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Published on 11 April 2011

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EU guidelines for biosimilars development

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Begoña Calvo
PhD

Leyre Zuñiga
PhD
Pharmaceutical Technology Department
Faculty of Pharmacy
University of the Basque Country
Vitoria-Gasteiz
Spain

The expiration of a biotechnology drug patent allows other manufacturers to make copies of the original drug. These products, termed ‘biosimilars’ in the EU and ‘follow-on protein products’ in the USA, are biological drugs similar, but not identical, to the innovator drug.

It is well known that biosimilars cannot be considered as generic drugs, since they are not exact copies of the original drug due to the complexity of its protein nature. Biosimilars, unlike chemical synthesis generics, can only obtain marketing approval through a centralised procedure overviewed by the European Medicines Agency (EMA). In order to test the efficacy, safety and quality of biosimilars, the EMA has established a mandatory guidelines system (see Figure 1).

The overarching guideline1 defines the term ‘biosimilar’ and lays down the requirements for the approval of a product. A biosimilar medicine is a medicine which is similar to a biological medicine that has already been authorised (the ‘biological reference medicine’). The active substance of a biosimilar medicine is similar to that of the biological reference medicine. Biosimilar and biological reference medicines are used in general at the same dose to treat the same disease. Since biosimilar and biological reference medicines are similar but not identical, the decision to treat a patient with a reference or a biosimilar medicine should only be taken following the recommendation of a qualified healthcare professional. The name, appearance and packaging of a biosimilar medicine differs from those of the biological reference medicine. It may also contain different inactive ingredients. As for all medicines, where precautions are necessary because of any inactive ingredient, these will be described both on the label and in the package leaflet.2 The remaining general and specific guidelines for biosimilar medicines product issued by the EMA are under the peer review of this guideline.3

Advances and limitations of the methods and the techniques available to date for the complete characterisation of such drugs, have led the EMA Committee for Medicinal Products for Human Use (CHMP) to develop specific guidelines on the quality, non-clinical aspects and important considerations that clinicians should take into account in the development of biosimilar drugs.

Requirements to demonstrate the quality of biosimilars are set in another guideline.4 This guideline includes the criteria to be considered in the production of biosimilars, and the standards of analytical methods used to demonstrate the physico-chemical, biological activity and the degree of purity and possible impurities. The guideline CHMP/42832/055 details the preclinical and clinical studies to be carried out. The preclinical development includes binding studies of the active protein to its receptors and studies of pharmacodynamic and toxicological effects in animals.

Clinical studies are required to provide biosimilar pharmacokinetic data compared with the reference product as it is necessary to demonstrate the relationship between dose and efficacy. Phase III clinical trials are essential for biosimilars. In these studies, the drug is compared to the reference product and a large number of patients are involved. In addition to general guidelines, EMA provides product-specific guidelines.6–9 Currently, product guidelines approved by the EMA include biosimilar erythropoietin, insulin, somatropin and filgrastim.

European guidelines on similar biological medicinal products
A company aiming to develop a biosimilar medicine should make comparative studies with the reference product (innovator drug, previously approved in the EU) to show the similar nature in terms of quality, safety and efficacy. These are known as ‘comparability studies’.10,11

As previously mentioned, biological drugs are usually more difficult to characterise than chemically synthesised drugs due to the molecular complexity of these products (recombinant DNA derived from blood or plasma, immunological and gene therapy products, etc). In addition, some parameters such as the three-dimensional structure, the amount of acid-base variants or the post-translational modifications, such as glycosylation profile, can be altered significantly due to changes in the manufacturing process that may initially be considered ‘minor’. Therefore, the safety-efficacy profile of these products depends largely on the robustness and monitoring of the quality aspects.

Specific guidelines of ‘biosimilar medicines’ must be followed. Due to its complexity, the standard generic approach (demonstration of bioequivalence compared to the reference medicinal product through bioavailability studies) applying to products obtained by chemical synthesis is not scientifically appropriate for biological products. Therefore, the ‘similar biological medicinal products’ approach, based on a comparability exercise, must be employed.

With regard to the quality data, the biosimilar medicine must fulfil all requirements listed in Module Three of the Common Technical Document – presentation of the application dossier (Directive 2001/83/EC)12 and the European Pharmacopoeia monographs technical requirements, as well  as relevant requirements defined by the CHMP and International Conference on Harmonisation guidelines.

Data used to demonstrate safety and efficacy of biosimilar medicines must comply with the requirements listed in Annex I of Directive 2001/83/EC. EMA/CHMP guidelines provide general and product-specific technical provisions. If there are no product-specific guidelines, the applicant company should ask for advice from the EMA authorities.

