Biological. Medicines. A Focus on Biosimilar. Medicines

Transcription

1 TM Biological Medicines TM EuropaBio is the voice of the European biotech Industry. It represents the interests of the industry towards the European institutions so that legislation encourages and enables biotechnology companies in Europe to innovate and provide for our society s unmet needs. The European Association for BioIndustries was created in 1996 and represents 62 corporate and 7 associate members operating worldwide, 2 Bioregions and 19 national biotechnology associations representing some 1800 small and medium sized enterprises. Our corporate members are involved in a wide range of activities: human and animal healthcare, diagnostics, bio-informatics, chemicals, biofuels, crop production, agriculture, food and environmental products and services. EuropaBio also welcomes associate members such as international commercial, financial asset management and other service providing companies, regional biotechnology development organisations and scientific institutes. The common denominator among all our members is the use of biotechnology at any stage of research, development or manufacturing. A Focus on Biosimilar Medicines Avenue de l Armée, 6 B-1040 Brussels Tel: Printed on recycled paper

2 EXECUTIVE SUMMARY Biotechnology has enabled the discovery of treatments for a variety of serious diseases. Worldwide, over 350 million patients have benefited from approved medicines manufactured through biotechnology. Currently, over 650 new biological medicines and vaccines are be developed to treat more than 100 diseases. As the exclusive rights for these biological medicines expire, similar biological medicines, or biosimilars, are being developed, with some already available on European markets. Biological medicines are comprised of proteins and other substances that are often naturally produced in the human body. In healthcare, biotechnology is being used in three primary areas: therapeutic medicines, vaccines and diagnostics. When compared to chemical medicines, biological medicines are generally more complex and usually much larger in size than chemical medicines. The complexity is predominantly due to the manufacturing process for biological medicine, as they are developed in living system the exact characteristics and properties are highly dependent on the manufacturing process. Chemical medicines can be approved either by national medicines authorities or by the centralised procedure carried out by the European Medicines Agency (EMA), however all biological medicines products must follow the centralised procedure for approval. Due to the composition and large molecule size of biological medicines, they have the inherent potential to induce (unwanted) immune reactions. Therefore, in order to identify unwanted immune reactions, and for post regulatory approval commitments, treating physicians should state the brand name and batch number, as opposed to the International Non-Proprietary Name (INN) when prescribing. Furthermore, due to the unique nature of biosimilars, there should not be automatic substitution of the reference product, this decision should be left with the treating physician. Generics and Biosimilars have an important role to play in fostering competition in the market place, and thereby contributing to the sustainability of healthcare budgets. However, as the research and development costs of biosimilars are much higher than generics, suitable pricing and reimbursement environments are needed to foster the development of new products. Furthermore, adequate intellectual property protection is vital to ensure that companies are able to fund research and development of biological medicines, and therefore develop and produce more potential treatments. Upon expiry of such protection, biosimilar products (unlike chemical generics these are not exact copies, as they are made in living systems the exact characteristics are dependent upon the manufacturing process) can enter the market to compete with the original reference product. So far the European Union has approved 7 biosimilars, across 3 product classes. In the United States, the Biologics Price Competition and Innovation Act, signed into law in March 2010, created a statutory framework for the approval of biosimilars by the Food and Drug Administration (FDA). Over the last two years, the biosimilar market shares have steadily increased in most countries. In several European countries, biosimilars now have a higher volume market share than the reference product, and this trend appears to be accelerating. Biological Medicines A Focus on Biosimilar Medicines

