2017 trends in biosimilars report - Amgen Biosimilars

2017 TRENDS IN BIOSIMILARS REPORT Navigating the Path to Biosimilars

MESSAGE FROM AMGEN DEAR COLLEAGUES, Over the past several years, the U.S. healthcare system has experienced seismic shifts. We have witnessed transformations in coverage, care delivery, new technologies and outcomes-based reimbursement. We have also seen notable growth in the U.S. biosimilars market: the FDA approval of several biosimilar products, health plans and pharmacy benefit managers identifying coverage models and providers adding available biosimilars to their treatment plans for patients. While the biosimilar market continues to develop, we expect that the next year will bring another strong phase of growth and market maturity for biosimilars. We anticipate additional regulatory and legal activity surrounding these agents across a range of therapeutic areas. Growth and maturity also come with important lessons. It is clear that our journey with biosimilars is still in its early stages, and continued acceptance and adoption by various stakeholders will be gradual as confidence builds over time. At Amgen, we believe that building greater confidence in biosimilars will require wide-ranging conversations among relevant stakeholders, including manufacturers, clinicians, patients, regulators, administrators, employers and insurers – each of whom will bring their own perspectives on the development, adoption and reimbursement of biosimilars in the U.S. As an active participant in this ongoing national conversation, we are pleased to share with you the fourth annual edition of our Trends in Biosimilars Report, which was developed in collaboration with our Editorial Council, an expert panel representing a broad mix of the U.S. reimbursement community. This report provides an overview of the key issues facing stakeholders in the biosimilar market and represents part of Amgen’s commitment to being at the forefront of biosimilar education.

DUANE H. BARNES Vice President & General Manager U.S. Value and Access, Amgen

02 :: 2017 TRENDS IN BIOSIMILARS REPORT

MESSAGE FROM EDITORIAL COUNCIL DEAR COLLEAGUES, In 2015, the first biosimilar was approved by the U.S. Food and Drug Administration (FDA). Since that time, there has been a dramatic increase in applications submitted to the FDA for review, and many more are expected in the near future. The U.S. healthcare community has firmly taken the first step into a new reality, which includes assessing the addition of biosimilars to the specialty drug portfolio. Biosimilar adoption and utilization will be placed in the hands of several key stakeholders, including manufacturers, payers and prescribers – all of whom will make their own decisions regarding the value and use of biosimilars and design strategies to assess each new biosimilar’s place in the care continuum. Likewise, patients may now affect the integration of biosimilars into the treatment landscape, given that their familiarity with this category of medicines and the financial implications will drive acceptance. It is important to note the current uncertainty regarding healthcare and regulation reform within the U.S. and the potential for the biosimilars market to continue to evolve and shift. As members of the reimbursement community, we play a leading role in shaping the market and continuing to improve patient access to medicines that deliver the best care possible. We are proud to contribute to the 2017 Trends in Biosimilars Report, which we hope will serve as a guide for you to navigate the parameters of a biosimilar’s launch into the market and provide insight into trends pertinent to biosimilar adoption and utilization. The following pages provide background information on biosimilars and outline the key considerations stakeholders should take into account to successfully manage this exciting next step in the biosimilar journey. Bret Brodowy, PharmD Director of the Medication Outcomes Center, University of California School of Pharmacy

Michael Einodshofer, RPh, MBA Chief Innovation Officer, Maxor National Pharmacy Services

Manpreet Chahal, PharmD, PhD

President, Global Healthy Living Foundation

Clinical Oncology Pharmacist, Medical Oncology Associates

Mike Cunningham, PharmD Principal, Rx 2020 LLC

Seth Ginsberg Cheryl Larson Vice President, Midwest Business Group on Health

Katie McMillen, PharmD, MPH Director of Pharmacy, Froedtert & Medical College of Wisconsin Elan Rubinstein, PharmD, MPH Principal Consultant, EB Rubinstein Associates Kenneth L. Schaecher, MD Medical Director, Select Health

This report offers insights from our Editorial Council, comprising highly experienced medical and pharmacy directors representing the broad mix of managed care organizations throughout the U.S., as well as employer and benefit design consultants and patient advocates. This report includes contributions from additional healthcare industry professionals who prefer not to be listed. Editorial Council members are participating independently and their views may not reflect the interests of their respective companies.

2017 TRENDS IN BIOSIMILARS REPORT :: 03

TABLE OF CONTENTS THE BIOSIMILAR OPPORTUNITY ......................................................................................................................................................................................................................................................... 4 UNDERSTANDING BIOSIMILARS ........................................................................................................................................................................................................................................................... 5 PATIENT AND PHYSICIAN PERCEPTIONS OF BIOSIMILARS ................................................................................................................................................................................................ 10 THE NEW REALITY: CONSIDERATIONS FOR FORMULARY DECISION-MAKERS ...................................................................................................................................................... 15 LOOKING AHEAD .......................................................................................................................................................................................................................................................................................... 29 REFERENCES ................................................................................................................................................................................................................................................................................................... 37


THE BIOSIMILAR OPPORTUNITY Over the past three decades, biologic medicines have played an increasingly significant role in healthcare around the world1 and changed standards of care for patients. Now, a continued pursuance of biopharmaceutical research and commitment to value-based healthcare has prompted the pursuit of biosimilars, or biological products that are “highly similar” to approved biologics.

Biosimilars are viewed as a future source of value and potential savings for the healthcare system.2 Abbreviated but rigorous biosimilar development programs will enable the healthcare system to achieve savings without compromising quality.3,4 The current healthcare landscape demands additional therapeutic choices for healthcare providers and patients, and biosimilar development may present opportunities for competition in key therapeutic areas as more biologics approach patent expiration.5 Biosimilars may serve as lower-cost options and hold the potential to create a more sustainable healthcare system by making room for innovation so more patients continue to receive the best possible care. As the biosimilar market grows in the U.S., all stakeholders will assess this new category of medicines with a focus on driving value-based healthcare, which includes delivering quality care, effectively managing costs and achieving intended patient outcomes.

UNDERSTANDING BIOSIMILARS


UNDERSTANDING BIOSIMILARS WHAT ARE BIOLOGICS?

U.S. FDA Approval Pathway for Biosimilars

Therapeutic proteins that are made from natural sources, such as human and animal cells, yeast and bacteria. 6

When the Biologics Price Competition and Innovation Act (BPCIA) was signed into law in 2010, it established the approval pathway for biosimilars in the U.S.7 Based on the provisions in the BPCIA, the FDA has further established a framework outlining a step-wise approach in which all data for a biosimilar – analytical, nonclinical and clinical – is evaluated in a head-to-head comparison with the reference product.3

WHAT ARE BIOSIMILARS? • A biologic that is “highly similar” to an approved biologic (or reference product) already being used to treat patients is known as a “biosimilar.” 6 • To achieve a biosimilar designation from the FDA, the protein must have no clinically meaningful differences in terms of safety and effectiveness from the original protein, known as the reference product.7

BIOSIMILARS ARE NOT GENERICS

Clinical Studies (Safety, efficacy, immunogenicity) Clinical Pharmacology (PK/PD)

While it might seem logical to compare biosimilars to generic drugs, there are fundamental differences in their complexity and development. Compared to small molecule drugs and generic medicines, biologics and biosimilars are: 8

Nonclinical Studies

Analytical Characterization (Structure and function assessment)

Biosimilar Development9 Demonstrate biosimilarity to the reference product

2001,000 Times larger

Reference Product Development9 Demonstrate safety, purity and potency

Far more structurally complex

Manufactured in living cells instead of via chemical synthesis

While a biosimilar may require fewer clinical trials than its reference product to attain FDA approval, it may also require a greater preponderance of analytical characterization, as well as nonclinical and clinical pharmacology data. Currently, the FDA does not require comparative analytical or clinical studies between biosimilars, meaning biosimilar candidates will be evaluated only against the designated reference product.3


