Biologics comprise an extensive variety of products, including vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and proteins. Manufactured in living systems through the use of recombinant DNA technology, biologics have transformed the treatment of many debilitating conditions, such as cancer, rheumatoid arthritis, and Crohn’s disease, and have provided therapeutic alternatives where previously none existed.1 More than 200 biologics have been developed since 1982, when recombinant human insulin, the first biotechnological therapy, was approved by the Food and Drug Administration (FDA).2 However, these significant advancements usually are accompanied by substantial expense given the costs associated with biologic development and manufacturing and the absence of therapeutically equivalent products. These expenses frequently translate into high acquisition prices for many biologic drugs, which can impact patient access to needed medications.
Numerous strategies have been considered to address the continually escalating costs of biologic medications. One strategy, the introduction of competing products, now known as biosimilars, is close to becoming a reality. While intended to occupy a place in therapy comparable to that of generics, the structural and manufacturing complexities of biologics will require a more detailed formulary evaluation of biosimilars.3,4 As such, pharmacists must take a leadership position to ensure the appropriate review, use, and monitoring of this new class of drugs.
Background of Biosimilars: A Quick Review
On March 23, 2010, President Obama signed into law the Biologics Price Competition and Innovation (BPCI) Act, which created an approval pathway for biological products demonstrated to be highly similar—that is, biosimilar—to previously approved, FDA-licensed biologics.3 Just as the 1984 Hatch-Waxman amendments established the abbreviated new drug application (ANDA) for generic medications, the BPCI Act created a licensure pathway, wherein a follow-on product could rely on existing scientific knowledge regarding the originator’s reference biologic.3 Given the abbreviated nature of the approval process, biosimilars are expected to cost less than their reference originator product.5 However, whereas the ANDA process requires no additional clinical trial information, the complexity of biologic medications necessitates that a biosimilar application includes data substantiating that it does not differ in a clinically meaningful way from the reference product in terms of safety, purity, or potency.6 Given these complexities, biosimilars will require greater scrutiny by pharmacy and therapeutics (P&T) committees than what is traditionally devoted to the review of generic medications.
As their name implies, small molecule medications are less complex therapeutic entities and are developed through well-defined chemical manufacturing processes.7 Due to the simplicity and consistency of their molecular structure, identical copies, or generics, can be created by other manufacturers.7 As such, generics are usually not subjected to P&T review prior to use, with the exception of select drugs with a narrow therapeutic index.8
Conversely, biologics are manufactured through highly complex, proprietary processes involving living organisms. The living systems used can be highly sensitive to even minor procedural changes; thus, the manufacturing process can impact the efficacy, safety, and performance of the end product.6 Even branded biologics demonstrate variation from lot to lot and from batch to batch.9 Therefore, a biosimilar manufacturing process will result in a product that is comparable, but not identical, to the originator. This inherent variation necessitates additional clinical trials to support approval and the need for facilities to review biosimilars prior to formulary addition.
Leveraging Existing Expertise
While biosimilars may be new, effective formulary management techniques are not. Most organizations are familiar with therapeutic interchange initiatives for both small molecule and biologic drugs.10 Health care systems have historically selected preferred, therapeutically equivalent agents within the antibiotic, antifungal, and anticoagulant drug classes. Even within the transplant and oncology settings, pharmacists have helped implement successful standardization strategies for products such as generic tacrolimus and for preferential use of either short- or long-acting erythropoietic agents.11 Likewise with intravenous immune globulin (IVIG), many organizations choose to use only a few select products.11
Therefore, the concept, competencies, and infrastructure already exist for the successful management of biosimilars. Now pharmacists must familiarize themselves with the nuances of the biosimilar regulatory and marketing processes.
