Consultation outcome

Consultation document: MHRA guidance on the licensing of biosimilar products

Updated 10 May 2021

1. Introduction

The purpose of this guidance is to provide developers of similar biological medicinal products (also known as biosimilars) with a clear outline of the requirements for biosimilar products in the UK.

Applicants should also take into account the principles contained within the Committee for Medicinal Products for Human Use (CHMP) guidelines:

• Guideline on similar biological medicinal products
• Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues
• Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues
• Guideline on immunogenicity assessment of therapeutic proteins
• relevant product-specific biosimilar guidelines

This UK guidance contains some revisions to these CHMP guidance documents, to be implemented at the end of the transition period (1 January 2021). These revisions take into account the scientific and regulatory experience gained since the first biosimilar product was licensed in 2006, with complex biosimilars licensed from 2013.

Clarification about this guidance can be sought by sending an email to MHRA in the first instance: [email protected]; or by seeking MHRA scientific advice.

2. General principles

2.1 Legislative requirements

Please refer to UK legislation - specifically to the Human Medicines Regulations 2012, as amended by the Human Medicines (Amendment etc.) (EU Exit) Regulations 2019, SI 775.

Applications for biosimilar products should conform to Regulation 58, amending Regulation 53 of The Human Medicines Regulations 2012.

For risk management, refer to HMR Schedule 8 paragraphs 12 and 13; regulations 59(2)(6), 61(1)(14), regulation 59(4A)(4B); regulation 59(4D)(4E); HMR 182(2) and 203(2)(d); Schedule 12A paragraphs 22, 23, 24 and 25.

2.2 Choice of Reference Medicinal Product

The Reference Medicinal Product, or Reference Product (RP), should comply with Regulation 48 of the Human Medicines Regulations 2012, as amended by the Human Medicines (Amendment etc.) (EU Exit), SI 775 Regulations 2019. This includes:

• products that are, or have been, authorised for at least 8 years in the UK (including those authorised by conversion from EU marketing authorisations)
• products that had an EU marketing authorisation at the end of the transition period, but which did not convert into a UK product licence, as the marketing authorisation holder opted out of the process
• products for which an EU marketing authorisation had ceased to be in force before the end of the transition period, for reasons not relating to quality, safety or efficacy

The UK RP (or an RP representative of the UK product) must be used for the comprehensive physicochemical and biological comparability studies, including in vitro analysis. This could include an RP sourced from the EU with evidence that the RP is licensed in the EU via the centralised procedure. In order to use a non-UK RP in clinical studies, evidence should be provided that the non-UK RP is representative of the UK RP, with suitable analytical bridging data. Note that all non-UK RPs must be authorised in and sourced from a country with similar scientific and regulatory standards as the UK (examples would be EU/EEA countries, Switzerland, USA, Canada, Australia, and Japan).

The RP must have been authorised on the basis of a complete dossier (i.e., Common Technical Document (CTD) Modules 3, 4 and 5, in addition to Modules 1 and 2).

Data and market exclusivity period entitlements for RPs approved before the date of EU exit will continue to apply in the UK.

2.3 Biosimilarity principles

A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product (the reference product (RP)) in the UK. The guiding principle of a biosimilar development programme is to establish similarity between the biosimilar and the RP based on a comprehensive comparability exercise, ensuring that the previously proven safety and efficacy of the RP also apply to the biosimilar.

A biosimilar should be highly similar to the RP in physicochemical properties, biological activity/potency and clinical profiles. In addition, biosimilar development requires that the impurity profile and the nature of excipients of the biosimilar itself do not give rise to concerns. Any observed differences must be duly justified with regard to their potential impact on safety and efficacy.

The active substance of a biosimilar must be highly similar, in molecular and biological terms, to the active substance of the RP. For example, for an active substance that is a protein, the amino acid sequence is expected to be the same.

The posology and route of administration of the biosimilar must be the same as those of the RP. Deviations from the RP that regard strength, pharmaceutical form, formulation, excipients or presentation require justification and may need additional data.

There is no regulatory requirement to repeat the demonstration of biosimilarity against the RP (for example, in the context of a change in the manufacturing process), once a UK product licence for the biosimilar has been granted.

