vfa/vfa bio Position Paper
27. May 2011
Biosimilars
The original document as pdf-download
Biopharmaceuticals are manufactured with the help of living cells (e.g. hamster cells) or microorganisms (bacteria like E. coli or yeasts). In contrast to chemical-synthetic pharmaceuticals, their quality is essentially determined by the living organisms used and the manufacturing process. Even small modifications to the manufacturing process may lead to differences in the product that can change the drug's efficacy or tolerability in a sustained manner.
With regard to the expiration of the first patents for biopharmaceuticals, the question arose in the EU how copycat products of biopharmaceuticals should be regulated. In this respect, the EU legislature coined the term "medicine which is similar to a biological reference medicine" (biosimilar), since a copycat biopharmaceutical can only be similar but not identical to the original product. The term has quickly taken hold in the EU and is also used in other parts of the world.
For many years, there have been generic versions in the market of those pharmaceuticals whose active ingredient is manufactured chemically. These are drugs that are largely identical to the product of the original manufacturer and specifically contain the same active ingredient in the same amount. Such generic drugs can be granted marketing authorisation after patent expiration without the company having to conduct its own trials for efficacy and safety, since it can refer to the corresponding documents of the original manufacturer (without knowing them). Since generic drug manufacturers save the largest share of research and development costs for a new pharmaceutical of up to USD 800 million this way, they can offer their drugs at much lower cost than the original manufacturers.
For a high-quality biopharmaceutical, on the other hand, extensive development work with regard to a suitable manufacturing process is required. Furthermore, to prove efficacy and tolerability, it is also necessary to conduct elaborate pre-clinical and clinical trials. Biosimilars can only be similar to the biopharmaceutical originals, since the complete imitation of the complex manufacturing process and mere referencing of the original manufacturer's documents is not possible. Instead, each new producer of a biopharmaceutical, i.e. also those of a biosimilar, must largely pursue their own development in the interest of patient safety.
The active ingredients of biopharmaceuticals are characterized by the following properties:
As part of the revision of EC pharmaceutical legislation concluded at the end of March 2004, a regulation for biological medicines similar to a biological reference medicine (biosimilars) was also included among others. Article 10 Section 4 of the amended Directive 2001/ 83/ EC reads as follows:
"Where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided. The type and quantity of supplementary data to be provided must comply with the relevant criteria stated in the Annex and the related detailed guidelines."
The criteria for registration of a biosimilar product have to be applied for biopharmaceuticals, because their drug substances are manufactured based on genetic engineering. Furthermore, they have to be used for low molecular weight heparins, since these products are complex drug substance mixtures whose characteristics are determined mainly via their production process and its control. Several product-specific guidelines or annexes have already been adopted by the EMA (see below).
According to Annex I, Part II "Specific Marketing Authorisation Dossiers and Requirements" Item 4: "Similar Biological Medicinal Products," information to be supplied for a marketing authorisation for a biological medicinal product which refers to an original medicinal product shall not be limited to pharmaceutical, chemical and biological data as well as data on bio-equivalence and bio-availability. The type and amount of additional data (i.e. toxicological and other non-clinical and appropriate clinical data) shall be determined on a case-by-case basis in accordance with relevant scientific guidelines. Due to the diversity of biological medicinal products, the need for identified studies foreseen in Module 4 (Pre-clinical Reports) and Module 5 (Reports on Clinical Studies) shall be required by the competent authority, taking into account the specific characteristic of each individual medicinal product.
The revised Directive 2001/ 83/ EC including Annex I became effective at the end of 2005. The relevant scientific guidelines mentioned in the directive are available. Since October 2005, the Guideline on Similar Biological Medicinal Products (CHMP/ 437/ 04) has to be applied, which contains the concept of biosimilars, the basic principles, e.g. for the choice of the reference product, and information regarding the relevant guidelines.
Furthermore, since June respectively July 2006, the following additional guidelines by the EMA have to be applied: the Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance – Quality Issues (CHMP/ 49348/ 05), the Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance – Non-Clinical and Clinical Issues (EMEA / CHMP / BMWP / 42832 / 05 as well as the corresponding product-specific annexes for insulin, erythropoietins, somatropins, G-CSF products (granulocyte- colony stimulating factor), interferon alpha products and low molecular weight heparins. For FSH (follicle stimulation hormone) and interferon beta products corresponding concept papers were recently published for commenting. In addition, in November 2009, a Concept Paper on the Development of Similar Biological Medicinal Products Containing Monoclonal Antibodies (EMEA/CHMP/BMWP/632613/2009) was published for commenting.
