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Biosimilars: Considerations for Payers
Biosimilars are similar versions of originator biologics. Biologics are complex molecules that are manufactured using living cells and used in the treatment of several chronic inflammatory diseases and cancer. Access to biologics is limited, and the availability of biosimilars has the potential to provide additional biologic drug options and to decrease the overall cost burden to the health care system.1,2 The European Union (EU) pioneered the establishment of a regulatory pathway for the development and approval of biosimilars, with the first biosimilar approved in 2006. To create a regulatory pathway for biosimilars in the U.S., Congress passed the Biologics Price Competition and Innovation Act of 2009 (BPCIA), authorizing the Food and Drug Administration (FDA) to implement an abbreviated regulatory pathway (i.e., section 351(k) under the Public Health Service Act) for the development and approval of biosimilars.1 A biosimilar is defined in the statute as a biologic that (1) is “highly similar to the reference product notwithstanding minor differences in clinically inactive components” and (2) has “no clinically meaningful differences” from the reference product in terms of safety, purity, or potency.1
Although biosimilars have been available in the EU for more than a decade, the initial market uptake of the products was slow.3–5 Many reasons for this have been cited, including a lack of provider confidence in these similar biologics, potential minor differences from the reference products, uncertainty about substitution, certain financial incentives favoring the use of originator biologics (e.g., higher reimbursement limits for reference biologics), and a lack of patient awareness and education.3,5–7 Although uptake has been slow, more than 40 biosimilars have been authorized for use in the EU, with three having been withdrawn.8,9 As of October 10, 2018, 12 biosimilars have been approved in the U.S.: filgrastim-sndz (ZARXIO®, Sandoz Inc.), infliximab-dyyb (INFLECTRA®, Hospira, Celltrion, Inc.), etanercept-szzs (ErelziTM, Sandoz Inc.), adalimumab-atto (AMJEVITATM, Amgen Inc.), infliximab-abda (RENFLEXISTM, Merck Sharp & Dohme Corp., manufactured by Samsung Bioepis Co., Ltd.), adalimumab-adbm (CYLTEZO®, Boehringer Ingelheim International GmbH), bevacizumab-awwb (MVASITM, Amgen Inc.), trastuzumab-dkst (OgivriTM, Mylan GmbH), infliximab-qbtx (IXIFITM, Pfizer Inc), epoetin alfa-epbx (RETACRIT®, Hospira), pegfilgrastim-jmdb (FulphilaTM, Mylan GmbH), and filgrastim-aafi (NIVESTYMTM, Pfizer Inc., manufactured by Hospira, Inc.) (see
This review discusses key considerations about biosimilars that are relevant to different U.S. payers, including private payers (e.g., pharmacy benefit managers [PBMs], private insurers) and Medicare perspectives. We explore factors promoting the uptake of biosimilars, cost considerations, a broader perspective on value beyond price reduction, and the current U.S. experience.
UPTAKE OF BIOSIMILARS
Although acquisition-cost considerations are likely the primary factor driving the uptake of biosimilars, additional considerations are also important in deciding to select a biosimilar over the reference biologic or another biosimilar of the same reference biologic (
TOTALITY OF EVIDENCE FOR BIOSIMILARS
To appreciate the challenges and potential of biosimilars, it helps to understand the complexities of their development, manufacturing, and regulatory approval. The regulatory review process for biosimilars is based on the totality of evidence generated to support the claim of biosimilarity.22,23 The successful biosimilar development program is designed to minimize potential differences between the proposed biosimilar and its reference product, and to establish robust manufacturing processes that can consistently and reliably produce a biosimilar product that meets preset specifications.