3 TABLE OF CONTENTS INTRODUCTION 02 INTRODUCTION 03 HEALTHCARE BIOTECHNOLOGY: INTRODUCTION TO THE SCIENCE 03 What are biological medicines and how do they work? 03 How do biological medicines differ from chemical medicines? Key differentiating factors. 03 How are biological medicines manufactured? 05 Intellectual property for biotech medicines 06 BIOLOGICAL MEDICINES CURRENT ISSUES 06 Naming, Pharmacovigilance and Risk Management Plans 07 Interchangeability 07 Substitution 08 Impact on healthcare budget and pricing 08 The regulation of biologicals in Europe, including biosimilars 09 THE MARKET FOR BIOSIMILARS 09 Which biosimilars are currently available in Europe? 09 What about the rest of the world? 09 What does the entry of biosimilars in the market mean to originator products? 10 THE POTENTIAL IMPACT OF BIOSIMILARS 10 For patients 10 For healthcare professionals 10 For payers 11 GLOSSARY OF KEY TERMS 12 REFERENCES Biotechnology has enabled the discovery of treatments for a variety of serious diseases. Worldwide, more than 350 million patients have already benefited from approved medicines manufactured through biotechnology. These medicines help treat or prevent many rare and severe diseases including cancers, heart attacks, stroke, multiple sclerosis, diabetes, rheumatoid arthritis and autoimmune diseases. In addition, over 650 new biological medicines and vaccines are currently being developed to treat more than 100 diseases 1. As the exclusive rights (patents and other data protection) for certain biological medicines expire, similar biological medicines, or "biosimilars", are being developed. Several biosimilars are already available on European markets. This document is intended to explain the complexities and specificities of biological medicines, including biosimilar medicines. Biological medicines are comprised of proteins and other substances that are often naturally produced in the human body. 1. "Engaging with the global monoclonal antibody and biologicals markets" Jean-Claude Muller; Special Advisor, Innovation and International Relationships; Formerly Senior Vice President, R&D Prospective and Strategic Initiatives; Sanofi-Aventis 01 02

4 HEALTHCARE BIOTECHNOLOGY: INTRODUCTION TO THE SCIENCE What are biological medicines and how do they work? Biological medicines are comprised of proteins (such as growth hormone, insulin, erythropoietin, enzymes, and antibodies) and other substances that are often naturally produced in the human body. Biotechnology uses the great potential in living systems (plant or animal cells, bacteria, viruses and yeasts) and modern technologies to produce biological medicines to treat diseases and genetic disorders in humans. Biotechnology in healthcare is currently being used in three primary areas: therapeutic medicines (also including advanced therapies such as cell and gene therapy), vaccines and diagnostics. In this brochure, we use the term biological medicine or biotech medicine as a synonym for therapeutic proteins and monoclonal antibodies. How are biological medicines manufactured? Manufacturing biological medicines is more complex than the production of chemical pharmaceuticals. There are a number of reasons for this, including the nature of the starting material and How do biological medicines differ from chemical medicines? Key differentiating factors. Biological medicines are generally more complex and usually much larger in size than chemical medicines, which are produced by chemical synthesis. As biological medicines are made in living systems, their exact characteristics and properties are highly dependent on the manufacturing process. Therefore, manufacturing and precise characterisation tends to be more difficult when compared to chemical medicines, the ingredients of which are more easily identifiable and can be exactly reproduced. Biological medicines may have higher variability. As biological medicines are produced by living systems, such as cell lines, they may show a higher variability in their structure and characteristics than traditional pharmaceuticals produced by chemical synthesis, unless processes are carefully controlled. This variability is highly dependent on the master cell line selected and used by each manufacturer, as well as materials and manufacturing conditions used throughout the production process. Biological medicines are more complex. Because biological medicines are generally far more complex than chemical pharmaceuticals, modifications to their manufacturing process need to be evaluated carefully, to ensure the drug's efficacy and tolerability are not compromised. Furthermore, the complexity of biological medicines makes their analytical characterisation more challenging than that of small molecules (chemically synthesised). Small changes in the manufacturing processes of biological medicines can lead to major changes in the products, as these changes could alter their tri-dimensional structure and their safety and efficacy profile. Biological medicines have the potential to provoke immune reactions. Biological medicines have the potential to be recognised by the body as foreign and therefore have the inherent potential to induce (unwanted) immune reactions, due to their composition and large molecular size. Chemical medicines, on the other hand, are usually too small to be recognised by the immune system and are of a different composition. The potential to induce an immune reaction in the body (immunogenicity) is a double-edged sword for biological medicines. Vaccines specifically exploit their immunogenic potential by provoking an immune response that recognises and "fights off" an "invader" substance. However, for some medicines based on the very high level of precision required. Most biological medicines are made using a geneticallymodified cell construct or cell line. Each biotech company has its own master cell bank producing unique cell lines replicated for manufacturing and develops its own proprietary (unique) manufacturing