In order to support pharmacovigilance monitoring, all appropriate measures should be taken to clearly identify any biological medicinal product which is the subject of a suspected adverse reaction report, with due regard to its brand name and batch number.

3. Content of a biosimilar application

3.1 Quality

The CHMP guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues, lays down the quality requirements for a biological medicinal product claiming to be similar to a RP already granted a marketing authorisation on the basis of a complete dossier. This guideline also details the requirements for the manufacturing processes of a biosimilar product and analytical considerations for the expected comparability exercise, including physicochemical properties, purity/impurities, quantity, biological activity and immunochemical properties (where relevant). These remain valid and will not be repeated in this UK guidance.

The guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues addresses the extent of the non-clinical studies required to confirm biosimilarity. Differences observed in the physicochemical and biological analyses will require additional in vitro studies, taking into consideration the mechanism of action of the active substance in all the authorised indications of the RP and pathogenesis of the diseases included in the therapeutic indications.

The in vitro studies are more appropriately addressed alongside the related quality data in the biosimilar comparability evaluation (CTD Module 3.2.R) and there should not be separate in vitro data reported in the non-clinical (CTD Module 4) section.

Reference medicinal product

The RP used in the biosimilar comparability exercise at the quality level must be clearly identified. For example, it should include the brand name, batch/lot number, source (country where purchased), pharmaceutical form, formulation, strength, number and age of batches at the time of analysis. Where several strengths or presentations are available, their selection should be appropriately justified.

Multiple different batches/lots of RP should be sourced from the appropriate market over a period of time (months to years) to reflect the manufacturing variability of the RP. The RP batches should be stored under the recommended (label) conditions and tested within their approved shelf life. The age of the RP batches (relative to expiry dates) at the time of testing should be considered during the analysis. All RP analytical data generated should be presented in the dossier, in summary tables and annexes.

The mechanism(s) of action (MOA) should be known and demonstrable, if possible. Critical quality attributes (CQA) should be defined at an analytical and in vitro functional level. Functional assays should be relevant to the MOA in all therapeutic indications (for example, ADCC, CDC, antibody-dependent cellular phagocytosis (ADCP), binding to Fc receptors, apoptosis etc.).

Multiple different batches of the RP should be used in order to generate a representative quality target product profile (QTPP) and provide robust comparability data. The number of RP batches regarded as sufficient depends on the quality attribute tested and the data generated (for example, fewer batches of RP would be required for confirmation of higher order structure). For CQA, multiple (tens of) batches sourced over a suitable period of time would be required to provide robust comparability data. Exceptions can be justified in certain cases (for example, orphan drug products).

Analytical methods need to be sensitive, qualified and sufficiently discriminatory to detect possible differences. Robust data require the application of suitable orthogonal methods.

Biosimilar comparability exercise

An extensive comparability exercise is required to demonstrate that the biosimilar has a highly similar quality profile when compared to the RP. This should include comprehensive analyses of the proposed biosimilar and RP, using state-of-the-art methods with suitable sensitivity and orthogonal methods to determine not only similarities but also potential differences in quality attributes. These analyses should include side-by-side comparative studies unless otherwise justified.

Quantitative ranges should be established for the biosimilar comparability exercise, where possible. These ranges should be based primarily on the quality attribute ranges measured for the RP and should not be wider than the range of variability of the RP batches (the QTPP), unless otherwise justified. The relevance of the ranges should be discussed, taking into account the number of RP batches tested, the quality attribute investigated, the age of the batches at the time of testing and the test method used. A descriptive statistical approach to establish ranges for quality attributes can be used, if appropriately justified. However, wide similarity ranges based on inappropriate statistical methods should not be used.

Ideally, batches of the biosimilar candidate would undergo analysis of biological activity (for example, cell-based assays) and in vitro functional activity at the same time as RP batches. Otherwise, an established and characterised reference standard, calibrated against international reference standards wherever possible, should be employed to minimise day-to-day assay variability.

All relevant batches of the biosimilar candidate, including clinical study batches, stability batches and process performance qualification batches (manufactured at the proposed commercial scale and site) should be analysed and compared with the RP.

