Tag Archives: immunogenicity

EMA Publish Closed Workshop on Biosimilar Monoclonal Antibodies and Immunogenicity of Monoclonal Antibodies

The aim of the workshop was to create a forum for discussion among stakeholders – academia, learned societies, regulators and industry around the European Medicines Agency (EMA) Draft guideline on ‘Similar biological medicinal products containing monoclonal antibodies’ (0TEMA/CHMP/BMWP/403543/20100T) and Draft guideline on ‘Immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use’ (EMA/CHMP/BMWP/86289/2010), which were being finalised and were open for public consultation from November 2010 to May 2011.

For further details, please view the document below.

EMA Publish Guideline on Immunogenicity Assessment of Monoclonal Antibodies Intended for In-Vivo Clinical Use

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

For further details, please view the document below.

EMA publishes guidelines on clinical investigation of recumbent humanplasma derived factor IX products

This guideline developed by the EMA is to assist companies in providing the documentation that is required for when making and marketing authorisation application for recombinant human plasma derived factor 9 product. Specifically the product being used to treat patients the prevention of bleeding in haemophilia B. The guidance covers the clinical investigations to be conducted the prick and post marketing authorisation, this guide is also provides information when there is a significant change in the manufacturing process.

excerpt from guidance

full text here

This guideline describes the information to be documented when an application for a marketing authorisation for recombinant or human plasma-derived factor IX products is made for use in treatment and prevention of bleeding in patients with haemophilia B. The guideline covers clinical investigations to be conducted pre- and post-marketing authorisation. Guidance is also provided for authorised products where a significant change in the manufacturing process has been made.
Timeline history of guideline: The original Note for Guidance on Clinical Investigation of Human Plasma Derived FVIII and FIX Products (CPMP/BPWG/198/95) came into operation on 14 February 1996. The first revision (CPMP/BPWG/198/95 Rev. 1) came into operation in April 2001. The original Note for Guidance on Clinical Investigation on Recombinant FVIII and FIX Products (CPMP/BPWG/1561/99) came into operation in April 2001. Draft revisions of CPMP/BPWG/1561/99 and CPMP/BPWG/198/95 were released for public consultation in July 2007. Following this consultation, it was decided to reorganise the guidance to have separate documents: The Guideline on clinical investigation of recombinant and plasma derived factor VIII products (EMA/CHMP/BPWP/144533/2009) and the Guideline on clinical investigation of recombinant and plasma derived factor IX products (EMA/CHMP/BPWP/144552/2009).

 

DMA publishes concept paper on bio similars containing proteins

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.

excerpt from concept paper

full text here

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.

EMA Publish Concept Paper on Bio-Similar products containing Active Proteins: Clinical and Non-Clinical

EMA Publish Concept Paper on Bio-Similar products containing Active Proteins: Clinical and Non-Clinical

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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.



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EMA Publish Guideline on Immunogenicity assessment of Monoclonals for Clinical Use

EMA Publish Guideline on Immunogenicity assessment of Monoclonals for Clinical Use

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.

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EMA Publish Guideline on Immunogenicity Assessment of Monoclonals

EMA Publish Guideline on Immunogenicity Assessment of Monoclonals

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.

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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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FDA Guidance, Assay For Immunogenicity Testing of Proteins

FDA Guidance, Assay For Immunogenicity Testing of Proteins

Full text Here

This guidance provides recommendations to facilitate industry’s development of immune assays for assessment of the immunogenicity of therapeutic proteins during clinical trials. This document includes guidance for binding assays, neutralizing assays, and confirmatory assays. While the document does not specifically discuss the development of immune assays for animal studies, the concepts discussed are relevant to the qualification and validation of immune studies for preclinical evaluation of data.

This document does not discuss the product and patient risk factors that may contribute to immune response rates (immunogenicity).

