Guidance

Types of application for marketing authorisations (legal basis of applications)

You must include the appropriate legal basis for your application when you apply to MHRA for a marketing authorisation.

From:
Medicines and Healthcare products Regulatory Agency
Published
30 March 2021
Last updated
30 June 2025 — See all updates

Applications submitted to MHRA for a marketing authorisation for a medicinal product must state the legal basis under which the application is made. The available legal bases are set out in the Human Medicines Regulations 2012 (as amended) (‘the HMRs’).

Regulations covering marketing authorisations (including homoeopathic national rules) are in Part 5 of the HMRs, certification of homoeopathic medicinal products in part 6 and registration of traditional herbal medicinal products in part 7.

Overview

The appropriate legal basis for a marketing authorisation (MA) application will depend on the type of application and will determine the nature and extent of the data required concerning the quality, safety and efficacy of the product to support the application.  The legal bases for a UK-wide MA applicable from 1 January 2025 are set out below, each one is explained in more detail in subsequent sections. 

For applications for Northern Ireland only (PLNIs) reference should also be made to Directive 2001/83/EC (as amended) on the Community code relating to medicinal products for human use and to guidance published by the European Commission

  • full application -  HMR Regulations 49 and 50 (previously Article 8(3) of Directive 2001/83/EC)
  • generic application – HMR Regulation 51 (application for UKMA(NI); regulation 51B (application for UKMA(UK)) (previously Article 10.1 of Directive 2001/83/EC)
  • hybrid application – HMR Regulation 52 (application for UKMA(NI)); regulation 52B (application for UKMA(UK)) (previously Article 10.3 of Directive 2001/83/EC)
  • similar biological application – HMR Regulation 53 (application for UKMA(NI)); regulation 53B (application for UKMA(UK)) (previously Article 10.4 of Directive 2001/83/EC)
  • well-established use application – HMR Regulation 54 (previously Article 10a of Directive 2001/83/EC)
  • fixed-combination application – HMR Regulation 55 (equivalent Article 10b of Directive 2001/83/EC)
  • informed consent application – HMR Regulation 56 (previously Article 10c of Directive 2001/83/EC)
  • traditional herbal registration – HMR Regulation 125 (previously Article 16a of Directive 2001/83/EC)
  • certificate of homeopathic medicinal products - (the Simplified Registration scheme) –  HMR Regulation 102 (previously Article 14(1) of Directive 2001/83/EC)
  • national homeopathic products (the National Rules Scheme) – HMR Regulation 50(6)(g) and Schedule 10 (previously Article 16(2) of Directive 2001/83/EC)

UK-EU Mapping Table- focused sections

Application Type Legal basis under Human Medicines Regulations 2012  (as amended) Legal basis under Directive 2001/81/EC (as amended)
Full (including mixed) application Regulation 50 Article 8(3)
Generic Regulation 51 - UK MA (NI)

Regulation 51B – UK MA(UK)		 Article 10(1)
Hybrid Regulation 52 - UK MA (NI)

Regulation 52B – UK MA (UK)		 Article 10(3)
Biosimilar Regulation 53 - UK MA (NI)

Regulation 53B – UK MA (UK)		 Article 10(4)
Well-Established Use (WEU) Regulation 54 Article 10a
Fixed Combination Regulation 55 Article 10b
Informed Consent Regulation 56 Article 10c
Homoeopathic National Rules Regulation 50(6)(g), Schedule 10 (National Rules Scheme [NR]) Article 16(2)
Homoeopathic Simplified Registration Regulation 103 (Simplified Registration Scheme [HR]) Article 14(1)
Traditional Herbal Registration Regulation 125   (Traditional Herbal Registration [THR]) Article 16a

2.1  Regulation 50 – A full or stand-alone application

Regulation 49(1)(a) of the HMRs sets out the power for the MHRA as the licensing authority for the UK to grant a marketing authorisation.  Data requirements are set out in Regulation 50 and Schedule 8 of the HMRs.

