Perspectives on the EU and US non-clinical regulatory requirements for biosimilar products: a case of spot the difference

There are currently over ten biopharmaceuticals with blockbuster sales, in excess of $1billion per annum. It is expected that within the next five years, this number will exceed two dozen, as more biologics, particularly monoclonal antibodies, enter the market and increase their penetration. It is clear that this trend is resulting in companies of all sizes filling their portfolio with such products in efforts to continue the successful development of new biological entities. However, by 2015, biologics worth $20billion in annual sales will undergo patent expiration, leaving their manufacturers open to competition from biosimilar/ similar biological products.

Unlike the process for development of generic versions of NCEs, which is well defined and highly prescriptive, the process and regulations surrounding biosimilar development are highly product type specific and are still in active development. This reflects the fact that large biological molecules have complex product characteristics and are produced by multifaceted, proprietary manufacturing processes, small changes in which can have a large impact on product characteristics. In turn, changes in these characteristics can have a marked impact on product safety and efficacy.

An illustration of the impact of manufacturing changes on product quality and subsequent efficacy and safety is the much cited example of pure-red-cell aplasia (PRCA) attributed to the formation of autoantibodies to erythropoietin (EPO) following dosing of patients with recombinant EPO. A single definitive cause was not identified but it is likely that manufacturing changes were in part responsible. Another example of biological product differences affecting regulatory approval as a result of concerns of the impact of such factors on safety and efficacy is that of Myozyme. The FDA determined that differences highlighted between product already licenced and manufactured at Genzymes Framingham facility and that made at it’s Allston facility indicated that they were not “similar”.

In recognition of the importance that manufacturing processes have on the product attributes (quality/safety and efficacy) of similar biological products guidance for manufacturers is emerging from regulators in different regions. This guidance shares a number of key features (and a few differences) which will be reviewed in this article.

The EMA position

Arguably furthest advanced in terms of requirements, the EMA guidance surrounding biosimilar development is organised as overarching guidance’s which contain important product definitions and discuss quality or non-clinical and clinical issues. These are underpinned by eight adopted and two draft product specific guidance’s.

The overarching guidance(1) allows the definition of similar biological medicinal product to be applied to many biological derived therapeutics including recombinant DNA derived proteins, immunologicals e.g. vaccines, blood/plasma derived products, and even advanced therapies such as gene and cell therapy products. Importantly, the initial guidance issued in 2005 highlights the need to identify a specific reference medicinal product at the outset of the development of a similar biological product marketed within the EU community. This reference product and the similar biological product are then used to generate a weight of evidence to demonstrate “similarity” of both products in a programme of quality, non-clinical and clinical studies. This is different to the recommendation by the WHO in their 2007 document “Guidelines on Evaluation of Similar Biotherapeutic Products” which allows for the use a reference product licenced in any country, provided it has a full data package of quality, safety and efficacy data and a suitable duration of marketed use.

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