Wednesday, September 23, 2015


 Manufacture of “similar biologics” by entrepreneurs other than the original inventors give rise to ‘products’, which will always be different from the original ‘inventor’s products’ because of one reason or the other. Even if the “similar biologics” are manufactured using the same human “gene/s” as those used by the   ‘inventor companies’, cloning of the gene/s into a “DNA vector” followed by its/their transfer into “host cells”, where production will take place can be different. Host cells can generally either be “bacterial cells” or “yeast cells” or “mammalian cells”. Usually to have access to the same host cells is always not feasible and practical. However, near equivalent “host cells” can be obtained where the cloning of the “target human gene” can be carried out using a “suitable DNA vector” for  effecting transfer into “host cells”.

‘Host cells’ are the cells where the “similar biologics” are transcribed and translated (produced). Currently world over, three kinds of “host cells” are used as mentioned above. Among the “bacterial cells”, a wide range of Escherichia coli (E. coli) are used for expressing “similar biologics”. Among the “yeast cells”, use is made of a wide range of Saccharomyces cerevisiae, Pichia pastoris and Hansenula polymorpha. Among the “mammalian cells”, used as host cells are the  Chinese Hamster Ovary (CHO), Bos primigenius (Bovine), Mus musculus (Mouse), Human Embryonic Kidney(HEK) cells and Baby Hamster Kidney (BHK) cells; among these again the most widely used and characterized cell lines are the CHO cell lines.

By using specific types of “host cells” close to the inventor’s host cells, while the expressed “similar biologics” would be ‘similar’ to the inventor’s products, the other metabolites remaining adherent to the “similar biologics” would be different and therefore the downstream processing technologies would have to take care of purifying/isolating the active “similar biologics” in a manner that would make the “similar biologics” closely similar to the inventor’s product. Often this is not exactly feasible to be duplicated as the downstream processing methods of different companies are different.

Further, once the bulk “similar biologics” are manufactured, these are to be formulated into finished medicines; during the manufacture of formulated products also, differences can crop up. Because of these inherent limitations, “similar biologics” are never considered to be the ‘exact copies’ of the inventor’s products, although the “similarities” would certainly be very high and often more than 99.5% coherent in physic-chemical , biological and clinical manifestations. The small differences in many situations cannot even be quantified by the instruments that are available presently to people. Generally therefore, ‘Regulators’ all over the world define physic-chemical and biological properties of the inventor’s products and ask the manufacturers of “similar biologics” to comply with such defined properties. In addition, the Regulators also insist on developing clinical data on human subjects to ensure that the “similar biologics” are mimicking all the properties of the inventor’s products in terms of efficacy and safety.

 It is also the desire of the Regulators to get information generated through clinical trials for “similar biologics” to demonstrate comparable safety and efficacy to the “inventor’s/reference products” in terms of PK/PD comparability data from the Phase I trial onwards. If the Phase I clinical trial data show congruence in PK/PD comparability data moving to the Phase III trials becomes easier. Merely based on Phase III trials without supporting PK/PD data through Phase I is usually not acceptable. On a risk based approach, the three-arm Phase I trials are increasingly being used to demonstrate comparability between the “similar biologics” and the inventor’s products/reference products.

PK refers to ‘pharmacokinetic’ and PD refers to ‘pharmacodynamic’ modeling , which are techniques that require studies of time course of effects of intensity of dose -response of  ‘similar biologics’ formulations in patients/target study populations . The study is integrated in to a set of mathematical expressions that enable description of the effect of the dose of ‘similar biologics’ formulations over a period of time. Presently, there exist several models of studying the PK/PD values and the manufacturers of ‘similar biologics’ are required to generate data in accordance with the requirements of the ‘Regulators’ in each country.

 Even with such stringent regulatory requirements, several manufacturers have come out to develop “similar biologics” after the expiry of the patents as the market  for ‘similar biologics’ is very large, the prices are quite high (remunerative), thus guaranteeing faster paybacks even though the prices are lower than the prices of the inventor’s products. Presently, some 425 “similar biologics” are in the development pipeline world over and more than 350 companies are globally involved in the development of “similar biologics”. The global interest in developing “similar biologics” is increasing very fast as is evidenced by some eight fold increase in the number of clinical trials of “similar biologics” between 2007 and 2014 (rising from 5 trials in 2007 to over 40 trials in 2014).
(Source:  , Challenges in Global Biosimilar development: A regulatory perspective-CONTRACTPHARMA.COM, Jun 02, 2015 Issue).

 Almost all countries are coming out with guidelines for introducing “similar biologics” within their territory as these would ease availability of such life saving products in the local market. The European Union came out with its guidelines on “similar biologics” in 2005. Following suit came out Australia in 2007; Malaysia, Turkey and Taiwan in 2008; Japan, Korea, Singapore and WHO in 2009; Brazil, Canada, Saudi Arabia and South Africa in 2010; Argentina, Cuba, Iran, Mexico and Peru in 2011; Columbia, Egypt, Jordan, Thailand, India and USA (Draft) in 2012; European Union with their revised guidelines in 2014; and China in 2015. At present, there are globally more than 150 reference products for “similar biologics” to emulate and that about 40 of these have sales of more than USD 1 billion per year. If any one of more of “similar biologics” companies can capture even 5-10% of the market, these would mean considerable profits besides establishment of the image of global presence.  This is therefore the right time and precious opportunity  for the entrepreneurs of venturing in to right  projects on ‘similar biologics’ in developing and developed world.

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