The Access Group, Berkeley Heights, NJ
Dr. Stefanacci is the Chief Medical Officer for The Access Group, a managed markets agency for pharmaceutical companies. He has received speaking fees from Allergan and Pfizer; serves on advisory boards for AbbVie, the ASCP Foundation, and the AMDA Foundation; and has provided consulting services to AstraZeneca, Baxter, Boehringer Ingelheim, Lundbeck, Otsuka, and Leo Pharma. Dr. Guerin is the Senior Director for Government Policy System and Analytics for The Access Group, a managed markets agency for pharmaceutical companies.
J Clin Pathways. 2015;1(2):25-26.
Payers and at-risk providers are developing clinical pathways with great specificity regarding the preferred drugs that be used. Increasingly, these pathways will include biosimilar products. There are three major factors that will be used to determine the placement of a biosimilar in clinical pathways: economic incentives, administrative burden, and adverse events. Organizations that are able to make these assessments before deciding to include biosimilars in their pathways will be best able to deliver on the Triple Aim for the patient population they serve.
Payers, at-risk providers, and others are developing clinical pathways and are making them very specific with regard to the preferred drugs that be used in accordance with the pathway. Increasingly, these preferred drugs will include biosimilars, which can be used for the treatment of autoimmune diseases and certain cancers. With the approval by the US Food and Drug Administration (FDA) of the first biosimilar product in March of 2015 (Zarzio, Sandoz), a flood of biosimilars is expected to be released in the coming years.1
Biosimilars are approved based on data showing they are highly similar to an FDA-approved biological product, known as a reference product, and have no clinically meaningful differences from the reference product in terms of safety and effectiveness. Only minor differences in clinically inactive components are allowable in biosimilars. An interchangeable biological product is one that meets additional standards for interchangeability with an FDA-approved reference product. In contrast with an interchangeable biological product, for which substitution can be automatic, for biosimilars that do not meet the FDA standard for an interchangeable biological product, substitution with a biosimilar may not be automatic. In such cases, the selection of a biosimilar rather than a reference product may require significant consideration on the part of clinical pathway decision-makers.
An important point to consider is that, just as a pharmacist may substitute an equivalent non-biological product (or generic) without the approval of the prescribing health care provider,2 so can they switch to an interchangeable biologic treatment. This means that substitutions may occur regardless of whether the biosimilar or the reference product is designated on the clinical pathway. This will differ by states, as certain US states are currently considering laws to require prescriber approval before making such substitutions.
When considering biosimilars as a treatment option for inclusion on a clinical pathway, there are three major factors that will decide the inclusion of each product, after similar clinical efficacy has been firmly established: economic incentives, administrative burden, and adverse events.
Because the research, development, and commercialization processes of biosimilars are less complex than those of their reference products, price concessions are ~20%. A recent survey of medical and pharmacy directors predicted that a biosimilar will cost 10% to 20% less than the branded biologic.3 In Europe, however, biosimilars have often provided just a 10% cost savings versus the originator biologic.4 The exact extent of the discount for biosimilars will depend on market competition.
A low discount weighed against the cost of changing to a biosimilar may make it reasonable for stakeholders to maintain their use of the original biologic products. Thus, the decision to use a biosimilar in a clinical pathway will depend on economic factors weighed against perceived costs. Examples of these costs include the administrative burden placed upon stakeholders like prescribers and payers for managing the switching to a biosimilar. For prescribers, this means additional time discussing a change with a patient. For payers, this means communicating a change in coverage to prescribers and plan members as well as managing any appeals for coverage of the original biologic.
The administrative burden of substituting biosimilars for their reference products comes in three forms. One is the need to motivate providers and patients to embrace the change. This may require some system-wide adjustments as well as political navigation, depending on how embedded the originator biologic is in the protocols. This burden largely falls on payers and health care providers, increasingly at the level of integrated delivery systems as providers move to these from private practices.
The second administrative burden, which falls on health care providers, is in the form of the supportive services required to navigate issues surrounding health care coverage, restrictions to access, patient assistance, and in many cases, supporting appropriate use of the product with patient-focused support and adherence services. The provision of services to support the use of biosimilars will ultimately increase costs to provider organizations.
