FeatureThe search for biosimilars and biobetters
Introduction
During the past two decades, many new innovative biologics have been developed by companies for the treatment of cancer and non-cancer diseases. These products include rHuDNA-derived peptides and proteins for replacement therapy of hormones, hematopoietic and other growth factors, blood coagulation products, targeted immunotherapies and humanized monoclonal antibodies. By far the largest group of therapeutic proteins that has emerged comprises humanized monoclonal antibodies for the treatment of cancer and rheumatic diseases. Based on the therapeutic and economic successes of these products, a highly competitive industry has emerged to develop biosimilar drugs 1, 2, 3, 4, 5, 6, 7, 8. In addition, with increased experience with biologics, major efforts are underway to make novel products that have optimized efficacy and safety properties. These products are referred to as biobetters. As shown in Fig. 1, there are hundreds of biosimilars and biobetters currently under development globally. Biobetters are regulated as new drugs and as such require full safety and efficacy testing. Biobetters have been designed to make improvements in the pharmacokinetics, bioavailability or pharmacologic actions of existing biologic drugs profile. Often, a decrease in immunogenicity for biobetters is also a key goal. This article will update the development of biosimilars currently approved by the EMA and FDA.
The EMA created a pathway in 2004 and then established overarching guidelines supporting biosimilar development between 2004 and 2006, with recent guidance updates [9] (https://www.ema.europa.eu/documents/leaflet/biosimilars-eu-information-guide-healthcare-professionals_en.pdf). In general, applications for EMA approvals have proceeded at a more rapid rate than in the USA 10, 11, 12. The slow development of biosimilars in the USA has been attributed to several factors, including a lack of clear regulatory guidelines [13]. For example, the FDA introduced the concept of interchangeability, which added regulatory confusion 14, 15. In addition, anticompetition practices, lack of understanding about biosimilars in the medical community, the complexity of US reimbursement and medical payments, and the US legal and patent systems have all been attributed as factors impacting the establishment of biosimilar entrants, and all of these factors have probably contributed to the initially slow development of biosimilars in the USA. There are now 36 countries or regions that have a streamlined process for expedited biosimilar approvals. Biosimilars were foreseen to increase competition, thereby driving the costs of these agents down, ultimately benefitting patients and consumers.
The EU has been somewhat ahead of the USA in the number of approved biosimilar products, with the first product approved in 2006. At the time of writing, there are 46 biosimilar products approved by the EMA (Table 1). The products generally fall into two categories: (i) rHuDNA-derived peptides and proteins >100 AA; and (ii) monoclonal antibodies. One key point is that several large biotech and pharmaceutical companies have already entered this market; or have formed partnerships with smaller companies. In addition, there are also several new entrants into the areas of manufacturing, drug development and testing. It is also clear that multiple biosimilar products have been approved that will compete for market share.
The Center for Biologics Evaluation and Research (CBER) within the FDA regulates a wide range of biological products, including allergenic extracts (e.g., for allergy shots and tests), blood and blood components, gene therapy products, devices and test kits, human tissue and cellular products used in transplantation, and vaccines. The Center for Drug Evaluation and Research (CDER) within the FDA regulates other categories of biological products mostly produced by biotechnology methods, including monoclonal antibodies designed as targeted therapies in cancer and other diseases, cytokines, growth factors and enzymes. Human monoclonal biosimilars are therefore regulated by the CDER through a Biologics License Application (BLA) process. In the USA, the Biologics Price Competition and Innovation Act (BPCIA) of 2009 Section 351(k) of the PHS Act [42 U.S.C. 55 262(k)], added by the BPCIA, defined an Abbreviated Biologic License Application (aBLA) regulatory framework that would provide a pathway for the expedited process of development and marketing of biosimilars. The biosimilar development pathway with legislation passed as part of the Affordable Care Act was signed into law March 2010 [16]. However, many concerns were expressed concerning legal uncertainties and the amount of data that would be required for clinical trials, and it was predicted that the aBLA process might not be utilized by many companies [17]. Most companies have chosen the traditional BLA route for developing biosimilars, in the hope that they might prove to actually find innovative biobetters [17]. In addition, patient acceptance and physician use of biosimilars might require significant education to recognize the cost savings initially targeted by the BPCIA [18].
The first approval for a biosimilar drug in the USA occurred in 2015 under a 351(k) pathway (Table 2). However, in reality other biosimilars had been approved before this date in the USA under the 505(b)(2) route, effectively an abbreviated NDA relying on literature and other data not generated by the applicant (e.g., insulins used this path for approval but, being <100 AA in length, they are not covered by current biosimilar legislations). Therefore, this is still a relatively new market in the USA. Eight of the 12 FDA-approved products have previously been approved by the EMA. It is also clear that the rate of approvals in the USA is increasing.
Section snippets
Requirements for biosimilar development
The FDA and the EMA have issued many guidance documents pertaining to the development of biosimilars. Since the EU approved the first biosimilar in 2006, the EMA has played an active role in defining the regulatory framework for the development of these drugs. The EMA has defined overarching guidelines for the development of similar biological medicinal products (CHMP/437/04 Rev. 1) detailing nonclinical and clinical considerations. The EMA has also published general guidelines detailing the
A general regulatory strategy for biosimilar development
Given the current regulatory environment and the competitive nature of the marketplace, it is obviously important that companies developing biosimilars have strategies for drug development, testing and filing with global regulatory agencies that consider timelines and expenses. It is not uncommon for a biosimilar drug to take 5 years to complete all phases of development and testing at an expense approaching US$200 million. In developing a biosimilar drug, a stepwise approach is needed
General considerations for biobetters and concluding remarks
Although this article has focused on the development of biosimilars (Fig. 1), there are also many biobetters that are currently in development. Companies are developing many novel products that are truly designer proteins with increased PD properties and increased safety. These products are tested as new chemical entities requiring full preclinical and clinical testing. There have been several recent reviews on the types of structural changes that are being made in biobetters to achieve
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