processes. The production of biological medicines involves processes such as fermentation and purification. Even very minor variations to these manufacturing processes, for example in temperature, can result in significant changes in the physical and clinical properties of the biological medicine produced. It is therefore vital to control precisely the manufacturing processes and the environment inside a production facility, to obtain consistent results and to guarantee the safety and efficacy of the end product. Production also requires a high level of monitoring and quality testing: typically around 250 in-process tests are conducted for a biological medicine, compared to around 50 tests for a traditional chemical medicine. proteins, stimulating an immune response is regarded as undesirable (with the notable exception of vaccines where this immune response is the expected effect). Most of the immune responses that occur are mild and do not have negative effects on the patient. However in rare cases, unwanted immune reactions can lead to severe and detrimental effects on the health of a patient. One example is the appearance of so-called "neutralising" antibodies that can make the therapeutic protein in the medicine ineffective. Neutralising antibodies can be of particular concern for biological medicines that resemble the patient's own proteins (to replace insufficient substance levels in the patient), as they can trigger the body to fight off the protein injected in the medicinal product and, in rare cases, any remaining protein produced by the patient's own body. This immunogenic reaction can take years to develop and can happen at any time during treatment (after short-, medium and long-term use). This reaction can persist for years after the biological medicine has stopped being administered to the patient. Therefore, immunogenicity assessment through clinical studies plays a major role in the development of biological medicines. Biological medicines are typically administered via injections or infusions. A molecule of a biological medicine is typically a protein made of one or several chains of several hundred amino acids within a complex three-dimensional structure. Because proteins are digested when taken orally, typically biological medicines must be administered by injection. Medicines based on small molecules (traditional pharmaceuticals) usually come in tablet or capsule form. Biological medicines usually need special transport and storage conditions. Biological material generally degrades quickly when handled inappropriately, particularly if they are subject to high temperature. Therefore, biological medicines usually need to be stored in a refrigerator and should only be handled under specific conditions. the complexity of biological medicines makes their analytical characterisation more challenging than that of small molecules

5 Biological Medicines BIOLOGICAL MEDICINES CURRENT ISSUES Naming,Pharmacovigilance and Risk Management Plans Biological medicines made by unrelated manufacturers after the expiry of intellectual property protection are not exact copies of the original biological medicines. Each active ingredient in a medicine has an International Non-proprietary Name (INN for example acetylsalicylic acid is the INN of the active ingredient in aspirin ) as well as a brand name. Intellectual property for biotech medicines Innovative medicines benefit from a certain period of intellectual property protection, via patents and other exclusive rights, such as data protection. Patent rights give the patent holder (often, but not always, the manufacturer) the right to prevent others from manufacturing, selling, using and importing the product during a limited period of time. A patent also grants the right to prevent others from using a specific process, or selling a product made by that process, during a limited period of time. Patents benefit both companies and society at large, as they enable important scientific information to be made publicly available, which might otherwise remain hidden. Patents also make investments in biotechnology R&D more attractive, which in turn leads to more innovation, and therefore more potential treatments. Data exclusivity grants a period of time after Marketing Authorisation, during which competitors are not allowed to enter the market with a followon product (i.e. generic or biosimilar). The follow-on product generally uses an abbreviated regulatory approval procedure. Intellectual property protection is vital for companies that develop and manufacture new medicines, as it enables them to recoup their investments and further invest in the research and development of new medicines. As such, the provision of an adequate intellectual property protection system is critical to ensure a steady stream of new medical advances, to great public benefit. Small molecule medicines, produced by chemical synthesis, can generally be replicated fairly easily by unrelated manufacturers after the expiry of intellectual property protection. Such copies of the original chemical medicines are called "generics". In contrast, biological medicines made by unrelated manufacturers after the expiry of intellectual property protection are not exact copies of the original biological medicines because they are made in living systems