Biosimilar drugs may be expected to gain marketing authorisation after expiry of their reference drugs’ patents. But interchangeability is not guaranteed, so pharmacists need to be able to assess them.
Director, Pharmacy Department
Johannes Gutenberg University Hospital
Biosimilar medicines (short form: biosimilars) are biological medicinal products which may be expected to obtain a marketing authorisation in the EU after the original product (biological reference medicine) has run out of patent.1 As a prerequisite, studies including clinical trials are to be conducted to compare the quality, safety and efficacy of the biosimilar and reference medicine. Due to the specific characteristics of biopharmaceuticals – including complex three-dimensional (glyco)protein structure, immunogenicity, production in living organisms which causes heterogenicity, complex manufacturing processes and complexity of analysis2 – the interchangeability of the biosimilar with its reference-drug product is not guaranteed by the licensing process.3 The pharmacist, as the medicines expert, is expected to be able to assess the quality and safety of a biopharmaceutical, so needs to know which criteria to use for evaluation and needs experience and knowledge of the pharmaceutical market.1,4 In addition, INN (international non-proprietary name) allocation, pharmacovigilance and traceability are subjects for discussion driven by scientific, professional or marketing interests.
Interchange of biopharmaceuticals
Medication management in hospitals is usually based on a formulary system which is the responsibility of a committee. The committee selects medicines to be included in the formulary and used in the hospital setting by considering the relative clinical, quality-of-life, safety and pharmacoeconomic outcomes. Usually, it is the pharmacist’s responsibility to select a medicine from a range of generically equivalent products. The quality assessment of biological products to be purchased, like blood products, vaccines, and biopharmaceuticals, requires special care, as such assessment is influenced by the complexity and variability of the biological, pharmacological and physicochemical properties of these products.
During a hospital stay, generic substitution and therapeutic interchange of medicines at the individual patient’s level are done in accordance with the institution’s policy. Generic substitution (aut idem) is defined as the substitution of drug products that contain the same active ingredient(s) and are identical to the drug prescribed in strength, concentration, dosage form and route of administration. Typically, prescribing physicians in the hospital prospectively authorise generic substitution and usually notification of generic substitution is not provided to the prescriber at the time of dispensing. There are some situations where generic substitution requires special attention, ie, substitution of critical-dose drugs and different dosage forms or administration devices (eg, inhalation systems or pre-filled syringes).
Therapeutic substitution (aut simile substitution) is defined as the interchange of various therapeutically equivalent drug products. Therapeutic equivalents are products with different chemical structure but of the same pharmacological and/or therapeutic class, eg “me-too” products in a class, and are expected to have similar therapeutic and adverse effects. Depending on the institution’s policy, therapeutic interchange proposed by the pharmacist usually needs to be authorised by the prescriber. Substituting a biopharmaceutical product on an individual-patient basis – eg, genetically engineered factor VIII or human growth hormone – requires critical evaluation especially when the product is to be administered chronically. Currently, the substitution of one biopharmaceutical product by another is regarded as a therapeutic interchange rather than as a generic substitution (compare Figure 1), as the biosimilar and the reference product will not be identical. Therapeutic interchange may not be appropriate for all patients and requires agreement between the pharmacist and the prescriber.
It may be that the substitution itself is not critical, but biosimilars and the reference product and even different batches of the products may exhibit different safety features. Therefore, concerns about substitution include not only substitution of a biosimilar for a reference product, but also substitution of one innovative product for another or one biosimilar for another biosimilar. The decision to treat a patient with an original product (the reference product) or a biosimilar medicine should be taken following the opinion of a qualified healthcare professional.3
The INN naming of biosimilars is especially a matter of discussion, as the use of INNs is increasing in the EU member states in the prescription process. INNs are selected by a World Health Organization (WHO) expert advisory panel upon request/application of the manufacturer. Thus, INNs are not a part of the regulatory review process. The aim of the INN classification has been to identify a pharmaceutical substance or active pharmaceutical ingredient by a unique name that is globally recognised and nonproprietary.
The past and present INN situation in the field of biological and biotechnological substance is summarised in a WHO working document.5 With regard to glycosylated compounds (glycoproteins, glycopeptides), the general policies are identification of the group using a stem, eg, erythropoietin with the stem -(e)poetin, identification of differences in the amino-acid chain with a random prefix (eg darbe- in darbepoetin), and indication of differences in the glycosylation pattern using the name of a Greek letter added as a second component of the name (eg, epoetin alfa, epoetin beta, epoetin delta). The Greek letters are used in Greek alphabetic order.5 The situation will become even more complex with the classification of biosimilars (see Table1).6,7 Glycoproteins may occur in different isoforms (they exhibit microheterogenicity) and isoform patterns depending on the host cell and production process, which are always different for different biopharmaceuticals. This causes questions to arise such as: how similar is similar enough to use the same INN name, or will the use of a different INN name for the biosimilar and the reference product not be even more confusing? The two different epoetin alfa biosimilars currently approved with reference to epoetin alfa (Eprex®) will probably carry different INN names (HX 575 = epoetin alfa, B03XA01 = epoetin zeta; requested by the manufacturer). In addition, there are three brand-name products on the market that contain HX 575 as active substance and which are produced by the same manufacturer, and there will shortly be two brands containing B03XA01 on the market. Moreover, the two manufacturers of the biosimilars are different from the marketing authorisation holders.
