US Pharm. 2017;42(11)(Specialty&Oncology suppl):6-8.
ABSTRACT: Biological products require substantial investments of time and money to gain approval. As a result, the cost of procuring these products is often very high. Opportunities to decrease costs and improve accessibility are essential to mitigating healthcare costs and improving the management of disease states. Abbreviated licensure pathways to market entry, similar to the abbreviated approval pathway developed for generic small-molecule drugs, were created to increase competition among biological products. Healthcare providers should stay abreast of recent developments in order to ensure the appropriate integration of biological products into the U.S. healthcare system.
Biological products (also known as biologics) have led to major advances in disease-state management. The composition and size of biologics heighten the complexity of product development compared with traditional small-molecule drugs, increasing the cost and limiting access to these products.1,2 In an effort to lower the cost and improve accessibility, Congress passed an amendment to the Public Health Service Act (PHSA), creating an abbreviated pathway for biological products proven to be “highly similar” to a reference (also known as originator or innovator) biologic.3 Although the increase in competition created by this amendment may lead to lower-cost biological products, several challenges limit substantial cost reductions.4 Furthermore, varying levels of understanding and confusion associated with replicated versions of originator biologics may adversely affect the use of these products.2,5,6 Therefore, it is imperative that healthcare providers be knowledgeable about available biological products in order to successfully manage their incorporation into clinical practice.
Pathway and Regulation of Biological Products
Manufacturers of novel biologics submit a Biologics License Application (BLA) to the FDA for approval under the 351(a) pathway of the PHSA.3,7 The BLA contains information about the product and manufacturing process and, to obtain approval, must provide evidence that the biologic is safe, pure, and potent.3 The Patient Protection and Affordable Care Act amended the PHSA to establish a legal abbreviated pathway for biological products deemed to be highly similar to or interchangeable with an FDA-approved reference biological product.8 This statute is known as the Biologics Price Competition and Innovation Act of 2009 (BPCIA).3,7,8 The purpose of the BPCIA is similar to that of the Drug Price Competition and Patent Term Restoration Act of 1984 (also called the Hatch-Waxman Act).8 The Hatch-Waxman Act developed an abbreviated approval pathway for small-molecule drugs, such as generics, under the Federal Food, Drug, and Cosmetic (FD&C) Act that allowed generic manufacturers to avoid costly clinical trials, thus saving time and resources.1,3,8,9
The BPCIA defines products that are highly similar to a reference biologic as biosimilar.2 Biological products may be deemed biosimilar if studies prove that the products are highly similar with no clinically meaningful differences (not including minor differences between inactive components) between the replica biological product and the reference originator biological product in terms of safety, purity, and potency.7,8 The FDA outlines a stepwise biosimilarity assessment for manufacturers to prove biosimilarity.2,7 Several types of studies (e.g., analytical, animal, and clinical) may be used to substantiate biosimilarity. Biosimilars must be approved for one or more FDA-approved indications of the originator biologic and must have the same strength, dosage form, and route of administration.3 Biosimilars are approved or licensed through the 351(k) pathway of the PHSA.7 Manufacturers preferring to create another version of an FDA-approved biologic without using the biosimilar 351(k) pathway must submit a BLA through the standard (nonabbreviated) 351(a) pathway.7 This approach does not require comparison with the originator biologic.7
Although most biological products are regulated under the PHSA, several are regulated as drugs under the FD&C Act. Examples include insulin, glucagon, human growth hormone, infertility hormones, hormones used in the treatment of menopause and osteoporosis, and some medical enzymes.1,10 These products must gain approval beyond the biosimilar 351(k) pathway. In addition to the Abbreviated New Drug Application (ANDA) pathway used for generic drugs or small-molecule drugs, the Hatch-Waxman Act created an abbreviated pathway for drugs that differ substantially from the originator drug, but may still be considered similar under section 505(b)(2) of the FD&C Act.1,3 Since biological products regulated under the FD&C Act are not small-molecule drugs, manufacturers creating replica versions of these products must use the 505(b)(2) pathway. Drugs approved through this pathway are termed follow-on, not biosimilar, because of the distinct regulatory pathway. Starting on March 23, 2020, approved applications for biological products regulated by section 505 of the FD&C Act will be considered a BLA under section 351 of the PHSA.11 This transition may eliminate some confusion regarding the differences and appropriate designation of follow-on versus biosimilar products in the United States. Biosimilar products are often referred to as follow-on biologics in the literature.1,3,4
