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The Human Medicines Regulations 2012

Type Statutory-Instrument

Publication 2012-07-19

Last updated 2026-03-31

State In force

Department King's Printer of Acts of Parliament

Source legislation.gov.uk

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articles 4

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(a) review any list it publishes under paragraph (1) to determine if a country still satisfies the criteria for inclusion in the list specified in paragraph (2), and if it is not so satisfied, remove that country from the list; and

(b) undertake such a review at least every three years beginning with the date on which the country is included in that list.

Addition of vitamins or minerals

List of herbal substances, preparations and combinations for use in traditional herbal medicinal products

Licensing authority list as to herbal substances, preparations and combinations for use in traditional herbal medicinal products

126A

(1) The licensing authority may establish, and publish a list of, herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products for which a THR(GB) may be granted.

(2) A list established under paragraph (1) must contain, with regard to each herbal substance—

(a) the indication;

(b) the specified strength and posology;

(d) any other information necessary for the safe use of the herbal substance as a traditional medicinal product.

(3) The licensing authority may review and amend any list it publishes under paragraph (1) at such intervals as it considers appropriate.

Procedure where less than 15 years use of traditional herbal medicinal product

130A

(1) Where an application for a THR(GB) (other than an application under the unfettered access route) has been made and the licensing authority considers that—

(a) the traditional herbal medicinal product does not satisfy regulation 125(5)(b) (Condition D); but

(b) otherwise satisfies the conditions in regulation 125,

the licensing authority may refer the matter to the appropriate committee for relevant advice, and the procedure in Part 3 of Schedule 11 applies (referral to the appropriate committee for traditional herbal registrations).

(2) In this regulation—

“appropriate committee” has the same meaning as in paragraph 2(4) of Schedule 11;

“relevant advice” means advice as to whether—the conditions in regulation 125, other than condition D, are met in relation to the application; andthe licensing authority should exercise its powers under regulation 143A to establish a herbal monograph.

Classification of traditional herbal registration

Establishment of herbal monographs

143A

(1) The licensing authority may establish herbal monographs for herbal medicinal products and traditional herbal medicinal products to be placed on the market in Great Britain.

(2) Subject to paragraph (3), the licensing authority must—

(a) consult the appropriate committee, within the meaning of paragraph 2(4) of Schedule 11, on a proposal to establish herbal monographs under paragraph (1); and

(b) take the advice of the appropriate committee into account in determining whether to proceed with that proposal.

(3) Where an application for a traditional herbal registration has been referred to the appropriate committee by the licensing authority under regulation 130A, the licensing authority must consider whether to exercise its powers under paragraph (1), taking into account any relevant advice of the appropriate committee given under Part 3 of Schedule 11 in relation to that application.

(4) The licensing authority must publish a list of any herbal monographs established under this regulation.

(5) Until the licensing authority exercises the power under paragraph (1), the Community herbal monographs published from time to time under Article 16h(3) of the 2001 Directive continue to apply, and holders of a traditional herbal registration and the licensing authority must continue to take them into account in exercising any function or in relation to any obligation to which they are relevant under this Part.

Obligation following new herbal monograph

Obligation to provide information relating to safety etc

Obligation in relation to product information

Record-keeping obligations

Obligation to ensure appropriate and continued supplies

Urgent safety restrictions

148A

(1) Where, in the event of a risk to public health, the holder of a traditional herbal registration takes urgent safety restrictions on its own initiative, it must inform the licensing authority immediately.

(2) If the licensing authority has not raised objections within 24 hours following receipt of that information, the urgent safety restrictions are deemed to be accepted by the licensing authority.

(3) In the event of a risk to public health, the licensing authority may impose urgent safety restrictions.

(4) Where an urgent safety restriction is taken by the holder of a traditional herbal registration, or imposed by the licensing authority, the holder must submit an application for variation of that registration in relation to that restriction within 15 days beginning with the date of the initiation of that restriction.

Requests from EU member States

186A

The licensing authority must collaborate with the World Health Organisation in matters of pharmacovigilance, and must in particular—

(a) take the necessary steps to promptly submit to the World Health Organisation appropriate and adequate information regarding the measures taken in the United Kingdom which may have a bearing on public health protection in other countries; and

(b) make available promptly all suspected adverse reaction reports occurring in the United Kingdom to the World Health Organisation.

Recording obligations on holders

Reporting obligations on holders

Major safety review by the licensing authority

196A

(1) The licensing authority may conduct a major safety review where—

(a) on the basis of concerns resulting from the evaluation of data from pharmacovigilance activities it considers—

(i) suspending or revoking a UK marketing authorisation or traditional herbal registration of a medicinal product or in respect of a class of medicinal products,

(ii) prohibiting the supply of a medicinal product or a class of medicinal products,

(iii) refusing the renewal of a UK marketing authorisation or traditional herbal registration, or

(iv) action is necessary to vary a UK marketing authorisation or traditional herbal registration or a class of such authorisations or registrations, including to impose new conditions; or

(b) it is informed by a holder that, on the basis of safety concerns, the holder has—

(i) interrupted the sale or supply, or offer of sale or supply, of the product to which a UK marketing authorisation or traditional herbal registration relates,

(ii) taken action to have that product's authorisation or registration cancelled or intends to do so, or

(iii) not applied for the renewal of that product's authorisation or registration.

(2) If the licensing authority conducts a review under paragraph (1), it must—

(a) announce the initiation of that review on the UK web-portal as soon as reasonably practicable;

(b) include in that announcement—

(i) an outline of its reasons for conducting a major safety review, the medicinal products concerned and, where applicable, the active substances concerned, and

(ii) the proposed structure and time-scale of the review;

(c) notify a holder if the product to which that holder's authorisation or registration relates is within the scope of the review; and

(d) publish the outcome of that review, including any recommendations it is making, or action it is proposing to take, as soon as reasonably practicable after the conclusion of that review.

(3) A holder who is notified under paragraph (2)(c)—

(a) must provide to the licensing authority such information as the licensing authority notifies that holder it requires, within such time period as the licensing authority specifies; and

(b) may, where such information contains confidential data relevant to the subject matter of the review, because the data relates to a manufacturing process or trade secret, notify the licensing authority that that data is provided in confidence.

(4) Where the licensing authority proposes that action should be taken in respect of any UK marketing authorisation or traditional herbal registration—

(a) during the conduct of the major safety review, because urgent action is necessary to protect public health; or

(b) upon the conclusion of such a review,

it may exercise its powers under Part 5 or 7 (as the case may be) in relation to that authorisation or registration.

EU urgent action procedure

Medicinal products subject to additional monitoring

Licensing authority power in relation to medicinal products subject to additional monitoring

202A

(1) The licensing authority may establish a list of medicinal products that are subject to additional monitoring.

