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1 I N S I D E T H E M I N D S Recent Developments in Food and Drug Law Leading Lawyers on Dealing with Increased Enforcement, Keeping Up-To-Date with FDA Requirements, and Developing Compliance Practices 2014 EDITION

2 2013 Thomson Reuters/Aspatore All rights reserved. Printed in the United States of America. No part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, except as permitted under Sections 107 or 108 of the U.S. Copyright Act, without prior written permission of the publisher. This book is printed on acid free paper. Material in this book is for educational purposes only. This book is sold with the understanding that neither any of the authors nor the publisher is engaged in rendering legal, accounting, investment, or any other professional service. Neither the publisher nor the authors assume any liability for any errors or omissions or for how this book or its contents are used or interpreted or for any consequences resulting directly or indirectly from the use of this book. For legal advice or any other, please consult your personal lawyer or the appropriate professional. The views expressed by the individuals in this book (or the individuals on the cover) do not necessarily reflect the views shared by the companies they are employed by (or the companies mentioned in this book). The employment status and affiliations of authors with the companies referenced are subject to change. For customer service inquiries, please West.customer.service@thomson.com. If you are interested in purchasing the book this chapter was originally included in, please visit

3 Helping Clients Understand Biosimilar Product Regulations and the Biosimilar Litigation Process Lisa Mueller Partner Michael Best & Friedrich 3

4 By Lisa Mueller Introduction The worldwide market for biosimilar drugs is expected to reach a value of around $2.44 billion in 2013, an increase of 20 percent from In March 2010, the United States passed the Patient Protection and Affordable Care Act (Affordable Care Act), 2 which included the Biologics Price Competition and Innovation Act of 2009 (the Biosimilar Act). 3 The Biosimilar Act provides an abbreviated pathway for the US Food and Drug Administration (FDA) to approve follow-on biologics (biosimilars). Although this law was enacted over three years ago, not a single biosimilar application has yet been filed with the FDA. Because of their higher development, regulatory and manufacturing costs, biosimilars will never provide the same cost savings to consumers as generic drugs. However, biosimilars should provide a tremendous cost savings when compared to the price associated with innovator biologic products. Once the first biosimilars are approved and marketed in the US, these products will create a new pharmaceutical marketplace having their own economic dynamics and competitive complexities. Statutory Framework to Approve Biosimilars One of the current issues in food and drug law relates to the implementation of the abbreviated FDA approval pathway for biosimilars and the various state laws being passed regarding biosimilar substitution. A biosimilar is a product that is similar to, but not the same as an innovator biologic drug. 4 Biologics are medicines created through a combination of living organisms (such as bacteria, yeast, mammal cells or enzymes) and are commonly referred to as protein-based drugs. 5 1 Lynn Taylor, Biosimilar drugs global revenues to hit $2.44B this year, PHARMATIMES ONLINE (May 14, 2013), global_revenues_%e2%80%9cto_hit_2_44b_this_year.aspx. 2 Patient Protection and Affordable Healthcare Act, Pub. L. No , 124 Stat. 119 (2010) (codified in scattered sections of 42 U.S.C.). 3 Patient Protection and Affordable Healthcare Act, Pub. L. No , , 124 Stat.119, (2010) (codified in scattered sections of 42 U.S.C.). 4 Katherine N. Addison, The Impact of the Biosimilars Provision of the Health Care Reform Bill on Innovation Investments, 10 J. MARSHALL REV. INTELL. PROP. L. 553, 557 (2011). 5 Id. at

5 Helping Clients Understand Biosimilar Product Regulations Biologics are large and more complex than traditional pharmaceuticals composed of small molecules. 6 It is much more difficult to demonstrate the comparability of two biological products than to small molecule products. It is critical to note that biosimilars are not generic drugs. 7 A generic drug is a copy of an innovative drug (small molecule) that is similar in composition and safety, and has met the same FDA standards as the underlying innovative drug. 8 It is relatively simple to make an exact copy of a small molecule drug; however, the same is not true with respect to biologics, which are large and complex molecules. In fact, the manufacturing process for biologics is far more complicated than for small molecules due to the fact that most biologics must be grown in living organisms and many involve modified DNA. 9 Biologics are approved by the FDA after submission of a biologics license application (BLA) pursuant to section 351(a) of the Public Health Service Act (PHSA) 10 (a section 351(a) application ). Until recently, manufacturers of follow-on biologics had no alternative but to submit a full section 351(a) application to seek licensure of their product, regardless of the degree of similarity between the follow-on biologic and the innovator biologic. Thus, FDA approval of follow-on biologics was a very time-consuming and expensive endeavor. However, the passage of the Affordable Care Act on March 23, 2010, included the Biosimilar Act, which, for the first time, provided an abbreviated pathway for FDA approval of follow-on biologics (as either a biosimilar to, or interchangeable with, a single FDA-licensed biological (or biologic) reference product ). 11 Additional provisions in the Biosimilar Act provided a biological reference product with a certain exclusivity period; provided the FDA with discretion in implementing the approval 6 Id. 7 Id. at Id. 9 Id. at U.S.C. 262(a) (1944). 11 A reference product is a single biological product licensed under subsection (a) of Section 351 of the PHSA (against which a biological product is evaluated in an application filed under Section 351(k) of the PHSA (42 U.S.C. 262(k). 5

