By Alex Kanarek (akanarekbptccom) , Susan Jones (sjonesbptccom) , and Howard Levine (hlevinebptccom)
Following its trail-blazing issuance of guidelines for the approval of biosimilar well-characterized molecules such as insulin and human growth hormone, the EMA recently issued a draft guideline on biosimilar medicines containing monoclonal antibodies (MAbs).
Considering the complexity of MAbs, this brave step forward in the regulation of biosimilars is a welcome one. Unlike small proteins that are the subject of previously issued EMA guidances, the large size and highly variable glycan structures of MAbs make it difficult to fully define the exact composition of a MAb product. Even if one could, the clinical relevance of biochemical differences between the biosimilar and reference product is not always obvious. For example, XOMA and Genentech separately produced batches of efalizumab that were found to have only minor physicochemical differences, but gave notably different clinical results.
The draft guideline tackles these challenges in a rational and appropriate manner, laying out a well thought-out, stratified approach to the comparability studies that will be required for approval of a biosimilar MAb. As expected, the most critical component of these studies will be human pharmacokinetic and pharmacodynamic studies. The guidance also makes it clear that the focus in clinical trials for biosimilar MAbs should be the demonstration of similar efficacy and safety between the biosimilar product and the reference product, not patient benefit per se, and recommends that the most sensitive patient population and clinical endpoint should be used to better identify potential product-related differences.
The ability to extrapolate “clinical efficacy and safety data to other indications of the reference mAb, not specifically studied during the clinical development of the biosimilar mAb” will certainly accelerate their development and reduce the overall costs of bringing these products to market. While the possibility that post-market risk-management and pharmacovigilance programs may exceed those of the original innovator product, we believe such an approach is reasonable given the complexities of these products and the associated risk of unforeseen issues that may arise post-approval. This may deter some smaller companies from entering the biosimilar MAb race but larger companies are not likely to be discouraged and will undoubtedly see the guidance as a green light for development.
It is gratifying to see the EMA issuing guidances for all types of biosimilars. Europe continues to take the lead in establishing clear regulatory guidelines and requirements for biosimilars and is working diligently to allow European patients access to all types of biosimilar products. Canada will probably continue to follow the EMA’s lead so we expect a similar guidance from Health Canada soon. Meanwhile in the US, there are still no clear signposts on a regulatory pathway. FDA recently held a public hearing to discuss such a pathway but no clear progress has been made to date. Fortunately, the Senate preserved the mandate for biosimilars when it rejected the House’s recent vote to repeal the 2010 healthcare reform act. We hope that FDA now moves diligently to implement clear, reasonable guidelines and regulations for the development and approval of biosimilars in the US.