Biosimilar

Approval of medicines in the EU relies on a solid legal framework, which in 2004, introduced a dedicated route for the approval of biosimilars. The EU has pioneered the regulation of biosimilars since the approval of the first one (the growth hormone somatropin) in 2006. Since then, the EU has approved the highest number of biosimilars worldwide, and consequently has the most extensive experience of their use and safety. All medicines produced using biotechnology and those for specific indications (e.g. for cancer, neurodegeneration and auto-immune diseases) must be approved in the EU through the EMA (via the so-called 'centralised procedure'). Nearly all biosimilars approved for use in the EU have been approved centrally, as they use biotechnology for their production. Some biosimilars may be approved at national level, such as some low-molecular weight heparins derived from porcine intestinal mucosa. When a company applies for marketing authorization at EMA, data are evaluated by EMA's scientific committees on human medicines and on safety (the CHMP and PRAC), as well as by EU experts on biological medicines (Biologics Working Party) and specialists in biosimilars (Biosimilar Working Party). The review by EMA results in a scientific opinion, which is then sent to the European Commission, which ultimately grants an EU-wide marketing authorization.[8]

In the United States, the Food and Drug Administration (FDA) held that new legislation was required to enable them to approve biosimilars to those biologics originally approved through the PHS Act pathway.[9] Additional Congressional hearings have been held.[10] On March 17, 2009, the Pathway for Biosimilars Act was introduced in the House.[2] See the Library of Congress website and search H.R. 1548 in 111th Congress Session. Since 2004 the FDA has held a series of public meetings on biosimilars.[11][12]

The FDA gained the authority to approve biosimilars (including interchangeables that are substitutable with their reference product) as part of the Patient Protection and Affordable Care Act signed into law by President Obama on March 23, 2010.

The FDA has previously approved biologic products using comparability, for example, Omnitrope in May 2006, but this like Enoxaparin was also to a reference product, Genotropin, originally approved as a biologic drug under the FD&C Act.[13]

On March 6, 2015, Zarxio obtained the first approval of FDA.[14] Sandoz's Zarxio is biosimilar to Amgen's Neupogen (filgrastim), which was originally licensed in 1991. This is the first product to be passed under the Biologics Price Competition and Innovation Act of 2009 (BPCI Act), which was passed as part of the Affordable Healthcare Act. But Zarxio was approved as a biosimilar, not as an interchangeable product, the FDA notes. And under the BPCI Act, only a biologic that has been approved as an "interchangeable" may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. The FDA said its approval of Zarxio is based on review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen.

In March 2020, most protein products that were approved as drug products (including every insulin currently on the market as of December 2019) are scheduled to open up to biosimilar and interchangeable competition in the United States.[15] However, "chemically synthesized polypeptides" are excluded from this transition, which means that a product that falls within this category won't be able to come to market as a biosimilar or interchangeable product, but will have to come to the market under a different pathway.[15]

Cloning of human genetic material and development of in vitro biological production systems has allowed the production of virtually any recombinant DNA based biological substance for eventual development of a drug. Monoclonal antibody technology combined with recombinant DNA technology has paved the way for tailor-made and targeted medicines. Gene- and cell-based therapies are emerging as new approaches.

Recombinant therapeutic proteins are of a complex nature (composed of a long chain of amino acids, modified amino acids, derivatized by sugar moieties, folded by complex mechanisms). These proteins are made in living cells (bacteria, yeast, animal or human cell lines). The ultimate characteristics of a drug containing a recombinant therapeutic protein are to a large part determined by the process through which they are produced: choice of the cell type, development of the genetically modified cell for production, production process, purification process, formulation of the therapeutic protein into a drug.

After the expiry of the patent of approved recombinant drugs (e.g., insulin, human growth hormone, interferons, erythropoietin, monoclonal antibodies and more) any other biotech company can develop and market these biologics (thus called biosimilars). Every biological (or biopharmaceutical products) displays a certain degree of variability, even between different batches of the same product, which is due to the inherent variability of the biological expression system and the manufacturing process.[16] Any kind of reference product has undergone numerous changes in its manufacturing processes, and such changes in the manufacturing process (ranging from a change in the supplier of cell culture media to new purification methods or new manufacturing sites) was substantiated with appropriate data and was approved by the EMA. In contrast, it is mandatory for biosimilars to take a both non-clinical and clinical test that the most sensitive clinical models are asked to show to enable detection of differences between the two products in terms of human pharmacokinetics (PK) and pharmacodynamics (PD), efficacy, safety, and immunogenicity.

The current concept of development of biosimilar mAbs follows the principle that an extensive state of the art physicochemical, analytical and functional comparison of the molecules is complemented by comparative non-clinical and clinical data that establish equivalent efficacy and safety in a clinical "model" indication that is most sensitive to detect any minor differences (if these exist) between biosimilar and its reference mAb also at the clinical level.

The European Medicines Agency (EMA) has recognized this fact, which has resulted in the establishment of the term "biosimilar" in recognition that, whilst biosimilar products are similar to the original product, they are not exactly the same.[17] Every biological displays a certain degree of variability. However, provided that structure and function(s), pharmacokinetic profiles and pharmacodynamic effect(s) and/or efficacy can be shown to be comparable for the biosimilar and the reference product, those adverse drug reactions which are related to exaggerated pharmacological effects can also be expected at similar frequencies.