6 By Lisa Mueller pathway; and specified certain procedures for filing patent infringement, including preliminary injunction and declaratory judgment actions. What is a Biosimilar? What is an Interchangeable Biological Product? A biosimilar is a biological product that: (1) is highly similar to a reference product notwithstanding minor differences in clinically inactive components, and (2) exhibits no clinically meaningful differences with respect to the reference product in terms of the safety, purity, and potency of the product. 12 A clinically meaningful difference includes a difference in the expected range of safety, purity, and potency of the proposed and reference products. 13 Slight differences in the rates of occurrence of adverse events between two products are not considered clinically meaningful differences. 14 In contrast, a biological product is deemed interchangeable if the product: (1) is biosimilar to the reference product, (2) can be expected to produce the same clinical result as the reference product in any given patient, and (3) when administered more than once to an individual, has a risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product that is not greater than the risk of using the reference product without such alternation or switch. 15 Establishing interchangeability for a proposed biological product is expected to be extremely difficult. Not all biological materials are regulated under the PHSA. A biological product 16 is defined as a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any U.S.C. 262(i)(2). 13 U.S. Food and Drug Administration, Guidance for Industry Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, Draft Guidance 8 (2012) available at /UCM pdf [hereinafter FDA Scientific Considerations]. 14 Id U.S.C. 262(k)(4). 16 An application for a biological product must be submitted under section 351 of the PHSA, subject to certain exceptions during the 10-year transition period ending on March 23, 2020 described in section 7002(e) of the Affordable Care Act. 6

7 Helping Clients Understand Biosimilar Product Regulations chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings. 17 Hormones, such as insulin, glucagon and human growth hormone, are not considered to be biological products and are regulated as drugs under the Federal Food, Drug, and Cosmetic Act (FD&C Act). 18 While the definition of biological product encompasses proteins 19 it excludes chemically synthesized polypeptides. The Biosimilar Act does not provide any guidance on the distinction between a protein and a chemically synthesized polypeptide. However, the FDA has published guidance 20 that describes how it intends to interpret the term protein as recited in the definition of biological product. 21 According to the FDA, the term protein refers to any alpha amino acid polymer having specific defined sequence that is greater than forty amino acids in size. 22 Any polymer containing forty or fewer amino acids is considered to be a peptide and not a protein. 23 FDA considers a chemically synthesized polypeptide to be any alpha amino acid polymer that: (1) is made entirely by chemical synthesis, and (2) is less than 100 amino acids in size. 24 Both peptides and U.S.C. 262(i)(1). 18 U.S. FDA, Frequently Asked Questions About Therapeutic Biological Products, ed/approvalapplications/therapeuticbiologicapplications/ucm htm (last updated 12/24/2009). 19 The Biosimilar Act amended the definition of biological product to include a protein (except any chemically synthesized polypeptide) and provides that an application for a biological product must be submitted under section 351 of the PHSA subject to a 10-year transition period ending on March 23, See U.S. Food and Drug Administration, Guidance for Industry Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009, Draft Guidance 12 (2012) available at [hereinafter FDA BPCIA Guidance]. 20 The FDA has issued four draft guidance documents to assist applicants with the process of preparing and submitting an application for licensure of a proposed biosimilar product. These guidance documents are: (1) Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009; (2) Scientific Considerations in Demonstrating Biosimilarity to a Reference Product; (3) Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product; and (4) Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants. 21 FDA BPCIA Guidance, supra note 19, at Id. at Id. 24 Id. 7

8 By Lisa Mueller chemically synthesized polypeptides will be regulated as drugs under the FD&C Act. 25 Requirements of a Biosimilar Application The Biosimilar Act added section 351(k) 26 to the PHSA, which sets forth the requirements for licensure of an application of a biological product as biosimilar or interchangeable to a single 27 reference product (a section 351(k) application ). If a proposed biological product is demonstrated to be biosimilar to a reference product, the sponsor is allowed to rely on certain existing scientific knowledge about the safety, purity, and potency of the innovator reference product to support licensure of its proposed biological product. 28 Specifically, the FDA will license a proposed biological product if it determines that the information submitted in a section 351(k) application is sufficient to show that the biological product is biosimilar to the reference product and the section 351(k) applicant (or other appropriate person) consents to an inspection of the facility that is the subject of the application (a facility in which the proposed biological product is manufactured, processed, packed, or held). 29 Specifically, a section 351(k) application must contain the following: information that the proposed biological product is biosimilar to a reference product based upon data derived from: o analytical studies that demonstrate that the proposed biological product is highly similar to the reference product (notwithstanding minor differences in clinically inactive components); 30 o animal studies (including an assessment of toxicity); 31 and o a clinical study or studies (including an assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate the safety, purity and potency 25 Id. at U.S.C. 262(k). 27 The abbreviated pathway under section 351(k) of the PHSA is not available for combination biologics that consist of multiple biologics. 28 FDA Scientific Considerations, supra note 13 at Id. at U.S.C. 262(k)(2)(A)(i)(I)(aa) U.S.C. 262(k)(2)(A)(i)(I)(bb). 8