(2) The list referred to in paragraph (1) is to include the names and active substances of—

(a) medicinal products authorised in the United Kingdom that contain a new active substance which, on 1st January 2011, was not contained in any medicinal product authorised in the United Kingdom;

(b) any biological medicinal product not covered by sub-paragraph (a) that was authorised in the United Kingdom after 1st January 2011;

(c) medicinal products that are authorised pursuant to these Regulations, subject to the conditions referred to in regulation 50I, 59(2)(b) or (c), 60 or 61(4);

(d) any MM medicinal product;

(e) any POC medicinal product.

(3) If the licensing authority considers it appropriate, medicinal products that are authorised pursuant to these Regulations, subject to the conditions referred to in regulation 59(2)(a), (d), (e) or (f), 61(5) or 183(2), may also be included in the list referred to in paragraph (1).

(4) For medicinal products included in the list referred to in paragraph (1)—

(a) the summary of product characteristics and the package leaflet must include a symbol and statement as follows: “▼ This medicinal product is subject to additional monitoring”; and

(b) that symbol must be proportional to the font of the subsequent standardised text, and each side of the triangle must have a minimum length of 5 millimetres.

(5) In the cases referred to in paragraph (2)(a) and (b), the licensing authority must, unless paragraph (6) applies, remove a medicinal product from the list after five years, beginning with the day after the UK reference date referred to in regulation 193.

(6) In the cases referred to in paragraph (2)(c) and (3), the licensing authority must remove a medicinal product from the list once the condition or obligation under a provision specified in those paragraphs has been fulfilled.

(7) Until the licensing authority publishes a list of medicinal products under paragraph (1), the reference to that list is instead to be read as a reference to the list referred to in Article 23 of Regulation (EC) No 726/2004, as that list may be amended from time to time.

Further obligations in respect of pharmacovigilance activities

205A

(1) Schedule 12A applies in relation to medicinal products for sale or supply under a UKMA(GB) , UKMA(UK)(Category 1) or THR(GB) and makes further provision as to the obligations of a holder and the licensing authority in respect of the performance of pharmacovigilance activities under this Part.

(2) The Secretary of State may by regulations ... amend Schedule 12A.

(3) Regulations under paragraph (2) may make provision regarding the performance of pharmacovigilance activities under this Part as to—

(a) the content and maintenance of the pharmacovigilance system master file kept by the holder;

(b) the minimum requirements for the quality system for the performance of pharmacovigilance activities by the holder and the licensing authority;

(c) the use of internationally agreed terminology, formats and standards for the performance of pharmacovigilance activities;

(d) the minimum requirements for the monitoring of data recorded by the licensing authority pursuant to regulation 185 (recording obligations on the licensing authority) to determine whether there are new risks or whether risks have changed;

(e) the format and content of electronic transmission of suspected adverse reactions by a holder;

(f) the format and content of electronic periodic safety reports and risk management plans; and

(g) the format of protocols, abstracts and final study reports for the post-authorisation safety studies.

Guidance in respect of pharmacovigilance

Guidance in respect of good pharmacovigilance practice and post authorisation efficacy studies

205B

(1) The licensing authority may publish—

(a) guidance on good pharmacovigilance practices for both the licensing authority and UK marketing authorisation holders;

(b) scientific guidance on post authorisation efficacy studies.

(2) Subject to paragraph (3), the guidance issued by the Commission under Article 108a of the 2001 Directive on the matters specified in paragraph (1)(a) and (b) continues to apply until the date on which the licensing authority publishes guidance under paragraph (1).

(3) The licensing authority—

(a) may determine that provisions of the guidance specified in paragraph (2) no longer apply, or apply subject to specified modifications, from a date that it specifies; and

(b) must, if it so determines, publish its determination.

(4) Guidance published under paragraph (1), or which applies by virtue of paragraph (2) (as modified by any determination under paragraph (3), as the case may be), is to be taken into account in consideration of whether there has been any failure to comply with a provision in this Part, or Schedule 12A, to which the guidance is relevant.

Requirements for prescriptions: approved country health professional

Electronic Prescriptions: approved country health professionals

Application of Part

256ZA

This part applies to Northern Ireland only.

Interpretation

Person who may sell medicinal products by information society services

Notification requirements for sellers of medicinal products at a distance

Procedure for listing persons who may supply medicinal products at a distance

Removal of a person’s entry from the list

Provision of information to the licensing authority

Grant or refusal to list a person

Conditions to be met by a person entered on the list

Power to suspend, vary or remove a person’s entry on the list

Procedure where the licensing authority proposes to suspend, vary or remove a person’s entry on the list

Suspension of a person’s entry on the list in cases of urgency

Variation of a person’s entry on the list on the application of that person

Offences: breach of regulations and false information

Penalties

Packaging requirements: advanced therapy medicinal products

257C

(1) The information specified in Part 4 of Schedule 24 must appear—

(a) on the outer packaging of an advanced therapy medicinal product ... (other than an exempt advanced therapy medicinal product); and

(b) on the immediate packaging of that product, unless paragraph (2) or (3) applies to the packaging.

(2) This paragraph applies to the immediate packaging if the packaging is in the form of a blister pack and is placed in outer packaging which complies with the requirements of Part 4 of Schedule 24.

(3) This paragraph applies to immediate packaging if the packaging is too small to display the information required by Part 4 of Schedule 24.

(4) The information specified in Part 5 of Schedule 24 must appear on immediate packaging to which paragraph (2) or (3) applies.

(5) Nothing in this regulation applies to an advanced therapy medicinal product that is a POC medicinal product, if the entirety of the product is to be administered immediately after manufacture.

Guidance as to packaging and package leaflets

257D

(1) The licensing authority may publish guidance on packaging and package leaflets applicable to products for sale or supply in the whole United Kingdom or parts of the United Kingdom, as appropriate.

(2) Guidance published under paragraph (1) may, in particular, include—

(a) the wording of certain special warnings for certain categories of medicinal products;

(b) the particular information needs relating to products that are a pharmacy medicine;

(d) the methods of identification and authentication of medicinal products;

(e) the list of excipients which must feature on the labelling of medicinal products and the way in which these excipients must be indicated.

(3) Until such time as the licensing authority publishes guidance under paragraph (1), any guidance published by the Commission pursuant to Article 65 of the 2001 Directive, insofar as that guidance was in force immediately before IP completion day, continues to apply as if it had been published by the licensing authority under paragraph (1).

Regulation-making power as to certain forms of labelling

257E

The Ministers may by regulations require the use of certain forms of labelling of a medicinal product in order to make it possible to ascertain—

(a) the price of the medicinal product;

(b) any reimbursement conditions of the National Health Service;

(c) the legal status for supply to the patient in accordance with regulation 5 (classification), insofar as not already provided for in Schedule 25;

(d) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Packaging requirements: specific provisions

Package leaflets

Use of pictures and symbols etc

Labelling requirements for radionuclides

Leaflets relating to radionuclides

Homoeopathic medicines

Additional requirements for traditional herbal medicinal products

Language requirements etc

Submission of mock-ups of packaging and leaflets to licensing authority

Offence relating to packaging and package leaflets in Northern Ireland: holder of authorisation etc

268A

(1) This regulation applies to the holder of a UKMA(UK), UKMA(NI), EU marketing authorisation, Article 126a authorisation, certificate of registration or traditional herbal registration for a medicinal product who sells or supplies, offers to sell or supply, or possesses for the purpose of sale or supply, in Northern Ireland, a medicinal product to which the authorisation, certificate or registration relates.