Characteristics and Designation of Biological Products
Both biologics and traditional small-molecule products may be used in the prevention, treatment, or cure of a disease; however, biological products differ greatly from small-molecule drugs in terms of size, structure, manufacturing processes, stability, common route of administration, and immunogenicity.2,7 Biologics are produced from living cells (e.g., bacteria, plant or animal), whereas small-molecule drugs are created through chemical reactions.2,3 Because biological products are dependent on the manufacturing process, changes to the process may affect the effectiveness and safety of the product.7 Neither biosimilar nor generics manufacturers have access to the manufacturing processes of the innovator product; however, it is feasible for generics manufacturers to create an identical molecule because of the relative simplicity of the manufacturing process.2,12
Developing a generic biological product is virtually impossible because of the product composition, proprietary manufacturing processes, and trade secrets unique to each manufacturer.3,7 Variations are possible from batch to batch in biological products using the same manufacturing process, highlighting the unlikelihood of producing an exact replica through different manufacturing processes.3 Therefore, biosimilars or follow-on biologics should not be considered generic biologics. Despite these challenges, biosimilars have been used in Europe with largely positive results, although a manufacturing change in the European version of epoetin (Eprex) resulted in an increased number of cases of a rare anemia syndrome, pure red cell aplasia (PRCA).5 It should be noted that the incidence of PRCA declined because of a minor manufacturing modification and adherence to storage, handling, and administration recommendations.
As was discussed, a product licensed by the BPCIA may be designated as a biosimilar or an interchangeable biosimilar.7 The standard for an interchangeable biosimilar goes beyond biosimilarity, requiring evidence that the product may be expected to produce the same clinical result as the reference product in any given patient.3,7,13 Additionally, if an interchangeable biological product is administered multiple times, the risk of substitution between the interchangeable biologic and reference biologic should be no more than the risk of continuing the reference biologic.1 The FDA has not provided guidance on what criteria must be met to achieve status as an interchangeable biosimilar; therefore, no biological products have achieved this designation.2 An interchangeable biosimilar may be substituted for the reference product without intervention of the prescribing healthcare provider, according to the BPCIA; however, state regulations may require additional criteria for substitution.5
Concerns and Opportunities
The competition created as a result of the ANDA pathway for generic drugs has greatly affected the healthcare landscape, with generic medications costing an average of 80% to 85% less than their brand counterparts.7,9,14 Biosimilars are expected to cost 20% to 30% less than the reference biologic.5,15 Although the BPCIA provides manufacturers with an abbreviated pathway to develop biological products, significant market-entry hurdles remain that lessen the competition in the biological-product development field.2,4 The cost of development is substantial, particularly given the extensive resource and time investments.4 More data are necessary to prove biosimilarity between biological products compared with achieving bioequivalence with generics because of the inherent risk associated with biologics.4
The molecular structure of biologics is typically 100 to 1,000 times larger than that of small-molecule drugs, thereby increasing the complexity of replication and the potential for immunogenicity.1,5 In addition, the manufacture of biologics requires sophisticated techniques.3 Minor differences in the manufacturing process can affect a product’s stability, structure, safety, purity, and/or potency, further heightening the challenge of creating a biosimilar.2,3 To reward innovation, the BPCIA grants manufacturers of originator biologics a 12-year exclusivity period, which is much longer than the 5-year exclusivity period granted to brand-name small-molecule drugs. The BPCIA also requires manufacturers of biosimilars to share their applications with the originator manufacturer to address the potential for patent infringement. This requirement could compel biosimilar manufacturers to disclose trade secrets (nonpatented manufacturing information regarding product development). Although this requirement has been disputed, it may deter some manufacturers from using this pathway.4