In addition, this document does not specifically discuss how results obtained from immunoassays relate to follow-on biologic therapeutic proteins. However, elements of assay validation may affect comparability determinations of immune responses. FDA guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

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EMA, the European Drug Regulator Publishes Reflection paper on Quality, Non-Clinical and Clinical Issues related to the Development of Recombinant Adeno-Associated Viral Vectors

EMA, the European Drug Regulator Publishes Reflection paper on Quality, Non-Clinical and Clinical Issues related to the Development of Recombinant Adeno-Associated Viral Vectors

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Recombinant adeno-associated viral (rAAV) vectors are derived from the single stranded DNA virus adeno-associated virus which belongs to the genus dependovirus within the Parvoviridae family. As the name suggests the wild type virus is incapable of independent replication and relies on co-infection of a helper virus to enable a lytic replication cycle (Gonclaves, 2005). Adenovirus (Ad), herpes simplex virus (HSV), pseudorabies virus (PrV) and human papilloma virus (HPV) are known to support wild type AAV replication.
Infection with wild-type AAV is not associated with any pathogenic disease, and in the absence of a helper virus co-infection, the virus may integrate into the host cell genome or remain as an extrachromosomal form (Schnepp, 2005). In both situations the virus appears to remain latent. In-vitro studies suggest that wild-type viral DNA integration can occur occasionally in a site specific manner (19q13.3) (Kotin, 1990 and 1991 and 1992), but only at very high multiplicities of infection (Hüser, 2002), and this was originally considered to be a safety feature of vectors derived from this virus. However, it has been subsequently shown that site specific integration is dependent on the presence of both the inverted terminal repeats (ITR) and the Rep gene products (Weitzman, 1994; Linden, 1996), the latter of which is not present in rAAV; as such the site specific integration feature of these vectors is lost. The level of integration of DNA into the cellular chromosome in in-vivo models, however remains contentious. Nonetheless, long term protein expression (in-vivo) from the gene of interest inserted into rAAV vectors has been observed (Flotte, 1993; Kaplitt, 1994; Conrad, 1996; Monahan, 1998; Donahue, 1999; Stieger, 2006), even in the absence of identifiable genetic integration (Miller, 2004; Song, 2004; Flotte, 1994). This persistence is thought to be derived from stable concatemerized duplex genome forms (circular or linear molecules) that are transcriptionally active (Duan, 1998; Yang, 1999; Fisher, 1997).
Examples of diseases studied include haemophilia B (Manno, 2006 and 2003), cystic fibrosis (Flotte, 2003), Parkinson’s disease (Kaplitt, 2007), rheumatoid arthritis (www.targen.com [tgAAC94]), Leber’s congenital amaurosis (Bainbridge, 2008; Maguire, 2008; Jacobson, 2006), infantile neuronal ceroid lipofuscinosis (Worgall, 2008) and muscular dystrophy (Xiao, 2000). Furthermore non-clinical studies indicate rAAV expressing heterologous antigenic sequences (HPV16 – Kuck, 2006; HIV – Xin, 2001 and 2002; SIV – Johnson, 2005; malaria – Logan, 2007) can illicit both humoral and cellular immune responses, and modest immunogenicity has been reported in a phase I/II study using rAAV2 encoding HIV antigens (Mehendal, 2008). However, it has been suggested that cellular responses to the transgene products of rAAV vectors may be impaired (Lin, 2007), as such the utility of these vectors when used for prophylactic purposes needs further investigation.
There are currently 6 confirmed serotypes of adeno-associated virus (AAV-1 to -6) and 2 tentative species (AAV-7 and 8) (source: International Committee on Taxonomy of Viruses [ICTV]). However there are a number of publications describing additional serotypes (i.e. 9 and 10) which are currently not recognized by the ICTV. It is likely therefore, that there are significantly more serotypes circulating that have currently not been formally identified or recognized (Pacak, 2006; Limberis, 2006; Gao, 2004). Nonetheless, the majority of the 67 clinical trials undertaken to date using rAAV for gene delivery have used serotype 2 (Gene Therapy Clinical Trials Worldwide. J. Gene Med. March 2009 Update, http://www.wiley.co.uk/genmed/clinical ).
Evidence is accumulating which suggests that different AAV serotypes may have different tissue tropisms, for example AAV-8 is suggested to have a preferred tropism to the liver (Davidoff, 2005), while for AAV-1, -6 and -7 the preferred tropism is to skeletal muscle (Duan, 2001; Chao, 2000), AAV-4 is highly specific to the retinal pigmented epithelial cells in several animal species (Weber, 2003) and the ependymal cells (Zabner, 2000) and AAV-9 is described as being tropic to cardiacmuscle (Pacak, 2006), thought it also tranduces liver (Van den Driessche, 2007) and brain (Foust, 2009). Vectors based on these serotypes, in-vitro selected AAV with altered tropisms and hybrid vectors (i.e. ITR and Rep from AAV-2, Cap (protein coat) from another serotype i.e. 8) are being investigated (in-vitro and in animal models) to evaluate further the utility of the preferred tropisms and their potential for avoiding pre-existing immunity to AAV-2.
A new development in the field of AAV vectors is the use of self complementary (sc) AAV. Conventional rAAV vectors require 2nd strand synthesis before genes can be expressed, and it is theorized that scAAV bypass this step by delivering a duplex genome. This is achieved by deleting the nicking site of one ITR so that it no longer serves as a replication origin but still forms an AAV hairpin structure. The result is a single stranded, dimeric inverted repeat genome with the altered ITR sequence situated in the middle of the molecule and a wild-type ITR at each end. Following infection and uncoating, the DNA is folded to form a double stranded molecule. A closed hairpin end is formed from the altered ITR, and an open end formed from the two wild-type ITR’s, thus mimicking the structure of a single stranded rAAV after 2nd strand synthesis (McCarty, 2003). It is anticipated that such vectors will improve transduction efficiency and improve the level of protein expression from the transgene. The coding capacity of these vectors, however, is reduced by a factor of two.
Given the basic biology of the ‘parent’ virus as described above, the methods for manufacture and quality control of product are complicated, and the long-term fate of the administered vector is at present unknown. There are a number of manufacturing strategies that can be used to produce rAAV vectors and these are discussed further below, however the basic functional requirements for manufacture are:

