commission Regulation (EC) No 1234/2008” substitute

• (i) in the case of a UKMA(NI) or UKMA(UK), Article 2(4) of Commission Regulation (EC) No 1234/2008;

• (ii) in the case of a UKMA(GB), paragraph 1 of Schedule 10A to the Human Medicines Regulations

; and

• (c) in sub-paragraph (3), for “Article 2(2) of Commission Regulation (EC) No 1234/2008” substitute

• (a) in the case of a UKMA(NI) or UKMA(UK), Article 2(2) of Commission Regulation (EC) No 1234/2008;

• (b) in the case of a UKMA(GB), paragraph 1 of Schedule 10A to the Human Medicines Regulations

• (4) In paragraph 23—

• (a) in sub-paragraph (a), for “paragraph 1 (changes to active substances) or paragraph 2 (changes to strength, pharmaceutical form and route of administration) of Annex I to Commission Regulation (EC) No 1234/2008 applies” substitute in the case of a UKMA(NI) or UKMA(UK), paragraph 1 (changes to active substances) or paragraph 2 (changes to strength, pharmaceutical form and route of administration) of Annex I to Commission Regulation (EC) No 1234/2008 applies or, in the case of a UKMA(GB), sub-paragraph (a) (changes to active substances) or sub-paragraph (b) (changes to strength, pharmaceutical form and route of administration) of the definition of “extension of a UK marketing authorisation” in paragraph 1 of Schedule 10A to the Human Medicines Regulations applies;

• (b) in sub-paragraph (b), for “Article 2(3) of Commission Regulation Commission Regulation (EC) No 1234/2008” substitute in the case of a UKMA(NI) or UKMA(UK), Article 2(3) of Commission Regulation (EC) No 1234/2008 or, in the case of a UKMA(GB), paragraph 1 of Schedule 10A to the Human Medicines Regulations; and

• (c) in sub-paragraph (c), for “Commission Regulation (EC) No 1234/2008” substitute in the case of a UKMA(NI) or UKMA(UK), Commission Regulation (EC) No 1234/2008 or, in the case of a UKMA(GB), paragraph 1 of Schedule 10A to the Human Medicines Regulations.

• (5) For the table in paragraph 24, substitute—

• (6) After paragraph 24, insert—

(24A) (1) This paragraph applies where, before IP completion day — (a) an application has been made to the EMA for a European Union marketing authorisation; (b) day 120 has passed; and (c) no final decision has been made by the European Commission in relation to the grant of an European Union marketing authorisation under Article 10 of Regulation (EC) No 726/2004. (2) Where this paragraph applies and the applicant for the European Union marketing authorisation applies for a UK marketing authorisation in accordance with paragraph 31(2) of Schedule 33A to the Human Medicines Regulations, the fee payable under regulation 12(1) shall be waived. (3) In this paragraph, “day 120” means the day during the assessment of an application for a European Union marketing authorisation on which the Committee for Medicinal Products for Human Use adopts the list of questions, as well as the overall conclusions and review of the scientific data, to be sent to the applicant.

• (7) In paragraph 27—

• (a) in sub-paragraph (2), for paragraphs (a) to (c) substitute—

(a) in respect of the first or only marketing authorisation applied for by that secondary applicant— (i) in the case of an application relating to a medicinal product that has received an opinion favourable to the granting of a marketing authorisation from the Committee for Medicinal Products for Human Use, £17,330; or (ii) in any other case, the amount payable in respect of a complex application under paragraph 24; (b) in respect of each additional marketing authorisation applied for by that secondary applicant which relates to a medicinal product of the same dosage form— (i) in the case of an application relating to a medicinal product that has received an opinion favourable to the granting of a marketing authorisation from the Committee for Medicinal Products for Human Use, £6,350; or (ii) in any other case, the amount payable in respect of a standard application under paragraph 24; (c) in respect of the first additional marketing authorisation applied for by that secondary applicant relating to that medicinal product which is of a different dosage form— (i) in the case of an application relating to a medicinal product that has received an opinion favourable to the granting of a marketing authorisation from the Committee for Medicinal Products for Human Use, £17,330; or (ii) in any other case, the amount payable in respect of a complex application under paragraph 24; (d) in respect of any other additional marketing authorisation applied for by that secondary applicant relating to that medicinal product which is of a different dosage form— (i) in the case of an application relating to a medicinal product that has received an opinion favourable to the granting of a marketing authorisation from the Committee for Medicinal Products for Human Use, £6,350; or (ii) in any other case, the amount payable in respect of a standard application under paragraph 24.