Various types of biological products are available in different countries, with inconsistent definitions and nomenclature, causing confusion and some apprehension about using biosimilars.2,5 Understanding the differences, similarities, and risks between different biological products is essential to optimizing disease-state management. Patients and healthcare professionals may expect biosimilars to share the same active-ingredient name (similar to the naming system used with generic drugs); however, a consensus has yet to be reached on the nonproprietary naming of biosimilars, despite recommendations from several organizations.7 A standard naming system could forestall confusion about which biological product should be dispensed, in addition to preventing errors in reporting. Since no biosimilars have achieved the status of interchangeability, pharmacists are unable to substitute biological products at this time. Pharmacists should be aware of state pharmacy-practice laws, as several states have created additional requirements beyond the BPCIA requirements in order to permit substitution.2 The FDA has published a series of articles providing guidance on the BPCIA that may be helpful to healthcare providers as they seek to understand the nuances associated with biosimilars and follow-on biologics.2 In addition, the FDA’s Purple Book, a resource similar to the Orange Book for small-molecule drugs, may be used to identify a biological product’s license date, reference-product exclusivity, biosimilarity, or interchangeability, if licensed under the BPCIA.7
Biological products have provided important contributions to the management of many disease states; however, their use has presented new challenges. It is expected that more manufacturers may pursue approval through an abbreviated pathway as originator biologic patents expire. Pharmacists and other healthcare providers will play a critical role in successfully managing the incorporation of biological products into clinical practice to optimize patient care.
1. Johnson JA. Congressional Research Service. FDA regulation of follow-on biologics. https://primaryimmune.org/advocacy_center/pdfs/health_care_reform/Biosimilars_Congressional_Research_Service_Report.pdf. Accessed February 22, 2017.
2. Olech E. Biosimilars: rationale and current regulatory landscape. Semin Arthritis Rheum. 2016;45(suppl 5):S1-S10.
3. Worthy SL, Kozak JF. Follow-on biologics: protecting consumers through state pharmacy law in light of FDA actions. http://dcbalaw.com/aimedalliance/wp-content/uploads/2014/10/Follow-On-Biologics.pdf. Accessed February 22, 2017.
4. Sarpatwari A, Avorn J, Kesselheim AS. Progress and hurdles for follow-on biologics. N Engl J Med. 2015;372:2380-2382.
5. Lucio SD, Stevenson JG, Hoffman JM. Biosimilars: primer for health-system pharmacists. Am J Health Syst Pharm. 2013;70:2004-2017.
6. Zelenetz AD, Ahmed I, Braud EL, et al. NCCN biosimilars white paper: regulatory, scientific, and patient safety perspectives. J Natl Compr Cancer Netw. 2011;9(suppl 4):S1-S22.
7. Li E. Biologic, biosimilar, and interchangeable biologic drug products. Background paper prepared for the 2015–2016 APhA Policy Committee. www.pharmacist.com/sites/default/files/files/Biosimilar%20Policy%20Background%20Paper%20-%20FINAL.PDF. Accessed February 22, 2017.
8. FDA. Implementation of the Biologics Price Competition and Innovation Act of 2009. www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm215089.htm. Accessed February 22, 2017.=
9. Manigault KR, Marcheva GA, Peasah SK. Insights into effective generic substitution. US Pharm. 2016;41(6)(Generic Drugs suppl):29-33.
10. FDA. Follow-on protein products. Statement of Janet Woodcock, M.D. before the House Committee on Oversight and Government Reform. www.fda.gov/NewsEvents/Testimony/ucm154070.htm. Accessed February 22, 2017.
11. Sherman R. Biosimilar biological products. www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM292463.pdf. Accessed February 22, 2017.
12. Gupta D, Prashanth GN, Lodha S. A CMO perspective on quality challenges for biopharmaceuticals. BioProcess Int. 2013;11:22-26.
13. FDA. Scientific considerations in demonstrating biosimilarity to a reference product. www.fda.gov/downloads/drugs/guidances/ucm291128.pdf. Accessed February 22, 2017.
14. FDA. Facts about generic drugs. www.fda.gov/drugs/resourcesforyou/consumers/buyingusingmedicinesafely/understandinggenericdrugs/ucm167991.htm. Accessed February 22, 2017.
15. Creating a viable biosimilars market. Drug Store News. www.drugstorenews.com/article/creating-viable-biosimilars-market. Accessed February 22, 2017.
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