When a medicinal product has been granted a UK marketing authorisation under regulation 49(1)(a) in accordance with the provisions of regulation 50 (”the initial marketing authorisation”), any additional strengths, pharmaceutical forms, administration routes, presentations, variations and extensions in relation to which a UK marketing authorisation is granted under that regulation or which are included in the initial UK marketing authorisation, belong to the same ”global marketing authorisation”.

Any medicinal product which belongs to the global marketing authorisation is treated for the purposes of the application for generic, hybrid or biosimilar products as if it had been authorised on the date of authorisation of the medicinal product to which the initial marketing authorisation relates.  Refer to section 4 on circumstances where extensions to the periods of data protection or market exclusivity may be permitted.

Regulation 50 requires the applications to be supported by comprehensive pharmaceutical, non-clinical, and clinical data as set out in Schedule 8 of the HMRs in order to demonstrate that the product has a positive balance of benefit to risk in the indications claimed for. 

Supporting data may be all original data generated by, or for, the MA applicant (referred to as a full application) or it may be a combination of original data and information available in the public domain (referred to as a mixed application).  Information such as public assessment reports published by competent authorities and any published information still within a data protection period cannot be used for this purpose.   

The data should have been generated in line with current clinical knowledge and scientific guidelines.

Products authorised under this legal basis can be cited as reference medicinal products for generic, hybrid and biosimilar applications once the 8-year period of data exclusivity has expired.  The products may not be marketed until a further period of market exclusivity has expired.

New active substances are generally expected to be submitted under this regulation, but it may also be appropriate for example, for new uses and presentations of established medicinal substances.  A new active substance is an active substance that has not been previously authorised in the UK.

Additional requirements apply in specific circumstances:

  • Regulation 50A, 50B, 50C & 50D – Paediatric Investigation Plans (PIPs) and waivers

Circumstances relating to whether there is a requirement to investigate the use of the medicinal product in children.

See Procedures for UK paediatric investigation plan (PIPs).

  • Regulation 50E – Paediatric Use Marketing Authorisation (PUMAs)

Relating to a marketing authorisation with appropriate dosage forms developed exclusively for use in children. 

  • Regulation 50F – Other applications with paediatric indications
  • Regulation 50G – Orphan medicinal products

Requirements and rewards for products that have been developed to treat rare diseases.

See Orphan medicinal products

  • Regulation 50H – Advanced Therapy Medicinal Products (ATMPs)

Relating to additional requirements on follow up of efficacy of the product and any adverse reactions to it.

Guidance on licensing of ATMPs in UK including the classification of products falling within the definition of an ATMP.

See Advanced therapy medicinal products: regulation and licensing in UK

  • Regulation 50I – Conditional Marketing Authorisations (CMAs)

Relating to circumstances where comprehensive clinical data referring to the safety and efficacy of the medicinal product have not been supplied;

See Conditional marketing authorisations, exceptional circumstances MAs, scientific advice

Refer also to Regulation 60 below on Exceptional Circumstances.

  • Regulation 50J - Medicinal products containing or consisting of genetically modified organisms

Relating to environmental consents and environmental risk assessments for these products.  

2.2  Regulation 51B – A generic application

Generic applications are based on a derogation from the requirements for a full application.   Applicants for a UK-wide MA for a generic medicinal product may omit from their application the results of pre-clinical tests and of clinical trials if the product can be shown to be a generic of a reference medicinal product (RMP) which is or has been authorised in the UK for not less than eight years under regulation 49(1)(a).  

The generic product is one that:

  • has the same active substance* as the reference medicinal product**
  • has the same pharmaceutical form as the reference medicinal product
  • has been shown to be bioequivalent to the reference medicinal product

For the purpose of demonstrating bioequivalence under this legal basis, the various immediate-release oral pharmaceutical forms are considered to be the same pharmaceutical form.

*Under this regulation a salt, ester, ether, isomer, mixture of isomers, complex or derivative of an authorised active substance are regarded as the same active substance unless they differ significantly in properties with regard to safety or efficacy from the active substance in the reference medicinal product.  In that case the application must supply additional information providing proof of the safety or efficacy of the salt, ester, ether, isomer, mixture of isomers, complex or derivative.