9 Helping Clients Understand Biosimilar Product Regulations of the proposed biological product in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought; 32 information that the proposed biological product and reference product utilize the same mechanism or mechanisms of action for the condition or conditions of use prescribed, recommended or suggested in the proposed labeling (but only to the extent the mechanism or mechanisms of action are known for the reference product); 33 information that the condition or conditions of use prescribed, recommended, or suggested in the labeling for the proposed biological product have been previously approved for the reference product; 34 information that the route of administration, the dosage form, and the strength of the proposed biological product are the same as those of the reference product; 35 and information that the facility in which the proposed biological product is manufactured, processed, packed or held meets standards designed to ensure that the biological product continues to be safe, pure and potent. 36 In its guidance documents, the FDA has indicated it will use a risk-based totality-of-the-evidence approach to assess all data and information submitted in support of a section 351(k) application. The FDA recommends that sponsors use a stepwise approach to develop all data and information necessary to support a demonstration of biosimilarity. 37 Although the FDA will determine the type and amount of analysis and testing sufficient to demonstrate biosimilarity on a product-by-product basis, the administration has indicated that a stepwise approach should begin with an extensive structural and functional characterization of the proposed biological product and the reference product U.S.C. 262(k)(2)(A)(i)(I)(cc) U.S.C. 262(k)(2)(A)(i)(II) U.S.C. 262(k)(2)(A)(i)(III) U.S.C. 262(k)(2)(A)(i)(IV) U.S.C. 262(k)(2)(A)(i)(V). 37 FDA Scientific Considerations, supra note 13 at Id. 9

10 By Lisa Mueller The FDA considers comprehensive and robust structural and functional characterizations that identify differences between the proposed biological product and the reference product useful when determining which additional studies to require. 39 Examples of the types of characterizations that should be conducted with the proposed biological product and reference product include a comparison of primary structures (such as amino acid sequence); higher-order structures, such as secondary, tertiary, and quaternary structures (including aggregation); enzymatic post-translation modifications (such as glycosylation and phosphorylation); potential variants (such as protein deamination and oxidation); and intentional chemical modifications (such as PEGylation sites and other characteristics). 40 Sponsors can use in vitro or in vivo assays (such as bioassays, biological assays, binding assays, and enzyme kinetics) to evaluate the pharmacologic activity of the proposed biological and reference products. 41 Regarding animal data, sponsors must include information demonstrating biosimilarity derived from animal studies, including an assessment of toxicity (unless the FDA determines such studies are not necessary). The types of animal studies the FDA considers useful for demonstrating biosimilarity include animal toxicity studies, animal pharmacokinetic (PK) and pharmacodynamic (PD) 42 measures, and animal immunogenicity studies. The FDA considers data from animal toxicity studies useful when, based on the results of extensive structural and functional characterization, uncertainties remain about the safety of the proposed biological product that must be addressed before initiation of clinical studies in humans. 43 However, animal toxicity studies are not generally useful if there are no animal species available that can provide pharmacologically relevant data for the proposed biological product (meaning there is no species in which the biologic activity of the proposed biological product mimics the human response) Id. 40 Id. at Id. at A PK study measures how a body acts on a drug namely, how the drug is absorbed, distributed, metabolized, and eliminated. In contrast, a PD study measures how the drug acts on the body, assessing a measure or measures related to the drug s biochemical and physiologic effects on the body. 43 FDA Scientific Considerations, supra note 13 at Id. 10

11 Helping Clients Understand Biosimilar Product Regulations Under certain circumstances, animal PK and PD measure studies 45 may contribute to the totality of the evidence supporting biosimilarity; however, animal PK and PD assessments do not negate the need for human PK and PD studies. 46 Although animal immunogenicity studies generally do not predict potential immunogenic responses to biological products in humans, when differences in manufacturing (such as in impurities or excipients) between the proposed biological product and the reference product may result in differences in immunogenicity, the FDA believes that measurement of anti-protein antibody responses in animals may provide useful information that is relevant to patient safety. 47 Finally, sponsors must conduct comparative clinical studies to demonstrate that the proposed biological product exhibits no clinically meaning differences with respect to the reference product in terms of safety, purity, and potency in one or more conditions of use for which the reference product is licensed. 48 According to the FDA, the scope and magnitude of such clinical studies will depend on the extent of residual uncertainty about the biosimilarity of the two products after conducting structural and functional characterization and possible animal studies. 49 In addition, the frequency and severity of safety risks and other safety and effectiveness concerns for the reference product may also affect the design of the clinical program. 50 Nonetheless, the clinical studies should be designed to demonstrate that the proposed biological product has neither decreased nor increased activity compared to the reference product. 51 The FDA has indicated decreased activity would preclude licensure of a proposed biological product and increased activity might be associated with more adverse effects or indicate the proposed biological product should be treated as an entirely different product having superior efficacy (in which licensure under section 351(a) of the PHSA would be more appropriate) Such as a single-dose study in animals comparing the proposed biological product and reference product using PK and PD measures. 46 FDA Scientific Considerations, supra note 13 at Id. 48 Id. 49 Id. 50 Id. 51 Id. at Id. 11