The AAV ITR’s flanking the ‘gene of interest’ (this construct contains the cis elements necessary for packaging and replication of its single stranded DNA genome).

Genetic sequences (Rep and Cap) necessary for AAV replication and viral capsid proteins (generally provided in trans within a plasmid or in a packaging cell line).

Helper virus functions: either co-infection of the helper virus or co-transfection/infection of a plasmid/chimeric virus encoding the helper genes (adenovirus: E1a/1b, E2a, E4orf6, VA1 RNA; herpes simplex virus: UL5, UL8, UL52 and UL29).

A cell line capable of supporting helper virus and AAV replication.
The aim of this paper is to discuss quality, non-clinical and clinical issues that should be considered during the development of medicinal products derived from AAV, and to indicate requirements that might be expected the time of a market authorisation application (MAA). The issues raised are specific only to the development of rAAV vectors as medicinal products; general requirements for MAA are not within the scope of this paper. It is recommended that this paper is read in conjunction with the guidance documents referenced in section 4.2.

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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.”

Drug Regulators, FDA, CDER, Publish Draft Guidance on Assay Development for Immunogenicity Testing of Therapeutic Proteins

Drug Regulators, FDA, CDER, Publish Draft Guidance on Assay Development for Immunogenicity Testing of Therapeutic Proteins

Full Text Here

This guidance provides recommendations to facilitate industry’s development of immune assays for assessment of the immunogenicity of therapeutic proteins during clinical trials. This document includes guidance for binding assays, neutralizing assays, and confirmatory assays. While the document does not specifically discuss the development of immune assays for animal studies, the concepts discussed are relevant to the qualification and validation of immune studies for preclinical evaluation of data.

