Biosimilars: Building a Foundation for Clinical Use

Transcription

1 Biosimilars: Building a Foundation for Clinical Use INTRODUCTION Recent and upcoming patent expirations for some of the most commonly used biologic agents have led to the development of biosimilar products compounds that are designed to be highly similar to the original, or reference, product; but cannot be identical due to the complexities of producing biologic products. As of the release of this monograph, one biosimilar product, filgrastim-sndz, is available in the United States. Several other biosimilars are currently under FDA review and many more are currently undergoing testing. Biosimilar agents have the potential to reduce costs associated with biologic therapy due to the introduction of competition between companies making the biosimilar and the reference product; though the actual overall economic impact may vary widely in different markets and remains to be seen. Physicians will need to stay abreast of the latest development in the rapidly evolving area of biosimilars, as their use will directly impact delivery of patient care. NEED FOR BIOSIMILARS Biologic therapies have revolutionized the treatment of diseases across the fields of medicine, providing quite effective; and, in some cases, better tolerated treatment options. Biologic agents also play a key role in supportive care for patients with various medical conditions. The advantages of biologic agents are not without challenges one of which is their associated cost. Recent years have seen the US patent expiration of several widely used biologic agents, including insulin glargine, filgrastim, and epoetin alfa. 1 Within the next 5 years, patents are due to expire for a number of other commonly used biologics (Table 1). Page 1

2 Table 1. Commonly used biologics approaching patent expiration 1 Agent FDA-Approved Indications Expected US Patent Expiration Bevacizumab Metastatic CRC, non-squamous 2019 NSCLC, glioblastoma, metastatic RCC, cervical cancer, platinumresistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer Trastuzumab HER2-overexpressing breast 2019 cancer; HER2-overexpressing metastatic gastric or GEJ adenocarcinoma Adalimumab RA, PsA, AS, CD, UC, PsO 2016 Palivizumab Prevention of serious lower 2015 respiratory tract disease caused by RSV in children at high risk of RSV disease Cetuximab Head and neck cancer, K-Ras wild 2016 type, EGFR-expressing, metastatic CRC Infliximab RA, PsA, AS, CD, UC, PsO 2018 Rituximab NHL, CLL, RA, GPA and MPA 2016 Pegfilgrastim Decrease incidence of infection as manifested by febrile neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia 2015 AS = ankylosing spondylitis; CD = Crohn s disease; CLL = chronic lymphocytic leukemia; CRC = colorectal cancer; EGFR = epidermal growth factor receptor; GEJ = gastroesophageal junction; GPA = granulomatosis with polyangiitis; HER2 = human epidermal growth factor receptor 2; MPA = microscopic polyangiitis; NHL = non-hodgkin s lymphoma; NSCLC = non-smallcell lung cancer; PsA = psoriatic arthritis; PsO = plaque psoriasis; RA = rheumatoid arthritis; RCC = renal cell carcinoma; RSV = respiratory syncytial virus; UC = ulcerative colitis This list includes a number of monoclonal antibodies, which are more complex (and costly) to manufacture than other types of biologic agents. 1 With these patent expirations impending, competitor agents have been developed with the intent of gaining regulatory approval for commercial release shortly after the patent expiration date. It has been predicted that the development of these competitor products may increase affordability of, and access to, biologic drugs. 2 In the case of small-molecule drug development, these competitor products are called generics. Generic drugs are designed to be structurally identical to the reference product and must generally demonstrate bioequivalence, which the FDA defines as showing no significant difference in the rate and extent of Page 2