Any differences detected in the quality attributes have to be appropriately justified with regard to their potential impact on safety and efficacy. It is not expected that all quality attributes of the biosimilar product are identical to the RP. However, where qualitative and/or quantitative differences are detected, these need to be justified as unlikely to impact on clinical efficacy and safety, based on characterisation and/or in vitro analysis and available literature.

Any differences which may have an impact on clinical safety and efficacy (for example, increased levels of aggregation or impurities) should be reduced by modifications in the manufacturing process, rather than being justified.

The potential impact of a different formulation/excipient(s) should be discussed in terms of product stability and compatibility, as well as clinical efficacy and safety.

Release/stability specification limits

It should be noted that similarity ranges used for the biosimilar comparability exercise should be handled separately from release and stability specifications of the biosimilar product (CTD Module 3.2.P.5.1). Release and stability specification limits should be based on biosimilar batch data, but can also take into consideration data generated from the RP during the biosimilar comparability studies, with limits set to prevent future drift/shift in critical quality attributes after demonstration of biosimilar comparability at the time of granting a UK product license.

The specification limits should be suitably justified at the time of approval of the biosimilar, since afterwards each product will have their own lifecycle.

3.2 Non-clinical

This section of the guidance describes the expected content of Module 4 submitted to the MHRA for consideration of a UK licence for a biosimilar product.

All in vitro pharmacology studies should be presented in Module 3; this includes studies that are comparative in nature between the biosimilar and the RP and those conducted only with the biosimilar. As the same data should not be presented in both Modules 3 and 4, it is acceptable for Module 4 to contain no experimental results.

No in vivo studies from animals are requested as these are not relevant for showing comparability between a biosimilar candidate and its RP: this includes pharmacodynamic studies, kinetic studies and toxicity studies. However, where toxicity studies have been done in compliance with Good Laboratory Practice (GLP), study reports are to be submitted. It is not expected that any review of these would elicit questions from the MHRA, as it is a given that such studies do not contribute to an understanding of comparability. Where such studies have been done with a RP that is not the same as that in the UK, this should be stated in the non-clinical overview in Module 2.

The non-clinical overview, in Module 2, should be brief but it should explain why any in vivo studies were done (for example, at the request of another regulatory body) and it should give a discussion of the reasons for use of any excipient used in the biosimilar product that is not in the RP.

Where investigations in the quality dataset suggest the possibility that a biosimilar candidate may not be highly similar to the RP, conduct of in vivo studies in animals does not contribute to resolving this and in vivo studies should not be done with this intent. If there are a number of differences, or differences which cannot be ruled out as having no clinical impact, development as a new biological product should be considered. Safety studies should not be done to characterise a newly identified impurity in either the RP or the biosimilar candidate.

Excipients

Use of excipient(s) in the proposed biosimilar product that are not used in the RP is not encouraged. However, where different excipient(s) are used, a discussion should be presented that addresses the safety of that excipient by the route intended. It is anticipated that in most instances, there will be use of the excipient(s) by the route intended at similar amounts with other products and if so, a discussion to establish this can be sufficient. However, if a novel excipient, or a novel route for an excipient, is used in the proposed biosimilar product, this should be justified, and includes the possibility that results from new safety studies are presented, if appropriate. As studies intended to characterise the safety of the excipient, compliance with GLP is expected.

Relation to other guidelines

The MHRA is aware that a range of guidelines may exist that require in vivo studies to support development of biosimilar products. The MHRA is aware that companies will not develop products only for the UK market and that developers need to meet requirements of other regulators. Nevertheless, the content of Module 4 for the UK can be limited to those studies that are GLP compliant, requirements of other regulators notwithstanding. In this case, Module 4 in the UK may not be part of the CTD supporting the product in other regions and the MHRA will accept this deviation.

3.3 Clinical

Confirmatory PK trial

The clinical comparability exercise should always include a pivotal comparative PK trial, which may include the measurement of PD markers if available. It is strongly recommended to use biosimilar product derived from the commercial manufacturing process representing the quality profile of the batches to be commercialised.

