Biologics_and_Biosimilars_Overview-1.pdf

Biologics and biosimilars An overview

1Contents

An introduction to biotechnology ................................................................................ 3A brief history of medicine development ................................................................................... 4What are biologic medicines? ................................................................................................... 5How are biologic medicines developed? ................................................................................... 6The value of biotechnology ....................................................................................................... 8 What are biosimilar medicines? .............................................................................................. 10How do biosimilars differ from the original innovator medicines? .......................................... 11The emerging role of biosimilars ............................................................................................ 12The cost of developing biosimilars ......................................................................................... 12

Regulating biosimilars ...................................................................................................... 13Approval pathways for biologic and biosimilar medicines ...................................................... 14Biosimilar regulations ............................................................................................................. 18

Pharmacovigilance, traceability & naming ........................................................... 21Naming, tracking and tracing medicines ................................................................................. 22WHO biologic naming policy .................................................................................................. 23

Substitution and interchangeability ......................................................................... 25The variation in global substitution guidelines ....................................................................... 26

Manufacturing biologics ................................................................................................. 31The manufacturing process is unique to every manufacturer .................................................. 34Striving to ensure a consistent supply .................................................................................... 35

Glossary ................................................................................................................................... 37

Works cited ............................................................................................................................. 43

2014 Amgen Inc. All rights reserved. March 2014.

An introduction to biotechnology

An introduction to biotechnology

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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, Amgens 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.

3An 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)

A brief history of medicine developmentThe 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 sedative- hypnotic. 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.

5Acetylsalicylic 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 patients body and individual patient responses can depend on how a biologic is made.

6How 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 todays 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 cells 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 treatments safety, efficacy and/or shelf life, and to increase the risk of an unwanted immune response.

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7The 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.

The biologic is modified to ensure it functions as intended. Specific chemicals are added to control the function of the biologic.

The unique cell line is grown in bioreactors and carefully monitored. The biologic drug is then isolated and purified using sophisticated technology.

Translating high science: from laboratory to better patient care

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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.

Discover more on the manufacturing of biologic medicines by visiting the Amgen YouTube channel at youtube.com/user/Amgen

8The value of biotechnologyTodays 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, Alzheimers disease, cancer, cardiovascular disease and autoimmune disorders. (3)

A 2013 report (1) from the European Commission looking at Europes 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: http://ec.europa.eu/enterprise/ sectors/healthcare/files/docs/

biosimilars_report_en.pdf

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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)

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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)

Defining biosimilarsThe 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)

Original biologic

Similar to snowflakes, biosimilars from different manufacturers differ from their originator biologic medicines and from each other.

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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 products 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 biologics manufacturing process and the final product approved by regulators. (12)

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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 2020. (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 non-clinical and clinical issues. In addition, class specific guidelines for growth hormones, monoclonal antibodies, GCSFs, recombinant follicle stimulating hormones, interferons, low-molecular weight heparins and recombinant insulin products have been developed.

The biologic medicines market is expected to grow to $190-200 billion by 2015, with biosimilars a small but growing proportion at $2-2.5 billion. (17)

Biosimilar manufacturers must invest in clinical trials, manufac-turing 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 $75-250 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)

The cost of developing biosimilars

Regulating biosimilarsRegulating

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

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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 by local regulatory authorities seeking to develop national standards. (8) (25)

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)

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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 products efficacy and safety profile. Extensive analytical chemistry, manufacturing and control (CMC), non-clinical and clinical evidence will likely be required for the relevant therapeutic area. (7) (26)

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 effectiveness. (7) (8)

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)

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Not to scale. Comparison of originator and biosimilar marketing approvals process in the US and EU (28) (29)

Due to the varied nature of biotechnology products and their potential risks, manufacturers of both biologic medicines and

Quality

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biosimilars are required to submit pharmacovigilance and risk management plans as part of their application. (8) (30)

Cross reference

Cross reference(extrapolation?)