(2) A person to whom this regulation applies is guilty of an offence if—

(a) a package or package leaflet relating to the product does not comply with the applicable requirements of this Part ... or Article 28 or 32 of the Paediatric Regulation; or

(b) the product is not accompanied by a package leaflet when one is required by virtue of this Part.

Offences relating to packaging and package leaflets in Great Britain: other persons

Offences relating to packaging and package leaflets in Northern Ireland: other persons

269A

(1) This regulation applies to a person, other than the holder of a UKMA(UK), UKMA(NI) ..., Article 126a authorisation, certificate of registration or traditional herbal registration for a medicinal product, who, in the course of a business carried on by that person, sells or supplies, or offers to sell or supply the product, or possesses the product for the purpose of sale or supply in Northern Ireland.

(2) A person to whom this regulation applies is guilty of an offence if the person sells or supplies, or offers to sell or supply, the product, or possesses the product for the purpose of sale or supply, in Northern Ireland knowing or having reasonable cause to believe—

(a) that a package or package leaflet relating to the medicinal product does not comply with the applicable requirements of this Part ... or Article 28 or 32 of the Paediatric Regulation; or

(b) that the product is not accompanied by a package leaflet when one is required by virtue of this Part.

Non-compliance with requirements of this Part

Offences: penalties

Medicines with differing classification status in Great Britain and Northern Ireland

284A

In the case of a medicinal product for sale or supply in Great Britain where the product concerned is not a prescription only medicine in Great Britain but is either—

(a) a prescription only medicine in Northern Ireland; or

(b) not authorised for sale or supply in Northern Ireland,

any advertisement to the public must include a statement that the medicinal product is not available without a prescription, or is not available for sale or supply, in Northern Ireland (as the case may be).

Narcotic and psychotropic substances

Material relating to diagnosis

Material about effects of medicinal product

Material about status of medicinal product

Recommendations by scientists etc

Advertisements directed at children

Form and content of advertisement

Campaigns relating to the suspected or confirmed spread of pathogenic agents etc.

Exception for approved vaccination campaigns

Guidelines on inspections

331A

(1) The licensing authority may publish guidelines specifying the principles applicable to inspections referred to in this Part.

(2) Guidelines under paragraph (1) may include the form and content of reports under regulation 331 and of certificates of good manufacturing practice or good distribution practice.

(3) Until the licensing authority exercises its power under paragraph (1), the guidelines adopted by the European Commission under Article 111a of the 2001 Directive, as they had effect immediately before IP completion day, are to continue to apply.

Restrictions on disclosure of information

Protection for inspectors

Supplementary provisions and offences

Modifications to deal with serious shortages

344A

(1) The Ministers may by regulations modify the application of any of the specified provisions in circumstances where the United Kingdom, or any part of the United Kingdom, is experiencing or may experience a serious shortage of medicinal products, or of medicinal products of a specified description, arising from the withdrawal of the United Kingdom from the European Union.

(2) Regulations may only be made under paragraph (1) for the purposes of preventing, remedying or mitigating the serious shortage that is being or may be experienced.

(3) For the purposes of paragraph (1), the “specified provisions” are the provisions of Parts 1, 3 to 5, 10 to 13 and 16, and of the associated Schedules.

(4) The reference in paragraph (1) to a serious shortage arising from the withdrawal of the United Kingdom from the European Union includes reference to a serious shortage where the withdrawal of the United Kingdom from the European Union is one but not the only significant factor contributing to the shortage.

(5) No regulations under paragraph (1) may be made, or have effect, after the end of the period of two years beginning with IP completion day.

Regulation making powers

344B

(1) Regulations made under a power in the regulations listed in paragraph (2)—

(a) are to be made by statutory instrument;

(b) may make different provision for different purposes and different areas; and

(c) may include incidental, supplemental, consequential, transitional, transitory or saving provisions, including consequential amendments to these Regulations.

(2) The regulations referred to in paragraph (1) are—

(a) regulation B17(1) and (4) (good manufacturing practice);

(b) regulation 50(5A) (Annex I to the 2001 Directive);

(d) regulations 59(3A) and 61(7A) (post-authorisation efficacy studies);

(e) regulation 65C(7) (variations of UK marketing authorisations);

(f) regulation 102(7) (homoeopathic medicinal products);

(g) regulation 205A(2) (further obligations in respect of pharmacovigilance activities);

(h) regulation 257E (certain forms of labelling); and

(i) regulation 344A (modifications to deal with serious shortages).

(3) A statutory instrument containing regulations made under the powers listed in paragraph (2) is subject to annulment in pursuance of a resolution of either House of Parliament.

Transitional provision in relation to EU exit

347A

Schedule 33A contains transitional provision in relation to the EU Exit Regulations.

Amendments to existing law

Repeals and revocations

SCHEDULE 2A — Modifications of Commission Directive 2003/94/EC

14A

A licence holder—

(a) in Great Britain may only supply a special medicinal product to a person in Northern Ireland, and

(b) in Northern Ireland may only supply a special medicinal product to a person in Great Britain,

in response to an order which satisfies the requirements of regulation 167.

23A

A licence holder—

(a) in Great Britain may only supply a special medicinal product to a person in Northern Ireland, and

(b) in Northern Ireland may only supply a special medicinal product to a person in Great Britain,

in response to an order which satisfies the requirements of regulation 167.

41A

A licence holder—

(a) in Great Britain may only supply a special medicinal product to a person in Northern Ireland, and

(b) in Northern Ireland may only supply a special medicinal product to a person in Great Britain,

in response to an order which satisfies the requirements of regulation 167.

12A

(1) In Northern Ireland, the qualified person is responsible for securing—

(a) that each batch of medicinal products manufactured in Northern Ireland has been manufactured and checked in accordance with these Regulations and the requirements of the marketing authorisation, Article 126a authorisation, certificate of registration or traditional herbal registration relating to those products; and

(b) in the case of medicinal products imported from a country other than an EEA State, irrespective of whether the products have been manufactured in Northern Ireland or an EEA State, that each batch has undergone—

(i) a full qualitative analysis,

(ii) a quantitative analysis of all the active substances, and

(iii) all other tests or checks necessary to ensure the quality of medicinal products in accordance with the requirements of the marketing authorisation, Article 126a authorisation, certificate of registration or traditional herbal registration relating to those products.

(2) This paragraph does not apply in relation to listed NIMAR products in Northern Ireland.

23

For medicinal products included on the list referred to—

(a) in the case of a UKMA(NI) or a UKMA(UK)(Category 2), in Article 23 of Regulation (EC) No 726/2004, the symbol and statement “▼ This medicinal product is subject to additional monitoring”, or

(b) in the case of a UKMA(GB) or a UKMA(UK)(Category 1), in regulation 202A, the symbol and statement “▼ This medicinal product is subject to additional monitoring”.

