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This guideline lays down the non-clinical and clinical requirements for monoclonal antibody (mAb) containing medicinal products claiming to be similar to another one already marketed. The non-clinical section addresses the pharmaco-toxicological requirements and the clinical section the requirements for pharmacokinetic, pharmacodynamic, efficacy and safety studies as well as pharmacovigilance aspects.
As regards non-clinical development, a risk-based approach to evaluate mAb on a case-by-case basis is recommended to decide on the choice and extent of in vitro and in vivo studies. In vitro studies should be conducted first, and a decision then made as to the extent of what, if any, in vivo work will be required. If an in vivo study is deemed necessary, the focus of the study (pharmacokinetics, pharmacodynamics, and/or safety; normally comparative in nature) depends on the need for additional information, and the availability of a relevant animal model. The conduct of large comparative toxicological studies in non-human primates is not recommended. As regards clinical development, a comparative pharmacokinetic study in a sufficiently sensitive and homogeneous study population (healthy volunteers or patients) normally forms an integral part of biosimilar mAb development, usually in a parallel group design due to the long half-life of mAbs and potential interference of immunogenicity. The design of a pharmacokinetic study will depend on various factors, including
55 clinical context, linear versus non-linear pharmacokinetics etc. Pharmacokinetic data can be helpful to extrapolate data on efficacy and safety between different clinical indications of the reference mAb. It may, on a case-by-case basis, be necessary to undertake multidose pharmacokinetic studies in patients, or even to perform pharmacokinetic assessment as part of the clinical study designed to establish similar efficacy and safety. Pharmacokinetic studies can be combined with pharmacodynamic (PD) endpoints, where available. Sponsors should always explore possibilities to study dose concentration-response relationships since this approach, if successful, may provide strong evidence of biosimilarity. Normally, similar clinical efficacy should be demonstrated in adequately powered, randomised, parallel group comparative clinical trial(s), preferably double-blind, normally equivalence trials. To establish biosimilarity, deviations from disease-specific guidelines issued by the CHMP (for example, choice of endpoint, timepoint of analysis of endpoint, nature or dose of concomitant therapy, etc) may be warranted. The focus of the biosimilarity exercise is to demonstrate similar efficacy and safety compared to the reference product, not patient benefit per se, which has already been shown for the reference product. In principle, the most sensitive model and study conditions (pharmacodynamic or clinical) should be used in a homogeneous patient population, since this reduces variability and thus the sample size needed to prove similarity, and can simplify interpretation. In cases where comparative pharmacodynamic studies are claimed to be most suitable to provide the pivotal evidence for similar efficacy, Applicants will have to choose clinically relevant markers and also provide sufficient reassurance of clinical safety, particularly immunogenicity. It may be difficult to define an appropriate equivalence margin for pharmacodynamic equivalence based on clinical relevance, and to provide reassurance that all relevant aspects of a biosimilar mAb as regards similar clinical efficacy are covered. Comparable safety with respect to pharmacologically mediated adverse reactions could also be considered as a measure of biosimilarity. Extrapolation of clinical efficacy and safety data to other indications of the reference mAb, not specifically studied during the clinical development of the biosimilar mAb, is possible based on the results of the overall evidence provided from the biosimilarity exercise and with adequate justification. As regards post-authorisation follow-up, the concept to be proposed by Applicants may have to exceed routine pharmacovigilance, and may have to involve more standardized environments.

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Damien Bové is THE Drug Development and Regulatory Consultant (pharmaceutical or biotechnology), I work with my clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

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“Please note that the pages on this website are designed to provide you with general information only. We make no warranties, representations or undertakings about any of its content. This includes the completeness, accuracy and fitness for any particular purpose, or the content of any third party site referred to or accessed through it. You are personally responsible for ensuring that the information is correct and we will not be held liable or accountable for any mistakes that occur.”

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This guideline addresses issues relating to the unwanted immunogenicity of monoclonal antibodies intended for clinical use. These include the variability of immunogenicity of mAbs and its consequences, prediction and minimizing immunogenicity, the clinical consequences of immunogenicity, assay related problems, assessing neutralizing antibodies induced by monoclonal antibodies and consideration of a risk-based approach for the evaluation of immunogenicity of monoclonal antibodies.

Unwanted immunogenicity can be a significant problem in the treatment of patients with therapeutic biologicals. The importance of the unwanted immunogenicity problem has led to the preparation and adoption of the ‘Guideline on Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins’ by the CHMP (adopted April 2008, referred to henceforth as ‘the general guideline’), which in principle is applicable to monoclonal antibodies (mAbs). However, some specific aspects of immunogenicity are exclusively or primarily relevant for mAbs, novel mAb derivatives (eg Fab fragments, scfv, nanobodies, minibodies) or biosimilar mAbs and these are addressed in this guideline. Monoclonal Antibodies (mAbs) comprise a large important class of therapeutic biologicals. The range of clinical indications with potential for treatment with mAbs is very wide. Many mAb products are known to be associated with unwanted immunogenicity and in some cases the immunogenicity causes impaired clinical responses or rarely serious adverse reactions which require clinical intervention. The wide range of mAbs in development, and approved for different clinical indications precludes specific guidelines that are pertinent to all situations. This guideline addresses the major quality and clinical aspects that are important to consider in order to adequately address the problems with detection of and risk related to the development of an immune response to the particular mAb in the particular clinical indication sought.

