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European Biopharmaceutical Review

Western Influence

Since its first guidelines were released in 2005, the EMA has developed a detailed set of requirements, including three overarching sections, to govern biosimilars – Guideline on similar biological medicinal products; Guideline on similar biological medicinal products containing biotechnologyderived proteins as active substance: quality issues; and Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: nonclinical and clinical issues.

There are also sections to address products containing active substances, including recombinant folliclestimulating hormone, interferon beta, monoclonal antibodies, recombinant erythropoietins, low molecular weight heparins, recombinant interferon alpha, recombinant granulocyte-colony stimulating factor and somatropin, as well as recombinant human insulin and insulin analogues. In addition, other areas concern immunogenicity and comparability assessment. The guidelines are revised on a regular basis to incorporate new experience gained through approvals, and evolving science and technology.

Despite facing some issues – including how more complex biosimilars should be regulated – the EMA guidelines are considered to be the most comprehensive and sophisticated. As a result, biosimilar recommendations from other authorities around the world have mainly followed the European approach, and among them is China. The Centre for Drug Evaluation of the China Food and Drug Administration (CFDA) issued Guidelines on biosimilars: research, development and evaluation in February 2015. These guidelines cover a number of subjects, such as: definition of biosimilars; choice of reference product; general principles of establishing biosimilarity including comparability exercise and stepwise approach; non-clinical and clinical studies; and pharmacovigilance (PV).

However, although the regulatory approaches of the CFDA and EMA are similar in general scientific content, there are some notable differences:

Definition of Biosimilars
The EMA guidelines define a biosimilar as a biological medical product that contains a version of the active substance of an already authorised original biological product. Similarity to the reference product in terms of quality characteristics, biological activity, safety and efficacy – based on a comprehensive comparability exercise – must be established.

Meanwhile, according to the CFDA, a biosimilar is: “a therapeutic biological product similar to an authorised reference product in terms of quality, safety and efficacy.” A biosimilar should contain the same active substance as the reference product, and variations such as different host cells and expression systems should be justified. Unlike the EMA’s overarching guidelines, which in principle apply to all categories of biosimilar products, the Chinese guidelines specifically emphasise that theirs only apply to therapeutic recombinant protein products with clear structures and functions.

Choice of Reference Product
The EMA requires that a single EU authorised reference medicinal product should be used as the comparator throughout the entire comparability exercise. However, with the aim of facilitating global development, the organisation does allow the use of non-EU authorised products in certain clinical studies and in in vivo non-clinical studies where needed, provided that the applicant can demonstrate that the non-EU authorised comparator is representative of the EU authorised product. This can be shown through extensive analytical comparison with convincing bridge data.

Guidance in China has adopted a similar approach, but requires that the reference product to be used in clinical trials must be authorised within the country, and biosimilar products cannot be used as comparators during the comparability exercise.

EMA’s guidelines do not provide recommendations on whether a biosimilar should be used interchangeably with its reference product, and substitution policies are within the remit of EU member states. No interchangeability requirements are provided in the Chinese guidelines.

Non-Clinical Studies
The European guidelines suggest that analytical and in vitro pharmaco-toxicological studies should be conducted first, before deciding whether, and to what extent, in vivo testing in animals is required. Although the EMA agrees that immunogenicity assessment in animals is generally not predictive of immunogenicity in humans, blood samples should be taken and stored for future evaluations of the pharmacokinetic (PK)/toxicokinetic data. Differences such as product-related variants and process-related impurities that may have an effect on immunogenic potential and the possibility to cause hypersensitivity should also be assessed in clinical studies, as these effects are difficult to predict from animal models.

Meanwhile, it is not recommended to conduct standard repeated dose toxicity safety studies in non-human primates, but only investigations with refined design or in-life evaluation of safety parameters. In addition, testing in non-relevant species to assess unspecific toxicity only based on impurities is to be avoided, as such safety risk can be minimised by reducing the level of impurities.

The Chinese guidelines do not provide details explaining how in vitro investigations should be carried out, and only suggest that PK and pharmacodynamic (PD) studies, immunogenicity assessment, repeated dose toxicity testing and other toxicity studies should be conducted using the same models and animal species as the reference product, and when different models and species are justified. Specifically, the CFDA advises that if differences such as impurities are discovered between the proposed and the reference product which could affect the safety and efficacy of the biosimilar, then repeated toxicity studies using relevant animal species should be conducted for at least four weeks, in order to observe toxicity and immunogenic responses.