This document does not discuss the product and patient risk factors that may contribute to immune response rates (immunogenicity).

In addition, this document does not specifically discuss how results obtained from immunoassays relate to follow-on biologic therapeutic proteins. However, elements of assay validation may affect comparability determinations of immune responses. FDA guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

Drug Regulators Publish Draft Guidance on Clinical Investigations for Factor IX Products

EMEA Publishes Draft Guidance On the Clinical Investigations for Recombinant and Human Plasma Derived Factor IX Products

GUIDELINE ON THE CLINICAL INVESTIGATION OF RECOMBINANT AND HUMAN PLASMA-DERIVED FACTOR IX PRODUCTS

This guideline describes the information to be documented when an application for a marketing authorisation for recombinant or plasma-derived factor IX products is made for use in treatment and prevention of bleeding in patients with haemophilia B. The guideline covers clinical investigations to be conducted pre- and post-marketing authorisation. The guideline is also provided for authorised products where a significant change in the manufacturing process has been made.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Drug Regulators Publish Draft Guidance on Clinical Investigations for Factor VIII Products

EMEA Publishes Draft Guidance on Clinical Investigations of Recombinant and Human Plasma-Derived Factor VIII Products

GUIDELINE ON THE CLINICAL INVESTIGATION OF RECOMBINANT AND HUMAN PLASMA-DERIVED FACTOR VIII PRODUCTS

This guideline describes the information to be documented when an application for a marketing authorisation for recombinant or plasma-derived factor VIII products is made for use in treatment and prevention of bleeding in patients with haemophilia A. The guidance covers clinical investigations to be conducted pre- and post-marketing authorisation. The guideline is also provided for authorised products where a significant change in the manufacturing process has been made.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Drug Regulators Publish Reflection Paper – Development of Similar Interferon Alfa

The Drug Regulator, EMEA, has published Guidance on developing Generic Interferon Alfa

The EMEA, published a reflection paper on the Non-Clinical and Clinical Development of Similar Medicinal Products Containing Recombinant Interferon Alfa.  in 2007, and has re-published the document on their website again.

This reflection paper lays down considerations on the non-clinical and clinical development of recombinant Interferon alfa-containing medicinal products claiming to be similar to another such product already authorised. Human interferon-alfa 2a or 2b are well-known and characterized proteins consisting of 165 amino acids. The non-glycosylated protein has a molecular weight of approx. 19,240 D. It contains two disulfide bonds, one between the cysteine residues 1 and 98, and the other between the cysteine residues 29 and 138. The sequence contains potential O-glycosylation sites. Physico-chemical and biological methods are available for characterisation of the proteins.

Recombinant Interferon Alfa 2a or 2b is approved in a wide variety of conditions such as viral hepatitis B and C, leukaemia, lymphoma, renal cell carcinoma and multiple myeloma. The sub-types Interferons alfa 2a and 2b have different clinical uses. IFN-alfa is used alone or in combination. Interferon alfa may have several pharmacodynamic effects. The relative importance of these effects in the different therapeutic indications is unknown. In general, interferon-alfa 2a or 2b use in oncology indications has reduced considerably and been superseded by other treatments.

Scope

This product specific reflection paper presents the current view of the CHMP on the non-clinical and clinical data for demonstration of comparability of two recombinant, on-pegylated, Interferon alfa containing medicinal products and should be read in conjunction with the requirements laid down in the EU Pharmaceutical legislation and other relevant CHMP guidelines (see References).

Non-Clinical Studies

Before initiating clinical development, non-clinical studies should be performed. These studies would be comparative in nature and designed to detect differences in the pharmaco-toxicological response between the similar Interferon alfa and the reference Interferon alfa and not just assess the response per se. The approach taken will need to be fully justified in the non-clinical overview.

