The rise of the biosimilar

Keywords::

• access
• affordability
• biologic
• biosimilar
• BPCIA
• comparability
• highly similar
• recombinant

Recombinant biologics have had an incredible impact on diseases such as arthritis and cancer by targeting specific receptors or disease mediators; however, access to these drugs is increasingly limited in part due to a combination of high costs and steadily growing demand. Biosimilars are needed in the USA, the world’s largest market, in order to increase the access and affordability of these critical products for all patients who can benefit from their use.

Biosimilars are biologics containing the same active ingredient as the originator

Biosimilars have the exact amino acid sequence and highly similar glycosylation patterns that overlap with the originator reference product. They can only be licensed by the US FDA 12 or more years after the originator to which they refer was approved, at which point there will be considerable real-world clinical experience available with the active ingredient. Uniquely, the new US law [101] specifies that a biosimilar can be designated as interchangeable with its reference, meaning that it can be substituted for that reference by the pharmacist without the involvement of the original prescriber.

Variability of the reference product sets the target

Biologics vary over time with modifications to the manufacturing process. Biosimilars are developed through head-to-head studies with a specifically identified, previously approved reference product. Hence the first step in developing a biosimilar is to carefully examine multiple samples of that reference product collected over its lifetime. The latest, state-of-the-art analytical techniques, used in an orthogonal manner [102], will show just how variable the chosen reference product is both over time and during its shelf life.

Biologics vary batch to batch and with any manufacturing change, such as additional facilities added to increase capacity [103]. The variations observed during manufacturing changes must be approved by the regulatory authorities to ensure that the changes do not alter the clinical effects of the product [1]. This experience with the originator product, including its manufacturing variability, creates the premise that a highly similar biosimilar will behave in exactly the same way clinically in any given patient provided it has overlapping product attributes [104]. In general, the in vitro chemical and biological characterization capabilities are far more sensitive than in vivo physiological systems or clinical trial testing [2]. Nonetheless all variation, whether potentially clinically relevant or not, will need to be justified or shown to have no impact on clinical performance.

Biosimilar manufacturers must develop and validate their analytical tools and use this complex matrix of tests on multiple batches of the originator product and the candidate biosimilar throughout the multiple years of the development cycle.

Data or trade secret information from the originator files or regulatory application is neither available nor necessary to the biosimilar manufacturer since their analytical tools are independently developed and applied. Hence, the data on the reference product in the dossier of a biosimilar is that of the biosimilar sponsor, and not that of the originator.

Global biosimilars to match global reference biologics

Most biosimilar manufacturers take a global approach in developing biosimilars yet regulatory authorities generally prefer comparative data to the originator product approved in their region. Hence, it may be necessary to repeat entire clinical trials using regionally approved reference comparators. To avoid duplicating all studies, the biosimilar manufacturer must demonstrate that the regional products made by the same originator company are comparable, for example, that the reference products distributed in the USA and the EU are indistinguishable [1]. This will necessitate doing analytical studies on originator reference samples from multiple countries and showing how they do, or do not, represent the same product. European authorities have already indicated that studies with a non-EU-sourced reference product will be acceptable if such a data-driven case is made [3]. The FDA has acknowledged that they intend to avoid unnecessary clinical studies as these would be unethical [105]. The FDA has addressed the issue to some extent in the draft biosimilar guidances issued February 2012 [106].

Biosimilar development is challenging & requires substantial innovation

A biosimilar candidate will be developed iteratively to match the attributes of the originator. Hence, it is the analysis of the originator reference over its lifetime that forms the design space for the biosimilar [107,108]. Each biosimilar sponsor’s own independent analysis will define the ‘goalposts’ for the range of each attribute acceptable in the biosimilar that they propose to FDA [102]. This complex matrix of analytics will create the ‘fingerprint’ [4] of the reference originator product that the biosimilar will match, and the attributes will include both analytical measurements and functional ones such as binding, CDC, ADCC. These attributes will be product and sponsor specific.

The subsequent iterations in the development of a biosimilar will depend on the sponsor’s in-depth understanding of the impact of adjusting each particular manufacturing input on the final attributes of the manufactured drug substance. This reverse engineering is not a trivial undertaking and it will require considerable innovative and creative thinking, and careful execution. The iterative process to achieve product attributes within the goalposts makes creating the active ingredient in a biosimilar more expensive and more time-consuming than that for a novel biologic medicine.

The totality of the preclinical data support biosimilarity

For a biosimilar, as a regulatory matter, the demonstration of analytical high similarity is integral to the pathway, and the FDA is proposing to assess this in-depth, early in the development phase [109]. Once the FDA is assured of the analytical comparability, all subsequent development is confirmatory to fulfill regulatory requirements. Thus, the totality of the data supports biosimilarity before any clinical study is completed and the clinical studies simply confirm biosimilarity. A biosimilar sponsor is not expected to demonstrate a priori the safety, purity or potency of the active moiety in their biosimilar product, but to show biosimilarity to the originator product.

Clinical studies will confirm biosimilarity

While the FDA has the authority to waive any unnecessary studies, it is expected that the first generation of biosimilars in the USA will be filed with clinical studies that include both Phase I and III studies (perhaps in only one indication or just the most sensitive patient population). Phase II studies are not expected to be required because the dose of the biosimilar will match that of the originator reference product.

Conclusion

Given an appropriate regulatory and market framework, biosimilars have the potential to significantly increase patient access to these important and often life-saving therapies – both by providing treatment where none exists or by enabling therapy to start earlier in their disease when treatment can often prevent disabilities. Regulatory science is sufficiently developed to evaluate and approve biosimilars to have the same efficacy and safety as the originator biologic approved decades earlier.

Financial & competing interests disclosure

M McCamish is Head of Global Biopharmaceutical Development at Sandoz International. Sandoz is the leading sponsor of approved similar biological medicinal products in Europe, with three products: somatropin, epoetin alfa and filgrastim. G Woollett is Vice President at Avalere Health, LLC and works with multiple stakeholders in healthcare including, but not limited to, biopharmaceutical companies (originator and generic). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.