Biologics and biosimilars. An overview

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1 Biologics and biosimilars An overview

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3 Contents An introduction to biotechnology... 3 A brief history of medicine development... 4 What are biologic medicines?... 5 How are biologic medicines developed?... 6 The value of biotechnology... 8 What are biosimilar medicines? How do biosimilars differ from the original innovator medicines? The emerging role of biosimilars The cost of developing biosimilars Regulating biosimilars Approval pathways for biologic and biosimilar medicines Biosimilar regulations Pharmacovigilance, traceability & naming Naming, tracking and tracing medicines WHO biologic naming policy Substitution and interchangeability The variation in global substitution guidelines Manufacturing biologics The manufacturing process is unique to every manufacturer Striving to ensure a consistent supply Glossary Works cited Amgen Inc. All rights reserved. March

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5 An introduction to biotechnology An introduction to biotechnology

6 An introduction to biotechnology Amgen was one of the first companies to recognize the potential of modern biotechnology in developing valuable medicines for patients and to assemble the diverse set of skills necessary to advance from hard to applied science. A leader in biotechnology since 1980, Amgen is focused on serving patients by discovering, developing and manufacturing innovative human therapeutics. By pioneering the development of novel products based on advances in cellular and molecular biology, Amgen s therapeutics have changed the practice of medicine and helped millions of people around the world to fight cancer, kidney disease, rheumatoid arthritis and other serious illnesses.

7 An introduction to biotechnology The term biotechnology was first coined in 1919 to describe the interaction between biology and human technology for the conversion of raw materials into socially valuable products. At the time, the focus was on food production but by the 1940s early advances in the technology had led to the development of medicines; enabling the mass production of antibiotics, such as penicillin, which continue to be used to control infectious diseases. The breakthrough that laid the groundwork for modern biotechnology came when the structure of DNA was discovered in the early 1950s. A standard definition of biotechnology was not reached until the United Nations and World Health Organization accepted the 1992 Convention on Biological Diversity and defined biotechnology as any technological application that uses biological systems, living organisms or derivatives thereof, to make or modify products and processes for specific use. (1) 3

8 A brief history of medicine development The first medicinal drugs came from natural sources and existed in the form of herbs, plants, roots, vines and fungi. Until the mid-nineteenth century these natural remedies were all that was available to treat some conditions. The first synthetic drug, chloral hydrate, was discovered in 1869 and introduced as a sedativehypnotic. The first pharmaceutical companies were spin-offs from the textiles and synthetic dye industry and owe much to the rich source of organic chemicals derived from the distillation of coal (coal-tar). (2) For many years, the pharmaceutical industry traditionally developed chemical drugs (also referred to as small molecules), including well-known medicines such as acetylsalicylic acid, to treat a wide range of illnesses. Since the 1970s, a revolution in biotechnology has resulted in a new class of medicine: the biologic.

9 Acetylsalicylic acid Small molecule 21 atoms IgG1 antibody Biologic medicine > 20,000 atoms What are biologic medicines? A biologic medicine is a large molecule typically derived from living cells and used in the treatment, diagnosis or prevention of disease. Biologic medicines include therapeutic proteins, DNA vaccines, monoclonal antibodies and fusion proteins. Biologic medicines are often 200 to 1,000 times the size of a small molecule drug and are far more complex structurally. They are also highly sensitive to their manufacturing and handling conditions, making them more difficult to characterize and produce than small molecule drugs. Due to both their size and sensitivity, biologic medicines are almost always injected into a patient s body and individual patient responses can depend on how a biologic is made. 5