The Approval Process
Understanding the biosimilar approval process is a prerequisite to conducting a balanced review of a medication to determine formulary status. Prior to the creation of the biosimilar pathway under the BPCI Act (also known as a 351(k) application), the only biologic approval mechanism available was the Biologics License Application (BLA), also known as a 351(a).3 The 351(a) is the pathway for approval of new biologic entities and requires a complete demonstration of safety, purity, and potency.12 Products approved via a 351(a) are usually evaluated through multiple phase 3 clinical trials. This expectation is a key differentiator for the abbreviated 351(k) pathway. The purpose of the 351(k) approval process is not to replicate in its entirety the clinical development actions of the originator. Instead, through a robust foundation of analytical characterization supported by pharmacokinetic, pharmacodynamic, and immunogenicity studies, as well as targeted clinical trial data, an applicant must prove that a product so closely resembles the originator reference biologic that the biosimilar would be expected to behave in a similar fashion in terms of safety and efficacy.13
FDA describes this process as a totality of the evidence approach, with each phase of biosimilar approval meant to resolve any residual uncertainty from previous steps.13 It is possible that approved biosimilars will achieve such a high degree of analytical characterization that the clinical trial requirement could be small, perhaps only a few hundred patients. This reality may diverge greatly for physicians accustomed to clinical evidence of thousands of patients. Pharmacists must work diligently to set the appropriate expectations for biosimilar clinical data.
While the clinical data requirement for FDA approval may be limited, other avenues of information exist. The European Union (EU) biosimilar process has been in place for several years, and multiple versions of biosimilars of epoetin and filgrastim have been approved.7 It is fully expected that many of those same products will be submitted to FDA for marketing in the US. Therefore, European clinical trial data could supplement the formulary analyses of US health systems in addition to the information made available. In addition, to assist with pharmacovigilance efforts post-approval, the Academy of Managed Care Pharmacy (AMCP) is developing a biosimilars collective intelligence system that continually analyzes available data and documents biosimilars’ safety and efficacy.14 The AMCP dossier format was recently updated to reflect the availability of biosimilars.15 AMCP dossiers are available upon request from the manufacturer.
Expert organizations also will weigh in on the appropriate place in therapy for biosimilars. Given the greater maturation of biosimilars in the EU, the European League Against Rheumatism (EULAR) has included references to biosimilars in its latest guidelines.16 The National Comprehensive Cancer Network (NCCN) has published a white paper on the subject of biosimilars and included references to the separately licensed product, tbo-filgrastim (Granix; Teva), in its guidelines.7,17
As part of the 351(k) pathway, applicants can choose to pursue all or only a subset of the indications for which the originator reference product is licensed.18 In addition, clinical trial data could be extrapolated for one use to other indications for the reference biologic under certain circumstances.13 Therefore, if the mechanism of action is well characterized and the sponsor provides sufficient scientific justification to support a finding that the biosimilar would function the same as the reference biologic, FDA potentially could approve indications that were not directly assessed through a clinical trial. The European Medicines Agency has granted extrapolated indications for all of the biosimilars it has approved, including the biosimilar version of infliximab (Remsima; Celltrion).19 However, Health Canada approved that same biosimilar version of infliximab only for a subset of the indications related to the conditions in which the product was studied.19 The approach FDA will take remains to be determined and could vary by molecule and applicant.
Naming and Interchangeability
Two aspects of the generic approval process greatly facilitate their use. Upon approval, generic medications receive the same generic or non-proprietary name as the reference product.20 In addition, they receive a therapeutic equivalency rating, also known as an Orange Book code, allowing their direct substitution.20 Neither of these aspects may be true for a biosimilar upon initial approval.
There is currently a robust debate centering on the non-proprietary name for biosimilars.21 Because biologic drugs cannot be exactly duplicated, some have suggested that biosimilars be differentiated using a unique identifier. Conversely, others suggest that creating a different name would limit uptake and create confusion regarding similarity to the originator molecule. This debate is occurring not only within the US, but worldwide as well. Recently, the World Health Organization issued a proposed rule to support consistency of identification for biosimilars globally.22 Under this plan, a biosimilar would receive a unique, four-letter suffix to the non-proprietary name.22 This proposal has not been finalized, and it is unknown whether FDA will adopt this approach. Keep in mind that should biosimilars receive a unique identification, formulary adoption will require the modification of order sets, protocols, inventory management, and automated dispensing software, and potentially many other documentation and administration systems to distinguish products accurately.20
The BPCI Act also gives FDA permission to designate certain biosimilars as interchangeable, meaning that a pharmacist could dispense the product in place of the originator without the involvement of the prescriber.3 FDA has stated that while it has authority to grant interchangeability status, it does not expect to make such a determination upon initial approval of the biosimilar.18 Nevertheless, this subject has been contested in many settings, particularly in state legislatures across the country. As of August 4, 2014, eight states have enacted biosimilar statutes; 14 states filed bills that are pending or failed; and California passed a bill through both chambers, but it was vetoed by the governor.23 Ultimately, each state’s pharmacy practice act will determine the process for interchanges and/or substitutions, including issues such as physician notification, patient consent, documentation, and record retention. For products designated by the FDA as interchangeable with the originator product, determining next steps in the acute-care setting may be relatively straightforward, but potentially more complex in the outpatient, specialty pharmacy, and retail environments.