and their exact characteristics and properties are highly dependent on the manufacturing process. These new versions of biological medicines are called "similar biological medicinal products" or "biosimilars". In both cases, the originator product is called the "reference product". In the case of biological, INN can be either identical or different for similar products made by different manufacturers. For instance, the INN for recombinant growth hormone, is the same (somatropin) for all growth hormones made by different originators or biosimilar companies. By contrast, the INN for recombinant human erythropoietin is different for different originator products (epoetin alpha, beta or theta) and can be identical or different for biosimilar products (epoetin alpha or zeta). European Medicine Agency (EMA) guidance indicates standard reporting of brand name, manufacturer s name and batch number for all adverse events caused by biological medicines. Therefore, biological medicines should only be prescribed by their brand name, and not by their INN, which identifies medicines by their active pharmaceutical ingredients. Despite the fact that it may be possible for active ingredients in different biological medicines to share the same INN, patients may experience different immunogenic reactions with different products. Additionally, not all biological medicinal products have the same indications, administration schedules, administration systems or side effect profiles. The need for correct and precise identification is strengthened by the need to have robust pharmacovigilance carried out after marketing authorisation. Due to the variability of biologicals, the correct product identification in case of adverse events is important. Biosimilars may be approved by regulatory authorities on the basis of demonstrated comparability to the reference product, a limited clinical database and often data on the main indication only. Holders of marketing authorisations for biological medicines, reference products as well as biosimilars, may have post-approval commitments defined in risk management plans, to characterise safety profiles more fully, to establish long-term safety. As already discussed, biologicals have the inherent potential to induce (unwanted) immune reactions. Immune reactions may take years to develop, therefore biologicals are usually treated differently to chemical medicines by regulatory authorities. Whilst much is now known about the features of biological medicinal products that cause immune reactions (for example high content of host cell proteins and certain routes of administration), it is not currently possible to accurately predict immunogenicity in humans. Immunogenicity is however assessed through nonclinical assessment in animals, and in humans within the scope of clinical trials and thorough post-marketing surveillance. At the time of approval (for both originator and biosimilar biologicals), information on the safety of the medicinal product is relatively limited for several reasons, including a limited number of patients in clinical trials, limited time of exposure to the medication and, usually, a rather strictly defined patient population. The specific characteristics of biologicals are taken into account by the European legislator and regulator: 1. The updated European legislation on pharmacovigilance, due to be implemented mid-2012, establishes that Member States must make sure that all appropriate measures are taken to identify when biological medicinal products are prescribed, dispensed, or sold in their territory which is the subject of a suspected adverse reaction report, with due regard to the name of medicinal product ( ) and the batch number. 2. All biological medicines, originator and biosimilar products, need to have a "Risk Management Plan" in place. This Risk Management Plan defines a set of "pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicinal products, and the assessment of the effectiveness of these interventions". Assessment of the immunogenicity is a key measure in the Risk Management Plan of any biological medicine

6 Interchangeability Interchangeability of medicinal products refers to the situation where one product can be interchanged for another equivalent product in a clinical setting, without the risk of a negative health outcome. In order to gain a marketing authorisation in Europe, biosimilar applicants need to demonstrate similarity to the reference product. Assessments of interchangeability and substitutability are not part of the scientific evaluation by the (EMA) and therefore, no conclusion on interchangeability or automatic substitution can be made based on the grant of a market authorisation. Decisions on automatic substitution lie within the responsibility of the Member States. Unless products are designated as substitutable (see below), the decision as to which product should be used and whether treatment should or could be changed to another product lies with the treating physician. Substitution Automatic substitution (or generic substitution) is when a pharmacist substitutes a generic medicine for the brand name version of the same active ingredient, with no obligation to inform the treating physician. Some countries make generic substitution mandatory under certain conditions, for example where the