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This guideline lays down the non-clinical and clinical requirements for erythropoietin containing medicinal products claiming to be similar to another one already marketed. The non-clinical section addresses the pharmaco-toxicological assessment and the clinical section the requirements for pharmacokinetic, pharmacodynamic, efficacy and safety studies as well as the risk management plan. Criteria for extrapolation of clinical data to other indications approved for the reference medicinal product are discussed.

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Full Guidance Here.

This guideline lays down the non-clinical and clinical requirements for erythropoietin containing medicinal products claiming to be similar to another one already marketed. The non-clinical section addresses the pharmaco-toxicological assessment and the clinical section the requirements for pharmacokinetic, pharmacodynamic, efficacy and safety studies as well as the risk management plan. Criteria for extrapolation of clinical data to other indications approved for the reference medicinal product are discussed.

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

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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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

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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