10 How are biologic medicines developed? Biologic medicines are made in living organisms to produce proteins to treat various diseases, often by genetically modifying cell constructs or cell lines. DNA technology is often used to insert desirable genes or remove undesirable ones within a living cell or via a vector such as a virus, prompting a specific function such as the production of a protein to treat disease. Biotechnology has led to the development of many of today s most important medicines, including monoclonal antibodies for the treatment of cancer, human insulin for the treatment of diabetes and the cloning of the naturally occurring protein, erythropoietin to stimulate the production of red blood cells in the treatment of chronic anemia. (3) The genetic code of a chosen protein, such as human insulin or an immune system antibody, is identified and replicated by combining different segments of DNA to build a functional DNA sequence. The DNA sequence is introduced into the host cell of a living organism, such as bacteria, yeast or mammal cells, altering the cell s genetic makeup and coding it to produce the chosen protein. Genetically modified cell lines are carefully selected and cultured in large bioreactors before the biologic medicine is extracted through complex and lengthy purification processes. Each of the thousands of steps is intricate, sensitive and often specific to a particular medicine, requiring robust quality systems, significant experience, expertise and financial investment. Even minor alterations may lead to changes in cell behavior and differences in the structure, stability or other quality aspects of the end product. Any of these differences have the potential to affect the treatment s safety, efficacy and/or shelf life, and to increase the risk of an unwanted immune response. Chromosome Gene T A T A G C A C T G A T A T C G C A G T C C A A G G T T A T A T C G C G DNA 6

11 01 Biologic medicines are made in living organisms by genetically engineering DNA. DNA is inserted into living cells, such as bacteria, yeast or cultured animal cells, to code for the production of a particular protein. 02 The biologic is modified to ensure it functions as intended. Specific chemicals are added to control the function of the biologic. Translating high science: from laboratory to better patient care 03 The most effective cell line is selected for expansion. During selection, the cells that can produce the biologic most effectively are identified and expanded to manufacture the medicine. This cell line is unique to each manufacturer and is the source of all future product. 04 The unique cell line is grown in bioreactors and carefully monitored. The biologic drug is then isolated and purified using sophisticated technology. Discover more on the manufacturing of biologic medicines by visiting the Amgen YouTube channel at youtube.com/user/amgen 7

12 The value of biotechnology Today s biologic medicines have made a significant difference to the lives of patients with serious illnesses, including cancer, blood conditions, auto-immune disorders such as rheumatoid arthritis (RA) and psoriasis, and neurological disorders like multiple sclerosis. Recreating human proteins into biologic medicines has revolutionized how we treat disease. (5) Worldwide, nearly 200 biologic medicines have transformed the lives of over 800 million patients with serious illnesses. (3) By understanding the mechanisms of diseases, such as multiple sclerosis, biologic medicines can be developed to target and modify underlying causes of disease, potentially altering the course of disease rather than simply treating symptoms. (6) The development of new biologic medicines may be the best hope for effectively treating diseases for which there are currently no cures. The mapping of the human genome one of the most significant advances in biotechnology has led to an escalation in biotechnology research, including experimental therapies such as stem cell and gene therapy. Today, over 400 biologic medicines worldwide are being studied in serious illnesses, such as HIV/ AIDS, Alzheimer s disease, cancer, cardiovascular disease and autoimmune disorders. (3) A 2013 report (1) from the European Commission looking at Europe s strong regulatory and commercial foundation for biosimilars found that biosimilars are helping improve competition and are thus increasing access to biologic medicines for patients. Read the report here: sectors/healthcare/files/docs/ biosimilars_report_en.pdf 8

13 Targeting disease pathways to benefit patients Cancer: Following cancer pathways and determining the molecular basis of cancer has led to the development of new targeted diagnostics and treatments. Traditionally, cancer has been treated with surgery, radiation and chemotherapy. Biotechnology has contributed to significant advances in cancer treatment, including hormone therapies, biologic medicines and targeted therapies such as monoclonal antibodies. (3) An introduction to biotechnology 9

14 Defining biosimilars What are biosimilar medicines? Unlike generic medicines where the active ingredients are identical, biosimilars are similar to but not identical copies of the originator biologic. They are similar, but not the same. Biologics made by different manufacturers differ from the original product and from each other. The complexity of biologics precludes identical copies and are therefore not the same as generic drugs. Due to the complex structure of biologic medicines and the processes involved in production, biosimilars must be determined on the basis of analytical, non-clinical and clinical data to be similar to an original biologic in terms of structural characteristics, and safety and efficacy. Minor differences with the active ingredient are expected and permitted so long as any such differences are demonstrated not to be clinically meaningful. (7) The patents of a growing number of biologic medicines have already expired or are due to expire, which has led to an increased interest in the development of biosimilars. (11) Original biologic The World Health Organization: A biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product. (8) The European Medicines Agency: A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorized original biological medicinal product (reference medicinal product). A biosimilar demonstrates similarity to the reference product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise. (9) The U.S. Food and Drug Administration: A biological Product that is highly similar to a U.S. licensed reference biological product notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity and potency of the product. (10) Biosimilars 10 Similar to snowflakes, biosimilars from different manufacturers differ from their originator biologic medicines and from each other.