To support the identification of biosimilars, including those that are interchangeable, FDA recently published its Purple Book,24 which, similar to the Orange Book, will identify products that have been approved as biosimilar and interchangeable with their originator reference product.
Additional Product Characteristics
An assessment of product characteristics, such as shelf life, storage requirements, and available dosage forms, will be a key component in the formulary review process. Adopting a new biosimilar may be challenging if its characteristics are less desirable than the reference drug. Conversely, if the biosimilar has slight benefits—for example, the product has a longer shelf life or the storage requirements are not as stringent—these improvements might tilt the decision in favor of the biosimilar.
Separately Licensed Biologics
It is important to note that not all follow-on biologics may be approved as biosimilars. It is anticipated that most competing biologic products approved after patent expiration of the originator will be licensed via the 351(k), or biosimilars, approval pathway. However, that may not always be the case. An example of this is the approval process for tbo-filgrastim.
Prior to the approval of the biosimilar pathway, Teva chose to submit a full BLA for its product, tbo-filgrastim.20 FDA approved the application and the product is now available for use. While approved as a biosimilar in Europe, this product is considered a separately licensed agent in the US.20 Therefore, this product was granted a distinct, non-proprietary name and cannot be designated as interchangeable with the originator, filgrastim. In addition, the agent received approval for only the indication for which it was studied—the treatment of chemotherapy-induced neutropenia. Should Teva desire to pursue more indications for the product, it will have to conduct additional trials in those patient populations, as extrapolation of indications is not a consideration.
The 351(k) pathway likely will be the avenue for most biosimilar approvals. However, pharmacists should be cognizant that various patent or indication litigation challenges could direct competitors to seek approval as separately licensed biologics to expedite their entry into the market.
While generic medications typically cost about 80% less than brand-name drugs, the savings realized by adding biosimilars to formulary will not be as substantial. A 20% to 30% cost savings is anticipated for biosimilar drugs compared with reference biologics.7,20 Although the lower cost of biosimilars is undoubtedly attractive to control drug spending in health systems, decision-makers must take into account a host of additional considerations.
Identifying the savings level at which hospitals are willing to switch from a biologic to a biosimilar is a subject of debate. Some health systems have indicated that even a 10% savings may be sufficient for them to switch to a biosimilar, although this determination may also depend on volume of use. For example, a 10% reduction in price for a high-use drug is more financially impactful than a 30% savings on a low-use medication.
Beyond cost, actual reimbursement will be a significant consideration. To determine the ultimate impact on the budget, particularly for biosimilars that are commonly used in the outpatient setting, rebates will need to be factored into decisions along with the actual purchase price. Reimbursement for biosimilars will vary by payer (ie, Medicare versus private insurance) and will be impacted by each payer’s decision to confer preferred product status. Therefore, when determining whether it is prudent to add a particular biosimilar to the formulary, the ultimate cost-savings generated must be measured. The contract price a hospital is eligible to receive undoubtedly will play a role in formulary decision-making.
While some originator manufacturers offer price discounts, they may do so only within certain settings, or classes of trade. The increased competition brought by biosimilars could result in price discounts being extended to practice settings for which they were not previously available.
