The FDA is provided guidance to assist sponsors in developing vaccine to protect against global infectious diseases. The guidance focuses on development of licence of vaccines for infectious diseases or conditions endemic in areas outside the United States. It aims to clarify regulatory status and guidance already published for development of these products.
Full guidance given below
Posted in clinical, pre-clinical
Tagged FDA, global, guidance, infectious disease, vaccine development
The FDA is provided this guidance in order to make recommendations to industry for describing the nonclinical late radiation toxicity studies to determine potential late radiation effects of therapeutic radiopharmaceutical agents. This is to help minimise the risk of late occurring radiation toxicities in clinical trials. Other guidance are available for conventional non-safety studies but this guidance focuses solely on late radiation safety concerns that are unique to therapeutic radiopharmaceuticals. The unique safety concerns result from the risk of irreversible toxicity when these agents deliver high dose of ionising radiation to normal organs.
full guidance given below
Posted in pre-clinical
Tagged FDA, late radiation, Nonclinical, safety evaluation, therapeutic radiopharmaceuticals
EMA has publishes guidelines to assist companies understand key elements required for validation of a bioanalytical method. It focuses on the validation geared towards quantitative concentration data used for pharmacokinetic and toxicokinetic parameter definitions. Guidance on criteria of application of these validated methods in the routine analysis of study samples from animals and humans.
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This guideline defines key elements necessary for the validation of bioanalytical methods. The guideline focuses on the validation of the bioanalytical methods generating quantitative concentration data used for pharmacokinetic and toxicokinetic parameter determinations. Guidance and criteria are given on the application of these validated methods in the routine analysis of study samples from animal and human studies.
Measurement of drug concentrations in biological matrices (such as serum, plasma, blood, urine, and saliva) is an important aspect of medicinal product development. Such data may be required to support applications for new actives substances and generics as well as variations to authorised drug products. The results of animal toxicokinetic studies and of clinical trials, including bioequivalence studies are used to make critical decisions supporting the safety and efficacy of a medicinal drug substance or product. It is therefore paramount that the applied bioanalytical methods used are well characterised, fully validated and documented to a satisfactory standard in order to yield reliable results.
Acceptance criteria wider than those defined in this guideline may be used in special situations. This should be prospectively defined based on the intended use of the method.
Posted in biotechnology, Diagnostic, pre-clinical
Tagged analyses, bioanalytical method, CHMP, EMEA, Guideline, validation
In the current EMA guideline on similar biological medicinal products containing biotechnology derived proteins as active substances, nonclinical and clinical issues lays down the requirements of such products to determine its similarity to one another. This guidance came into effect in June 2006, however since then several by a similar products have come to the market and the number of guidance is in this area has increased significantly and the regulatory framework is becoming wider.
The EMA considers it necessary to update these guidance and bring together a number of issues into a single document. In order to tackle the complex issues that are arising. And to allow for the WHO guidelines on evaluation of similar biotherapeutic products. And also to be compliant with the Three R principals (replacement, reduction and refinement) with regard to the use of animal experiments.
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The Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (EMEA/CHMP/BMWP/42832/2005) lays down the nonclinical and clinical requirements for a biological medicinal product claiming to be similar to another one already marketed. This guideline came into effect in June 2006. Since then several biosimilar products
have come into the EU market, the number of scientific advices given by the CHMP on the development of biosimilar products has increased significantly and the regulatory framework is becoming wider, e.g. the draft guideline of the biosimilar monoclonal antibodies is being finalised. .An increasing number of biosimilar products are under development, especially biosimilar monoclonal antibodies. The development of more complex biosimilar medicinal products is challenging, and several issues in the development are under re-evaluation. These include the selection of relevant species for
non-clinical studies, need for clinical equivalence studies and other issues of the design of the pivotal clinical studies, role of biomarkers, amount of immunogenicity data needed, and the possibility to
extrapolate to other indications. The WHO Guidelines on Evaluation of Similar Biotherapeutic Products with detailed recommendations on clinical development were published in October 2009. In addition,
the EMA is emphasizing the need to follow the 3 R principles (replacement, reduction and refinement) with regard to the use of animal experiments. All these factors suggest revising the current guideline.
