A1: Are all biosimilars approved in Europe produced under GMP conditions?

It is important to track down and check how EMA deals with the quality status of active pharmaceutical ingredients (APIs), excipients and finished products. This is relevant in when the manufacturing process is undertaken by a third party. Directive 2011/62/EU lays down considerations separately for APIs and finished medicinal products.26

Pharmaceutical companies in Europe are obliged to establish and implement GMP. When the marketing authorisation holder (MAH) asks for approval of a medicinal product, it must comply with GMP. When an applicant brings a new medicinal product to the market, EMA has to inspect the manufacturer for GMP and good clinical practice (GCP).27 ,28

This criterion is adequately covered by EMA and is not included in the final set of selection criteria.

A2: Is the exact production site of API and final product always known to EMA?

Since 2 January 2013 a new European requirement exists for importing APIs. All APIs must have been manufactured at a GMP site (GMP must be equivalent to EU’s GMP as a minimum). From 2 July 2013 onwards, according to article 46b2b of the EU Directive 2011/62/EU, the importer needs to request a document by the local competent authority in which it is written that the manufacturer complies with GMP standards to at least the same standard as EU GMP.26 The ICH Q7 document provides guidelines for manufacturing quality management of APIs and harmonises GMP standards in the EU, the USA and Japan.29

All sites involved in the production of the finished medicinal product and of the active substances must be described (name and detailed address, including building reference) in Module 1.2 of the application for a marketing authorisation together with a description of the steps performed. This should include, among other things, active substance and finished product manufacture.30

This criterion is adequately covered by EMA and is not included in the final set of selection criteria.

A3: Have all production facilities of API and final product been checked by EMA or other authorities?

The production site is subject to inspection by EMA inspectors or other authorities. A finished product can be formulated with APIs or excipients produced under Chinese and or Indian GMP (which is estimated to be 80% of bulk APIs). It is EMA’s role to review this process as a part of the registration procedure.

In relation to the document for third country manufacturers published by EMA, information about any previous EEA (European Economic Area) inspection in the last 2–3 years and/or any planned EEA inspections should be provided and should include details of the inspection dates, product category inspected and the name of the inspecting competent authority.30

Documents that should be attached to Module 1 of the application include the following.

For all sites (other than active substance manufacturers) located in third countries where a Mutual Recognition Agreement (MRA) or other relevant agreement is in place, a MRA certificate (not older than 3 years) from the local competent authority that carried out the inspection and/ or a GMP certificate from the EEA inspecting competent authority (if the site has been inspected by an EEA competent authority in the last 2–3 years) is required.

For all sites other than active substance manufacturers, located in third countries with no MRA, a GMP certificate from the EEA inspecting competent authority (if the site has been inspected by an EEA competent authority in the last 2–3 years) is necessary. Alternatively, a reference can be made to the appropriate entry in the EudraGMP database.

In addition to the above, a copy of the registration or other document analogous to the manufacturing authorisation from the local competent authority must demonstrate that the site is authorised to manufacture a product or pharmaceutical form. Also details of any inspection performed by authorities other than the EEA authorities (eg, a GMP certificate or similar statement from the competent authority which carried out the inspection) must be provided.30

According to EMA an operational MRA provides assurance that equivalent GMP standards are applied by the parties of the MRA and removes the need for additional inspection and re-controls at import. This is applicable for production plants located in the following countries: Australia, Canada, Switzerland, Japan, New Zealand, the USA.30

Once validated, adding a new site or changing the steps of manufacture/batch release described under Module 1.2 (ie, application form) of the application is normally not allowed during the 210-day review period. Any additional site or change in the manufacturing or batch release arrangements should be submitted as a variation after the granting of the marketing authorisation.30

In the case of Omnitrope, during its development, several changes were introduced, such as a transfer to a production plant in the USA and a re-transfer to a production plant in Austria. Several improvements to the purification process were implemented at these manufacturing sites. Due to these major changes, additional similarity information had to be submitted and reviewed by EMA.31

During the process development of Ratiograstim, the site of fermentation and purification was changed when the manufacturing was transferred to a GMP production facility. In a public assessment report for Ratiograstim, EMA rapporteurs explained that the master cell bank and working cell bank complied with current GMP.32

This criterion is adequately covered by EMA and is not included in the final set of selection criteria.

A4: Are all recalls reported to EMA?

