Biosimilars: Review of the Global Approval Policies and Market in 2014

发布日期:2015-03-18访问次数: 信息来源:Bioon.com字号:[ ]

Zarzio, developed by Novartis as a biosimilar of Neupogen, an oncology drug patented by Amgen, has recently gained unanimous support from the FDA appraisal panel and it will most probably become the first biosimilar ever launched in the United States. The selling price of a biosimilar is lower than the reference listed drug by 20% - 30% on average and will help save up to US$ 25 billion in a decade.

There are certain differences in the definition of biosimilar in various countries. It is stipulated in the relevant FDA guidance that there should be no clinical difference between a biosimilar and its reference listed drug. The European Medicines Agency, or EMA, rules that they both should be made up of the identical biological substances in nature. The manufacturing process indicates that the products of any one batch produced under either genetic or cell engineering may be regarded as the biosimilars of the standard reference drugs, because “shifting” may take place in the products during the manufacturing process compared with the reference drugs as time goes by, which is particularly the case with the glycosylation level of proteins.

Significant Cost Reduction Expected

In order to successfully launch a biosimilar, the manufacturer must demonstrate the drug’s structural and functional characteristics in detail as well as the toxicity data of animal tests. In addition, the clinical research data based on the comparative immunogenicity and pharmacokinetics/ pharmacodynamics must be made available to evidence that the product is very similar to or identical with the reference drug and is safe and effective. The biosimilars may help save the costs for patients, government and insurance companies. For instance, the generic drugs of EPO helps reduce the cost by 35% to 50%.

2013 will be remembered as the most brilliant year for biosimilars, with the landmark event to be the launch in Europe of the generic drugs of Infliximab produced by Celltrion and Hospira. In comparison, the launch trend of biosimilars in 2014 has returned to a “normal” level, in spite of the poor performances with some products.

The launch in Europe of the generic drugs of Infliximab in 2013 has drawn extensive concerns in the industry due to many reasons. For instance, that was the first time for the biosimilars of polyclonal antibodies to be launched in Europe and that has also demonstrated a positive attitude held by the EMA in obtaining the generic drugs’ indications by means of extrapolation. The so-called extrapolation means that if a biosimilar is highly similar to the original bio-product and shares the similar pharmacokinetics, it’s OK if only the safety and efficacy data similar to the reference listed drug are available, while material evidences may not be required of the other indications. However, due to disputes over the intellectual property rights, the generic drugs made by Celltrion and Hospira can be launched in a couple of small counties in Europe for the time being. That suggests that the prospects for the monoclonal antibody biosimilars in Europe are not optimistic.

Norway has always been in a leading position in terms of application of biosimilars. In the market sector of anti-TNF monoclonal antibodies, the brand drugs seem to be less concerned about the competition from the generic drugs. Nevertheless, with the launch of the generic drugs made by Celltrion and Hospira in 5 European countries in February 2015, those brand drug manufacturers may be exposed to the pressure of competition. The 12 biosimilars that have been launched globally as approved also include the generic drugs of infliximab as launched in Canada. Differed from the EMA, Canada does not approve the generic drugs to be used in treatment of all indications of the reference listed drugs. And that may have an impact on the extent of the FDA’s implementation of the method of extrapolating the indications.

Difficulty in Classifying the Tiers of Generic Drugs

In July 2014, the FDA accepted an application for biosimilar as submitted by Sandoz, under which Amgen’s Filgrastim (recombinant human granulocyte colony-stimulating factor) would be duplicated. That was the first time for the FDA to have handled an application for biosimilars. The FDA has indicated recently that the oncology drug team as affiliated to it would organize an assessment in January 2015. However, the FDA has not yet published a guidance of comparison, which will help clarify whether or not a biosimilar is identical to the reference listed drug. And this guidance will bring about considerable impact on the market sector of biological products, especially monoclonal antibodies, in the United States.

Nevertheless, it may be pretty hard to distinguish the “identical generic drugs” and the “ordinary generic drugs” because even the latter are produced in accordance with very high standards. There are 2 ways, none of them is perfect, to help distinguish. Firstly it is stipulated that the identical generic drugs must have no difference in terms of the performance indicators, while the ordinary generic drugs may have non-significant difference as permitted. Secondly, it is stipulated that the identical generic drugs must have the identical therapeutic values as proved through clinical researches. So far, the EMA has issued no rule on the “identical generic drugs”, although it’s been stipulated in France that biosimilars may be deemed to have no difference from the reference listed drugs in pharmacies.

Although the EMA has approved the launch of the generic drug of Sanofi’s Lantus in September 2014, it imposes no looser administrative control compared with the drug regulatory authorities in other countries. For instance, the EMA has requested additional clinical researches over the generic drug of Herceptin by Celltrion, a South Korea-based pharmaceutical company.

The naming issue of the “identical generic drugs” has also drawn extensive attention. The WHO proposed in 2014 that the “identical generic drugs” should adopt the same names (such as the chemical drug names). However, the EMA, the FDA, as well as the reference listed drug producers and the generic drug producers prefer to adopt different names.

A Number of Drugs Prove to Have Remarkable Clinical Efficacy

A glimpse of the Phase-III clinical research results of a variety of biosimilars in 2014 suggests that the monoclonal antibodies, insulin, erythropoietin and granulocyte colony-stimulating factors etc. prove to have remarkable therapeutic values. Motivated by the increasing R&D initiatives, the reference listed drug manufacturers have been striving hard to safeguard their vested interests. In 2014, Johnson & Johnson and Amgen have filed litigations against, and won the lawsuits over, Sandoz and Celltrion in the US courts. Due to the court awards and extension of the patent terms, the launch of biosimilars may be extended for a couple of years in the United States, according to some analysts. Nevertheless, the case of Novartis’ Zarzio suggests that the launch of the first biosimilar in the United States will most probably be ahead of schedule.

Although the cooperation between the biosimilar R&D institutions and manufacturers has been declining over the past few years, there are 15 acquisition and cooperation events in 2014 and a number of them have taken place in the emerging markets.

A glimpse of the global layout suggests that at present, in all other areas than Russia, China, Central Asia and Africa, the control over biosimilar approval has basically been loosened up. By the end of 2014, there are a total of 280 biosimilars undergoing clinical trials around the world, with an annual growth rate of 20%. A total of 57 biosimilars are in Europe, the United States and India.

Pros and Cons over the Development in the Future

2015 is doomed to be an important year. The statistics indicate that after 2011, the patents of those best-selling biopharmaceutical products will expire one after another, rendering a market value of up to US$ 160 billion as expected, including Sanofi’s Lantus, which has been ranking among the top few in the global sales volumes over the years and Amgen’s Neulasta. Therefore, the potential opportunities of biosimilars may hit a crest value in 2015.

Someone argues, however, that the launch process of biosimilars may be very slow and in the course of appraisals, there are disagreements even inside the FDA and it is predicted that things may get done rather smoothly in about a decade. In terms of clinical application, many doctors still hold suspicion over the safety and efficacy of biosimilars and many relevant personnel have indistinct understanding of biosimilars. Therefore, maybe only time can prove whether or not the real situation of the biosimilar market in the future is as promising as demonstrated by the forecast data.


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