Furthermore, in April 2008, the specific Guideline on Immunogenicity Assessment of Biotechnology-derived Therapeutic Proteins (EMEA/ CHMP/ BMWP/ 14327/ 2006) became effective, in which it was explicitly pointed out that studies on immunogenicity are also required for biosimilars.
Since November 2007, the Guideline EMEA/ CHMP/ BMWP/ 101695/ 2006 (Guideline on Comparability of Biotechnology-derived Medicinal Products after a Change in the Manufacturing Process – Non-clinical and Clinical Issues) has been effective, in which the comparability of a biopharmaceutical after a change in the manufacturing process at a manufacturer's production facility or that of a subcontractor is described. Such changes in production process become necessary during the development of a drug and after its marketing authorisation. Since the process changes are made at the same manufacturer, who already has comprehensive experience with the active substance, proof of comparability must basically be distinguished from the proof of similarity between a biosimilar and the biopharmaceutical original, since these products come from different manufacturers (see below – vfa/vfa bio position).
At the start of 2008, applications for marketing authorisation for three insulin biosimilars were withdrawn, since the company was unable to answer the questions asked by the CHMP with regard to the manufacturing process and the efficacy within the mandated deadline.
In June 2006, the CHMP had already given a negative rating to an interferon alpha 2a biosimilar, because the submitted data were viewed as insufficient for demonstrating efficacy and safety.
Regulations in other countries
In the United States, biological/biotechnological products governed by the Public Health Service Act are exempt from the regulations of the Federal Food Drug & Cosmetic Act for generic marketing authorisation (ANDA). The regulations for biological/biotechnologi-cal copycat products are currently the object of various legislative initiatives. Regardless of this fact, a copycat product (a growth hormone) was for the first time authorised by the FDA due to a special legal situation in June 2006. The development of a legal framework for copycat products of biopharmaceuticals is expected in the United States in the near future.
Almost all guidelines that have either been passed or are being discussed in other parts of the world (e.g. Switzerland, Turkey, Malaysia, Australia, Japan, Mexico, Taiwan, Korea) largely correspond to the European body of regulations for biosimilars.
The recently published WHO-guideline for biosimilars basically follows the same principles as are prevalent in the EU and is meant to serve as a basis for those countries that do not yet have any biosimilar legislation.
The manufacturing process for a biological active ingredient significantly defines the drug manufactured from it, since the manufacturing processes are based on living cells or organisms whose functions inevitably vary. In contrast to chemical products, biopharmaceuticals are heterogeneous at the molecular level, as a result of the variability of the live processes through which they are produced. This also applies to biosimilars, since they, too, are manufactured in living cells like the biopharmaceutical originals.
Due to the complexity of biopharmaceuticals, it is not possible after the patent expiration of the original products to develop copycat products that are identical to the reference product. Therefore, it is not acceptable to only collect data on the quality and prove bio-equivalence as is customary for chemical generics. In addition, due to the heterogeneity as a consequence of the biological manufacturing process, one cannot conclude that biosimilars have identical clinical properties to the original products; this also applies, if there are no apparent differences in in-vitro tests.
The original manufacturer has a comprehensive data analysis available for all production steps and for all important intermediate products and has established in-process controls and reference standards. For him, modifications (process changes) that become necessary over the course of time will generally be small changes in a well-understood and comprehensively validated process. All other aspects of production remain unchanged. Potential impacts of the implemented changes must be examined in detail by the manufacturer. Often, the customized processes developed for the production of biopharmaceuticals are valuable intellectual property or trade secrets. The original manufacturer is in a position to compare the manufactured product before and after the change in order to demonstrate to the marketing authorisation agency that the change has no negative impact on the product's efficacy and safety. To this effect, the original manufacturer may also have to submit new clinical data if necessary before the introduction of process changes. This depends on the results of the characterization studies for the product comparison, which are used to determine the impact of the change.
