Following its adoption by the Committee for Medicinal Products for Human Use (“CHMP”) on 18 December 2014, the European Medicines Agency (“EMA”) recently published a finalised version of its Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (hereafter “EMA Guideline”). The revised EMA Guideline is expected to come into force in July 2015 and will replace the current guideline which came into effect in June 2006.
The EMA Guideline outlines the following non-clinical and clinical requirements for demonstrating a biosimilar’s comparability with the reference biological medicinal product:
- design of non-clinical studies;
- the use of pharmacodynamic markers;
- clinical study design;
- choice of appropriate patient population;
- choice of surrogate and clinical endpoints in efficacy trials;
- clinical safety (including design of immunogenicity studies);
- risk management plans;
- pharmacovigilance; and
- extrapolation of safety and efficacy data.
The EMA Guideline indicates that the nature and complexity of the reference medicinal product will impact the scope of the non-clinical and clinical studies required to demonstrate biosimilarity.
The EMA Guideline presents a step-by-step approach concerning the design of non-clinical studies for evaluating biosimilarity.
The EMA Guidance, however, cautions that the approach presented in the Guideline should be specially adjusted to the medicinal product in question and will need to be fully justified in the non-clinical overview submitted as part of an application for marketing authorisation of the biosimilar product.
The EMA Guideline also provides guidance on the design of the clinical studies required to demonstrate clinical biosimilar comparability. The guidance focuses on:
- pharmacokinetic (PK) studies;
- pharmacodynamic (PD) studies;
- clinical efficacy and safety trials; and
- confirmatory PK/PD studies for demonstrating clinical biosimilar comparability.
According to the EMA Guideline, if biosimilar comparability has been demonstrated in one therapeutic indication, extrapolation of clinical data to other indications of the reference product could be acceptable. This would, however, need to be scientifically justified and additional data may be required. The EMA Guideline indicates that additional data may be required in the following circumstances:
- the active substance of the reference product interacts with several receptors that could have a different impact on the tested and non-tested therapeutic indications;
- the active substance itself has more than one active site and the sites could have a different impact in different therapeutic indications;
- the therapeutic indication assessed as part of the studies is not relevant for other therapeutic indications on the basis of efficacy or safety considerations.
The Guideline stresses that extrapolation should be considered in the light of all the date presented, including quality, non-clinical and clinical data.