24

The name of the medicinal product followed by its strength and pharmaceutical form.

25

The qualitative and quantitative composition, using the usual common name or chemical description, of the medicinal product in terms of—

(a) the active substances; and

(b) those excipients of which knowledge is essential for proper administration of the medicinal product.

25A

In the case of an advanced therapy medicinal product ... which contains cells or tissues, a detailed description of those cells or tissues and of their specific origin, including the species of animal in cases of non-human origin.

26

The pharmaceutical form of the medicinal product.

27

Clinical particulars in relation to the medicinal product, covering—

(a) therapeutic indications;

(b) posology and method of administration for adults and, where necessary, for children;

therapeutic indications;

(d) special warnings and precautions for use and, in the case of immunological medicinal products any special precautions to be taken by persons handling such products and administering them to patients, together with any precautions to be taken by the patient;

(e) interaction with other medicinal products and other forms of interactions;

(f) use during pregnancy and lactation;

(g) effects on ability to drive and to use machines;

(h) other undesirable effects; and

(i) information on overdose (including symptoms, emergency procedures and antidotes).

28

The pharmacological properties of the medicinal product, covering—

(a) pharmacodynamic properties;

(b) pharmacokinetic properties; and

29

Pharmaceutical particulars in relation to the medicinal product, covering—

(a) a list of excipients;

(b) major incompatibilities;

(c) shelf life after reconstitution of the medicinal product or when the immediate packaging is opened for the first time (as appropriate);

(d) special precautions for storage;

(e) nature and contents of container; and

(f) special precautions for disposal of the used medicinal product or waste materials derived from the medicinal product (as appropriate).

30

The holder of the UK marketing authorisation.

31

The number of the UK marketing authorisation.

32

The date of the first UK marketing authorisation or, where the UK marketing authorisation has been renewed, the date of the last renewal.

33

The date of any revisions of the text of the summary of the product characteristics.

34

For radiopharmaceuticals, full details of internal radiation dosimetry.

35

For radiopharmaceuticals, additional detailed instructions for extemporaneous preparation and quality control of such preparation and, where appropriate, maximum storage time during which any intermediate preparation such as an eluate or the ready-to-use pharmaceutical will conform with its specifications.

36

In the case of an advanced therapy medicinal product for sale or supply in Great Britain—

(a) references in this Part of this Schedule to administration of a product include references to the advanced therapy medicinal product's use, application or implantation; and

(b) descriptions, instructions and warnings must include explanatory drawings and pictures where necessary.