A biosimilar product may be approved for one or more disease indications for which the reference product is approved without undergoing clinical testing in these conditions. This is called extrapolation. Based on the analytical and clinical data submitted to demonstrate biosimilarity to the reference product in one studied indication, the FDA may allow approval of additional indications if scientific justification is provided by the biosimilar sponsor. Scientific justification for extrapolation should address the following issues for the tested and extrapolated indications of use: mechanism of action, pharmacokinetics, immunogenicity and differences in expected toxicities in different patient populations.3

Determination of Interchangeability An interchangeable designation requires additional evidence beyond that required for FDA approval as a biosimilar.7 Receiving this designation means that a biosimilar may be substituted for the reference product at the retail or

INTERCHANGEABILITY

BIOSIMILARITY • Highly similar, notwithstanding minor differences in clinically inactive components7 • No clinically meaningful differences in safety, purity and potency of the product7

Approved as a biosimilar AND:7 • Expectation of same clinical result as the reference product in any given patient; and • For a product that is administered more than once, no additional risk to safety or efficacy as a result of alternating or switching

specialty pharmacy without the intervention of the prescriber in states that have approved legislation or regulation establishing state standards for biosimilar substitution.10 The long-awaited FDA draft guidance on interchangeability, issued in January 2017, outlines the FDA’s expectation of a totality-of-the-evidence and step-wise approach toward the demonstration of interchangeability.11 Per the draft guidance document, the FDA expects:11 • At least one switching study involving three or more switches between the biosimilar and its U.S.-licensed reference product; and • Data showing that the biosimilar can be expected to produce the same clinical result as the reference product in all of the reference product’s conditions of use. The FDA recommends that the biosimilar manufacturer provide scientific rationale to extrapolate data supporting interchangeability in one condition of use to the remaining conditions of use for which the reference product is licensed.11 The draft guidance also outlines considerations for variations in proposed presentations (container closures or delivery devices) of an interchangeable biosimilar product. In general, the FDA cautions against new presentations that may lead to administration failures, especially by patients or caregivers.11


EVOLUTION OF THE U.S. BIOSIMILAR MARKET

JULY

MARCH

DECEMBER

FDA accepts application for first biosimilar in the U.S.12

• FDA approves the first biosimilar in the U.S.15

Six active filings for biosimilars pending review as of December 31, 2015 13,22-25

2014

• CMS issues guidance documents on the treatment of biosimilar products under Medicare Part B, Medicare Part D and Medicaid Drug Rebate Program16,17,18

2015

OCTOBER APRIL

DECEMBER Three active filings for biosimilars pending review by December 31, 201412,13,14

FDA issues two final guidance documents on Scientific and Quality Considerations in Demonstrating Biosimilarity to a Reference Product 19

CMS finalizes reimbursement provisions for biosimilars21

SEPTEMBER Launch of first biosimilar in the U.S.20


APRIL FDA approves second biosimilar, first monoclonal antibody (mAb)15

JANUARY

AUGUST FDA approves third biosimilar15

• FDA finalizes guidance on Nonproprietary Naming of Biological Products31 • U.S. Supreme Court agrees to hear lawsuits on information exchange and 180-day notice provisions governing biosimilars in BPCIA32,33

SEPTEMBER FDA approves fourth biosimilar15

2016

• FDA releases draft guidance on Considerations in Demonstrating Interchangeability with a Reference Product19

2017 JULY

DECEMBER

U.S. Court of Appeals for the Federal Circuit rules 180-day notice must be given to reference product sponsor before commercial marketing of biosimilar may begin 26

• FDA issues final guidance on Clinical Pharmacology Data to Support Demonstration of Biosimilarity to a Reference Product19 • Six active FDA filings for biosimilars pending review as of December 31, 2016 23,27-30

PATIENT AND PHYSICIAN PERCEPTIONS OF BIOSIMILARS


PATIENT AND PHYSICIAN PERCEPTIONS OF BIOSIMILARS Since only four biosimilars have been approved by the FDA (and only two of those are on the market) as of January 2017,15,20,34 biosimilars lack a long-term track record in the U.S. Until more data is compiled, questions about their performance in the real-world setting will remain. Some payers have already integrated biosimilars into their formularies, and others are working to do so. The success of biosimilars in the next few years depends partly on how quickly and completely physicians and patients trust, adopt and use them. The majority of U.S. patients, even those who are active in their respective patient communities, indicate that they are not familiar with biosimilars.35 A 2014 survey conducted by Pfizer, Inc. of 635 U.S. patients diagnosed with inflammatory disease or cancer indicates that 54% of respondents had not heard of biosimilars.35 Although many patients may not be familiar with biosimilars, a separate 2014-2015 survey of 1,181 patients in Europe diagnosed with inflammatory bowel disease revealed that the majority of patients with previous or current use of tumor necrosis factor (TNF) inhibitors would accept a biosimilar product if their physician prescribes and explains it to them.36

…patients are, “…knowledgeable about and fiercely loyal to the brands that are keeping them well” – Patient Advocate, Editorial Council Member A 2016 survey by InCrowd Inc. revealed that some U.S.-based physicians (n=150), comprising dermatologists, endocrinologists, gastroenterologists, oncologists and rheumatologists, may appear to feel more comfortable prescribing biosimilars for treatment-naïve patients rather than switching stable patients to biosimilars.37

30% Physicians likely to alter a patient’s treatment regimen if he/she is stable on the current branded therapy

49% Physicians anticipate prescribing biosimilars for treatment-naïve patients

n=150

Other surveys conducted by Precision for Value have corroborated these findings, including a smaller 2016 U.S. study in which only 1 of 8 rheumatologists surveyed said they would switch a stable patient from a reference product to a biosimilar. Conversely, 5 of the 8 rheumatologists would prescribe biosimilars to patients failing on an alternative biologic therapy, as well as 7 out of 8 endocrinologists who were also surveyed.38 An additional 2015 survey of U.S. prescribers sponsored by the Alliance for Safe Biologic Medicines and administered by Industry Standard Research, LLC seems to suggest that adoption of biosimilars may initially be slow and incremental due to respondents’ lack of familiarity; only 20% of the 400 prescribers surveyed stated they were “very familiar” with biosimilars.39 In a February 2016 survey conducted by InCrowd Inc. of 150 U.S. physicians who routinely treat patients with biologics and are familiar with biosimilars, only 17% expect biosimilars to “become the norm or replace biologics” in the next three years.37


SOME THOUGHTS ON BIOSIMILARS: A PATIENT ADVOCATE’S PERSPECTIVE While we understand the rationale behind payers’ efforts to control costs through prior authorization requirements or “step” therapy, patients and patient advocates like myself feel that these pathways ignore the physical and psychological impacts they create. Biologics impact our lives. They enable many of us to get back to our lives, both professionally and personally. We are extremely loyal to and have an intense emotional connection with biologics, not just as medication, but for the profound impact they have on our lives. We aren’t willing to let financial and bureaucratic obstacles stand between us and the biologics we depend on. We recently helped write a bill, adopted into law in New York State, which allows for an appeal process and accelerated approval pathway when an insurer requires a patient to obtain prior authorization or go through steps to get their meds. Prior to that legislation, patients and physicians had little recourse if insurance companies required a step edit. While we are excited about the idea of lower-cost biologics, we want to know that they are effective. We need to know that in the real world – beyond the highly controlled clinical trial setting where manufacturers can define which patients they include and exclude – that biosimilars are as safe and effective as the branded product. If you want us (and our physicians) to be confident in our choice of biologic or biosimilar, we want post-market surveillance information about each biosimilar’s performance and full transparency at the manufacturer level. We want to know who’s making the product, how it’s made and what their track record is. We also want the data and labeling to be clear to consumers and identify any differences between reference biologics and biosimilar products.

