The MHRA has drafted new guidance on “The licensing of biosimilar products” to provide developers of similar biological medicinal products (biosimilars) with a clear outline of the requirements for biosimilar products in the UK following the end of the transition period.
The new guidance is mainly based on the current CHMP (Committee for Medicinal Products for Human Use) guidelines. Some distinct key features are:
- UK reference products: The Reference Product (RP) should comply with Regulation 48 of the Human Medicines (Amendment, etc.) (EU Exit) Regulations 2019; the UK RP (or an RP representative of the UK product) must be used for the required comparability studies which could include an EU RP 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; data and market exclusivity period entitlements for RPs approved before the date of EU exit will continue to apply in the UK. It is interesting to 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, United States, Canada, Australia, and Japan).
- products that are, or have been, authorised for at least eight 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 license, as the marketing authorisation holder opted out of the process; and
- 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.
- Biosimilarity principles: A biosimilar should be highly similar to the RP in physicochemical properties, biological activity/potency, and clinical profiles; 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 biosimilar must have the same molecular and biological structure and the same posology and route of administration.
Importantly, 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 license for the biosimilar has been granted.
- No requirement for in vivo studies in animals: No in vivo studies in animals are requested to be submitted to the MHRA for consideration of a UK license for a biosimilar product as these are not relevant for showing comparability between a biosimilar candidate and its RP; conduct of in vivo studies in animals does not contribute to resolving the possibility that a biosimilar candidate may not be highly similar to the RP and in vivo studies should not be done with this intent.
- Changes in the requirement for a comparative efficacy trial in most cases: A comparative efficacy trial is not considered necessary in most cases; a well-argued justification for the absence of an efficacy trial, supported by sufficient comparative analytical and functional data, should be included in the submitted application; there may still be cases requiring a comparative efficacy/safety trial, for example, 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.
- No requirement for repeat demonstration of biosimilarity: There is no regulatory requirement to repeat the demonstration of biosimilarity against the RP once a UK product license for the biosimilar has been granted (for example, in the context of a change in the manufacturing process).
- Relation to other guidelines: The MHRA offers some flexibility in relation to guidelines applicable in other jurisdictions in relation to in vivo studies: the content of Module 4 for the UK can be limited to those studies that are GLP compliant, requirements of other regulators notwithstanding; 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.
- Risk management plan (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, preferably 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.
- 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 (however, like all biologicals, biosimilars must be prescribed by brand name); substitution at the pharmacy level without consulting the prescriber is not permitted for biological medicines, including biosimilars.
- Clarification about this guidance can be sought by sending an email to MHRA in the first instance: email@example.com or by seeking MHRA scientific advice.
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