MAHs, manufacturers and importers are obliged to report to EMA whenever a centrally authorised product is not available because of a shortage of supply or when a recall has to be done. In addition, MAHs are requested to inform EMA of any prohibition or restriction imposed by the responsible competent authority of any country in which the medicinal product is placed on the market and of any other new information.33

The following FDA webpage has a section that shows current biological product shortages, including the reasons for the shortage and if they have been resolved:http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/Shortages/default.htm. On the current version of the EMA website it is not possible to run a search on the criteria ‘show me all medicines with shortages’. This requirement has been noted and this type of functionality is expected to become available in the future. Currently, when a search is performed for a medicine by product name on the website, the medicine page returned will show any information available on shortages on the right-hand side of the page.

EMA only communicates on shortages if they concern a centrally authorised medicine. This is the case if the shortage is affecting more than one EU Member State and once the EMA has issued a recommendation. EMA asks the National Competent Authorities (NCAs) of individual member states for a more complete picture on shortages of nationally authorised products and centrally authorised products in a particular member state. This criterion is adequately covered by EMA and NCAs and is not included in the final set of selection criteria.

A5: Is the manufacturer experienced in the production of biopharmaceuticals?

This criterion is included in the final set of criteria.

Experience of biopharmaceuticals production: score 10% per year of experience. Therefore, the score is 40% if the company has been in production for 4 years.

A6: Which national authorities are responsible for inspecting the manufacturing site?

This information is covered in Module 1 of the EMA application where administrative information is requested. On the following link information can be assessed about the national authorities inside the EU:

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/general/general_content_000155.jsp&mid=WC0b01ac0580036d63.

This criterion is adequately covered by EMA and is not included in the final set of selection criteria.

A7: How long has the biopharmaceutical been on the market?

This criterion is included in the final set of criteria. The criterion is introduced as an estimate of the guaranteed safety of the biosimilar.

This is a standard SOJA criterion: 10% for every year on the market. This is used for a comparison of different chemical entities of small molecules. Because biosimilars are similar to the reference product, a flatter scale is used for biosimilars: 25% per year. If a biosimilar is on the market for 3 years, this product will score 75%.

A8: How extensive is the clinical experience with each individual biosimilar? Expressed as the number of patient days worldwide

This criterion is included in the final set of criteria. The criterion is introduced as an estimate of the guaranteed safety of the biosimilar.

This is a standard SOJA criterion: 1% for every million days of experience. This is used for a comparison of different chemical entities. Because biosimilars are similar to the reference product, a flatter scale is used for biosimilars: 10% per million patient days of experience. If the clinical experience with a biosimilar is 4 million patient days, this product will score 40%.

A9: Does the manufacturer guarantee active information about major changes of the manufacturing process?

Quality control and changes in the production process are included to the list of criteria set up by Krämer et al.4 The erythropoietin case has made clear that changes in the production process may affect the properties of the final product in a negative way.

Erythropoietin α (EPO α; Eprex) was used extensively for the treatment of anaemia associated with chronic renal failure. An increase in the incidence of pure red cell aplasia associated with EPO α occurred in 1998. After that, investigations were initiated to identify the cause of the increase in the immunogenicity of Eprex. Rubber stoppers were in use since the introduction of Eprex pre-filled syringes for subcutaneous administration. The replacement of human serum albumin with polysorbate 80 in 1998 appears to have resulted in a change in the leaching of potentially immunogenic compounds from the uncoated rubber stoppers.34 In addition, it was discussed that the new formulation was less stable and an increased aggregation rate caused immunogenic reactions. This example shows that it is necessary to inform EMA about any changes in the manufacturing process because it might affect the efficacy and safety.

The ICH guidance (ICH-Q5E) concludes that products must have highly similar quality characteristics before and after changes of the manufacturing process and that safety and efficacy of the drug product is not affected.35 EMA published a document that underlines the importance of performing a proper comparability exercise in its guideline on comparability of medicinal products containing biotechnology-derived products as active substance non-clinical and clinical issues.8

