Biosimilar Development

Overview

What are Biosimilars?
The FDA defines a biosimilar as “a product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product” (Tierney 2016). More simply, it is a biologic that is almost identical to a previously approved biological product that demonstrates the same clinical safety and efficacy.

Originator biologics have provided lifesaving treatments for cancer, inflammatory bowel disease, and other diseases. However, the exorbitant cost of a biologic treatment regimen (up to $200,000 per year) is considered cost-prohibitive for many patients and a financial burden on insurance payers and national health agencies. In spite of these exorbitant costs, global sales of biologics are increasing rapidly and currently account for 20% of the global pharmaceutical market (Visiongain 2016).

Why is the Cost of a Biologic so High?
The high price is driven in part by the considerable investment required by pharmaceutical companies, approximately $2.6 billion to develop a new biologic, and development time of over a decade (DiMasi et al. 2016). As modern health care expands into developing nations, governments and insurers are seeking less costly alternatives to bring affordable, life-saving biologic therapy to patients worldwide. In addition, the upcoming patent expirations for several bestselling biologics have incentivized many pharma and biotech companies to pursue development of biosimilars, which are less expensive to develop, but that also contain biologic properties similar to their reference drug. The European Union (EU) approved its first biosimilar in 2006 and leads the global biosimilar market with 35 approved products. In addition, they were the first to develop product-specific development guidelines.

However, uptake of biosimilars is slower than expected globally. Patients, prescribing physicians, and pharmacists are concerned about safety and efficacy, non-approved indications, and the lack of a standardized naming system among global regulatory bodies. In addition, insurance payers and pharmaceutical companies are concerned that the introduction of biosimilars into the pharmaceutical market is economically unpredictable and may negate the cost advantage.

How Similar Does a Biosimilar Need to Be to Its Reference Product?
Although the definition of a biosimilar varies, all regulatory bodies state that a biosimilar must be a biologic, have a biologic reference product — the so-called originator that is licensed based on a non-abbreviated drug submission — and be highly similar to the reference product in terms of safety, quality, and efficacy (Choy and Jacobs 2014).

Unlike the production of a chemically identical generic small-molecule drug, biologic manufacturing uses a unique cell line and a complex, proprietary manufacturing process that is impossible to replicate entirely. All biologics have microheterogeneity, e.g., in protein isoforms or glycosylation patterns. Changes to the manufacturing process mean that even an originator biologic may not be identical across production batches. Thus, to ensure that quality, safety, and efficacy are unaffected, biologic products undergo physicochemical and functional comparability experiments before and after manufacturing modifications. Similarly, biosimilar development requires extensive physicochemical and biological characterization of the reference originator product using multiple analytical techniques to ensure similarity. Based on the results of this characterization, preclinical studies and clinical trials are undertaken to resolve uncertainty about the biosimilarity of the new biosimilar product.

Demonstrating Biosimilarity: Comparison of Efficacy, Safety, and Quality
Although regulatory processes for establishing biosimilarity vary among countries, all require the use of a single reference originator product for comparisons of efficacy, safety, and quality. The biosimilar is submitted for both preclinical studies and clinical trials analogous to those for a new drug approval.

Preclinical Studies
In preclinical studies, comparison is required for the proposed vs. the reference originator product to examine protein structure, enzymatic posttranslational modifications, potential protein variations, and intentional chemical modifications in multiple representative lots. In vitro, in vivo, and functional assays should demonstrate that the proposed product has highly similar biologic activity and potency and no clinically meaningful differences from the reference product (Ventola 2013).

Clinical Trials
Authorities generally agree that data on human pharmacokinetic/pharmacodynamic (PK/PD) responses are fundamental for supporting biosimilarity and require a clinically relevant study population, dose, and route of administration.

The design of comparative clinical studies for biosimilars to investigate efficacy, safety, tolerability, and immunogenicity vary based on the findings and limitations of previous testing, the extent to which human PK/PD data predict clinical outcomes, and the extent of clinical experience with the reference originator and proposed biosimilar. An equivalence design is usually used to confirm that the proposed biosimilar is neither inferior nor superior to its reference originator product. Assessment of immunogenicity is critical because it can alter the PK or promote development of antidrug antibodies, thereby affecting safety and efficacy of the proposed drug. Because the required sample size for clinical trials is smaller for biosimilars than for originator biologics, careful monitoring of immunogenicity and other side effects is important in post-marketing surveillance of biosimilars (US FDA 2015).