The reference drug used for comparability studies should be a drug licensed in the EU based on a complete dossier as referred to in the aforementioned Directive and amendments. The reference product will be used throughout the whole comparability programme for studies of quality, safety and efficiency during the biosimilar development in order to obtain consistent data and conclusions. Data generated in studies of comparability of medicinal products authorised outside the EU can only provide supporting information.

The pharmaceutical dosage form, strength and route of administration of biosimilar medicine should be the same as that of the reference medicinal product. When the dosage form, strength and/or administration route is different, additional data in the context of the comparability exercise should be provided. Any difference between the biosimilar and the reference product will be justified by appropriate studies on a case-by-case basis.

It should be noted that biosimilar medicines are not generics and differences between biosimilars from different manufacturers, or between reference products, are evident, as we have experienced in its use. Therefore, in order to strengthen the monitoring of pharmacovigilance, the drug administered to the patient must be clearly identified, specifying its international generic name, trade name and/or manufacturer.13,14

Pharmacovigilance is essential in the biopharmaceuticals market because of the limited ability to predict the clinical consequences of seemingly innocuous changes in the manufacturing process and the scientific information gap. In the absence of adequate predictors of immunogenicity outside the clinical trial setting or specific precautions to be considered, biosimilar products should be evaluated in the same way as any originator.

Detailed pharmacovigilance programmes should be implemented according to the Eudravigilance project developed by the EMA.15 This will lead to an appropriate response if an adverse event emergency occurs.

The EU has so far approved a small number of biosimilar medicines, mainly recombinant somatropin, erythropoietin and filgrastim biosimilar products. Table 1 lists the currently marketed biosimilars in Europe.

Conclusions
Biotechnological drugs are a therapeutic class with specific characteristics different from conventional drugs obtained by chemical synthesis. Therefore, biosimilars cannot be regulated in the same way as generics and they can only get approval in Europe through a centralised procedure.

To develop a biosimilar medicine, the manufacturer should carry out comparative studies to show the similar nature to the reference product in terms of quality, safety and efficacy. These are known as ‘comparability studies’. However, since biosimilars are obtained by manufacturing processes whose quality is controlled in a similar manner to those of innovative biological products, it is possible to ensure their effectiveness and safety, which are based on non-clinical and clinical studies. Moreover, the manufacturer must implement the pharmacovigilance and risk management plans after marketing the drug.

References
1. EMEA/CHMP/437/04. Guideline on similar biological medicinal products. Available online at: 
www.ema.europa.eu/ (2005).
2. EMEA/74562/2006. Questions and answers on biosimilar medicines (similar biological medicinal products). Available online at: www.ema.europa.eu/ (2007).
3. Zuñiga L and Calvo B. Trends Biotechnol 2009;27:385–7.
4. EMEA/CHMP/49348/05. Similar biological medicinal products containing biotechnology-derived proteins as active substance: Quality issues. Available online at: 
www.ema.europa.eu/ (2006).
5. EMEA/CHMP/42832/05. Similar biological medicinal products containing biotechnology-derived proteins as active substance: Non-clinical and clinical issues. Available online at: www.ema.europa.eu/ (2006).
6. CHMP/31329/05. Guidance on biosimilar medicinal products containing recombinant granulocyte-colony stimulating factor. Available online at: www.ema.europa.eu/ (2006).
7. CHMP/94528/05. Guidance on similar medicinal products containing somatropin. Available online at: 
www.ema.europa.eu/ (2006).
8. CHMP/32775/05. Guidance on similar medicinal products containing recombinant human insulin. Available online at: www.ema.europa.eu/ (2006).
9. EMEA/CHMP/BMWP/301636/08. Similar biological medicinal products containing recombinant erythropoietins. Available online at: www.ema.europa.eu/ (2010).
10. Zuñiga L and Calvo B. Regul Toxicol Pharmacol 2010;56:374–7.
11. Schellekens H and Moors E. Nat Biotechnol 2010;28:28–31.
12. The European Parliament and the Council of the European Union (2001) Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. In Official Journal of the European Union, L311,  67–128 .
13. Kuhlmann M et al. Int J Pharm Med 2007;21:199–206.
14. Zuñiga L and Calvo B. Drug Saf 2010;19:1–9.
15. EudraLex [Homepage]. Volume 9A Guidelines on Pharmacovigilance for Medicinal Products for Human Use. In: The rules governing medicinal products in the European Union. 2007; Available online at: http://ec.europa.eu.



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