EMA Finalises Guidelines for Biosimilar mAbs

The European Medicines Agency (EMA) has finalised its guidelines on biosimilar monoclonal antibodies (mAbs). According to the EMA, the guidelines focus on demonstrating that the safety and efficacy of the original biotech drug is also present in the biosimilar. The guidance, which contains guidelines for non-clinical and clinical studies, thus details out a "step-wise" approach from in-vitro testing through to in-vivo testing if necessary.

Non-Clinical Studies: In Vitro and In Vivo Studies

As per the guidelines, the in vitro studies should be designed to be comparative and allow for sufficient sensitivity in order to be able to rule out any concentration-activity relationship between the biosimilar and the original drug. The EMA therefore added a list of assays that the studies should include.

In terms of determining whether in vivo studies will be required, the EMA lists a few factors based on which the need for in vivo studies will be determined. If the comparability is considered to be satisfactorily determined in the in vivo studies, however, and no factors "of concern" from the abovementioned list are determined or these factors would "not block the direct entrance to humans" then in vivo studies may not be deemed necessary.

Depending on the additional information required, the focus of the in vivo studies could be pharmacokinetic, pharmacodynamic, and/or, safety related, and should be designed by taking replacement, refinement, and reduction into consideration.

Clinical Studies

The guidelines stress the importance of always conducting comparative clinical studies between the biosimilar and the originator. The pharmacokinetic studies should therefore be designed to be sufficiently sensitive to show comparability. Furthermore, the guidelines advise that the studies should be conducted in a homogenous population, as this reduces variability and simplifies interpretation. The EMA further advises on the choice between healthy volunteers or patient groups for the study. As per the guidelines, if a mAb is licensed in several indications, pharmacokinetic studies will generally not be needed for all indications. In the case that the mAb is indicated for use in distinct therapeutic areas, however, separate pharmacokinetic studies may be required if the target mediated clearance for the therapeutic areas differs.

The guidelines indicate that the pharmacodynamic parameters may contribute to the comparability assessment for certain particular mAbs and in certain indications. Pharmacodynamic endpoints can be combined with pharmacokinetic studies where possible, as these could potentially add further information for the overall comparability assessment.

Efficacy

In cases where comparability cannot be proven through pharmacodynamic and dose-comparative studies, similar clinical efficacy will have to be demonstrated in an adequately powered, randomised, parallel group comparative clinical trial (preferably double-blind, normally equivalence trials).

The choice of population is to be determined by homogeneity and sensitivity, with clinical trials in special populations such as paediatric and elderly populations not normally requires.

The EMA also states that it is generally possible to include patients from non-European countries, if there are no intrinsic differences.

Immunogenicity

Separate guidance has been issued by the EMA addressing issues related to immunogenicity. The guidance includes advice on several aspects of immunogenicity including factors that affect immunogenicity of mAbs, the clinical consequences of immunogenicity, and assay-related problems. The full immunogenicity guidance is available here.

Additional Considerations for Anticancer mAbs

The EMA recognises that determining efficacy and safety may be particularly difficult in the "anticancer setting". Although the efficacy endpoints in cancer indications—progression-free/disease-free survival (PFS/DFS) or overall survival (OS)—are necessary in order to establish patients' benefit from the new anticancer drug, they may not be feasible or sensitive enough to establish comparability between the biosimilar and the originator. The guidelines suggest that it may be worthwhile assessing the overall response rate measured at a certain time point or the percentage change in tumour mass from baseline or pathological complete response in some clinical settings. PFS and OS should be recorded where possible, according to the EMA guidelines. PFS would be the preferred outcome measure (compared with objective response rate) in cases where it is more sensitive.

Clinical Safety

The guidelines recommend that the same definitions are to be used as those used for the reference mAb in its original development programme, or those used in the post-authorisation follow-up. Furthermore, under certain settings, safety data may be collected in the post-authorisation follow-up.

Extrapolation of Indications

It is possible to extrapolate data on clinical efficacy and safety to other indications of the reference mAb that are not studied specifically during the clinical development of the biosimilar mAb, "based on the overall evidence of comparability and with adequate justification". The EMA recognises that extrapolation may be particularly challenging if the extrapolation is between two indications where one is an immunomodulator and the other anticancer. The agency leaves open the possibility for allowing extrapolation based on a literature review, however—as long as it includes review of the antigen receptors and the mechanism of action—without requiring additional clinical studies.

Pharmacovigilance

During the process of Marketing Authorisation Application a risk-management plan should be provided. Additionally, the EMA sets out certain aspects that should be included in the comprehensive concept on how the post-authorisation safety studies will be conducted.

Outlook and Implications

The fact that the guidelines have been finalised and are fairly close to the draft mAb guidelines is highly positive for companies involved in biosimilars development (see Europe: 29 November 2010: EMA Publishes Stringent Guidelines for Biosimilar mAbs). The final guidelines are fairly close to the draft ones, meaning companies at advanced stages of biosimilar mAb development will not face development delays.

As in the draft guidelines, the finalised version makes it possible to use data on clinical efficacy and safety in other indications, thus making it more advantageous for companies developing biosimilar mAbs in cases when the reference drug is approved in several indications. Not requiring additional clinical studies in order to extrapolate to other indications is highly positive for biosimilar developers. A number of mAb biosimilar approval applications are expected to be submitted to the EMA, and considering that the development of some products is at a fairly advanced stage, approvals are expected sooner rather than later. Payors in Europe are expected to embrace biosimilar mAbs, given the huge potential for savings, but gaining acceptance from clinicians is likely to take a while.

The publishing of guidelines for biosimilar mAbs maintains the EU's position at the forefront of biosimilar development, considering that other countries are yet to introduce mAb development guidelines, and may potentially influence any future guidelines to be set up in other countries, such as Australia and Canada.