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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 them as a basis for their own regulations. (31) (32)

Guiding the way for biosimilars development

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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)

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The EMA published the first biosimilar regulatory approval pathway for

the EU member states

The EMA published the first directive relating to differences in raw materials or manufacturing processes between biosimilar and reference products

As more governments develop biosimilar pathways, the WHO and EUs established

guidelines will continue to serve as a template, as demonstrated by Australias

unadulterated adoption of the EU guidelines The WHO biosimilar guideline, aimed at providing a consistent scientific standard, is the reference for many

newly developed biosimilar pathways

Biosimilar regulationsThe EMA was the first Regulatory Agency to create biosimilar guidelines in 2005, swiftly followed by the first approved biosimilar products in 2006. 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)

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)

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.

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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.

Biosimilar RegulationsGlobal guideline/regulation development

WHO = World Health Organization * Update to the 2006 guidelines; in consultation until October 2013 Update to the 2006 guidelines; in consultation until November 2013

Pharmacovigilance, traceability & naming

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

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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 post-marketing 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)

Pharmacovigilance, traceability & naming

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Naming, tracking and tracing medicinesThe 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 Non-proprietary 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 UKs Medicines and Healthcare products Regulatory Agency (MHRA). (40)

Connecting worldwide adverse event reportingThe 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)

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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 1995.

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)

WHO biologic naming policyIn March 2013 WHO published minutes from the 55th INN Consultation meeting in October 2012 that outline the INN Committees proposed options for adopting a policy of distinguishable non-proprietary names for biologic medicines. The minutes outline the WHOs 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.

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:

Facilitate prompt identification and resolution of product problems

Facilitate manufacturer accountability Avoid incorrectly implying that the

molecules are identical

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Distinguishable names for all biologics will reduce the likelihood of inadvertent and inappropriate product switching and strengthen the accuracy of tracing via post-marketing safety monitoring systems.

In 2012, the FDA embodied a patient safety-focused approach to naming biologic medicines. Two biologics approved through the FDAs 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 Regenerons Eylea (aflibercept) and Amgens Neupogen (filgrastim) respectively. (41) (42)

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)

Amgen supports policies to create distinguishable non-proprietary names for all of our biologic (innovator and biosimilar) medicines.

Substitution and interchangeability


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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 doesnt 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.

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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)

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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:

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)

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)

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The variation in global substitution guidelines

Canada does not support automatic

substitution (25)

29

As the biosimilar market expands and biosimilars become more complex, it is important to ensure clarity in prescribing regulations.

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)

Manufacturing

biosimilars

Manufacturing biologics

A biologic medicine typically has around 250 in-process tests during manufacturing, compared with around 50 tests for a small molecule, to demonstrate safety and equivalent efficacy and to ensure safe, reliable production of therapies for patients. (13)

Man

ufac

turin

g bi

osim

ilars

31

Manufacturing biologics

Transforming complex therapeutic proteins from the laboratory into the large-scale production of safe and effective medicines requires highly specialized knowledge, processes, scientific standards and ongoing investment in quality.

The challenge in manufacturing biologic medicines is to control variability in this process to ensure compliance with quality standards so that every patient can be treated with a medicine of consistent quality, every time.

Manufacturing and quality control issues can impact patient safety and result in a loss of confidence in the

quality of biologics. They can also cause product recalls and drug shortages, which

can have profound effects on patients, treatment practices and overall

confidence in biologics.

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Good manufacturing practice for large molecules and small molecule medicines

Biologics have more GMP-requirements than small molecules

Purificationmultiple steps

Remove impuritiesHighly selective resinSpecific process conditions

Large moleculeProcess GMP requirements

(Good Manufacturing Practice)GMP requirements(Good Manufacturing Practice)

Small molecule

STEP 1

STEP 2

STEP 3

STEP 4

STEP 5

STEP 6

STEP 7

STEP 8

STEP 9

STEP 10

STEP 11

STEP 1

STEP 2

STEP 3

STEP 4

STEP 5

STEP 6

STEP 7

Room temperature

Process

Good Manufacturing Practice (GMP)Clean room & sterile equipment (prevention and control of potential bacterial contamination)

