A visible difference: clinical packaging

6 July 2015

The current biosimilar labelling policy in the EU and the US includes no detail of the data used to demonstrate similarity to the reference product, potentially causing confusion for doctors and patients. The European Association for BioIndustries (EuropaBio), with colleagues from AbbVie, Amgen and Pfizer, explores the need for sufficiently detailed and transparent information on the packaging of these medicines.

A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorised biological drug. Biosimilars are developed to be similar in terms of quality characteristics, biological activity, safety and efficacy to a biological already on the market (commonly referred to as either the reference, originator or innovator product).

But, although biosimilars are designed to be comparable to their reference biological, due to the complexity of the products themselves - and to the difficulty and sensitivity of the manufacturing process - all biological medicines are structurally unique. Bearing this in mind, one should anticipate that each drug belonging to this category will contain specific details derived from their development.

Globally, there are a variety of regulatory pathways that may lead to authorisation and marketing of biosimilars.

The development of such medicines is supported by global regulations - for example, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) - as well as regional and national rules, many of which contain the same key principles.

Biosimilars explained

"Over the last few years a generic approach has been adopted, and the labels of reference and biosimilar products are now virtually indistinguishable." 

The development of a biosimilar is determined using a stepwise approach, starting with a comprehensive physicochemical and biological characterisation of originator and biosimilar.

The extent and nature of the non-clinical in-vivo studies and clinical trials required to confirm biosimilarity depend on the degree of analytical similarity determined during the characterisation studies. Therefore, in comparison with traditional development of new molecules, biosimilars require less clinical data, but rely more on comprehensive analytical and functional information to support approval.

Europe has led global development of biosimilars, with 21 marketing authorisation applications (MMAs) approved since 2006, corresponding to six product classes: somatropin, epoetins, filgrastim, follitropin alfa, insulin glargine and infliximab. During this time there has been some evolution of the biosimilar label. Initially, there was relative transparency, but over the last few years a generic approach has been adopted, and the labels of reference and biosimilar products are now virtually indistinguishable.

The only discernible part of the biosimilar label is in section 5.1 of the Summary of Product Characteristics (SmPC), where the market authorisation holders (MAHs) are required to include a sentence stating that the product is, in fact, a biosimilar. The practice of regulators is to summarise the data used to demonstrate biosimilarity in the European Public Assessment Report (EPAR), which is not directly hyper-linked within the SmPC. The SmPC also forms the basis for the preparation of the patient information leaflet (PIL), an important document for relaying information on medicines to the people taking them.Consequently, the EPAR is probably not the most relevant vehicle for facilitating a dialogue between the patient and the prescriber.

In Europe, a template exists that provides a broad outline of how product labels are structured; namely, the EMA's Quality Review of Documents template (EMA/627621/2011). It allows flexibility with respect to language and content, depending on the class of products. EuropaBio considers there is no need to modify the QRD template; but there is a need for regulators to provide more transparency within the labellingtext of the SmPC with respect to:

  • comparative clinical data (ideally to be placed in section 5.1)
  • statement of biosimilarity (to be moved to section 2)
  • unique safety signals (ideally to be placed in section 4.8)
  • definition of sensitive patient population (ideally to be placed in section 5.1)
  • extrapolated indications of biosimilars (ideally to be placed in section 5.1).

The lack of granularity provided in the product label for biosimilars could undermine confidence in this class of products among healthcare providers, who consider that transparency and accuracy of information is critical in ensuring confident use of the medicines they prescribe. In a recent article by the European Biopharmaceutical Enterprises in Generics and Biosimilars Initiative Journal, the organisation made recommendations on biosimilar labelling, which are aligned withthe aforementioned proposals.

Plenty of recently conducted surveys indicate physicians' confidence will be necessary to support the uptake of biosimilars and enhance the understanding of these products. For instance, a 2013 Alliance for Safe Biologic Medicines (ASBM) study of European doctors showed a very low level of knowledge of biosimilars by the surveyed sample of 470 prescribers. Other data from the same study suggested that the SmPC is the main conduit of product information that physicians in the EU rely upon when prescribing the medicine, and in the follow-up of use in patients and when communicating treatment options to them.

"In 2015, ASBM released the results of a survey suggesting physicians in the US support transparent, clear labels with data that enables prescribers to learn about and evaluate the medicines available to their patients." 