Producing a biosimilar is more complicated than replicating a traditional, small-molecule generic drug manufactured via chemical synthesis (i.e., a medication created to be the same as a marketed brand-name drug in dosage, safety, strength, administration, quality, and intended use). Manufacturing biosimilars requires an in-depth understanding of the reference product’s physiochemical, biological, and clinical attributes, establishing a target profile, and evaluating potential differences in analytical, functional, and clinical safety and efficacy. This process is accomplished via side-by-side comparison of the proposed biosimilar with the reference product, using an iterative approach (e.g., quality by design) that “begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.”24 Manufacturers initially develop a quality target-product profile, which is a prospective summary of quality characteristics that ideally will be achieved, to ensure quality and account for the safety and efficacy of the product.24
In the first step toward evaluating biosimilarity, comparative analytical and functional in vitro assays are used to assess the above-mentioned quality objectives and to compare the proposed biosimilar with its reference product regarding structure and functional activity.22,23 This serves as the foundation of the stepwise process for establishing biosimilarity. Manufacturing a product with the knowledge and understanding of the amino acid sequence of the reference product does not guarantee that the structural and functional properties of that product will be similar to the reference product. A broad array of physiochemical and functional properties also must be characterized and compared (e.g., primary, secondary, tertiary, and quaternary structures; posttranslational modifications such as glycosylation; and binding and biological activity such as antibody-dependent cellular cytotoxicity).
After assessment for analytical and functional similarity has been completed, preclinical studies specific to the proposed biosimilar are considered. These analyses may include but are not limited to pharmacokinetic and pharmacodynamic assays, as well as toxicology and interspecies cross-reactivity studies.22,23 These assessments help alleviate some of the uncertainty concerning the proposed biosimilar and may potentially minimize the extent of in-human testing needed.
The ultimate development goal is to demonstrate that a proposed biosimilar is similar to the reference product based on analytical assessments, and that it does not have clinically meaningful differences from the reference molecule, which is achieved by conducting comparative clinical studies. The extent of the clinical development plan is dependent on the results of the analytical and preclinical assessments, including physiochemical, functional, pharmacologic, pharmacokinetic, and pharmacodynamic studies. Finally, at least one comparative clinical trial designed to address residual uncertainty regarding the similarity of safety, efficacy, and immunogenicity in a representative indication is recommended.23 The goal of the biosimilar clinical program is to demonstrate that the proposed biosimilar is not different from the reference product with respect to clinical performance. To this end, clinical study designs select endpoints that may differ from those selected for pivotal clinical trials for new biologics; comparative biosimilar clinical studies are conducted in a representative population using sensitive endpoints (i.e., clinically relevant, readily assessable, and in which the size of the treatment effect is large enough to detect differences between similar treatments), such that the overall treatment effect between two very similar products may be identified. Clinical trials designed to assess biosimilarity aim to help resolve whether any residual, clinically meaningful differences might exist between a proposed biosimilar and its reference product (
A unique component of the biosimilar development program is the concept of extrapolation.22,23 This supports the use of an approved biosimilar product in indications that the reference product is approved for but in which the biosimilar product was not evaluated clinically. The justification for extrapolation is expected to address whether the same mechanism of action applies in each indication and in the similarity of the products’ pharmacokinetic, biodistribution, and immunogenicity profiles in different patient populations. It is also expected to identify potential toxicities for each indication or patient population and any other factors that may affect the safety and efficacy for each new indication or patient population.22 However, in the U.S., a biosimilar may not be approved for any indication of the reference product protected by regulatory exclusivity, such as orphan drug or pediatric exclusivity.