Virus segregation (prevention of potential virus contamination)

Segregation: Personnel and material

Harvest Remove cells from product Compress (solid dosage)Filling (liquid dosage)

Packaging & storage

Quality assurance& characterization

Stability

PressureFilling method(no human contact)

Cell culture Bioreactor media pH, temperature Mix Mixing speed, time

Cell expansion Weigh Weigh API& inactive chemicals

Cell line developmentDNA - Cloning TransfectionSelect "best" cell

ReactionAdd ingredientspressure, temperaure

Finishing LyophilizationSyringe-fill

Packaging & storageControlled temperatureEnsure no foamingNo particles


Highly precise methodsReference standards

Stability Testing to ensure product remains stable through shelf life

Testing to ensureproduct remains stablethrough shelf life

Filling Filling methodNo human contact

Easy methodsVirus inactivation/removal Dedicated steps to ensure viruskilling or reduction

Media pH, temp cell density

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GMP requirements(Good Manufacturing Practice)

Small molecule

STEP 1

STEP 2

STEP 3

STEP 4

STEP 5

STEP 6

STEP 7

Room temperature

Process

Compress (solid dosage)Filling (liquid dosage)

Packaging & storage


Stability

PressureFilling method(no human contact)

Mix Mixing speed, time

Weigh Weigh API& inactive chemicals

ReactionAdd ingredientspressure, temperaure

Testing to ensureproduct remains stablethrough shelf life

Easy methods

To manufacture safe and effective biologic and biosimilar medicines, more steps and more stringent processes for each step are required than for small molecule medicines.

Much like the way in which varieties of wine have common

characteristics but may vary in quality and taste depending upon region, vineyard,

growing conditions and so on, the characteristics of a protein may vary depending upon the

manufacturing process, including the growing conditions, for the protein. This sensitivity to

environmental factors in production is an inherent and important difference between

biologic medicines and traditional, chemical medicines.

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The manufacturing process is unique to every manufacturerThere is a strong relationship between the manufacturing processes of a biologic medicine and the characteristics of the final product. Due to proprietary knowledge, it is impossible for biosimilar manufacturers to precisely replicate the manufacturing process of the original biologic or the active ingredient of the protein product. (50)

The starting materials for most biologic medicines are genetically- modified cells. Once scientists design and select a cell that produces a medically valuable protein, they replicate it to create a cell line. Each cell line is unique to the manufacturer.

The major steps involved with the manufacture of biologic medicines include:

Modifying the selected cell

Growing a cell line from the original modified cell

Growing a large number of cells from the cell line

Cultivating them to produce the desired protein

Separating the protein from the cells

Purifying the collected protein

Cell expansion

Unit Operation

Cell production in bioreactors

Recover through filtration or centrifugation

Purification throughchromatopgraphy

Characterisation and stabilityPurified bulk drug

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Striving to ensure a consistent supplyProblems or interruptions to the manufacturing process of biologic medicines may not only affect quality and safety, but could also lead to delayed supplies and distribution of urgently needed medicines.

Along with regulators, manufacturers have a responsibility to ensure strategies are in place to minimize incidences of drug shortages and possible disruption. Manufacturer risk management is a continuous and holistic process designed to ensure a consistent supply. Strong governance can also help to integrate and manage supply risk across manufacturing plants and functions.

A consistent supply of high-quality products requires commitment, expertise and high-quality science.

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Amgen biosimilars Biosimilars are therapeutic alternatives for originator biologic medicines, and offer the potential for increased access and reduced cost.

Amgen is a pioneer in the field of biologic medicines. Science-based medicine and patient safety are fundamental to our values.

Amgen is uniquely equipped to leverage its leading position in biotechnology to produce biosimilars.

Amgen has six biosimilar molecules in development. We expect to launch the first biosimilar in 2017.

Glossary

Glossary

Glossary

37

Adverse event: The occurrence of an undesirable, unpleasant, or life-threatening reaction to a medicinal product.

Amino acid: One of several molecules that join together to form proteins. There are 20 common amino acids found in proteins.