12 By Lisa Mueller Sponsors must perform both human PK and PD studies (assuming a relevant PD measure exists). According to the FDA, such studies are fundamental components in supporting a demonstration of biosimilarity (unless a sponsor can scientifically justify why such studies are unnecessary). 53 The FDA suggests sponsors provide a scientific justification for the selection of the human PK and PD study population (such as patients versus healthy subjects) and parameters, taking into consideration the relevance of the population and parameters, the population and parameters studied for licensure for the reference product, as well as the current knowledge regarding the intra-subject and inter-subject variability of human PK and PD for the reference product. 54 Additionally, the sponsor must perform at least one clinical study comparing the immunogenicity of the proposed biological product to that of the reference product. Immunogenicity studies must be conducted both prior to pre-market approval and post-market approval. The extent and timing of these studies depends on several factors, such as the extent of analytical similarity between the proposed biological product and the reference product and the incidence and clinical consequences of immune responses for the reference product. 55 Generally, premarket immunogenicity studies are used to detect major differences in immune response between the proposed biological product and the reference product. 56 Post-market immunogenicity studies are used to detect subtle differences in immunogenicity between the products. 57 Finally, if any residual uncertainties remain about the biosimilarity of a proposed biological product and a reference product based on the structural and functional characterizations, animal testing, human PK and PD data, and clinical immunogenicity assessment, comparative safety and effectiveness data will be necessary to support a demonstration of 53 Id. at Id. 55 Id. at Id. 57 Id. 12

13 Helping Clients Understand Biosimilar Product Regulations biosimilarity (unless the sponsor can provide a scientific justification as to why it believes that such data is not necessary). 58 In certain instances, a sponsor may be able to rely on data derived from animal or clinical studies comparing a proposed biological product with a non-us licensed product; however, the FDA has indicated that in such instances, the sponsor should produce adequate data or information to scientifically justify the relevance of this comparative data to an assessment of biosimilarity and to establish an acceptable bridge to the US-licensed reference product. 59 In addition to providing information derived from structural and functional characterizations and animal and human clinical studies, a sponsor must also demonstrate that: the proposed biological product and reference product use the same mechanism of action (provided the mechanism of action is known); the conditions of use for the proposed biological product are the same as those for the previously approved reference product; the identical route of administration, dosage form, and strength of the proposed biological product are the same as for the reference product; and manufacturing facilities used to prepare the proposed product meet the standards designed to ensure the proposed product continues to be safe, pure, and potent. 60 Benefits of Interchangeable Biological Products Biological products found to meet the higher standard of being interchangeable with a reference product have a number of benefits. First, interchangeable biological products may be substituted for the reference product without the intervention of the prescribing physician. 61 In other words, a pharmacy is permitted to substitute a biosimilar that is interchangeable without obtaining the approval of the prescribing physician. In contrast, a pharmacy cannot substitute a biosimilar product for a reference product without obtaining approval of the prescribing physician. Second, a first biological product that receives a determination of 58 Id. at Id. at U.S.C. 262(k)(2)(A)(i)(II)-(V) U.S.C. 262(i)(3). 13

14 By Lisa Mueller interchangeability is entitled to a certain period of marketing exclusivity in such instances, the FDA cannot make an interchangeability determination for a second biological product (also known as a follow-on biological product ) until the earlier of: one year after the first commercial marketing of the first interchangeable biological product; eighteen months after a final court decision in favor of the applicant with respect to all patents in suit or the dismissal of the complaint with or without prejudice; forty-two months after approval of the first interchangeable biological product if patent litigation is still ongoing; or eighteen months after approval of the first interchangeable biological product if the sponsor of the first interchangeable biological product has not been sued. 62 Biosimilar Substitution Regulation Substitution refers to the practice in which pharmacists are permitted to substitute a biosimilar product for a reference biological (or branded) product prescribed by a physician. Such substitution is governed at the state level. Thus far, Virginia, North Dakota, Utah, Florida, and Oregon have passed laws regulating biosimilar substitution. Virginia Biosimilar Regulations Even though the FDA has yet to approve any biosimilars, on March 21, 2013, Virginia became the first state to pass a law regulating the substitution of biosimilar products. 63 Specifically, under Virginia s law, automatic substitution of a biosimilar 64 product for a prescribed biological (branded) product is not permitted pharmacists are permitted to dispense a biosimilar product in place U.S.C. 262(k)(6). 63 Va. Code Ann (2013). 64 A biosimilar is defined as a biological product that is highly similar to a specific reference biological product, notwithstanding minor differences in clinically inactive compounds, such that there are no clinically meaningful differences between the reference biological product and the biological product that has been licensed as a biosimilar pursuant to 42. U.S.C. 262(k) in terms of safety, purity, and potency of the product. See Va. Code Ann (2013). 14