The current regulatory requirements quality, nonclinical and clinical development of influenza vaccines are currently stated in several regulatory documents. These guidelines were drafted and appointed a different time points over several years before the onset of the major pandemics in 2009 - 2010.
The EMA has recognised a need to update the guidance of requiring the manufacturing, nonclinical and clinical development of complaints of vaccines. Especially in the light of novel vaccine technologies such as recombinant proteins, viruslike particles (the LPs) DNA or live viral vectors.
For these reasons the EMA may has issued this concept paper.
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Regulatory requirements for the quality, non-clinical and clinical development of influenza vaccines are
currently stated in several documents including multidisciplinary guidelines such as
EMEA/CPMP/4986/03, CHMP/VWP/263499/06, the Note for guidance on harmonisation of requirements
for influenza vaccines CPMP/BWP/214/96 and the Guideline on dossier structure and content for
pandemic influenza vaccine marketing authorisation application (EMEA/CPMP/VEG/4717/03 rev. 1).
These guidelines were drafted and adopted at different time points and over several years before the
onset of the 2009-2010 influenza pandemic and each addresses one of seasonal influenza vaccines,
pre-pandemic or pandemic vaccines.
The need to update the available guidelines regarding the manufacturing, non-clinical and clinical
development of influenza vaccines was recognised during and following the 2009-2010 influenza
pandemic. More recently, issues encountered and experience gained during requests for CHMP
scientific advice and the processing of several applications for marketing authorisation of influenza
vaccines have underlined the desirability of updating the existing guidelines. In addition, it is
anticipated that novel influenza vaccines could be based on e.g. recombinant proteins, virus-like
particles (VLPs), DNA or live viral vectors and there is a need to consider the regulatory expectations
that would apply to such products.
Although current and future influenza vaccines may vary in nature and composition they all aim to
prevent clinically manifest influenza by means of eliciting a protective immune response. Therefore the
development of a single consolidated guidance document on the quality, non-clinical and clinical
requirements for influenza vaccines seems to be both feasible and appropriate.
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The Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (EMEA/CHMP/BMWP/42832/2005) lays down the nonclinical and clinical requirements for a biological medicinal product claiming to be similar to another one already marketed. This guideline came into effect in June 2006. Since then several biosimilar products have come into the EU market, the number of scientific advices given by the CHMP on the development of biosimilar products has increased significantly and the regulatory framework is becoming wider, e.g. the draft guideline of the biosimilar monoclonal antibodies is being finalised.
An increasing number of biosimilar products are under development, especially biosimilar monoclonal antibodies. The development of more complex biosimilar medicinal products is challenging, and several issues in the development are under re-evaluation. These include the selection of relevant species for non-clinical studies, need for clinical equivalence studies and other issues of the design of the pivotal clinical studies, role of biomarkers, amount of immunogenicity data needed, and the possibility to extrapolate to other indications. The WHO Guidelines on Evaluation of Similar Biotherapeutic Products with detailed recommendations on clinical development were published in October 2009. In addition, the EMA is emphasizing the need to follow the 3 R principles (replacement, reduction and refinement) with regard to the use of animal experiments. All these factors suggest revising the current guideline.
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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This guidance describes an approach to estimating possible human developmental or reproductive risks associated with drug or biological product exposure when a nonclinical finding of toxicity has been identified, but definitive human data are unavailable. The guidance is intended for applicants of new drug applications (NDAs) and biologics licensing applications (BLAs). The recommendations included here will also help to ensure a consistent review of reproductive and developmental toxicity data among Center for Drug Evaluation and Research (CDER) review staff.
This guidance does not (1) give detailed advice about labeling or placement of toxicity information in product labeling (for information on labeling, see 21 CFR 201.57); or (2) discuss clinical data or the integration of nonclinical and clinical data.