Antibody (pl: antibodies): Antibodies (also known as immunoglobulins, abbreviated to Ig) are proteins that are found in blood or other bodily fluids. Antibodies are used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses.

Automatic substitution and substitution: The practice by which a product other than the one specified on the prescription is dispensed to the patient, without the prior informed consent of the treating physician. A variation of substitution is practiced in some countries where, if the physician prescribes by international non-proprietary name (INN), the pharmacist may dispense any product with the same active ingredient.

Biologic: A product derived from a living organism (from animal products or other biological sources) that is used in the diagnosis, prevention or treatment of disease. Examples of biologic medicines include recombinant proteins, allergy shots, vaccines and hematopoietic growth factors.

Glossary

38

Biologic License Application (BLA): An application submitted to the FDA seeking approval to market a biologic in the United States. The application contains a description of the trials and results, formulation, dosage, drug shelf life, manufacturing protocols, packaging information, etc. There are two different types of BLAs: full, stand-alone BLAs filed for approval of an originator biological product, and abbreviated BLAs filed for approval of a biosimilar product.

Biosimilar: Defining biosimilars

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 biological medicine that is developed to be similar to an existing biological medicine (the reference medicine). When approved, a biosimilars variability and any differences between it and its reference medicine will have been shown not to affect safety or effectiveness. (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)

Biotechnology: Technology based on biology, especially when used in agriculture, food science and medicine. The United Nations Convention on Biological Diversity defines biotechnology as any technological application that uses biological systems, living organisms, or derivatives thereof, to make or modify products or processes for specific use.

The Center for Drug Evaluation and Research (CDER): As part of the US Food and Drug Administration (FDA), CDER regulates over-the-counter and prescription drugs, including biologic therapeutics and generic drugs.

Chemical drug or chemical medicine: Refers to medicines that are manufactured without the involvement of living organisms.

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Chemistry, manufacturing and control (CMC): The CMC stage of product development focuses on how a drug was created. It should be demonstrated that the manufacturing method is proper and valid on a technological level and that quality is ensured through consistent production in accordance with the WHOs Good Manufacturing Procedure. Many aspects of both the active ingredients and the product as a whole will be reviewed, including characterization, control and stability.

Clinical trial: A test in which a drug or biologic is given to humans to establish how it works in the body and measure the nature and extent of any intended or unintended consequences.

Committee for Medicinal Products for Human Use (CHMP): The CHMP is the scientific committee responsible for formulating the opinion of the European Medicines Agency on any question concerning the evaluation of human medicinal products.

Comparability exercise: The head-to-head comparison of a biotherapeutic product with a licensed originator product, with the goal of establishing similarity in quality, safety, and efficacy. Products should be compared in the same study using the same procedures.

Data exclusivity: The period of time during which the clinical testing data that supported approval of the innovator medicine is protected, so that the prior approval of that originator based on those data may not be relied upon by another applicant to help approve a copy of that product.

DNA (Deoxyribonucleic Acid): DNA is a nucleic acid that contains the genetic information used in the development and functioning of all cellular organisms. Molecular systems interpret the sequence of these nucleic acids to produce proteins.

Efficacy: The desired impact that a medicine or treatment has when administered to a human.

European Medicines Agency (EMA): The EMA is responsible for evaluating marketing applications for medicinal products to be approved in the European Union.

Federal Food, Drug and Cosmetic Act: The federal law that regulates FDAs licensing of drugs but not the majority of biologic medicines. Instead, most biologic medicines are licensed by FDA under the Public Health Service Act. Once licensed by FDA, however, most of the other

40

provisions set forth in the Federal Food, Drug and Cosmetic Act concerning the marketing and other regulatory requirements are applicable to both drugs and biologic medicines.

U.S. Food and Drug Administration (FDA): The federal agency responsible for evaluating marketing applications and/or otherwise regulating the U.S. marketing of medicinal products, medical devices, food and cosmetics to be approved in the United States.