15 Helping Clients Understand Biosimilar Product Regulations of a prescribed biological product 65 only if the biosimilar product meets the FDA safety standards for interchangeability. 66 Additionally, substitution of a prescribed biological product with a biosimilar product is not permitted if the prescribing physician specifies brand medically necessary (namely, do not substitute ) on the prescription or gives specific oral dispensing instructions, or if the patient insists on receiving the prescribed biological product. Moreover, the law requires a pharmacist dispensing a biosimilar product to: inform the patient prior to dispensing the biosimilar product that the substitution is being made; notify the prescribing physician of the substitution (electronically, in writing, or by telephone within five days or within a timeframe established by a collaborative agreement between the pharmacist and the physician); provide retail cost information (the actual cost paid by a retail purchaser to a pharmacy for a drug at the prescribed dosage and amount) to the patient for both the prescribed biological product and the biosimilar product; both the pharmacist and prescribing physician must maintain records regarding the substitution for a period of at least two years from the date of dispensing; record the brand name or, in case of a biosimilar product, the product name and the name of the manufacturer or distributor of the biosimilar product on the dispensing record and prescription label; and include on the label the name of the biosimilar product, followed by the phrase substituted for, followed by the name of the prescribed biological product. Finally, the requirements that the pharmacist notify the prescribing physician of the substitution and provide retail cost information to the patient expire on July 1, 2015, which is likely to occur before any biosimilar product becomes commercially available. 65 Virginia has essentially adopted the FDA s definition of biological product meaning a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings. 66 Interchangeable is defined as a biosimilar that meets safety standards for determining interchangeability pursuant to 42 U.S.C. 262(k)(4). See Va. Code Ann (2013). 15

16 By Lisa Mueller North Dakota Biosimilar Regulations On March 29, 2013, North Dakota became the second state to pass a law regulating the substitution of biosimilars. 67 Specifically, under the law passed in North Dakota, a pharmacist may substitute a biosimilar product for a prescribed biological product if the: FDA has determined the biosimilar product to be interchangeable 68 with the prescribed biological product; prescribing physician has not prohibited the substitution (namely, the physician has not written brand medically necessary or given specific oral dispensing instructions); pharmacist informs the patient receiving the biosimilar product that the prescribed biological product may be substituted with the biosimilar product and the patient has the right to refuse the biosimilar product, and the patient chooses not to refuse the biosimilar product; pharmacist notifies the prescribing physician in writing or via electronic transmission within 24 hours of the substitution; and pharmacy and prescribing physician retain a written record of the biosimilar substitution for a period of not less than five years. Unlike Virginia s law, none of the above requirements have an expiration date. Utah Biosimilar Regulations On April 1, 2013, Utah became the third state to pass a law regulating the substitution of biosimilars. 69 Specifically, under the law passed in Utah, a pharmacist may substitute a biosimilar product for a prescribed biological product if the: FDA has determined the biosimilar 70 product to be interchangeable with the prescribed biological product; 67 N.D. Sess. Laws ch. 181 (2013). 68 A biological product, biosimilar, interchangeable, interchangeable biological product and reference product are defined as having the same meaning as provided for in Section 351 of the PHSA (42 U.S.C. 262) N.D. Cent. Code Ann (West 2013). 69 Utah Code Ann b (West 2013). 70 The words biological product, biosimilar and interchangeable are defined in accordance with 21 U.S.C See, Utah Code Ann b-605.5(1) (West 2013). 16

17 Helping Clients Understand Biosimilar Product Regulations interchangeable biosimilar product is permitted to move in interstate commerce; prescribing physician has not prohibited the substitution (namely, the physician has not written dispense as written or given specific oral dispensing instructions prohibiting the substitution); pharmacist communicates the substitution to the patient; patient specifically requests or consents to the substitution; pharmacist counsels the patient on the use and expected response to the prescribed biological product, regardless of whether it is a substitute; biosimilar product container is labeled with the name of the biosimilar product; pharmacist (but not the prescribing physician) maintains records regarding the substitution; specifically, the name of the prescribed biological product and the name of the biosimilar product dispensed in its place; pharmacist notifies the prescribing physician by fax, telephone or electronic transmission of the substitution as soon as possible, but no later than three business days after dispensing the biosimilar product for the prescribed biological product, including the name and manufacturer of the biosimilar product (this requirement expires on May 15, 2015); and substitution is not otherwise prohibited by law. Additionally, Utah requires out-of-state mail-service pharmacies to comply with the requirements of this law with respect to biosimilar products substituted for another prescribed biological product, including labeling and recordkeeping. Florida Biosimilar Regulations On May 31, 2013, Florida became the fourth state to pass a law regulating the substitution of biosimilars. 71 Specifically, under the law passed in 71 Fla. Stat. Ann (West 2013). 17