The third administrative burden is the supply chain management required to implement biosimilars use. Imagine, for example, that a supply issue occurs for the biosimilar. Acute and chronic shortages of various pharmaceuticals, particularly of sterile injectable products, are being reported on a global scale. Survey results indicate that the majority of hospitals and practicing oncologists have experienced drug shortages, critically affecting the supplies of first-choice drugs such as liposomal doxorubicin and 5-fluorouracil.5 These shortages may have compromised patient safety and clinical outcomes and may have increased health care costs, due to delays or changes in treatment regimens. The FDA and the European Medicines Agency have identified manufacturing problems, delays in supply, and lack of available active ingredients as the most frequent causes of recent or ongoing drug shortages and have released specific guidance to monitor, manage, and reduce the risk of shortages.6 The consideration of these issues is one that organizations will need to assess based on the reliability of each biosimilar manufacturer.5
The most critical safety concern relating to biopharmaceuticals is immunogenicity,7-10 the ability of a treatment to induce an immune response. Biosimilars, like all biopharmaceuticals, are biologically active molecules derived from living cells and have the potential to evoke an immune response. There are additional concerns about immunogenicity related to the variations between batches of the same biosimilars product. Although the immunogenic potential cannot be predicted through chemical or structural analyses of the biopharmaceutical, several factors are known to affect a product’s immunogenic potential. The presence of impurities in the final product, structural modifications resulting from the manufacturing process, and/or storage conditions can all increase immunogenicity. Quality control procedures integrated into the manufacturing process are of paramount importance in ensuring the manufacture of safe products of consistent quality. The route of administration of the biopharmaceutical can also affect immunogenicity, with intravenous administration being less immunogenic than intramuscular or subcutaneous administration. Patient factors are also important, such as the genetic background and HLA-expression of the patient, what type of disease is being treated, and the patient’s immune status.
An example illustrating the severe consequences of small manufacturing changes is that of Eprex® (epoetin alfa; Johnson & Johnson). One of its applications is for the treatment of patients with anemia secondary to chronic kidney disease, as these individuals are unable to produce adequate amounts of endogenous erythropoietin. A minor change in the formulation of this epoetin alfa product resulted in the development of neutralizing antibodies not only to the drug itself but also to native erythropoietin in certain patients. A number of patients developed anti-epoetin antibodies that neutralized both endogenous erythropoietin and injected epoetin, rendering the bone marrow aplastic for erythropoietic progenitor cells.7
In general, since biosimilar molecules lack extensive clinical testing, are manufactured using completely different processes, and are structurally and biochemically different than reference products, their safety cannot be guaranteed to the extent of their counterparts.
As payers and at-risk providers move to develop detailed clinical pathways that include biosimilars, a rigorous assessment will be needed to weigh the economic benefits against the costs of administrative burdens and adverse events. Those organizations that are able to make this assessment will be best able to deliver on the Triple Aim11 for the population they serve by offering cost-effective care while maintaining clinical outcomes and patient satisfaction. Through these efforts, clinical pathways can include the treatments that provide the best overall value for patients and payers.
1. Global & USA BioSimilar Market Analysis to 2021; Product Pipelines, Trends, Key Players, Regulations and Strategic Outlook. PRNewswire. http://www.prnewswire.com/news-releases/global--usa-biosimilar-market-analysis-to-2021-product-pipelines-trends-key-players-regulations-and-strategic-outlook-300130242.html. Published August 18, 2015. Accessed November 15, 2015.
2. US Food and Drug Administration. Biosimilars. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/. Accessed November 14, 2015.
3. Mulcahy AW, Predmore Z, Mattke S. The cost savings potential of biosimilar drugs in the United States. Rand Corporation. https://www.rand.org/content/dam/rand/pubs/perspectives/PE100/PE127/RAND_PE127.pdf. 2014. Accessed December 5, 2015.
4. Howel PR. AmerisourceBergen Counseling Services. http://www.contractpharma.com/issues/2012-05/view_features/access-to-biosimilars#sthash.VUOqGYLz.dpuf. Published May 4, 2012. Accessed November 13, 2015.
5. Li E, Subramanian J, Scott Anderson S, Thomas D, McKinley J, Jacobs IA. Development of biosimilars in an era of oncologic drug shortages. Drug Des Devel Ther. 2015;9:3247–3255.
6. US Food & Drug Administration Center for Drug Evaluation and Research. Manual of Policies and Procedures. Drug Shortage Management. FDA website. http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesProcedures/ucm079936.pdf. Effective September 3, 2014. Accessed December 5, 2015.
7. Simon D, Roger A, Mikhail A. Biosimilars: Opportunity or Cause for Concern? J Pharm Pharmaceut Sci. 2007;10(3):405-410.
8. Schellekens H. Bioequivalence and the immunogenicity of biopharmaceuticals. Nat Rev Drug Discov. 2002;1:457-462.
9. Schellekens H. Biosimilar therapeutic agents: issues with bioequivalence and immunogenicity. Eur J Clin Invest. 2004;34:797-799.
10. Schellekens H, Casadevall N. Immunogenicity of recombinant human proteins: causes and consequences. J Neurol. 2004;251(Suppl 2):II4-II9.
11. Berwick DM, Nolan TW, Whittington J. The triple aim: care, health, and cost. Health Aff. 2008;27(3):759-769.