The approach presented here for assessing nonclinical reproductive and developmental toxicity data involves the integration and careful consideration of a variety of different types of nonclinical information: reproductive toxicology; general toxicology; and toxicokinetic and pharmacokinetic information, including absorption, distribution, metabolism, and elimination data. The approach is used when there is a toxicity finding and focuses on assessing the likelihood that a drug will increase the risk of adverse human developmental or reproductive outcomes. The approach includes noting when studies were not conducted or when they were not performed using relevant model systems or at appropriate dose ranges. The general principles described here (i.e., a comprehensive analysis of available data) will typically be relevant to both drug and biological products, although some factors may not apply to biological products, because data may not be available for all factors considered in this guidance (e.g., cross-species concordance, dose-response, metabolism, relative exposure (animal : human) of >25-fold). For some oncology products (e.g., cytotoxics), certain aspects of the guidance may not apply because patients may be dosed at the maximum tolerated dose (MTD). Note: Available clinical information to evaluate a drug’s potential to increase the risk of an adverse developmental or reproductive outcome in humans should be evaluated separately and, when definitive, can supersede any nonclinical findings.
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.
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.
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There has been a significant interest to develop drug delivery methods for potent albeit sometimes toxic, highly lipophilic/poorly water soluble, unstable compounds, or for tissue targeting of highly water soluble compounds. One of the strategies has been encapsulation of the active substance(s) in the aqueous phase of a liposome, or incorporation or binding to the lipid components. Liposomes are classically described as vesicles composed of one or more concentric lipidic bi-layers. Such variants include, but are not limited to, multi-vesicular liposomes, polymer-coated vesicles and lipidic complexes. In any given product, a proportion of the active substance could also be extra-liposomal, free in bulk solution.
Early parenteral liposomal products were found to have a number of critical pharmacokinetic properties including rapid recognition and removal by the monocyte phagocyte system (MPS) and premature drug-release (instability). It was also recognized that the physicochemical properties of the liposomes, such as particle size, membrane fluidity, surface-charge and composition were relevant determinants of such in vivo behaviour. Some formulations were found to benefit from the addition of sterols (e.g. cholesterol), size reduction and surface modification with covalently linked polymers (e.g. polyethylene glycol [PEG]), to provide significant improvements.
Contrary to products where the active substance is in simple solution, liposomal medicinal products have formulation-specific distribution characteristics in-vivo and similar plasma concentrations may not correlate to equivalent therapeutic performance. The complete characterisation of the pharmacokinetics and tissue distribution of a new liposomal product is critical to establish safe and effective use because formulation differences may substantially modify efficacy/safety due to specific cell interactions and distribution characteristics which are not detectable by conventional bioequivalence testing alone. The aims of developing the originator and the evidence supporting its use should be taken into account when designing the non-clinical and clinical programme for the liposomal products developed with reference to that particular originator.
The reference liposomal product used for comparability investigations should be sourced from within the EU and should be used as a comparator in all proposed characterization studies.
This document discusses the principles for assessing liposomal products developed with reference to an innovator liposomal product but does not aim to prescribe any particular analytical, nonclinical or clinical strategy.
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.
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.”
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The existing guideline on local tolerance is dated 1 March 2001 (1). Over the past years, newer routes of administration, e.g. transdermal systems, are being used more frequently and a shift has been observed towards the regulatory acceptance of scientifically valid in vitro methods as well as formally validated in vitro methods as part of an integrated testing strategy. In addition, recently the ICH Guideline M3(R2) – Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorisation for Pharmaceuticals (2) – came into force and included a section on local tolerance.
The focus on local tolerance testing has broadened over the last few years, with newer methods of drug delivery being developed. In vitro methods are becoming an integral part of the non-clinical testing local tolerance testing programme of human medicinal products and approaches aiming at reducing or refining animal studies are routinely implemented in regulatory guidelines, where applicable.