3 absorption when administered at the same molar dose under similar conditions. 3 However, generic drugs are not completely identical to the reference product due to some variation that is allowed in the pharmacokinetics testing. The concept of a generic drug does not carry over to the setting of biologics due to the complexity of manufacturing these products. Biologic products developed to be alternatives for existing biologics are called biosimilars. Research from an independent Rand Corporation report estimates that biosimilars will lead to a direct cost savings in the US of $44.2 billion from 2014 to 2024, representing about 4% of the total spending on biologics. 4 It should be noted however, that estimates regarding potential cost savings have varied widely. Biosimilar products are not expected to provide nearly the same relative reduction in cost as generics have historically provided due to their high manufacturing costs. However, the cost of some generic drugs has increased dramatically in recent years with potential causes including drug shortages, disruptions in supply, and industry consolidations all of which may decrease competition. 5 Moreover, in the case of biosimilars, even a 20% price reduction could make a significant absolute difference in cost, given the present costs of biologics. 6 According to cost models conducted in Europe, savings of biosimilar filgrastim over reference filgrastim range from 33 to 785 for a 4-day course of therapy to 458 to 2747 for a 14-day course of therapy. 7,8 In one study, however, the savings of biosimilar filgrastim over pegfilgrastim decreased over time. 8 In a hypothetical model of 10,000 patients, the savings associated with use of biosimilar filgrastim rather than the reference product increased over time (yet the savings over pegfilgrastim decreased over time) and use of biosimilar filgrastim was associated with expanded access to targeted antineoplastic treatment. 8 In general, market forces will determine the actual costs of biosimilars. In some instances, there may be only one or two biosimilar competitors; in others, there may be more. The economic impact of biosimilars may also vary greatly depending upon the healthcare system of a particular country. Insurers will also play a role in the pricing of biologics. There are many considerations regarding the production, testing, regulatory approval, clinical use, dispensing, and safety monitoring of biosimilar products. This monograph is intended to provide an Page 3

4 overview of these considerations and to highlight the current state of biosimilars in the US for the practicing clinician. DEVELOPMENT OF SMALL MOLECULES VS PROTEINS The concept of a generic drug that is designed to be an almost identical but incomplete copy of the original product does not apply to biologic agents due to the structural complexity of the proteins being produced and the manufacturing processes required to produce them. The manufacturing of biologic products relies on live cell culture systems that will have inherent differences (Figure 1). Moreover, the FDA has noted that biologic agents produced by different manufacturers should be expected to differ both from the original product and from each other due to differences in cell lines, raw materials, equipment, and other aspects of the manufacturing process. 9 Figure 1. Manufacturing Process of Biologic Products and Potential Sources of Variation Between Reference Product and Biosimilars 10 Some have expressed concern that these differences may translate into differences in efficacy and safety, in particular immunogenicity. Table 2 outlines the factors that account for the Page 4

5 substantial differences between generic drugs and biosimilars in their regulatory requirements, indications, and monitoring. Table 2. Comparison of biosimilar products versus generic drugs 9,11,12 Parameter Biosimilar Products Generic Drugs Synthesis Structure in comparison to reference product Structural complexity Potential for immunogenicity Interchangeability with reference product Automatic substitution Produced in living systems; generally use recombinant DNA technology Designed to be similar; cannot be 100% identical Many layers of structure, including post-translational modification Immunogenicity possible; requires testing and pharmacovigilance monitoring Not interchangeable except for products that meet higher standard of interchangeable Guidance pending; may or may not be substituted Nomenclature Draft guidance proposes unique INN reference product with a 4-letter suffix INN, International Nonproprietary Name (generic) Produced through chemical synthesis Designed to be almost completely identical Typically simple molecular structure Less likely to be immunogenic though allergic reactions can occur Legislation allows for interchange between reference drug and generic, assuming standards of purity and bioequivalence have been met Generally allowed, depending on state law and if physician permits substitution INN generally same as reference product REQUIREMENTS FOR BRINGING BIOSIMILARS TO MARKET Biosimilars have been used outside the United States, including in Europe and Canada, for nearly a decade. Regulatory guidance for biosimilars was first introduced in Europe in 2005, with the approval of biosimilar somatotropin following in Today, the European Medicines Agency (EMA) reviews biosimilar products based on general measures of quality, safety, and efficacy in addition to specific guidance based on the individual product and drug class. 2 As of the release of this monograph, biosimilar products are available in Europe for insulin glargine, epoetin alfa, epoetin zeta, filgrastim, follitropin alfa, and somatotropin, and for one monoclonal antibody, infliximab (Table 3). Page 5