The goal of the comparability exercise is to ensure the quality, safety and efficacy of a drug product after changing the manufacturing process. Therefore all relevant data must be registered and evaluated that might have any impact on the drug product characteristics. Comparability can be assessed on a combination of analytical testing, biological assays, and in some cases, non-clinical and clinical data. The manufacturer should confirm that the specifications after the process change are appropriate to ensure product quality. Of course, this is also true for the reference product. Schiestl et al36 investigated the variability in quality characteristics of different batches of Aranesp, Mabthera and Enbrel. Major structural changes in protein composition that can alter the pharmacokinetics and biological activity were found by chemical analysis of these products. The observed changes occurred because of changes in growth conditions or purification steps. All batches of the products remained on the market during the investigation period. The health authorities did not reason that the observed changes would affect the safety and efficacy profiles of these originator products. Therefore it can be concluded that the considerations to maintain a product on the market after production process changes are multifactorial and are not solely based on the chemical characteristics of the questioned protein products. The extent of the comparability exercise depends on what is known about its possible impact on safety and efficacy of the product. Sometimes additional comparative information is needed at the preclinical and clinical level. The objective of the ICH Q5E document is to provide principles for assessing the comparability of biotechnological or biological products before and after changes that are made in the manufacturing process for the drug substance or drug product.35

For hospital pharmacists and clinicians it would be useful to check whether there is a causal relation between an observed adverse drug event and a product change. The EMA webpage provides information about changes in the manufacturing process of specific biological medicinal products .37

This criterion is adequately covered by EMA and is not included in the final set of selection criteria.

A10: Is the reference medicinal product authorised in the European Community?

At the moment this is a prerequisite according to the biosimilar authorisation legislation. The reference medicinal product must be a medicinal product authorised in the European Community. However, changes are under discussion.

Because this is a valid prerequisite, this criterion was not included in the final set of selection criteria.

A11: How has it been validated that the production of the API and final product is always performed under the same conditions?

The EU has introduced new rules as an amendment of Directive 2011/62/EU for importing APIs to stop the import of substandard or counterfeit pharmaceutical ingredients.26 Competent authorities of the exporting country must confirm to the broker that the production site of an API complies with EU GMP rules and that the production plant is subject to control. Manufacturing standards for APIs are those of the ICH Q7.29

The manufacturing and purification processes have to be properly described and the process validation studies and the in-process control system must be considered acceptable to EMA. Product European public assessment reports (EPARs) explain that validation programmes were developed or implemented and have limits set. In these documents individual physicians and pharmacists cannot access further information, but there is a general view of the validation.

This criterion is adequately covered by EMA and is not included in the final set of selection criteria.

A12: Has EMA checked quality control systems of the producers of API and final product?

These data are described in the EPARs of the individual products. See Filgrastim Hexal and Nivestim documents as examples.38 ,39

This criterion is adequately covered by EMA and is not included in the final set of selection criteria.

A13: Are data concerning batch reproducibility (inter-batch and intra-batch variability) available at EMA before and after approval?

These data are described in the EPAR scientific discussions of the individual products. See Nivestim scientific discussion as an example.39

This criterion is adequately covered by EMA and is not included in the final set of selection criteria.

A14: Are specifications of quality control of the MAH/manufacturer known to EMA and assessed by EMA?

Analytical aspects of validation are covered by the EMA document ‘Guideline on bioanalytical method validation’.40

The manufacturer has to present quality data to EMA for a marketing authorisation application. The registration dossier includes data to establish the quality of the product, including

definitions and descriptions of the manufacturing process, and associated quality checks and standards;

data on consistency of manufacturing (quality control of the process); data on analytical tests (molecular structure, potency and purity profile); data on stability of the product. Most of these data are to be presented as a comprehensive comparability exercise with the reference product.41

It may be the case that these data are protected by EMA as confidential information. Even a company developing a biosimilar monoclonal antibody usually has no data on critical in-process controls and intermediates in the manufacturing process of the innovator.

This criterion is adequately covered by EMA and is not included in the final set of selection criteria.

A15: Is it taken into consideration whether materials of animal origin or potentially allergenic materials are used during the production or formulation?

If an application relates to a medicinal product which contains or uses in the manufacture materials of animal origin or these are used during the production process, applicants are requested to complete tables and information established on ‘Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via medicinal products’ and this information will be included in Module 3.2.R of the common technical document (CTD).42

For materials of animal origin other than those covered by the ‘Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via medicinal products’ applicants are requested to complete table B on ‘Other materials of animal origin’. If an application relates to a medicinal product which contains materials of human origin or these are used during the production process, applicants are requested to complete table C on ‘Albumin and other human tissue derived products’.30

When cell cultures are used for the production of the API, the information is given in the EPAR. The type of cells (expression systems) that are used to produce these products are mentioned. For instance, in the case of EPO the originator used mammalian Chinese hamster ovary cells as host cells and the biosimilar product Dynepo was produced by human cell lines.