15 How do biosimilars differ from the original innovator medicines? The active ingredient of a biosimilar is expected to closely resemble that of the original biologic. Unlike generic medicines (small molecules) where the active ingredient is required to be identical, the manufacturing process through which a biologic (large molecule) is made cannot be exactly duplicated by another manufacturer. (12) There are naturally occurring differences between an originator and biosimilar medicine: Biologic medicines are not made using a set of standard materials, but are developed using unique biological systems and living cells. As a result, the active ingredient is impossible to recreate exactly and the selected cell lines from which the biologic medicine originates are unique to each manufacturer. (13) The manufacturing process for biologic medicines requires dozens of steps involving hundreds of variables and is generally more complex than manufacturing processes for chemical drugs. Any variation in this complex process can affect a biologic product s stability, efficacy, safety and/ or immunogenicity. Unlike small molecule drugs, biologic medicines are produced in genetically-engineered living cells that are sustained in a highly-controlled environment. The protein produced by the cells will be influenced by individual cell characteristics as well as the environment and nutrients provided. The manufacturer has different processes that create distinctive characteristics in the product, which are specific to the manufacturer. This creates a unique relationship between a biologic s manufacturing process and the final product approved by regulators. (12) 11

16 The emerging role of biosimilars Countries around the world face a growing, aging population and an increase in chronic disease. (14) With expanding demand for good-quality healthcare comes the challenge of controlling healthcare expenditure. The regulated introduction of biosimilars into the market has been forecasted to increase access to much needed biologic medicines and reduce costs. (12) Over the next few years, we will continue to see a new generation of complex biosimilars being developed as numerous leading biologic medicines, worth an estimated $81 billion in global annual sales, will lose their patents by (15) Fusion proteins and monoclonal antibodies used in cancer and autoimmune diseases are expected to form a substantial proportion of this new line of biosimilars. (16) Based on experience gained by the European Medicines Agency (EMA) since the introduction of a regulatory mechanism for developing, reviewing and approving biosimilars in the European Agency, the EMA has updated its overarching guidance on the general principles of Biosimilar development, quality and nonclinical and clinical issues. In addition, class specific guidelines for growth hormones, monoclonal antibodies, GCSFs, recombinant follicle stimulating hormones, interferons, lowmolecular weight heparins and recombinant insulin products have been developed. The biologic medicines market is expected to grow to $ billion by 2015, with biosimilars a small but growing proportion at $2-2.5 billion. (17) The cost of developing biosimilars Biosimilar manufacturers must invest in clinical trials, manufacturing and post-approval safety monitoring programs similar to that of the original innovator companies. According to Sandoz, the cost of developing a generic small molecule is around $2-3 million, whereas biosimilars have been estimated to cost around $ million to reach approval, (18) largely due to the clinical studies and comparability exercise required to demonstrate biosimilarity. Because of this investment, cost savings achievable with biosimilars may not be as great as can be experienced with small molecule generics. (12) 12

17 Regulating biosimilars Regulating biosimilars

18 Regulating biosimilars The approach established for generic medicines is not suitable for development, evaluation and licensing of similar biotherapeutic products (SBPs) since biotherapeutics consist of relatively large and complex proteins that are difficult to characterize. (8) The World Health Organization

19 Regulating biosimilars In 2009 the World Health Organization developed a set of globally accepted standards to assure the safety, efficacy and quality of biosimilar medicines. These have been developed in the wake of increased interest in biosimilars (8) (25) by local regulatory authorities seeking to develop national standards. Reference product The reference product should be authorized in the country or region in question Quality All aspects of quality and heterogeneity should be assessed including head-to-head comparisons with the reference product Non-clinical data Should include pharmacodynamic, pharmacokinetic and comparative repeat-dose toxicity studies in a relevant species Clinical studies Required to demonstrate similar safety and efficacy. Immunogenicity should always be investigated in humans before authorization Pharmacovigilance and risk management A pharmacovigilance plan is required when an application is submitted and a risk management plan may be necessary in some cases World Health Organization (WHO) guidance on biosimilar development standards (25) 13