Fusion protein: A protein made from a fusion gene, which is created by joining parts of two different genes. Fusion genes may occur naturally in the body by transfer of DNA between chromosomes.

Generic medicine: A generic drug is the same as a brand name drug in dosage, safety, strength, how it is taken, quality, performance, and intended use. A generic drug product must contain the identical amounts of the same active ingredient(s) as the brand name product. Drug products evaluated as therapeutically equivalent can be expected to have equal effect and no difference when substituted for the brand name product.

Genetic engineering: The direct manipulation of an organisms genes by introducing, eliminating or rearranging specific genes using the methods of modern molecular biology, particularly those techniques referred to as recombinant DNA techniques. These techniques entail producing a piece of DNA (the recombinant DNA or synthetic rDNA construct) and introducing it into an organism so that new or altered traits can be imparted to that organism.

Guidance: A document issued by a regulatory agency to provide interpretation of a law that the regulatory agency is responsible for administering and/or enforcing and recommendations as to how to proceed with particular issues.

Immune system: The collection of mechanisms within the body that protect against disease by identifying and attacking foreign substances in the body.

Immunogenicity: The ability of a substance to trigger an immune response or reaction (eg: development of specific antibodies, T-cell response, allergic or anaphylactic reaction).

INN (International non-proprietary name): Allocated by the World Health Organization, an INN identifies pharmaceutical substances or active pharmaceutical ingredients. Each INN

41

is a unique name that is globally recognized and is public property. A non-proprietary name is also known as a generic name.

Innovator: Describes a company that invested considerably in research and development to develop a new medicine through innovative technologies, such as biotechnology.

Innovator product: Original approved biologic medicine.

Insulin: A hormone that affects metabolism and causes the bodys cells to take up glucose (sugar) from the blood and store it as glycogen in the liver and muscles.

Interchangeability: Where two products, that are judged to be similar, can be exchanged one with another without a significant risk of an adverse health outcome.

Large molecule drugs: Are therapeutic proteins also known as biologic medicines. Essentially, these are copies or optimized versions of endogenous human proteins.

Mechanism of action: The specific way by which a medicine achieves the desired outcome.

Medicines and Healthcare products Regulatory Agency (MHRA): UK government agency that is responsible for ensuring that medicines and medical devices work and are acceptably safe.

Monoclonal antibody: An antibody produced in the laboratory by a single clone of cells or a cell line and consisting of identical antibody molecules.

Originator: See above for innovator.

Originator product: See above for innovator product.

Pharmaceutical medicine: Also referred to as medicine or medication any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.

Pharmacodynamics: Studies performed to determine what a drug does to the body.

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Pharmacokinetics: Studies performed to determine what the body does to a drug.

Pharmacovigilance: Procedures that monitor the safety of medicines to detect, assess, understand, and prevent adverse effects or any other safety-related issue.

Preclinical trials (or studies): Tests that take place in a scientifically-controlled setting using cell culture and/or animals as disease models.

Proteins: Compounds (chains of amino acids) constituting the ultimate expression product of a gene. Created through the synthesis performed by ribosomes, proteins are the workhorses of living systems, causing chemical processes and changing as their environment changes.

Recombinant: In genetics, recombinant means DNA, proteins, cells, or organisms that are made by combining genetic material from two different sources. Recombinant substances are made in living cells and are being studied in the treatment of cancer and for many other uses.

Reference product: The innovator/originator product that the biosimilar product is intended to copy.

RNA: Ribonucleic acid is a nucleic acid which is central to the synthesis of proteins.

Similar biotherapeutic product (SBP): A biotherapeutic product which is similar in terms of quality, safety and efficacy to an already-licensed, reference biotherapeutic product.

Small molecule drugs: Chemical compounds that have a defined structure and characteristics.

Switching: The decision of a physician to change a patient from one drug to another drug with the same therapeutic intent, in order to optimise therapy and reduce adverse effects.

Vaccine: A biological preparation which is used to establish or improve immunity to a particular disease.

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Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 www.amgen.com

For more information on Amgen and biosimilars, visit: www.amgen.com/science/amgen_biosimilars

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