An imitator must have a comprehensive data collection for all production steps, starting with his own cell banks, continuing with the manufacturing process and the most important intermediate products, and ending with the in-process controls and reference standards. However, since he does not have access to the original manufacturer's data or to his cell construct, cell banks, most important intermediate products, reference standards and reagents, and to the complex and often customized, validated methods (e.g. bioassays), he cannot make a complete direct comparison between his process and his biosimilar and those of the original manufacturer.
Therefore, it is neither scientifically explainable nor justifiable in terms of patient safety to simply assume that a biosimilar has the same clinical properties as the original manufacturer's product. Therefore, in this context, so-called "biosimilar prescription quotas" as planned in the master agreement between the National Association of Statutory Health Insurance (SHI) Funds and the National Association of SHI-accredited Physicians must also be rejected with regard to patient safety and economic efficiency.
The only possibility to capture the similarity of the biosimilar's clinical properties with the reference product is to determine it in comparative clinical studies, which are designed in such a manner as to demonstrate both efficacy and safety. Furthermore, biosimilars must also be monitored in their broader application after marketing authorisation in order to capture potential immunogenicity reactions and rare side effects.
To be consistent, marketing authorisation applications of biosimilars must include detailed comparative data on the quality as well as non-clinical and clinical data in order to demonstrate that a biosimilar is pharmaceutically and clinically equivalent in comparison to the original product in question. This is also ensured by the EU body of regulations for biosimilars, which served as a model for the regulations in other countries and which is welcomed by vfa and vfa bio.
The vfa and vfa bio welcome the existing body of regulations for marketing authorisation of biosimilars of the EMA, which served as a model for the regulations in other countries. The current draft of the WHO also largely corresponds to the EMA marketing authorisation requirements for biosimilars.
A recent announcement by the Federal Institute for Drugs and Medical Devices (BfArM) underscores the necessity of these firm marketing authorisation requirements for biosimilars. A marketing authorisation study for an epoetin alfa biosimilar with subcutaneous application in anemia patients had to be discontinued due to a case of PRCA (pure red cell aplasia) and the occurrence of neutralizing antibodies in another patient. This clinical study was conducted in order to be able to also apply for marketing authorisation of this epoetin alfa biosimilar for subcutaneous application in renal anemia. At the time the study was discontinued, 338 patients that were previously not treated with epoetin had been included in the study. Typically, PRCA occurs significantly more rarely – in one out of 10,000 patients. This case shows that an extrapolation from one application form to another should not be made for biopharmaceuticals without separate clinical data.
A recent analysis by Schöffski et al. ("Verbrauch von Erythro¬poese-stimulierenden Faktoren in der Therapie der renalen Anämie – eine „real life“-Analyse der Versorgungssituation in Deutschland" [Consumption of erythropoiesis-stimulating factors in renal anemia therapy – a real-life analysis of the health care situation in Germany], Kongress für Nephrologie [Nephrology Convention], September 2009, Poster P150), which was based on more than 15,000 treatment cases, determined the actually consumed doses of epoetin products in Germany: Compared to the direct reference product (epoetin alfa), a 30% additional consumption in biosimilars was identified. The marketing authorisation report of the EMA (EPAR – European Assessment Report) already described differences of the epoetin alfa biosimilars with regard to both glycosylations and the required dosages. Additional detailed analyses will be required to answer the question of economic relief to the health care system based on epoetin biosimilars. Alleged savings effects based on biosimilars must be questioned, if this finding is confirmed in further studies.
Substitution of biopharmaceutical originals through biosimilars?
Due to the proven, existing differences between the original product and the biosimilar, automatic substitution in pharmacies in Germany and other EU countries is prohibited according to the legislature. A biosimilar may only be substituted for an original product if expressly ordered by a physician. In order to facilitate an unambiguous documentation, especially with regard to potential reports of side effects, biosimilars should be clearly identifiable, i.e. based on a distinct non-proprietary name for the active substance (INN = international non-proprietary name – the brief name for a pharmaceutical active substance assigned by the WHO) and/or based on a separate brand name, as is the case for the previously available biopharmaceutical original products developed independently of each other by different manufacturers. Unfortunately, this was not implemented for several biosimilar products. For example, one epoetin biosimilar and two filgrastim biosimilars have the same active substance name as the original product; as a result, it can not be determined from the active substance name alone whether the/an original product or the/a biosimilar was applied. This fact is illustrated below by the example of the epoetin products.
