I just came across,
fantastic news about the
first time Biosimilar versions of a monoclonal antibody (mAb) drug that have
been recommended for approval in the European Union (EU), opening a new chapter in the developing
market for cheaper copies of biologic medicines. CHMP has issued positive
opinions on biosimilar versions of Johnson & Johnson's arthritis and
Crohn's disease treatment Remicade (infliximab) filed by Celltrion Healthcare
and Hospira. The reference product posted European sales of over $2bn last
year.
To date a total of 12 medicines have been approved under the biosimilar regulatory pathway first laid out by the EMA in 2006, covering a range relatively small protein-based drugs including epoetins, filgrastims, growth hormones and recombinant human interferon alfa-2a.
The first time that the biosimilar concept has been successfully applied to such a complex molecule as the increased size and complexity of mAbs makes it more challenging to be able to demonstrate that their biosimilars do not have any meaningful differences from the reference medicine in terms of quality, safety or efficacy. So above news is fantastic in that sense.
It’s interesting to know some simple facts of biological drugs. But these simple cornerstones will help understand regulatory guidelines on biosimilars. Before understanding biological drugs let’s see them in comparison to chemical drugs. It would help understand the difference in regulatory requirements of both.
Biological drugs (Bios) are different from small molecule medicines in many aspects first of it is they are made in living system such as microorganisms or animal cells. Small molecule medicines are typically manufactured by chemical synthesis. Both types of drugs differ in their manufacturing techniques, molecular size and complexity.
The production of biological medicines is a complex process which requires a very high level of technical expertise with typically about 250 in-process tests being conducted compared to about 50 tests for a small molecule medicine. The production of biological medicines involves processes such as fermentation and purification.
Size matters….....acetylsalicylic acid (ASA), aspirin's active ingredient with a molecular weight of about 180 g/mol or 180 Da and biologics molecule (protein) which are composed of more than 1,300 amino acids and can be as heavy as 150,000 g/mol (or 150 kDa).
Small molecule medicines generally have well-defined chemical structures. Bios have variability in the molecule (protein) as they are made in living systems and same protein exists in different forms.
For example enzyme Creatine kinase, the presence of which in the blood can be used as an aid in the diagnosis of heart attack, exists in 3 isoforms. Another source of variability is due to the type and length of sugar or carbohydrate group attached to the protein called glycosylation.
Due to the variability in structure of bios molecules it is more difficult to characterize it and exactly reproduce. Therefore batch to batch variation is controlled by manufacturers and regulators within accepted pre-defined limit.
Biological medicines have the potential to be recognized by the body as foreign due to their big size and therefore have the potential to induce immune reactions whereas chemical medicines are usually small molecule, to be recognized by immune system. This potential to induce immune reaction is called immunogenicity.
Biosimilar is a regulatory term used in the EU to denote the comparability between biosimilar and its reference medicinal product. Biosimilar products are systematically developed and their comparability is performed in several steps.
1. First step - quality comparability (physicochemical and biological comparability).
2. Second step - non-clinical comparability (comparative non-clinical studies)
3. Third step - clinical comparability (comparative clinical studies)
Comparability is an additional element to the normal requirement of the quality dossier.
The exhaustive comparability exercise at quality level may allow reduction of the non-clinical and clinical data.
Differences in impurity profile and significant differences in product related substances may have consequences with regards to the amount of non-clinical and clinical data requirement in order to make satisfactory justification of the safety and efficacy of the biosimilar.
Quality comparability is established with regard to the molecular structure as well as with regard to the functionality. Structural analysis is done using apt analytical methodology to deduce primary structures such as amino acid sequence; higher order structures including secondary, tertiary and quaternary structures, enzymatic post translational modifications such as glycosylation; other modifications such as protein deamidation, oxidation and intentional chemical modifications.
Functional assays include bioassays, binding assays and enzyme kinetics. This information helps design clinical immunogenicity.
The non-clinical and clinical comparability then provides the confidence that any differences observed at the quality level have no impact on the safety and efficacy of the biosimilar medicinal product when compared to the reference medicinal product.
Animal data requires toxicity and PK PD profile. Immunogenicity studies are performed in animals when there is difference in impurity profile and excipients of biosimilar and reference medicinal product. Clinical studies include PK, PD studies and analysis of immunogenicity.