**A reference medicinal product is a product that has been authorised on the basis of a full application (that is a product authorised under Regulations 50 as a full or mixed dossier), 54 (well-established use), 55 (fixed combination) or 56 (informed consent providing that the original dossier was not a generic, hybrid or biosimilar).

If an application for grant or variation of a UKMA is made in relation to a new indication for a well-established substance; and significant pre-clinical or clinical studies were carried out in relation to the new indication, a generic submission for the substance may not refer to those studies for one year from the date on which the new indication was approved. (Regulation 51B(8))

Bioequivalence studies should be conducted in line with the following guidelines published by the European Medicines Agency and the International Council for Harmonisation of technical requirements for pharmaceuticals for human use (ICH):  

Bioavailability studies may be omitted if the applicant can demonstrate that the generic medicinal product meets the relevant criteria as specified in the above guidelines.

The MHRA may publish guidelines specifying the criteria to be met by generic medicinal products for the purpose of omitting bioavailability studies from an application. Until that time, the above guidelines continue to apply.  

The generic product must not be sold or supplied, or offered for sale or supply, in the UK before the expiry of ten years beginning with the date on which the UK marketing authorisation for the reference medicinal product was granted (Regulation 51B(6) HMRs). Refer to section 4 concerning extensions to expiry dates.

At the time of authorisation, a generic medicinal product cannot be authorised for different or more extensive indications than those authorised for the reference medicinal product.  Indications can be amended subsequently through a post-authorisation variation application supported by relevant data. 

Where the UK RMP is a converted Union authorisation (a centrally authorised product (CAP)), the data and market exclusivity period which was in effect on 31 December 2020 will apply unless market exclusivity has been subsequently extended through an application direct to MHRA (refer to section 4)

2.3 Regulation 52B – A hybrid application

A hybrid application for a medicinal product can be made when the active substance is the same as that in a reference medicinal product but the strict definition of a generic medicinal product is not met.  This covers cases where:

  • bioequivalence to the reference medicinal product cannot be demonstrated through bioavailability studies, for example, because the product acts locally. This legal basis should not be used for applications for which it is feasible to demonstrate bioequivalence through bioavailability studies, but the applicant failed to submit results of such studies successfully demonstrating bioequivalence.
  • the product differs from the reference medicinal product for example because:
    • the active substance is a different strength
    • The active substance is a different salt, ester, isomer, mixtures of isomer, complex or derivative which differs significantly in properties with regard to safety and/or efficacy from the active substance in the reference medicinal product.
    • the pharmaceutical form and/or route of administration differ
    • the clinical indications are different***

The definition of the reference medicinal product and the periods of data exclusivity and market protection apply as in the case of a generic application (Regulation 52B HMRs). Where the UK RMP is a converted Union authorisation (a centrally authorised product (CAP)), the data and market exclusivity period which was in effect on 31 December 2020 will apply unless market exclusivity has been subsequently extended through an application direct to MHRA.

Depending on the reason for a submission under this legal basis, module 4 (pre-clinical) and module 5 (clinical) of the submission should include appropriate original data to support the application and the proposed indications and posology.

***If an application for grant or variation of a UKMA is made in relation to a new indication for a well-established substance; and significant pre-clinical or clinical studies were carried out in relation to the new indication, a hybrid submission for the substance may not refer to those studies for one year from the date on which the new indication was approved. (Regulation 51B(8)).

2.4 Regulation 53B - Biosimilar Applications

A biosimilar application can be made for a biological medicinal product which cannot meet the definition of a generic medicinal product owing to differences relating to raw materials or differences in manufacturing processes when compared to the reference medicinal product (RMP).

The principle of a biosimilar development programme is to establish similarity between the biosimilar and the RMP based on a comprehensive comparability exercise, ensuring that the previously proven safety and efficacy of the RMP also apply to the biosimilar. This includes a comprehensive physicochemical and biological characterisation, and a pivotal comparative pharmacokinetic (PK) study which may include the measurement of pharmacodynamic (PD) markers, if available. In most cases a comparative efficacy trial may not be necessary if sound scientific rationale supports this approach.

