The United States has the largest biologic drugs market and high prices for biologics, such as monoclonal antibodies, therapeutic proteins, immunomodulators, and growth factors. Cancer treatments utilize traditional chemical-based drugs and, increasingly, biologic-based drugs. The improved safety and efficacy of biologics offer treatment advantages for newly diagnosed patients with cancer, as well as for those with late-stage and terminal cancers.
For many employers as health plan sponsors, biologics are among the highest claim cost year-over-year and fastest area of growth, with cancer drug cost in the top 4 for most employers.1
Many biologics in the US market are supplied through specialty pharmacies and are not distributed via traditional channels. Biologics and other specialty drugs represent the highest US growth rate, outpacing traditional pharmaceuticals. Biologics are expected to assume approximately 20% of the global market by 2017.1
Today, much of the highest spending on drugs is for brand-name biologics, such as infliximab, rituximab, bevacizumab, trastuzumab, and epoetin alfa, which do not yet have generic equivalents. As a result, there is interest in less expensive alternatives, which now include biosimilars as a result of the enactment of the Affordable Care Act (ACA).
What the Law Says About Biosimilars
Until 2010, no regulatory authority existed for the FDA to approve a biosimilar. Having clarity about the legal issues surrounding biosimilars is important for employers and payers for their benefit design. This is a complex area that has been further complicated by the FDA, along with other interest groups that are eager to tout, and in some cases cloud, the availability of a biosimilar. When advising patients, it is important to be an informed consumer before making an important decision involving health, so knowing this area of the law is critical to employer plans.
The Biologics Price Competition and Innovation Act of 2009 (BPCIA), a statutory provision of the ACA, created an abbreviated Biologic License Application (aBLA) pathway for the licensure of biosimilar drugs under §351(k) of the Public Health Service Act.2 To facilitate the process, referred to as a “totality-of-the-evidence” approach, the FDA has issued several guidance documents, which establish the core regulatory framework for biosimilars in the United States.3 It is important to understand that, when it comes to biosimilars, we operate on a guidance with little to no regulation, despite having a legal basis to move forward.
The latest FDA guidance pertains to biosimilar naming, which proposes to require a unique 4-letter suffix so a biosimilar can be distinguished from the reference drug to allow for traceability and to prevent “inadvertent substitution.”4
The FDA’s proposal has been met with fierce opposition by 2 opposing camps—one that includes biosimilar makers, insurers, and pharmacists; and another that includes referenced drug manufacturers, healthcare providers, and patient advocacy groups—which has resulted in the stalling of the final regulation. The FDA intends to publish guidances for referenced interchangeability, labeling, and statistical evaluations to support biosimilarity. The 351(k) process is an evolving one, and the need for clinical trials will be evaluated on a case-by-case basis.5
The BPCIA sets forth definitions (see Glossary), basic requirements, and patent litigation processes. A biosimilar is defined as a biologic drug that is highly similar to the reference drug, even if there are minor differences in their clinically inactive components. There are no clinically meaningful differences between the biosimilar and the reference drug in terms of their safety, purity, and potency; however, not all biosimilars are interchangeable.
Interchangeable means that the biologic is biosimilar to the reference drug; can be expected to produce the same result as the reference drug; and for a drug administered more than once, the safety and reduced efficacy risks of alternating or switching are no greater than with repeated use of the reference drug. The FDA is still considering what information is needed for demonstrating interchangeability, so no applications have been submitted for an interchangeable biosimilar.
In 2005, the European Medicines Agency became the first regulatory body to establish an approval process and guidelines for biosimilars.6 Biosimilars exist worldwide, although with varying quality, safety, and efficacy. In May 2015, the first biosimilar, Zarxio (filgrastim-sndz) was approved by the FDA, although litigation delayed its marketing until September 2015.7,8 Additional biosimilar applications for adalimumab, etanercept, pegfilgrastim, infliximab, and epoetin alfa have recently been submitted to the FDA.
Can Biosimilars Be Used Like Generics?
Under the BPCIA, interchangeable biosimilars may be substituted for the reference drug without the intervention of a healthcare provider. Analogizing the BPCIA with the Hatch-Waxman Act, like the Orange Book for generic drugs, the FDA has created the Purple Book, which will include interchangeable biosimilars.