6 Table 3. Biosimilar products available in Europe as of September Date of Approval Active substance Monoclonal Therapeutic area Antibody? 4/12/2006 Somatotropin No Pituitary dwarfism, Prader-Willi syndrome, Turner syndrome 8/28/2007 Epoetin alfa (3 products) No Anemia, cancer, chronic kidney failure 12/18/2007 Epoetin zeta (2 products) No Anemia, autologous blood transfusion, cancer, chronic kidney failure 9/15/2008 Filgrastim (3 products) No Cancer, hematopoietic stem cell transplantation, neutropenia 2/6/2009 Filgrastim (2 products) No Cancer hematopoietic stem cell transplantation, neutropenia 6/8/2010 Filgrastim No Cancer, hematopoietic stem cell transplantation, neutropenia 9/27/2013 Follitropin alfa No Anovulation 10/9/2013 Infliximab (2 products) Yes Psoriatic arthritis, rheumatoid arthritis, ulcerative colitis, Crohn s disease, psoriasis, ankylosing spondylitis 10/18/2013 Filgrastim No Neutropenia 3/27/2014 Follitropin alfa No Anovulation 9/9/2014 Insulin glargine No Diabetes mellitus 9/18/2014 Filgrastim No Neutropenia The groundwork for the introduction of biosimilar products in the US was first laid in 2009 in conjunction with the Affordable Care Act. At that time, the US Food and Drug Administration (FDA) put forth a formal definition of biosimilar products as a part of the Biologics Price Competition and Innovation (BCPI) Act. 9 According to the FDA definition, biosimilarity means that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components and that there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product. 9 In order to demonstrate these elements of biosimilarity, data must be derived from 3 types of studies analytic studies, animal studies, and at least one clinical study unless the FDA determines one of these elements unnecessary. 9 Page 6

7 It is important to keep in mind that a biosimilar product does not have to independently demonstrate efficacy and safety to gain FDA approval, as is required for the reference product. Instead, the biosimilar product must only demonstrate similarity to the reference product. Thus, biosimilarity studies may include studies that compare the structure, function, animal toxicity, human pharmacokinetics and pharmacodynamics, clinical immunogenicity, and clinical safety and effectiveness between the biosimilar product and the reference product, according to FDA guidance released in Given these differences in requirements, registrational studies of biosimilar products may differ in their design and endpoints from studies of the reference product. 6 Pharmacokinetic (PK) and pharmacodynamic (PD) studies play a key role in the evaluation of biosimilar products. The FDA has proposed that in certain cases where there is meaningful correlation between PK and PD parameters and clinical efficacy, comparative efficacy studies may be unnecessary. 9 However, in the absence of such an exception, studies demonstrating clinical similarity between the biosimilar product and the reference product are required. IMMUNOGENICITY TESTING REQUIREMENTS The potential immunogenicity of biosimilar products is an important consideration in the registration and monitoring process. The development of neutralizing, anti-drug antibodies could have serious safety implications, and could potentially affect the therapeutic efficacy of a drug. To address this concern, the FDA has proposed risk-based requirements for testing the immunogenicity of biosimilars based on expected risks, analytical similarity, and clinical findings, with monitoring requirements varying by product. 14 Safety monitoring requirements will also vary by product. Postmarketing safety will be particularly important to detect any immunogenicity or other safety events that may not occur at a sufficient frequency during initial clinical testing. Manufacturing changes will also require new assessments, as even small manufacturing changes could potentially affect product safety or efficacy. 15 Page 7