Seth Ginsberg President, Global Healthy Living Foundation Member of the Editorial Council


PATIENT AND PHYSICIAN PERCEPTIONS OF BIOSIMILARS Barriers to Acceptance Can Be Overcome A key factor that can foster patient and physician acceptance of biosimilars is education. A 2014 survey by Pfizer, Inc. of 2,134 patients across the U.S. and European Union (EU) found that the more patients are educated about biosimilars, the more likely they are to have positive perceptions of this category of medicines. Likewise, 48% of U.S. patients surveyed who were aware of biosimilars indicated that they would be comfortable switching to a biosimilar. The results of this survey seem to indicate that patients who are educated on biosimilars and actively participate in making informed treatment decisions with their physicians may be more willing to use biosimilars.35 Physicians have asserted that trial data will play a critical role in their adoption of biosimilars, suggesting that materials clearly showing how each biosimilar performed in clinical trials will be essential.38,40 Employer groups and payers agree that there is a growing need to educate their covered populations.41 Pharmacists also recognize their role in providing biosimilar education as they often serve as a bridge between patients and physicians.

“Many health plans indicate they are ‘actively dialoguing’ with physicians to more clearly understand their concerns and knowledge gaps. This is a critical consideration in the development of payer policies (e.g., utilization of biosimilars for all patients or naïve patients only).” – Employer Consultant, Editorial Council Member “As organizations, we’re all getting more familiar with biosimilars. I’m having to bring quality of care committees up to speed on biosimilars. We’ve done some education for our P&T membership, but it’s an ongoing process.” – Health System Representative, Editorial Council Member


PATIENT AND PHYSICIAN PERCEPTIONS OF BIOSIMILARS Patient Co-Pays May Factor into Physicians’ Treatment Decisions Some U.S. physicians consider a patient’s out-of-pocket cost to be a factor in the treatment that is ultimately prescribed, with some physicians expecting availability of co-insurance support for those patients in need. A 2016 survey showed that prescribers believe their patients will accept a biosimilar treatment if they recommend it, especially if the biosimilar is less costly for the patient.38 However, the costs for Medicare Part D patients may not always favor biosimilars. According to an April 2016 analysis conducted by Avalere Health, patients facing the coverage gap under Medicare Part D may experience higher out-of-pocket costs for biosimilars than for the branded reference product. In a hypothetical analysis of costs associated with a $30,000 per year reference product and a biosimilar available at a 25% discount, Part D beneficiaries taking the biosimilar would pay approximately 39% (or $1,536) more in the coverage gap in 2017. 42 (See Page 27 for more information on the cost of biosimilars to Medicare Part D patients in the coverage gap).

Example of Biosimilar Costs Under Medicare Part D, Assuming a 25% Discount42

$30,000

vs.

Reference Product

$22,500 Biosimilar

Medicare Part D beneficiaries would pay $1,536 more per year in out-of-pocket costs for the biosimilar Biosimilar

Up to 39% higher

Reference Product

39% higher

By clicking on these links, you will be leaving the 2017 Trends in Biosimilars Report. Please be aware that the sponsors of the Report are not responsible for the content on these linked sites.

Additional Resources for Biosimilar Information/Education: • Academy of Managed Care Pharmacy (AMCP) – Biosimilar Resource Center43

• Biologics Prescribers Collaborative (BPC)49

• AMCP Biologics & Biosimilars Collective Intelligence Consortium (BBCIC)44

• Biotechnology Innovation Organization (BIO) Biosimilars – MYTH vs. FACT50

• American Journal of Managed Care (AJMC) – Biosimilars Essentials45

• International Alliance of Patients’ Organizations (IAPO) – Biosimilars Toolkit51

• Alliance for Safe Biologic Medicines (ASBM) – Biosimilars 10146

• Patients for Biologics Safety & Access (PBSA) – Biosimilars Overview52

• Biosimilars Council (A Division of the Association for Accessible Medicines)– The Next Frontier for Improved Access to Medicines: Biosimilars and Interchangeable Biologic Products47

• Pharmaceutical Research and Manufacturers of America (PhRMA) – Biologics & Biosimilars53

• Biosimilars Forum

48

• U.S. Food and Drug Administration (FDA) – Information on Biosimilars54

THE NEW REALITY:

CONSIDERATIONS FOR FORMULARY DECISION-MAKERS


THE NEW REALITY As of January 2017, there are four biosimilars approved in the U.S.15 but only two of the four approved biosimilars are currently on the market. 20,34 Challenges facing biosimilars include disputes about the interpretation of certain provisions of the BPCIA statute. In January 2017, the U.S. Supreme Court agreed to hear a lawsuit on BPCIA provisions governing information exchange (the “patent dance”) between the biosimilar applicant and the reference product sponsor, as well as the 180-day notice required to be provided to the reference product sponsor before commercial marketing of the biosimilar may begin.32,33 Litigation has become a common occurrence for many biosimilar applicants. A single infringement lawsuit by the reference product sponsor could delay a product launch; alternatively, a biosimilar applicant may decide to launch at risk. An at risk launch could result in withdrawal of the product from the market and/or royalties for the reference product sponsor at the end of the lawsuit. As of January 2017, all four FDA-approved biosimilars are currently involved in lawsuits. Both of the biosimilars currently on the market in the U.S. (as of January 2017) were launched at risk.34,55 Most companies engaged in litigation may limit external communications about their products to avoid impacting court proceedings. As a result, some information (including date of product launch, drug price and distribution channel) may not be communicated by biosimilar applicants until all legal proceedings are resolved. Payers and other formulary decision-makers are not able to integrate biosimilars into their formularies until a biosimilar launches, but they are actively evaluating the available data and considering appropriate coverage criteria for each approved biosimilar.56

Some issues that payers and other formulary decision-makers should consider when evaluating a biosimilar include:57,58,59 Product Considerations • Extrapolation • Curative treatment vs. supportive care • Product dosing considerations • Delivery device • Formulation, storage and handling • Distribution channels Manufacturer Considerations • Supply chain reliability • Patient support programs Operational Considerations • Pharmacovigilance • Pricing and contracting • Reimbursement • Information technology


PRODUCT CONSIDERATIONS It is generally understood that there are acceptable variabilities that exist between the biosimilar and the branded reference product, and an approved biosimilar will have no clinically meaningful differences from the reference product in terms of efficacy and safety. However, it is important to note that there may be some nonclinical differences between the biosimilar and the reference product, such as delivery device, packaging or distribution channels, which could have potential implications for payers, integrated delivery networks (IDNs), healthcare providers and patients.

