Since the EMA’s overarching 2005 guidelines introducing its “similar biological medicinal products” approach, the EMA has published additional productbased guidance.
The EMA followed its 2005 general guidance with more specific guidance for biotechnology-derived proteins in 2006. See EMEA/CHMP/BWP/49348/2005 & EMEA/CHMP/ BMWP/42832/2005. It has since provided product-specific guidance for individual proteins in this subclass of products, for example, recombinant granulocyte-colony stimulating factor, recombinant human soluble insulin, recombinant erythropoietin containing proteins, recombinant interferon alfa, etc., all of which can be found in the EMA’s Document Library. More recently, the EMA also laid out guidelines for biosimilar monoclonal antibody products, a major subclass of biotechnology-derived proteins. See EMA/CHMP/ BMWP/403543/2010.
Highlights from the EMA’s guidance on biosimilar biotechnology- derived proteins and monoclonal antibodies are provided below. The focus of the biosimilarity exercises outlined by the EMA is to demonstrate similar efficacy and safety compared to the reference product, not patient benefit per se (which has presumably already been shown for the reference product).
- Guidelines for biosimilar “biotechnology-derived proteins”
In 2006, the EMA followed its general guidelines with more specific directives for “quality issues” as well as “non-clinical and clinical issues” in the development and approval of “biotechnology-derived proteins.” The products covered under these guidelines are proteins expressed by recombinant DNA techniques.
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Regarding quality issues, the EMA stated that structural and quality differences between a biosimilar protein and reference product may be allowed but must be justified by comparability exercises on a case-by-case basis. These could include minor structural differences in the active substance and differences between the purity profiles of the biosimilar and reference products. Suitable analytical techniques must be chosen for comparability exercises under the EMA guidelines with regard to the complexity and inherent heterogeneity in the molecule in consideration.
The EMA also addressed the following particular quality concerns in development:
- Physiochemical properties: A physicochemical characterization program should be chosen to determine the composition, physical properties, and primary and higher order structures of the active substance, including any inherent structural heterogeneity due to the biosynthetic manufacturing process (e.g., in post-translational modifications).
- Biological activity: Assays using different approaches to measure activity should be considered in comparing the biosimilar and reference products.
- Purity and impurities: Product- and process-related impurities of the active substance and medicinal product should be assessed by a combination of analytical procedures.
The EMA also instructed that, before initiating clinical studies, the Applicant should conduct a limited number of non-clinical in vitro and in vivo studies. However, the EMA stated that several routine toxicological studies, such as, safety pharmacology, reproduction toxicology, mutagenicity and carcinogenicity studies, would not be required for similar biological medicinal products.
With respect to non-clinical studies, the EMA suggested that these should include:
- In vitro studies: These consist of assays, such as, receptor-binding studies or cell-based assays.
- In vivo studies: These include animal studies designed to maximize the information obtained in the relevant species with regard to pharmacodynamics effect and non-clinical toxicity.
Regarding clinical data, the EMA explained that normally comparative clinical trials would be required to demonstrate clinical comparability. However, in certain cases, comparative pharmacokinetic (PK) and pharmacodynamics (PD) studies between the biosimilar and the reference product may be sufficient, provided certain conditions (set forth in the guidance documents) are met.
- Guidelines for biosimilar monoclonal antibodies
In developing biosimilar monoclonal antibodies (mAbs), the EMA referenced its previous guidelines regarding biosimilar biotechnology-derived proteins (described above). But it also provided guidance tailored to mAbs. It explained that, in addition to non-clinical studies, clinical studies will be needed to compare safety and efficacy for this category of products.
With regard to non-clinical development, the EMA proposed the following three-step approach:
Step 1: In vitro concentration/activity studies covering functional aspects of the mAb.
- 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)
Step 2: For the next step in non-clinical development, the EMA provided exemplary factors to be considered in designing and assessing the need for in vivo studies.
- Differences in process-related impurities
- The presence of a mixture of product- and/or process-related impurities
- Significant differences in formulation
- The need to test the biosimilar mAb directly at a therapeutic dose in patients, rather than in healthy volunteers
- Availability of a relevant in vivo model
Step 3: The need for in vivo studies.
- According to the EMA, if the comparability exercise in the in vitro PD studies in step 1 is considered satisfactory and no factors of concern are identified in step 2, an in vivo animal study may not be necessary.
- However, if the outcome of steps 1 and 2 raises concerns, the need for comparative in vivo studies should be decided on a case-by-case basis.
With regard to clinical studies, the EMA provided guidance on the design and types of clinical studies that may be required. Below we highlight some of the considerations set forth in the guidelines.
- Pharmacokinetic (PK): Under the EMA’s guidelines a comparison of the PK properties of the similar biological medicinal product and the reference product form an integral part of biosimilar mAb development. The guidelines discussed considerations for study design, choice of population, dosing, endpoints, etc.
- Pharmacodynamic (PD): Where possible, PK studies can be combined with PD endpoints. Also, the EMA indicated that it may emphasize non-clinical PD evaluations, e.g., in vitro testing, in its PD evaluation.
- Clinical efficacy: With regard to efficacy studies, the EMA stated that “if dose comparative and highly sensitive PD studies cannot be performed convincingly showing comparability in a clinically relevant manner, similar clinical efficacy between the similar and the reference product should be demonstrated in adequately powered, randomized, parallel group comparative clinical trial(s), preferably double-blinded and normally equivalence trials.”
- Clinical safety: With regard to clinical safety, the EMA noted that this is normally studied as part of the clinical efficacy studies and should use the same definitions of safety parameters as used for the reference product.