Since its first biosimilar guidelines were released in 2005, the European Medicines Agency (“EMA”) has developed a detailed set of guidelines (collectively “The EMA Guidelines”) including three overarching biosimilar guidelines, Guideline on Similar Biological Medicinal Products, Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Quality Issues, and Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Non-clinical and Clinical Issues, along with product-specific guidelines. There are also other guidelines relevant to biosimilars such as guidelines addressing immunogenicity assessment and comparability assessment. The EMA Guidelines are revised on a regular basis to incorporate experience gained with biosimilar approvals as well as evolving science and technology.
Although facing some issues, including regarding how more complex biosimilars should be regulated, the EMA Guidelines are considered thus far the most comprehensive and sophisticated. Biosimilar guidelines issued by authorities in other countries have mainly followed the EMA approach, including most recently in China. The Centre for Drug Evaluation (“CDE”) of the China Food and Drug Administration (“CFDA”) issued Guidelines on Biosimilars: Research, Development and Evaluation (“The Chinese Guidelines”) on 28 February 2015. Although the regulatory approaches are similar in general scientific content, there are differences between the above two guidelines in some respects which are addressed below.
General regulatory requirements
A. 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 medicinal product in the EEA. Similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise needs to be established.
According to the Chinese Guidelines, a biosimilar is a “therapeutic biological product similar to an authorised reference product in terms of quality, safety and efficacy” which biosimilar should contain the same active substance as the reference product, and differences such as different host cell and expression system should be justified. Unlike the EMA overarching guidelines, which in principle apply to all categories of biosimilar products, the Chinese Guidelines specifically emphasized that the guidelines only apply to therapeutic recombinant protein products with clear structures and functions.
B. Choice of Reference Product
The EMA Guidelines require 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 EMA does allow using non-EU authorised products in certain clinical studies and in in vivo non-clinical studies where it is needed, provided that the applicant can demonstrate that the non-EU authorised comparators used are representatives of the EU authorised product through extensive analytical comparison with convincing bridge data. The Chinese Guidelines adopted a similar approach, but require that the reference product used for clinical trials must be authorised in China and biosimilar products cannot be used as comparators during the comparability exercise.
The EMA 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 the EU member states. No interchangeability requirements are provided in the Chinese Guidelines.
The EMA Guidelines recommend that analytical studies and in vitro pharmaco-toxicological studies should be conducted first before deciding whether and to what extent that in vivo work in animal studies will be required. The EMA agrees that immunogenicity assessment in animals is generally not predictive for immunogenicity in humans but blood samples should be taken and stored for future evaluations of pharmacokinetic/toxicokinetic data for interpretation of in vivo studies in animals. Differences such as product-related variants and process-related impurities that may have an effect on immunogenic potential and the potential to cause hypersensitivity should be assessed in clinical studies as these effects are difficult to predict from animal studies. The EMA does not recommend conduct of standard repeated dose toxicity studies in non-human primates for safety studies but only studies with refined design or an in-life evaluation of safety parameters, nor toxicity studies in non-relevant species assessing unspecific toxicity only based on impurities as such safety risk can be minimised by reducing the level of impurities.
The Chinese Guidelines do not provide details regarding how in vitro studies should be carried out but only suggest that pharmacokinetic(“PK”) studies, pharmacodynamic (“PD”) studies, immnuogenicity assessment, repeated dose toxicity studies and other toxicity studies should be conducted using same models and animal species as the reference product, where different models and species should be justified. Specifically, the CFDA suggests that if differences such as impurities are discovered between the proposed product and the reference product which effects as to safety and efficacy are unclear, repeated dose toxicity studies using relevant animal species should be conducted for at least four weeks to observe toxicity and immunogenic responses.
The EMA 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, PK/PD studies. The potential for immunogenicity of a biosimilar should be investigated in a comparative manner to the reference product, immunogenicity testing should be conducted within the biosimilar comparability exercise by using the same assay format and sampling schedule, and 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 immunogenicity study and follow-up should be justified. Increased immunogenicity as compared to the reference product may question biosimilarity while a lower immunogenicity would not preclude approval.
The Chinese Guidelines suggest that clinical trials should start with PK and PD studies based on which outcome the applicant should then determine whether the clinical efficacy and safety studies should be conducted. Where no difference or minimum differences are discovered from the quality assessment and non-clinical studies, and where clinical PK, PD and PK/PD studies predict efficacy endpoints, comparability between the biosimilar and the reference product can then be determined; 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 assessment and when such assessment suggests biosimilarity, only limited clinical assessment is required.
Extrapolation of indications
The reference product may have more than one therapeutic indication. The EMA Guidelines allow extrapolation of clinical data to other indications of the reference product when biosimilar comparability has been demonstrated in one indication which extrapolation needs to be scientifically justified. Additional data are required in certain situations such as where the active sites of the active substance have a different impact in different therapeutic indications. Extrapolation should be considered in the light of the totality of quality, non-clinical and clinical data. As immunogenicity is related to multiple factors including the route of administration, dosing regimen, patient-related factors and disease-related factors and could differ among indications, extrapolation of immunogenicity from one indication to the other 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 should be based on appropriately selected indications which have been thoroughly studied in clinical trials. Safety and immunogenicity in relation to the extrapolated indications should be sufficiently assessed. Extrapolation of immunogenicity should be justified by immunogenicity assessments assessing different immunogenic responses from different patient population directing different indications.
Clinical safety and pharmacovigilance
Clinical safety of biosimilars must be monitored closely during the post-marketing authorisation phase as data from pre-authorisation clinical studies are usually insufficient to identify rare adverse effects. The EMA suggests that the biosimilar applicant should present a description of the pharmacovigilance system and a risk management plan (“RMP”) which should take into account identified and potential risks associated with the use of the reference product and should detail how issues will be addressed in post-marketing follow-up. The RMP should also adequately address immunogenicity and include risk minimisation activities in place for the reference product as well as 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 the marketing authorization with no further guidance provided.
As the EU is one of the six founding parties of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”), EMA plays a key role in the development of ICH guidelines and publishes EMA guidelines that are harmonised between Europe, Japan and the US by the ICH. The EMA is continuing to revise its guidelines for more complex biological medicinal products such as monoclonal antibodies and to date the EMA has approved 19 biosimilar products containing active substances such as epoetin alfa, epoetin zeta, filgrastim, follitropin alfa, infliximab, insulin glargine and somatropin.
Unlike the EMA Guidelines, the Chinese Guidelines have not yet incorporated many ICH recommendations, especially in relation to the quality, efficacy and safety requirements from scientific and technical aspects, better use of human, animal and material resources as well as elimination of unnecessary delay in the global development and availability of new medicines. Although the Chinese Guidelines adopted a similar stepwise comparability approach, the issued guidelines arguably do not contain sufficient details to be regarded as overarching guidelines. It is also not clear whether the CFDA will continue to follow the EMA approach and take further steps to develop product-specific guidelines and guidelines addressing issues such as immunogenicity assessment. The CFDA thus has some way to go before its biosimilar regulation can be brought in line with international practice.
‘This article is taken from European Biopharmaceutical Review, October 2015 issue, pages 26-29. © Samedan Ltd 2015’