For Assistance with Toxicology Planning and Interpritation Click Here

Damien Bové is THE Drug Development and Regulatory Consultant (pharmaceutical or biotechnology), I work with my clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

Avoid Expensive Mistakes, Keep On Top of New and Changing Regulations for Free!

Sign up for the most value add free newsource you can get for free. We spend a huge amount of time and effort monitoring the main drug / device regulators websites for changes in the regulatory environment, and capture between 20 and 40 new regulations, rules and initiatives each month, and summaries them in a fantastic FREE monthly Regulatory and Market Round Up. You can Un-Subscribe at any time and we don not share your details with anybody. You can’t afford to miss out on this service. Just fill in the form below.

“Please note that the pages on this website are designed to provide you with general information only. We make no warranties, representations or undertakings about any of its content. This includes the completeness, accuracy and fitness for any particular purpose, or the content of any third party site referred to or accessed through it. You are personally responsible for ensuring that the information is correct and we will not be held liable or accountable for any mistakes that occur.”

Full Text Here

This guideline lays down the non-clinical and clinical requirements for monoclonal antibody (mAb) containing medicinal products claiming to be similar to another one already marketed. The non-clinical section addresses the pharmaco-toxicological requirements and the clinical section the requirements for pharmacokinetic, pharmacodynamic, efficacy and safety studies as well as pharmacovigilance aspects.

As regards non-clinical development, a risk-based approach to evaluate mAb on a case-by-case basis is recommended to decide on the choice and extent of in vitro and in vivo studies. In vitro studies should be conducted first, and a decision then made as to the extent of what, if any, in vivo work will be required. If an in vivo study is deemed necessary, the focus of the study (pharmacokinetics, pharmacodynamics, and/or safety; normally comparative in nature) depends on the need for additional information, and the availability of a relevant animal model. The conduct of large comparative toxicological studies in non-human primates is not recommended. As regards clinical development, a comparative pharmacokinetic study in a sufficiently sensitive and homogeneous study population (healthy volunteers or patients) normally forms an integral part of biosimilar mAb development, usually in a parallel group design due to the long half-life of mAbs and potential interference of immunogenicity. The design of a pharmacokinetic study will depend on various factors, including clinical context, linear versus non-linear pharmacokinetics etc. Pharmacokinetic data can be helpful to extrapolate data on efficacy and safety between different clinical indications of the reference mAb. It may, on a case-by-case basis, be necessary to undertake multidose pharmacokinetic studies in patients, or even to perform pharmacokinetic assessment as part of the clinical study designed to establish similar efficacy and safety. Pharmacokinetic studies can be combined with pharmacodynamic (PD) endpoints, where available. Sponsors should always explore possibilities to study dose concentration-response relationships since this approach, if successful, may provide strong evidence of biosimilarity. Normally, similar clinical efficacy should be demonstrated in adequately powered, randomised, parallel group comparative clinical trial(s), preferably double-blind, normally equivalence trials. To establish biosimilarity, deviations from disease-specific guidelines issued by the CHMP (for example, choice of endpoint, timepoint of analysis of endpoint, nature or dose of concomitant therapy, etc) may be warranted. The focus of the biosimilarity exercise is to demonstrate similar efficacy and safety compared to the reference product, not patient benefit per se, which has already been shown for the reference product. In principle, the most sensitive model and study conditions (pharmacodynamic or clinical) should be used in a homogeneous patient population, since this reduces variability and thus the sample size needed to prove similarity, and can simplify interpretation. In cases where comparative pharmacodynamic studies are claimed to be most suitable to provide the pivotal evidence for similar efficacy, Applicants will have to choose clinically relevant markers and also provide sufficient reassurance of clinical safety, particularly immunogenicity. It may be difficult to define an appropriate equivalence margin for pharmacodynamic equivalence based on clinical relevance, and to provide reassurance that all relevant aspects of a biosimilar mAb as regards similar clinical efficacy are covered. Comparable safety with respect to pharmacologically mediated adverse reactions could also be considered as a measure of biosimilarity. Extrapolation of clinical efficacy and safety data to other indications of the reference mAb, not specifically studied during the clinical development of the biosimilar mAb, is possible based on the results of the overall evidence provided from the biosimilarity exercise and with adequate justification. As regards post-authorisation follow-up, the concept to be proposed by Applicants may have to exceed routine pharmacovigilance, and may have to involve more standardized environments.

For Assitance with Developing Biotechnology Products Click Here

Damien Bové is THE Drug Development and Regulatory Consultant (pharmaceutical or biotechnology), I work with my clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

Avoid Expensive Mistakes, Keep On Top of New and Changing Regulations for Free!

