A biosimilar is a medicinal product that is similar to a biological medicinal product that has already been authorized. Biologicals are comprised of proteins, such as hormones (growth hormones, insulins, erythropoietins), enzymes, that are naturally produced in the human body, or monoclonal antibodies. Biologicals are derived through three main sources: yeast cells, bacterial cells and mammalian cells.
Biologicals are derived from living cells and therefore demonstrate molecular complexity and heterogeneity. This makes them very difficult to reproduce, as even very small changes in the manufacturing process can cause variations in the final drug, even between different batches of the same product. For this reason biosimilars must be ‘similar but not identical’ to their reference biological with regards to quality, safety, and efficacy.
Biological medicines have the potential to be recognized by the body as ‘foreign’ and therefore have the inherent potential to induce unwanted immune reactions, due to their composition and large molecular size. For this reasons both originator biologicals and biosimilars are required to have a risk management plan in place before they can market a product in the European Union.
As with prescribing any medicine the physician is responsible for taking into account factors such as age, gender, disease state and medical history. An approved biosimilar is expected to have the same efficacy and safety as the reference biological, but may not necessarily be authorized for all indications approved for its reference medicinal product.
Establishing ‘biosimilarity’ for a biosimilar is done through a stepwise ‘comparability exercise’ in a tailor-made development programme which takes into account the safety and efficacy established for the reference biological.
Quality, efficacy and safety of biosimilars
Biosimilars, like any biological, are very sensitive to changes during their manufacturing process, transport and storage. It is therefore important that these are precisely controlled in order to obtain consistent results and to guarantee the safety and efficacy of the final product. To ensure this all manufacturers and importers of biosimilars to the EU are required to hold a valid good manufacturing practice (GMP) certificate. To verify GMP compliance, manufacturers and importers are regularly inspected.
European public assessment reports (EPARs)
Information on the pharmacokinetics, safety, immunogenicity and interchangeability studies on biologicals and biosimilars is published by the European Medicines Agency (EMA) on their website: www.ema.europa.eu in the form of a European public assessment report (EPAR).
Pharmacovigilance requirements for biologicals
Biologicals have the potential to induce an unwanted immune response. This fact will impact the design of post-authorization follow-up studies and risk management plans (RMPs) to ensure that rare immune-related safety issues can be detected by collecting safety information for a longer period and from larger numbers of patients. Larger patient numbers and longer treatment exposures allow for the greater statistical sensitivity required to capture low frequency events and to enable reliable safety signal detection.
Switching between original biologicals and biosimilars
There is relatively little data available on the number of patients that have been switched between biopharmaceuticals in clinical practice. There are several publications describing such switches, but it remains unclear how often these occur. Moreover, the studies reported in the literature were generally too short to show the possible long-term side effects of switching.
Long-term data for biosimilars
Manufacturers routinely collect long-term data from post-approval clinical trials, patient registry studies and long-term follow up of patients who participated in the pre-approval clinical trials for biosimilars. RMPs include data from large numbers of patients and longer treatment exposures. It is the obligation of the manufacturers to report the findings of their RMP-derived data to EMA and to propose changes to the product information if necessary.
The European Commission requires biosimilars to be identified by brand-name and batch number , and this should be clearly recorded (or stated) in the patient file.
Cost of biosimilars
In general biosimilars are introduced to the market at a lower price than their originator reference biologicals. However, price is determined through market forces, by national competent authorities and competition between originator and biosimilars’ manufacturers.
Adverse effects in biosimilars
Review of regulatory information resources for all currently approved biosimilars to date shows that there have been no safety related updates to their respective product information documents which have been the consequence of reports of adverse effects following changes in manufacturing process, transport and storage.
Extrapolation of indications
Information on which indications have been extrapolated and for which ones head-to-head comparative clinical trials have been performed against the reference biological is published by EMA on their website: www.ema.europa.eu
Clinical trials with biosimilars
Information on the assessment of clinical trials for biosimilars can be found in the EPAR pages of each authorized medicine.
Biosimilars: what patients need to know
EU publishes consensus report on biosimilars
1. European Commission, Enterprise and Industry Directorate-General. Consensus Information Paper 2013. What you need to know about Biosimilar Medicinal Products. 2013 [cited 2014 Feb 7].
2. GaBI Online - Generics and Biosimilars Initiative. Biosimilars in EU to be identified by brand names [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Feb 7]. Available from: www.gabionline.net/Policies-Legislation/Biologicals-in-EU-to-be-identified-by-brand-names
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