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:
http://www.contractpharma.com/issues/2015-06-01/view_features/challenges-in-global-biosimilar-development-a-regulatory-perspective/ ,
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.