20 Approval pathways for biologic and biosimilar medicines Before marketing authorization is granted by regulators such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA)/European Commission (EC), originator companies and biosimilar manufacturers must submit robust data to demonstrate a product s efficacy and safety profile. Extensive analytical chemistry, manufacturing and control (CMC), non-clinical and clinical evidence will likely be required for the relevant (7) (26) therapeutic area. The approval pathway for a biosimilar medicine may be abridged in comparison to the originator product. Where there are approval pathways, in order to gain approval as a biosimilar, the manufacturer must provide substantial data to show that its product is sufficiently similar to the original product. This demonstration should be step wise in approach, firstly demonstrating similarity in physic-chemical inspection of the biosimilar to the reference medicinal product, then in non-clinical studies and finally in clinical trials. Overall, the biosimilar must demonstrate that it has no significant clinical differences to the reference product, but some limited variation is permitted. This is because biosimilar approval is based on a demonstration of similarity to a previously approved originator product rather than a de novo demonstration of safety and (7) (8) effectiveness. A decision on how extensive clinical data needs to be depends on each individual case. However, the amount of clinical efficacy and safety data is likely to be less for a biosimilar than the original biologic. (27) The 2012 draft FDA biosimilar guidance provides a list of factors that a sponsor should consider when assessing the similarity of its proposed products including: Expression system Manufacturing process Physicochemical properties Functional activities Receptor binding and immunochemical properties Impurities Characterization of the reference product and reference standards Characterization of the finished drug product Stability (10) 14

21 Due to the varied nature of biotechnology products and their potential risks, manufacturers of both biologic medicines and biosimilars are required to submit pharmacovigilance and risk management plans as part of their (8) (30) application. United States Originator Biosimilar Clinical S&E Clinical Pharm Non clinical Quality Clinical S&E Clinical Pharm Non clinical Quality European Union Originator Cross reference Biosimilar Clinical Non clinical Cross reference (extrapolation?) Clinical Non clinical Comparability data Quality Quality (28) (29) Not to scale. Comparison of originator and biosimilar marketing approvals process in the US and EU 15

22 Guiding the way for biosimilars development Europe The European Medicines Agency (EMA)/European Commission (EC) was the first major regulatory authority to implement a framework for the marketing authorization of biosimilars and has one of the most detailed and stringent guidelines for developing biosimilars. The guidelines outline an approach for comparing the proposed biosimilar to the original biologic, in terms of quality, safety and efficacy. (7) Product-specific guidelines for some biosimilar medicines, eg: recombinant erythropoietin, are provided by the EMA/Committee for Medicinal Products for Human Use (CHMP), outlining the data requirements and studies necessary to demonstrate comparability. The EMA/CHMP guidelines are widely considered the gold standard, with countries such as Australia, Canada, Japan, Korea and South Africa using (31) (32) them as a basis for their own regulations. 16

23 United States In March 2010, the U.S. biosimilar pathway was signed into law as part of the Affordable Care Act. In February 2012, the Food and Drug Administration (FDA) issued three draft guidance documents on biosimilar product development to assist industry in developing such products in the United States. What, if any, additional guidance FDA may issue, and when, is uncertain. (26) The FDA recommends a stepwise approach to demonstrate biosimilarity between a proposed medicine and the original biologic. The aim is to demonstrate no clinically meaningful difference in terms of safety, potency and purity. The guidance provides advice on the types of rigorous studies that should be undertaken by the manufacturer to address uncertainty about the proposed product. To comply with this approach, a sponsor should include:»» Structural analysis: Using state-of-the-art technology to display, for example, primary and higher order structures, post-translational modifications and intentional chemical modifications.»» Functional assays: Appropriate studies including: bioassays, biological assays, binding assays and enzyme kinetics. FDA recommends that any functional assays performed should be comparative so they can provide evidence of similarity or reveal differences...»» Animal data: Including toxicity studies, pharmacokinetic and pharmacodynamic measurements and immunogenicity studies.»» Human clinical studies: Including pharmacokinetic and pharmacodynamic measurements, immunogenicity results and safety and efficacy data. Studies should demonstrate that the proposed product has neither decreased nor increased activity compared to the reference product.»» The FDA has discretion to waive any requirement deemed unnecessary. (26) 17