Clinical Studies
EMA’s guidelines propose that the clinical comparability exercise is a stepwise procedure that should begin with PK and PD studies, followed by clinical efficacy and safety trials or, in certain cases, additional PK/PD studies. The potential for immunogenicity of a biosimilar should be investigated in a comparative manner to the reference product, with testing conducted using the same assay format and sampling schedule. In addition, the incidence and nature of antibodies and antibody titres should be assessed and interpreted in relation to their potential effects on clinical efficacy and safety parameters. Duration of the study and follow-up should also be justified. Usually, increased immunogenicity compared to the reference product may question biosimilarity, while lower immunogenicity does not preclude approval.

In China, clinical trials should start with PK and PD studies and then, depending on the outcome, the applicant should determine whether further clinical efficacy and safety tests are needed. Where no difference or minimum differences are discovered from the quality assessment and non-clinical investigations, and where clinical PK, PD and PK/PD studies predict efficacy endpoints, comparability between the biosimilar and reference product can be proven; otherwise, further efficacy and safety studies should be conducted. The CFDA also suggests that clinical immunogenicity assessment should be based on the outcome of non-clinical immunogenicity testing and, when such results imply biosimilarity, only limited clinical assessment is required.

Extrapolation of Indications
Occasionally, the reference product may have more than one therapeutic indication. In these instances, the EMA allows extrapolation of clinical data to other indications of the reference product, provided biosimilar comparability has already been demonstrated in another area; however, extrapolation must be scientifically justified. Additional data is required in certain situations – for example, when the active sites of the substance have a different impact depending on the therapeutic indication – and extrapolation should be considered in light of the totality of quality, non-clinical and clinical data. As immunogenicity is related to a number of factors – including the route of administration, dosing regimen, patient-related features and disease-related issues – and could differ among indications, extrapolation of immunogenicity from one indication to another should be justified based on the knowledge obtained with the reference product.

The Chinese guidelines suggest that extrapolation of indications should be product-specific and based on appropriately selected indications which have been thoroughly studied in clinical trials. Safety and immunogenicity should also be sufficiently assessed, with tests evaluating different immunogenic responses from different patient populations.

Clinical safety of biosimilars must be monitored closely during the post-marketing authorisation phase, as data from pre-authorisation clinical studies is usually insufficient to identify rare adverse effects. The EMA recommends that biosimilar applicants present a description of the PV system, as well as a risk management plan (RMP), which should take into account the identified and potential risks associated with use of the reference product and detail how issues will be addressed in post-marketing follow-up. In particular, the RMP should adequately address immunogenicity and include risk minimisation activities for the reference product, in addition to any specific safety monitoring imposed on the reference product or product class.

The Chinese guidelines simply suggest that a RMP should be in place assessing safety and immunogenicity after marketing authorisation, with no further guidance provided.

In Harmony

As the EU is one of the six founding parties of the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, the EMA plays a key role in the development of ICH guidelines and publishes guidance that are harmonised between Europe, Japan and the US. The organisation is continuing to revise its regulations for more complex biological medicinal products – such as monoclonal antibodies – and, to date, has approved 19 biosimilar products containing active substances.

Unlike with the EMA, the Chinese guidelines have not yet incorporated many ICH recommendations, especially in relation to: the quality, efficacy and safety requirements of technical aspects; better use of human, animal and material resources; and the elimination of unnecessary delay in global development and availability of new medicines. Although a similar stepwise comparability attitude has been adopted, the issued regulations do not contain sufficient details to act as overarching guidelines. It is also unclear whether the CFDA will continue to follow the EMA lead and take further steps to develop a product-specific approach and introduce requirements to address issues like immunogenicity assessment. As a result, China still has some way to go before its biosimilar regulation can be brought in line with international practice.

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Nick Beckett is Managing Partner of the Beijing office at law firm CMS, where he is also the Asia-Pacific Head of Lifesciences. Nick has extensive experience in advising on all aspects of intellectual property and commercial matters affecting life sciences clients, and his practice spans both contentious and non-contentious issues. In particular, his work in the areas of parallel trade, anti-counterfeiting, due diligence, trademarks, patent opinions and litigation spans international borders.

Jane Lin is a lawyer in the Intellectual Property Litigation team at CMS, London, within the Commercial, Regulatory and Disputes Group. She specialises in cross-border patent litigation, patent right protection and implementation, lifecycle management, patent strategy planning, freedom-to-operate, validity opinions and enforcement support, as well as emerging market legal affairs supervision, especially in the life sciences sector.
Nick Beckett
Jane Lin
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