This criterion is adequately covered by EMA and is not included in the final set of selection criteria.

A16: Does EMA take into consideration where clinical studies were performed or is only the quality of the study an item of discussion?

This has been published on the EMA web page. On 16 April 2012, the document published is based on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of the EU/EEA and submitted in marketing authorisation applications to the EU regulatory authorities.

This document strengthens existing processes to provide assurance to regulators and stakeholders that clinical trials meet the required ethical and GCP standards, no matter where in the world they have been conducted. The reflection paper is part of the Agency's strategy developed to address the challenges arising from the increasing globalisation of clinical research: no matter where you stand today, most clinical trials are being conducted somewhere else in the world, under a different regulatory framework and in a different cultural setting. Yet regulators, healthcare professionals and patients worldwide all rely on the same trial data when making decisions on whether to authorise a medicine to come to the market or not and on whether to use a medicine or not.43 Nowadays, applicants and/or MAHs will be inspected (GCP inspection) within routine inspections required to ensure that information is available. Moreover, the conduct of clinical trials in accordance with ethical requirements will be checked.

When a GCP inspection is performed, the reasons for inspection should be described. Relevant information from the inspection report may be made publicly accessible. The actions taken should be reflected in the public assessment reports.43

This criterion is adequately covered by EMA and is not included in the final set of selection criteria.

A17: How is batch consistency ensured by the manufacturer and/or by third party?

Small variations are an indicator of a consistent manufacturing process. In some cases it might be that the manufacturer lacks experience in batch conformity because of a limited number of batches produced. Access to batch certificates of three recently produced batches by the MAH allows EMA to check and document pharmaceutical quality and also strengthens mutual trust.

This criterion is adequately covered by EMA and is not included in the final set of selection criteria.

B1: Are there any differences in isoform pattern in comparison to the reference product or other biosimilars?

The therapeutic relevance of a difference in isoform patterns between a biosimilar and the originator product is addressed by ICH and EMA guidelines. See EMA and ICH guidelines.8 ,35

This criterion is adequately covered by EMA and is not included in the final set of selection criteria.

B2: Are there any differences in drug formulation and administration in comparison to the reference product or other biosimilars?

The packaging material may affect the integrity of a biological medicinal product. Protein instabilities caused by adsorption from equipment surfaces or due to shed particles, such as plasticisers, can be caused by operational or procedural changes or by changing the surface or equipment type itself (eg, membranes, pumps and tubing). Similarly, compatibility studies can identify problems with particular container closures and delivery devices.44 In STEPSelect tenders such an assessment is undertaken based on the National Quality Control and Risk Assessment of licensed medicinal products to assess and score individual entities and this methodology would be applicable.19

This is included in the final set of criteria, as separate criteria. The first four criteria are relevant from a patient’s perspective; the last two are relevant from a pharmacy perspective.

The scoring is dependent on the product classes. General scoring is not possible.

1. Dosage form or route of administration. A patient intuitive device will score higher than a standard prefilled syringe or injection vial.

2. Route of administration (higher score when more routes of administration are possible, eg, subcutaneous, intramuscular, intravenous).

3. More strengths available. The higher the number of strengths available and the more patient friendly, the higher the score.

4. Dosage frequency: higher score for less frequent administration.

5. Room temperature>fridge>frozen: decreasing scoring.

6. Extended stability: higher score.

B3: What is the number of registered indications for the biopharmaceutical/biosimilar?

This criterion is included in the final set of criteria.

This is a standard SOJA criterion and is relevant from a pharmacy perspective. The higher the number of approved indications and the higher the applicability, the higher the scoring. This depends on the drug class in question and no general scoring is possible.

C1: Does the supplier reliably guarantee the supply of the biosimilar over a long time period?

In this section, we have included the lead time that the supplier guarantees and the actions taken after stock outs to evaluate how the manufacturer and supplier manage these problems. Availability of the drug product is important because otherwise unwanted switches are necessary.

A continuous and reliable supply is a prerequisite. Do not consider formulary inclusion if the local supplier cannot give guarantees about timely delivery for the contract period.