; and

• (b) in sub-paragraph (3), for paragraph (a), substitute—

(a) where the amount payable by the primary applicant is that in respect of a complex application, the fee payable under regulation 12(1)(a) by the secondary applicant is— (i) in the case of an application relating to a biological medicinal product that has received an opinion favourable to the granting of a marketing authorisation from the Committee for Medicinal Products for Human Use, £6,350; or (ii) in any other case, the amount payable in respect of a standard application under paragraph 24;

• (8) In paragraph 28—

• (a) in sub-paragraph (2), for paragraphs (a) to (c) substitute—

(a) in respect of each additional marketing authorisation applied for which relates to a medicinal product of a different dosage form with a different route of administration— (i) in the case of an application relating to a medicinal product that has received an opinion favourable to the granting of a marketing authorisation from the Committee for Medicinal Products for Human Use, £17,330; or (ii) in any other case, the amount payable in respect of a complex application under paragraph 24; (b) in respect of each additional marketing authorisation applied for which relates to a medicinal product of a different dosage form but with the same route of administration— (i) in the case of an application relating to a medicinal product that has received an opinion favourable to the granting of a marketing authorisation from the Committee for Medicinal Products for Human Use, £6,350; or (ii) in any other case, the amount payable in respect of a standard application under paragraph 24; and (c) in respect of each additional marketing authorisation applied for which relates to a medicinal product of the same dosage form but of a different strength of active ingredient or different combination of active ingredients— (i) in the case of an application relating to a medicinal product that has received an opinion favourable to the granting of a marketing authorisation from the Committee for Medicinal Products for Human Use, £6,350; or (ii) in any other case, the amount payable in respect of a standard application under paragraph 24.

; and

• (b) in sub-paragraph (3), for paragraphs (b) and (c), substitute—

(b) in respect of each additional marketing authorisation applied for which relates to a medicinal product of a different dosage form but with the same route of administration— (i) in the case of an application relating to a biological medicinal product that has received an opinion favourable to the granting of a marketing authorisation from the Committee for Medicinal Products for Human Use, £6,350; or (ii) in any other case, the amount payable in respect of a standard application under paragraph 24; and (c) in respect of each additional marketing authorisation applied for which relates to a medicinal product of the same dosage form but of a different strength of active ingredient or different combination of active ingredients— (i) in the case of an application relating to a biological medicinal product that has received an opinion favourable to the granting of a marketing authorisation from the Committee for Medicinal Products for Human Use, £6,350; or (ii) in any other case, the amount payable in respect of a standard application under paragraph 24.

• (8A) After paragraph 28 (application for multiple authorisations) insert—

(28A) (1) Where an applicant for a United Kingdom marketing authorisation submits material in accordance with regulation 50(5) of the Human Medicines Regulations for pre-assessment by the licensing authority rather than as part of the submission of a full application for that marketing authorisation, the fee payable in respect of pre-assessment of each of the following Modules (as defined in Annex I to the 2001 Directive) is— (a) £23,188.25 in respect of Module 3 (chemical, pharmaceutical and biological information); (b) £23,188.25 in respect of Module 4 (non-clinical reports); (c) £23,188.25 in respect of Module 5 (clinical study reports). (2) Where an applicant for a United Kingdom marketing authorisation for a similar biological medicinal product submits material in accordance with regulations 53, 53A or 53B of the Human Medicines Regulations for pre-assessment of a complex abridged application by the licensing authority rather than as part of the submission of a full application for that marketing authorisation, the fee payable in respect of pre-assessment of each of the following Modules (as defined in Annex I to the 2001 Directive) is— (a) £4,332.50 in respect of Module 3 (chemical, pharmaceutical and biological information); (b) £4,332.50 in respect of Module 4 (non-clinical reports); (c) £4,332.50 in respect of Module 5 (clinical study reports). (3) The fee payable under sub-paragraphs (1) and (2) must be paid within a period of 14 days, commencing on the date of the written notice issued by the licensing authority requiring payment of the fee. (4) Where a fee has been paid under this paragraph, any fee payable under regulation 12(1) in connection with an application for the grant of a United Kingdom marketing authorisation in respect of the same product is reduced by the amount paid under this paragraph provided that no further assessment of the Module concerned is required.

• (9) In paragraph 38—

• (a) in sub-paragraph (4)(b), after “Commission Regulation (EC) 1234/2008” insert “and of marketing authorisations in force in Great Britain”;

• (b) after sub-paragraph (6)—

• (i) for Table 1 substitute—

• (ii) in Table 2—

• (aa) in the heading to the table, after “Commission Regulation (EC) No 1234/2008” insert “and of marketing authorisations in force in Great Britain”;

• (bb) after row 8 insert—

• (10) In paragraph 39—

• (a) in sub-paragraph (1), after “Subject to sub-paragraph (3)” insert “ and paragraph 39A ”;

• (b) in sub-paragraph (2), for “in respect of an orphan medicinal product”, substitute “ an orphan marketing authorisation ”; and

• (c) in sub-paragraph (3), for “an orphan medicinal product” substitute “ a medicinal product which meets the orphan criteria listed in regulation 50G(2) of the Human Medicines Regulations ”.