The definition of the RMP and the period of data exclusivity and market protection apply as in the case of a generic application. Where the UK RMP is a converted Union authorisation (a centrally authorised product (CAP)), the data and market exclusivity period which was in effect on 31 December 2020 will apply unless market exclusivity has been subsequently extended through an application direct to MHRA.

The biosimilar medicinal product cannot be authorised for different or more extensive indications than those authorised for the reference medicinal product.

If an application for grant or variation of a UKMA is made in relation to a new indication for a well-established substance; and significant pre-clinical or clinical studies were carried out in relation to the new indication, a biosimilar submission for the substance may not refer to those studies for one year from the date on which the new indication was approved.  (Regulation 51B(8))

2.5 Regulation 54 – Well-established Use

This legal basis can be used for applications for medicinal products containing active substances that have been in well-established use in the UK and/or the EU for at least 10 years with recognised efficacy and an acceptable level of safety in the claimed indications. 

They must be supported by appropriate scientific literature to replace pre-clinical tests and clinical trials for the specific therapeutic use claimed.  Except for comparability studies with other products to show relevance of the literature to the proposed product, original non-clinical or clinical trials data cannot be submitted.  If original data are needed to supplement the scientific literature on safety or efficacy then an alternative legal basis should be used. Submission under Regulation 50 or Regulation 52B could be considered. 

The evidence provided must demonstrate systematic and documented use. The nature and extent of supporting data must consider the prevalence of the condition to be treated, the time over which the substance has been used, quantitative aspects of the use including geographic spread and degree of scientific interest and the coherence of scientific assessments. Use should be shown to be continuous and whilst it may include some evidence of unlicensed use, the extent of pharmacovigilance monitoring is relevant.

Information such as public assessment reports published by competent authorities and any published information still within a data protection period cannot be used as evidence to support a well-established use application.   

Authorisations granted under Regulation 54 can be used as reference medicinal products after the 8-year period of data protection has expired.  A product referring to such an RMP may not be marketed until the further period of market exclusivity has expired.

2.6 Regulation 55 – Fixed Combination Products

In the case of medicinal products containing active substances used in authorised medicinal products, but not previously used in the proposed combination for therapeutic purposes, the results of new pre-clinical tests or new clinical trials relating to that combination must be provided in accordance with Regulation 50 and Schedule 8 of the HMRs.  It is not necessary to provide scientific references relating to each individual active substance.  An application made under this legal basis cannot rely solely on references to scientific literature.  If the supporting evidence comprises only scientific literature, the application could be made under Regulation 54, provided that all other requirements of that regulation are met.

The application must be for the combination of active substances within a single pharmaceutical form, not a co-packaged combination of two (or more) separate medicinal products.

Authorisations granted under this regulation can be used as reference medicinal products after the 8-year period of data exclusivity has expired. A product referring to such an RMP may not be marketed until a further period of market exclusivity has expired.

2.7 Regulation 56 - Informed Consent

A marketing authorisation holder may permit another marketing authorisation applicant to make use of their pharmaceutical, pre-clinical and clinical documentation to obtain a marketing authorisation.  Both medicinal products (i.e the authorised medicinal product and the product to be applied for) must have the same qualitative and quantitative composition in terms of active substance(s), and the same pharmaceutical form.

All other licence details of the two products must be identical with the exception of the following, if supported with appropriate documentation:

  • name and address of the Marketing Authorisation Holder
  • product name (must be different if an invented name is used)
  • sites of assembly and importation
  • sites for batch release and control testing
  • identification markings on solid dosage forms
  • simple change of flavour

A letter of consent confirming permanent access of the applicant to the data supporting the already authorised product for the purpose of an informed consent application and possession of Module 3 of the data is required. 

An informed consent application can only be made in relation to a currently authorised product in the UK.

2.8 Regulation 125  - Traditional herbal registrations

An application for a traditional herbal registration can be made for herbal medicinal products with a long tradition of use.  The applications must be supported by evidence demonstrating 30 years of continuous medicinal use of the product (or a corresponding product) including at least 15 years continuous medicinal use within the EU/EEA.