Taking into account the progress in the development of newer drug delivery strategies, a revision of the Guideline on Non-Clinical Local Tolerance Testing of Medicinal Products is warranted. The revision will also aim to harmonise local tolerance testing requirements with those out lined in the ICH Guideline M3(R2) – Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorisation for Pharmaceuticals (2).
Local tolerance should be evaluated prior to human exposure of a product in order to ascertain whether the product (both active substance and excipients) is tolerated at contact sites of the body following clinical use. Local tolerance testing should be conducted according to “state of the art” methods.
Although non-clinical studies still heavily rely on animal data, adherence to the 3Rs principles is clearly evident both at the EU and ICH level. Various in vitro test systems are currently used for different purposes and at different time-points within the non-clinical development programme. Wherever possible, studies on animals, including studies on local tolerance, should be substituted by validated in vitro tests.
The introduction of tailor-made non-clinical testing strategies, involving both in vivo and in vitro testing, is expected to entail a reduction of animal use.
The full revision of Directive 86/609/EC was recently completed and resulted in the adoption of Directive 2010/63/EU on the protection of animals used for scientific purposes on 3 June 2010 [3]. This Directive will take effect on 1 January 2013. Different articles relate to the application of the 3R’s. As such, article 4 clearly states that:
Member States shall ensure that, wherever possible, a scientifically satisfactory method or testing strategy, not entailing the use of live animals, shall be used instead of a procedure. Member States shall ensure that the number of animals used in projects is reduced to a minimum without compromising the objectives of the project.
Member States shall ensure refinement of breeding, accommodation and care, and of methods used in procedures, eliminating or reducing to the minimum any possible pain, suffering, distress or lasting harm to the animals.
Therefore, the Guideline on Non-Clinical Local Tolerance Testing of Medicinal Products (1) should be revised in order to take into account scientific and legislative progress and to also to formulate guidance on when and how 3R alternatives (replacement, reduction and refinement) can be considered for regulatory acceptance.
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.
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.”
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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.
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.”
Posted in pre-clinical
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The Guideline on Similar Medicinal Products containing Low-Molecular-Weight Heparins (LMWH) lays down the non-clinical and clinical requirements for the development of LMWH claimed to be similar to a
reference product already authorised in the EU. This guideline came into effect in October 2009. So far, no biosimilar LMWH has been licensed in the EU.
LMWHs are complex sugar molecules and difficult to characterise. Structure-activity relationship is not fully elucidated and other mechanisms of action beyond Anti-Xa and Anti-IIa activity may be important for the pharmacological activity. The current CHMP guidance requires a comparative clinical trial demonstrating similar efficacy and safety of the biosimilar versus the reference LMWH in the prevention of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery. Based on scientific and analytical progress, e.g. in the field of physicochemical characterisation, it can
be discussed if in exceptional cases convincing analytical data can substitute for clinical data, at least for clinical efficacy.
The BMWP suggests discussing the inclusion of considerations about the possibility to modify clinical data requirements in the guideline taking into account the extent and quality of characterisation and the possibility to convincingly ensure similar efficacy and safety (including immunogenicity) of the biosimilar and the reference LMWH by other means. It should be discussed if a reduction in clinical data requirements could, in exceptional cases, be possible.
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.
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.”
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There has been a significant interest to develop drug delivery methods for potent albeit sometimes toxic, highly lipophilic/poorly water soluble, unstable compounds, or for tissue targeting of highly water soluble compounds. One of the strategies has been encapsulation of the active substance(s) in the aqueous phase of a liposome, or incorporation or binding to the lipid components. Liposomes are classically described as vesicles composed of one or more concentric lipidic bi-layers. Such variants include, but are not limited to, multi-vesicular liposomes, polymer-coated vesicles and lipidic complexes. In any given product, a proportion of the active substance could also be extra-liposomal, free in bulk solution.
