Biosimilars: Is It Worth Taking On The Regulators?

Aug 01, 2010
Volume 22, Issue 8

The full version of this biosimilars feature can be read in the August issue of our digital magazine:

Peter Wittner
The different pathways to regulatory approval of a biosimilar vary worldwide, ranging from no pathways at all in some developing countries, to the complex and precise mechanism that exists in Europe. In general, however, regulated markets demand that the applicant conduct a series of studies designed to prove clinical equivalence of the copy to the original, as well as lack of immunogenicity. These requirements make the development phase much more expensive and the regulatory phase far more time consuming compared with generics where a simple bioequivalence study will suffice.

European authorities have had clear guidelines for biosimilars in place for several years. The European Medicines Agency (EMA) has also refined these guidelines to cover specific classes of biosimilar products in more detail. To quote one example by way of illustration: "The Guideline on similar biological medicinal products containing biotechnologyderived proteins as active substance: nonclinical and clinical issues (EMEA/CPMP/42832/05/) lays down the nonclinical and clinical requirements for soluble insulin containing products claiming to be similar to another one already marketed." The document then details what data are required in these categories and subcategories:

• Non-clinical studies

1. Pharmacodynamic studies

i. in vitro studies

ii. in vivo studies

2. Toxicological studies.

• Clinical studies

1. Pharmacokinetic studies

2. Pharmacodynamic studies

3. Clinical efficacy studies.

• Clinical safety

1. Immunogenicity

2. Local reactions

• Risk management /pharmacovigilance programme.

This example shows how thorough the EMA has been in setting out its requirements and leaves no doubt about what is required. The downside of this is the high cost of compliance with what is, in the opinion of some, an excessively cautious approach. Estimates suggest that clinical development costs for a product such as Filgrastim (GCSF) could range from approximately $0.5 million for unregulated markets up to around $5 million in more regulated countries.1 Writing in a recent Nature Biotechnology Commentary article, Professor Huub Schellekens and Dr Ellen Moors of Utrecht University in The Netherlands suggested: "Clinical trials required by European regulators to compare biosimilar products with corresponding biologic brands are surplus to requirements and may even be a barrier for the development of biosimilars of more complicated biologics".2

At the opposite end of the scale are lessdeveloped markets where regulators may ask for virtually no data before allowing a biosimilar product to reach the market, thereby risking exposing the local population to possible side effects from poorly manufactured medicines.

Will interchangeability ever be a reality?

Until the Obama government pushed the Healthcare Reform Bill (HR3590) through at the end of February, there was not even a legal basis for the FDA to create a regulatory mechanism for biosimilars. Instead, such products would have to go through a registration process virtually identical to that used by NCEs. Given the highly litigious nature of the US, the FDA will probably err on the side of caution when developing its own biosimilar approval process. It is also probable that the agency will model some processes that the EMA already has in place.

Now that a legislative framework exists to enable the FDA to create a biosimilar approval process, the agency is going to be under pressure to come up with a mechanism as soon as possible. The US Generic Pharmaceutical Association (GPhA) has cited examples of highcost medicines that could be replaced by biosimilars, such as Roche/Genentech's Avastin, which costs about $100000 per patient per year, and Genzyme's Cerezyme, which can cost more than $300 000 per patient per year. The association has estimated "projected savings from $42 billion on the low end to as high as $108 billion over the first 10 years of biogeneric market formation."

Interchangeability of an originator product and a biosimilar is directly addressed in the US legalisation. However, there is no guarantee that the FDA, once it has a mechanism in place, will ever actually deem any biological copy product to be 100% interchangeable with the originator.

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