The claimed indications must be conditions that do not need the diagnosis or supervision of a medical practitioner i.e.  indicated for the relief of minor conditions/symptoms.

Further guidance has been published in Apply for a traditional herbal registration (THR)

2.9 Regulation 102- Certificate of homeopathic medicinal products (the Simplified Registration scheme)

An application through the simplified registration scheme can be made for homoeopathic medicinal products which meet the definition of a homeopathic medicinal product given in the Human Medicines Regulations. The product must be:

  • placed on the market without therapeutic indications
  • administered orally or externally
  • sufficiently dilute to guarantee safety

Further guidance has been published in Register a homeopathic medicine.

2.10 Regulation 50(6)(g) and Schedule 10 - National homeopathic products (the National Rules Scheme)

Applications through the UK Homeopathic National Rules Scheme can be made for any homeopathic medicinal product which meets the definition of a homeopathic medicinal product given in the Human Medicines Regulations and does not satisfy the requirements of the Simplified Homeopathic Registration Scheme (Regulation 103 of the HMRs). Products must be indicated for the relief or treatment of minor symptoms or minor conditions which can be relieved or treated without the supervision of a medical practitioner.

Further guidance has been published in The UK Homeopathic National Rules Scheme.

3. Submission of a duplicate application

A duplicate application is not defined in the Human Medicines Regulations.  In practice it is an application supported by the same dossier as another application or authorised product leading to an independent marketing authorisation.  It is distinguished from an informed consent application submitted under Regulation 56 in that it is submitted under the same legal basis as the first application and must be supported by a copy of all modules of the application. These must be identical to the first application or authorisation except for the product name of the duplicate which (if an invented name) must be different from the product name of the first product.

Applicants should indicate in the cover letter that the application is a duplicate and include a declaration that the dossier is identical to the first application or marketing authorisation.

Submission of duplicates of products with Northern Ireland as a Concerned Member State should consider guidance applicable in the EU.

4. Extensions to the periods of data protection or market exclusivity of marketing authorisations

Under certain circumstances the period of 10 years of market exclusivity from authorisation of the first medicinal product in the global marketing authorisation is extended:

New indications added by the MA Holder

If during the first eight of the ten years referred to above the marketing authorisation holder for the reference medicinal product obtains UK authorisation for one or more new therapeutic indications; and during the scientific evaluation prior to their authorisation, the MHRA considers the new indications bring a significant clinical benefit in comparison with existing therapies, the period of ten years of market exclusivity is extended to eleven years.  This extension is only awarded once even if further new indications are authorised. (Regulation 51B(7) HMRs)

Paediatric studies conducted on an orphan medicinal product.

In the case of products authorised as orphan medicinal products, the market exclusivity period is extended by two additional years for an orphan-designated condition when the results of specific studies are reflected in the summary of product characteristics (SmPC) addressing the paediatric population and completed in accordance with a fully compliant paediatric investigation plan (PIP, Regulation 58D(5)). 

Where a change of classification of a medicinal product has been authorised on the basis of significant pre-clinical tests or clinical trials, the MHRA shall not refer to the results of those studies when examining another application by another applicant for a change of classification of the same substance for one year after the initial change was authorised. (Regulation 64A(5)).

New indication for a well-established substance

If an application for authorisation or variation of a UKMA is made in relation to a new indication for a well-established substance and significant pre-clinical or clinical studies were carried out in relation to the new indication, a generic applicant for the substance may not refer to those studies for one year from the date on which the new indication was approved.  In this context, a well-established substance is considered to be either (i) a substance in a medicinal product authorised under Regulation 54 or (ii) a substance in a medicinal product authorised under another regulation but not within a period of data protection (Regulation 51B(8)).

Further information

Questions about the legal basis for submissions should be submitted by email to RIS.NA@mhra.gov.uk.

Updates to this page

Published 30 March 2021
Last updated 30 June 2025 show all updates

  1. Additional information on the definition of each legal basis and requirements for supporting data.

  2. Regulations 51 to 53 have been updated to reflect the different types of application.

  3. First published.

Sign up for emails or print this page

Contents

Related content