Early parenteral liposomal products were found to have a number of critical pharmacokinetic properties including rapid recognition and removal by the monocyte phagocyte system (MPS) and premature drug-release (instability). It was also recognized that the physicochemical properties of the liposomes, such as particle size, membrane fluidity, surface-charge and composition were relevant determinants of such in vivo behaviour. Some formulations were found to benefit from the addition of sterols (e.g. cholesterol), size reduction and surface modification with covalently linked polymers (e.g. polyethylene glycol [PEG]), to provide significant improvements.
Contrary to products where the active substance is in simple solution, liposomal medicinal products have formulation-specific distribution characteristics in-vivo and similar plasma concentrations may not correlate to equivalent therapeutic performance. The complete characterisation of the pharmacokinetics and tissue distribution of a new liposomal product is critical to establish safe and effective use because formulation differences may substantially modify efficacy/safety due to specific cell interactions and distribution characteristics which are not detectable by conventional bioequivalence testing alone. The aims of developing the originator and the evidence supporting its use should be taken into account when designing the non-clinical and clinical programme for the liposomal products developed with reference to that particular originator.
The reference liposomal product used for comparability investigations should be sourced from within the EU and should be used as a comparator in all proposed characterization studies.
This document discusses the principles for assessing liposomal products developed with reference to an innovator liposomal product but does not aim to prescribe any particular analytical, nonclinical or clinical strategy.
This reflection paper should be read in connection with the following documents:
Directive 2001/83/EC, as amended
Part II of the Annex I of Directive 2001/83/EC, as amended
CHMP/437/04 Guideline on similar biological medicinal products
Annex II to Note for Guidance on Process Validation CHMP/QWP/848/99 and EMEA/CVMP/598/99 Non Standard Processes (CPMP/QWP/2054/03)
Guideline on similar medicinal products containing biotechnology-derived proteins as active substances: quality issues
ICH topic Q5E – Comparability of biotechnological/biological products
ICH topic S6 – Note for guidance on Pre-clinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (CPMP/ICH/302/95)
ICH topic E9 statistical principles for clinical trials – Note for guidance on statistical principles for clinical trials (CPMP/ICH/363/96)
ICH topic E10 – Note for guidance on choice of control group in clinical trials (Guideline on the choice of the non-inferiority margin (CPMP/EWP/2158/99)
Points to consider on switching between superiority and non-inferiority (CPMP/EWP/482/99)
Note for guidance of bioavailability and bioequivalence (CPMP/EWP/QWP/1401/98, rev 1 corr *)
This reflection paper is intended to assist in the generation of relevant quality, non-clinical and clinical data to support a marketing authorisation of intravenous liposomal products developed with reference to an innovator liposomal product. Hence, this document should facilitate a decision on the following issues:
pharmaceutical data needed as evidence of product comparability between test and reference or after changes to a liposomal product, to support comparative safety and efficacy
Necessity of pre-clinical and clinical studies (including ‘usual’ bioequivalence studies) and circumstances which may allow to waive certain studies
The principles outlined in this reflection paper might also be considered to be applicable to other novel types of “liposome-like” and vesicular products which may be under development including those to be administered by routes other than intravenous administration.
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.
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.”
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The current Guidance on Similar Medicinal Products containing Recombinant Human Insulin provides recommendations for the development of recombinant soluble (short-acting) human insulin claimed to
be similar to a reference product already authorised in the EU. This guideline came into effect in June 2006 but, so far, no biosimilar insulin has been licensed in the EU. Three products applied for by the same Applicant were withdrawn prior to Opinion.
More recently, several EMA scientific advices on the development of biosimilar insulins, particularly insulin analogues, have been requested. Insulin analogues and long-acting human insulin preparations are currently not covered by the above guideline. In addition, different study populations, study designs and insulin doses have been proposed for the pivotal PD study (clamp study). Moreover, the guideline does not appear to be clear on whether the PK study can be combined with the PD study. Questions were raised regarding the most suitable patient population and size of the clinical safety study. It has also been questioned whether non-clinical studies would always be needed in the development of biosimilar insulins.