The use of generic names, particularly for filling of prescriptions, may make post-approval pharmacovigilance difficult or impossible. Inadvertent substitution and lack of traceability with identical INNs for biosimilars and originator products are concerns clearly addressed by the biotech innovator
companies, which recommend distinct INNs.6
Today, the marketing authorisation holder (MAH) of a medicinal product is obliged to document post-marketing experience on safety and tolerance by a suitable pharmacovigilance system and post-marketing surveillance plan. Rare adverse drug reactions can only be detected when an appropriate number of patients are administered the drug (the rule of three says that 3,000 patients must be monitored to detect an adverse reaction of the frequency 1:1,000). Knowledge of the type, severity and frequency of adverse reactions of the biosimilar compared to the reference product is very important for the assessment of drug safety and in making formulary decisions. The MAH should inform the hospital pharmacist about any differences in restrictions on use (eg contraindications, warnings). In addition, the MAH should make available to hospital pharmacists and members of the formulary committee the safety data gained in post-marketing safety studies (eg phase IV studies).
Biopharmaceuticals are prone to eliciting an immune response with clinical consequences that are difficult to predict.8 Immunogenicity data are to be assessed after launch of the product in connection with clinical data.9,10 If the manufacturer has the obligation to perform antibody tests on the patients, the agreement itself and the management of the agreement should be disclosed by the MAH. It must be clarified in advance who is responsible for the antibody testing and how this will be financed. In any case, the tests are an additional effort for the physician and the patient. The patient furthermore needs to be informed.11
Repeated switching of biopharmaceuticals will prevent accurate pharmacovigilance. Automatic substitution could cause difficulty in establishing a temporal association between an adverse reaction and the responsible product and in identifying the specific product used by the patient.12 The latter difficulty is equivalent to restricted traceability of a special product used by the patient and accurate attribution of an adverse event to the biosimilar or reference drug product.
Provided that comparable quality, security of supply, clinical efficacy and safety of biosimilars and reference product are given, the assessment of cost-effectiveness plays a central role in the selection of products by the hospital pharmacist or the formulary committee. The calculations need to be based on the negotiated price and the dynamics of the clinical market. There may be different payment systems across the community-hospital boundary and these need to be taken into consideration.11 The manufacturer should provide pharmacoeconomic studies on the cost-effectiveness of the product, if such are available. ■
1. Crommelin D, Bermejo T, Bissig M, Damiaans J, Krämer I, Rambourg P, Scrocarro G, Strukelj B, Tredree R. Pharmaceutical evaluation of biosimilars: important differences from generic low-molecular-weight pharmaceuticals. EJHP-S 2005;11:11-17.
2. Crommelin DJA, Storm G, Verrijk R,et al. Shifting paradigms: biopharmaceuticals versus low molecular drugs. Int J Pharm 2003;266:3-16.
3. European Medicines Agency. Questions and answers on biosimilar medicines (similar biological medicinal products). EMEA/74562/2006. London: EMEA; 2007. Available online at: http://www.emea.europa.eu
4. Krämer I, Tredree R, Vulto A. Points to consider in the evaluation of biopharmaceuticals. EJHP Practice
2008, in press.
5. World Health Organization. International nonproprietary names (INN) for biological and biotechnological substances. Geneva: WHO; 2006. Available online at: http://www.who.int/medicines/services/inn/INN_Biorev11-06.pdf
6. Declerck P. Biologicals in the era of biosimilars: implications for naming and prescribing.
7. BioPlan. Nomenclature and registry systems for biopharmaceuticals and biogenerics. Rockville MD: BioPlan; 2007. Available online at:
8. Kromminga A, Schellekens H. Antibodies against erythropoietin and other protein-based therapeutics: an overview. Ann NY Acad Sci 2005;1050:257-65.
9. Thorpe R, Wadhwa M. Protein therapeutics and their immunogenicity. EJHP-P 2006;12:17-8.
10. Locatelli F, Roger S. Comparative testing and pharmacovigilance of biosimilars.
Nephrol Dial Transplant 2006;21:v13-16.
11. Bohn M, Dörje F, Krämer I. Checkliste zur Bewertung von Biopharmazeutika.
12. Nowicki M. Basic facts about biosimilars.
Kidney Blood Press Res 2007;30:267-72