This criterion is part of STEPSelect where shortages of stock clauses and penalties for failure to supply are included in the special terms and conditions of the contract for the purchase of pharmaceuticals to which companies must comply and hence is a prerequisite.19

This criterion should be a prerequisite for individual contracts between hospitals and suppliers and is not included in the final set of selection criteria.

D1: Is the biosimilar delivered according to good storage (GSP) and distribution practice (GDP)?

To maintain the original quality of pharmaceutical products, every party active in the distribution chain has to comply with the applicable legislation and regulations. Every activity in the distribution of pharmaceutical products should be carried out according to the principles of GSP and GDP as applicable.45 ,46 Manufacturers should apply principles of GDP in the distribution chain and in addition should select a shipping company that achieves quality requirements. Therefore the probability of supply chain related detriments, which could, for example, affect the immunogenic profile or shelf life, is reduced. Public health considerations demand that pharmaceutical products should not be treated in the same way as ordinary commodities. Their manufacture and subsequent handling within the distribution chain, nationally and internationally, must meet WHO guidelines and should be rigorously controlled. These precautions serve to assure the quality of products, and to prevent the infiltration of illicit products into the supply system.

For medicinal products imported from third countries, retesting of each batch within the EEA upon importation is required unless an MRA or other relevant agreement covering GMP for the product under consideration is operating within the country where the medicinal product is manufactured. If such an MRA is in operation, batch controls/tests carried out in the country where the product is manufactured are acceptable. It should be noted that MRAs cover batch control/testing and do not cover batch release. Batch release must take place in the EEA territory for every production batch released to market in the EEA, irrespective of whether an MRA with the exporting country is in place or not. Laboratories used for contract testing upon importation of medicinal products manufactured in third countries may be located in any EEA country.30

This criterion is adequately covered by EMA and is not included in the final set of selection criteria.

E1: Is the clinical development programme consistent with the current regulatory requirement?

This is extensively discussed in the various EMA assessments. Various additional guidelines were developed during the last few years (product specific and non-specific).

In most development programmes for biosimilar medicines comparability is demonstrated in a stepwise process that starts with pharmacokinetics and pharmacodynamics studies followed by clinical efficacy and safety trials. In efficacy trials an equivalence design is used in most cases. Endpoints for trials are clearly defined in certain product-class-specific guidelines by Committee for Medicinal Products for Human use experts. These primary endpoints do not necessarily have to be the same as those used in the trials with the originator product but deviations from these guidelines have to be justified. The margins of clinical comparability should be pre-specified with respect to statistical and clinical aspects by using the data of the reference product.8

In our opinion this criterion is adequately covered by EMA and is not included in the final set of selection criteria.

E2: Which clinical trials in which patient populations with which designs, endpoints and results were performed?

The criterion is introduced as an estimate of the documentation of the biosimilar in randomised clinical trials.

For biosimilar products that are very similar to the reference product abridged clinical development programmes can be performed because experience is gained with the originator product. Nevertheless biosimilars have to go through the whole registration process and in the end the average time to positive opinion issued by the EMA is longer than for originator biological medicines.47

For products that are less similar to their reference products, more extensive clinical studies are to be done and extrapolation of indications will be more unlikely. An extended clinical study programme would favour products that had not proven close similarity to the reference product because that product would have to demonstrate efficacy and safety in a study with a higher number of included patients. Therefore, this criterion was not included in the final set of criteria.

E3: Are there different results in comparison to the reference product?

This criterion is included in the final set of criteria.

This is a standard SOJA criterion and is usually assigned the highest weight of all selection criteria. No general scoring is possible. The higher the efficacy in randomised clinical trials, the higher the score. If there are no documented differences in clinical efficacy, both drugs will have identical scores.

F1: Which (serious and mild) adverse events and in which frequency were they reported in clinical trials with the biopharmaceutical?

This criterion is included in the final set of criteria.

This is a standard SOJA criterion and is usually given a high relative weight. No general scoring is possible. The numbers of patients included in clinical trials will usually be insufficient to identify rare side effects and to make statements concerning safety. Only the judgement of tolerability is possible here. To make statements on safety, many more patients would have to be included and the duration of studies would have to be much longer. The better the tolerability in clinical trials, the higher the score for the drug in question.

Besides clinical trials, data from pharmacovigilance studies will also be taken into consideration in the judgement of relative safety (see section G).

F2: Are there any contraindications, precautions or warnings which are different compared with the reference product?

