To meet this end, aspects such as patient population, primary endpoints, and study design (equivalence vs. non-inferiority) must be carefully considered by the sponsors. While the regulatory pathway for biosimilars in the U.S. was created as part of the Affordable Care Act in March 2010, the first biosimilar was only recently approved for the U.S. market in March 2015. Dougherty and her coauthors explain the history of the US biosimilar approval pathway as laid out by the BPCIA, which requires that a proposed biosimilar product demonstrate, through a stepwise development approach, that is has the same strength, route of administration, and dosage form as the FDA-approved reference biologic, and that it uses the same mechanism of action (MOA) for the proposed conditions of use that the reference product previously showed during its approval process. For instance, the study EMR200588-002 measured the PASI75 response rate at week 16 for the Fresenius Kabi molecule MSB11022 compared to the EU-sourced Humira (Table 5). Biosimilars are highly similar to the original biologics. Then the reference product sponsor has 60 days to respond with its own positions on infringement and patent validity, and then, following further negotiations, the reference product sponsor can bring action for patent infringement. InAmgen v. Sandoz(see docket entry #105), for instance, the Northern District of California said the 'dance' is not necessary, though Amgen also filed alawsuitalleging that Apotexs biosimilar of Neulasta (pegfilgrastim) infringes two Amgen patents, which was the first time companies actually conducted the 'dance'. Recently (March 2020), some of these products were deemed to be Biologic License Applications (BLAs) and have been removed from FDAs Orange Book and added to the FDAs Purple Book: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations [6,7]. And the label should be written in a manner that does not imply that the biosimilar product is approved for a reference product indication(s) or use(s) that has not been approved for the biosimilar product, the draft guidance says. In this guide, biologics refers to genetically engineered proteins produced by living cells. In part, this appears to be because it enables a biosimilar manufacturer to challenge a RBPs key patents in a single forum rather than multiple nation state patent courts. HHS Vulnerability Disclosure, Help Japans Ministry for Health, Labour and Welfare (MHLW) has approved nine biosimilars (which includes insulins) between 2009 and 2016, according to GaBI, and released industry guidance on biosimilars back in 2009 (for more perspective on Japans experience with biosimilars, check out this article in The Lancet from officials from Japans Pharmaceuticals and Medical Devices Agency). Although the BPCIA established the pathway whereby biosimilars can reach the market in the US, states (heavily influenced by lobbyists from the biopharma industry) have taken the matter of substituting biologics for biosimilars into their own hands. EMA questions and answers on biosimilar medicines (similar biological medicinal products), US FDAs Purple Book: Lists of Licensed Biological Products in the US with Reference Product Exclusivity and Biosimilarity or, Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 Guidance for Industry, From FDAs perspective: Biosimilar product labeling, FDA Webinar - FDAs Overview of the Regulatory Guidance for the Development and Approval of Biosimilar Products in the US, The Biologics Law Blog of Patterson Belknap Webb & Tyler, NCSL STATE LAWS AND LEGISLATION RELATED TO BIOLOGIC MEDICATIONS AND SUBSTITUTION OF BIOSIMILARS, Tags: biologics, biosimilar, biosimilars, BPCIA, dance, patent, savings, Regulatory Affairs Professionals Society (RAPS) Because of the complexity of biosimilars and the difficulty of manufacturing them, the cost of any given biosimilar is generally higher than the cost of a generic. Objectives: The purpose of this article is to explore the history of biosimilars, regulatory pathways, and barriers to biosimilar approval. Lastly, the market status for each biosimilar was checked in the Biosimilar Approval Status table provided by the Biosimilars Review & Report website [20]. The FDA has seen a steady increase in biosimilar development programs since the passage of the Biologics Price Competition and Innovation Act of 2009 (BPCIA), with 9 biosimilars approved by the end of 2017 and 68 active biosimilar programs in development. All studies presented in Table 4 are similarity studies, carried out in a similar number of healthy male and female adults, involving a single 40 mg subcutaneous (SC) injection. For reference, aspirin is 180 daltons and paclitaxel is 854 daltons. Biosimilars and generics differ not only in size, stability and characterization, but also in how they are made, how they behave over time and their mode of action. Before development of the