In the interest of patient safety, vfa and vfa bio believe that the following requirements for biosimilars are necessary:
Biopharmaceuticals are manufactured with the help of living cells (e.g. hamster cells) or microorganisms (bacteria like E. coli or yeasts). In contrast to chemical-synthetic pharmaceuticals, their quality is essentially determined by the living organisms used and the manufacturing process. Even small modifications to the manufacturing process may lead to differences in the product that can change the drug's efficacy or tolerability in a sustained manner.
With regard to the expiration of the first patents for biopharmaceuticals, the question arose in the EU how copycat products of biopharmaceuticals should be regulated. In this respect, the EU legislature coined the term "medicine which is similar to a biological reference medicine" (biosimilar), since a copycat biopharmaceutical can only be similar but not identical to the original product. The term has quickly taken hold in the EU and is also used in other parts of the world.
For many years, there have been generic versions in the market of those pharmaceuticals whose active ingredient is manufactured chemically. These are drugs that are largely identical to the product of the original manufacturer and specifically contain the same active ingredient in the same amount. Such generic drugs can be granted marketing authorisation after patent expiration without the company having to conduct its own trials for efficacy and safety, since it can refer to the corresponding documents of the original manufacturer (without knowing them). Since generic drug manufacturers save the largest share of research and development costs for a new pharmaceutical of up to USD 800 million this way, they can offer their drugs at much lower cost than the original manufacturers.
For a high-quality biopharmaceutical, on the other hand, extensive development work with regard to a suitable manufacturing process is required. Furthermore, to prove efficacy and tolerability, it is also necessary to conduct elaborate pre-clinical and clinical trials. Biosimilars can only be similar to the biopharmaceutical originals, since the complete imitation of the complex manufacturing process and mere referencing of the original manufacturer's documents is not possible. Instead, each new producer of a biopharmaceutical, i.e. also those of a biosimilar, must largely pursue their own development in the interest of patient safety.
Basic situation
The active ingredients of biopharmaceuticals are characterized by the following properties:
- They have proven biological activity.
- They have a high molecular weight and a highly complex structure compared to most chemically synthesised active ingredients.
- They are inevitably heterogeneous in terms of their molecular structure. The heterogeneity of the molecular structure and impurity profile can have significant impacts on the efficacy, action profile and safety of biological drugs.
- They can be influenced by differences of the biological or genetic starting material, the master cell bank, the expression system and the manufacturing process, which leads to different posttranslational modifications and therefore microheterogeneities of the molecule. These modifications can have impacts on the efficacy and safety, which in turn can only be discovered in clinical trials and later in the broader application in an everyday clinical setting.
- They may be very sensitive in their biological activity to physical conditions (temperature, shear forces, phases), enzyme activities in the manufacturing process (sensitivity toward process changes) and changes in the formulation.
- They may require very specific formulation conditions (e.g. excipients, conjugation or special chemical and physical conditions) to develop the specific and full biological activity upon administration.
- They require (a) bioassay(s) for characterization and stability assessment in addition to the chemical and physical tests to determine the identity and purity from batch to batch.
Basically, the following products must be distinguished:
Marketing authorisation of biosimilars- Biopharmaceutical original products
- Biosimilars (copycat products of biopharmaceutical originals after patent expiration) that are merely similar but not identical to the original product and therefore cannot automatically substitute it
- Special case: Biosimilars with multiple brand names (so-called secondary brands): Come from one and the same production facility of the imitator, are therefore identical with each other and are consequently also substitutable among each other
As part of the revision of EC pharmaceutical legislation concluded at the end of March 2004, a regulation for biological medicines similar to a biological reference medicine (biosimilars) was also included among others. Article 10 Section 4 of the amended Directive 2001/ 83/ EC reads as follows:
"Where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided. The type and quantity of supplementary data to be provided must comply with the relevant criteria stated in the Annex and the related detailed guidelines."
The criteria for registration of a biosimilar product have to be applied for biopharmaceuticals, because their drug substances are manufactured based on genetic engineering. Furthermore, they have to be used for low molecular weight heparins, since these products are complex drug substance mixtures whose characteristics are determined mainly via their production process and its control. Several product-specific guidelines or annexes have already been adopted by the EMA (see below).