SCHEDULE 8B — Modifications of Annex I to the 2001 Directive

Provision of Annex I	Modification subject to which that provision is to be read
Paragraph (1) of the Introduction and general principles	The reference to “Articles 8 and 10(1)” is to be read as a reference to regulation 50 of the Human Medicines Regulations 2012.
Paragraphs (1) and (2) of the Introduction and general principles	If the licensing authority has published guidelines under regulation 50(5B)(a) of the Human Medicines Regulations 2012, the reference to “the rules governing medicinal products in the European Community, Volume 2B, Notice to applicants, medicinal products for human use, presentation and content of the dossier, Common Technical Document” is to be read as a reference to that guidance.
Paragraph (4) of the Introduction and general principles	If the licensing authority has published guidelines under regulation 50(5B)(b) of the Human Medicines Regulations 2012, the reference to “the scientific guidelines relating to the quality, safety and efficacy of medicinal products for human use as adopted by the Committee for Proprietary Medicinal Products (CPMP) and the European Medicines Evaluation Agency (EMEA) and the other pharmaceutical Community guidelines published by the Commission in the different volumes of the rules governing medicinal products in the European Community” is to be read as a reference to those guidelines.
Paragraph (6) of the Introduction and general principles	The reference to “the requirements of Commission Directive 91/356/EEC laying down the principles of and guidelines of Good Manufacturing Practice for medicinal products for human use” is to be read as a reference to the Good Manufacturing Practice Directive, as defined in regulation 8(1) of the Human Medicines Regulations 2012.
Paragraph (6) of the Introduction and general principles	If the licensing authority has published principles and guidelines under regulation C17(1) of the Human Medicines Regulations 2012, the reference to “the principles and guidelines on GMP published by the Commission in the rules governing medicinal products in the European Community, Volume 4” is to be read as a reference to those principles and guidelines.
Paragraph (8) of the Introduction and general principles	References to “the European Community” are to be read as references to the United Kingdom.
Paragraph (8) of the Introduction and general principles	The references to “Directive 2001/20/EC of the European Parliament and of the Council on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use” are to be read as references to the Medicinal Products for Human Use (Clinical Trials) Regulations 2004.
Paragraph (9) of the Introduction and general principles	The reference to “Council Directives 87/18/EEC on the harmonisation of regulations and administrative provisions relating to the application of the principles of good laboratory practice and the verification of their application for tests in chemical substances and 88/320/EEC on the inspection and verification of good laboratory practice” is to be read as a reference to the Good Laboratory Practice Regulations 1999.
Paragraph (10) of the Introduction and general principles	The reference to “Council Directive 86/609/EEC of 24 November 1986 on the approximation of laws, regulation and administrative provisions of the Member States regarding the protection of animals for experimental and other scientific purposes” is to be read as a reference to the Animals (Scientific Procedures) Act 1986.
Paragraph (11) of the Introduction and general principles	The paragraph is to be read as follows: “In order to monitor the benefit/risk assessment, any new information not in the original application and all pharmacovigilance information shall be submitted to the licensing authority. After a marketing authorisation has been granted, any change to the data in the dossier shall be submitted to the licensing authority in accordance with the requirements of Schedule 10A to the Human Medicines Regulations 2012, as well as the requirements of Schedule 12A to those Regulations.”
Part I, paragraph 1.2, fourth paragraph	This paragraph is to be read as follows: “Annexed to the administrative data shall be copies of the manufacturing authorisation as defined in regulation 17 of the Human Medicines Regulations 2012.”
Part I, paragraph 1.3.1	The reference to “Article 11” is to be read as a reference to Part 2 of Schedule 8 to the Human Medicines Regulations 2012.
Part I, paragraph 1.3.2	The reference to “Title V” is to be read as a reference to Part I3 of the Human Medicines Regulations 2012, and the references to Articles 63 and 59 are to be read as references to regulations 260 and 266 of the Human Medicines Regulations 2012.
Part I, paragraph 1.3.4	This paragraph is to be read as omitted.
Part I, paragraph 1.4	The reference to “Article 12.2” is to be read as a reference to paragraph 11 of Schedule 8 to the Human Medicines Regulations 2012.
Part I, paragraph 2, first paragraph	The reference to “Article 12” is to be read as a reference to paragraph 11 of Schedule 8 to the Human Medicines Regulations 2012.
Part I, paragraph 3.2(5), first paragraph	The reference to a “Member State” is to be read as including the United Kingdom.
Part I, paragraph 3.2(5), second paragraph	The references to “the national pharmacopoeia of a Member State” are to be read as including references to the British Pharmacopoeia.
Part I, paragraph 3.2(6)	The reference to “the pharmacopoeia of a Member State” is to be read as including a reference to the British Pharmacopoeia.
Part I, paragraph 3.2(12)	The words “which is required by Community legislation” are to be read as omitted.
Part I, paragraph 3.2.1.2	If the licensing authority has published guidelines under regulation 50(5B)(c) of the Human Medicines Regulations 2012, the reference to “guidelines published by the Agency” is to be read as a reference to those guidelines.
Part I, paragraph 3.2.2.1, second paragraph	The reference to “Article 8(3)(c)” is to be read as a reference to paragraph 3 of Schedule 8 to the Human Medicines Regulations 2012.
Part I, paragraph 3.2.2.1, second paragraph, first indent	The reference to “the national pharmacopoeia of one of the Member States” is to be read as including the British Pharmacopoeia.
Part I, paragraph 3.2.2.1, fifth paragraph	The reference to “any Member State” is to be read as a reference to the United Kingdom and the reference to “the Member States” is to be read as a reference to the United Kingdom.
Part I, paragraph 3.2.2.3(a)	The reference to “Article 8(3)(d)” is to be read as a reference to paragraph 5 of Schedule 8 to the Human Medicines Regulations 2012.
Part I, paragraph 4.2.2, fifth paragraph	The reference to “this Directive” is to be read as a reference to the Human Medicines Regulations 2012.
Part I, paragraph 5.2(a)	The reference to “the clinical particulars provided pursuant to Articles 8(3)(i) and 10(1)” is to be read as a reference to those particulars provided pursuant to paragraph 10 of Schedule 8 to, and regulations 51A, 52A, 53A and 54 to 56 of, the Human Medicines Regulations 2012.
Part I, paragraph 5.2(c)	The references to “the European Community” are to be read as references to the United Kingdom.
Part I, paragraph 5.2(c), fifth paragraph	The reference to “Directive 2001/20/EC and implementing detail guidelines” is to be read as a reference to the Medicinal Products for Human Use (Clinical Trials) Regulations 2004.
Part I, paragraph 5.2.1, second paragraph	The reference to “Article 10(1)(a)” is to be read as a reference to regulation 51A of the Human Medicines Regulations 2012.
Part II, paragraph 1, first paragraph	The reference to “Article 10(1)(a)(ii)” is to be read as a reference to regulation 54 of the Human Medicines Regulations 2012.
Part II, paragraph 2(a)	The reference to “Article 10(1)(a)(i)” is to be read as a reference to regulation 56 of the Human Medicines Regulations 2012.
Part II, paragraph 2(b)	The reference to “Article 10(1)(a)(ii)” is to be read as a reference to regulation 51A of the Human Medicines Regulations 2012.
Part II, paragraph 4, first paragraph	The first sentence is to be read as omitted and the words “in accordance with regulation 53A of the Human Medicines Regulations 2012” are to be read as added at the end of the second sentence.
Part II, paragraph 5, first paragraph	The reference to “Article 10(1)(b)” is to be read as a reference to regulation 55 of the Human Medicines Regulations 2012.
Part II, paragraph 6, first paragraph	The reference to “Article 22” is to be read as a reference to regulation 60 of the Human Medicines Regulations 2012.
Part III, paragraph 1.1(a), first indent	The reference to “Directive 2000/70/EC of the European Parliament and of the Council of 16 November 2000 amending Council Directive 93/42/EC as regards medical devices incorporating stable derivatives of human blood or blood plasma” is to be read as a reference to the Medical Devices Regulations 2002.
Part III, paragraph 1.1(a), third indent	The reference to “the Agency or the competent authority” is to be read as a reference to the licensing authority.
Part III, paragraph 1.1(a), fourth indent	This indent is to be read as omitted.
Part III, paragraph 1.1(b)	The reference to “Article 109, as amended by Directive 2002/98/EC” is to be read as a reference to the Blood Safety and Quality Regulations 2005.
Part III, paragraph 1.1(b)(3), second paragraph	The reference to “medicinal products referred to in Article 2 of Directive 2001/20/EC of the European Parliament and of the Council relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use” is to be read as a reference to investigational medicinal products.
Part III, paragraph 1.1.(c), second indent	This indent is to be read as follows: “The Plasma Master File is subject to a scientific and technical evaluation by the licensing authority.”
Part III, paragraph 1.1(c), fourth indent	This indent is to be read as follows: “Changes subsequently introduced to the terms of a Plasma Master File must follow the variation procedure in Schedule 10A to the Human Medicines Regulations 2012.”
Part III, paragraph 1.1(c), final indent	This indent is to be read as omitted.
Part III, paragraph 1.2(c), first indent	The references to “a competent authority” and to “the Agency” are to be read as references to the licensing authority and the final two sentences are to be read as omitted.
Part III, paragraph 1.2(c), second indent	The reference to “the Community” is to be read as a reference to the United Kingdom.
Part III, paragraph 1.2(c), third indent	This indent is to be read as follows: “Changes in the content of a Vaccine Antigen Master File must follow the variation procedure in Schedule 10A to the Human Medicines Regulations 2012.”
Part III, paragraph 1.2(c), fourth indent	This indent is to be read as omitted.
Part III, paragraph 1.2(c), fifth indent	This indent is to be read as omitted.
Part III, paragraph 2.1	The reference to “applications based on Articles 6(2) and 9” is to be read as a reference to applications in relation to radionuclide generators, radionuclide kits, radionuclide precursors and radiopharmaceuticals.
Part III, paragraph 2.2, fourth paragraph	The reference to “Council Directives 87/18/EEC and 88/320/EEC” is to be read as a reference to the Good Laboratory Practice Regulations 1999.
Part III, paragraph 3, second paragraph	The reference to “Article 15” is to be read as a reference to regulation 103 of the Human Medicines Regulations 2012, the reference to “Article 14(1)” is to be read as a reference to regulation 102 of the Human Medicines Regulations 2012 and the words “referred to in Article 16(1)” are to be read as “which are not registerable homoeopathic medicinal products”.
Part III, paragraph 3(a)	The reference to “an official pharmacopoeia of a Member State” is to be read as including the British Pharmacopoeia and any pharmacopoeia used officially in a country that is included in a list published by the licensing authority for that purpose, and the reference to “the traditional names used in each Member State” is to be read as including the traditional name used in the United Kingdom.
Part III, paragraph 3(b), final paragraph	The reference to “an official pharmacopoeia of a Member State” is to be read as including the British Pharmacopoeia.
Part III, paragraph 3, penultimate paragraph	The reference to “Article 14(1)” is to be read as a reference to regulation 102 of the Human Medicines Regulations 2012.
Part III, paragraph 5, first indent	The reference to “an orphan medicinal product in the meaning of Regulation (EC) No 141/2000” is to be read as a reference to a medicinal product to which the orphan criteria are claimed to apply.
Part III, paragraph 5, second indent	The reference to “Article 10(1)(a)(ii)” is to be read as a reference to regulation 54 of the Human Medicines Regulations 2012 and the reference to “Article 5” is to be read as a reference to regulation 167 of the Human Medicines Regulations 2012.
Part IV, paragraph 1, first paragraph	The reference to “point (a) of Article 2(1) of Regulation (EC) No 1394/2007” is to be read as a reference to regulation 2A of the Human Medicines Regulations 2012.
Part IV, paragraph 2	This paragraph is to be read as omitted.
Part IV, paragraph 3.1, second paragraph	The reference to “Directive 2004/23/EC” is to be read as a reference to the Human Fertilisation and Embryology Act 1990and the Human Tissue (Quality and Safety for Human Application) Regulations 2007 and the reference to “Directive 2002/98/EC” is to be read as a reference to the Blood Safety and Quality Regulations 2005.
Part IV, paragraph 3.3.2.1(a)	The reference to “Directive 2004/23/EC” is to be read as a reference to the Human Fertilisation and Embryology Act 1990 and the Human Tissue (Quality and Safety for Human Application) Regulations 2007.
Part IV, paragraph 3.4.1, heading	The reference to “devices as referred to in Article 7 of Regulation (EC) No 1394/2007” is to be read as a reference to medical devices, bio-materials, scaffolds or matrices.
Part IV, paragraph 3.4.2, heading	The reference to “Article 2(1)(d) of Regulation (EC) No 1394/2007” is to be read as a reference to regulation 2A(10) of the Human Medicines Regulations 2012.
Part IV, paragraph 3.4.2(c)	The reference to “Commission Directive 2003/32/EC” is to be read as a reference to the Medical Devices Regulations 2002.
Part IV, paragraph 3.4.2(d)	The reference to “Directive 93/42/EEC or Directive 90/385/EEC” is to be read as a reference to the Medical Devices Regulations 2002.
Part IV, paragraph 3.4.2, final paragraph	The first sentence is to be read as follows: “The applicant shall make available on request of the licensing authority any information related to the assessment by the notified body which has carried out the assessment referred to in point (d) of this section.”