Pharmacodynamics Studies

In order to compare differences in biological activity between the similar and the reference medicinal product, data from a number of comparative bioassays could be provided.

To support the comparability exercise for the sought clinical indications, the pharmacodynamic activity of the similar and the reference medicinal product could be quantitatively compared in an appropriate pharmacodynamic animal model, a suitable animal tumour model OR a suitable animal antiviral model.

Toxicological Studies

Data from at least one repeat dose toxicity study in a relevant species should be considered (for example, human Interferon alfa may show activity in the Syrian golden hamster). The study duration should be at least 4 weeks. Data on local tolerance in at least one species should be provided in accordance with the “Note for guidance on non-clinical local tolerance testing of medicinal products” (CPMP/SWP/2145/00).

Clinical Studies

Pharmacokinetic Studies

The pharmacokinetic properties of the similar and the reference medicinal product could be compared in single dose crossover studies using subcutaneous and intravenous administration in healthy volunteers. The recommended primary pharmacokinetic parameter is AUC and the secondary parameters are Cmax and T1/2 or CL/F.

Pharmacodynamic Studies

There are a number of PD markers, such as β2 microglobulin, neopterin and serum 2´, 5´-oligoadenylate synthetase activity, which are relevant to the interaction between Interferon -alfa and the immune system. The selected doses should be in the linear ascending part of the dose-response curve. Whereas the relative importance of these effects in the different therapeutic indications is unknown a comprehensive comparative evaluation of such markers following administration of test and reference products could provide useful supporting data.

Efficacy

Patient Population

The mechanism of action of interferon comprises of several different unrelated effects. Demonstration of similar efficacy between test and reference products is required. This could be performed in treatment-naïve patients with chronic hepatitis C (HCV) as delineated by the indication for the reference product. Other patient population(s) might be studied depending on the indications desired.

Study Design and Duration

A randomised, parallel group comparison against the reference product over at least 48 weeks is recommended. If possible, the study should be double-blind at least until data to complete the primary analysis have been generated. If this is not feasible, justification should be provided and efforts to reduce/eliminate bias should be clearly identified in the protocol.

Endpoints

Primary: Virologic response as measured by the proportion of patients with undetectable levels of HCV RNA by quantitative PCR at week 12. The assay used to measure HCV RNA and the cut-off applied should be justified. A 2-log decrease in viral load may be a co-primary endpoint. Secondary: virologic response at week 4 and end-of-treatment; sustained virologic response (24 weeks after completion of treatment); change in liver biochemistry including transaminase levels and morbidity.

Safety

Safety data should be collected from patients after repeated dosing in a comparative clinical trial over the treatment period plus 24 weeks of follow-up. The number of patients should be sufficient for the comparative evaluation of the adverse effect profile. Laboratory abnormalities for immune mediated disorders should be included. The safety profile should be similar to the reference products for the common adverse events (such as flu-like illness, alopecia, myalgia, leucopenia, anaemia and thrombocytopenia).

Immunogenicity

Comparative immunogenicity data (antibody levels) should be presented during the treatment period plus 24 weeks of follow-up according to the principles described in the “Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: nonclinical and clinical issues” (EMEA/CPMP/42832/05/) and the “Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins” (EMEA/CHMP/BMWP/14327/2006).

Extrapolation of Evidence

In principle extrapolation from one therapeutic indication to another is appropriate where the mechanism of action and/or the receptor are known to be the same as the condition(s) for which similarity in efficacy has been established. If indication(s) are sought, where the mechanism of action is not known to be the same, such extrapolation
should be adequately justified.

Pharamcovigilance Plans

Within the authorisation procedure the applicant should present a risk management programme/pharmacovigilance plan in accordance with current EU legislation and pharmacovigilance guidelines. Attention should be paid to immunogenicity and potentially rare and/or delayed serious adverse events, especially in patients undergoing chronic administration. Safety should be collected from patients representing all approved indications.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com