Additionally, in 2015 ASBM released the results of another survey suggesting physicians in the US support transparent, clear labels with data that enables prescribers to learn about and evaluate the medicines available to their patients.

The survey questioned 400 physicians about what they expected and wanted to see when it comes to biosimilars labelling. Specialists in dermatology, endocrinology, oncology, nephrology, neurology and rheumatology - all disciplines that routinely treat patients with biologic medicines - were included in the research, which was carried out via a web-based questionnaire. Respondents were asked to rate how important they consider various types of approval information to be included on the label/product information sheet of a biosimilar. Options ranged from 1 (not important) to 5 (very important).

When it comes to the patient perspective, there has been some consultation between regulators and patient groups in Europe regarding the labelling of biological medicines. However, with respect to biosimilar labelling specifically, there has been limited discussion and it is not clear if patient opinion has been sought on this topic. US patient organisations have tended to be more vocal in expressing their viewpoint on this subject and generally appear to be in favour of clear biosimilar labelling so they can make more informed decisions.

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Transparency is essential to build patient confidence in this new category of drugs. With this in mind, EuropaBio advocates for greater outreach and discussion between patient groups and other stakeholders including regulators, industry and healthcare professionals.

Some countries have proved better on this issue than others. For example, the product label for the first monoclonal antibody (mAb) biosimilar approved in Canada was a combination of the biosimilar and reference product (RP). The adverse effects (AEs) section included clinical trial AEs described in tables. It also listed common AEs from the RP and biosimilar, in addition to other sections. The clinical trial section referenced biosimilar studies, comparative tables of pharmacokinetics, efficacy, immunogenicity and anti-drug antibody results. Also presented was an extensive table detailing in-vitro activity between RP and biosimilar.

In addition to Canada, Switzerland has also produced transparent labelling for its biosimilar products. In these countries the biosimilar label mentions the source of data (biosimilar or originator) as well as providing clarity on the indications that were included as a result of extrapolation. EuropaBio believes these approaches to biosimilar labelling should, at the very least, be regarded as a best practice and as a good first step in moving towards greater transparency in the packaging of these products.

In order to contribute to this debate, EuropaBio recently commissioned an online survey of prescribers from seven European countries to qualitatively and quantitatively assess their preferences regarding content of the biosimilar label. The output from this survey will be available later this year.

The organisation strongly believes that transparency is the main driver of physician and patient confidence in biosimilar medicines, and will support improved access to these drugs. While it also understands that it may be difficult to satisfy the needs of all stakeholders, it is hard to see the benefit to any associate of limiting access to meaningful information on this important class of products.

Moving forward, EuropaBio strongly advocates further consultation between regulators, healthcare professionals, industry, patients and other stakeholders, with the ultimate aim being issuance by the CHMP of specific guidance on the content of the biosimilar label.

For the reasons cited, EuropaBio concludes that the SmPC is the primary source for information on biosimilars and therefore should contain all relevant information in addition to the EPAR.


Keith Watson is director for global regulatory affairs within the Biologics Strategic Development Group at AbbVie. He has previously worked at Parexel and as biological senior quality assessor at MHRA in the UK.

Catherine Akers is regulatory affairs senior manager at Amgen. Akers has worked at Amgen for several years in the areas of CMC as well as in pre and post-marketing activities.

Edward Hume is EU regulatory lead for biosimilar mAbs at Pfizer. He advises on EU regulatory strategy for biosimilar mAbs, including numerous leading EMA scientific advice procedures and clinical trial regulatory oversight.

Aimad Torqui is associate director for EU regulatory policy at MSD. He previously worked for Novartis and in the Medicines Evaluation Board in the Netherlands.

Syed Numan is associate director for JAPAC/LATAM regulatory affairs within the Biologics Strategic Development Group at AbbVie. He is an MD by training and previously worked at Baxter.

Miriam Gargesi is director for healthcare biotechnology at EuropaBio. Prior to joining EuropaBio, she served for several years as director for public affairs and communications at EDMA, the European Diagnostic Manufacturers Association.

Riccardo Mezzasalma is manager for Healthcare Biotechnology at EuropaBio, where he coordinates activities on biosimilars and orphan medicines. Mezzasalma previously worked as EU consultant in healthcare policies.

The potential for confusion under current biosimilar labelling policies has sparked a call for change.

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