doctor prescribes by INN. Generic substitution is often linked to reimbursement, as some health insurance schemes will only reimburse the patient for the cost of the generic version of a product. The result of this can be that a patient who refuses the generic version and insists on the original product may be liable to pay the difference in cost. Generic versions of chemical pharmaceuticals that have demonstrated their bioequivalence may generally be substituted with no risk to patient safety. However, the EMA has specifically stated that "since biosimilars and biological reference products are not identical, the decision to treat a patient with a reference product or biosimilar medicine should be taken following the opinion of a qualified health professional". The physician s involvement is particularly relevant, as not all biological medicines will necessarily have the same indications, administration schedules, administration devices or side effect profiles. Furthermore, if automatic substitution were to take place, it could confound pharmacovigilance when adverse reactions occur, especially immune reactions, as it is more difficult to evaluate which product is responsible for the reaction if the product has been repeatedly switched during treatment. A number of countries have either established legislative measures to prohibit the automatic substitution of biological medicines or have given regulatory advice on the use of biologics (including prescription by brand names). Based on the above, countries that currently allow automatic substitution of biologicals should take the necessary measures to stop this practice in the absence of data that demonstrate interchangeability. Therefore, any change of treatment with a biological medicine should currently only be made under close medical supervision by the physician, with the patient s consent. Impact on Healthcare Budget and Pricing Generics and biosimilars have an important role to play to foster competition in the marketplace, contributing thereby to the sustainability of healthcare budgets. Price reductions for biosimilars are generally not as those for generic medicines for a number of reasons. Firstly, biological medicines, including biosimilars, are generally more complex and costly to produce and develop. Secondly, the regulatory approval requirements and post-marketing surveillance for biosimilars are more rigorous than for generic medicines, thus adding a further layer of cost to developing a biosimilar (e.g. unlike generics, biosimilars usually require independent non-clinical and clinical trials to be undertaken). Therefore, R&D costs required for the approval of a biosimilar - ranging on average from USD 75 to USD 250 (approximately 50 to 170 million) 2 - are much higher than those for a generic. The exact price level of a biosimilar will depend on a number of factors, namely the pricing and reimbursement environment of each country, competitiveness of the market and the desire to encourage the future development of new products. Currently the number of biosimilars is low partly because only a few biological medicines have lost their market exclusivity. Potential savings, due to their lower list prices, are therefore limited as the products compete in market segments that only represent a small portion of total healthcare expenditure. The regulation of biological in Europe, including biosimilars Depending on the disease category, chemical medicines can be approved either by the national medicines authorities of the individual EU Member States or by the "centralised procedure" for approval carried out by the European Medicines Agency (EMA). In contrast, all new biological medicinal products, including biosimilars, have to follow the centralised procedure. Applications submitted to the EMA are assessed by its Committee for Human Medicinal Products (CHMP), which can give a positive or negative opinion. Upon receipt of a positive opinion from the EMA, the European Commission issues a marketing authorisation, which is valid for all EU Member States. Since 2003, the European Union has created a legal and regulatory pathway to enable the development and marketing of biosimilar medicines. Directives 2003/63/EC and 2004/27/EC created the legislative route and the EMA has subsequently developed a number of regulatory guidelines concerning the data required for the approval of a biosimilar. The EMA defines biosimilars in "Questions and Answers on biosimilar medicines" as: Besides the "overarching" general guidelines on biosimilars, the EMA has also developed guidelines on quality, non-clinical and clinical issues, as well as product-specific guidelines annexes (for example insulin, epoetin, somatropin, granulocytestimulating growth factor, interferon-alfa and low-molecular weight heparin). At the time of publication of this document, further guidelines are being prepared, including guidelines on follicle stimulation hormone, interferon-beta and monoclonal antibodies. The EMA's "overarching" guidelines on biosimilars specifically state that biosimilar products are "by definition" not generics, and that the generic approach to approval "is scientifically not appropriate" for biosimilars. 