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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.
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
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.
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.
To date, biosimilars have had only limited success in taking business away from the original biotech products. For example, Amgen stated in its Q1 earnings call for 2010 that biosimilar versions of Filgrastim had only taken a 3% market share from its branded product.
Biosimilars of erythropoietin (EPO) and human growth hormones (HGH) are encountering similar difficulties, with originator products still retaining by far the major part of the market.
However, with some leading biological products totalling sales of approximately $5 billion in 2009 in Europe and the US alone, taking even a small share of the sales would benefit healthcare payers and, naturally, biosimilar manufacturers. According to data from IMS Health, sales in Europe and the US totalled $5 billion for Amgen's Enbrel and $4.4 billion for Centocor's Remicade in 2009.3 If biosimilars were to take only 5% of the market share for each of these, it would equate to $250 million and $220 million, respectively. Biosimilars selling at 75% of the originator's price would be worth $187.5 million and $165 million, respectively.
These are not huge numbers, but they would grow as pressure comes from various groups for prescribers and healthcare institutions to switch to lowercost copies.
A major obstacle so far for biosimilar suppliers has been interchangeability, which is why its mention in the US legislation is so significant. The European experience has been a combination of national legislation prohibiting any interchange and reluctance on the part of prescribers to switch. Where sales have come up to now is a result of prescribers using the copy on a new patient. Therefore, the rate of uptake is dependent on the rate at which new patients are diagnosed.
The key factors to consider when entering the biosimilars market depend on whether a company is planning to enter a regulated or unregulated market because the operating parameters vary considerably. The issue of interchangeability is almost irrelevant in unregulated markets where products are selected on the basis of price. In this situation, low manufacturing costs and the ability to respond quickly to new orders are paramount.
By contrast, in regulated markets, the key factors are a company's ability to reach decision makers, and promote and detail their biosimilar products. In addition, companies will need to have deep pockets to fund both the expensive promotional efforts and the extensive pharmacovigilance programme, which a company is required to maintain for as long as they sell the biological product.
To summarise, the key factors that a biosimilar market should consider would be:
In this respect, biosimilars in unregulated markets will come to strongly resemble the characteristics of small molecule generics in regulated markets, with price being a dominant factor.
Peter Wittner is an independent consultant.
1. Richard Dicicco. Presentation give at the SMi Generics & Supergenerics conference, London, May 2010.
2. H. Schellekens and E. Moors, Nature Biotechnology 28(1), 28–31 (2010).
3. Generic Medicines: Essential contributors to the long-term health of society (IMS, London, 2009).