Biosimilar Developers Face a Reference-Product Dilemma - Does global development have to entail multiple comparability studies? - BioPharm International


Biosimilar Developers Face a Reference-Product Dilemma
Does global development have to entail multiple comparability studies?

BioPharm International
Volume 25, Issue 3, pp. 74

The issue is further complicated by the fact that most originators are already manufacturing in various global locations to provide for multiple markets. Their reference products will have been established and authorized using existing comparability guidelines (e.g., ICH Q5E Comparability of Biotechnological/Biological Products) and may in fact be highly similar in different countries, although licensed by different authorities. However, the biosimilar manufacturer has no way of knowing this.

Is there a case for regulatory flexibility here? I think not where the legal pathways are already established. Neither do I see the possibility of a single global RP recognized by and acceptable to all regulatory authorities. Although such options may make sense scientifically, there are too many obstacles. For instance, who would choose, source, authenticate, stock, and supply such reference material? Originator companies would not likely volunteer to provide this service.

As an analytical scientist, I think that conducting multiple physical/chemical studies with multiple RPs makes scientific sense. Carrying out such work may be costly but also provides key knowledge regarding the originator product, including quality changes tied to the product's life cycle and manufacturing location. Tracking the originator product and building a database of knowledge is therefore extremely important. However, the clinical and nonclinical issues are a different matter. Is it ethical to duplicate animal studies and clinical trials with the same biosimilar but "different" RPs?

The biosimilars industry is discussing this exact concern. Several suggestions have been mooted, mostly by companies aiming to streamline development of products targeted at more than one country or region. Proposals have included using just one RP from one ICH region but adding bridging studies to RPs from other ICH regions, or using different RPs up to Phase I and then using only one RP for Phase III. Other ideas involve recommending that the regulatory agencies collaborate to determine "sameness" of originators product in different regions. However, for any change to happen, the existing legal guidelines would need to be altered—and that is not a quick fix.

In the meantime, there appears to be no alternative. Global biosimilar development companies must adhere to the legal requirements of the individual countries where they seek authorization, no matter how costly and time-consuming it may be to repeat biosimilarity comparability studies.

Fiona Greer, PhD, is the global director of BioPharma Services Development at SGS M-Scan,


1. US Public Law 111-158, Patient Protection and Affordable Healthcare Act (March 2010).

2. EMA, Guideline on Similar Biological Medicinal Products (CHMP/437/04), (Sept. 2005).

3. FDA, Draft Guidances for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product; Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product; and Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (Feb. 2012).

4. WHO, Guideline on Evaluation of Similar Biotherapeutic Products (October 2009).

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