2. Industry average source: Sandoz internal estimates. Conversion in done in July 2011 "A biosimilar medicine is a medicine which is similar to a biological medicine that has already been authorised (the 'biological reference medicine'). The active substance of a biosimilar medicine is similar to the one of the biological reference medicine. Biosimilar and biological reference medicines are used in general at the same dose to treat the same disease. Since biosimilar and biological reference medicines are similar but not identical, the decision to treat a patient with a reference or a biosimilar medicine should be taken following the opinion of a qualified healthcare professional. The name, appearance and packaging of a biosimilar medicine differ to those of the biological reference medicine." Furthermore, the EMA Questions and Answers document states that the "legislation defines the studies that need to be carried out to show that the biosimilar medicine is similar and as safe and effective as the biological reference medicine". To this end, the biosimilar approval pathway requires the manufacturer to demonstrate similarity with the reference product for quality, safety and efficacy. Specifically, the biosimilar must demonstrate that it has no significant clinical differences to the reference product. Biosimilar manufacturers must provide all of the non-clinical, pre-clinical and clinical data required to demonstrate the similarity of their product to the reference product, without the need to repeat unnecessary tests and trials

7 THE MARKET FOR BIOSIMILARS THE POTENTIAL IMPACT OF BIOSIMILARS Which biosimilars are currently available in Europe? So far, the European Union has approved 7 biosimilars, across 3 product classes: human growth hormones, erythropoietins and granulocyte colony stimulating factors. Name Abseamed Binocrit Biograstim Epoetin alfa Hexal Filgrastim Hexal Filgrastim ratiopharm Nivestim Omnitrope Ratiograstim Retacrit Silapo Tevagrastim Valtropin Zarzio What about the rest of the world? Active substance epoetin alfa epoetin alfa epoetin alfa somatropin epoetin zeta epoetin zeta somatropin In the United States, the Biologics Price Competition and Innovation Act, signed into law in March 2010, created a statutory framework for the approval of biosimilars by the Food and Drug Administration (FDA). Almost all guidelines that have either been passed or are being discussed in other parts of the world (for example Australia, Japan, Korea, Malaysia, Mexico, Switzerland, South Africa, Taiwan and Turkey) largely correspond to the European body of regulations for biosimilars. Lastly, the World Health Organisation s guideline for biosimilars fundamentally follows the EU principles and is meant to serve as a basis for countries to develop their own biosimilar legislation. Therapeutic area Kidney Failure, Chronic Anemia Cancer Kidney Failure, Chronic Anemia Hematopoietic Stem Cell Transplantation Neutropenia Cancer Kidney Failure, Chronic Anemia Cancer Neutropenia Cancer Hematopoietic Stem Cell Transplantation Neutropenia Hematopoietic Stem Cell Transplantation Cancer Hematopoietic Stem Cell Transplantation Cancer Neutropenia Turner Syndrome Dwarfism, Pituitary Prader- Willi Syndrome Neutropenia Cancer Hematopoietic Stem Cell Transplantation Cancer Anemia Kidney Failure, Chronic Blood Transfusion, Autologous Anemia Blood Transfusion, Autologous Cancer Kidney Failure, Chronic Neutropenia Cancer Hematopoietic Stem Cell Transplantation Dwarfism, Pituitary Turner Syndrome Cancer Hematopoietic Stem Cell Transplantation Neutropenia What does the entry of biosimilars in the market mean to originator products? Market success for all medicines, including biological medicines and biosimilars, in the EU depends upon a number of factors, including pricing and reimbursement and physician and patient expectations. Biosimilar products compete with originator biologicals, which already compete with other originator products made by different biopharmaceutical companies. Experience so far indicates that biosimilar uptake varies by product class and country. Naturally, biosimilars are versions of older biological medicines that have lost IP protection. Continued innovation Date of authorisation 28/08/ /08/ /09/ /08/ /02/ /09/ /06/ /04/ /09/ /12/ /12/ /09/ /04/ /02/2009 Status Source: (June 2011) has often led to secondgeneration biological medicines providing increased therapeutic benefits to patients. This means that the biosimilar products mainly compete with older biological medicines, with which they are comparable, rather than with the most recent innovative treatments. Over the last 2 years, the biosimilar market shares have steadily increased in most countries. In several European countries, biosimilars now have a higher volume market share than the reference products, and this trend appears to be accelerating. For patients Patients need and deserve to be fully informed about any medical treatment that they are receiving. If a physician chooses to prescribe a medicine to a patient, the patient should be involved in that decision, meaning that the patient understands why the choice has been made as well the specific therapeutic needs of the patient must always be taken into account. as what it will mean for his or her treatment. Patients may not be completely aware of the complexities of biologicals, including biosimilars, and the implications of using them. This includes the