Originally the complexity of biological molecules led to requests for substantial efficacy and safety data for a biosimilar approval. This has been progressively replaced with a greater dependence on assays, from quality through to clinical, that show assay sensitivity sufficient to detect any significant difference in dose.[18] However, the safe application of biologics depends on an informed and appropriate use by healthcare professionals and patients. Introduction of biosimilars also requires a specifically designed pharmacovigilance plan. It is difficult and costly to recreate biologics because the complex proteins are derived from living organisms that are genetically modified. In contrast, small molecule drugs made up of a chemically based compound can be easily replicated and are considerably less expensive to reproduce. In order to be released to the public, biosimilars must be shown to be as close to identical to the parent innovator biologic product based on data compiled through clinical, animal, analytical studies and conformational status.[19][20]

Generally, once a drug is released in the market by the FDA, it has to be re-evaluated for its safety and efficacy once every six months for the first and second years. Afterward, re-evaluations are conducted yearly, and the result of the assessment should be reported to authorities such as FDA. Biosimilars are required to undergo pharmacovigilance (PVG) regulations as its reference product. Thus biosimilars approved by the EMA (European Medicines Agency) are required to submit a risk management plan (RMP) along with the marketing application and have to provide regular safety update reports after the product is in the market. The RMP includes the safety profile of the drug and proposes the prospective pharmacovigilance studies.

Several PK studies, such as studies conducted by Committee for Medicinal Products for Human Use (CHMP), have been conducted under various ranges of conditions; Antibodies from an originator's product versus antibodies from an biosimilar; combination therapy and monotherapy; various diseases, etc. on the purpose to verify comparability in pharmacokinetics of the biosimilar with the reference medicinal product in a sufficiently sensitive and homogeneous population. Importantly, provided that structure and function(s), pharmacokinetic profiles and pharmacodynamic effect(s) and/or efficacy can be shown to be comparable for the biosimilar and the reference product, those adverse drug reactions which are related to exaggerated pharmacological effects can also be expected at similar frequencies.

The European Union has the largest number of approved biosimilar medicines up to date. The EMA's scientific committees evaluate the majority of marketing authorization applications for biosimilar medicines before they can be approved and marketed in the EU. The EMA evaluates biosimilars according to the same standards of pharmaceutical quality, safety and efficacy that apply to all biological medicines approved in the EU.

Source: European Medicines Agency (June 2020) https://www.biosimilars-nederland.nl/wp-content/uploads/2020_06_01-Table-EU-licensed-biosimilars-by-molecule_May_2020agv.pdf

The 2012–2019 patent cliff.[83] Period of market exclusivity up to date of patent expiration for the ten top-selling biologics for 2011. *Enbrel has been granted approval in 2011 for a patent filed in 1995, extending its patent life further 17 years.

The legal requirements of approval pathways, together with the costly manufacturing processes, escalates the developing costs for biosimilars that could be between $75–$250 million per molecule.[83] This market entry barrier affects not only the companies willing to produce them but could also delay availability of inexpensive alternatives for public healthcare institutions that subsidize treatment for their patients. Even though the biosimilars market is rising, the price drop for biological drugs at risk of patent expiration will not be as great as for other generic drugs; in fact it has been estimated that the price for biosimilar products will be 65%-85% of their originators.[83] Biosimilars are drawing market's attention since there is an upcoming patent cliff, which will put nearly 36% of the $140 billion market for biologic drugs at risk (as of 2011), this considering only the top 10 selling products.[83]

The global biosimilars market was US$1.3 billion in 2013 and is expected to reach US$35 billion by 2020 driven by the patent expiration of additional ten blockbuster biologic drugs.[84][85]

Certain companies (in some cases subsidiaries) tend to operate as generic drug manufacturers, with major ones including Teva, Mylan, and Sandoz[86] and may also extend that focus to biosimilars. Sandoz, for example, introduced the first biosimilar in the United States, and plans to introduce another in 2020.[87] Newer companies such as India-based Sun Pharma, Aurobindo Pharma, and Dr. Reddy's Laboratories as well as Canada-based Apotex have taken share in traditional generics, which has led older companies to shift their focus to complex drugs such as biosimilars.[88]

• Udpa N, Million RP (January 2016). "Monoclonal antibody biosimilars". Nature Reviews. Drug Discovery. 15 (1): 13–4. doi:10.1038/nrd.2015.12. PMID 26678619.
• Jelkmann W (October 2010). "Biosimilar epoetins and other "follow-on" biologics: update on the European experiences". American Journal of Hematology. 85 (10): 771–80. doi:10.1002/ajh.21805. PMID 20706990.
• "New guide on biosimilar medicines for healthcare professionals". Prepared Jointly by the European Medicines Agency and the European Commission. Retrieved 10 May 2017.
• https://www.pbs.org/newshour/bb/whats-keeping-generic-version-biologic-drugs-u-s-market/
• Therapeutics, Initiative (November 2019). "Biosimilars or Biologics: What's the difference?". Therapeutics Letter 123.