24 The EMA The published EMA published the first the directive first directive relating relating to differences to differences in raw in materials raw materials or manufacturing or manufacturing processes processes between between biosimilar biosimilar and reference and reference products products Guideline Guideline development development EU EU EU EU Legal Legal Pathway Pathway Overarching Overarching Guidelines Guidelines Biosimilars are a relatively new, emerging market. Regulatory guidelines and standards are still being developed in some countries and they are constantly evolving as technology develops. Biosimilar regulations The EMA was the first Regulatory Agency to create biosimilar guidelines in 2005, swiftly followed by the first approved biosimilar products in As of December 2013, 16 biosimilar products were approved by the EMA. (17) These approvals cover five classes of Biosimilar: Recombinant erythropoietins (epoetin alfa, epoetin zeta) Recombinant granulocyte-colony stimulating factors (filgrastim) Recombinant human growth hormone (somatropin) Recombinant follicle stimulating hormone (follitropin alfa) Monoclonal antibodies (infliximab) The EMA The published EMA published the first the biosimilar first biosimilar regulatory regulatory approval approval pathway pathway for for the EU the member EU member states states AUS AUS As more As governments more governments develop develop biosimilar biosimilar pathways, pathways, the WHO the WHO and EU s and established EU s established guidelines guidelines will continue will continue to serve to serve as a as a template, template, as demonstrated as demonstrated by Australia s by Australia s unadulterated unadulterated adoption adoption of the of EU the guidelines EU guidelines Regulation has evolved rapidly with many countries establishing national guidelines based on the WHO and EMA/EC framework. Guidelines are helping to open up the development and approval of biosimilars worldwide, but definitions and terminology for biosimilarity vary, as does guidance on the original reference product for comparability studies and the scope of data required for marketing approval. (31) 18

25 Biosimilar Regulations Global guideline/regulation development TUR KOR CAN ARG USA (draft) EU Revised Guidelines* MYS TWN JPN SIN ZAF BRA MEX CUB COL (draft) EU Non-clinical and clinical Guidelines WHO SAU IRI JOR (draft) The WHO biosimilar guideline, aimed at providing a consistent scientific standard, is the reference for many newly developed biosimilar pathways IND THA (draft) PER WHO = World Health Organization * Update to the 2006 guidelines; in consultation until October 2013 Update to the 2006 guidelines; in consultation until November 2013 EU Update to Quality Issues Guideline Some emerging markets have developed their own regulatory pathways for biosimilars, hoping to meet a growing demand for biologic medicines. Singapore and Malaysia amended their guidelines mainly in accordance with the EMA guidelines, while Brazil and Cuba chose the WHO and Canadian guidelines as the basis for developing regulations. (31) India released official guidelines in June 2012, (33) before which around 20 biosimilars were approved for use within India under an ad hoc abbreviated process. (34) The WHO will continue to monitor progress. 19

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27 Pharmacovigilance, traceability & naming Pharmacovigilance, traceability & naming

28 Pharmacovigilance, traceability & naming It should be recognized that, by definition, similar biological medicinal products are not generic medicinal products, since it could be expected that there may be subtle differences between similar biological medicinal products from different manufacturers or compared with reference products, which may not be fully apparent until greater experience in their use has been established. Therefore, in order to support pharmacovigilance monitoring, the specific medicinal product given to the patient should be clearly identified. (36) The European Medicines Agency