potential of different products to provoke different immunogenic reactions in the patient. It is important that patients are not obliged to "switch" their treatment from one biological to another purely on cost grounds, the specific therapeutic needs of the patient must always be taken into account. According to a survey by the International Alliance of Patients' Organizations (IAPO), the key interests of patients with regards to biosimilars are: Cost and the potential to increase access to biological treatments; Safety and efficacy; Patient information and decision-making; Regulatory process; and Interchangeability. Therefore, it is very important that the label and other product information relating to the biosimilar reflect the specific characteristics (such as reference product, potential side effects etc). For healthcare professionals Healthcare professionals need to understand the EMA approval process for biosimilars and be aware of the scientific data underlying their approval (in particular the abridged clinical data requirements, which can allow the extrapolation of indications). For physicians too, it is very important that the label and other product information relating to the biosimilar reflect the specific characteristics (such as reference product, potential side effects, etc). The summary of product information on biosimilars should also list the available data in order to show which applications were substantiated by studies and which were derived from the biological medicine of the original manufacturer without separate data via extrapolation. Furthermore, healthcare professionals must be aware that the interchangeability between the biosimilar and its reference product has not been evaluated by the regulatory authority. Physicians should not be obliged to prescribe a certain medication purely on the grounds of cost, but should be allowed to exercise appropriate clinical judgment. With regards to patients, it is very important for healthcare professionals that the label and other product information of the biosimilar reflect its specific characteristics (clinical data, reference product, etc.). For payers Payers, such as national health systems and health insurance funds, are interested in the costsaving potential of biosimilars. Biological medicines have brought great benefit to patients, often treating so far untreatable or insufficiently treatable, severe diseases. Biosimilars offer opportunities for savings upon loss of IP protection for the originator products. Biosimilars have brought enhanced competition to prices of biological medicines, which in turn have resulted in significant price decreases in the majority of markets. It is important however that physicians and patients retain the flexibility to make informed decisions about the different treatment options. It is important that payers understand that, due to the precautionary principle, automatic substitution for biologics should not occur and the choice to use any biological product should remain in the hands of the treating physician. Any future decisions need to be based on appropriate data. The physician must be allowed to exercise appropriate clinical judgment to select the best available treatment for the individual patient, and such choices should never be mandated purely on the basis of product prices

8 GLOSSARY OF KEY TERMS REFERENCES Advanced therapies: New and emerging therapies, including cell, gene and tissue therapies Adverse event: The occurrence of an undesirable, unpleasant or lifethreatening reaction to a medicinal product Amino acid: Building block of 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 neutralise foreign objects, such as bacteria and viruses Autoimmune disease: A disease caused by the body producing an excessive immune response against its own tissues. Thereby, the immune system ceases to recognise one or more of the body's normal constituents as "self" and will create auto-antibodies that attack its own cells, tissues, and/or organs. Inflammation and tissue damage are common symptoms of autoimmune diseases Automatic 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 decide to dispense any product with the same active ingredient Biological/biotech medicine: A medicinal product or a vaccine that consists of, or has been produced by the use of, living organisms. Often recombinant DNA (a form of DNA that does not exist naturally and which combines DNA sequences that would not normally occur together in order to establish new functions) forms the basis for biotechnologically manufactured products. Examples include therapeutic proteins such as antibodies, insulins or interleukins; but also vaccines, nucleic acid or tissues and cells. For the purpose of this document, the term biological/biotech medicine refers to therapeutic proteins Biosimilar: A similar, but not identical, version of an existing biological medicine made following the patent expiry of the original product (must be made by a different manufacturer) Biotechnology: Any technological application that uses biological systems, living organisms, or derivatives thereof, to make or modify products or processes for specific use Cell line (including master cell line): A well-established, living system of cultured (grown in a laboratory) cells that will continue to grow and produce new