On November 26, 2010, the European Medicines Agency released its proposed guideline for regulatory approval of similar biological medicinal products containing monoclonal antibodies ("Guideline"). Although the EMA has had a framework for approving biosimilar medicines for several years, and has approved over a dozen biosimilar products, to date it has not approved any biosimilar antibodies. The long-awaited Guideline sets forth the non-clinical and clinical requirements for monoclonal antibody-containing medicinal products claiming to be similar to another one already marketed, i.e., biosimilars. The Agency will be accepting public comments on the proposed Guideline until May 31, 2011. On the same day the Guideline for biosimilar monoclonal antibodies ("mAbs") was released, the Agency also released a related guideline on the immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use. That guideline is applicable to all biological medicinal products contaning mAbs, not just biosimilars.

In general, the Guideline requires that a biosimilar antibody not be inferior to the reference antibody, which is a lesser standard than for a new non-generic drug. In particular, the Guideline states that "[t]he focus of the biosimilarity exercise is to demonstrate similar efficacy and safety compared to the reference product, not patient benefit per se, which has already been established by the reference product." Deviations from the Guideline are permissible only if scientifically justified. Clinical trials will be required, including safety trials. The Guideline stresses that the scope and amount of testing, both in vitro and in vivo, will be determined on a case-by-case basis. Following is a summary of the key points in the Guideline.

SCOPE OF GUIDELINE

The Guideline states that it is intended to provide product-specific guidance that presents the current view of the Agency on the demonstration of biosimilarity of two mAb-containing medicinal products. The Guideline further states that it is intended to complement EMEA/CPMP/42832/05, the general guideline for demonstrating the similar nature of two biological products in terms of safety and efficacy, which the EMA released previously. While the new Guideline is specifically directed to mAbs, it states that "the principles discussed may also, on a case-by-case basis, be relevant to related substances like for example fusion proteins based on IgG Fc (-cept molecules)." However, the Guideline specifically excludes from its scope "biobetters," which it defines as "[s]econd- or nextgeneration biologicals . . . that are structurally and/or functionally altered, in comparison to already licensed reference products, to gain an improved or different clinical performance."

NON-CLINICAL STUDIES

In general, the Guideline calls for a risk-based approach to evaluate a mAb on a case-by-case basis. Non-clinical studes are to be performed before the initiation of clinical development. Moreover, in vitro studies are to be conducted first, then a decision will be made as to what, if any, in vivo nonclinical work will be required.

More specifically, the Guideline states that data from a number of comparative in vitro studies should be provided. These will include relevant studies on:

  • Binding to the target antigen
  • Binding to all Fcgamma receptors, FcRn and complement
  • Fab-associated functions (e.g., neutralization, receptor activation or receptor blockade)
  • Fc-associated functions (ADCC and CDC assays, complement activation)

These concentration/activity studies should be comparative in nature and should not just assess the response per se, but should be designed to exclude all differences of importance in the concentration-activity relationship between the biosimilar product and the reference product. Taken together, these assays should cover all functional aspects of the mAb even though some may not be considered necessary for the mode of action in the clinic.

Once the above-studies have been completed, the need for additional in vivo non-clinical studies must be evaluated. Factors that will be considered include:

  • Differences in process related impurities due to a different cell expression system compared with the reference medicinal product
  • The presence of a mixture of product- and/or process related impurities that can be less well characterized
  • Significant differences in formulation, use of not widely used excipients
  • The need to test the biosimilar mAb directly at therapeutic dose in patients, rather than in healthy volunteers
  • Availability of a relevant in-vivo model

According to the Guideline, if the in vitro pharmacodynamic (PD) studies are considered satisfactory, and none of the above factors is considered a concern, then an in vivo animal study will not be considered necessary. However, if that is not the case, then comparative studies should be decided on a case-by-case basis. If an in vivo study is deemed necessary, animal studies are to be designed to maximise the information obtained. However, the conduct of large comparative toxicological studies in non-human primates is not recommended, nor is the conduct of toxicity studies in nonrelevant species.

CLINICAL STUDIES

Study Goal/Design

  • Biosimilarity should be demonstrated in scientifically appropriately sensitive human models and study conditions, and the applicant should justify that the model is relevant and sensitive to demonstrate comparability in relation to efficacy and safety in the indication(s) applied for.
  • In principle, the most sensitive clinical model should be used in a homogeneous patient population, since this reduces the variability and sample size needed to prove equivalence, and can simplify interpretation.
  • In general, the most sensitive patient population and clinical endpoint is preferred to be able to detect product-related differences and to reduce patient and diseaserelated factors to a minimum in order to increase precision.

Pharmacokinetics (PK)

  • Biosimilar applicants should focus on the patient population where pharmacokinetic equivalence to the reference antibody can be studied with sufficient sensitivity. This patient population may be different than those in the efficacy trial.
  • Equivalence margins will need to be defined a priori and appropriately justified.
  • For cytotoxic mAbs in anticancer indications, the design of the study should take into account that the pharmacokinetics of cytotoxic mAbs may be time dependent, since the tumor burden may change after multiple dosing.
  • Where multiple therapeutic regimens are licensed for the reference mAb, the comparative PK study should be designed to demonstrate clinical comparability selecting the most sensitive key PK parameters. However, there will generally be no need to test all therapeutic dosage regimens.

Pharmacodynamics

  • PK studies can be combined with PD endpoints, where available.

Clinical Efficacy

  • If PD studies do not convincingly demonstrate comparability in a clinically relevant manner, similar clinical efficacy should be demonstrated in adequately powered, randomized, parallel group comparative clinical trial(s).
  • The Guideline notes that "[e]stablishing similar clinical efficacy and safety of biosimilar and reference mAb[s] may be particularly challenging in an anticancer setting."

Clinical Safety

  • Applicants will have to provide sufficient reassurance of clinical safety, including immunogenicity.
  • Study of unwanted immunogenicity is especially important where a different expression system is used for the biosimilar mAb compared to the reference mAb.
  • Prelicensing safety data should be obtained in a number of patients sufficient to determine the adverse effect profiles of the biosimilar mAb.

EXTRAPOLATION

  • Extrapolation of clinical efficacy and safety data to other indications of the reference mAb not specifically studied during the clinical development of the biosimilar mAb may be possible based on the overall evidence of biosimilarity provided from the comparability exercise and with adequate justification.
  • If the reference mAb is licensed both as an immunomodulator and as an anticancer (cytotoxic) antibody, the scientific justification as regards extrapolation between the two (or more) indications is more challenging.
  • For the mechanism of action, e.g., the depletion of immune cells, several mechanisms may play a role, and at the present stage of knowledge it cannot be assumed that the same mechanisms of cell depletion are of the same importance in different disease states.

PHARMACOVIGILANCE

  • Rare adverse events are unlikely to be detected preauthorization, so biosimilar applicants need to propose pharmacovigilance and risk management activities for the post-authorization phase.
  • In general, similar pharmacovigilance activities as those of the reference product will be required, although it may sometimes exceed routine pharmacovigilance.
  • Additional long-term immunogenicity and safety data might be required postauthorization, particularly where the study duration for establishing similar clinical efficacy is limited.

CONCLUSION

Despite the release of the product-specific Guideline for mAbs, the EMA does not expect to be flooded with applications for biosimilars. Due to the complex nature of mAbs and the requirements for clinical trials, the EMA is anticipating only 2-3 new applications per year. The U.S. FDA, which is under pressure to implement a regulatory framework for the recently passed Biologics Price Competition and Innovation Act, is expected to look to the EMA Guideline as a model for how to handle biosimilar antibodies under the new statute.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.