development of subcutaneous ( SC ) formulations which are designed to be self-administered at home . This innovation serves to reduce the burden on hospital outpatient services and enhance patient convenience . It is therefore paramount to obtain ‘ buy-in ’ from both prescribers and patients through appropriate patient-centered education and clinical support as these are likely to improve treatment adherence and ultimately better clinical outcomes .
The Affordable Care Act and the abbreviated approval process for the FDA approval of biosimilars The enactment of the 2009 Patient Protection and Affordable Care Act ( ACA ) included the adoption of the Biologics Price Competition and Innovation Act ( BPCIA ), which encouraged the drug development process geared towards manufacture of biosimilars . 4 Congressional approval was provided for an abbreviated licensure process for drug products that were demonstrated to be biosimilar to drug products already approved by the US FDA . The major driving factor for this congressional process was the need to significantly reduce US health care-associated costs and ameliorate the burden on the consumer as the end-user . At time of writing , the FDA has approved 39 biosimilars in total , with 22 in the oncology and supportive care space . 4
Although it takes time to collect substantial cost data regarding the use of biosimilars , studies conducted using biosimilars manufactured using the abbreviated approval process show significant gains in cost reduction . Mulcahy et al analyzed the market share for the first-ever FDA-approved biosimilar drug called filgrastim-sndz ( Sandoz ’ s Zarxio ® ), a biosimilar of the filgrastim reference biologic Amgen ’ s Neupogen ® , which was approved via the abbreviated drug approval process . The authors found that Zarxio ® , approved in 2015 , had a 30 % lower pre-rebate price than the reference biologic in 2016 . 5
Biosimilar manufacturing process Although designated as clinically equivalent to a reference biologic compound , it is important that patients understand that biosimilars should not be perceived as the equivalent of a generic drug . Manufacturing a traditional small molecular medicine might include about 50 critical tests . Up to 250 or more critical tests need to be implemented during the process of manufacturing the large molecular biosimilar medicines . Biologics are complex , structural protein molecules or mixture of molecules and , because of their complexity , are manufactured in a highly controlled environment with complicated multi-step processes using living cells . Biologics and biosimilars are produced similarly via a process using genetic and bioengineering technology , however , it is almost impossible to produce an exact copy of the product . 6 One way to reduce the overall cost and uncertainty of supplies , and control and maintain the standards and specifications is to replace the traditional ‘ batch ’ production with an ‘ end-to-end ’ holistic and integrated manufacture process ( Figure 1 ).
First , the gene of interest which produces the relevant biosimilar protein has to be identified and once this has occurred , it is isolated and inserted into an expression vector or plasmid and then introduced into host cells that produce further copies of the protein . Commercially available host cell lines include bacteria ( for example , E . coli ), yeast , and even human cells , although Chinese hamster ovary ( CHO ) cells are commonly used . 7 The master cell lines producing the biosimilar protein are then extracted
FIGURE 1
End-to-end biosimilar manufacturing process
Cloning and protein expression
Source DNA incorporating target DNA
Production , purification and validation
Cell culture and cell bank
Recovery through filtration or centrifugation
Insertion of target DNA into expression vector
Purification processes
Insertion of vector into host cell ( e . g . CHO cells )
Characterisation and stability of final biosimilar product
to create the cell bank and cultured to produce a much larger quantity of the protein which is recovered through either filtration or centrifugation . Then a complex series of tests and analyses ( for example , amino acid analysis , peptide mapping , mass spectrometry , nuclear magnetic resonance , X-ray crystallography , CD spectroscopy , surface plasmon resonance , and the analysis of post-translational modifications ) follows to confirm that the structure , function and chemical identity of the biosimilar harvested is uniform in its quality attributes and similar to the reference biological drug . 6 Finally , the purified drug substance is formulated with other excipients , placed in a container and stored under the appropriate conditions .
While the aim of the manufacturing process is to create a biologic drug that has a high degree of similarity to the reference product , a major disadvantage for the traditional ‘ batch ’ biosimilar manufacturer is that it does not have access to the original starting material , that is , the recombinant DNA and mast cell line or clone . In addition , the impurity profile from the biosimilar manufacturer may also be slightly different from the reference product , and any changes in the cell culture medium or production methods can have an impact on the structure of the final protein . Nevertheless , the manufacturer is required to undertake a series of analyses to ensure that any differences to the reference product , such as structural changes , or slight differences in the production process , do not impact the biosimilar ’ s safety and clinical efficacy . Given these disparities , patients need to realize that a biosimilar is ‘ like ’ the reference product , but not an identical copy of their biologic reference product , which can lead to questions and concerns by healthcare professionals and patients about extrapolation . Extrapolation allows biosimilars successfully tested for one approved indication to extrapolate the safety and efficacy for additional indications that have been tested and approved for the reference biologics . Extrapolation significantly improved the patient access to biosimilars . Nevertheless , patients can be reassured that due to the rigorous testing requirements of the FDA , a biosimilar will provide the same safety , efficacy and purity , that
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