Extrapolation One of the biggest unknowns expressed by patients and physicians is whether a biosimilar can be used in all the same indications as the reference product. In a 2016 survey of 1,201 U.S. specialty physicians conducted by the Biosimilars Forum, only 12% of respondents said they were completely comfortable with the concept of extrapolation.60 Post-marketing surveillance and data from observational studies may help address concerns around extrapolation. The first four approved biosimilars in the U.S. received approval for all available (i.e., non-orphan) indications. However, some indications may be initially excluded from an approved biosimilar’s label due to FDA-established exclusivity periods. The FDA provides seven years of exclusivity for orphan indications (diseases or conditions that affect fewer than 200,000 patients in the U.S.) to encourage the development of drugs to meet the needs of patients with rare diseases.61

Oncologists in the EU have had access to some biosimilar products for more than eight years. While they were originally cautious in their use of biosimilars, particularly in extrapolated or pediatric populations, the first available granulocyte colony-stimulating factor (G-CSF) biosimilar agents have been used for more than five years. Further, the products were endorsed by groups such as the European Organization for Research and Treatment of Cancer as early as 2010.62

“While a plan formulary might continue covering a biosimilar for the larger patient populations, formularies will need to keep some kind of relationship with the reference product manufacturer to cover those orphan indications.” – Distribution Advisor, Editorial Council Member


PRODUCT CONSIDERATIONS Curative Treatment vs. Supportive Care

Product Dosing Considerations

It is also important to consider how a biosimilar might be used in particular clinical settings. In oncology, for example, utilization of biosimilars may depend on whether the drug is being administered for supportive use or with curative intent.63

A biologic may be available in a variety of forms (also called presentations): prefilled syringe, auto-injector, single-use pen, vial, etc. Descriptions of a product’s delivery options appear in Section 16 (“How Supplied/Storage and Handling”) of its prescribing information (PI).65

“I’m more willing to let economics drive supportive care instead of therapeutic medications. I’d like a higher standard of data in a therapeutic indication.”38 – Oncologist Even EU physicians have not yet had the opportunity to prescribe therapeutic oncology biosimilars; as of January 2017, there are no approved therapeutic oncology biosimilars in the EU.64 A 2016 survey of 150 U.S.-based specialty physicians found that oncologists were the only specialists likely to prescribe biosimilars to the majority of their treatment-naïve patients and patients who had previously taken an originator biologic and required retreatment.37 With access and affordability being issues in oncology, physicians and patients may be willing to use therapeutic oncology biosimilars once they become available.

“The FDA is a very important organization in policing the use of these drugs. If they say that this is going to work well, then I definitely see a benefit.”38 – Oncologist

Physicians, pharmacists, nurses, patients and caregivers must be aware of any differences in indications, corresponding doses and available dosage forms between the branded reference product and the biosimilar product. For example, the first FDA approved biosimilar is only available as a prefilled syringe (as of January 2017), while the reference product is available as a prefilled syringe and a vial.65,66 Some prefilled syringes, depending on their design, may not be able to accurately deliver the correct dose of medication to some patient populations. Additionally, another biosimilar approved by the FDA received all the available indications of the reference product but does not, as of January 2017, have a dose formulation for all patient populations.67 Longer-term, what happens as more biosimilars for the same reference product become available? What if each one has its own particular packaging that differs from that of the reference product? The question then becomes more complex: how many differences can a market accommodate and how many “highly similar” products will have nonclinical differences that need to be noted and tracked in electronic systems?


“Prescription approval systems simply need to be programmed to flag clinical presentation differences if the biosimilar is prescribed at a low dose to an infant. An alert or hold would be placed on the prescription, allowing the pharmacist to intervene.” – Distribution Advisor, Editorial Council Member

Delivery Device A manufacturer’s choice of delivery device for a biologic medicine can make a difference in a patient’s compliance and adherence.68 The FDA acknowledged this in its draft guidance document on interchangeability, which outlines considerations for variations in proposed presentations (i.e., container closures or delivery devices) of an interchangeable biosimilar product. In general, the FDA cautions against new presentations that may lead to administration failures, especially by patients or caregivers.11 Some biosimilar manufacturers have already chosen to use delivery devices different from that of the reference product. Whether that choice is due to patent protection on the original device or to introduce a competitive advantage (e.g., a more patient-friendly device that increases patient adherence),69 patients and healthcare professionals will require education about the different devices and their proper use and handling.

A manufacturer’s choice of delivery device for a biologic medicine can make a difference in a patient’s compliance and adherence.68


PRODUCT CONSIDERATIONS Formulations, Storage and Handling Another potentially important point of differentiation is formulation. Distributors and healthcare professionals who administer biosimilars need to know about – and take precautions when dealing with – differences between a biosimilar’s storage, handling and route of administration and those of the reference product.

Distribution Channels Biologics may be distributed through full-line wholesalers or through specialty distribution. While the former is the traditional channel through which biologics have been distributed, the specialty channel has been more frequently employed for biologics launched in recent years. The specialty channel may enhance the efficiency of biologics distribution, with respect to issues such as inventory management, product dating, product storage, cost and delivery. In comparison, the full-line wholesaler channel integrates handling logistics for ordered products, including biologics.

“…When manufacturers switch from a standard full-line distribution model to specialty distribution, it upsets institutions because the price point for product increases substantially.” — Distribution Advisor, Editorial Council Member


MANUFACTURER CONSIDERATIONS

Disruptions to drug supply have become common, particularly for oncology drugs. In order to avoid treatment delays and unplanned switching between biologics during the course of treatment, it is important to consider the robustness of the manufacturer’s supply chain when evaluating biosimilars. It is also important to consider a manufacturer’s history of shortages and recalls related to quality concerns and evaluate its capability to maintain adequate production and stock to support demand.70

Drug Shortages and Implications for Biosimilars Unfortunately, drug shortages are common and have been the subject of numerous articles in recent years.71,72 Due to their highly specialized manufacturing process, sterile injectables make up a large percentage of these shortages.73 The number of new shortages has decreased overall since 2011. However, the number of ongoing shortages remains high (See Table 1).74 When available drug supplies are insufficient to meet medical needs, serious logistical, ethical and financial issues may occur and potentially lead to a variety of other health and safety issues.72

“It’s horrible and incredibly challenging when you experience drug shortages. In oncology, for example, if there isn’t an alternative you have to look at intensive treatment versus curative or supportive and determine if any patients can discontinue treatment early.” – Pharmacy Director, Editorial Council Member

Table 1. Number of Drug Shortages from January 2010 through December 201574 500

Number Of Drug Shortages

Supply Chain Reliability

400

100 0

136

289

277

291

2013

2014

2015

135

262

2012

257

300 200

179

193

201

127

184

2010

2011

New shortages, by year first reported

Ongoing shortages, which began in prior years


MANUFACTURER CONSIDERATIONS In a 2013 survey conducted by the American Society of Health-System Pharmacists, 99% of 214 surveyed pharmacy directors reported at least one oncologic drug shortage during the prior year, with the following consequences:75 Consequences of Oncologic Drug Shortages and Percent of Respondents Reporting as an Issue75

62%

25%

47%

21%

Used alternative drug regimens due to shortages

Changed the drug dose

Reported one or more safety events had occurred

Referred patients to other facilities

43%

Reported treatment delays

A 2010 survey of 353 pharmacy directors conducted by the American Society of Health-System Pharmacists found that the time and labor their staff spends managing drug shortages are significant and the information available to manage drug shortages was suboptimal.76 Responding to this crisis, an executive order was issued in 2011 that required all manufacturers to alert the FDA of any interruptions that could lead to a meaningful supply disruption or discontinuation.77 Several websites are available to monitor the status of drug shortages, including ones from the FDA and American Society of Health System Pharmacists (ASHP). By clicking on these links, you will be leaving the 2017 Trends in Biosimilars Report. Please be aware that the sponsors of the Report are not responsible for the content on these linked sites.

