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Published on 10 July 2009

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Biosimilars: the need to tick all the right boxes

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A pharmacy checklist guides evaluation and differentiation of biopharmaceuticals, according to experts at a Hospira-sponsored satellite symposium at the EAHP Congress in March 2009

Christine Clark
BSc MSc PhD FRPharmS
FFCP(Hon)

Editor
HPE

Biosimilars are products of inbuilt high-quality design from production through to delivery, explained Roger Tredree (visiting professor, Kingston University, London). This is of critical importance because patents on some biological products have already expired and biosimilar products are now being marketed.

The European Medicines Evaluation Agency (EMEA) has published guidelines for the development and approval of biosimilar products, but pharmacists also need to use a systematic checklist to ensure that decisions to introduce products to their formularies are robust and evidence-based.[1] A summary checklist is given in Table 1.

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In this symposium, epoetin zeta (Retacrit; Hospira) was used as an example to illustrate the steps taken during manufacture and procurement to ensure that the product is safe, effective and suitable for use as an erythropoietinstimulating agent (ESA).

Obtaining EMEA approval
To gain approval from the EMEA, biosimilars must demonstrate comparability to the originator reference product. For ESAs the reference product is epoietin alfa (Eprex®/Erypo®).

Numerous analytical tests are required involving all stages of the production process to establish comparability of biosimilars. Whereas typically 100 tests may be required for a small drug molecule, as many as 2,000 tests may be required for a biosimilar, said Alfonso Domi­nguez-Gil Hurle (professor of pharmacy, University of Salamanca, Spain). Such tests serve to demonstrate comparability at all levels, including nonclinical aspects such as physicochemical and biological characterisation, as well as clinical aspects such as pharmacokinetic and pharmacodynamics in humans. Finally, clinical trials are required to demonstrate safety and efficacy.

Hartmut Hampl (Norbitech GmbH, Uetersen, Germany) explained how the production processes for Retacrit are designed and controlled to ensure the quality of the product elements covered by the first three items on the checklist. One critical feature that must be tested is batch consistency. As biologically derived products are subject to a certain amount of
natural variation, manufacturers must show that there is consistency between batches with respect to a number of features, including isoform distribution, particulate matter and biological activity, said David Schwinke (Hospira, Inc., Lake Forest, Illinois, USA).

Dr Schwinke also pointed out that the formulation of Retacrit has been designed with a view to minimising the risk of pure red-cell aplasia (PRCA) – a problem that arose with subcutaneous epoietin-alfa when the human serum albumin component was replaced with polysorbate 80. Retacrit does not contain polysorbate 80, but uses polysorbate 20 as a solubilising agent with a mixture of amino acid stabilisers.

Clinical efficacy
Clinical studies show that epoetin zeta administered intravenously is therapeutically equivalent to epoietin alfa in the correction of low haemoglobin concentration in patients with chronic kidney disease undergoing haemodialysis, said Rossen Koytchev (Cooperative Clinical Drug Research and Development [CCDRD], Neuenhagen, Germany).

Moreover, epoetin zeta is effective in maintaining stabilised Hb levels within the target range in patients on long-term haemodialysis, and it shows good overall long-term tolerability. Of critical importance was the observation that no patients developed non-neutralising or neutralising antierythropoietin antibodies, and there were no cases of PRCA.

Concerning chemotherapy-induced anaemia, epoetin zeta, administered subcutaneously, is well tolerated and effectively manages haemoglobin levels in anaemic patients with cancer who are receiving chemotherapy and are otherwise likely to receive blood transfusions.

The results of these studies provide satisfactory answers to the points in the pharmacy checklist under clinical efficacy, safety and tolerability, concluded Dr Koytchev.

PMS
Several presenters emphasised the important of postmarketing surveillance (PMS) in determining the long-term risks and identifying rare side-effects. Islah Ahmed (Hospira, Inc., Lake Forest, Illinois, USA) explained the company strategy to undertake ongoing evaluation of the risks of events such as immune-mediated PRCA with epoietin zeta. Market surveys will be performed to monitor potential off-label use, added Dr Ahmed.

A number of risk minimisation measures have been built into the Summary of Product Characteristics to alert users to recognised dangers such as the risk of thrombotic events with a target haemoglobin of more than 12 g/dl and tumour growth potential. In addition, Retacrit is contraindicated for anyone who has previously experienced PRCA with any other erythropoietin.

An ongoing study – the Post-Authorization Safety Cohort Observation (PASCO) study of epoietin zeta administered for the treatment of renal anaemia – is now in progress. It involves centres in Germany, Spain, the UK, France and Italy and will include 1,500 patients. Together, these measures allow completion of the checklist items concerned with postmarketing safety and risk management, noted Dr Ahmed.

Conclusion
Professor Tredree concluded that the pharmacy checklist can support pharmacists in assessing biopharmaceuticals in a robust and systematic way and that this was clearly illustrated by the information presented about Retacrit.

“Decisions to include medicines on the hospital formulary should be evidence-based and not rely on subjective judgement, to ensure patients receive the best possible treatment,” he added.

Reference
1. Kramer I, Tredree R, Vulto AG. Points to consider in the evaluation of biopharmaceuticals. EJHP Pract 2008;14(1):73-6.



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