• (11) After paragraph 39, insert—

(39A) (1) Subject to sub-paragraph (2), if an application to vary an orphan marketing authorisation is made by, or on behalf of, a small or a medium company within 12 months of the date of grant of the marketing authorisation, the fee payable for that variation application shall be waived. (2) Sub-paragraph (1) does not apply to an application to authorise use of the medicinal product in a new therapeutic area which does not meet the orphan criteria listed in regulation 50G(2) of the Human Medicines Regulations.

• (12) After paragraph 40, insert—

(40A) (1) Paragraph (2) applies where, before IP completion day — (a) an application for a variation to which paragraph 11(7) of Schedule 33A to the Human Medicines Regulations applies, has been made to the EMA; and (b) the Committee for Medicinal Products for Human Use has adopted a request for supplementary information to be sent to the applicant, or, in the case of an extension, day 120 has passed. (2) Where this paragraph applies and the holder of a converted EU marketing authorisation submits the application to the licensing authority in order to have the variation made to the converted EU marketing authorisation, the fee payable under regulation 19(1) shall be waived. (3) In this paragraph— - “day 120” means the day during the assessment of an extension on which the Committee for Medicinal Products for Human Use adopts the list of questions, as well as the overall conclusions and review of the scientific data, to be sent to the applicant; - “converted EU marketing authorisation” has the meaning given in paragraph 6(1) and (2) of Schedule 33A to the Human Medicines Regulations; and - “extension” has the meaning given in paragraph 1 of Schedule 10A to the Human Medicines Regulations.

• (13) For Part 6 substitute—

(56) Unless paragraph 57 applies, the fee payable under regulation 27A in connection with an application for the renewal of a United Kingdom marketing authorisation is— (a) in respect of an application for renewal of a UKMA(GB) granted under the unfettered access route, £747; (b) in respect of an application for renewal of a UKMA(GB) where the medicinal product concerned has already been granted a European Union marketing authorisation under Regulation (EC) No 726/2004 (an automatic recognition application), £747; (c) in all other cases, £9,682. (57) (1) This sub-paragraph applies if more than one application falling within regulation 27A is made by the same applicant at the same time, each of which relates to medicinal products which have the same active ingredient or combination of ingredients, dosage form and therapeutic indications, and the marketing authorisations for those products have the same date for renewal. (2) The fee payable under regulation 27A for applications to which sub-paragraph (1) applies is— (a) in respect of applications for renewal of more than one UKMA(GB) granted under the unfettered access route or UKMA(GB) where the medicinal product concerned has already been granted a European Union marketing authorisation under Regulation (EC) No 726/2004 (an automatic recognition application), and provided a corresponding renewal application has been made to the related European Union marketing authorisation or UKMA(NI) for the same product— (i) £747 for the first application considered by the licensing authority; and (ii) £747 for each other application; (b) in all other cases— (i) £9,682 for the first application considered by the licensing authority; and (ii) £747 for each other application. (57A) The fee payable under regulation 19D(1) in connection with the carrying out of a major safety review is— (a) £51,286, where one or two active ingredients, or combinations of active ingredients, are included in the assessment; (b) £59,595, where three active ingredients, or combinations of active ingredients, are included in the assessment; (c) £67,904, where four active ingredients, or combinations of active ingredients, are included in the assessment; or (d) £76,213, where five or more active ingredients, or combinations of active ingredients, are included in the assessment. (57B) (1) Unless sub-paragraph (2) applies, the fee payable under regulation 19F(1) in connection with the submission of a sample of a batch of a medicinal product of a kind described in column 1 of the following table is the fee specified in the corresponding entry in column 2 of that table. (2) This sub-paragraph applies where— (a) the holder of the marketing authorisation submits, with a sample of a batch of medicinal product, a certificate issued by a laboratory in a designated country for batch testing and certification of biological medicinal products that relates to the sample of the batch submitted; and (b) on the basis of the documentation submitted with the sample, the appropriate authority considers that it is only necessary to carry out a paper based assessment of the sample. (3) Where sub-paragraph (2) applies, the fee payable under regulation 19F(1) in connection with the submission of a sample of a batch of medicinal product of a kind described in column 1 of the following table is the fee specified in the corresponding entry in column 3 of that table. (4) Where a product falls within more than one of the Bands referred to in the following table, the product is to be treated as if it only falls within the Band which attracts the highest fee.