While the 2011 executive order has enabled the FDA to intervene and even prevent shortages,78,79 it has not addressed the lack of a universal grading system that would allow formulary managers to assess a manufacturer’s reliability or the quality of its product, although such a plan was proposed in 2013 by the Director of the Center for Drug Evaluation and Research (CDER).80


Patient Support Programs A medicine can only help if it is used properly and consistently in accordance with a physician’s prescription. Poor adherence to a prescription is a wellknown issue affecting healthcare and a leading cause of preventable morbidity, mortality and cost in chronically ill patients.81

“A biosimilar manufacturer must build comparable support programs, and if patient assistance isn’t there, it’s a non-starter for us.” – Distribution Advisor, Editorial Council Member

Patient support programs are critically important for some patients and can influence physician behavior or serve as a point of differentiation between biosimilars, raising questions about the breadth and depth of programs needed for a biosimilar to be competitive with branded reference products. Patient support programs may include reimbursement and financial support or educational programs, clinical support (e.g., a nurse hotline, lab testing), adherence/compliance programs and injection training.82 Biosimilar manufacturers will likely consider providing meaningful patient support services as part of their value proposition in order to meet patient and provider needs.

Poor adherence to a prescription is a well-known issue affecting healthcare and a leading cause of preventable morbidity, mortality and cost in chronically ill patients.81


OPERATIONAL CONSIDERATIONS Tracking Biologics – Pharmacovigilance Pharmacovigilance, the monitoring and tracking of drug safety over time, is particularly important for biologics and biosimilars in order to detect any emerging safety signals, particularly in specific indications and patient populations.57 In order to help facilitate pharmacovigilance, the FDA released final guidance on nonproprietary naming of biological products in January 2017. Under this guidance, each originator biologic, related biologic and biosimilar will be assigned a nonproprietary name consisting of a core name and a hyphenated distinguishing suffix made up of four lowercase letters. The FDA believes that this naming convention will help ensure accurate identification of products and their associated manufacturers while also minimizing the inadvertent substitution of biologics not deemed to be interchangeable.31 Biologics may be covered under the medical benefit or the pharmacy benefit.83 Self-administered medicines (often delivered by a specialty pharmacy) are typically covered under the pharmacy benefit while those injected or infused under the supervision of a physician are typically paid for as medical benefits.84 From the payer’s perspective, a key difference between these two payment systems is that specialty pharmaceuticals covered under the pharmacy benefit are reimbursed based on their national drug codes (NDCs). This enables anyone analyzing the use of that medicine to track utilization and know the drug, manufacturer, strength and package size. Under the medical benefit, drugs are most commonly tracked and reimbursed using the Healthcare Common Procedure Coding System (HCPCS) codes that identify the chemical name of the drug but not the manufacturer, strength or package size.83

For biosimilar products that appear under the same HCPCS code under Medicare Part B, CMS announced that it will issue and assign modifiers that help to identify the manufacturer of the specific product and distinguish between biosimilar products that are made by different manufacturers. The modifier will provide CMS with the ability to track claims payment and to develop a better understanding of the use of specific biosimilars in Medicare Part B.85

Pricing and Contracting The expected trend in utilization of biosimilars versus originator products may be a proxy for biosimilar adoption. A 2016 survey of 228 executives at medical practices, hospitals, large healthcare systems, benefit management organizations, health plans, long-term care organizations, group purchasing organizations and consulting firms showed that respondents feel biosimilars hold great promise in reducing the specialty drug spend, but only 8.5% of survey respondents foresee this happening in 2017; 21.4% of respondents expect to see reduction in 2018, 13.4% in 2019 and 25.0% in 2020.86 Percentage of Respondents Who Foresee Biosimilars Reducing Drug Spend for Specialty Drugs in Coming Years86

8.5%

21.4%

13.4%

25.0%

2017

2018

2019

2020


Creating a sustainable U.S. biosimilar market requires an ongoing commitment to driving competition. A 2016 report from the IMS Institute for Healthcare Informatics notes that biosimilars enable stakeholders – including payers, physicians and patients – to benefit from increased choice in therapeutic options. Competition lies at the center of the biosimilar value proposition, driving pharmaceutical innovation and affirming healthcare system sustainability.87 Many purchasers and providers consider biosimilars to be branded products available as an alternative to reference products. In some situations, group purchasing organizations (GPOs) may select preferred agents to represent the vast majority of provider and member needs, and then work to raise member awareness in order to optimize contract performance. In this way, GPOs may play an important role in building and maintaining the market for biosimilars.57 The first biosimilar was launched in the U.S. in September 2015 with a wholesale acquisition cost (WAC) that was 15% lower than that of its reference product.88 Based on CMS’ published Average Sales Prices (ASPs) for 2016, it can be assumed that select customers received additional discounts beyond the published WAC price.89 It is interesting to note that the second biosimilar also launched with a WAC that was 15% lower than that of its reference product.34

A pharmaceutical purchase or discount agreement for an individual biosimilar may also be negotiated across a manufacturer’s product portfolio. Given that biosimilar manufacturers’ portfolios vary, this could be a differentiating point when negotiating contracts with various manufacturers. Although competitive bidding (or tendering) for pharmaceutical products is often employed by various countries in the EU, it is not typically seen in the U.S. However, competitive bidding (or choosing to utilize only one brand for a product) may be considered a type of payer management strategy with potential implications. In considering competitive bidding-type contracting for reference products and their biosimilars, it is important to consider the following:90 • Choosing a single source supplier may limit the initial number of suppliers or cause a reduction in the number of suppliers over time • A single source supplier may increase the risk of product supply issues, and securing a new source in these instances is time-consuming and disruptive to treatment • Initial choice of a single source supplier and any subsequent changes in the supplier may lead to increases in switching costs for health systems • Patients and physicians may be concerned about a lack of choice in therapies and the potential consequences of being forced to switch between therapeutic options not designated as interchangeable


OPERATIONAL CONSIDERATIONS Reimbursement

Medicare Part B

Third-party drug coverage, benefit designs and related policies will impact uptake of biosimilars. Policies may vary, depending on whether the drug falls under the pharmacy or medical benefit. To date, none of the biosimilars marketed in the U.S. as of January 2017 are covered primarily under the pharmacy benefit. In order to encourage the use of biosimilars covered under the pharmacy benefit, payers will likely utilize some of the following mechanisms: prior authorization, step therapy edits, formulary tiers and differential copays.

The Affordable Care Act (ACA) includes language to help incentivize provider utilization of biosimilars by requiring physician reimbursement at the biosimilar’s ASP plus 6% (4.3% after sequestration) of the reference biologic’s ASP.91,92 In implementing the law, though, CMS has adopted a Part B policy that is more consistent with generics – reimbursement is based on the blended, weighted ASP of all biosimilars of the same reference product grouped together in a single HCPCS code.91 Table 2 shows a hypothetical example of physician office payment methodology for a biosimilar under Part B.

Table 2. Physician Office Payment Methodology for Biosimilars in Medicare Part B93 Biologic Product

WAC (List Price)

ASP

Reference

$1000.00*

$800.00

Biosimilar A

$800.00

Biosimilar B

$700.00

Biosimilar C

$650.00

$716.67 (blended ASP)

6% of Reference Product’s ASP

Physician Office Payment Rate (ASP+6%)

Patient Cost-Share (20%)

$848.00

$169.90

$764.67

$152.93

$48.00

*Note: This hypothetical example assumes that the reference biologic’s ASP is 20% less than the WAC based on rebates over time, and each biosimilar is equally weighted in the calculation of the blended ASP.


Medicare Part D As decision-makers determine their ongoing formulary structure, they will be paying close attention to therapeutic categories and the requirements that are dictated by CMS. Under Medicare Part D, biosimilars are being treated in a manner similar to generics since they are not subject to the 50% discount required for brand drugs when the Medicare Part D beneficiary is in the coverage gap.94 See Table 3 below.

As a result, Medicare Part D beneficiaries may be required to pay higher coinsurance costs for biosimilars through 2019 while they are in the coverage gap. Higher patient costs will result in beneficiaries reaching their out-of-pocket thresholds and moving into catastrophic coverage more quickly, at which time the beneficiary will pay 5%, the plan will pay 15% and Medicare will pay 80% of additional drug costs.95 See Table 4 below.

