Biological medicinal products have rapidly become one of the fastest growing areas of medicine and for many conditions they offer a new and more effective form of treatment.  It is therefore unsurprising that biosimilars, since they were first introduced onto the EU market in 2006 (when Sandoz got a marketing authorisation (MA) for Omnitrope), have become an important part of the treatment landscape.  Biosimilars being inherently cheaper than the biological medicinal product are preferred by the payers of medicinal products and therefore their use is encouraged.  Therefore, in many jurisdictions there is increasing financial pressure for healthcare professionals (HCPs) to prescribe biosimilars rather than the ‘reference medicinal product’[1]. However, this financial benefit must be carefully balanced against potential patient safety concerns.

This article briefly sets out what biosimilars are then discusses the concept of interchangeability and substitution. It then goes on to discuss the regulatory framework regarding interchangeability and substitution in different jurisdictions and the different factors influencing changes to this framework.

Key definitions

What is a Biosimilar?

A biosimilar is a ‘biological medicinal product’[2] that is similar (but not identical) to another biological medicinal product that has obtained a marketing authorisation on the basis of a complete dossier (i.e. the “reference medicinal product”).

Biosimilars benefit from a simplified procedure to obtain an MA, the legal basis for which is set out in Article 10(4) Directive 2001/83/EC (the “Medicinal Code”), which states “Where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided…”. Therefore, biosimilars are not required to provide the full set of data to demonstrate their quality, safety and efficacy. Instead biosimilars must conduct comparability studies to demonstrate their ‘biosimilarity’ to the reference medicinal product. If the studies are conclusive then the biosimilar would be able to rely on the safety and efficacy data generated by the reference medicinal product in support of its own MA (as long as the periods of regulatory data protection and marketing protection have expired[3]).

The concepts of ‘Interchangeability’ and ‘Substitution’ of biosimilars

The terms “interchangeability” and “substitution” are rather confusing and are not used consistently in scientific publications. They are not specifically defined in the EU pharmaceutical legislation, and both relate to the action of replacing one medicine for another; however the EU Commission[4] distinguishes the two practices as follows:

• Interchangeability: the medical practice of changing, on the initiative of a HCP or with their agreement, one prescribed medicine for another with the expectation that it will achieve the same clinical effect in a given clinical setting and in any patient; and
• Substitution: the practice of dispensing one medicine instead of another equivalent medicine at the pharmacy level without consulting the prescriber. This is common practice in relation to identical molecules (i.e. generics of each other).

We have adopted these definitions throughout this article, although it should be noted that these definitions are not standard as different countries may use different terms and/or definitions (e.g. the FDA in the US define interchangeability differently[5]). At the time of writing, discussions are on-going to try to develop standardised terms that can be used in MedDRA (a highly specific standardised medical terminology used to facilitate sharing of regulatory information internationally, developed by the ICH) and so this should help to align the different systems.

Is interchangeability and/or substitution possible?

In order to grant an MA for a biosimilar the EMA will review extensive amounts of comparability data (e.g. analytical studies, in vitro and in vivo non-clinical studies and clinical studies) produced to establish similarity between the biosimilar and the reference medicinal product to ensure that the “previously proven safety and efficacy of the reference medicinal product also applies to the biosimilar”. However, this review does not include a recommendation regarding whether said biosimilar should be used interchangeably with its reference medicinal product.

Decisions regarding interchangeability and substitution of biosimilars are outside the EMA’s remit; however, the EMA has stated in guidance that “[i]t is possible to switch from a biological reference medicine to a biosimilar medicine and this is a growing practice in some Member States. Any decision on switching should be taken by your doctor in consultation with you, and taking into account any policies that your country might have regarding the use of biological medicines[6].”Therefore, it appears in principle that the EMA accepts the possibility of interchangeability but not substitution.

However, it is clear that Member States retain the discretionary power to legislate on the interchangeability and substitutability of biosimilars. Therefore, there is variation between different countries’ legislative frameworks and this is discussed below.