The PK trial should be designed to demonstrate equivalence to the RP. The design should be robust and justified, including the choice of crossover or parallel design. A crossover design is more sensitive to detect differences but may not be suitable for RPs with a long half-life or notable immune response. If appropriate population PK or PK-PD models are available for the RP in the literature, modelling and simulation should be considered for optimising study design - for example, selection of the most sensitive dose(s) and study population to detect PK differences, and choice of sample size. Linear (nonspecific) clearance and nonlinear (target-mediated) clearance should be addressed - for example, through dose selection and assessment of partial areas under the curve (AUCs). Protein content adjustments or covariates to be used in the statistical analysis of a parallel group trial (e.g., body weight, subject sex) should be predefined in the statistical analysis plan. The equivalence margins must be prespecified; an interval of 80.00 - 125.00% is generally acceptable but narrower limits may sometimes be required.

The PK trial should demonstrate equivalence of the primary PK parameters, usually AUC0-∞ and Cmax . Extrapolated AUC0-∞ >20% in >20% of observations requires discussion of the validity of the study. In the event of a failed PK study (i.e., 90% confidence intervals for the primary PK parameters are not contained completely within the pre-specified acceptance limits), root cause analysis should be provided with conclusions adequately reflected in the planning and conduct of a subsequent PK study. If no root cause is identified and another study is conducted and is positive, the initial study should not be ignored when reaching conclusions on PK similarity.

If available, PD parameters can be measured during the PK trial and descriptive results should be presented to support a conclusion of biosimilarity.

In all cases, safety and immunogenicity data should be collected during this trial and should be presented. These specifically include injection site or infusion-related reactions, anti-drug antibody (ADA) rate and kinetics as well as assessment of their impact on PK (and PD) through prespecified group analysis of ADA-negative and -positive subjects.

Confirmatory efficacy trial

In most cases, a comparative efficacy trial is not considered necessary. A well-argued justification for the absence of an efficacy trial should be appended to CTD Module 1 of the submitted application. Applicants are encouraged to seek scientific advice to discuss this approach as soon as they have sufficient comparative analytical and functional data to support it. However, final acceptance of this approach would only be considered after submission of the complete data package. The general principles to be used in this justification are summarised hereafter.

Justification for comparable efficacy:

Although precise correlations between clinical efficacy and pharmacological effects are usually lacking, the efficacy of the RP can usually be derived from its MOAs. Therefore, a justification should be provided that comparable efficacy can be derived from comparable binding properties and functional characteristics. Any observed differences must be justified as not clinically relevant, based on specific experiments and available literature.

Justification for comparable safety and immunogenicity:

The safety profile of the RP is largely predicted from on-target side effects, i.e., exaggerated and adverse pharmacologic effects at the target, including on normal tissues. Other common adverse drug reactions are injection-related reactions, which are triggered by various mechanisms, some being mediated by ADAs. Extensive clinical experience with the RP informs a risk-based assessment of the immunogenicity of the biosimilar, potential rates of binding or neutralising ADAs and their clinical relevance.

The quality attributes, including drug product release characteristics (protein aggregates, impurities), and formulation of the biosimilar candidate should form the basis for justification that safety and immunogenicity are comparable to those of the RP.

This argument should be supported by data from the confirmatory PK trial showing comparable safety and immunogenicity to the RP.

Need for an efficacy or safety trial:

There may still be cases requiring a comparative efficacy/safety trial, for example, where the main MOA of the RP is not known or where it is difficult to predict the impact of analytical differences which have not been resolved by adaptations to the manufacturing process.

Exceptionally, additional clinical safety data may be required where safety uncertainties cannot be resolved without patient exposure pre-licensing. For example, where serious ADRs to the RP have unpredictable root causes (e.g., pure red cell aplasia with epoetin), exposure of a significant patient cohort to the biosimilar candidate is considered the most appropriate approach to resolve any residual uncertainty around safety and immunogenicity.

Applicants are encouraged to seek scientific advice to discuss the design of any potential additional study.

Indications claimed for the biosimilar candidate

Once a biosimilar candidate has been shown to be highly similar to the RP in terms of analytical characteristics and functional properties related to the MOA(s) of the RP, all the indications granted to the RP can be claimed by the biosimilar candidate without further justification.