According to Annex I, Part II "Specific Marketing Authorisation Dossiers and Requirements" Item 4: "Similar Biological Medicinal Products," information to be supplied for a marketing authorisation for a biological medicinal product which refers to an original medicinal product shall not be limited to pharmaceutical, chemical and biological data as well as data on bio-equivalence and bio-availability. The type and amount of additional data (i.e. toxicological and other non-clinical and appropriate clinical data) shall be determined on a case-by-case basis in accordance with relevant scientific guidelines. Due to the diversity of biological medicinal products, the need for identified studies foreseen in Module 4 (Pre-clinical Reports) and Module 5 (Reports on Clinical Studies) shall be required by the competent authority, taking into account the specific characteristic of each individual medicinal product.
The revised Directive 2001/ 83/ EC including Annex I became effective at the end of 2005. The relevant scientific guidelines mentioned in the directive are available. Since October 2005, the Guideline on Similar Biological Medicinal Products (CHMP/ 437/ 04) has to be applied, which contains the concept of biosimilars, the basic principles, e.g. for the choice of the reference product, and information regarding the relevant guidelines.
Furthermore, since June respectively July 2006, the following additional guidelines by the EMA have to be applied: the Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance – Quality Issues (CHMP/ 49348/ 05), the Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance – Non-Clinical and Clinical Issues (EMEA / CHMP / BMWP / 42832 / 05 as well as the corresponding product-specific annexes for insulin, erythropoietins, somatropins, G-CSF products (granulocyte- colony stimulating factor), interferon alpha products and low molecular weight heparins. For FSH (follicle stimulation hormone) and interferon beta products corresponding concept papers were recently published for commenting. In addition, in November 2009, a Concept Paper on the Development of Similar Biological Medicinal Products Containing Monoclonal Antibodies (EMEA/CHMP/BMWP/632613/2009) was published for commenting.
Furthermore, in April 2008, the specific Guideline on Immunogenicity Assessment of Biotechnology-derived Therapeutic Proteins (EMEA/ CHMP/ BMWP/ 14327/ 2006) became effective, in which it was explicitly pointed out that studies on immunogenicity are also required for biosimilars.
Since November 2007, the Guideline EMEA/ CHMP/ BMWP/ 101695/ 2006 (Guideline on Comparability of Biotechnology-derived Medicinal Products after a Change in the Manufacturing Process – Non-clinical and Clinical Issues) has been effective, in which the comparability of a biopharmaceutical after a change in the manufacturing process at a manufacturer's production facility or that of a subcontractor is described. Such changes in production process become necessary during the development of a drug and after its marketing authorisation. Since the process changes are made at the same manufacturer, who already has comprehensive experience with the active substance, proof of comparability must basically be distinguished from the proof of similarity between a biosimilar and the biopharmaceutical original, since these products come from different manufacturers (see below – vfa/vfa bio position).
In Europe, the following biosimilars have received marketing authorisation so far:
For a detailed overview of the biosimilars authorised in Europe and their reference products, please visit www.vfa.de/biosimilars-overview-original-products.pdf- Two somatropin biosimilars (for treatment of growth disturbance) by two different manufacturers, only one of them is market-relevant in Germany
- One epoetin alfa biosimilar (for treatment of anemia) with three brand names
- One epoetin zeta biosimilar (for treatment of anemia) with two brand names
- One filgrastim biosimilar (for treatment of neutropenia) with two brand names
- One filgrastim biosimilar (for treatment of neutropenia) with three brand names
- One filgrastim biosimilar (for treatment of neutropenia) with one brand name
At the start of 2008, applications for marketing authorisation for three insulin biosimilars were withdrawn, since the company was unable to answer the questions asked by the CHMP with regard to the manufacturing process and the efficacy within the mandated deadline.
In June 2006, the CHMP had already given a negative rating to an interferon alpha 2a biosimilar, because the submitted data were viewed as insufficient for demonstrating efficacy and safety.
Regulations in other countries
In the United States, biological/biotechnological products governed by the Public Health Service Act are exempt from the regulations of the Federal Food Drug & Cosmetic Act for generic marketing authorisation (ANDA). The regulations for biological/biotechnologi-cal copycat products are currently the object of various legislative initiatives. Regardless of this fact, a copycat product (a growth hormone) was for the first time authorised by the FDA due to a special legal situation in June 2006. The development of a legal framework for copycat products of biopharmaceuticals is expected in the United States in the near future.
