The European Medicines Agency has published for public consultation a revised version of the guideline on similar biological medicinal products containing biotechnology-derived proteins as active substances.
IHS Global Insight perspective | |
Significance | The European Medicines Agency has submitted for public consultation an amended version of the guideline on similar biological medicinal products containing biotechnology-derived proteins. |
Implications | The draft guideline introduces significant amendments concerning key elements such as a risk-based approach for the design of non-clinical studies; the use of pharmacodynamic markers; study design, choice of appropriate patient population and choice of surrogate endpoints in efficacy trials; design of immunogenicity studies; and extrapolation of indication and pharmacovigilance. |
Outlook | The comments to the revised version of the guideline can be submitted until 30 November. |
The European Medicines Agency (EMA) has issued a revised version of the guidelines on similar biological medicinal products containing biotechnology-derived proteins. The updated guideline aims to amend guideline EMEA/CHMP/BMWP/42832/2005, which came into effect on 1 June 2006. The guideline comprises general principles for clinical and non-clinical generation and evaluation of the marketing authorisation applications of candidate biosimilars containing recombinant proteins as active substance. In particular, the revision focuses on some key aspects, namely a risk-based approach to the design of non-clinical studies; the use of pharmacodynamic (PD) markers; study design, choice of appropriate patient population and choice of surrogate endpoints in efficacy trials; design of immunogenicity studies; and extrapolation of indication and pharmacovigilance. The draft guideline is open for public consultation until 30 November. The full draft guideline is available here.
Risk-based approach to design of non-clinical studies
Non-clinical studies represent the first stage of study of biosimilarity and are required to be performed before the start of clinical trials. The revised version of the guideline clearly specifies that the outcome of the physical-chemical and biological characterisation studies needs to be reviewed taking into consideration potential impact on efficacy and safety. In addition, in vitro studies are required to include assays on "binding to target" and "signal transduction and functional activity/viability of cells" that are relevant to pharmaco-toxicological effects of the reference product. Furthermore, the guidance stresses that the applicant is requested to explicitly indicate how in vitro assays are predictive for in vivo studies.
Use of pharmacodynamic markers
With regard to clinical studies, the revised guideline recommends the use of clinically relevant PD markers. Comparative efficacy clinical studies are generally required to demonstrate clinical comparability. However, comparative pharmacokinetic (PK) and PD studies between the candidate biosimilar and the comparator may be sufficient to prove clinical comparability, given conditions concerning dose-response relationship and the acceptability of the PD marker/biomarker are met. Furthermore, as evidence regarding PD marker/biomarker surrogacy is generally limited, a combination of markers selected on the ground of established pharmacological principles is accepted.
Study design, choice of appropriate patient population, and choice of surrogate endpoints in efficacy trials
The revised guideline expands on the indications concerning criteria for designing the clinical trials. The guideline stresses that an equivalence study design is required. However, the use of non-inferiority design may be accepted provided a justification based on a "strong scientific rationale". Furthermore, concerning the selection of primary endpoints, the guideline recommends the applicants follow the EMA's Committee for Medicinal Products for Human Use (CHMP) product-class-specific guidelines. If such guidance is not available, the applicant is required to choose the most sensitive endpoint.
Design of immunogenicity studies
Indications on the design of immunogenicity studies are also provided in the amended version of the guidance. In particular, immunogenicity studies need to take place within the comparability exercise by using the same assay format and sampling schedule. Furthermore, the studies should be conducted in parallel with the candidate biosimilar compound and the reference product to assess the immune response against the product. The duration of immunogenicity studies is to be justified on a case-by-case basis. In case of chronic administration, the guidance specifies that one-year follow up data is generally necessary. However, a shorter data follow-up pre-licensing might be justified based on the immunogenicity profile of the reference product.
Extrapolation of indication and pharmacovigilance
In addition, when the comparator has more than one therapeutic indication, the efficacy and safety of a candidate biosimilar product needs to be demonstrated individually for each indication subject to approval. Finally, with regard to pharmacovigilance, as pre-authorisation trials do not usually provide a sufficient basis for assessing rare adverse effects, clinical safety of biosimilar drugs needs to be thoroughly monitored on an ongoing basis throughout the post-approval phase including continued benefit-risk assessment.
Outlook and implications
The publication of the revised guideline complements the revision of the European Union guideline on biosimilar medicinal products issued for consultation in May (see Europe: 9 May 2013: EMA publishes draft guideline on biosimilars for public consultation). In particular, EMA work to amend earlier biosimilar guidance is likely to provide the applicants that wish to have their products approved with solid indications for the marketing authorisation process. A smoother marketing authorisation application process for biosimilar products should boost access for biosimilar drugs in the EU member states.
The amended guidance appears to devote closer attention to a risk-based approach as well as to pharmacovigilance principles that may have positive outcomes for patients. Stakeholders have the opportunity to send comment on the draft until 30 November, meaning the final guideline may differ from the current draft.