Although similar considerations and scientific principles may apply to biosimilar insulin analogues and long-acting human insulin preparations as to soluble insulins, some thoughts may need to be given to the sensitivity of the clamp study for detection of potential differences in the duration of action or other summary measures between long-acting insulin formulations due to the flat PK profile of these insulins
and high variability in the tail part of the clamp study. In addition, further considerations regarding the study population (patients with type 1 diabetes versus healthy volunteers), study design (e.g. with
versus without basal insulin infusion) and insulin dose in the clamp study could be included. It may be clarified that the comparative PK evaluation is usually expected to be part of the clamp (PD) study. It could also be clarified that no formal non-inferiority testing for antibody frequency is expected in the safety study and that inclusion of patients with type 1 and type 2 diabetes may be appropriate. Regarding non-clinical requirements, a risk-based approach may be introduced.
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.
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.
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For generic products containing a small molecule it is generally accepted that once the molecule is in the blood – free in solution or bound to plasma proteins – the further fate of the molecule in the generic product will not be different from the molecule in the reference product. The physicochemical features (including the size of the molecules) will be identical and regarding their tissue uptake, metabolism and finally excretion no differences are expected. This postulate is the basis of regulatory approval of generic products, which is based on a comparison of physicochemical features and plasma concentrations of the active ingredient in the generic and in the reference medicinal product. Accordingly, for products with small molecules in solution for intravenous use specific bioequivalence studies are not required. For nanoparticle medicinal products this approach is generally not valid.
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.
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.
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Posted in pre-clinical
Tagged comparability studies, Iron nanoparticles, Non-clinical, tissue distribution
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The European Medicines Agency has launched a public consultation on the need to revise its position on the replacement of animal studies with alternative models.
The concept paper on the need for revision of the position on the replacement of animal studies by in-vitro models, published this week, discusses the need to update the Agency’s 1997 position paper on the feasibility of replacing methods using animals during the development of medicines.
The Agency is considering updating its position, because the past few years have seen a shift towards greater acceptance of in-vitro methods by medicines regulators. Focus has also broadened from an emphasis on the replacement of animal testing to the inclusion of all three ‘R’s: replacement, reduction and refinement.
The concept paper was prepared by the Safety Working Party and adopted by the Committee for Medicinal Products for Human Use (CHMP). It is open for consultation until 30 June 2011.
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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A Position on the Replacement of Animal Studies by in vitro Models was adopted by the Committee for Medicinal Product for Human Use (CHMP) in February 1997 [1]. This paper addresses the feasibility of replacing in vivo animal studies by in vitro investigations in the non-clinical development of medicinal products. Furthermore, considerations regarding validation procedures for in vitro methods and their incorporation into CHMP guidelines are presented.
Over the past years a shift has been observed towards the regulatory acceptance of scientifically valid in vitro methods as well as formally validated in vitro methods as part of an integrated testing strategy. Moreover focus has broadened to the application of all 3 R’s, replacement, reduction and refinement, whilst historically much emphasis has been placed only on replacement of animal studies by one or more in vitro or in silico approaches. Large EU initiatives such as the European Centre for the Validation of Alternative Methods (ECVAM) and the European Partnership for Alternative Approaches to Animal Testing (EPAA) facilitate progress in this field. Finally, the application of all 3 R’s is currently embedded the drafting process of non-clinical regulatory guidance both at EMA and ICH level.
In vitro methods are already an integral part of the non-clinical testing programme of human medicinal products, either as pivotal, supportive or as exploratory studies. Moreover, approaches aiming at reducing or refining animal studies are routinely implemented in regulatory guidelines, where applicable. As such, although regulatory acceptance of 3R alternatives is currently possible via multiple and flexible approaches, at present there is no clearly defined process for regulatory acceptance of all 3R alternatives (refinement, reduction and replacement).
