Comparative efficacy trials have played an important role in biosimilarity assessments. However, with recent technological advances, their role is now being questioned. Research published in Drug Discovery Today  outlines the reasons why biosimilar assessments can now be carried out without these trials [2, 3]. It also lays out the requirements for prospective applications without efficacy trials.
The authors separate the key requirements for biosimilar applications without comparative efficacy trials into the quality assessment, the pharmacokinetic (PK) assessment, the immunogenicity assessment, and pharmacovigilance requirements. Their clear summary of the key requirements for the quality assessment is reproduced below.
Key requirements for the quality assessment
In-depth knowledge of the reference product
- The main mechanism of action (MoA) is known and is demonstrable
- Critical quality attributes (CQAs) are known
- Enough batches of the reference are analysed to reflect its variability over a period of time, and within its shelf-life
- Analytical methods are sensitive, qualified and sufficiently discriminatory, with orthogonal methods used where possible
- The variability range is defined at analytical and in vitro functional levels
- Functional assays are relevant for the MoA in all indications
- All relevant batches demonstrate variability within the analytical range of the reference
- Wide ‘similarity ranges’ obtained inappropriately should not be used
- Any differences between the reference and biosimilar are characterized and justified as unlikely to impact clinical efficacy and safety
- Additional orthogonal analysis, including in vitro functional assays are used to evaluate differences
- Differences that might have a clinical impact should be addressed by manufacturing modifications
- The manufacturing process is well controlled with stringent release and stability specification limits
Key requirements for the PK assessment
When it comes to clinical documentation. The authors outline the importance of having a robust comparative PK study that demonstrates equivalence of primary PK parameters. Key requirements for PK assessment are summarized as follows:
Robust clinical study design and statistical analysis plan
- Subject selection: the most sensitive and homogeneous to detect clinically meaningful differences in PK between reference and biosimilar
- Parallel versus cross-over design should be justified
- Selection of most sensitive dose(s) to detect clinically meaningful differences
- Linear (non-specific) clearance and non-linear (target mediated) clearance should be addressed
- The equivalence margins must be prespecified; 80%–125% is generally acceptable
- Standardization of investigational medicinal product (IMP) handling and administration together with PK sampling, sample handling and analysis
- In a parallel group trial, covariates to be used in the analysis, e.g. body weight or subject sex, should be predefined
- If appropriate population PK or PK–pharmacodynamic (PD) models are available for the reference in the literature, modelling and simulation should be considered for optimizing study design
- Collection of safety and immunogenicity data with prespecified subgroup analysis of anti-drug antibody (ADA)-negative and ADA-positive subjects where high incidence of ADA formation is expected
Batch selection and protein content correction
- Product intended for commercialization should be used
- Protein content adjustments should be prespecified
Interpretation of results
Extrapolated AUC > 20% in >20% of observations requires discussion of the validity of the study.
In case of a failed PK study, root cause analysis should be given, with conclusions reflected in the planning of a subsequent study. If no root cause is identified and another study is conducted and is positive, the initial study should not be ignored.
The authors noted that in some cases PD markers can be measured during PK trials and these can be used to support a biosimilarity assessment.
Justification of comparable efficacy, safety and immunogenicity
The authors noted that precise correlations between clinical efficacy and pharmacological effects are often lacking and instead, the reference product’s efficacy can be derived from its MoA. In light of this, it is necessary to justify that comparable efficacy can be derived from comparable binding properties and functional characteristics. If there are observed differences these must be explained and justified as not clinically relevant.
The authors also noted that a biosimilar’s safety and immunogenicity comparability to the reference should be based on its quality attributes and formulation. Here, extensive clinical experience with the reference informs a risk-based assessment of the biosimilar’s immunogenicity, potential rates and clinical relevance of issues with ADAs. PK studies can also demonstrate comparable rates of some reactions and ADAs.
An application’s risk management
In the EU, a drug application requires a risk management plan. That of a biosimilar should reflect that of the reference product. The authors noted that the biosimilar must be included in disease registries to collect post-approval information and help in detection of any safety issues related to either the biosimilar or reference. In addition, if the reference has any additional risk minimization measure in place, these should be implemented for biosimilars.
The above is a summary of the revised evidence-based approach to establish biosimilarity outlined in Drug Discovery Today. The authors state that this should be applicable to most biosimilar candidates and this would save time and money for drug developers. However, in cases where the reference products’ MoA is not known, or when the impact of analytical differences are difficult to predict, comparative efficacy trials may still be required.
They also note that additional clinical safety data may be needed where safety uncertainties cannot be resolved without patient exposure pre-licencing. Here, for serious adverse drug reactions with unpredictable root causes, exposing patients to the biosimilar candidate is thought to be an appropriate approach to resolve residual uncertainty in immunogenicity and safety.
Overall, they hope that this will form the basis of a new streamlined biosimilar assessment pathway that can facilitate global access to more affordable medicines.
Conflict of interest
The authors of the paper  did not provide the conflict of interest statement.
The authors disclaim that the publication reflects the views of the individual authors and should not be understood to represent official views or policies of the UK Medicines and Healthcare products Regulatory Agency (MHRA).
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1. Bielsky M-C, Cook A, Wallington A, et al. Streamlined approval of biosimilars: moving on from the confirmatory efficacy trial. Drug Disc Today. 2020. In press. doi.org/10.1016/j.drudis.2020.09.006
2. GaBI Online - Generics and Biosimilars Initiative. Role of efficacy trials in biosimilar assessments questioned [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Nov 13]. Available from: www.gabionline.net/Biosimilars/Research/Role-of-efficacy-trials-in-biosimilar-assessments-questioned
3. GaBI Online - Generics and Biosimilars Initiative. Rationale for biosimilar assessment without efficacy trials [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Nov 13]. Available from www.gabionline.net/Biosimilars/Research/Rationale-for-biosimilar-assessment-without-efficacy-trials
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