Howard Levine (hlevinebptccom) , Sheila Magil (smagilbptccom) , and Alex Kanarek (akanarekbptccom)
The EMEA (now EMA) issued its first guideline for similar biological medicinal products in 2005, followed by detailed guidelines for specific products in subsequent years. Citing such issues as the development of biosimilar monoclonal antibodies, The WHO Guidelines on Evaluation of Similar Biotherapeutic Products, and EMA’s emphasis on the 3 R principles (replacement, reduction and refinement) in animal testing, EMA issued a few weeks ago a concept paper on revising their 2005 guideline to bring it more in line with these newer guidances. Recognizing that repeat dose toxicity studies in non-human primates recommended in it’s the earlier guidelines are of little relevance, the concept paper recommends that a risk-based approach for the design of non-clinical studies be used which takes into account the results of biochemical comparability studies, the availability of sensitive in vitro functional assays which are predictive of in vivo pharmacodynamics, and the feasibility and relevance of in vivo testing in a relevant species. With regards to human clinical trials, the concept paper recommends that the biosimilar guidelines should be revised to address the need for pharmacodynamic markers in Phase 1 studies and whether or not a biosimilar product can proceed to pivotal Phase 3 clinical trials if similarity to selected PK parameters have been met but relevant pharmacodynamics markers are not available. The concept paper also recommends updating the guideline to include examples of acceptable surrogate endpoints already recommended in guidelines for specific classes of biosimilar products, defining considerations for acceptance of pharmacodynamics markers for demonstration of clinical similarity, and the possibility of using a non-inferiority design for certain Phase 3 studies.
Given the technical advancements in the development of biosimilars over the past couple of years, it is encouraging to see EMA acknowledging this rapidly changing environment and embracing the idea of updating its original guidelines. The clarification on non-clinical requirements, especially the importance of defining reliable PK/PD markers for biosimilarity, and the possibility of using non-inferiority as an end-point for clinical trials should help accelerate the development and introduction of biosimilar products. The use of non-inferiority as a criterion for approval should allow faster, smaller, and less expensive clinical trials but comes with the disadvantage that such trials may make it more difficult to demonstrate interchangeability of a biosimilar product with the original innovator product. Neither the original guideline nor the current concept paper addresses what criteria would be necessary to establish interchangeability, the holy grail of biosimilars. Our reading of the concept paper and other recent activities and announcements from EMA, as well as the US FDA, suggest we are not likely to see any meaningful pathway towards interchangeability in the US or Europe anytime soon. This is a shame since the true potential for biosimilars will not be met until we have established guidelines for using these products completely interchangeably with the original innovator product as is currently the case for small molecule generic drugs.