8 EXTRAPOLATION OF INDICATIONS When a generic drug receives FDA approval in the US, the approval extends to all of the FDA-approved indications that the index drug received. This extension to additional indications of the reference drug is referred to as extrapolation. In the case of biosimilars, extrapolation does not automatically occur; a biosimilar product may in fact be licensed for fewer indications than the reference drug. 9 In Europe, for example, extrapolated indications those that are outside the scope of regulatory phase 3 trials of the biosimilar are required to undergo postmarketing pharmacovigilance studies. In the US, manufacturers of biosimilar products may apply for a product to be licensed for one or more additional indications that are beyond the indication for which the clinical studies were conducted but are within the list of approved indications for the reference drug. This extrapolation of clinical data across indications requires sufficient scientific justification to address the mechanisms of action relevant to each condition and characterization of the PK, biodistribution, immunogenicity, efficacy, expected toxicities, and any other factors that may affect the safety or efficacy of the product in the populations being considered. 9 Dr. Goldman, once biosimilars are incorporated into clinical practice in rheumatology, how might physicians monitor for safety? What role do patients have in monitoring? NAMING OF BIOSIMILARS The US FDA has proposed guidance on the naming of biosimilars but, as of the release of this monograph, a final rule on nomenclature has not been established. Under the current draft guidance, all biosimilar products will have a unique name consisting of the core reference product name followed by a 4-letter designated suffix. 12 This naming convention has been proposed to ensure that physicians, pharmacists, and patients are all aware of what product a patient is receiving. Having a unique identifier for each biosimilar that may also assist with pharmacovigilance. Page 8

9 PRESCRIBING AND DISPENSING Policies on how and when nonproprietary or generic drugs may be substituted for brand-name drugs are regulated at the state level. Generic drugs are generally interchangeable with the reference product; meaning that a pharmacist can substitute a generic drug for a reference product without the permission of a physician, unless the physician specifies or a patient requests that a branded product be dispensed (according to state laws). Due to the differences between small-molecule agents and biologic products, concern has been raised by some physicians about how and when biosimilar products may be substituted for reference biologic products. The potential for patients to receive a biologic product other than the prescribed agent has created controversy and raised new issues for policymakers and physicians as well as for pharmacists, who will be in a primary position to navigate regulations that insurers may place regarding coverage of reference products versus biosimilars. Substitution Laws State laws govern policies on whether biologic products may be substituted by a dispensing pharmacist. As of July 2015, bills or resolutions related to biologics and/or biosimilar products had been filed in 31 states, of which 15 states have subsequently signed such laws. 16 Although the specific legislation varies between states, the laws generally address when substitution is allowable, whether any notification would be required between pharmacists, physicians, and/or patients, and what records must be retained by the pharmacist and physician (Table 4). Table 4. Typical mandates included in state legislation on biologics and biosimilar substitution 16 Any biologic product being considered for substitution must be approved as interchangeable by the US FDA The physician can prevent substitution by written instruction The physician must be notified of any allowable substitution that has been made The patient must be notified that a substitution has been made (in some cases, patient consent is required) The pharmacist and physician must retain records of substituted biologic agents The pharmacist would not be liable for substituting an interchangeable biologic if allowed by state law The state must keep a public list of allowed interchangeable biologic products Page 9

10 When considering the issue of substitution, it is important to keep in mind that there is a difference between biosimilar and interchangeable. Not all biosimilars are considered interchangeable and therefore potentially eligible for automatic substitution. Only biosimilar products that meet the more stringent interchangeable designation by the FDA have the possibility of being considered for substitution. However, these standards have not yet been defined and no biosimilar products are yet considered interchangeable. STATUS OF BIOSIMILARS IN THE UNITED STATES As previously noted, biosimilars have been available in Europe, Canada, Asia, and South America for years. Biosimilar products on the market outside the US include various epoetin formulations, somatotropin, filgrastim, insulin glargine, and infliximab. Filgrastim The first biosimilar made available in the US was the filgrastim biosimilar filgrastim-sndz, approved in March 2015 for use in the US for the same indications as the reference product. 17 Note that filgrastimsndz is not an interchangeable biosimilar, a more stringent standard that has not yet been defined. The approval of the biosimilar product filgrastim-sndz was based on structural and functional data, animal studies, human pharmacokinetic and pharmacodynamic studies, clinical immunogenicity, and a phase 3 noninferiority trial in which filgrastim-sndz was compared against filgrastim in women eligible for neoadjuvant or adjuvant chemotherapy for breast cancer. 18 In its phase 3 comparative study, filgrastim-sndz showed no clinically meaningful differences from the reference product in efficacy or safety for the prevention of severe neutropenia. This similarity was observed whether patients received only the biosimilar or whether they alternated between the biosimilar and the reference filgrastim. 18 Infliximab The development of a biosimilar to infliximab represents a significant step in the development of biologics, as monoclonal antibodies are more complicated than other biologics in their manufacturing. In both Europe and Canada, the infliximab biosimilar CT-P13 received regulatory approval based on a randomized, phase 3 trial in which CT-P13 showed equivalent efficacy to infliximab in patients with Page 10