Almost all guidelines that have either been passed or are being discussed in other parts of the world (e.g. Switzerland, Turkey, Malaysia, Australia, Japan, Mexico, Taiwan, Korea) largely correspond to the European body of regulations for biosimilars.
The recently published WHO-guideline for biosimilars basically follows the same principles as are prevalent in the EU and is meant to serve as a basis for those countries that do not yet have any biosimilar legislation.
The vfa/vfa bio position
The manufacturing process for a biological active ingredient significantly defines the drug manufactured from it, since the manufacturing processes are based on living cells or organisms whose functions inevitably vary. In contrast to chemical products, biopharmaceuticals are heterogeneous at the molecular level, as a result of the variability of the live processes through which they are produced. This also applies to biosimilars, since they, too, are manufactured in living cells like the biopharmaceutical originals.
Due to the complexity of biopharmaceuticals, it is not possible after the patent expiration of the original products to develop copycat products that are identical to the reference product. Therefore, it is not acceptable to only collect data on the quality and prove bio-equivalence as is customary for chemical generics. In addition, due to the heterogeneity as a consequence of the biological manufacturing process, one cannot conclude that biosimilars have identical clinical properties to the original products; this also applies, if there are no apparent differences in in-vitro tests.
The original manufacturer has a comprehensive data analysis available for all production steps and for all important intermediate products and has established in-process controls and reference standards. For him, modifications (process changes) that become necessary over the course of time will generally be small changes in a well-understood and comprehensively validated process. All other aspects of production remain unchanged. Potential impacts of the implemented changes must be examined in detail by the manufacturer. Often, the customized processes developed for the production of biopharmaceuticals are valuable intellectual property or trade secrets. The original manufacturer is in a position to compare the manufactured product before and after the change in order to demonstrate to the marketing authorisation agency that the change has no negative impact on the product's efficacy and safety. To this effect, the original manufacturer may also have to submit new clinical data if necessary before the introduction of process changes. This depends on the results of the characterization studies for the product comparison, which are used to determine the impact of the change.
An imitator must have a comprehensive data collection for all production steps, starting with his own cell banks, continuing with the manufacturing process and the most important intermediate products, and ending with the in-process controls and reference standards. However, since he does not have access to the original manufacturer's data or to his cell construct, cell banks, most important intermediate products, reference standards and reagents, and to the complex and often customized, validated methods (e.g. bioassays), he cannot make a complete direct comparison between his process and his biosimilar and those of the original manufacturer.
Therefore, it is neither scientifically explainable nor justifiable in terms of patient safety to simply assume that a biosimilar has the same clinical properties as the original manufacturer's product. Therefore, in this context, so-called "biosimilar prescription quotas" as planned in the master agreement between the National Association of Statutory Health Insurance (SHI) Funds and the National Association of SHI-accredited Physicians must also be rejected with regard to patient safety and economic efficiency.
The only possibility to capture the similarity of the biosimilar's clinical properties with the reference product is to determine it in comparative clinical studies, which are designed in such a manner as to demonstrate both efficacy and safety. Furthermore, biosimilars must also be monitored in their broader application after marketing authorisation in order to capture potential immunogenicity reactions and rare side effects.
To be consistent, marketing authorisation applications of biosimilars must include detailed comparative data on the quality as well as non-clinical and clinical data in order to demonstrate that a biosimilar is pharmaceutically and clinically equivalent in comparison to the original product in question. This is also ensured by the EU body of regulations for biosimilars, which served as a model for the regulations in other countries and which is welcomed by vfa and vfa bio.
The vfa and vfa bio welcome the existing body of regulations for marketing authorisation of biosimilars of the EMA, which served as a model for the regulations in other countries. The current draft of the WHO also largely corresponds to the EMA marketing authorisation requirements for biosimilars.
A recent announcement by the Federal Institute for Drugs and Medical Devices (BfArM) underscores the necessity of these firm marketing authorisation requirements for biosimilars. A marketing authorisation study for an epoetin alfa biosimilar with subcutaneous application in anemia patients had to be discontinued due to a case of PRCA (pure red cell aplasia) and the occurrence of neutralizing antibodies in another patient. This clinical study was conducted in order to be able to also apply for marketing authorisation of this epoetin alfa biosimilar for subcutaneous application in renal anemia. At the time the study was discontinued, 338 patients that were previously not treated with epoetin had been included in the study. Typically, PRCA occurs significantly more rarely – in one out of 10,000 patients. This case shows that an extrapolation from one application form to another should not be made for biopharmaceuticals without separate clinical data.