18 By Lisa Mueller Florida, a pharmacist may substitute a biosimilar 72 product for a prescribed biological product if: the FDA has determined the biosimilar product is biosimilar to, and interchangeable for, the prescribed biological product; the prescribing physician does not express a preference against substitution in writing, verbally or electronically; the pharmacist notifies the patient of the substitution; and the pharmacist (but not the prescribing physician) keeps a written or electronic record of the substitution for a period of at least two years. Unlike Virginia, North Dakota, Utah and Oregon, Florida s law does not contain any physician notification requirements regarding the substitution. Oregon s Biosimilar Regulations On June 6, 2013, Oregon became the fifth state to pass a law regulating the substitution of biosimilars. 73 Specifically, under the law passed in Oregon (which will take effect on January 1, 2014), a pharmacist may substitute a biosimilar product 74 for a prescribed biological product if: the FDA has determined the biosimilar product 75 is interchangeable 76 with the prescribed biological product; the prescribing physician does not prohibit the substitution; the patient is informed of the substitution prior to dispensing; the pharmacist provides written, electronic, or telephonic notification of the substitution to the prescribing physician or the physician s staff within three business days of dispensing the biosimilar product (which expires on December 31, 2015); and the pharmacist (not the prescribing physician) retains records of the substitution for a period of at least three years. 72 The words biological product, biosimilar and interchangeable are defined in accordance with Section 351 of the PHSA (42 U.S.C. 262 ). Id. 73 S. B. 460, 77th Legis. Assemb, Reg. Sess. (Or. 2013) (to be codified at Or. Rev. Stat. 689). 74 A biosimilar product is defined as a biological product licensed by the United States Food and Drug Administration pursuant to 42 U.S.C. 262(k)(3)(A)(i). Id. 75 Oregon has essentially adopted the FDA s definition of biological product but with some minor wording changes. Specifically, Oregon defines biological product to mean that with respect to the prevention, treatment or cure of a disease or condition of human beings, a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component, blood derivative, allergenic product, protein other than a chemically synthesized polypeptide, analogous products or arsphenamine or any other trivalent organic arsenic compound. Id. 76 Interchangeable is defined as meaning, in reference to a biological product, that the United States Food and Drug Administration has determined that a biosimilar product meets the safety standards set forth in 42 U.S.C. 262(k)(4). Id. 18

19 Helping Clients Understand Biosimilar Product Regulations Summary of State Laws on Substitution of Biosimilar Products The table below provides a comparison of some of the key aspects of the laws in each of Virginia, North Dakota, Utah, Florida and Oregon regulating the substitution of biosimilar products. State Automatic substitution permitted? Virginia No must be interchangeable North Dakota No must be interchangeable Utah No must be interchangeable Inform patient of substitution? Patient consent for substitution required? Time period for notifying prescribing physician of the substitution Yes No Within 5 days (absent other agreement) Expires: 7/1/15 Yes Yes Within 24 hours Yes Yes Within 3 business days Expires: 5/15/15 Record retention by pharmacy and/or prescribing physician regarding substitution At least 2 years At least 5 years Required (no minimum retention period specified) Provide retail cost of the branded biological product and the substituted biosimilar interchangeable product? Yes Expires: 7/1/15 Not required Not required 19

20 Florida No must be interchangeable Oregon No must be interchangeable By Lisa Mueller Yes No None At least 2 years Yes No Within 3 business days Expires: 12/31/15 At least 3 years Not required Not required FDA Guidance for Demonstrating Biosimilarity While the FDA has issued several guidance documents detailing the approach the agency intends to take for determining biosimilarity of a proposed biological product to a reference product, it has not yet issued any guidance describing the approach the agency intends to take for determining interchangeability of a proposed biological product to a reference product. The lack of any indication by the FDA to provide a timeframe for when it might issue such guidance suggests that the FDA does not anticipate licensing an interchangeable biological product anytime in the foreseeable future. In one guidance document, 77 the FDA indicated that it will participate in five types of formal meetings with biosimilar sponsors and applicants. These include: Biosimilar Initial Advisory (BIA) Meetings. This meeting is limited to a general assessment of whether licensure under section 351(k) of the PHSA is feasible for a proposed biological product. 78 If the FDA determines licensure to be feasible, it will provide general advice regarding the expected content of the development program. When requesting this type of meeting, a sponsor or applicant should provide preliminary comparative analytical similarity data sufficient to allow the FDA to make a preliminary determination as to 77 U.S. Food and Drug Administration, Guidance for Industry Formal Meetings between the FDA and Biosimilar Product Sponsors or Applicants, Draft Guidance (2013) available at UCM pdf [hereinafter FDA Formal Meetings]. 78 Id. at 3. 20