Table 3. Closing the Coverage Gap94

Table 4. Standard Medicare Part D Prescription Drug Benefit, 201796 Generics / Biosimilars

100%

50%

40%

35%

30%

10%

15%

20%

50%

0%

2017

50%

2018

50%

2019

Beneficiary

25%

25%

50%

2020

% Contribution of Total Drug Costs

% Contribution of Total Drug Costs

Reference Products

Plan

100% 51%

44%

37%

Benefit Phase: Catastrophic Coverage

25%

Coverage Gap 50%

Total Drug Spending: $8,000

Enrollee pays 5%

$7,000

Brand-name drugs Enrollee pays 40% Plan pays 10% Manufacturer discount 50%

$6,000 $5,000

49%

56%

63%

$4,000

75%

Plan pays 15%; Medicare pays 80%

Generic drugs Enrollee pays 51% Plan pays 49% Initial Coverage Limit = $3,700 in Total Drug Costs

$3,000 0%

2017

2018

2019

2020

Initial Coverage Period

$2,000

Catastrophic Coverage Threshold= $8,071 in Estimated Total Drug Costs

Enrollee pays 25%

Plan pays 75%

$1,000

Manufacturer Deductible

$0

Deductible = $400


OPERATIONAL CONSIDERATIONS Medicaid

Information Technology

CMS’ generic-like treatment of biosimilars in Medicare does not cross over into Medicaid. In late December 2016, CMS issued a notice reinforcing its position that biosimilars do not qualify as authorized generic drugs for the purpose of the Medicaid Drug Rebate program and are subject to brand level rebates. The notice adds that the “best price of the reference biologic and the biosimilar biologic should be determined separately as the lowest price available from each manufacturer.”97

Another consideration for payer and provider organizations is the need to adapt their information technology (IT) systems to accurately manage and track biosimilars. This process will likely involve changes to ensure capabilities of distinguishing between multiple versions of biologic products and biosimilars. The system must be able to accurately track and trace product preference, conversions, utilization and reported adverse events, as well as identify specific products for reimbursement and rebate tracking.59

340B Drug Pricing Program

Systems may need to be reprogrammed to support various coding and pricing schemes, and to account for new insurance authorizations for different HCPCS codes.57,58 Evaluation of the potential costs associated with making needed IT system changes in addition to the total cost of full formulary conversion to a biosimilar may be compared to potential savings to help determine if a change will be beneficial in the short and long term.59

The 340B program requires drug manufacturers to sell outpatient drugs at a discount to providers serving high numbers of low-income Medicare, Medicaid and Supplemental Security Insurance patients. Sites within a healthcare system that qualify as 340B entities can obtain federally mandated “ceiling price” discounts for covered outpatient drugs, while other sites that are not 340B eligible pay a higher net price.98 Ceiling prices for 340B drugs are not publicly disclosed, but it has been estimated that 340B entities save 15-60% on prescription drug costs through this program.99,100 Medicare Part B pays both 340B and non-340B entities at the same rate for certain 340B treatments, such as biologic drugs used to treat cancer and rheumatoid arthritis, despite the fact that 340B entities are able to obtain those treatments at a discount.99 Formulary decision-makers should ensure awareness of any differences between a biosimilar and reference product with respect to the 340B Drug Pricing Program.

LOOKING AHEAD


LOOKING AHEAD The coming year promises to be a dynamic and informative year for the biosimilar market. As 2016 drew to a close, there were four approved biosimilars15 and six active filings pending FDA review in 2017.23,27-30 Simultaneously, U.S. regulatory bodies committed necessary resources to support the review of biosimilar applications as they continue to form final guidance around the biosimilar path-to-market.101 The events that unfold in 2017 may increase experience and understanding of biosimilars, which in turn could increase confidence and utilization of these medicines in the U.S. Limited exposure to biosimilars in the U.S. has resulted in the cautious uptake of biosimilars and identified knowledge gaps impacting downstream user trust in these products.60 However, a 2015 study in Europe found that 40% of surveyed physicians had increased confidence in the use of biosimilars as compared to three years prior, suggesting that gains in clinical experience could also reduce hesitation around biosimilar use in the U.S.2 Discussion among patient groups, healthcare professionals, administrators, regulators and manufacturers to share the experiences of early adopters may facilitate acceptance. As such, one may expect education to build confidence in these treatments to remain a primary goal for the industry in 2017. The complexity of the legal landscape may also pose a significant challenge for manufacturers planning to bring biosimilars to market in 2017. Likewise, court decisions on complex issues regarding patent protection and data exclusivity that are reviewed in ongoing litigation between biosimilar manufacturers and reference product manufacturers will likely inform future decisions on applications and launch strategies for biosimilar manufacturers.

The future of the ACA, and consequently, the BPCIA, is uncertain under the new government administration. Repealing the legislation could have implications for several regulations affecting biosimilars, including: Medicare Part D Coverage Gap Discount Program: As of January 2017, CMS is treating biosimilars as generic or multiple source drugs* in Medicare, so they are not currently subject to the Part D Coverage Gap Discount Program.17 This affects the Medicare Part D enrollee’s cost share, causing a biosimilar to be more expensive than the reference biologic for the Medicare-eligible population while they are in the Medicare Part D coverage gap.95 “Deemed to be a License” Provision: This provision under the BPCIA requires certain protein products, specifically those larger than 40 amino acids, such as insulin, somatropin and hyaluronidase products, to be transitioned from the 505(b)(2) New Drug Application (NDA) to the 351(a) or 351(k) Biologics License Application (BLA) by March 23, 2020.102 Regulation Freeze: An executive order was issued on January 20, 2017, notifying all agencies, including the FDA, that any new or pending regulations or guidance documents must first be reviewed and approved by a department or agency head appointed or designated by the President.103 This freeze could potentially delay finalization of guidance documents, including the FDA’s draft guidance on interchangeability that was issued in early 2017. *CMS’ decision around biosimilars does not apply to interchangeable biosimilars. CMS has suggested that it may provide further guidance in this area in the future.17


The biosimilar journey continues onward, as does the evolving role of the payer in determining the potential of biosimilars for the greater market. As payers individually assess each biosimilar that is approved, their contracting decisions will determine the direction of the pharmaceutical community as it seeks to innovate and create value. Continued education, negotiation and federal regulation will be increasingly important for stakeholders to form more enriched answers to the questions of competitive and financial impact of biosimilars on the larger healthcare system and build the value of a long-term biosimilar market in the U.S.

The biosimilar journey continues onward, as does the evolving role of the payer in determining the potential of biosimilars for the greater market.

RESOURCE GUIDES

UNDERSTANDING BIOSIMILARS: A RESOURCE GUIDE FOR PATIENTS

WHAT ARE BIOLOGICS AND BIOSIMILARS?

BIOSIMILARS ARE NOT GENERICS

Biologic medicines are therapeutic proteins made from natural sources, such as human and animal cells, yeast and bacteria.1 These medicines are big and very complex molecules that may be up to 1,000 times the size of conventional medicines (also called small-molecule medicines), such as aspirin or penicillin.2

A generic drug is, by definition, an identical copy of its reference small-molecule medicine.3

Unlike generic medicines, biosimilars will not be identical to their reference biologics.1

A biosimilar is a biologic medicine that is approved based on showing that it is highly similar to an existing FDA-approved biological product, known as a reference product.1

While a biosimilar is not expected to be identical to its reference product, it must be shown to have no clinically meaningful differences in terms of safety and effectiveness from the reference product.1

Illustrations are not to scale. Biologic medicines are much more complex and may be 200-1000x the size of conventional medicines. 2

PROPERTIES

SMALL MOLECULES & GENERICS

BIOLOGICS & BIOSIMILARS

Size

Small1

Large1

Structure

Simple and well defined1

Complex1

Production

Chemically made1

Grown in living cells1

Administration

Most can be swallowed4

Usually injected4

UNDERSTANDING BIOSIMILARS: A RESOURCE GUIDE FOR PATIENTS

In recognition of the unique and complex biological properties of biologics, Congress established a distinct, abbreviated pathway for approval of biosimilars. This pathway requires additional evidence beyond the requirements for generic drug approval, including additional analytical characterization, as well as nonclinical and clinical data.5

How is a biosimilar tested for FDA approval?