Although the extrapolation of data collected for a biosimilar reduces the need for duplicative clinical studies, it must be justifiably supported by scientific data, and thus regulatory agencies may differ in their approval decisions.27 For example, Korean regulators in 2012, the European Medicines Agency (EMA) in 2013, and the FDA in 2016 granted approval for the biosimilar infliximab (Remsima, Celltrion, Inc., also known as Inflectra) for the full range of indications of the reference product, although it had only been studied in rheumatoid arthritis and ankylosing spondylitis, whereas Health Canada did not initially support the extrapolation of clinical data to Crohn’s disease or ulcerative colitis in its approval in 2014.27 However, after the sponsor provided additional data, Health Canada extended approval of their infliximab biosimilar in 2016 for gastrointestinal indications, including Crohn’s disease, fistulizing Crohn’s disease, and ulcerative colitis.27
As biologic molecules, biosimilars have the potential to induce an immune response. The immunogenic potential of a biologic can be affected by differences in manufacturing processes, delivery components, or formulation, 28,29 which can lead to slight structural differences (e.g., glycosylation profiles) or differences in agglutination.30 Therefore, demonstrating a similar immunogenic profile (e.g., infusion reactions, neutralizing antibodies) is critical for establishing biosimilarity. Immunogenicity is assessed during clinical assessments that evaluate immunogenic responses, typically first in healthy subjects as the most sensitive model––often during phase 1 pharmacokinetic/pharmacodynamic studies––then in patients who are usually enrolled in phase 3 studies. However, these studies designed to assess biosimilarity may not detect infrequent immunogenic events that are related to potential differences between a biosimilar and its reference product.31–33 Thus, data on newly introduced products may initially be limited, and ongoing safety monitoring (pharmacovigilance) is needed.32–35 Manufacturers are expected to closely monitor their products postmarket, and to further aid postmarketing surveillance, the Biologics and Biosimilars Collective Intelligence Consortium was established.36 This task force engages in epidemiologic studies, sequential data analysis, and data mining to monitor biosimilar safety and efficacy through ongoing comparisons to their reference products.36
When generating the totality of evidence to support biosimilarity, it is important to bear in mind that the greater the level and quality of evidence provided at each step of the development pyramid (
Interchangeability is an FDA designation unique to the U.S. that provides the basis for one-to-one substitution by a pharmacist without notification of, or permission from, the prescriber. Manufacturers decide if they wish to pursue this optional designation, which requires additional supporting evidence beyond that required for biosimilars without the designation. To earn interchangeability designation, federal law requires manufacturers to demonstrate that their product is “expected to produce the same clinical result as the reference product in any given patient” and, if the product is administered more than once to an individual, the sponsor must demonstrate that “the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.”39 An interchangeability designation requires approval of the product as a biosimilar as well as additional biosimilar clinical switching studies (i.e., studies evaluating multiple switches between products).39,40 According to the 2017 FDA Guidance for Industry on Interchangeability, simply providing postmarketing data that have been collected for products licensed as biosimilars without including corresponding data derived from appropriately designed, prospective, controlled switching studies with at least three switches, would generally not be considered sufficient to support the interchangeability designation.39
Autonomous substitution by pharmacists is the practice whereby a pharmacist may dispense a biosimilar product instead of the prescribed biologic without requiring prior approval from the prescriber. Although the FDA has not yet granted an interchangeable designation to any licensed biosimilar, most states and Puerto Rico have passed state-specific legislation regulating substitution.41 These laws generally require that (1) biosimilars are first approved by the FDA with the interchangeable designation, (2) prescribers are permitted to prevent substitution by writing “dispense as written” or “brand medically necessary” on prescriptions, (3) the dispensing pharmacy must notify both prescribers and patients if an allowable substitution is made, and (4) records are retained by pharmacies and prescribers. A few states have included provisions to ensure that pharmacists who make compliant substitutions of biologics have immunity from prosecution. Also, pharmacists must explain the cost/price of both the reference biologic and the interchangeable biosimilar to patients.41,42
The potential for substitution may lead to the practice of alternating between reference products and biosimilars, particularly for treatments with a long course of therapy. The potential risks (e.g., immunogenicity, diminished efficacy) associated with switching between related biologics are evaluated in switching studies. A recently published, systematic literature review identifying publications on switching studies conducted before June 30, 2017, evaluated the possibility that switching from reference products to biosimilars could alter clinical safety or efficacy outcomes.43 This analysis identified 90 publications with primary data on proteins that were available for review.43 Although the analysis suggested there were low safety and efficacy risks associated with switching to biosimilars, its conclusion is limited by a small final sample size, the inclusion of a large number of abstracts or letters (n = 36) versus articles (n = 54), and the inclusion of more studies based on real-world evidence (n = 47) rather than randomized, controlled trials (n = 40).43 Furthermore, the majority of these studies were single-switch studies and were not powered to detect switch-related differences.43
To our knowledge, four studies evaluating multiple switches between biosimilars and their reference products have been conducted or initiated44–47, but three were completed before publication of the draft FDA guidance for demonstrating interchangeability and they do not meet all the recommendations (e.g., primary endpoints are clinical efficacy measures rather than pharmacokinetic/pharmacodynamic measures). The remaining study is the only one initiated to date that was designed to demonstrate interchangeability after publication of the guidance.47 Also notable is that a few phase 3 clinical studies have included a single transition in their study designs.48–50 However, although these provide information on the efficacy, safety, and particularly, immunogenicity after a single transition from the reference product to the proposed biosimilar, the FDA considers them insufficient to support the interchangeability designation. The current paucity of multiple-switch trials may be because “substitution” is essentially permitted in hospitals under the purview of pharmacy and therapeutics (P&T) committees; manufacturers may decide to launch their new biosimilars after receiving regulatory approval, and determine if interchangeability studies are needed at a later date. It is noteworthy that an interchangeability designation, because it pertains to automatic pharmacy substitution, would have little or no impact on medical benefit products and would only affect retail pharmacy products, for which there is a possibility that pharmacists might alternate between reference products and biosimilars.