21 Helping Clients Understand Biosimilar Product Regulations whether licensure under section 351(k) of the PHSA is possible for a proposed biological product. 79 Additionally, a sponsor or applicant should provide an overview of its proposed biological product development (BPD) program. During a BIA meeting, the FDA will not review summary data or full study reports. The FDA has 21 days after its receipt of a request and meeting package to respond to a BIA meeting request. The meeting should occur within 90 calendar days of the FDA s receipt of the written meeting request and meeting package; BPD Type 1 Meetings. Type 1 meetings are conducted when necessary to allow otherwise-stalled BPD programs to proceed. 80 These meetings may involve discussions related to clinical holds, important safety issues, and special protocol assessments. 81 The FDA has twenty-one days after receiving a request and meeting package to respond to a Type 1 meeting request. The meeting should occur within 30 calendar days of the FDA s receipt of the written meeting request and meeting package; BPD Type 2 Meetings. Type 2 meetings are meetings to discuss a specific issue or questions (such as a proposed study design or endpoint), during which the FDA provides targeted advice regarding an ongoing BPD program. 82 During a Type 2 meeting, the FDA will conduct a substantive review of summary data; 83 however, this type of meeting will not include a review by the FDA of full study reports. 84 The FDA has 21 days after receiving a request and meeting package to respond to a Type 2 meeting request. The meeting should occur within 75 calendar days of the FDA s receipt of the written meeting request and meeting package; BPD Type 3 Meetings. Type 3 meetings involve the FDA s in-depth review of data. Additionally, the FDA will provide advice regarding an ongoing BPD program. 85 Specifically, a Type 3 meeting involves the FDA s substantive review of full study reports, FDA advice regarding the similarity between the proposed biological product 79 Id. 80 Id. 81 Id. 82 Id. 83 Id. 84 Id. 85 Id. at 4. 21

22 By Lisa Mueller and the reference product, and FDA advice regarding the need for additional studies, including design and analysis. 86 The FDA has 21 days after receiving a request and meeting package to respond to a Type 3 meeting request. The meeting should occur within 120 calendar days of the FDA s receipt of the written meeting request and meeting package; and BPD Type 4 Meetings. Type 4 meetings involve a discussion of the format and content of a proposed biological product application or supplement to be submitted under Section 351(k) of the PHSA. 87 The FDA has 21 days after receiving a request and meeting package to respond to a Type 4 meeting request. The meeting should occur within 60 calendar days of the FDA s receipt of the written meeting request and meeting package. If the FDA grants a meeting request, it notifies the sponsor or applicant in writing of the decision and schedules the meeting, determining the meeting type, date, time, length, place, format (face-to-face meeting, teleconference, or videoconference), and expected FDA participants. 88 If the FDA denies a meeting request, it will include an explanation of the reason for denial. The FDA has indicated that denials will be based on a substantive reason, not merely on the absence of a minor element of the meeting request or a minor element of the meeting package. 89 BPD Meeting Fees No fees are required for a sponsor or applicant to participate in a BIA meeting; however, a sponsor or applicant must pay an annual per-product fee to participate in a Type 1, 2, 3, or 4 meeting. Three types of fees are required. An initial fee is due when a sponsor or applicant submits data in an investigational new drug (IND) application for an investigation the FDA determines is intended to support an application for a biosimilar, or within five calendar days of the FDA s decision to grant a Type 1, 2, 3, or 4 meeting, whichever occurs first. 90 The 86 Id. 87 Id. 88 Id. at Id. at Id.at 4; 21 U.S.C.A. 379j-51 et seq. (2012). 22

23 Helping Clients Understand Biosimilar Product Regulations initial fee is 10 percent of the fee rate established under the Prescription Drug User Fee Act (PDUFA) 91 for a human drug application requiring clinical data; thus, for fiscal year 2013, the initial fee is $195, An annual fee is assessed for the product on a yearly basis until the sponsor or applicant submits a marketing application that is accepted for filing, or discontinues participation in the BPD program for the proposed biological product. 93 Payment of the annual fee begins the next fiscal year following payment of the initial BPD fee. The annual fee is 10 percent of the fee rate established under the PDUFA for a human drug application requiring clinical data; thus, for fiscal year 2013, the initial fee is $195, A reactivation fee is required if a sponsor or applicant discontinues a BPD program for a proposed biological product and subsequently decides to again engage in the BPD program for development of the proposed biological product. 95 The sponsor or applicant must make payment on the date the sponsor or applicant submits an IND application for an investigation the FDA determines is intended to support a biosimilar biological product application for the proposed biological product, or within five calendar days after the FDA grants the sponsor s or applicant s request for a BPD Type 1, 2, 3, or 4 meeting for the proposed biological product, whichever occurs first. 96 The annual fee is 20 percent of the fee rate established under the PDUFA for a human drug application requiring clinical data; thus, for fiscal year 2013, the initial fee is $391, The FDA will deny and cancel a scheduled BPD Type 1, 2, 3, or 4 meeting if granting such a meeting request triggers an obligation for the sponsor or applicant to pay an initial BPD fee or a reactivation fee for the product and the sponsor or applicant fails to pay the fee within five U.S.C.A. 379j-51 et seq. 92 Biosimilar User Fee Rates for Fiscal Year 2013, 77 Fed. Reg. 148, (Aug. 1, 2012). 93 FDA Formal Meetings, supra note 77, at See Biosimilar User Fee Rates for Fiscal Year 2013, supra note FDA Formal Meetings, supra note 77, at Id. 97 See Biosimilar User Fee Rates for Fiscal Year 2013, supra note