11 rheumatoid arthritis (RA) and ankylosing spondylitis (AS); and showed comparable pharmacokinetics, immunogenicity, and safety. 19,20 Although CT-P13 was primarily evaluated in RA and AS, the European Commission extrapolated its approval to include other indications in rheumatology, dermatology, and inflammatory bowel disease (IBD). Some physicians take issue with the concept of extrapolation, arguing that therapies should be tested in each indication. Some regulatory authorities have, in fact, disallowed some instances of extrapolation. Canadian regulatory authorities allowed extrapolation of CT-P13 to psoriatic arthritis and plaque psoriasis but not to IBD, citing observed in vitro differences between CT-P13 and infliximab, potential differences in mechanism of action in the different conditions, and a lack of clinical data with CT-P13 in IBD. 21 Dr. Cohen, how should gastroenterologists interpret the extrapolation of anti-tnf biosimilars from other conditions, such as RA and dermatology, to IBD? It has been noted that patients in the RA study of CT-P13 received concomitant methotrexate. The addition of methotrexate to the biologic has the potential to suppress the development of antidrug antibodies and, in turn, limit the ability to detect differences in immunogenicity between CT-P13 and infliximab. 22 This is particularly relevant in the context of IBD, as these patients are more commonly treated with infliximab monotherapy (ie, without a concomitant immunosuppressant), and therefore are more likely to develop anti-drug antibodies. 22 However, in vitro studies from Ben-Horin and colleagues suggest that infliximab and CT-P13 are similar in their immunogenicity, as anti-infliximab antibodies present in the serum of patients with IBD are able to bind and neutralize CT-P Biosimilars for infliximab are currently under review by the FDA. Epoetin Alfa An epoetin biosimilar has been developed and was recently evaluated in two randomized, open-label, active-controlled studies in healthy volunteers. In results presented at a 2015 meeting, the biosimilar product showed similar pharmacokinetics and pharmacodynamics to reference epoetin and was Page 11

12 concluded to have no clinically significant differences in in vivo activity. 24,25 The product was submitted to the FDA for review in late Adalimumab The adalimumab biosimilar ABP 501 demonstrated pharmacokinetic equivalence to adalimumab in healthy subjects 27 and was evaluated in a phase 3 study in patients with moderate-to-severe RA. The company announced positive results of the trial in early Insulin Glargine An insulin glargine biosimilar was approved for use in Europe in In the United States, insulin glargine is not considered a biosimilar; although it has the same amino acid sequence as the reference product. 28 An alternative insulin glargine product has demonstrated similar efficacy and glucose control as the reference product in randomized, phase 3 studies conducted in patients with type 1 and type 2 diabetes. 29,30 In 2014, the FDA granted tentative approval to the new insulin glargine product, which is subject to an automatic stay of up to 30 months. 31 Other Biosimilars Other biosimilars currently under FDA review include pegfilgrastim and a second filgrastim biosimilar. Many other biosimilars are currently undergoing required testing; including biosimilars for adalimumab, trastuzumab, bevacizumab, rituximab, and cetuximab. BIOSIMILARS AND CLINICAL PRACTICE GUIDELINES Following the approval of the first biosimilar available in the US (filgrastim-sndz), the American Society of Clinical Oncology (ASCO) in July 2015 published updated guidelines for the use of white blood cell (WBC) growth factors that include the use of filgrastim-sndz. 32 ASCO guidelines include filgrastim-sndz among the list of potential granulocyte-colony stimulating factors (G-CSF) products, noting that filgrastim-sndz (and other biosimilars as they become available) can be used for the prevention of treatment-related febrile neutropenia, with the choice of agent depending on clinical factors, cost, and convenience. ASCO guidelines note that the dosing and administration of filgrastim-sndz should be the same as filgrastim. 32 Page 12