SCHEDULE 8C — Material to accompany an application for a UK marketing authorisation under the unfettered access route

1

A copy of the application submitted in connection with the granting of the ... UKMA(NI) which authorises the sale or supply of the medicinal product in Northern Ireland.

2

A copy of all material submitted in support of the application for the ... UKMA(NI) which authorises the sale or supply of the medicinal product in Northern Ireland.

3

A copy of the ... UKMA(NI) which authorises the sale or supply of the medicinal product in Northern Ireland.

SCHEDULE 9A — Meaning of terms used in the orphan criteria and in regulation 58D

Prevalence of a condition in Great Britain

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 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.

Potential for return on investment

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 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.

Existence of other methods of diagnosis, prevention or treatment

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 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—greater efficacy;greater safety in a substantial portion of the target population, as evidenced where appropriate through comparative clinical trials; orin 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 10A — Variations to a UK marketing authorisation

Interpretation

1

In this Schedule—

“change of, or addition of a new, route of administration”, in relation to parenteral administration, includes any change or addition as between intra-arterial, intra-venous, intramuscular, subcutaneous and any other route;

“extension of a UK marketing authorisation” or “extension” means a variation which consists of—a change to one or more active substances that involves—replacement of a chemical active substance by a different salt, ester, complex or derivative, with the same therapeutic moiety, where the efficacy and safety characteristics are not significantly different,replacement by a different isomer, a different mixture of isomers, of a mixture by an isolated isomer (for example, racemate by a single enantiomer), where the efficacy and safety characteristics are not significantly different,replacement of a biological active substance with one of a slightly different molecular structure where the efficacy and safety characteristics are not significantly different, with the exception of changes to the active substance of a seasonal, pre-pandemic or pandemic vaccine against human influenza,modification of the vector used to produce the antigen or the source material, including a new master cell bank from a different source, where the efficacy and safety characteristics are not significantly different,a new ligand or coupling mechanism for a radiopharmaceutical, where the efficacy and safety characteristics are not significantly different, orchange to the extraction solvent or the ratio of herbal drug to herbal drug preparation where the efficacy and safety characteristics are not significantly different; ora change to strength, pharmaceutical form and route of administration that involves—change of bioavailability,change of pharmacokinetics, for example change in rate of release,change or addition of a new strength or potency,change or addition of a new pharmaceutical form, orchange or addition of a new route of administration;

“holder” means UK marketing authorisation holder;

“major variation of type II” means a variation which is not an extension and which may have a significant impact on the quality, safety or efficacy of the medicinal product concerned namely—variations related to the addition of a new therapeutic indication or to the modification of an existing one;variations related to significant modifications of the summary of product characteristics due in particular to new quality, pre-clinical, clinical or pharmacovigilance findings;variations related to changes outside the range of approved specifications, limits or acceptance criteria;variations related to substantial changes to the manufacturing process, formulation, specifications or impurity profile of the active substance or finished medicinal product which may have a significant impact on the quality, safety or efficacy of the medicinal product;variations related to modifications in the manufacturing process or sites of the active substance for a biological medicinal product;variations related to the introduction of a new design space or the extension of an approved one, where the design space has been developed in accordance with international scientific guidelines; orvariations related to changes to the active substance of a seasonal, pre-pandemic or pandemic vaccine against human influenza;

“minor variation of type IA” means a variation which has only a minimal impact, or no impact at all, on the quality, safety or efficacy of the medicinal product concerned namely—variations of purely administrative nature that are related to the identity and contact details of—the holder,the manufacturer or supplier of any starting material, reagent, intermediate, active substance used in the manufacturing process or finished product;variations related to the identity, location and contact details of the qualified person for pharmacovigilance, or the location of the pharmacovigilance system master file;variations related to the deletion of any manufacturing site, including for an active substance, intermediate or finished product, packaging site, manufacturer responsible for batch release, site where batch control takes place;variations related to minor changes to an approved physico-chemical test procedure, where the updated procedure is demonstrated to be at least equivalent to the former test procedure, appropriate validation studies have been performed and the results show that the updated test procedure is at least equivalent to the former;variations related to changes made to the specifications of the active substance or of an excipient in order to comply with an update of the relevant monograph of the European Pharmacopoeia or of the British Pharmacopoeia, where the change is made exclusively to comply with the pharmacopoeia and the specifications for product specific properties are unchanged;variations related to changes in the packaging material not in contact with the finished product, which do not affect the delivery, use, safety or stability of the medicinal product;variations related to the tightening of specification limits, where the change is not a consequence of any commitment from previous assessment to review specification limits and does not result from unexpected events arising during manufacture;

“minor variation of type IB” means a variation which is not a minor variation of type IA, a major variation of type II nor an extension; and

“urgent safety restriction” means an interim change in the terms of the UK marketing authorisation due to new information having a bearing on the safe use of the medicinal product.