29 Pharmacovigilance, traceability & naming Rigorous pharmacovigilance programs are needed to protect patients and ensure any adverse events are quickly detected, reported and attributed to the correct product and manufacturer. An important concern with all biologic medicines is the risk of an unwanted immune response, where the patient reacts against proteins in the medicine, limiting its efficacy or affecting its safety. (30) Healthcare systems must ensure all biologic medicines, including biosimilars, can be rapidly and accurately identified by national regulators, healthcare providers and patients. Safety monitoring and ongoing pharmacovigilance of medicines involves detection, assessment, understanding and prevention of adverse effects. As clinical trials involve a relatively small number of patients, potential adverse events may be unknown at the time of launch. (8) As with all medicines, the safety of biosimilars is monitored post marketing to assess and identify any long-term or rare adverse events. In Europe and the U.S., it is obligatory for the manufacturers of all biologic medicines to submit comprehensive pharmacovigilance and risk management plans when applying for approval. Potential pharmacovigilance programs may be a greater consideration for biosimilars, where the clinical safety and efficacy package is likely to be more limited at launch than that of the original biologic. (11) Risk management and postmarketing pharmacovigilance considerations should include: Pre and post-authorization comparative testing Regular tests to ensure that the manufacturing processes are the same, as biosimilarity and immunogenicity are dependent on this Risk management in case of adverse drug reactions (35) 21

30 Connecting worldwide adverse event reporting The WHO Program for International Drug Monitoring is based on the principle of international collaboration in the field of pharmacovigilance. Over 100 member nations have systems in place that encourage healthcare professionals to record and report adverse drug reactions in their patients. These reports are assessed locally and may lead to action within the country. Through membership of the WHO program, one country can know if similar reports are being made elsewhere. (37) Naming, tracking and tracing medicines The ability to track and trace all biologic medicines and biosimilars throughout the product lifecycle is critical to protecting patient safety. Physicians need accurate data on adverse events linked to treatments to ensure they are prescribing safe and effective medicines to patients. Scientific names are the foundation of product identification and therefore, accurate record keeping and attribution of adverse events. Currently, the International Nonproprietary Name (INN) for a new biosimilar may be the same as that of the original biologic medicine. In such a case, if only the INN, without a distinguishable name, is used when prescribing a biologic medicine, the treating physician may not know precisely which medicine a pharmacist gave the patient. Without distinguishable INNs, a reporter may be unable to immediately identify which medicine was given when a patient experiences an adverse event. It could then be unclear which medicine caused the adverse event, which may lead to a delay in establishing the root cause of the problem. (38) Regulations are being tightened to improve identification and traceability of biologic medicines. In August 2013 the Therapeutic Goods Administration in Australia issued guidance for the evaluation of biosimilars which includes guidance on distinguishable names for biosimilars. A similar naming program is recommended by the WHO and national regulatory bodies, such as the UK s Medicines and Healthcare products Regulatory Agency (MHRA). (40) 22

31 In 2012, the European Commission introduced new pharmacovigilance legislation (made up of a regulation and a directive), which was the biggest change to the regulation of human medicines in Europe since It is now a legal requirement for EU Member States to take all necessary measures to clearly identify the biological medicines that are prescribed, dispensed and sold in their country. Member States are empowered to impose these requirements on doctors, pharmacists and other healthcare professionals. (39) Amgen who develops both originator and biosimilar medicines believes prompt identification and resolution of product problems can be enabled by distinguishable, non-proprietary names for all biologics. This would help: WHO biologic naming policy In March 2013 WHO published minutes from the 55th INN Consultation meeting in October 2012 that outline the INN Committee s proposed options for adopting a policy of distinguishable non-proprietary names for biologic medicines. The minutes outline the WHO s objective to improve the current INN naming system to allow for global consistency and avoid inadvertent switching of products between patients, in a sustainable way. Amgen believes that healthcare systems globally must ensure all biologic medicines, including biosimilars, can be rapidly and accurately identified by national regulators, healthcare providers and patients. Facilitate prompt identification and resolution of product problems Facilitate manufacturer accountability Avoid incorrectly implying that the molecules are identical 23

32 Amgen supports policies to create distinguishable non-proprietary names for all of our biologic (innovator and biosimilar) medicines. Distinguishable names for all biologics will reduce the likelihood of inadvertent and inappropriate product switching and strengthen the accuracy of tracing via postmarketing safety monitoring systems. In 2012, the FDA embodied a patient safety-focused approach to naming biologic medicines. Two biologics approved through the FDA s 351(a) BLA pathway required distinguishable, non-proprietary names by adding a prefix with a hyphen: ziv-aflibercept (Zaltrap ) and tbo- filgrastim (GRANIX ). These biologics are related to previously approved products Regeneron s Eylea (aflibercept) and Amgen s Neupogen (41) (42) (filgrastim) respectively. The FDA concluded that the non-proprietary names for ziv- aflibercept and tbo-filgrastim should be different to their reference biologics, to avoid patients receiving the incorrect product and to reduce confusion among healthcare providers who may perceive them to be clinically the same, because they have the same non-proprietary name. (41) The FDA has also made the broader conclusion that the use of distinguishable non-proprietary names will help post-marketing safety monitoring, allowing better traceability of medicines in the case of an adverse event. In addition, the use of brand names alone was determined to be insufficient as brand names are often not used by healthcare professionals for prescribing, and many pharmacovigilance systems do not require them. (41) 24

