Challenges for the regulation of biosimilars

The European Medicines Agency (EMA) was the first agency to issue guidelines for the approval of biosimilars via an abbreviated registration process back in 2006. Since then the agency has developed many general and specific guidelines for biosimilars, as well as approved 18 biosimilars to date [1]. Tsiftsoglou and co-authors, however, believe that many challenges still lie ahead for this class of biologicals, some of which are discussed here [2].

Biosimilar versus reference biological
Since the development of the originator drug, technology has improved and therefore the biosimilar may, for example, be purer than the original reference product. This, however, does not necessarily mean that the new product is better than the reference product or that a comparability exercise would no longer be needed or would even be counterproductive. Better purification does not mean better clinical efficacy and safety profile. Any claims of being ‘better’ would have to be substantiated by appropriate data and could possibly contradict ‘biosimilarity’. On the contrary, a biosimilar is expected to be similar, or equivalent, in clinical efficacy and safety, and not better or worse than the reference drug.

Interchangeability and substitution
In the EU, EMA does not have the authority to designate biosimilars as being interchangeable with the reference product. However, in the US, the Biologics Price Competition and Innovation (BPCI) Act gives the US Food Drug and Administration (FDA) the authority to designate a biosimilar as interchangeable with its reference product [3]. FDA has not, however, released specific requirements for interchangeability, but they are expected to be stringent and conducting appropriate studies is also expected to be difficult [4]. Since it will be highly challenging to establish interchangeability of biosimilars, it has been questioned whether the ‘higher’ standard required for designation of interchangeability adds to the benefit for patients [5].

This subject has been hotly debated, especially in the current climate of budget restrictions. This has been recently demonstrated by the decision in France to introduce legislation allowing the substitution of biosimilars [6].

More complex biologicals
Although biosimilars have already reached a high level of complexity with the introduction of monoclonal antibody biosimilars, far more complex biologicals exist, for example, coagulation factors, vaccines, or advanced therapy medicinal products like gene therapies or cell-based medicinal products. When trying to apply the principle of ‘biosimilarity’ to such products, it will have to be considered whether physicochemical and biological tests are sensitive enough to compare a biosimilar to the reference product. Other questions include: what should be measured and compared, especially when comparing cells; are the methods sensitive enough to find differences; how should findings be interpreted; and how to decide if a finding is relevant or not?

In fact, FDA has even been lobbied by patient and industry groups to exclude plasma protein therapies (including coagulation factors) from its pathway for the approval of biosimilars. They argue that FDA should restrict these therapies from the biosimilar pathways until the science advances significantly, claiming that current science cannot confirm that any two of these products will have the same clinical outcome, or that there will be no additional risks if patients switch from one product to another [7].

The more complex a biological, the more it may be prone to inherent variability, which may hamper any comparability exercise and require large trials to be carried out. This may not only call into question whether biosimilars of more complex biologicals are possible, but also whether they are feasible.

Conflict of interest
The authors of the research paper [2] declared that there were no conflicts of interest.

Editor’s comment
Readers interested to learn more about biosimilars in Europe are invited to visit www.gabi-journal.net to view the following manuscript published in GaBI Journal:

Biosimilars in the European market

If you are interested in contributing a research paper in a similar area to GaBI Journal, please send us your submission here.

References

1. GaBI Online - Generics and Biosimilars Initiative. Biosimilars approved in Europe [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Apr 25]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe

2. Tsiftsoglou AS, Ruiz S, Schneider CK. Development and regulation of biosimilars: current status and future challenges. BioDrugs. 2013;27(3):203-211.

3. Chow S-C, Ju C. Assessing biosimilarity and interchangeability of biosimilar products under the Biologics Price Competition and Innovation Act. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(1):20-5. doi: 10.5639/gabij.2013.0201.004

4. GaBI Online - Generics and Biosimilars Initiative. Assessment of interchangeability under the BPCI Act [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Apr 25]. Available from: www.gabionline.net/Biosimilars/Research/Assessment-of-interchangeability-under-the-BPCI-Act

5. Ebbers HC, Chamberlain P. Interchangeability. An insurmountable 5th hurdle? Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(2): In print. Available from: www.gabi-journal.net/interchangeability-an-insurmountable-5th-hurdle.html

6. GaBI Online - Generics and Biosimilars Initiative. France to allow biosimilars substitution [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Apr 25]. Available from: www.gabionline.net/Policies-Legislation/France-to-allow-biosimilars-substitution

7. GaBI Online - Generics and Biosimilars Initiative. FDA urged to exclude plasma protein therapies from biosimilar pathway [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Apr 25]. Available from: www.gabionline.net/Biosimilars/General/FDA-urged-to-exclude-plasma-protein-therapies-from-biosimilar-pathway

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