FDA biosimilar path, a series of biological, including follow-on, products had been approved as New Drug Applications by the FDA. Drug, biologic and biosimilar companies, meanwhile, are debating (in comments on FDAs draft guidance on biosimilar labeling) over whether to include a biosimilars interchangeability status on each new product's label. The relevant regulatory authority applies stringent criteria in their evaluation of the studies comparing the quality, safety and effectiveness of the two medicines. A research study using human subjects to evaluate biomedical or health-related outcomes. Developing the Totality of Evidence for Biosimilars: Regulatory Considerations and Building Confidence for the Healthcare Community. Only one adalimumab biosimilar, Pfizers Abrilada, that holds an FDA approval but does not hold an EMA approval, was not included in this case study. The Biosimilar Regulatory Approval Pathway . European Medicines Agency (EMEA, currently EMA) and Food and Drug Administration (FDA) repositories were searched to identify all biosimilar medicines approved before December 2019. The growth of the EU biosimilar market between 20062019 (see Figure 2) has not been steady and several approval surges were found. FOIA Troein P., Newton M., Pate J., Scott K. The Impact of Biosimilar Competition in Europe. The World Health Organization (WHO) refers to them as similar biotherapeutic products (SBPs) and defines them as highly similar to an original biotherapeutic product [3] and developed and assessed according to the regulatory guidelines that ensure an adequate comparison of the SBP with its RBP [3]. However, the Biosimilars Councilopposed FDA's proposal, claiming that "adding a suffix is unnecessary and does not achieve the Agency's stated goals as it will lead to confusion among prescribers and patients." Data taken from [12,18]. Studies that examine the relationship between dose, plasma concentrations, and therapeutic or toxic effects. The health information contained herein is provided for educational purposes only and is not intended to replace discussions with a healthcare provider. 7 The most sensitive population group must be chosen in order to allow an accurate detection of clinically meaningful differences [26]. This work looked into the landscape of the European and US biosimilar products, their regulatory authorization, market availability, and clinical evaluation undergone prior to the regulatory approval. Long before the BPCI Act was enacted, the regulatory pathway for the approval of biosimilar products (similar biological medicinal products) has been established in the EU in 2003 , . The FDA bases evaluations of substitutability, or therapeutic equivalence, of generic drugs on scientific evaluations. As the US Food and Drug Administration (FDA) notes: Both biologics and biosimilars are isolated from a variety of natural sources human, animal or microorganism and can be composed of sugars, proteins, nucleic acids or complex combinations of these substances, or they may even be living entities, such as cells and tissues. Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK; Received 2020 Nov 17; Accepted 2020 Dec 28. All rights reserved. Eight EU-approved biosimilar products, corresponding to five different originators, for the monoclonal antibody adalimumab were found (Table 3), three of which also held an FDA approval. The information provided in this website is intended only for healthcare professionals in the United States. The chronological evolution of BS legislation and guidelines by the WHO, FDA, and EMA is outlined in Figure 1. The EU and the US have some differences in the way they approach biosimilars. 2022 MJH Life Sciences and Center for Biosimilars. According to Goodwin Proctor, the reference product sponsor may not list a greater number of patents than the biosimilar applicant does. EPO has 38 contracting states and provides unified patent prosecution and opposition with the option for national patents by applicant choice after prosecution. The webinar provides an overview of the regulatory requirements at different stages of biosimilar development - CMC, pre-clinical and clinical and approval process in India. Biosimilars require robust regulatory pathways The biosimilar approval pathway requires the manufacturer to demonstrate similarity with the reference product for quality, safety and efficacy. Additional Resources: Supplemental materials/activities. The US system then tried to shoot itself in the foot with the "patent dance," which also does not exist in the EU. The latter represents a highly challenging area that requires further research, as many healthcare professionals are trying to grasp the basis of extrapolation in order to determine the suitability of biosimilars for their patients [23]. The biosimilar manufacturer should assemble all available knowledge of the reference product with respect to the type