FIGURE 1
Differences in emphasis on elements of product approval
Originator biologic 351 ( a ) Biosimilar 351 ( k )
Clinical studies ( I , II , III )
Clinical pharmacology
Clinical studies
Nonclinical studies
Clinical pharmacology
Analytical
Nonclinical studies
Analytical a case-by-case basis by the FDA working with the biosimilar manufacturer to develop an overall plan to demonstrate biosimilarity . It involves a step-bystep process to determine additional studies needed to reduce any uncertainty regarding similarity to the reference product . 9
Immunogenicity studies Owing to their complexity and size , biologics may induce a range of immunologic responses including a loss of efficacy ( anti-drug / neutralizing antibodies ), adverse reactions including infusion reactions , or even anaphylaxis . 10 Therefore , immunogenicity studies are an important component of the biosimilar regulatory process and approval of biologics in general . 11
The biosimilar and the reference biologic might be manufactured using different cell lines . Owing to other intricacies in the manufacturing process , as well as the size and complexity of the molecules , no two biologics can be completely identical . In fact , even the reference product cannot be exactly identical to itself over time . Manufacturing processes can evolve due to changes in the manufacturing site , changes in the process to increase yield , changes in technology , extraction methods , or inactive ingredients . Any of these changes could potentially affect the structure and activity of the drug . 4 , 12
In order to account for these differences , the FDA has worked with manufacturers to establish critical quality attributes ( CQAs ) for each molecule , and the regulatory process assures that the product characteristics fall within specifications in order to determine that any variability does not have an impact on clinical efficacy or safety . This assures that different batches of a biologic are highly similar to other lots of the same product . Similarly , the regulatory process for biosimilars also assures that the CQAs for the biosimilar fall within the same specifications as the reference biologic . 13
While the regulatory process assures that major changes in CQAs do not occur , one of the concerns with the biosimilar regulatory process is that over time there could be patterns of ‘ drift ’ or ‘ evolution ’ that could theoretically lead to clinically meaningful differences , or divergence . 14 The FDA and other regulators are sensitive to this potential issue and continue to monitor manufactured product lots of all biologics to prevent the development of clinically significant divergence .
Biosimilar drug approval process The Food , Drug and Cosmetic Act granted the FDA the authority to approve small molecule drugs though an NDA , utilizing the 505 ( b ) 1 or 505 ( b ) 2 pathway . This regulatory pathway requires a full data package demonstrating clinical efficacy and safety for the indications being sought . The Hatch- Waxman Act created an abbreviated process for the approval of small molecule generics ; the abbreviated new drug application known as the 505 ( j ) pathway . The pathway requires the submission of limited data showing pharmacokinetic bioequivalence . No additional clinical efficacy and safety data are required , so the development costs for smallmolecule generics are less and result in lower costs . 3
Biosimilars and interchangeable biosimilars Similar to the NDA process for small molecule drug approvals , new biologics are approved through a BLA ( the 351 ( a ) pathway ). 15 This regulatory pathway requires a full data package for the biologic including demonstration of clinical efficacy and safety . The BPCIA created an abbreviated ‘ biosimilar ’ pathway ( also known as the 351 ( k ) pathway ) for approval of follow-on versions of approved biologics . Unlike the regulatory framework in Europe , this legislation created two categories of follow-on biologics : biosimilars and interchangeable biosimilars . 16
The FDA ’ s biosimilar approval approach assesses whether the biosimilar is similar enough in terms of its physicochemical structure and CQAs so that clinically significant differences with the reference biologic are unlikely . Therefore , the primary focus is on a very thorough physicochemical analysis and
The biosimilar must also have the same route of administration , dosage form , and strength as the reference product
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