Sign up for the most value add free newsource you can get for free. We spend a huge amount of time and effort monitoring the main drug / device regulators websites for changes in the regulatory environment, and capture between 20 and 40 new regulations, rules and initiatives each month, and summaries them in a fantastic FREE monthly Regulatory and Market Round Up. You can Un-Subscribe at any time and we don not share your details with anybody. You can’t afford to miss out on this service. Just fill in the form below.

“Please note that the pages on this website are designed to provide you with general information only. We make no warranties, representations or undertakings about any of its content. This includes the completeness, accuracy and fitness for any particular purpose, or the content of any third party site referred to or accessed through it. You are personally responsible for ensuring that the information is correct and we will not be held liable or accountable for any mistakes that occur.”

Full Text Here

This guideline addresses issues relating to the unwanted immunogenicity of monoclonal antibodies intended for clinical use. These include the variability of immunogenicity of mAbs and its consequences, prediction and minimizing immunogenicity, the clinical consequences of immunogenicity, assay related problems, assessing neutralizing antibodies induced by monoclonal antibodies and consideration of a risk-based approach for the evaluation of immunogenicity of monoclonal antibodies.

Unwanted immunogenicity can be a significant problem in the treatment of patients with therapeutic biologicals. The importance of the unwanted immunogenicity problem has led to the preparation and adoption of the ‘Guideline on Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins’ by the CHMP (adopted April 2008, referred to henceforth as ‘the general guideline’), which in principle is applicable to monoclonal antibodies (mAbs). However, some specific aspects of immunogenicity are exclusively or primarily relevant for mAbs, novel mAb derivatives (eg Fab fragments, scfv, nanobodies, minibodies) or biosimilar mAbs and these are addressed in this guideline. Monoclonal Antibodies (mAbs) comprise a large important class of therapeutic biologicals. The range of clinical indications with potential for treatment with mAbs is very wide. Many mAb products are known to be associated with unwanted immunogenicity and in some cases the immunogenicity causes impaired clinical responses or rarely serious adverse reactions which require clinical intervention. The wide range of mAbs in development, and approved for different clinical indications precludes specific guidelines that are pertinent to all situations. This guideline addresses the major quality and clinical aspects that are important to consider in order to adequately address the problems with detection of and risk related to the development of an immune response to the particular mAb in the particular clinical indication sought.

For Assistance with the Development on Monoclonal Antibodies Click Here

Damien Bové is THE Drug Development and Regulatory Consultant (pharmaceutical or biotechnology), I work with my clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

Avoid Expensive Mistakes, Keep On Top of New and Changing Regulations for Free!

Sign up for the most value add free newsource you can get for free. We spend a huge amount of time and effort monitoring the main drug / device regulators websites for changes in the regulatory environment, and capture between 20 and 40 new regulations, rules and initiatives each month, and summaries them in a fantastic FREE monthly Regulatory and Market Round Up. You can Un-Subscribe at any time and we don not share your details with anybody. You can’t afford to miss out on this service. Just fill in the form below.

“Please note that the pages on this website are designed to provide you with general information only. We make no warranties, representations or undertakings about any of its content. This includes the completeness, accuracy and fitness for any particular purpose, or the content of any third party site referred to or accessed through it. You are personally responsible for ensuring that the information is correct and we will not be held liable or accountable for any mistakes that occur.”

Full Text Here

Monoclonal Antibodies (mAbs) comprise a large important class of therapeutic biologicals. Different mAb products share some properties, e.g. on a functional level, but differ in aspects like the mechanism of action. The complexity of mAbs is a challenge for the development of new mAb products that are claimed to be similar to marketed mAbs. Nevertheless, such mAbs are being developed, and CHMP has given scientific advice for the development of some individual products. This guideline lays down the non-clinical and clinical requirements for monoclonal antibody-containing medicinal products claiming to be similar to another one already marketed, i.e. similar biological medicinal products (biosimilars). It may also include a chapter on quality aspects more pertinent to biosimilar monoclonal antibodies, should BWP/BMWP consider it necessary. The non-clinical section addresses the pharmaco-toxicological assessment. The clinical section addresses the requirements for pharmacokinetic, pharmacodynamic, efficacy and safety studies as well as the risk management plan.

Guidance for development of biosimilars is already available, including class-specific guidance. With monoclonal antibodies, a next step is taken towards more complex and large molecules. Whilst available guidances (Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues, CHMP/49348/05; Production and Quality Control of Monoclonal Antibodies and Related Substances, CHMP/BWP/157653/07) appear to provide sufficient guidance on quality of biosimilar mAbs, there are several issues pertinent to non-clinical and clinical development that are not sufficiently covered by current guidances. There are several areas of increased complexity as regards design of a biosimilar development programme in these fields, which require careful consideration and exploration of further science-based approaches.
The guideline has in its main focus monoclonal antibodies, but principles may also be applicable to related proteins like, for example, fusion proteins.

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

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“Please note that the pages on this website are designed to provide you with general information only. We make no warranties, representations or undertakings about any of its content. This includes the completeness, accuracy and fitness for any particular purpose, or the content of any third party site referred to or accessed through it. You are personally responsible for ensuring that the information is correct and we will not be held liable or accountable for any mistakes that occur.”