The legal and regulatory challenges of getting a biosimilar product to market

After a pharma view on biosimilars was provided in the previous Expert View column, a legal perspective is provided by Nick Beckett, managing partner at CMS Beijing and global co-head of the firm's lifesciences sector group.

The global biosimilars market is expected to reach $10.9 billion by 2021, according to the Biosimilars Global Forecast.

Although biosimilar products represent a major opportunity for the pharmaceutical industry, compared to small molecule drugs, bringing these complex proteins to market can be a real challenge, as we explore below.

Manufacturing changes

Biologics manufacturers make frequent manufacturing changes to improve the manufacturing process and product stability, and also to increase scale. Such manufacturing changes can occur both during the development process and after regulatory approval, which can lead to batch-to batch variability.

Unlike small molecule drugs, manufacturing changes of biological products have to be controlled and maintained within defined and approved limits to ensure that the changes will not have an adverse impact on the quality, safety and efficacy of the products.

Manufacturers have to follow the guidelines and prove comparability of the products before and after the changes which requires collection and submission of a considerable amount of relevant technical information as evidence.

Interchangeability and automatic substitution

Unlike small molecule generic medicines, automatic substitution at the pharmacy level without consulting the prescriber is not appropriate for biosimilar products unless the manufacturers can also demonstrate ‘interchangeability,’ a separate standard to ‘biosimilarity’ which requires additional data to achieve.

However, guidelines on interchangeability are still developing. In the European Union (EU), decisions on interchangeability and substitution are made at the national level as there are no European Medicines Agency (EMA) guidelines on interchangeability and the EMA does not evaluate biosimilars for interchangeability designation.

Due to the lack of legislation and regulation, most EU countries currently prohibit pharmacy-level substitution of biosimilars.

In the USA, the Food and Drug Administration published draft guidance on interchangeability in January 2017 but, to date, no biosimilars have been approved as interchangeable.

Naming and labelling

Naming and labelling must identify biological products as either biosimilar or interchangeable, as well as identify the source of clinical data to assure that specific adverse reactions are attributed to the correct biologic manufacturers and to enable optimal patient safety monitoring and prescribing.

However, different naming and labelling conventions and standards including naming using international non-proprietary names (INNs) and brand names adopted by different countries and regions have caused a lot of confusion.

In the EU, no naming convention or labelling outline for biosimilar medicinal products have been established so far, where biosimilar medicinal products are generally referred to by their trade names and INNs which are identical to those of their biological reference products.

The FDA, meanwhile, published its new naming guidance in January 2017 under which biosimilar products will use proper names, a combination of the core name and a distinguishing suffix that is devoid of meaning and composed of four lowercase letters.

The FDA also issued draft guidance on Labelling for Biosimilar Products in March 2016 which recommends that the biosimilar product name used in the labelling text should be specific to the biosimilar product or refer solely to the biosimilar product.

Immunogenicity

Unlike small molecule drugs, a major concern associated with the use of both biological medicines and biosimilar medicines is immunogenicity.

Treatment of patients with therapeutic protein products may result in immune responses of varying clinical relevance, ranging from antibody responses with no apparent clinical manifestations to life-threatening reactions.

Unwanted immune responses may neutralize the protein’s biological activities and result in adverse events not only by inhibiting the efficacy of the product, but also by cross-reacting to an endogenous protein counterpart and mediating its physiological function.

Such immunologically-based adverse events including anaphylaxis, cytokine release syndrome and cross-reactive neutralization of endogenous proteins may pose problems for both patient safety and product efficacy.

The unwanted immune responses can be influenced by various factors including patient, disease and product related factors, and the risk of immunogenicity varies between products and product categories as well as between individuals and patient groups.

It is therefore essential to evaluate immunogenicity throughout different phases of the clinical development including post-marketing pharmacovigilance.

The planning and evaluation of immunogenicity is a multidisciplinary exercise and the leading authorities, such as the EMA and the FDA, require a risk assessment on a case-by-case basis to justify the selected approach which requirements are not always easy to satisfy.

Intellectual property

Patent disputes including patent litigation infringement between the owners of reference products and the biosimilar products may also arise.

The subject matter of biologic product patents may include claims to molecules, nucleic acid sequences, amino acid sequences, antibodies as well as cell lines. The biosimilar products may not fall within the scope of a claim covering the reference product because the biosimilar compound may vary from the molecule or sequence claimed in the reference product patents, and structural differences often exist between a biosimilar and its reference product.

Therefore, biosimilar manufacturers may be able to satisfy the ‘biosimilarity’ requirements while maintaining sufficient differences from the reference products to avoid infringement. When a biosimilar does not literally infringe a claim, the patent holder will have to rely on different means, such as the doctrine of equivalents (for example, under US law) to show infringement. Compared to literal infringement, the doctrine of equivalents plays a more important role in analyzing biologic patent disputes.

However, there have not been many relevant rulings issued in the major jurisdictions such as the USA and the EU. The proceedings could therefore be very complex, lengthy and unpredictable due to lack of precedent.

This article was first published in Pharma Letter.