Interchangeability

Concerns have been raised by some stakeholders about interchanging reference medicinal products and biosimilars. As stated above, while biosimilars must prove that the previously established quality, safety and efficacy of the reference medicinal product applies to them, interchangeability of a particular biosimilar with its reference medicinal product is not tested. Therefore, there are concerns that interchanging could impact patient health as switching to biosimilars could lead to different immunogenic reactions and side effects. There is evidence that changes in manufacturing process can lead to unexpected adverse events and so changes in manufacturing and/or presentation between the reference medicinal product and the biosimilar may be of concern. For example, as detailed in a paper by C L Bennett et al.[7] the formulation of the drug Eprex was changed and this led to increased immunogenicity in the form of pure red cell aplacia (PRCA). Another example was in the case of peginesatide, which was given to 20,000 patients in the US in dialysis centres and severe anyphylaxis occurred in 28 patients leading to 5 deaths (this was thought due to the addition of preservatives as preapproval trials used single-use vials without preservatives whereas post-approval patients were treated with multi-use vials with preservatives).

However, there is growing evidence of the safety of biosimilars. For example, in a recent guide published by the EMA and European Commission[8] it stated “The evidence acquired over 10 years of clinical experience shows that biosimilars approved through EMA can be used as safely and effectively in all their approved indications as other biological medicines”. Therefore, use of biosimilars instead of their counterpart reference medicinal product should not be seen as unsafe for patients.

There is also growing evidence of the safety of ‘interchangeability’, for example, in the position paper published by Fimea (the Finnish medical agency)[9] it was noted that immunogenicity was unlikely to occur due to the fact that biosimilars have comparable structures, the active substances have the same amino acid sequence and similar post-translational profile and inferior quality (impure) biosimilars are not allowed. The paper goes on to give examples of switching between biological medicinal products that could help agencies to evaluate the risks involved in interchanging. For example, it has been shown that switching between two non-similar but related biological products has not led to higher immunogenicity. Fimea concluded that switches between biological products are common and usually not problematic (e.g. during hospital tenders), currently there is no evidence for adverse effects due to switching from a reference medicinal product to a biosimilar, the theoretical basis for such adverse effects is weak and the risk of adverse effects can be expected to be similar to the risk associated with changes in the manufacturing process of any biological product. Therefore, Fimea’s position is that biosimilars are interchangeable with their reference medicinal product under the supervision of an HCP. This is in line with the position of the French regulatory authorities which have taken a relatively relaxed position on interchangeability.  Indeed, in May 2016 a report was released stating that while the advice had previously been to not switch during the course of a treatment, this practice would no longer be excluded so long as the patient consents, there is adequate clinical monitoring and there is traceability.

While there is some variation between the different regulatory frameworks, due to the growing body of evidence regarding the safety of interchangeability, many Member States have taken the position that interchanging between a reference medicinal product and a biosimilar is acceptable if it is managed by the prescriber and patient, plus (in many cases) that it is monitored. For example, in the UK, interchangeability is allowed and NICE advice states that “[t]he choice of whether a patient receives a biosimilar or originator biological medicine rests with the responsible clinician in consultation with the patient”[10]. However, as the biosimilar and its reference medicinal product will have the same international non-proprietary name (INN) it is good practice for HCPs to use the brand name of the biological medicinal product when prescribing to ensure substitution does not occur. Prescribing by brand name is also important for the purposes of traceability and pharmacovigilance.

Substitution

As stated above, substitution occurs at a pharmacy level without the intervention of an HCP. This practice is well established for traditional chemical medicinal products where generic medicinal products are identical to the reference medicinal product. Automatic substitution of generics is common as generics are almost always significantly cheaper than the reference medicinal products and substitution is both in the interest of the national health authorities (the ‘payers’) and the pharmacists who benefit from the difference between the purchasing price of the generics and the reimbursement price of the INN.