A recent analysis by Schöffski et al. ("Verbrauch von Erythro¬poese-stimulierenden Faktoren in der Therapie der renalen Anämie – eine „real life“-Analyse der Versorgungssituation in Deutschland" [Consumption of erythropoiesis-stimulating factors in renal anemia therapy – a real-life analysis of the health care situation in Germany], Kongress für Nephrologie [Nephrology Convention], September 2009, Poster P150), which was based on more than 15,000 treatment cases, determined the actually consumed doses of epoetin products in Germany: Compared to the direct reference product (epoetin alfa), a 30% additional consumption in biosimilars was identified. The marketing authorisation report of the EMA (EPAR – European Assessment Report) already described differences of the epoetin alfa biosimilars with regard to both glycosylations and the required dosages. Additional detailed analyses will be required to answer the question of economic relief to the health care system based on epoetin biosimilars. Alleged savings effects based on biosimilars must be questioned, if this finding is confirmed in further studies.
Substitution of biopharmaceutical originals through biosimilars?
Due to the proven, existing differences between the original product and the biosimilar, automatic substitution in pharmacies in Germany and other EU countries is prohibited according to the legislature. A biosimilar may only be substituted for an original product if expressly ordered by a physician. In order to facilitate an unambiguous documentation, especially with regard to potential reports of side effects, biosimilars should be clearly identifiable, i.e. based on a distinct non-proprietary name for the active substance (INN = international non-proprietary name – the brief name for a pharmaceutical active substance assigned by the WHO) and/or based on a separate brand name, as is the case for the previously available biopharmaceutical original products developed independently of each other by different manufacturers. Unfortunately, this was not implemented for several biosimilar products. For example, one epoetin biosimilar and two filgrastim biosimilars have the same active substance name as the original product; as a result, it can not be determined from the active substance name alone whether the/an original product or the/a biosimilar was applied. This fact is illustrated below by the example of the epoetin products.
Epoetin original products:
- ERYPO®; INN: Epoetin alfa
- Aranesp®; INN: Darbepoetin alfa
- NeoRecormon®; INN: Epoetin beta
- A product with two brand names: Biopoin® and Eporatio®; INN: Epoetin theta
- A biosimilar with three brand names:
Abseamed®, Binocrit®, Epoetin alfa HEXAL®; INN: Epoetin alfa; Reference product: ERYPO® - A biosimilar with two brand names:
Retacrit®, Silapo®; INN: Epoetin zeta; Reference product: ERYPO®
In the interest of patient safety, vfa and vfa bio believe that the following requirements for biosimilars are necessary:
- Detailed comparative data on the quality as well as comparative non-clinical and clinical data.
- Observational studies after marketing authorisation of biosimilars in order to determine potential immuno-genicity reactions, rare side effects (pharmacovigilance studies) and the actually required doses.
- A switch from the original to biosimilars should only be made with the express consent of a physician (no automatic substitution at the pharmacy). This is in line with an express recommendation of the EMA (EMEA / 74562 / 2006).
- Quotas for biosimilars must be rejected, since the decision regarding the prescription in question must always remain with the physician and must be primarily based on medical reasons. Furthermore, quota requirements ignore the differences between original products and biosimilars, deprive physicians of part of their necessary medical decision-making freedom and shift the decision-making focus from medical to economic aspects. In addition, it cannot be excluded that quotas also bring about medically inappropriate product changes to the potential disadvantage of stable and safely adjusted patients.
- Biosimilars should be clearly identifiable based on a separate active substance name (INN) and/or a separate brand name, so that it can be recognized whether the drug at hand is an original product or a biosimilar. This also applies to parallel developments by original manufacturers. This rule serves the purpose of patient safety, since it can be traced unambiguously which product was prescribed by the physician and which product the patient actually received.
- The summary of product information on biosimilars should be comprehensive and list the available data in detail in order to show which applications were actually substantiated by studies and which were derived from the biopharmaceutical of the original manufacturer without separate data.
Suggest page
Print page
Bookmark page