As with generics, retail and specialty pharmacists may engage in substitution consistent with state laws. Drug substitution laws ultimately fall within the authority of individual states. In some states, substituting a lower-cost medicine is required (i.e., not optional) unless the prescriber affirmatively prohibits substitution, such as by marking “do not substitute” on the prescription. If a biosimilar is identified as interchangeable, then changing from one product to another for reasons other than the patient’s health or safety51 may occur. In these instances, pharmacists may use their medical knowledge to inform the responsible use of limited resources to dispense the pharmacy’s preferred biologic for its cost-effectiveness or another pharmacy-determined benefit, independently of what was prescribed, without required approval from the prescriber.41 In a hospital or health system with a P&T committee, the selection of a biosimilar based on formulary considerations can occur within the confines of that specific institution without the need for an interchangeability designation.32,52,53
Payers should evaluate the incorporation of biosimilars into formularies based on numerous factors, including product characteristics and evidence, manufacturer supply, dosage-form suitability for the covered population, patient adherence, and the economic impact on payers and patients.42 For patients with new prescriptions, incorporating biosimilars into treatment regimens will likely be relatively uncomplicated, but additional challenges exist for patients who are in the middle of treatment and stable on their current medications. As discussed, biosimilars are approved based on the totality of evidence, including extrapolated data, in comparison with their reference product, and are unlikely to be formally evaluated against other biosimilars of the same reference product.54 As each biosimilar varies uniquely from the same reference product, biosimilarity is not transitive among biosimilars. Therefore, biosimilars should not be treated like generic small-molecule drugs, and further evaluation and consideration on a case-by-case basis may be necessary to support alternating among biosimilars. This consideration is particularly relevant for health care organizations that periodically change preferences among multiple biosimilars of the same reference product, thus exposing patients to biosimilars that have never been directly compared with each other and potentially increasing the risk of immunogenicity, depending on the type of biologic in question.
The FDA’s 2017 guidance stipulated that licensed biologic products should be assigned distinguishable, nonproprietary names.55 For each originator biologic product, related biologic product, or biosimilar, the nonproprietary name will consist of the core name and an FDA-designated, distinguishable suffix of four letters, which is devoid of meaning.55 The addition of the distinguishable suffix to the naming convention facilitates the accurate identification of biologic products by health care providers and patients, thus assisting with pharmacovigilance. These suffixes also help minimize the inadvertent substitution of products that are not deemed interchangeable.55 Physician and pharmacist surveys have indicated the importance of clear labeling with regard to interchangeability.56,57 More than 50% of physicians and pharmacists surveyed assumed that even without an interchangeability designation, two biologics that share the same name (1) could be considered identical, (2) could be expected to produce the same clinical results, (3) could be safely substituted for one another, and (4) would be approved for the same indications.56,57
Biosimilars are expected to increase market competition, and thereby reduce health care expenditure. The expected reductions in acquisition costs in the U.S. generally range from 10% to 40%.42,58–60 Although this is lower than the reduction seen over time with generic drugs, the overall magnitude in terms of absolute savings may be similar owing to the higher cost of reference products. The wide range of expected cost reductions illustrates the lack of consensus on the extent of potential savings;61 however, the impact of these considerations remains to be determined. Regulatory changes that simplify the development processes for biosimilars versus reference biologics (e.g., fewer preclinical and clinical trials required) may ultimately translate to lower overall product costs (e.g., $100–$250 million for biosimilars vs. an average pre-tax cost of $2.6 billion for originator biologics).62,63 Given these differences, an estimated $44 billion in direct cost savings for biologics is expected between 2014 and 2024,64 which should help offset the incremental costs associated with introducing new and innovative medicines that are likely to be approved in the future. Ultimately, cost and cost savings will be key factors for biosimilar acceptance in the market.37,40,42,65