As a scientific matter, comparative safety and effectiveness data will be necessary to support a demonstration of biosimilarity if there are residual uncertainties about the biosimilarity of the two products based on structural and functional characterization, animal testing, human PK and PD data, and clinical immunogenicity assessment.
If interested refer following links.
http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/06/WC500144941.pdf
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf
http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_report_en.pdf
To date a total of 12 medicines have been approved under the biosimilar regulatory pathway first laid out by the EMA in 2006, covering a range relatively small protein-based drugs including epoetins, filgrastims, growth hormones and recombinant human interferon alfa-2a.
The first time that the biosimilar concept has been successfully applied to such a complex molecule as the increased size and complexity of mAbs makes it more challenging to be able to demonstrate that their biosimilars do not have any meaningful differences from the reference medicine in terms of quality, safety or efficacy. So above news is fantastic in that sense.
It’s interesting to know some simple facts of biological drugs. But these simple cornerstones will help understand regulatory guidelines on biosimilars. Before understanding biological drugs let’s see them in comparison to chemical drugs. It would help understand the difference in regulatory requirements of both.
Biological drugs (Bios) are different from small molecule medicines in many aspects first of it is they are made in living system such as microorganisms or animal cells. Small molecule medicines are typically manufactured by chemical synthesis. Both types of drugs differ in their manufacturing techniques, molecular size and complexity.
The production of biological medicines is a complex process which requires a very high level of technical expertise with typically about 250 in-process tests being conducted compared to about 50 tests for a small molecule medicine. The production of biological medicines involves processes such as fermentation and purification.
Size matters….....acetylsalicylic acid (ASA), aspirin's active ingredient with a molecular weight of about 180 g/mol or 180 Da and biologics molecule (protein) which are composed of more than 1,300 amino acids and can be as heavy as 150,000 g/mol (or 150 kDa).
Small molecule medicines generally have well-defined chemical structures. Bios have variability in the molecule (protein) as they are made in living systems and same protein exists in different forms.
For example enzyme Creatine kinase, the presence of which in the blood can be used as an aid in the diagnosis of heart attack, exists in 3 isoforms. Another source of variability is due to the type and length of sugar or carbohydrate group attached to the protein called glycosylation.
Due to the variability in structure of bios molecules it is more difficult to characterize it and exactly reproduce. Therefore batch to batch variation is controlled by manufacturers and regulators within accepted pre-defined limit.
Biological medicines have the potential to be recognized by the body as foreign due to their big size and therefore have the potential to induce immune reactions whereas chemical medicines are usually small molecule, to be recognized by immune system. This potential to induce immune reaction is called immunogenicity.
Biosimilar is a regulatory term used in the EU to denote the comparability between biosimilar and its reference medicinal product. Biosimilar products are systematically developed and their comparability is performed in several steps.
1. First step - quality comparability (physicochemical and biological comparability).
2. Second step - non-clinical comparability (comparative non-clinical studies)
3. Third step - clinical comparability (comparative clinical studies)
Comparability is an additional element to the normal requirement of the quality dossier.
The exhaustive comparability exercise at quality level may allow reduction of the non-clinical and clinical data.
Differences in impurity profile and significant differences in product related substances may have consequences with regards to the amount of non-clinical and clinical data requirement in order to make satisfactory justification of the safety and efficacy of the biosimilar.
Quality comparability is established with regard to the molecular structure as well as with regard to the functionality. Structural analysis is done using apt analytical methodology to deduce primary structures such as amino acid sequence; higher order structures including secondary, tertiary and quaternary structures, enzymatic post translational modifications such as glycosylation; other modifications such as protein deamidation, oxidation and intentional chemical modifications.
Functional assays include bioassays, binding assays and enzyme kinetics. This information helps design clinical immunogenicity.
The non-clinical and clinical comparability then provides the confidence that any differences observed at the quality level have no impact on the safety and efficacy of the biosimilar medicinal product when compared to the reference medicinal product.
Animal data requires toxicity and PK PD profile. Immunogenicity studies are performed in animals when there is difference in impurity profile and excipients of biosimilar and reference medicinal product. Clinical studies include PK, PD studies and analysis of immunogenicity.
As a scientific matter, comparative safety and effectiveness data will be necessary to support a demonstration of biosimilarity if there are residual uncertainties about the biosimilarity of the two products based on structural and functional characterization, animal testing, human PK and PD data, and clinical immunogenicity assessment.
If interested refer following links.
http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/06/WC500144941.pdf
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf
http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_report_en.pdf
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