Nitrosamine Impurities Affecting Drug-Drug Interaction Studies – Learn More

Backing the Biosimilar Boon

Biological therapies such as peptides, enzymes and antibodies have changed the face of medicine, providing crucial treatment for a number of devastating inflammatory, endocrine and oncological diseases. However, these drugs often come with a hefty price tag due to the complicated nature of manufacturing biological products which are derived from living systems. In an effort to reduce drug prices, especially among biologicals, the Biologics Price Competition and Innovation Act was passed in 2010, creating a regulatory framework for biosimilar drugs to advance on to the market.

Biosimilars are not an exact copy but are similar to the originally approved biological product. While innovator products must demonstrate pharmacokinetic (PK), dose finding, efficacy, safety and clinical benefit/risk for approval; a biosimilar product follows an abbreviated pathway and must demonstrate equivalent PK, toxicity, similarity, and no clinical change compared to the innovator. With this framework, the goal is to introduce cost-effective alternatives to innovator biological drugs that can help improve patient access to these treatments.

The Biosimilar Model:
Robust, vigorous analytical characterization, justification of cell lines, examination of post-translation products, and preclinical studies are emphasized in the biosimilar paradigm. Most biosimilar programs only require one Phase I or III study, reducing cohort sizes and study time from traditional drug approval processes. Immunogenicity data must be collected in patients, however this can be descriptive in nature and is not required to be powered.

In lieu of a comparative efficacy study, pharmacodynamic (PD) biomarkers related to the mechanism of action can be evaluated as a study outcome. For example, picture a biosimilar product like recombinant insulin binding to a cell receptor to initiate a chain of signaling events. PD biomarkers such as glucose concentrations from these early events of the signaling cascade tend to be more sensitive, while late PD biomarkers like HbA1c are related to clinical outcome yet tend to have lower sensitivity. Therefore, early PD biomarkers are recommended as they are apt to illustrate how a drug behaves and can be applied to simulate PK/PD dose response. Both PK and PD biomarkers are required to be within margins to show equivalency, for the FDA these margins are 80-125%. When no good PD biomarker is available for an indication, clinical endpoints should be the same as the innovator product.

The FDA’s Action Plan:
While the EU has benefited from biosimilars for close to 15 years, with 45 approved products and marked reductions in drug prices [1], the US has been slow to embrace this technology. To date, 19 biosimilars have been approved in the US, however 7 products are still not on the market mainly due to patent litigation [1]. In an effort to cut-red tape, increase drug competition and reduce prices for patients, the FDA released their Biosimilar Action Plan in June 2018. This plan outlines their four-pronged approach to expedite biosimilar product development through; increasing efficiency in the approval process, clarifying regulatory guidance, providing educational support for patients and prescribers, and supporting market competition. Progress towards these goals is evident through 60 biosimilar development programs, a newly released final guidance for interchangeability, and plans to license biosimilar and interchangeable insulin products.

Optimizing Biosimilar Product Development:
The following study design recommendations are aimed to optimize biosimilar programs when planning for multiple authorities or indications, or for interchangeability designation.

Multiple Jurisdictions – Consider a 3-way crossover study with US and EU innovator and reference product to establish bridging for various markets.

Extrapolation – Consider running the study in the most homogenous patient group, this will improve sensitivity. Once approved for one indication, approval can be extrapolated to all other approved indications with justification based on totality of evidence.

Interchangeability– Refers to pharmacists switching between products without the consent of the prescriber. In the EU, interchangeability of a product is dictated by member states. Elsewhere, Australia has recently granted interchangeability designation for adalimumab biosimilar products [2] . In the US, interchangeability of a biosimilar should be demonstrated in a randomized two-arm (switching vs non-switching) clinical study with a reference product lead-in period. In a crossover design, the switching arm should have at least 2 or more product switches. One major challenge with interchangeability study design is that many antibody biosimilars have long half-lives and which would require a long cross-over study. However, the added statistical power of the cross-over design may well be worth the long study duration. In addition, during such trials, it is important to closely monitor for safety and adverse immune responses. Alternative approach is an integrated study design to demonstrate no clinically meaningful difference between reference and the biosimilar product and evaluate the impact of switching.

Turn-key Solutions for Biosimilar Programs:
As a global leader in analytical and clinical studies for biological drug development, Celerion provides turn-key solutions for a number of biosimilar programs.

Adalimumab – Anti-TNFα biological for the treatment of arthritis, plaque psoriasis, ankylosing spondylitis, Crohn’s disease, and ulcerative colitis
Rituximab – CD20 antagonist for autoimmune diseases
Teripartide – Recombinant human parathyroid hormone for osteoporosis
Ustekinumba– IL-12/23 inhibitors for psoriasis
• See our full list of validated bioanalytical assays at

Altogether, biosimilars are primed to make a significant impact on access to vital medicines worldwide. Currently, of the marketed biosimilar products available in the US the cost for these products is an estimated 17-57% less than the originator price. With new, efficient tools to support biosimilar development, the FDA aims to see even more meaningful impact on drug prices.

1. Sarpatwari A, Barenie R, Curfman G, Darrow JJ, Kesselheim AS. The US Biosimilar Market: Stunted Growth and Possible Reforms. Clin Pharmacol Ther. 2019;105(1):92-100.