Classification of variations

2

(1) Except where sub-paragraph (2) applies, a variation which is not an extension, and whose classification is undetermined after—

(a) application of the provisions in this Schedule; and

(b) taking into account—

(i) the guidance referred to in regulation 65C(4) or (6) as the case may be), and

(ii) where relevant, any recommendations delivered pursuant to paragraph 3,

is to be treated by the licensing authority as a minor variation of type IB.

(2) The licensing authority must treat a variation that would otherwise fall within sub-paragraph (1) as a major variation of type II in the following cases—

(a) upon request from the holder when submitting the variation; or

(b) where the licensing authority concludes, following the assessment of validity of a notification in accordance with paragraph 7(1), and taking into account the recommendations given under paragraph 3, that the variation may have a significant impact on the quality, safety or efficacy of the medicinal product concerned.

Licensing authority recommendation on unclassified variations

3

(1) Prior to the submission of a variation whose classification is not provided for in this Schedule—

(a) the holder may request a recommendation on the classification of the variation from the licensing authority; and

(b) the licensing authority must notify the holder of its recommendation within 45 days of that request, beginning with the date on which the request is received by the licensing authority.

(2) The 45-day period referred to in sub-paragraph (1)(b) may be extended by 25 days where the licensing authority deems it necessary.

Variations leading to the revision of product information

4

Where a variation leads to the revision of the summary of product characteristics, labelling or the package leaflet, the revision must be considered by the licensing authority as part of that variation.

Grouping of variations

5

(1) Except where sub-paragraph (2) applies, where several variations are notified or applied for, a separate notification or application in accordance with paragraph 6, 7, 8 or 11 of this Schedule is to be submitted in respect of each variation sought.

(2) This sub-paragraph applies—

(a) where one or more of the same minor variations of type IA to the terms of one or more UK marketing authorisations owned by the same holder are notified at the same time to the licensing authority, in which case a single notification as referred to in paragraph 6 may cover all such variations;

(b) where several variations to the terms of the same UK marketing authorisation are submitted at the same time, a single submission may cover all such variations provided that the variations concerned fall within one of the relevant circumstances specified in sub-paragraph (3);

(c) where one or more of the same variation to the terms of one or more UK marketing authorisations held by the same holder are submitted at the same time and the variations do not fall within paragraph (a) or (b), a single submission may cover all such variations provided that the licensing authority agrees to such single submission.

(3) The relevant circumstances are—

(a) one of the variations in the group is an extension of the UK marketing authorisation;

(b) one of the variations in the group is a major variation of type II, but all other variations in the group are variations which are consequential to this major variation of type II;

(c) one of the variations in the group is a minor variation of type IB, but all other variations in the group are minor variations which are consequential to this minor variation of type IB;

(d) all variations in the group relate solely to changes of an administrative nature to the summary of product characteristics, labelling and package leaflet or insert;

(e) all variations in the group are changes to an Active Substance Master File, Vaccine Antigen Master File or Plasma Master File;

(f) all variations in the group relate to a project intended to improve the manufacturing process and the quality of the medicinal product concerned or one or more of its active substances;

(g) all variations in the group are changes affecting the quality of a human pandemic influenza vaccine;

(h) all variations in the group are changes to the pharmacovigilance system referred to in paragraph 12 of Schedule 8;

(i) all variations in the group are consequential to a given urgent safety restriction and submitted in accordance with paragraph 14;

(j) all variations in the group relate to the implementation of a given class labelling;

(k) all variations in the group are consequential to the assessment of a given periodic safety update report;

(l) all variations in the group are consequential to a given post-authorisation study conducted under the supervision of the holder;

(m) all variations in the group are consequential to a condition imposed under regulation 59(4C) or (4D).

(4) The submission referred to in sub-paragraph (2)(b) and (c) must be made by means of the following—

(a) a single notification in accordance with paragraph 7 where at least one of the variations is a minor variation of type IB and the remaining variations are minor variations;

(b) a single application in accordance with paragraph 8 where at least one of the variations is a major variation of type II and none of the variations is an extension; or

Notification procedure for minor variations of type IA

6

(1) Subject to sub-paragraph (2), where a minor variation of type IA is made, the holder must submit to the licensing authority a notification containing the elements listed in paragraph 9 within 12 months, beginning with the date on which the variation is implemented by the holder.

(2) The notification referred to in sub-paragraph (1) must be submitted immediately after the implementation of the variation in the case of minor variations requiring immediate notification for the continuous supervision of the medicinal product concerned.

(3) Within 30 days beginning with the date on which the licensing authority receives a notification under this paragraph, the measures provided for in paragraph 10 are to be taken.

Notification procedure for minor variations of type IB

7

(1) The holder must for minor variations of type IB submit to the licensing authority a notification containing the elements listed in paragraph 9, and if the notification contains those elements, the licensing authority must acknowledge receipt of a valid notification.

(2) If within 30 days beginning with the date on which the licensing authority acknowledges receipt of a valid notification, the licensing authority has not sent the holder an unfavourable opinion, the notification is deemed to be accepted by the licensing authority.

(3) Where the notification is accepted by the licensing authority, the measures provided for in paragraph 10 are to be taken.

(4) Where the licensing authority is of the opinion that the notification cannot be accepted, it must inform the holder, stating the grounds on which its unfavourable opinion is based.

(5) Within 30 days beginning with the date on which the holder receives the unfavourable opinion, the holder may submit to the licensing authority an amended notification in order to take due account of the grounds laid down in that opinion.

(6) If the holder does not amend the notification in accordance with sub-paragraph (5), the notification is deemed to be rejected.

(7) Where an amended notification has been submitted, the licensing authority must assess it within 30 days beginning with the date on which it receives the amended notification, and the measures provided for in paragraph 10 are to be taken.

(8) This paragraph does not apply where—

(a) a type IB variation request is submitted in a grouping that includes a variation type II and does not contain an extension: in such a case, the prior approval procedure in paragraph 8 applies; or

(b) a type IB variation request is submitted in a grouping that includes an extension: in such a case, the procedure in paragraph 11 applies.

Prior approval procedure for major variations of type II

8

(1) The holder must submit to the licensing authority an application containing the elements listed in paragraph 9, and if the application contains those elements, the licensing authority must acknowledge receipt of a valid application.

(2) Subject to sub-paragraph (3), within 60 days beginning with the date on which the licensing authority acknowledges receipt of a valid application under sub-paragraph (1), the licensing authority must conclude the assessment.

(3) The licensing authority may—

(a) reduce the period referred to in sub-paragraph (2), having regard to the urgency of the matter; or

(b) extend it to 90 days for—

(i) variations concerning a change to, or addition of, therapeutic indications, or

(ii) grouping of variations in accordance with paragraph 5(2)(c).

(4) Within the periods referred to in sub-paragraph (2) or (3), the licensing authority may request the holder to provide supplementary information within a time limit that it specifies, in which case—

(a) the procedure is suspended from the date on which such a request is made until the date on which that supplementary information has been provided; and

(b) the licensing authority may extend the period referred to in sub-paragraph (2) by the period for which the procedure is so suspended.