Taking into account the progress in the field of the 3R’s as described above, a thorough revision of the Position on the Replacement of Animal Studies by in vitro Models [1] is needed in order to ensure that:
the focus is extended to include replacement, reduction and refinement alternatives.
a process for regulatory acceptance of all 3R alternatives (replacement, reduction and refinement) is described.
different possible approaches for regulatory acceptance of 3R alternatives are clearly described, and therefore the need for formal validation studies versus proof of scientific validity should be discussed.
if applicable, formal validation requirements are updated according to the current state-of-the-art.
the legal requirements related to the application of the 3Rs as per Directive 2010/63/EC are adequately reflected.
This revision includes a change in title of the guideline to be developed as compared to the current position paper in order to take into account the above considerations.
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.
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.
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Posted in pre-clinical
Tagged in vitro, in vivo, reduction, refinement, regulatory acceptance, replacement, validation
Besides the ongoing efforts to develop preventive vaccines, other HIV prevention methods are currently also under development: oral and topical Pre-Exposure Prophylaxis (PrEP) for HIV sexual transmission.
After decades of research in these fields, the positive results of two recent studies have called the attention of the scientific community and regulators.
1- tenofovir 1% vaginal gel has been shown to reduce the risk of HIV acquisition by 39% (incidence rate ratio versus placebo = 0.61 (CI: 0.4 to 0.94; p=0.017) in the double blind placebo-controlled CAPRISA study performed in 889 women in South Africa.
2- the oral fixed dose combination Truvada (tenofovir and emtricitabine) has been shown to reduce the HIV incidence as compared to placebo by 44% (CI: 15 to 63; p=0.005) in the iPrEx study performed in 2499 men who have sex with men (MSM).
These approaches are developed as potential “complementary” tools to the standard prevention that still mainly relies on condom use.
This concept paper addresses the need for a reflection paper on the key aspects to be covered by the non clinical and clinical developments of oral and topical PrEP in view of potential future applications for marketing authorisation, including applications for a scientific opinion under article 58 for countries outside the EU.
Although it is acknowledged that different populations at risk could be targeted by oral and topical (genital and rectal) PrEP in different epidemiological contexts (from low level to generalised HIV epidemics) with varying HIV prevalences, both oral and topical PrEP approaches are being addressed in parallel in this document as they will raise similar issues.
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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Posted in clinical, pre-clinical
Tagged guidance, HIV, oral Pre-exposure Prophylaxis (PrEP), Prevention, topical PrEP
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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.
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.
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.
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The scope of this paper is restricted to consideration of differences in isomeric composition of a product compared to a racemic reference active substance. The question being addressed is “when should an enantiomer be regarded as a new active substance (NAS) in relation to a reference active substance which is a racemate and what level of evidence would be required to confirm the designation as a new active substance”?
According to the current legislation, Article 10.2.b of Directive 2001/83/EC, as amended, states that the different salts, esters, ethers, isomers, mixture of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance unless they differ significantly in properties with regard to safety and/or efficacy. In such cases additional information providing proof of the safety and/or efficacy of the various salts, esters or derivatives of an authorised active substance must be supplied by the applicant.
In addition according to the Notice to Applicant (Volume 2A Chapter 1), a new chemical, biological or radiopharmaceutical active substance includes:
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.
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.
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Posted in clinical, pre-clinical, regulatory
Tagged enantiomers, New active substance
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The aim of this question-and-answer document is to provide clarification and harmonisation of the ‘Guideline on the limits of genotoxic impurities’ (EMEA/CHMP/QWP/251344/2006), published in 2006.
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.
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.
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The FDA, are issuing this guidance to provide you, sponsors who are developing cellular therapies for the treatment of cardiac disease, with recommendations on the design of preclinical and clinical studies, and on the chemistry, manufacturing, and controls (CMC) information to include in an Investigational New Drug application (IND) for cellular theracardiac disease. This guidance also provides recommendations regarding the information thyou should submit on the product’s delivery system. Sponsors should consult with FDA concerning the regulatory pathway for the use of cell selection devices.
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.
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.”
BBC Health News