3.4 Product labelling

The content of the summary of product characteristics (SmPC) for a biosimilar should be consistent with that of the RP, (i.e., the information from the RP’s SmPC that applies to the biosimilar should be included in its SmPC).

The indications in section 4.1 should be in line with the indication of the RP. If the biosimilar does not have strength(s) and/or pharmaceutical form(s) that exist for the RP and are used in some subsets of the authorised patient population (for example, paediatric population), this should be mentioned in section 4.2 of the SmPC. An example of such wording is: “[Invented Name] is only available as [description of the pharmaceutical form]. Thus, it is not possible to administer [Invented Name] to paediatric patients that require less than a full [X] dose. If an alternate dose is required, other medicinal [INN] products offering such an option should be used.”

Section 4.8 should include the following statement: “[Invented Name] is a biosimilar medicinal product. Detailed information is available on the MHRA website; [add link]”.

The Applicant should discuss and justify any differences of the proposed SmPC to that of the RP, for example in relation to a different device. It may also be possible to justify a simplification of the immunogenicity data provided in the RP’s SmPC, i.e., omitting specific ADA rates as these are dependent on the assays used, which have greatly improved over time, and are not necessarily relevant.

The package leaflet should reflect the scientific content of the SmPC of the biosimilar, for the relevant information for patients. With the exception of differences based on scientific grounds, deviations from the RP’s package leaflet are expected to be justified by results of user testing consultation with target patient groups.

3.5 Risk management plan (RMP)

The RMP for a biosimilar candidate should reflect that of the RP in terms of safety concerns, additional pharmacovigilance activities and additional risk minimisation. If there are additional safety concerns for the biosimilar candidate these are unlikely to be due to the active molecule but rather factors such as excipient or device that are different from the RP - these should be included in the RMP.

Where ongoing additional pharmacovigilance activities are required for the RP (for example, participation in ongoing disease registries), these should also apply to the biosimilar candidate. This would preferably be through collaboration or participation in those studies or registries already in place for the RP to enable collection of real-world information to support signal detection of potential safety signals related to the RP and its biosimilars.

Any additional risk minimisation measures that continue to be required for the RP should also be implemented for the biosimilar candidate, for example educational materials for healthcare professionals and patients or patient alert cards.

3.6 Traceability

In the post-authorisation phase as a result of manufacturing, product variability over time within and across products with similar active substances is possible. Therefore, a key requirement for pharmacovigilance of biosimilars is the need to ensure continuous product and batch traceability in clinical use to support detection of any important safety issues that may be product- or batch- specific. Biosimilars with the same International Nonproprietary Name (INN) should be readily distinguishable, preferably with an invented brand name - this will allow newly emerged and potential product-specific safety concerns to be rapidly identified and evaluated throughout the product lifecycle, and for the product to be traceable to location and patients, as necessary.

Accurate traceability of biosimilars by brand name and batch number must be assured in the post-marketing setting. The importance and method of traceability needs to be highlighted in the product information and on the product packaging or labelling as appropriate. For example, removable sticky labels on the product detailing brand name and batch number that can be recorded on patient records or 3D barcoding may be more appropriate for electronic records. Traceability should be fully integrated in the healthcare settings, for example electronic data recording and record linkage etc. Where necessary, additional training to healthcare professionals should be provided to support reporting of brand name and batch number when reporting adverse reactions.

3.7 Interchangeability

Once a biosimilar is authorised, it is considered interchangeable with the RP, which means that a prescriber can choose the biosimilar over the RP (or vice versa) and expect to achieve the same therapeutic effect. Likewise, a biosimilar product is considered to be interchangeable with another biosimilar to the same RP.

As a result of interchangeability, switching patients from one product to another (RP or biosimilar) has become clinical practice. The decision rests with the prescriber in consultation with the patient, who needs to be aware of the brand name of the product received. No safety signal has been detected in more than a decade of experience with switching, including information from registries.

Substitution at the pharmacy level without consulting the prescriber is not permitted for biological medicines, including biosimilars.