The issue is that biosimilars are not identical to their reference medicinal product; they are ‘similar’. Therefore, while there are potentially very significant cost saving in prescribing biosimilars rather than their reference medicinal products, Member States have traditionally been resistant to allowing substitution. These concerns are illustrated by the legal requirement provided in Article 102(e) of the Medicinal Code that all Member States must take appropriate measures to “identify clearly any biological medicinal product prescribed, dispensed, or sold in their territory which is the subject of a suspected adverse reaction report” to ensure a proper application of the principles of pharmacovigilance and traceability.

To date, Member States have taken diverging positions towards the substitution of biosimilars.  For example, the UK and Spain do not permit automatic substitution of biosimilars at the pharmacy level. In contrast, in December 2016, France became the first EU country to pass a law to allow substitution of biological medicinal products by adopting the 2017 French Social Security Act (PLFSS). PLFSS allows for substitution of biosimilars for prescribed reference medicinal products both at the start of the course of medicine and during it. However, this is subject to the HCP prescribing the product not marking the prescription as “non-substitutable” and so substitution is to some extent controlled by HCPs.

It should be noted that while in principle this law is in force in France, in practice it is not possible to substitute biosimilars until a Decree has been passed that sets out the particulars of how substitution will work. As of 18^th October 2017 a Decree regarding the relevant article of PLFSS has not been passed and so substitution is not currently practised in France. The delay in passing the Decree might reflect that there are still diverging views on how to allow substitution and the challenges of ensuring a sufficiently robust pharmacovigilance system is in place in order to monitor and trace biosimilar products substituted for their respective reference medicinal products.

What does the future hold for biosimilars?

As biological medicinal products are a relatively new and ever increasingly important area of medicine the legislation surrounding their use will continue to develop as more data becomes available about their safety and efficacy. Healthcare payers are under ever increasing financial pressure to substitute /interchange biosimilars for their more expensive reference medicinal products, as this would not only reduce the cost of treatment but also increase patient access. Interchangeability is already widely accepted and used across the EU and there is an increasing amount of evidence indicating that this is not exposing patients to significant health risks. Despite these factors, Member States are still resistant to allowing substitution of biosimilars as there is insufficient evidence that it is safe and there are concerns about pharmacovigilance and traceability. Therefore, at this point in time, it seems that the economic benefit potentially enjoyed by ‘society’ does not outweigh the potential safety risks to ‘individuals’.

However, it is our view that, as long as there is no major adverse incident relating to the use of biosimilars, and driven by financial considerations, it is likely that substitution of biosimilars in some form will become acceptable. As deciding the rules on substitution is a Member State’s prerogative, all Member States will progress at different rates and may implement different systems. For example, some may decide there is sufficient evidence to use the same system as traditional generics (i.e. immediately becoming substitutable on authorisation) whereas others may implement a different system such as substitution may be allowed on a case-by-case basis if sufficient evidence is available that switching between the reference medicinal product and biosimilar is not putting patients at risk (i.e. after X years of commercialisation).

[1] Defined in Article 10(2)(a) of the Medicinal Code
[2] Defined in s3.2.1.1(b), Part I, Annex 1 of the Medicinal Code
[3] See Article 10(1) and (2) of the Medicinal Code
[4] Consent Information Document available at http://ec.europa.eu/DocsRoom/documents/8242
[5]https://www.fda.gov
[6]https://ec.europa.eu/growth/content/information-patients-what-i-need-know-about-biosimilar-medicines-0_en
[7]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404762/
[8] http://www.ema.europa.eu/docs/en_GB/document_library/Leaflet/2017/05/WC500226648.pdf (last updated April 2017)
[9] www.fimea.fi/documents/542809/838272/29197_Biosimilaarien_vaihtokelpoisuus_EN.pdf
[10] https://www.nice.org.uk/advice/ktt15/chapter/options-for-local-implementation