Despite the expected differences in unit cost between biosimilars and originators, payers may still need to negotiate with manufacturers to get the projected savings beyond the originator. For drugs covered under the retail pharmacy benefit, rebates and discounts66 for biosimilars may be set through negotiations between payers and manufacturers. Other avenues, such as government payment policies37 and accountable care organization (ACO) incentives,37 may also have an impact on unit cost.66,67
The Affordable Care Act (ACA) requires the Medicare Part B reimbursement value for a biosimilar to be based on the sum of the drug’s average selling price plus a fixed percentage of the reference product’s price (6% at present).42 This was intended to put Medicare payment for biosimilars on a level playing field with reference products. In July 2015, the Centers for Medicare & Medicaid Services (CMS) published a proposed rule in the Federal Register to have all biosimilars share the same reimbursement code (i.e., J-code).35,40 However, CMS recently issued new guidance on reimbursement for biosimilars;68,69 as of January 1, 2018, all approved biosimilars receive their own healthcare common procedure coding system (HCPCS) reimbursement code. This was implemented to encourage more biosimilar development, although its effect on prices remains to be seen. The full impact of this change probably will not be realized for several years, but these changes combined with distinguishable names will likely assist with pharmacovigilance using claims data.69
PBMS AND PRIVATE INSURER CONSIDERATIONS
Because of the market power of drugs covered under the retail pharmacy benefit, PBMs are likely to obtain significant rebates with respect to biologics paid for by the plans they administer. For example, one large U.S. PBM has already included biosimilars for filgrastim and insulin in its formulary to take advantage of lower pricing.70 Of note, insulin and low-molecular weight heparin currently are not considered biologics/biosimilars in the U.S. However, in draft guidance issued in March 2016, the FDA stated that by 2020, these “transitional products” will be treated as biologics under the Public Health Service Act, and thus some products could be subject to biosimilar guidances.71 Additional considerations for the use of biosimilars include the overall strength of the data supporting similar efficacy, safety, and potency between the biosimilar and its reference product; prescriber and patient education; and potential drug delivery advantages.
For drugs covered under the medical benefit, which are often administered and billed for by physicians, payment policies have been shown to be significantly correlated with uptake by physicians;7,72 however, there is a need for real-world evidence to truly evaluate biosimilar costs in relation to patient outcomes. One initiative developed through the ACA is the development of alternative payment models such as ACOs,73 which are groups of doctors, hospitals, and other health care providers that provide coordinated care to their Medicare patients and share cost savings.74 If a physician is part of an ACO, then the associated risk sharing may drive preferences. Furthermore, for specialists within large groups such as oncology practices or their own purchasing group, the group’s choice will likely drive utilization. If the ACO is part of the CMS Medicare Shared Savings Program, then these choices may be driven by contracts created between the ACO and public or private payers who issue rewards for controlling the cost of care, provided the quality of care is met and maintained.75,76 If successful, the ACOs receive part of the savings achieved by CMS through these policies.75,76 Together, these incentives may create a barrier to biosimilars being used in clinical practice, thereby limiting the overall savings that could be realized with biosimilars in these settings.