13 As additional biosimilar products receive FDA approval, physicians should stay abreast of relevant clinical guidelines and specialty organization statements (ie, ASCO, American College of Gastroenterology [ACG], American College of Rheumatology [ACR]) regarding individual drugs. However, updates to treatment guidelines should not be expected with each biosimilar approval, as physicians should expect that the efficacy of an FDA-approved biosimilar will be essentially the same as the reference product. Incorporation of biosimilars into clinical practice will also be guided by other factors such as availability and economic considerations. With drug shortages, drug budget issues, and the financial impact for patients (eg, copayment or coinsurance); physicians will be expected to consider alternatives that balance effectiveness, safety, and cost. Formulary decisions and insurance reimbursements may well contribute to the decision to prescribe a biosimilar product. When biosimilars are used, physicians and patients should monitor for the potential development of unforeseen side effects, given that phase 3 studies performed to bring a biosimilar to market contain far fewer patients as the original registration trials. Issues such as the rates of development of neutralizing antibodies, loss of response, and resultant immune reactions will need to be followed closely as biosimilars become available for use in clinical practice. In terms of how biosimilars will be incorporated into clinical practice, there are many potential scenarios being discussed in advance of the approval of the first monoclonal antibody biosimilars. One approach being advocated by some experts as a first step in a healthcare system or practice is a gradual introduction of biosimilars only in patients newly starting a biologic agent. At the other end of the spectrum is an instant switching over to biosimilars for patients currently receiving treatment. One point to consider is whether patients will be able to switch between the biosimilar and the reference drug on an alternating basis, depending upon pharmacy supply and drug product availability. While some of these issues may be addressed by legislation on the federal or state level; others may be dictated by the payers, which is not inconsequential given the high costs of drugs. Patients will share with physicians the responsibility of using biosimilars, including agents that may not have been tested for their specific indication. Patients therefore must be informed when a biosimilar is being used, just as they should be told when a generic medication is being used. 33 Page 13

14 One must also consider the current general patient copay assistance plans offered by companies producing the reference drugs, as the cost of the drug to the patient may be a stronger point for a prescribing physician than the cost to the payer. These copay plans may reduce the monthly copay by hundreds of dollars, enabling the patient to afford these pricey therapies. Currently, co-pay plans are essential for many patients who otherwise would not be able to receive treatments. Will the companies producing the biosimilars match these programs? Or, will insurance companies cover the full cost of the presumably cheaper biosimilar agent? These are important issues when assessing the real life impact that biosimilars will have in the US marketplace. ROLE OF PHARMACISTS Pharmacists will have an important responsibility to communicate about biosimilars with physicians and with patients. The introduction of biosimilar products on the marketplace will provide new opportunities for collaboration between pharmacists and prescribing physicians to maximize the efficacy and safety of biologic therapy in the context of available resources. As biosimilars enter the market, pharmacists are uniquely positioned to communicate with physicians about available products and to help navigate payer requirements or financial incentives that may arise with the introduction of biosimilars. Mr. Schneider, what steps can pharmacists take to promote an open dialogue with prescribers to ensure the most appropriate and safe use of biosimilars? An open dialogue between pharmacists, prescribing physicians, and patients will ensure that patients are receiving the most effective and safe therapies available while maximizing cost effectiveness. It is not clear that this type of dialogue will be required by all states; however, communication should be encouraged even in the absence of legislation. As patients start to receive biosimilars, pharmacists will also be uniquely positioned to assist with pharmacovigilance and, in some settings, ensure any adverse events are appropriately reported to the FDA through MedWatch. The pharmacist is likely to be affected by payer policies, such as a limited formulary that might not cover an expensive biologic or might require the substitution of a less expensive product, particularly if a drug Page 14