cells indefinitely, so long as the cells receive nourishment and have space to propagate Extrapolation: Extending the findings from one set of conditions to another, such as extending and applying the data from clinical studies regarding one medical condition to another medical condition or extending data from clinical studies in adults to children Generic (medicine): A copy of an existing (chemical) medicine, which is bioequivalent to the original medicine, but which may be made by a different firm after patent expiry of the originator product Immune system: The collection of mechanisms within the body that protect against disease by identifying and killing pathogens (e.g. viruses and bacteria) and tumour cells Immunogenic: The potential to cause immune reactions Indication: The medical condition, disorder or disease for which a certain test, medication, procedure, or surgery is used. Such tests and medications are often subject to official (regulatory) approval. Most countries and jurisdictions have a licensing body whose duty it is to determine whether to approve a drug for a specific indication, based on the relative safety of the drug and its efficacy for the particular indication (use) being investigated INN: International Non-proprietary Name Interchangeability: Where two products can be exchanged one with another without a significant risk of an adverse health outcome Marketing authorisation: The permission granted by a regulatory authority to a company to market a medicinal product in accordance with the conditions described in the label, following the company's submission of required documentation and data relating to testing and clinical trials of the product Molecule: The smallest particle of a substance that has all of the physical and chemical properties of that substance. Molecules are made up of one or more atoms. If they contain more than one atom, the atoms can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins, can be made up of many thousands of atoms Molecular: Of a molecule Nucleic acid: A macromolecule (i.e. a very large molecule) composed of chains of monomeric (having a single component) nucleotides, which are molecules that, when joined together, make up the structural units of RNA and DNA. In biochemistry these molecules carry genetic information or form structures within cells Patent: A patent is a set of exclusive rights granted by a state (national government) to an inventor or their assignee for a limited period of time in exchange for public disclosure of an invention. Typically, however, a patent application must include one or more claims defining the invention which must be new, non-obvious, and useful or industrially applicable Pharmacovigilance: Safety control procedures to which medicines are subject before, during and after their approval by regulatory authorities Protein: Large organic compounds made of amino acids. Proteins are essential parts of organisms and participate in virtually every process within cells Reference product: The original product to which a biosimilar or generic drug refers in its application for marketing approval Vaccine: A biological preparation which is used to establish or improve immunity to a particular disease Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. Article 10. Available at: CELEX:32001L0083:en:NOT Brochure - Biosimilar medicinal products; 2001;. Available at: library/brochure/2011/03/wc pdf Questions and Answers on biosimilar medicines (similar biological medicinal products); Oct 2008;. Available at: library/medicine_qa/2009/12/wc pdf All the following s guidelines are available at: special_topics/document_listing/document_listing_ jsp &murl=menus/special_topics/special_topics.jsp&mid=wc0b01 ac bf0 Guidelines on Similar Biological Medicinal Products containing Biotechnology-Derived Proteins as Active Substance: Non-Clinical and Clinical Issues; Feb 2006; European Medicines Agency Concept paper on the Revision of the guideline on similar biological medicinal products containing biotechnologyderived proteins as active substance: quality Issues; Feb 2011; Guidelines on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues; Feb 2006; Guidelines on Similar Biological Medicinal Product; Sep 2005; Guidelines on Similar biological medicinal products containing recombinant follicle stimulation hormone; Mar 2010; Guidelines on Similar biological medicinal product containing recombinant interferon beta; Mar 2010; Concept Paper on Guidelines on Similar biological medicinal products containing monoclonal antibodies; Nov 2010; Guidelines on Similar biological medicinal products containing recombinant Erythropoietins; Sep 2010; Guidelines on Similar biological medicinal products containing low-molecular-weight-heparins; Oct 2009; Guidelines on Non-clinical and clinical development of similar medicinal products containing recombinant interferon alpha; Apr 2009; Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs); Oct 2009; World Health Organization (WHO). Available at: therapeutics/biotherapeutics_for_web_22april2010.pdf CPME Position on Access to Medicines Biosimilars; Mar 2011; Comité Permanent des Médecins Européens. Available at: /cpme Position.Biosimilars.pdf Biosimilar Medicines; International Alliance of Patients Organizations; May Available at: showarticle. pl?id=727;n=