The reduced acquisition cost of a biosimilar compared with the reference product will primarily affect patients with high-deductible plans or those with coinsurance where out-of-pocket expenses are calculated as a percentage of the drug’s list price instead of a fixed copay.77 In such situations, it is likely that patients seeking to reduce their out-of-pocket costs will drive providers to prescribe biosimilars over the reference biologic.77 In the absence of a price differential, as it affects patients’ out-of-pocket costs, patients may be more likely to choose the branded originator product. Prescribers and pharmacists will likely support the patient’s drug choice if copay benefits and professional assurance are in place. Patients for Biologics Safety and Access (PBSA) is a national coalition of more than 20 patient advocacy organizations that aims to ensure that the voices and interests of patients are heard, as the FDA considers approval of biosimilars.78 PBSA believes that patients must have access to safe and effective biologic and biosimilar medicines and all the information necessary to make a fully informed choice about whether to use a biosimilar. PBSA also aims to support the appropriate tracking of adverse events (AEs) and the use of unique names. Such efforts help to instill more confidence about biosimilar safety and efficacy in the patients who receive them.79
VALUE BEYOND PRICE REDUCTION
A payer’s decision to adopt a biosimilar for formulary inclusion should be based on the quality and overall value as opposed to the price alone.5,32,42,53,60,61 Elements that contribute to the value of a drug include product quality established through extensive analytical and functional assessments during product development; provider-focused education; provider engagement; manufacturer reliability of quality and the supply chain; and additional services such as, for example, anticounterfeit protection).32,42,60,61
Manufacturing considerations, supply chain security, and logistics are also important when determining the relative value of a biosimilar.32,53,80 The strength of manufacturer records for quality is vital for developing brand acceptance, trust, and reliability,32 and for maintaining consistency in treatment. In addition, physicians may develop a preference for biosimilars from reliable manufacturers with a low likelihood of supply disruptions, a positive history regarding recalls, safe handling practices, supply chain security, and counterfeit protection.32,80,81 It is also important to consider potential differences between delivery devices for biosimilars and reference products that may provide added benefit to patients and health care providers.
As with generic medications, the reduced price of a biosimilar may also translate to other benefits in addition to cost savings. These may include improved medication adherence associated with lower copays, and enhanced motivation for originator and biosimilar manufacturers to invest in innovation to differentiate themselves in an increasingly competitive market.82
EXPERIENCE IN THE UNITED STATES
Currently, there are a number of challenges for all stakeholders40,42 that could limit the immediate uptake of biosimilars.61,83 Major considerations include provider and patient education, and an understanding of the regulatory approval process; differences in state and regional adoption practices and laws (especially as they relate to interchangeability and substitution); and administration strategies, the documentation of AE concerns, and cost or insurance coverage barriers.84,85 Educational opportunities (e.g., data on approval requirements, clinical study regulations, immunogenicity considerations) for physicians, patients, and payers are needed to facilitate the incorporation of biosimilars into formulary decision-making. Without education to increase biosimilar familiarity, physicians may be less inclined to prescribe this new category of biologics and may not be aware of which biosimilars are available on a payer formulary. Furthermore, laws, regulations, and guidance for biosimilar usage and substitution vary at state and regional levels and are influenced by factors including state board of pharmacy requirements, state insurance options, and state legislative and regulatory structures. Together, these factors affect pricing and reimbursement strategies.72,86 For biosimilars to be adopted into health care practice, pricing needs to be sufficiently low.72
There are many important considerations in addition to cost that payers should weigh when evaluating biosimilars. These include the totality-of-evidence approach for demonstrating biosimilarity (e.g., analytical/functional similarity, efficacy, and safety); the potential added value beyond cost; and manufacturing considerations, including the reliability of supply and logistics. Also, it is important that payers consider the impact of state laws regarding substitution, including how interchangeable biosimilars may be used. In the U.S., further real-world experience with biosimilars is needed to more fully appreciate their broader value and potential for increasing patient access to life-saving biologics.
Figure and Tables
Stepwise Process for Demonstrating Biosimilarity
Biosimilars Approved in the United States
|Nonproprietary Name||Trade Name||Indication|
Key Considerations for Evaluating Biosimilar Uptake
|Key Considerations||Supporting Points|
|Toxicity and immunogenicity||
|Supplier manufacturing capability||
|Cost savings to payer||
|Dosage format for target population||
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- RENFLEXIS (infliximab-abda) prescribing information Kenilworth, New Jersey: Merck & Co. 2017;
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- IXIFI (infliximab-qbtx) prescribing information New York, New York: Pfizer, Inc. 2017;
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- FulphilaTM (pegfilgrastim-jmdb) prescribing information Zurich, Switzerland: Mylan GmbH. 2018;
- NIVESTYM (filgrastim-aafi) prescribing information Lake Forest, Illinois: Pfizer Inc. 2018;
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