The BPCI Act authorised FDA to oversee a shortened path for the approval of biologicals that are ‘biosimilar’ to already approved products, and the Affordable Care Act established a path for approval of biosimilars. This is an enormous task for FDA, it faces technical and legal challenges and intensive scrutiny. It walks a tightrope between being an advocate for the consuming public that needs the drugs, and a hard-nosed regulator that challenges everything.

In November 2010, FDA held a two-day hearing on the potential approval pathway for biosimilars from pharmaceutical companies, pharmacy groups, academics and doctors who treat patients with biologicals, and allowed written submissions until the end of 2010 [1]. This was seen as the beginning of a dynamic process that would ‘never be finished’. The FDA’s Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research recently reported on progress [2].

The key technical challenge will be to demonstrate how similar a new biosimilar is. FDA points out that it has been assessing a variety of biosimilars since the mid-1990s, and has built up a considerable degree of expertise. For example, a generic low molecular weight heparin, enoxaparin, was examined by a ‘fingerprint’-like identification of very similar patterns in two different products. It hopes that the use of such techniques will reduce the need for additional animal and clinical studies on the biosimilar. FDA is also carefully analysing the data available from its counterparts in Europe at EMA, which published guidelines on biosimilars in 2005.

Initial EMA guidance has suggested product-specific requirements for structural, animal, and clinical studies. Given the complex nature of biologicals, it is unlikely that a ‘one size fits all’ systematic assessment of biosimilarity can be developed. The guidance is supportive of the totality-of-the-evidence approach favoured by FDA. FDA is at the same time designing the consultation process, by which companies considering applying to register a biosimilar approach the agency for guidance. The regulator has commented that ‘an extensive product review will be required to determine how much additional data are needed for a biosimilar’.

A risk-based approach is being developed that will consider a product’s complexity, formulation, stability and immunogenicity, among other things. Both originator and follow-on products will have to monitor safety during use, since in the past, slight changes to the manufacturing process have produced large changes in a product’s immunogenicity. A suitable pharmacovigilance system will have to be created.

The greatest technical challenge will be to establish to what extent the biosimilar is interchangeable with the originator product. Under the biosimilars statute, the new drugs will have the opportunity to meet a standard of ‘biosimilar’ or a higher standard of ‘interchangeable’. A biological will be considered interchangeable with a reference product if the developer demonstrates that it can be expected to produce the same clinical result in any given patient and that the risk associated with alternating or switching between the two products is not greater than that involved in continuing to use the reference product. This will extend the current practice in Europe, where biosimilars are regarded as similar, but not interchangeable.

So the agency will also develop standards to ensure that products not deemed interchangeable are not inadvertently substituted for a reference product without the prescriber’s consent.

It is therefore not surprising that the first applications for biosimilars to be marketed under the new rules have yet to be made. Patients will have to wait for years before competitor products become available to lower the price of their biological treatment.

Related article

FDA hearing on biosimilars: focus on characterisation and clinical trials

References

1. GaBI Online - Generics and Biosimilars Initiative. FDA holds public hearing on biosimilars pathway [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2011 November 04]. Available from: www.gabionline.net/Biosimilars/News/FDA-holds-public-hearing-on-biosimilars-pathway

2. Kozlowski S, Woodcock J, Midthun K, Sherman RB. Developing the Nation’s Biosimilars Program. N Engl J Med. 2011;365(5):385-8