(5) Within 30 days beginning with the date on which the licensing authority concludes its assessment of the application, the measures provided for in paragraph 10 are to be taken.

(6) This paragraph does not apply where a type II variation request is submitted in a grouping that includes an extension: in such case, the procedure in paragraph 11 applies.

Elements to be submitted

9

An application or notification under this Schedule must include—

(a) a list of all the UK marketing authorisations affected by the notification or application;

(b) a description of all the variations submitted, including—

(i) in the case of minor variations of type IA, the date of implementation for each variation described,

(ii) in the case of minor variations of type IA which do not require immediate notification, a description of all minor variations of type IA made in the last 12 months to the terms of any affected UK marketing authorisation, such period beginning with the day on which the application or notification is submitted, and which have not been already notified,

(iii) any documents specified in guidance published under regulation 65C(4) or (6) (as the case may be), insofar as relevant to the type of variation notified or applied for,

(iv) where a variation leads to or is the consequence of other variations to the terms of the same UK marketing authorisation, a description of the relationship between those variations, and

(v) the relevant fee provided for in the Fees Regulations.

Measures to close the procedures specified in paragraphs 6 to 8

10

Where reference is made to this paragraph, the licensing authority must take the following measures—

(a) inform the holder as to whether the variation is accepted or rejected;

(b) where the variation is rejected, inform the holder of the grounds for the rejection; and

(c) where necessary, amend the decision granting the UK marketing authorisation in accordance with the accepted variation within the time limit laid down in paragraph 15.

Extensions of marketing authorisations

11

(1) An application for an extension of a UK marketing authorisation must be assessed by the licensing authority in accordance with the same or equivalent procedure that applied under Part 5 to the initial UK marketing authorisation to which it relates.

(2) An extension must either be granted a UK marketing authorisation in accordance with the same or equivalent procedure as for the granting of the initial UK marketing authorisation to which it relates, or be included in that initial UK marketing authorisation.

Human influenza vaccines

12

(1) By way of exception from paragraph 8, the procedure laid down in sub-paragraphs (2) to (4) applies to the examination of variations concerning changes to the active substance for the purposes of the annual update of a human influenza vaccine.

(2) The holder must submit to the licensing authority an application containing the elements listed in paragraph 9, and if it does so, the licensing authority must acknowledge receipt of a valid application.

(3) The licensing authority must assess the application submitted, and where it deems it necessary, the licensing authority may request additional data from the holder in order to complete its assessment.

(4) The licensing authority must—

(a) adopt a decision within 45 days, beginning with the date on which it receives a valid application; and

(b) take the measures provided for in paragraph 10.

(5) The 45-day period referred to in sub-paragraph (4) is to be suspended from the date on which the additional data referred to in sub-paragraph (3) is requested until the date on which that data is received by the licensing authority.

Pandemic situation with respect to human influenza

13

(1) By way of exception to the provisions of this Schedule, where a pandemic situation with respect to human influenza is duly recognised by the World Health Organisation, or the licensing authority, the licensing authority may exceptionally and temporarily accept a variation to the terms of a UK marketing authorisation for a human influenza vaccine, where certain non-clinical or clinical data are missing.

(2) Where a variation is accepted pursuant to sub-paragraph (1), the holder must submit the missing non-clinical and clinical data within a time limit set by the licensing authority.

Urgent safety restrictions

14

(1) Where, in the event of a risk to public health, the holder takes urgent safety restrictions on its own initiative, it must forthwith notify the licensing authority.

(2) If the licensing authority has not raised objections within 24 hours following receipt of that information, the urgent safety restrictions are deemed to be accepted.

(3) In the event of a risk to public health in relation to a medicinal product, the licensing authority may impose urgent safety restrictions on the holder of the UK marketing authorisation in respect of that product.

(4) Where an urgent safety restriction is taken by the holder, or imposed by the licensing authority, the holder must submit the corresponding application for variation within 15 days beginning with the date on which that restriction is initiated.

Amendments to the decision granting the marketing authorisation

15

(1) Amendments to the decision granting the UK marketing authorisation resulting from the procedures laid down in this Schedule must be made by the licensing authority—

(a) in the case of major variations of type II, within two months, beginning with the date on which the information referred to in paragraph 10(a) is sent to the holder; or

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The Human Medicines Regulations 2012

Addition of vitamins or minerals

List of herbal substances, preparations and combinations for use in traditional herbal medicinal products

Licensing authority list as to herbal substances, preparations and combinations for use in traditional herbal medicinal products

126A

Procedure where less than 15 years use of traditional herbal medicinal product

130A

Classification of traditional herbal registration

Establishment of herbal monographs

143A

Obligation following new herbal monograph

Obligation to provide information relating to safety etc

Obligation in relation to product information

Record-keeping obligations

Obligation to ensure appropriate and continued supplies

Urgent safety restrictions

148A

Requests from EU member States

186A

Recording obligations on holders

Reporting obligations on holders

Major safety review by the licensing authority

196A

EU urgent action procedure

Medicinal products subject to additional monitoring

Licensing authority power in relation to medicinal products subject to additional monitoring

202A

Further obligations in respect of pharmacovigilance activities

Further obligations in respect of pharmacovigilance activities

205A

Guidance in respect of pharmacovigilance

Guidance in respect of good pharmacovigilance practice and post authorisation efficacy studies

205B

Requirements for prescriptions: approved country health professional

Electronic Prescriptions: approved country health professionals

Application of Part

256ZA

Interpretation

Person who may sell medicinal products by information society services

Notification requirements for sellers of medicinal products at a distance

Procedure for listing persons who may supply medicinal products at a distance

Removal of a person’s entry from the list

Provision of information to the licensing authority

Grant or refusal to list a person

Conditions to be met by a person entered on the list

Power to suspend, vary or remove a person’s entry on the list

Procedure where the licensing authority proposes to suspend, vary or remove a person’s entry on the list

Suspension of a person’s entry on the list in cases of urgency

Variation of a person’s entry on the list on the application of that person

Offences: breach of regulations and false information

Penalties

Packaging requirements: advanced therapy medicinal products

257C

Guidance as to packaging and package leaflets

257D

Regulation-making power as to certain forms of labelling

257E

Packaging requirements: specific provisions

Packaging requirements: information for blind and partially sighted patients

Package leaflets

Use of pictures and symbols etc

Labelling requirements for radionuclides

Leaflets relating to radionuclides

Homoeopathic medicines

Additional requirements for traditional herbal medicinal products

Language requirements etc

Submission of mock-ups of packaging and leaflets to licensing authority

Offence relating to packaging and package leaflets in Northern Ireland: holder of authorisation etc

268A

Offences relating to packaging and package leaflets in Great Britain: other persons

Offences relating to packaging and package leaflets in Northern Ireland: other persons

269A

Non-compliance with requirements of this Part

Offences: penalties

Medicines with differing classification status in Great Britain and Northern Ireland

284A

Narcotic and psychotropic substances

Material relating to diagnosis

Material about effects of medicinal product

Material about status of medicinal product