15 is deemed interchangeable by the FDA. A prescribing physician can always write dispense as written on a prescription, which obligates the pharmacist to provide the specific branded product to the patients if the branded product is included on the formulary. In a health-system setting where drug policy is established by the medical staff through a Pharmacy and Therapeutics Committee, these issues can be addressed proactively through the formulary system, local clinical guidelines, close monitoring and pharmacovigilance, and health system-specific therapeutic interchange programs in which similar drugs with comparable effects are used based on cost considerations. Pharmacists are typically involved in supporting Pharmacy and Therapeutics Committees IMPORTANCE OF PATIENT EDUCATION As biosimilar products enter the marketplace, it will be essential for healthcare professionals, including pharmacists and physicians, to educate patients about biosimilars what they are, how they are different from generics, how they might be used, and the potential safety concerns associated with their use. Patients should also be reassured that biosimilar products have undergone rigorous testing and have demonstrated a high similarity to the reference product. 6 Moreover, given that biosimilars have not been used as extensively in large phase 3 studies prior to FDA approval when compared with reference drugs, it will be important to monitor for the efficacy of the drug and then assess side effects to ascertain the safety, as is already done with biologics. SUMMARY The development of biosimilars is a rapidly evolving field. Following the approval of the first biosimilar for use in the US, several other products are currently under review and many more are undergoing testing. The rise of biosimilars will likely continue into the coming years as patents for some of the most commonly used biologic agents begin to expire. Although the entry of the US into the arena of biosimilars has been delayed compared with Europe, guidelines are now in place that establish the requirements necessary to demonstrate that a biosimilar product is highly similar to the reference Page 15

16 product and is suitable for use. In order for physicians to begin prescribing biosimilar agents, they must have confidence in these agents and the process through which they are evaluated. 37 Issues that remain to be solidified in the near future include establishing a stable naming system for biosimilars and identifying requirements for the more stringent interchangeable designation, which would make a product eligible for automatic substitution. It also remains to be seen how biosimilars will affect the marketplace for biologics and how they will be incorporated into clinical practice, particularly for extrapolated indications for which they have not been clinically tested. Physicians, pharmacists, and patients will all continue to have key roles in ensuring that all biologic medications are used appropriately and safely. To stay abreast of the evolving area of biosimilars, physicians, pharmacists and other prescribers are encouraged to consult the FDA Purple Book (similar to the Orange Book for generics) that lists all licensed biologic products, including products with reference product exclusivity and those with biosimilarity or interchangeability evaluations. Table 5. Key Resources on Biosimilars FDA website information for healthcare professionals on biosimilars ovalapplications/therapeuticbiologicapplications/biosimilars/ucm htm FDA website Purple Book ovalapplications/therapeuticbiologicapplications/biosimilars/ucm htm State laws and legislation related to biologics and substitution of biosimilars Page 16

17 Table 6. Key Educational Takeaways As patents of biologic products expire, there is an opportunity to develop alternative versions which may lower costs and increase access to these medications These biologic products are called biosimilar as they are similar to, but not identical to, the reference product Biosimilar products are designed to be highly similar to the reference product and must show no clinically meaningful differences in safety, purity, or potency Clinical studies of biosimilar products aim to demonstrate their similarity to the reference product rather than their independent efficacy and safety As of the release of this monograph, one biosimilar product, filgrastim-sndz, is FDA approved for use in the United States Biosimilar products may be approved in the US for other approved indications of the reference product beyond which a biosimilar was clinically tested; extrapolation of indication requires sufficient scientific justification Only biosimilar products that meet the higher standard of interchangeable (which has not yet been defined) are potentially eligible for automatic substitution An open dialogue between pharmacists, physicians, and patients about the use of biosimilars will maximize the efficacy and safety of biologic therapy while optimizing the resources available Page 17

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