of host cell, formulation and container closure system. As illustrated in the report Biosimilars in the USA [1], the introduction of biosimilars in the US market is more difficult due to the complexity of their healthcare system and financing. Adalimumab was chosen as case study as it was the biological reference product with the largest number of biosimilars and therefore, more documentation was available to review. The 70 results were reviewed individually to establish the reference medicine, approval date, and marketing authorization holder for each biosimilar. The practice of monitoring the safety of a marketed drug or biologic product. The authors declare no conflict of interest. Within 60 days of receiving that list, the biosimilar applicant is required to respond with its positions on infringement and patent validity, as well as with a list of other patents it believes could be asserted against it. Overall, the considerable interest in biosimilar development from the pharmaceutical industry alongside the development of biosimilar regulations worldwide has led to a growing biosimilar market. Interchangeability is defined by statute in the United States to mean that the product may be substituted for the reference product without the intervention of the physician who prescribed the reference product. Accordingly, the applicant may provide notice either before or after receiving FDA approval. Immunology and oncology are also therapeutic areas that represent a financial burden on the healthcare systems and in which biotherapies have a great impact on patient outcomes and therefore, there is a pressing need for biosimilar alternatives. United States Food and Drug Administration. Rigorous comparability exercises between the BS molecule and the RP comprise a totality of evidence approach which aims to demonstrate a high degree of similarity between the two molecules, but not to re-generate clinical benefit, safety, or quality data for the BS molecule as this would be a repetition of the RP data. Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Non-Clinical and Clinical Issues. [(accessed on 20 December 2020)]; Guideline on Similar Biological Medicinal Products. The corresponding EMA public assessment reports were scrutinized to gather the details of the clinical studies conducted during phases I and III of their clinical development. The current established legal pathway for the approval of biosimilars was achieved through the Biologics Price Competition and Innovation Act (BPCIA), signed by President Barack Obama on March. will also be available for a limited time. ", But an opposition has limited grounds to revoke a patent, Malkin notes, "including: (1) the subject matter is not patentable; (2) the invention was not disclosed clearly or completely enough for one skilled in the art to perform the invention; or (3) the subject matter extends beyond the content of the application filed. There is a close link between therapeutic areas, prevalence, and the cost of diseases and biosimilar development. Please see our Privacy Policy for more information. 175-B-2; 176-B-3 2. As far as industry concerns with FDAs interpretation of the BPCIA, Sanofi, Mylan, Novo Nordisk, and industry groups PhRMA and the Biosimilars Council in May 2016 called on FDA to amend its interpretation of the "deemed to be a license" provision of theAct as some are saying the current draft guidance could halt biosimilar development for a prolonged period. Opposition decisions in the EU may be appealed within two months, though he notes that median time for an appeal is close to three years. Bethesda, MD 20894, Web Policies In contrast, the therapeutic equivalents for Lovenox (enoxaparin sodium) were the object of Abbreviated New Drug Applications (ANDA) suggesting they were considered by the FDA as generic rather than biosimilar products. Rockville, Maryland 20852, 2022 Biosimilars (BS) are biological medicines that are highly similar to an already-approved biologic, called the reference product (RP). Mehr S., Brook R. Biosimilars in the USA: Will new efforts to spur approvals and access spur uptake and cost savings? * N = number of participants enrolled, initial number of patients enrolled in the study, not accounting for patient discontinuation. The number (N) of phase I and phase III studies alongside the condition investigated in Phase III trials for each product as stated by European Public Assessment Reports (EPARs). When analyzing the landscape of biosimilar approvals for the EU and the US, the timeline of regulatory science events should be carefully considered (Figure 1). Timeline for the development of World Health Organization (WHO), European Medicines Agency (EMA) and (Food and Drug Administration FDA) legislation and guidance for biosimilars between 2003 and 2019. An official website of the United States government. 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