Will a biosimilar work the same way as its reference biologic?

The manufacturer of a biosimilar must submit an application to the FDA showing that the biosimilar’s structure is very similar to the structure of the reference biologic.5 The manufacturer must also provide information demonstrating that the biosimilar is as safe and effective as the reference product, usually based on analytical studies, animal studies and clinical studies in humans.5 The FDA relies on its previous findings that the reference product is safe and effective.1

An FDA-approved biosimilar should have no clinically meaningful differences from its reference biologic in terms of safety and effectiveness. The biosimilar must have the same mechanism of action as its reference biologic, which means it will work the same way.1

How does the testing for a biosimilar approval compare to the testing for a reference biologic approval? In order to get approved, the reference biologic had to go through more clinical testing than is required for a biosimilar. The reference biologic manufacturer had to study the drug in each patient population and submit clinical information for each approved indication.5 © 2017 Amgen. All rights reserved. USA-BIO-044570(1)

1.

U.S. FDA. Information for Consumers (Biosimilars). Available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241718.htm. Accessed January 30, 2017.

2.

American Cancer Society Cancer Action Network. Understanding Biologic Medicines from the Cancer Patient Perspective. January 2013. Available at: http://action.acscan.org/site/DocServer/ACSCAN-Biosimilars-Primer.pdf?docID=22449. Accessed on January 30, 2017.

3.

U.S. FDA. Generic Drugs: Questions and Answers. Available at: http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ QuestionsAnswers/ucm100100.htm. Accessed January 30, 2017.

4. The Association of the British Pharmaceutical Industry. Understanding biological & biosimilar medicines: Frequently asked questions. July 2014. Available at: http://www.abpi.org.uk/our-work/library/medical-disease/Documents/understanding_ biological_biosimilar_medicines.pdf. Accessed January 30, 2017. 5.

U.S. Food and Drug Administration. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Final Guidance. April 2015.

UNDERSTANDING BIOSIMILARS: A RESOURCE GUIDE FOR HEALTHCARE PROFESSIONALS

Biotechnology has brought about the discovery and development of a new generation of human therapeutics – biosimilars, the next chapter in biotechnology, are expected to play an increasingly prominent role in healthcare.1 “Biosimilar” is a U.S. Food and Drug Administration (FDA) designation used to describe a biological product that is “highly similar” to an approved biologic (known as a reference product) already being used to treat patients. To be considered a biosimilar, a medicine must meet the following standards when compared to the reference product:

Highly similar notwithstanding minor differences in clinically inactive components2

No clinically meaningful differences in safety, purity and potency of the product2

U.S. Biosimilar Approval Pathway In recognition of the unique and complex properties of biologics, a distinct pathway for the approval of biosimilars was established in the Biologics Price Competition and Innovation Act of 2009 (BPCIA).2

BIOLOGICS: Approved via Public Service Health Act2,5 Biologics License Application (BLA)

Biosimilar BLA

351(a)

351(k)

Full reports of safety and efficacy investigations6

Highly similar to a 351(a) product

Applicant has right of reference to essential investigations

Demonstration of absence of clinically meaningful difference

Approved as a new biologic medicine

BPCIA requires analytical, animal and clinical studies. However, certain data requirements may be waived at the agency’s discretion.2

Approved as a biosimilar

European Union Experience Biosimilars have been approved and used in the European Union (EU), a highly regulated environment, for over a decade without demonstrating unique safety concerns.3 The uptake of biosimilars across the EU varies between countries and across therapeutic classes.4

Same clinical result in any given patient and no greater risk as a result of switching2

May be approved as an interchangeable biosimilar

UNDERSTANDING BIOSIMILARS: A RESOURCE GUIDE FOR HEALTHCARE PROFESSIONALS

While a biosimilar may require fewer clinical trials than its reference product in order to attain approval, it may also require a greater preponderance of analytical, nonclinical and clinical data to form the “totality of evidence” on which the FDA will base an approval decision.7 As of January 2017, the FDA does not require comparative analytical or clinical studies between biosimilars, meaning biosimilar candidates will be evaluated only against the designated reference product.7

The U.S. biosimilars pathway offers the opportunity for a drug manufacturer to demonstrate “interchangeability,” which is a separate standard than “biosimilarity” and requires additional evidence to achieve.7

INTERCHANGEABILITY

BIOSIMILARITY

Extrapolation Based on the “totality of evidence,” the FDA may approve one or more indications in which the biosimilar was not directly studied. The FDA may permit extrapolation of data intended to demonstrate biosimilarity in one condition of use across additional indications given sufficient scientific justification.7 Reference Product Development8 Demonstrate safety, purity and potency Clinical Studies (Safety, efficacy, immunogenicity) Clinical Pharmacology (PK/PD) Nonclinical Studies

Analytical Characterization (Structure and function assessment)

Biosimilar Development8 Demonstrate biosimilarity to the reference product

• Highly similar, notwithstanding minor differences in clinically inactive components2 • No clinically meaningful differences in safety, purity and potency of the product2

Approved as a biosimilar AND:2 • Expectation of same clinical result as the reference product in any given patient; and • For a product that is administered more than once, no additional risk to safety or efficacy as a result of alternating or switching

While the FDA designates interchangeability, states control drug substitution laws.9 Once an interchangeability designation is acquired, a biosimilar may be substituted for the reference product by the pharmacist at the retail or specialty pharmacy without the intervention of the prescriber in states that have approved legislation or regulation establishing state standards for biosimilar substitution.9 As of January 2017, there are no interchangeable biologics approved in the U.S.10 By clicking on this link, you will be leaving the 2017 Trends in Biosimilars Report. Please be aware that the sponsors of the Report are not responsible for the content on this linked site. For the most up-to-date information on state legislation related to biosimilars, visit: http://www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologicmedications-and-substitution-of-biosimilars.aspx

1. EuropaBio. EuropaBio Guide on Biosimilars in Europe: When Science Meets Policy. 2014: Brussels, Belgium. 2. Patient Protection and Affordable Care Act. Title VII. Sec. 7001-7003. 2010. 3. Morton DM, Stern AD, Stern S. The Impact of the Entry of Biosimilars: Evidence from Europe. Working paper 16-141. January 2017. 4. IMS. Assessing biosimilar uptake and competition in European markets. October 2014: Parsippany, NJ. 5. H.R. Public Health Service Act. Title III. 2013. 6. eCode of Federal Regulations. Title 21. Chapter I. Subchapter F. Part 601. Subpart A. §601.2. 7. U.S. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Final Guidance. April 2015.

© 2017 Amgen. All rights reserved. USA-BIO-044570(1)

8. Kozlowski S. U.S. FDA Perspectives on Biosimilar Biologic Products. Presented at: Biotechnology Technology Summit. June 13, 2014; Rockville, MD. 9. National Conference of State Legislatures. State Laws and Legislation Related to Biologic Medications and Substitution of Biosimilars. November 15, 2016. Available at: http://www.ncsl.org/research/health/state-laws-and-legislation-related-tobiologicmedications-and-substitution-of-biosimilars.aspx. Accessed January 30, 2017. 10. U.S. FDA. List of Licensed Biological Products. Available at: http://www.fda.gov/downloads/drugs/ developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/ biosimilars/ucm439049.pdf. Accessed January 30, 2017.

