2.1 Regulatory Frameworks
Generic drug manufacturers apply for marketing approval of generic drugs under the Abbreviated New Drug Application (ANDA) pathway established by FDA. Moreover, generic drug applications are termed “abbreviated” because they are generally not required to include preclinical and clinical data to establish safety and effectiveness. The generic manufacturer needs to demonstrate only pharmaceutical equivalence and bioequivalence between the generic and innovator products, in order to gain approval for their generic product. This approach cannot be extrapolated to biosimilars, however, because the active substance of a biopharmaceutical is a collection of large protein isoforms and not a single molecular entity, as is generally true for conventional small molecule drugs. Thus, the active substances in two products are highly unlikely to be identical and, therefore, unlike generics, biosimilars are only highly similar and not identical to the innovator products. These differences imply that biosimilars should not be approved and regulated in the same way as conventional generic drugs. The regulatory pathway for approval of biosimilars is more complex than for the generic innovator product because the design of a scientifically valid study to demonstrate the similarity of a highly process‐dependent product is not easy. Further, the analytical tests currently available are not sophisticated enough to detect the slight but important structural differences between innovator and biosimilar products. Modest differences may have clinical implications and pose a significant risk to patient safety. Therefore, it is considered necessary that biosimilars must be assessed for clinical efficacy and safety by valid preclinical and clinical studies before marketing approval.1
To maintain a sustainable launch of biosimilars, organizations must plan the market entry by considering the local administrative and regulatory conditions and aligning their launch strategy accordingly. Most developing markets that have such an administrative system have modeled it on those of the World Health Organization (WHO) or the European Medicines Agency (EMA). With the introduction of biosimilars, it was considered that the rules set up for generic small molecules were not reasonable to replicate for the approval of biosimilars. Starting with the EMA in 2005, regulatory jurisdictions around the globe started to create and execute explicit regulatory frameworks for biosimilars to guarantee the generation of safe and effective medications.
The approach established for generic medicines is not suitable for development, evaluation and licensing of similar biotherapeutic products (SBPs) since biotherapeutics consist of relatively large and complex proteins that are difficult to characterize.
– The World Health Organization
There are presently 36 nations, spread across most geographic regions of the world, that have biosimilar guidelines set up that regulate the approval and registration of these medications. Such guidelines provide biosimilar manufacturers/sponsors with guidance and direction on the most suitable method to demonstrate biosimilarity with the innovator/reference biologic including guidance on nomenclature/naming and demonstrating comparability for biosimilar drugs.2
2.2 Major Regulatory Jurisdictions
2.2.1 Food and Drug Administration
The Food and Drug Administration (FDA) regulates innovator biologics and biosimilar products through Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER). To obtain licensure for a new biologic, the sponsor (generally the manufacturer of the product) submits to the agency a biologics license application (BLA) with data demonstrating that the biologic, and the facility in which it is manufactured, processed, packed, or held, meet standards to assure that the product is safe, pure, and potent. The Biologics Price Competition and Innovation Act (BPCIA), enacted as Title VII of the Patient Protection and Affordable Care Act (ACA, P.L. 111–148), established an abbreviated licensure pathway for biosimilar biological products or biosimilars. To obtain licensure for a biosimilar, the sponsor submits to FDA a BLA that provides information demonstrating, among other things, biosimilarity based on data from analytical studies (structural and functional tests), animal studies (toxicity tests), and/or a clinical study or studies (tests in human patients).3
Since enactment of the BPCIA in 2009, as of 29 May 2019, 19 biosimilars, for nine reference products, have been licensed in the United States. However, many of these licensed biosimilars are not yet available to patients, primarily due to ongoing litigation, although various other factors may impact the uptake of biosimilars.4
2.2.2 European Medicines Agency
The EMA is the European Union (EU) body responsible for coordinating the existing scientific resources put at its disposal by Member States for the evaluation, supervision, and pharmacovigilance of medicinal products. The mission of the EMA is to foster scientific excellence in the evaluation and supervision of medicines, for the benefit of public and animal health. The agency provides the Member States and the institutions of the EU the best‐possible scientific advice on any question relating to the evaluation of the quality, safety, and efficacy of medicinal products for human or veterinary use referred to it in accordance with the provisions of EU legislation relating to medicinal products.5
2.2.3 Pharmaceuticals and Medical Devices Agency (Japan)
Until recently, reviews and related operations for pharmaceutical medications were handled by two organizations. The Pharmaceuticals and Medical Devices Evaluation Center (PMDEC) was the main product review body comprising of 8–10 specialists while the Organisation for Pharmaceutical Safety and Research (OPSR or KIKO or DO) was an independent consultation body. The PMDEC and KIKO worked closely together and both made use of “experts,” which would often comprise the same people. The Ministry of Health, Labour and Welfare (MHLW) supervised PMDEC and KIKO and granted approval. As part of the reforms that have been ongoing recently, the PMDEC and KIKO, along with the Japanese Association for the Advancement of Medical Equipment (JAAME), were merged in April 2004 to form the Pharmaceuticals and Medical Devices Agency (PMDA). The PMDA now handles the whole process from clinical study stage, providing “face to face” advice, through the approval phase and is also responsible for post marketing safety measures. The PMDA comprises 25 work sites, 6 groupings (or sections), and the Kansai and Hokuriku branches. The PMDA is currently attempting to accomplish objectives under the Third Medium Range Plan (2014–2018). The role of the PMDA is to provide consultations concerning the clinical trials of new drugs and medical devices, and to conduct approval reviews and surveys of the reliability of application data.6
2.2.4 Therapeutic Goods Administration (Australia)
The Therapeutic Goods Administration (TGA) is Australia's drug regulatory agency for therapeutic goods. It carries out appraisal and checking to guarantee therapeutic goods accessible in Australia are of an appropriate standard with the aim of guaranteeing that Australians have timely access to safe and efficacious therapeutic advances and innovative treatments.
The regulatory framework for biologicals medicines is based on the authorization premise of guidelines on human tissue and cell‐derived products and live animal cells, tissues, or organs that are provided and available in Australia
