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# The legal framework applicable to biosimilars in the EU

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Posted: 24 August 2016 | | 2 comments

Biosimilars are becoming increasingly important in the European Union’s biopharmaceutical landscape due to the increased growth of biologicals as key therapies and the financial pressure this puts on healthcare budgets.

Both generic and innovator companies are players in the biosimilars market, and such drug products can present potential savings for payers. In certain cases biosimilars have gained over 90% of the market share within one to two years of launch1 . This article examines the process for the approval of biosimilars in the EU; the way in which safety and risk management is conducted; and market access issues.

The approval process Biological products are large molecules that are typically derived from living cells. They are characterised as being highly sensitive to manufacturing and handling processes, which makes them more challenging to produce (and copy) than small molecules. A biosimilar product is defined as a biological medicinal product that is similar to a reference biological product, but that does not meet the conditions in the definition of a generic medicinal product owing, in particular, to differences in raw materials or manufacturing processes.

The approval of biosimilar products has been facilitated since the introduction of a specific provision in the Medicinal Code2 . So far, twenty biosimilar products have been approved via the centralised approval process relating to eight different reference biological products – the most recent being Benepali (etanercept)3 .

The legal basis for the approval of biosimilars, Article 10.4 of the Medicinal Code, sets out the definition of a similar biological product and clarifies that an application for a marketing authorisation for a biosimilar must include the results of appropriate preclinical tests or clinical trials demonstrating similarity with the reference biological product. The goal is to exclude any relevant differences between the biosimilar and the reference product and to confirm comparable clinical performance. This contrasts with the requirements for generic medicinal products, where the applicant need only provide the results of bioavailability studies demonstrating bioequivalence with the reference medicinal product.

The type and quantity of supplementary data to be provided is set out in Annex I of the Medicinal Code and in detailed biosimilar guidelines issued by the European Medicines Agency (EMA)4 . These guidelines consist of: (a) overarching guidelines on similar biological medicinal products, non-clinical and clinical issues and quality issues; (b) product-specific guidelines such as those that include recombinant follicle-stimulating hormone, interferon beta and recombinant erythropoietins; and (c) other relevant guidelines.

From the date of submission of the marketing authorisation application, the approval process for a biosimilar product generally takes between one and one and a half years. The average cost for developing a biosimilar is estimated to range from $40 million to$375 million – this compares with the $4 million price for developing a generic medicinal product. The first biosimilar product to be approved in the EU was Sandoz’s Omnitrope, containing the growth hormone somatropin, which was approved on the 12th of April 2006. Interestingly, Sandoz had tried to obtain a marketing authorisation for Omnitrope sometime before Medicinal Code 2004/27/EU came into effect using the process for bibliographic applications based on well-established medicinal use, but this approach was rejected by the European Commission. ## Safety and risk management ## Pharmacovigilance Due to the complexities in the manufacturing and production of biosimilars, it has been accepted that for the purposes of pharmacovigilance monitoring it is important to identify the product, manufacturer and batch number in adverse event reports. Article 102(e) of the Medicinal Code requires Member States to ensure that measures are taken to clearly identify any biological medicine which is the subject of an adverse event report, with due regard to name and batch number. It is interesting to note that the position of the EMA towards the monitoring of the safety profile of biosimilars appears to have evolved in recent years. Indeed, until recently the EMA’s position was rather cautious, and its overarching Guideline on Similar Biological Medicinal Products published in 2005 stated that “it should be recognised that, by definition, similar biological medicinal products are not generic medical products, since it could be expected that there may be subtle differences between similar biological medicinal products from different manufacturers or compared with reference products, which may not be fully apparent until greater experience in their use has been established. Therefore, in order to support pharmacovigilance monitoring, the specific medicinal product given to the patient should be clearly identified.” However, the 2014 version of this Guideline only states that: “in order to support pharmacovigilance monitoring … all appropriate measures should be taken to clearly identify any biological medicinal product which is the subject of a suspected adverse reaction report, with due regard to its brand name and batch number”. In the United Kingdom the Medicines and Healthcare products Regulatory Agency (MHRA) has highlighted in Drug Safety Updates that, in order for them to perform product/brand-specific pharmacovigilance, the brand name (or product licence number and manufacturer) and the specific batch-number should be included on reports for suspected adverse drug reactions for biological medicines5 . ## Naming of biosimilars There are ongoing debates regarding the naming of biosimilars. The EU’s current position is that biosimilars share the same common name as the reference product. Interestingly, in June 2015 the World Health Organization issued a consultation paper proposing the introduction of a biological qualifier (BQ) for all biological products consisting of a four letter sequence that would identity an active substance as being produced by the same corporate entity. The consultation closed in November 2015. However, in the EU the practice of providing brand names within adverse event reports appears to have worked well: a survey of 13,790 biologic entries in the EudraVigilance system showed a >96% ability to track the biosimilar6 . ## Risk management All biosimilars bear a ‘black triangle’, which indicates that the product is subject to additional monitoring. A European list of medicines under additional monitoring is published every month by the Pharmacovigilance Risk Assessment Committee (PRAC). A medicine usually remains under additional monitoring for five years or until the PRAC is satisfied that it can be removed from the list. Every biosimilar authorised by the European Medicines Agency will have a risk management plan in place, details of which will be in the European Public Assessment Report. The types of risk management activities that a biosimilar manufacturer may be required to undertake and be responsible for can include the provision of additional information, alert cards or educational materials/websites to patients and/or physicians. Patient registries are also common risk management activities for biological medicines and biosimilars may need to be incorporated into existing or new registries. There may need to be engagement and co-operation between healthcare professionals, patients and different manufacturers in relation to the management of these registries. The average cost for developing a biosimilar is estimated to range from$40 million to $375 million – this compares with the$4 million price for developing a generic medicinal product

Prescribing and substitution Unlike with generic versions of small molecules (which rapidly replace the branded product once they are approved and, where relevant, awarded tenders), the uptake of biosimilar products has been highly diverse across Member States and therapy areas. This is because although the authorisation of the biosimilar products has been through the centralised approval procedure, control over reimbursement, prescription and pharmacy substitution remains at a national member state level. It is generally accepted that the automatic substitution of biosimilar products at pharmacy level is not appropriate due to the nature of the products.