(5) In this paragraph— - “Band A” means a single component product, other than Botulinum toxin, requiring five or fewer in vitro tests; - “Band B” means Factor VIII, Factor IX or intravenous Immunoglobulin; - “Band C” means a multi-component product, or Botulinum toxin, requiring five or fewer in vitro tests; - “Band D” means a product requiring six to nine in vitro tests; - “Band E” means a product requiring— 1. ten or more in vitro tests, or 2. one or more in vivo tests; - “Band F” means a product— 1. which requires one or more tests that must be carried out under containment measures applicable to hazard Group 3 or 4 biological agents under the Control of Substances Hazardous to Health Regulations 2002 ; or 2. requires the use of human cells or tissues as part of its testing; - “Multi-component product” means a product containing two or more analytes that require testing; and - “Single component product” means a product containing a single analyte that requires testing.

Amendment of Schedule 4 (periodic fees for licences)

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In Schedule 4, in paragraph 1, in the definition of “limited use drug” for “which is in respect of an orphan medicinal product” substitute “ in respect of which an orphan marketing authorisation has been granted ”.

Amendment of Schedule 7 (waiver, reduction or refund of capital fees)

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In Schedule 7, after paragraph 7, insert—

(7A) Where the licensing authority grants an orphan marketing authorisation, the following percentage of the fee otherwise payable under regulation 12(1)(a) in connection with the application for that authorisation shall be refunded or, if it has not yet been paid, shall be waived— (a) in the case of an application made by or on behalf of a small or medium company, 100%; (b) in the case of a major application that is not made by or on behalf of a small or medium company but to which paragraph 6 of Part II of Annex 1 to the 2001 Directive applies, 50%; or (c) in any other case, 10%.

Amendment of Schedule 8 (Adjustment, reduction or refund of periodic fees)

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• (1) Schedule 8 is amended as follows.

• (2) In the heading, after “Adjustment”, insert “ , waiver ”.

• (3) After paragraph 2, insert—

(2A) (1) Where the licensing authority revokes a converted EU marketing authorisation in accordance with paragraph 6(3) of Schedule 33A to the Human Medicines Regulations, the periodic fee payable under regulation 38(1) in relation to that authorisation shall be refunded, or if it has not yet been paid, shall be waived. (2) In this paragraph, “converted EU marketing authorisation” has the meaning given in paragraph 6(1) and (2) of Schedule 33A to the 2012 Regulations.

Savings

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• (1) The provisions of the Medicines (Products for Human Use) (Fees) Regulations 2016 (“the 2016 Regulations”) omitted, substituted or amended by this Schedule shall continue to apply as if they had not been omitted, substituted or amended in relation to—

• (a) capital fees payable under the 2016 Regulations in respect of any application or inspection made before the date on which these Regulations come into force; and

• (b) any periodic fee payable under the 2016 Regulations in relation to the fee period during which these Regulations come into force or in relation to a fee period ending before the date on which these Regulations come into force.

• (2) The omissions, substitutions and amendments shall not affect any proceedings under the 2016 Regulations for the recovery of any fees due as debts to the Crown and for the purposes of those proceedings, the provisions omitted, substituted or amended by this Schedule shall continue to apply as if they had not been omitted, substituted or amended.

SCHEDULE 2 — Insertion of new Schedule 8B (modifications of Annex I to the 2001 Directive)

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After Schedule 8A to the Human Medicines Regulations 2012, insert—

SCHEDULE 8B

SCHEDULE 3 — Insertion of new Schedule 2A (modifications of Commission Directive 2003/94/EC)

1

After Schedule 2 to the Human Medicines Regulations 2012, insert—

SCHEDULE 2A

SCHEDULE 4 — Insertion of new Schedule 9A

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After Schedule 9, insert—

SCHEDULE 9A (1) (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 Great Britain. (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 Great Britain 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 Great Britain, 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) (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 Great Britain 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 Great Britain or any other country in relation to the development of the medicinal product; (d) where the medicinal product is already authorised in Great Britain 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 Great Britain and elsewhere during the first ten years that the medicinal product is authorised; and (h) information on the prevalence and incidence in Great Britain 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) (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 Great Britain, 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 Great Britain, 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 Great Britain; 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. (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— 1. greater efficacy; 2. greater safety in a substantial portion of the target population, as evidenced where appropriate through comparative clinical trials; or 3. 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.

SCHEDULE 5 — Insertion of new Schedule 10A (variations to a UK marketing authorisation)

1

After Schedule 10, insert—