On April 30, 2015, a new EU Guideline on biosimilar medicines took effect. The new Guideline defines a number of concepts applied by the EMA in its assessment of the ‘similarity’ between a biosimilar product and its reference products, and allows developers of biosimilars to file for EU approval using data from certain clinical trials conducted with non-EU authorized comparator products. This major change avoids unnecessary repetition of trials and facilitates the global development of biosimilars.
The new Guideline was adopted in October 2014 by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). It replaces an earlier guideline on similar biological medicinal products published in 2005. A series of other overarching biosimilar and product-specific guidelines, which are similarly subject to continuing updates, complements the new Guideline.
Contrary to U.S. laws (Section 351 of the Public Health Service Act (42 U.S.C. 262)), the EU Medicinal Products Directive (Directive 2001/83/EC) does not define a ‘biosimilar’, nor contains a specific benchmark for ‘similarity’ or ‘sameness’ between a biosimilar and its reference product. The new Guideline attempts to fill this gap by describing a biosimilar as “a version of the active substance of an already authorized original biological product (reference product) in the EEA [European Economic Area]” that should be “highly similar to the reference medicinal product in physicochemical and biological terms.” The Guideline also requires “similarity in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise.” This exercise normally requires head-to-head clinical trials.
Previously, clinical trials often had to be repeated to show similarity with an EU-approved reference product. The new Guideline introduces the possibility that trials conducted elsewhere, using a comparator reference product authorized outside the EEA (i.e., a non-EEA approved version of the reference medicinal product) may now be used in EU marketing authorization filings. This approach follows announcements by the European Commission and the EMA in 2012 that the guidance and practice would change, and that biosimilar applications containing clinical data with non-EU authorized comparator products would be accepted.
Building on experience gained over the past ten years, the new Guideline clarifies the EMA’s principles of establishing biosimilarity. Clinical data can address “slight differences,” but not “substantial differences in quality attributes.” The new Guideline also contains a short reference to extrapolation (whereby biosimilarity established in one indication is extrapolated to another indication without further clinical trials). Details on the conditions for extrapolation are set out in another of the EMA’s recently revised overarching guidelines for biosimilars, namely its guideline on non-clinical and clinical issues (see here), which was published in January 2015 and enters into force on July 1, 2015.
In addition to these Guidelines, developers of biosimilars should also refer to the EMA’s new version of its biosimilars quality guideline issued in June 2014 (see here), which came into effect on December 1, 2014.
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