Biosimilars on a global scale

Lini Subin, senior manager, regulatory affairs, ELC Group, discusses how EMA opens doors for global biosimilar development

The biosimilar regulatory framework in Europe is the most advanced in the world. The European Medicines Agency (EMA) has now taken initiatives that will lead to the global development of biosimilar drugs.

On 29 October 2014, the EMA adopted the revised overarching and long-awaited guideline on biosimilars, ‘Guideline on similar biological medicinal products’. The guideline will allow marketing authorisation holders to use non-EEA authorised reference medicinal products in clinical studies, facilitating global biosimilar development. With this new development, which will grow the biosimilar industry in the early clinical trial phase, it is hoped that costs can be reduced by avoiding repeated clinical trials with different reference medicinal products. The revised guideline can currently be applied to new marketing authorisations, however, it will come into force by 30 April 2015.

The EMA established the regulatory framework for similar biological products in 2005, and proposed substantial comparability studies to generate evidence for similar nature, in terms of quality, safety and efficacy, of the similar biologic medicinal product and the chosen reference medicinal product authorised in the EEA.

The new guideline provides the general principles for a ‘biosimilar approach’ for similar biological medicines. This guideline reconfirms the legal basis for biosimilar applications and need for additional consideration of other guidelines and consultation regarding the document requirements. It takes into account the need for a comprehensive comparability exercise, which includes comprehensive physiochemical and biological characterisation and comparison and requires knowledge to interpret any differences between a biosimilar and its reference medicinal product. Justification and additional data are required for any deviation from reference product in strengths, pharmaceutical form, formulation, excipients or presentation.

As per European regulations, a reference medicinal product is a medicinal product approved in the EEA with a complete dossier, in accordance with the provisions of Article 8 of the Directive 2001/83/EC.  In order to comply with the regulations and regulatory requirements in Europe, the biosimilar manufacturer has, until now, had to repeat the trials with EU-authorised reference medicines. With aim of facilitating a global development, the EMA is introducing the possibility of comparing a biosimilar in certain clinical studies and invivo non-clinical studies with a non-EEA-authorised comparator which is authorised by an authority with similar regulatory and scientific standard (for example, any of the ICH countries). This change could be a signal from EU regulators for the future acceptance of non-EU reference medicines in other types of marketing authorisation applications, enabling a global development of drugs in general.

Even though the EMA accepts the reference medicinal product from non-EEA regions, it will be applicant’s responsibility to demonstrate that the non-EEA reference medicine is representative of the EU reference product.  The guideline insists on comparability at the quality level with the EU reference medicine. It also recommends combined use of non–EEA authorised and the EEA authorised reference medicines in development initiatives from a quality perspective.

When the non–EEA product is used in the clinical/non clinical studies, it is expected to provide bridging data to the EU originator drug and this will include data from analytical studies which compares all three products (test biosimilar, EU reference drug and the non-EEA reference medicinal product) and may also include data from clinical PK and/or PD bridging studies for all three products. This approach again underlines the need for a proper scientific advice on a case-by-case basis.

The revised guideline also proposes a stepwise approach throughout the development programme, starting with a comprehensive physiochemical and biological characterisation. The step-by-step approach proposes the extent and nature of the safety/efficacy studies to be decided based on the evidence obtained from previous characterisation steps. Hence the biosimilar comparability exercise should be very much sensitive to detecting any differences between the biosimilar and reference medicinal product.

Apart from the above mentioned guideline, the EMA is working on the other two overarching guidelines;

Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1)  (03/06/2014)

Draft guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (10/06/2013)

These revised guidelines will come into effect very soon, facilitating overall biosimilar development. Earlier developmental initiatives, including the establishment of regulatory framework for biosimilars and a series of other guidelines, led to approval of approximately 19 biosimilars in the European Union to date, including the first two monoclonal-antibody biosimilars. Adoption of the new guideline allowing non–EEA reference products in development will open the doors to many similar biologic drugs, facilitating global development of similar biological medicinal products.