24 By Lisa Mueller calendar days after a meeting is officially granted, or if a sponsor or applicant is in arrears with respect to an annual BPD fee for a proposed biological product. 98 FDA Meeting Request Package It is important for a meeting request to include sufficient information to allow the FDA to assess the potential utility of a meeting, and identify the necessary FDA staff required to discuss the proposed agenda items. 99 The meeting request should include the following information: the product name; the application number (if applicable); the proposed proper name (or proper name if post-licensure); the structure (if applicable); the reference product name; the proposed indication(s) or context of product development; the meeting type requested, as well as the rationale for the meeting; a brief statement of the purpose of the meeting, including a brief background of the issues underlying the agenda; a list of specific objectives or outcomes the requester expects from the meeting; a proposed agenda, including estimated times for each agenda item; a list of precise questions, grouped by discipline, including a brief explanation of the context and purpose of each question; a list of all individuals, including their titles and affiliations, who will attend the requested meeting from the sponsor s or applicant s organization, including any consultants; a list of FDA staff, if known, or disciplines, asked to participate in the meeting; suggested dates and times for the meeting that are within the timeframe of the meeting type being requested; and the proposed format of the meeting (face-to-face, teleconference, or videoconference) FDA Formal Meetings, supra note 77, at Id. at Id. at

25 Helping Clients Understand Biosimilar Product Regulations The content of the meeting package should be organized according to the proposed agenda. Specifically, the meeting package should be a sequentially paginated document with a table of contents, appropriate indices, appendices, cross references, and tabs differentiating the various sections. 101 The meeting package should include at least the following information: the product name and application number (if applicable); the proposed proper name (or proper name if post-licensure); the structure (if applicable); the reference product name; the proposed indication(s) or context of product development; the dosage form, route of administration, dosing regimen (frequency and duration), and presentation(s); a list of sponsor or applicant attendees, affiliations, and titles; a background section that includes a brief history of the development program, and the status of product development (namely, the chemistry, manufacturing, and controls, nonclinical and clinical, including any development outside the United States, if applicable); a brief statement summarizing the purpose of the meeting; a proposed agenda; a list of questions for discussion grouped by discipline, with a brief summary for each question explaining the need or context for the question; and data to support the discussion organized by discipline and question. 102 It is important to submit a meeting package with the meeting request otherwise the FDA will consider the meeting request incomplete and is likely to deny it. Market Exclusivity for Reference Products A reference product is entitled to 12 years of market exclusivity, beginning on the date the FDA first licenses the product. 103 Reference products are 101 Id. at Id. at U.S.C. 262(k)(7)(A). 25

26 By Lisa Mueller also entitled to four years of data exclusivity from the date of first licensure, during which time the FDA cannot accept an application for a biosimilar or interchangeable version of a reference product for review. Moreover, reference products are also eligible for six months of pediatric exclusivity, which is added to both the market exclusivity and data exclusivity periods. 104 To be eligible for pediatric exclusivity, the sponsor or applicant must receive a formal request from the FDA to conduct a pediatric study and then conduct the study pursuant to the FDA s requirements. Finally, reference products are eligible for seven years of orphan drug exclusivity, if appropriate. However, none of the above exclusivities are applicable for any subsequent biological products approved under the full licensing process pursuant to section 351(a) of the PHSA. Moreover, no additional exclusivity is available for a supplemental BLA for the reference product. Likewise, there is no additional exclusivity for evergreening, namely, for any new BLA filed by the same reference product sponsor (or a related entity) for a change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength; or a modification to the structure of the reference product that does not result in a change in safety, purity, or potency. 105 Patent Exchange Process and Litigation Patents covering reference products are not publicly listed such as those covering small-molecules (which can be found in the Electronic Orange Book 106 ). Thus, during the development of a proposed biological product, the burden falls on the biosimilar sponsor or applicant to identify any patents it must design around, license, or challenge. A biosimilar sponsor or applicant should also keep in mind that the patent litigation process cannot begin on any patents owned or controlled by a reference product sponsor until after any data exclusivity period for the reference product has expired U.S.C. 262(m)(1) U.S.C. 262(k)(7)(C). 106 U.S. FDA, U.S. Department of Health & Human Services, Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations, (May 17, 2013), fda.gov/scripts/cder/ob/default.cfm. 26