The FDA determines interchangeability, but state boards of pharmacy control automatic substitution. The FDA has not yet determined interchangeability and it has no current plans to do so; however, before the FDA finished defining its aBLA process, biosimilar substitution bills were introduced in 31 states and were signed into law in 18 states.9 The patchwork of existing and proposed state laws contain provisions that range from prescriber veto power and prior notification to automatic substitution based on an FDA interchangeability determination. In states with mandatory generic drug substitution (eg, New York), biosimilar substitution laws do not invalidate those laws.9
Because only biosimilars deemed “interchangeable” by the FDA would be substitutable by a pharmacist without a prescriber’s intervention, and the FDA has not yet determined the requirements for this, the enactment of the laws is premature. A determination of interchangeability only applies to a specific biosimilar and reference drug, and it does not apply to multiple biosimilars that are approved for a single reference drug. In addition, multiple biosimilars to a reference drug may not share all of the same indications.
Future US market introductions of biosimilars offer hope for patients, as well as cost relief for the healthcare system. High-level or national 10-year cost-savings estimates for biosimilars ranged from $25 billion to $44 billion for the period of 2008 to 2016.10,11
Whether any savings will ensue from the approval of biosimilars for health plan sponsors depends on many factors, the most critical being the legal standing and promulgation of the FDA’s regulation of these drugs. Depending on the approval type and labeling scope, the issues of interchangeability or substitution come into play, along with state law and regulations.
Biosimilar: A biologic drug, notwithstanding minor differences in clinically inactive components, that is similar to the reference drug and for which there are no clinically meaningful differences from the reference drug in terms of safety, purity, and potency
Reference drug: A biologic drug that is FDA approved before the submission of an abbreviated Biologic License Application Interchangeable biosimilar: Requirements are (1) the biosimilar can be expected to produce the same clinical result as the reference drug in any given patient, and (2) for drugs that are administered more than once to a patient, switching between a reference drug and a biosimilar drug is safe and effective
Follow-on biologic: Earlier preferred term for biosimilars in the United States; biosimilars, biobetters, and biogenerics are all follow-on biologics
Biologic drug: A virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic drug, protein (except any chemically synthesized polypeptide), or analogous drug that is applicable to the prevention, treatment, or cure of a disease or condition
Biobetter: A newer version of a marketed biotherapeutic agent that is engineered for improved properties
Biogeneric: An interchangeable biosimilar
Extrapolation: The process of granting a clinical indication to a medication without the drug having its own or new clinical safety and efficacy data to support that indication
- IMS Institute for Healthcare Informatics. The Global Use of Medicines: Outlook through 2016. July 2012. www.imshealth.com/files/web/IMSH%20Institute/Reports/The%20Global%20Use%20of%20Medicines%20Outlook%20Through%202016/Medicines_Outlook_Through_2016_Report.pdf. Accessed March 17, 2016.
- The Biologics Price Competition and Innovation Act of 2009. HR3590-686. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM216146.pdf. Accessed January 16, 2016.
- US Food and Drug Administration. Fact Sheet: Issuance of Draft Guidances on Biosimilar Product Development. Updated February 9, 2012. www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm291197.htm. Accessed March 16, 2016.
- US Food and Drug Administration. Nonproprietary Naming of Biological Products: Draft Guidance for Industry. August 2015. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM459987.pdf. Accessed March 16, 2016.
- Ahmed I, Kasper B, Sharma U. Biosimilars: impact of biologic product life cycle and European experience on the regulatory trajectory in the United States. Clin Ther. 2012;34:400-418.
- European Medicines Agency. Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products. October 30, 2005. http:/www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003517.pdf. Accessed March 16, 2016.
- US Food and Drug Administration. FDA approves first biosimilar product Zarxio. Press release. March 6, 2015. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm436648.htm. Accessed March 16, 2016.
- Sandoz v Amgen and Hoffmann-LaRoche. 3:13-cv-2904-MMC (Cal 2013).
- National Conference of State Legislatures. State laws and legislation related to biologic medications and substitution of biosimilars. January 4, 2016. www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx. Accessed January 16, 2016.
- Mulcahy AW, Predmore Z, Mattke S; for The Rand Corporation. The cost savings potential of biosimilar drugs in the United States. Perspective; 2014. www.rand.org/content/dam/rand/pubs/perspectives/PE100/PE127/RAND_PE127.pdf. Accessed January 16, 2016
- Congressional Budget Office. Cost estimate of the Biologics Price Competition and Innovation Act of 2007. June 25, 2008. www.cbo.gov/sites/default/files/cbofiles/ftpdocs/94xx/doc9496/s1695.pdf. Accessed March 16, 2016.