In the UK automatic pharmacy substitution (being the practice of dispensing one medicine instead of another equivalent and interchangeable medicine at the pharmacy level without consulting the prescriber) is not permitted in relation to products that have been prescribed by brand name. International non-proprietary name (INN) prescribing is the established practice within the National Health Service (NHS) for most other products, so the MHRA has issued guidance stating that it is good practice to prescribe biological products by brand name to ensure that automatic substitution does not occur, in its Drug Safety Update for Biosimilar Products dated February 2008. In addition, NHS England Guidance issued in September 20157 clarifies that, whilst prescribers are always able to switch treatments for a given patient provided it is safe to do so and there are appropriate monitoring arrangements in place, automatic substitution is not appropriate for biosimilar products and the main way to ensure that this does not happen is through brand prescribing.

Prescribing practices are ultimately determined by the prescribing physician, however, in practice physicians will need to take into account national (or local) prescribing guidance from regulators, payers, or professional/academic associations which will influence their prescribing choice.

Prescribing and substitution practices do vary among the Member States, but in most cases either law or guidelines prohibit the automatic substitution of biosimilars. The notable exception is in France where, by law, pharmacists are allowed to substitute a biosimilar for the originator’s biological product provided that the treatment is the initiation of a new course of treatment and the physician has not indicated that the prescription is ‘non-substitutable’.

## Market access

The uptake of biosimilars has experienced variations at the molecule level, therapy area and country level, for several different reasons.

The payer environment and procurement model has in some cases been a key factor, and can set the tone for the other stakeholders involved in the substitution decision. For example, if a tender system is in place and a single national tender is awarded to a biosimilar, then the biosimilar may obtain almost the entire market share for that product. On some occassions even a minor cost saving will be enough to win a tender. As an example, the uptake of biosimilar infliximab in certain Nordic countries between 2014 and 2016 rose to over 90% of the market share, by winning tenders purely based on a price discount. However, there is not always a strong correlation between price differential and uptake.

HTA bodies and payers are starting to implement strategies to support the effective uptake of biosimilars, from a practical and clinical perspective. For example, in the UK in January 2015 the health technology appraisal body, the National Institute for Health and Care Excellence (NICE), published a position statement on evaluating biosimilar medicines, clarifying that where biosimilars are notified to the NICE topic selection process for referral to the technology appraisal programme, they will usually be considered in the context of a multiple technology appraisal, in parallel with their reference products in the indication under consideration.

In the case of the biosimilar infliximab, NICE produced an ‘adoption resource’ to help manage the introduction of biosimilars into care pathways safely and effectively, which included findings and shared experiences from NHS organisations. Some examples of these findings were the need to consult all stakeholders (including patients) to ensure confidence in the use of the biosimilar; the provision of information regarding the approval process by the EMA; identifying cost savings; seeking approval at the local formulary committee; identifying baseline data to be collected during and after the introduction of the biosimilar; and submitting data to national audits and registries.

Another example is the effort to collect real-world data regarding switching patients to biosimilars in Norway. The NOR-SWITCH study is being run and supported financially by the Norwegian government to evaluate the maintenance of efficacy and adverse event monitoring following patient switch from reference to biosimilar infliximab. The study will run over 12 months and the results are expected to be available at the end of 2016.

Clinical innovation factors such as second-generation products, which have recognised and/or added value, can also impact biosimilar uptake, but may not be decisive in the face of cost savings.

The uptake would also depend on whether the biosimilar qualifies as a ‘biobetter’, namely whether the biosimilar is an improved version of the reference biological product, by having an improved pharmacodynamic or pharmacokinetic profile resulting in enhanced safety, efficacy or manufacturing characteristics, different forms of delivery or even lower dosing. There are appealing commercial advantages to biobetters as opposed to biosimilars. Recent cases illustrate that companies are prepared to concentrate research and development resources into developing biobetters; see, for example, the development and launch of Neulasta (pegfilgrastim) and Aranesp (darbepoetin alfa)8.

## The future of biosimilars

What does the future hold for biosimilars? It is likely that in the future biosimilars will become more readily substituted at a prescribing (rather than pharmacy) level, as confidence grows in their use and strategies for monitoring before and after switching become more well used. It will remain important to track and record which product a patient receives, for safety reasons, and for biosimilars manufacturers to implement robust risk management activities. As pressure on healthcare budgets increases, cost saving is likely to become a key driver for the use of biosimilars where it is clinically appropriate to do so.

Hilary Jones is a Senior Associate in the Bristows IP Regulatory team, specialising in all aspects of EU and UK law in the biopharmaceutical and medical devices sectors. Hilary previously worked at Pfizer and at Gilead Sciences, supporting the global business units, bringing a strong business approach to her legal advice.

### 2 responses to “The legal framework applicable to biosimilars in the EU”

1. Doug says:

Great article.
Please could you supply the references?
Thanks – Doug

• Niamh Marriott says:

Hi Doug, we’re glad you enjoyed it. If you click here, you’ll be able to view the Digital version of the magazine which has all the references in footnotes at the bottom of each article. Hope that helps!

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