33 Substitution and interchangeability Substitution and interchangeability

34 Substitution and interchangeability

35 Substitution and interchangeability Most generics are considered to be therapeutically equivalent (or interchangeable) with their reference products, (43) meaning the effects of both drugs are expected to be identical and that consequently it doesn t matter which drug the patient receives at any time. (13) In the U.S. drugs that are interchangeable are given an AB-rating by the FDA. (44) By contrast, although biosimilars are similar to their reference products, they are not clinically identical and there is scope for differences in effects in patients. (12) Substitution (sometimes called automatic substitution) is often permitted for generics that are considered to be interchangeable or clinically identical. The practicalities of substitution vary from country to country. In some countries, the doctor is encouraged to prescribe substitutable medicines by INN, leaving the pharmacist to decide which brand (generic or reference product) to dispense, whereas in other countries the pharmacist may dispense a generic of a substitutable medicine even where the doctor has prescribed the reference product by brand. (38) In all cases, however, the essential features of substitution are that: it is the pharmacist (and not the doctor) who decides which brand the patient receives; the doctor is not routinely informed of which brand the patient has received; the patient may potentially receive a different brand every time their medicine is dispensed. 25

36 Because generic medicines are therapeutically equivalent with their reference products, substitution does not usually have any negative impact on the patient or on public health. (13) However, biosimilars are not identical to their reference products so substitution of biosimilars with their reference biological products can result in problems, such as: A lack of traceability in the case of an adverse event. If substitution has taken place, the doctor may not know which brand was used and so only the INN can be included in the adverse event report. This lack of traceability may prevent identification of the particular product responsible for the adverse reaction. (12) Confusion in tracing the cause of a delayed adverse event. Some adverse reactions, including many immunogenic reactions such as pure red cell aplasia (PRCA), are delayed in onset and may develop only after several months of treatment. (45) (46) With substitution and frequent switching between products, a patient may receive several different products prior to an immunogenic reaction. This makes tracing the medicine responsible for the reaction very difficult, even when each different product can be identified by brand. (13) Regulatory authorities recognize the risks of substitution for biologic medicines, and in Europe the EMA states that for questions related to switching from one biologic medicine to another, patients should speak to their doctor and pharmacist. (9) Across the EU, decisions on prescribing practices such as substitution are made at the national level. In many countries (eg: Italy and Germany), biologic medicines are specifically excluded from lists of products suitable for substitution (15), whereas in other countries where substitution is permitted only for INN-only prescriptions (eg: Sweden and UK) doctors are urged to prescribe biologics by brand. (47) 26

37 Substitution and interchangeability at a glance U.S. FDA The FDA can designate a biosimilar as an interchangeable biologic when the following criteria are met: 1. The biologic product is biosimilar to the reference biologic product; and 2. It can be expected to produce the same clinical results as the reference product in any given patient; and 3. For a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch. (47) Europe EMA Decisions on substitution are made at national level. In many EU countries, automatic substitution of biologics is officially prohibited or not recommended. (9) WHO The WHO does not define standards on interchangeability for biologic medicines. It recognizes that a number of issues associated with the use of biologics should be defined by the national authorities. (8) 27

38 Canada does not support automatic substitution (25) The variation in global substitution guidelines 28

39 UK and Belgium recommend prescribing by brand name to avoid substitution (15) Spain and Germany prohibit automatic substitution (15) Ireland, Poland and Portugal have no clear position (49) In Japan, substitution should be avoided during the post-marketing surveillance period (25) As the biosimilar market expands and biosimilars become more complex, it is important to ensure clarity in prescribing regulations. 29

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