REFERENCES


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2.

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3.

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Wroblewski MS, et al. Federal Trade Commission Report. Emerging Health Care Issues: Follow-on Biologic Drug Competition. June 2009. Available at: https://www.ftc.gov/reports/emerging-healthcare-issues-follow-biologic-drug-competition-federal-trade-commission-report. Accessed January 30, 2017.

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U.S. Food and Drug Administration. Information for Consumers (Biosimilars). August 2015. Available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ Biosimilars/ucm241718.htm. Accessed January 30, 2017.

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Patient Protection and Affordable Care Act. December 2009. Available at: http://www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM216146.pdf. Accessed on January 30, 2017.

8.

American Cancer Society Cancer Action Network. Understanding Biologic Medicines from the Cancer Patient Perspective. January 2013. Available at: http://action.acscan.org/site/DocServer/ ACSCAN-Biosimilars-Primer.pdf?docID=22449. Accessed on January 30, 2017.

9.

Kozlowski S. U.S. FDA Perspectives on Biosimilar Biologic Products. Presented at: Biotechnology Technology Summit. June 13, 2014; Rockville, MD.

10. National Conference of State Legislatures. State Laws and Legislation Related to Biologic Medications and Substitution of Biosimilars. November 15, 2016. Available at: http://www.ncsl.org/ research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-ofbiosimilars.aspx. Accessed on January 30, 2017. 11.

U.S. Food and Drug Administration. Guidance for Industry: Considerations in Demonstrating Interchangeability with a Reference Product. Draft Guidance. January 2017. Available at: http:// www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM537135.pdf. Accessed on January 30, 2017.

12. Sandoz. FDA accepts Sandoz application for biosimilar filgrastim. News release. July 24, 2014. Available at: http://www.sandoz-biosimilars.com/en/mediacenter/press_releases/140724_FDA_ accepts_Sandoz_application_for_biosimilar_filgrastim.shtml. Accessed on January 30, 2017. 13. Celltrion. Celltrion files for US FDA approval of Remsima. News Release. August 11, 2014. Available at: http://www.celltrion.com/en/pr/reportDetail.do?seq=327. Accessed on January 30, 2017. 14. Apotex. Apotex Announces FDA Has Accepted for Filing its Biosimilar Application for Pegfilgrastim. News release. December 17, 2014. Available at: http://www.apotex.com/global/about/ press/20141217.asp. Accessed on January 30, 2017. 15. U.S. Food and Drug Administration. List of Licensed Biological Products with (1) Reference Product Exclusivity and (2) Biosimilarity or Interchangeability Evaluations to Date. Available at: http://www. fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/ approvalapplications/therapeuticbiologicapplications/biosimilars/ucm439049.pdf. Accessed January 30, 2017. 16. Centers for Medicare and Medicaid Services. Food and Drug Administration Approval of First Biosimilar Product. MLN Matters. Available at: https://www.cms.gov/Outreach-and-Education/ Medicare-Learning-Network-MLN/MLNMattersArticles/Downloads/SE1509.pdf. Accessed on January 30, 2017. 17.

Centers for Medicare and Medicaid Services. Part D Requirements for Biosimilar FollowOn Biological Products. March 30, 2015. Available at: http://www.amcp.org/WorkArea/ DownloadAsset.aspx?id=19358. Accessed on January 30, 2017.

18. Centers for Medicare and Medicaid Services. Medicaid Drug Rebate Program Notice for Participating Drug Manufacturers. March 30, 2015. Available at: https://www.medicaid.gov/ Medicaid-CHIP-Program-Information/By-Topics/Prescription-Drugs/Downloads/Rx-Releases/ MFR-Releases/mfr-rel-092.pdf. Accessed on January 30, 2017. 19. U.S. Food and Drug Administration. Guidances (Biosimilars). Available at: http://www.fda.gov/ Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm Accessed on January 30, 2017. 20. Sandoz. Sandoz launches Zarxio™ (filgrastim-sndz), the first biosimilar in the United States. News Release. September 3, 2015. Available at: https://www.sandoz.com/news/media-releases/sandozlaunches-zarxiotm-filgrastim-sndz-first-biosimilar-united-states. Accessed on January 30, 2017. 21. Centers for Medicare and Medicaid Services. Proposed policy, payment, and quality provisions changes to the Medicare Physician Fee Schedule for Calendar Year 2016. October 30, 2015. Available at: https://www.cms.gov/Newsroom/MediaReleaseDatabase/Fact-sheets/2015-Factsheets-items/2015-10-30-2.html. Accessed on January 30, 2017.


22. Novartis. FDA accepts Sandoz regulatory submission for a proposed biosimilar etanercept. News release. October 2, 2015. Available at: https://www.novartis.com/print/61231. Accessed on February 28, 2017.

33. U.S. Supreme Court. Petition for a Writ of Certiorari: Sandoz Inc. v. Amgen Inc., et al. February 16, 2016. Available at: http://hr.cch.com/hld/SandozSCOTUSCertPetition.pdf. Accessed on January 30, 2017.

23. Apotex. Apotex Announces FDA Has Accepted for Filing its Biosimilar Application for Filgrastim (Grastofil™). News release. February 17, 2015. Available at: http://www.prnewswire.com/newsreleases/apotex-announces-fda-has-accepted-for-filing-its-biosimilar-application-for-filgrastimgrastofil-292257431.html. Accessed on January 30, 2017.

34. Pfizer. Pfizer Announces the U.S. Availability of Biosimilar INFLECTRA® (infliximab-dyyb). News Release. October 17, 2016. Available at: http://www.pfizer.com/news/press-release/press-releasedetail/pfizer_announces_the_u_s_availability_of_biosimilar_inflectra_infliximab_dyyb. Accessed January 20, 2017.

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BIOSIMILARS KEY CONSIDERATIONS CHECKLIST There has been tremendous growth in the biosimilar market over the past several years, from the approval and launch of the first biosimilar in the U.S. to the finalization of several key guidance documents. However, there are still some uncertainties that remain. As the biosimilar market continues to evolve, it is important to stay abreast of the available information for each individual product. Below is a checklist of certain key topics to consider when evaluating a biosimilar for formulary placement.57,58,59

PRODUCT CONSIDERATIONS

OPERATIONAL CONSIDERATIONS

Is the biosimilar approved for all the same indications as its reference product? Has it been determined by the FDA as interchangeable to its reference product?

Can the biosimilar and reference product be accurately tracked through each step in the organization’s information technology system?

Are there differences in how the biosimilar is supplied (e.g., syringe, vial) that will limit the ability to accurately dose the biosimilar in certain patient populations?

Are there programs in place to prevent potential medication errors and monitor transitions between the biosimilar and reference product?

Are there differences in the delivery device, formulation, storage and/or handling requirements for the biosimilar compared to its reference product?

What programs/materials will be needed to educate patients and providers on biosimilars?

Is the biosimilar available through full-line wholesalers or specialty distribution?

CONTRACTING CONSIDERATIONS What are the costs associated with putting patients on a biosimilar?

MANUFACTURER CONSIDERATIONS Has the reference product or biosimilar manufacturer experienced drug shortages? Does the biosimilar manufacturer provide support programs similar to the reference product manufacturer?

Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 www.amgen.com © 2017 Amgen. All rights reserved. USA-BIO-044570(1)

Have you considered the Medicare Part D coverage gap in contracting strategies? Will the biosimilar contract impact contracts for other products in a manufacturer’s portfolio?