EMA Invites Feedback on Biosimilar and Vaccine Concept Papers

Oct 10, 2011

EMA released two concept papers for consultation on Oct. 3, 2011, that address the need to revise existing guidelines on biosimilar medicines and influenza vaccines.

Biosimilar medicines:

The biosimilar medicines concept paper seeks the views of stakeholders on the revision of the guideline, titled Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Nonclinical and Clinical Issues, which came into effect in June 2006. Because of an increasing number of complex biosimilar products under development, especially biosimilar monoclonal antibodies, the regulatory framework is becoming wider. Key areas under scrutiny are:

  • selection of relevant species for nonclinical studies with emphasis on the need to follow the 3R principle (replacement, reduction, and refinement) regarding animal experiments
  • need for clinical equivalence studies
  • role of biomarkers
  • immunogenicity data required.

The Biosimilar Medicines Working Party (BMWP) has made a number of recommendations based on experience gained so far in the above areas. For nonclinical issues, the revised version of the guideline will consider a risk-based approach for designing an appropriate study. Factors to be taken into account include quality comparability exercises, pharmaco-toxicological properties of the active substance, availability/nonavailability of sensitive in vitro functional assays predictive for in vivo pharmacodynamics/toxicity, and the feasibility and relevance of comparative/noncomparative in vivo testing in a relevant species.

Clinical recommendations focus on several important areas. The need for clearer guidelines for pharmacodynamic markers is addressed, in particular whether or not, in the absence of such markers, products can proceed to pivitol Phase III studies when similarity has been shown with selected pharmacokinetic parameters.

The BMWP also plans to add examples of surrogate endpoints that are already being recommended in various other biosimilar guidelines. The possibility of using a noninferiority design as an alternative to the equivalence design for comparability is another key area. In this case, only the lower margin of comparable efficacy is defined, meaning that statistical analysis does not exclude the possibility of the biosimilar product being better.

Immunogenicity of biosimilars is a final, crucial discussion point. The BMWP will consider whether products with lower immunogenicity than the reference product (a possible result of modern production technologies) still qualify as biosimilar. Furthermore, current guidelines only request one-year follow up data for chronic administration, so the BMWP will include requirements for products not intended for chronic administration.

Influenza vaccines:

There are several guidelines identifying the regulatory requirements for the quality, nonclinical, and clinical development of influenza vaccines, but all were drafted and adopted over several years before the onset of the 2009–2010 influenza pandemic and cover seasonal, prepandemic, and pandemic vaccines separately. In addition, the likelihood of novel influenza vaccines based on recombinant proteins or DNA viral vectors is anticipated. As a result, there is a call for an updated single consolidated guidance on influenza vaccine requirements that takes into account all available evidence.

Recommendations for particular issues to be addressed in the new guideline are broken down into two sections. For seasonal, prepandemic, and pandemic vaccines, further guidance is requested for the nonclinical and clinical development of vaccines, including serological evaluation of immunogenicity, selection and evaluation of antibody assays, predictive value of immunogenicity data for vaccine efficacy, and evaluation of immune responses in population sub-groups. In terms of quality, improvements to the guidance would be modular, for example, seasonal versus pandemic vaccines, and focus on establishing the timely availability of reliable potency assays and alternative assays for antigen determination.

Specifically for pandemic vaccines, recommendations include development of ‘mock-up’ pandemic vaccines that would be optimally generated in advance of a pandemic situation, as well as additional or extension studies following the pandemic period to assess the emergence of potential drifted variants.

Both concept papers are available for a three-month consultation period and feedback can be submitted until Dec. 31, 2011.