This criterion is included in the final set of criteria.

This is a standard InforMatrix criterion.18 A large number of contraindications or many warnings or precautions may limit the usefulness of the drug for the treating physician. No general score is possible; scoring depends on the specific contraindications and warnings for specific drugs. The more contraindications and precautions, the lower the score.

F3: Is immunogenicity, as far as known, caused by a homogeneous type of antibody or is there a high intra-individual or inter-individual variability? Is there a difference between biosimilar products regarding drug antibody homogenicity?

This criterion is included in the final set of criteria.

Immunogenicity can affect the safety and efficacy of biosimilars that may lead to clinical consequences such as adverse effects and reduction of efficacy. Immunogenicity is influenced by factors relating to the pharmacological active substance itself. Aggregation of the protein product can also induce immunogenicity, including manufacturing changes, impurities as by products (leachates or leachables=lixiviate which may migrate from the primary packaging into the drug product). Plasticisers, antioxidants and allergens can be leached from rubber in container closures causing product impurities. The presence of degradation products, host cell products and formulation changes and the use of a different packaging system (containers and closures) are other factors that influence safety and tolerability.48–50 In addition to these aspects, immunogenicity may be influenced by factors related to the individual susceptibility of the patient (eg, patients who are immunocompromised), disease, treatment, dose, route or schedule of administration. It is worth mentioning that testing strategies or analytical methods should guarantee a correct immunogenicity assessment. The assessment of immunogenicity is covered in an EMA guideline.51 These immunogenicity assays should guarantee the safety and efficacy of biopharmaceuticals.

The immunogenicity of biopharmaceuticals/biosimilars often cannot be fully predicted using preclinical (non-clinical) in vitro and ex vivo studies and clinical immunogenicity studies are usually required before approval and sometimes also after approval. Moreover, patient-specific immunogenicity may sometimes only emerge after extensive exposure and usage. Further systematic immunogenicity testing may also be required after gaining marketing authorisation. Assessment of immunogenicity may be part of post-approval risk management plans (RMPs) and pharmacovigilance activities.51

No general score is possible. The score will depend on the available data for each individual biological medicinal product. The more (severe) reactions, the lower the score for the specific biosimilar.

F4: Are there differences in the incidence and severity of drug interactions?

This criterion is included in the final set of criteria.

This is a standard SOJA criterion. No general scoring is possible. The lower the incidence and severity of drug interactions, the higher the score for the drug in question. However, it seems unlikely that there will be relevant differences between the reference drug and biosimilars regarding this criterion.

F5: Are there differences in the incidence of local reactions?

This criterion is not included in the final set of criteria but is taken into consideration under criterion F1.

G1: Does the MAH have a 24 h phone number equipped with adequate personnel to report adverse events?

This criterion should be a prerequisite for individual contracts between hospitals and suppliers and is not included in the final set of selection criteria.

G2: How is pharmacovigilance controlled?

Pharmacovigilance is a continuous process as is the case for biosimilar medicinal products. Knowledge about the equilibrium between efficacy and safety from the pre-authorisation period can change over time after market access. The expanding number of patients exposed to the drug and their characteristics and subtle changes to a complex medicinal product can have an impact on this equilibrium. EMA considers the detection, assessment, minimisation and communication about the associated risks to be the responsibility of the MAH. The MAH must provide a RMP in the application as a part of the CTD. In addition, the MAH must have a qualified person who is continuously available to deal with pharmacovigilance issues. After approval, the MAH should promptly report to the competent authorities or directly to EMA for centrally authorised products in the case of pharmacovigilance issues.9

EU legislation about pharmacovigilance and reporting of non-serious unexpected adverse events is given in EC regulations EC726/2004 and EC 540/95, respectively.52 ,53 These regulations are supported by guidelines condensed in the Eudralex volume 9 ‘Pharmacovigilance’.54 This criterion is adequately covered by EMA.

Healthcare providers can access information about the focus areas of the RMP for the individual product during post-marketing surveillance by searching the website of the EMA where EPAR scientific discussion can be found.37

For healthcare providers, as part of the pharmacovigilance system, it is important to know that product identification is crucial when reporting an adverse event. Only the brand name and the batch number can identify the product in the case of biosimilar medicinal products.9 The use of international non-proprietary names (generic names) and misconceptions about interchangeability between biosimilar and originator medicinal products can stress problems of traceability of the incriminated product.