Finally, the competition brought by biosimilars may address another aspect of cost—the additional expense related to manufacturers’ limited distribution strategies. For example, biotechnology supplier Genentech recently announced its decision, effective October 1, 2014, to limit the availability of its products Avastin (bevacizumab), Herceptin (trastuzumab), and Rituxan (rituximab) to a set of six specialized distributors.25 Unlike primary wholesalers, which usually offer pricing to customers at less than the wholesaler acquisition cost, also known as cost minus pricing, such favorable terms do not exist with specialty distributors. Given the absence of competition, hospitals have no alternative but to incur any additional expense. It is hoped that biosimilar manufacturers, in an attempt to increase utilization of their products, will choose an unrestricted distribution model.
The Importance of Education
Because biosimilar use is uncharted territory in the US, comprehensive education is vital to making informed decisions. ASHP has stated that health-system pharmacists should take a leadership role in the multidisciplinary effort to evaluate biosimilars for formulary inclusion, as well as in educating administrators, physicians, other health care providers, and patients about the inherent variability among biopharmaceutical products, differences between innovator biologics and biosimilars, and the importance of post-marketing pharmacovigilance.26 This creates quite a challenge, as most prescribers and pharmacists currently have a limited understanding of biosimilars. A 2013 survey of pharmacists and other health care workers reports that widespread confusion surrounds the differences between biologics and biosimilars; while three-quarters indicated that continuing education on biosimilars is important or very important, two-thirds rated their understanding of the product differences as fair or poor.27
Pharmacists should avail themselves of the latest information without delay. Information is available on the ASHP Web site, the National Comprehensive Cancer Network (NCCN) published an informative white paper in 2011,7 and AJHP published an article last year discussing the implications of biosimilars for health-system pharmacists.20Pharmacy Purchasing & Products’ July 2014 biologics supplement contains information on specialty pharmacy and on developing pathways for biosimilar approvals.28 In addition, a great deal of useful information is available online through state pharmacy organizations.
Furthermore, pharmacists can use the approval of tbo-filgrastim to educate themselves, physicians, and nurses about biosimilars. Although tbo-filgrastim is not a biosimilar, it presents an illuminating example of biologic manufacturing, regulatory approval, biologic variability, and pharmacovigilance concerns. Specifically, pharmacists should be working with oncologists, gastroenterologists, and rheumatologists, as many biosimilars entering the market in the coming years will impact these specialties. It is within pharmacy’s purview to ascertain that physicians specializing in these areas understand biosimilars and are comfortable with their use.
As a group purchasing organization, Novation continues to spend significant time and effort ensuring that our members are well educated about biosimilars. Because health systems have been awaiting the introduction of biosimilars for 10 years, it may be difficult to believe that these products are finally coming to fruition; however, the biosimilar horizon is rapidly approaching.
In July 2014, Sandoz, a Novartis subsidiary, filed a biosimilar application with FDA for its filgrastim Zarzio, making it the first product to use the FDA’s new 351(k) process. A decision from the FDA is expected by March 2015.29 A few weeks later, Celltrion announced that it had filed for approval of its biosimilar version of infliximab, marketed in the US as Remicade (Janssen).30 The timing of biosimilar competition for infliximab will be determined not just by FDA review, but also by patent litigation.30 Still, these filings serve as encouragement for those who have waited many years for increased competition. FDA published two guidance documents in 2014 describing the expectations for biosimilar clinical pharmacology determinations and the exclusivity of originator reference products.31,32 Additional guidance documents addressing the labeling of biosimilars and interchangeability are anticipated by the end of the year.33
The market exclusivity for the top 10 bestselling originator biologics is set to expire between now and 2019, and current estimates suggest that by 2024, the savings from biosimilars in the US could reach $250 billion.34,35 To realize the full measure of benefit for patients, pharmacists must be prepared to support biosimilar evaluation as these products come to market.
Steven D. Lucio, PharmD, BCPS, is the senior director for clinical solutions and pharmacy program development for Novation in Irving, Texas. Steven holds a PharmD from Creighton University and a BS in pharmacy from the University of Texas at Austin. His professional interests include improving medication safety, mitigating the impact of drug shortages, benchmarking pharmacy costs for key drug classes, evaluating the expense of high-cost biologics, and expanding the practice of pharmacy to more effectively manage specialty pharmaceuticals.
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