Healthcare professionals should have a thorough understanding of the regulatory framework for the approval of biosimilars and interchangeable products , and this knowledge will enable better decision-making and improve communication regarding biosimilars with patients

James Stevenson PharmD FASHP FFIP Department of Clinical Pharmacy University of Michigan College of Pharmacy , Ann Arbor , MI , USA

Traditional small molecule drugs are manufactured through standard chemical processes and generally have simple , well-defined structures . Biologics , by contrast , are generally large , complex proteins and they are produced in living systems . ^{1 – 3} Biologic manufacturing is inherently variable and changes in the production process ( for example , cell culture , protein recovery and purification , and formulation ) may lead to variation that could potentially impact activity ( Table 1 ). ⁴ For these reasons , the traditional abbreviated regulatory pathway for follow-on products that is used for small molecule generic drugs is not appropriate for follow-on biologic approval . ⁵ With a small molecule drug ANDA , the cornerstones of the abbreviated regulatory approval are a demonstration of the identical chemical structure and bioequivalence within established parameters as determined by pharmacokinetic studies .

Biologics are regulated under the Public Health Services Act of 1944 . Until 2010 , an abbreviated regulatory process for approval of follow-on biologics was not available in the US . Originator biologics , also referred to as reference products , are approved through a biologics license application ( BLA ), which is similar to the new drug application ( NDA ) that is required for licensing of small molecule drugs . The BLA is also referred to as the 351 ( a ) pathway for biologic approval . This requires a complete data package that includes :

• Physicochemical analyses

• Pharmacokinetic and pharmacodynamic studies

• At least one pivotal clinical trial that demonstrates safety and efficacy compared with placebo for the indication ( s ) being sought . ⁷

The Biologics Price Competition and Innovation Act ( BCPIA ) established the authority to create an abbreviated regulatory pathway for biosimilars . The BPCIA defines a biosimilar as a product for which there is evidence “ to demonstrate safety , purity , and potency for one or more appropriate conditions of use for which the reference product is licensed .” ⁸ This legislation authorized the US Food and Drug Administration ( FDA ) to establish guidance for the abbreviated approval pathway for biosimilars ( the 351 ( k ) pathway ). Beginning in 2012 , the FDA issued a number of guidance documents clarifying the requirements for the approval of biosimilars .

A stepwise approach Unlike small-molecule generic drugs that only require pharmacokinetic studies demonstrating bioequivalence , the FDA uses a ‘ totality of the evidence approach ’ in reviewing applications for biosimilar products . ⁵ They have directed manufacturers to use a stepwise approach to demonstrate biosimilarity . This generally starts with extensive physicochemical analyses comparing the proposed biosimilar with the reference product as a foundation . Animal toxicity , and human pharmacokinetic and pharmacodynamic studies ( including clinical immunogenicity studies ) are also conducted . If there is confidence in the similarity of the proposed biosimilar to the reference product , then the clinical efficacy and safety is assessed in a sensitive population . This process is achieved on

TABLE 1

Comparison of small-molecule vs biologic drugs ⁶

Characteristics Small-molecule Biologic

Manufacturing Produced by chemical synthesis Produced by living cell cultures

Structure and characterization

Simple , well-defined structure ; completely characterized

Complex , heterogenous structure with multiple levels ( primary , secondary , tertiary , quaternary ); impossible to fully characterize

Immunogenicity Mostly non-immunogenic Potentially immunogenic

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