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Ready for the Next Decade of Biosimilar Development in the US
Re-Evaluating the Need for Comparative Clinical Studies
Sue Lim
Insight Biologics

t’s been ten years since the enactment of the Biologics Price Competition and Innovation Act, which created a new approval pathway for biosimilar products in the US. This new pathway was touted as a critical way to provide broader access to cost-effective biological treatments and has contributed to 26 approved biosimilars for nine different reference products as of March 2020. While much has evolved since the legislation was introduced, what has remained relatively constant is the comparative clinical study (CCS) as a necessary gateway to support the approval of biosimilar products. However, with advances in analytical techniques, improved understanding of the relationship between protein structure and function, and an ever-increasing body of global biosimilar experience, it’s time to re-evaluate the consistent need for CCSs in the next decade of biosimilar development.

The First Decade: What Was the Purpose of a CCS?

The foundation of any biosimilar development program has been, and always will be, comparative analytical data. Clinical studies, consisting of comparative human pharmacokinetic (PK) and/or pharmacodynamic (PD) data and a clinical immunogenicity assessment, help demonstrate that there are no clinically meaningful differences between products. Regulatory guidance recommends that biosimilar applicants take a stepwise approach to biosimilar development. If residual uncertainty about biosimilarity remains after conducting the PK and/or PD and immunogenicity assessments, an additional CCS (typically conducted in patients) is needed to provide further support that no clinically meaningful differences between products (i.e., similar safety and efficacy) exists.

Within this stepwise approach, FDA maintains authority to waive a CCS if it is deemed unnecessary to support approval based upon totality-of-the-evidence. However, multiple factors have continued to necessitate including a CCS as part of most biosimilar development programs. In retrospect, inclusion of a CCS has been beneficial because it generated data which helped engender patient and healthcare provider confidence in biosimilar products, and develop experience with this new regulatory approval framework in the US.

Trastuzumab: A CCS Case Example

At the time of trastuzumab’s original approval in 1998, there were no existing HER2-targeted therapies. As such, FDA granted the application Priority Review and Fast Track designation for the metastatic breast cancer indication. These designations likely permitted flexibility in study design considerations and are pertinent in considering the sample size which ultimately supported approval. Nonetheless, considering the goal of the CCS is not to re-establish de novo efficacy and safety of the biosimilar, the size of a CCS for a biosimilar to trastuzumab remains substantial. Select design elements of the original clinical trials which supported approval of the original (metastatic) trastuzumab indication, along with corresponding elements in the CCSs for biosimilars to trastuzumab approved in the US, are shown in Table 1.

Although the extrapolation of data for indications previously approved for a reference product remains a significant upside to biosimilar developers, challenges with conducting a CCS remain. For instance, it is estimated that a phase 3 clinical trial enrolling 600 patients can cost $50M US. Other factors like time investment (CCSs are often ≥ 1 year in duration) and recruitment (needing to share the same patient pool with novel therapeutic studies) could also create barriers for smaller companies to bring biosimilars to market.

Table of Comparison of Select Study Design Elements
Table 1: Comparison of select study design elements that supported approval of trastuzumab and biosimilars to trastuzumab
* A clinical study in either metastatic or neoadjuvant settings is acceptable for biosimilar approval; when these data are used to support extrapolation as part of totality-of-the evidence for biosimilarity, a biosimilar to trastuzumab can be approved for the same indications as trastuzumab
** Study 5 only; Study 6 was a single arm trial
*** Study 5 (n=469) and Study 6 (n=222)

Exploring New Approaches

To consider how to reduce or even eliminate the need for a CCS, one must first understand what information the CCS is adding to the determination of biosimilarity and identify other means for obtaining that same information (Table 2).
Table of Data and Information Supporting a Demonstration of No Clinically Meaningful Differences
Table 2: Data and information supporting a demonstration of no clinically meaningful differences
List for a Case example: Analytical Data vs. Clinical Endpoints

Potential Obstacles to Eliminating the CCS

While there may be possible alternative methods and sources to obtain the types of data and information that a CCS has historically provided to support a demonstration of no clinically meaningful differences, certain challenges remain.


From an efficacy perspective, it is acknowledged that clinical endpoints will never be as sensitive as analytical methods or PK and PD/biomarkers in detecting differences between molecules. In the absence of PD markers (which are not available for most monoclonal antibody products), clinical endpoints remain a tarnished gold standard for demonstrating efficacy as they relate to demonstration of no clinically meaningful differences. However, greater sensitivity to detecting differences with analytical techniques alone is not adequate to replace the CCS for efficacy. In addition to understanding the relationship between structure and function, there must be data correlating the extent of change in an attribute, its subsequent impact on function, and the impact of that structure-function relationship on clinical performance (see Figure 1).
Chart for Analytical Structure, Function and Clinical Performance
Figure 1: Analytical structure, function, and clinical performance
Availability of “structure-function-clinical performance” data would lessen the need to test a specific observed difference in an attribute between a reference product and biosimilar in a clinical setting. Those data, along with the demonstration of PK similarity, could be adequate to support demonstration of no clinically meaningful differences. Furthermore, significant inroads have been made in development of state-of-the-art analytical techniques to characterize complex molecules during the past decade. These enhanced capabilities, in conjunction with increased knowledge about structure-function-clinical performance, can help us move away from the need for a CCS to support efficacy and demonstrate biosimilarity.


What about the safety data that a CCS contributes to biosimilarity? Immunogenicity remains an outstanding question, as differences in immunogenicity cannot be predicted entirely with analytical data. Proponents advocating for “tailored” clinical development have suggested shifting the immunogenicity assessment to the human PK and/or PD study that is often conducted in healthy subjects. This would likely involve modifying the existing design of the PK and/or PD study and could provide a more sensitive population for the immunogenicity assessment. A risk-based strategy informed by knowledge of the products in question, and immunogenicity data from a healthy subject PK and/or PD similarity study, could be a starting point for assessing whether additional immunogenicity data from a CCS are necessary.


Finally, the CCS has also been used in support of extrapolation. Extrapolation allows a biosimilar to be approved for an indication that was previously approved for the reference product without direct studies of the biosimilar in that indication; the totality-of-the-evidence would need to sufficiently support biosimilarity for at least one of the reference product’s indications. Traditionally, extrapolation has relied in part upon the CCS. It remains to be seen whether there is scientific and regulatory latitude for extrapolation without a CCS, and how stakeholder acceptance and use of some biosimilar products would be affected if the biosimilar was approved without a CCS in at least one indication.

Scientific Flexibility

Over the past ten years, FDA has made advances, learned from their experiences, and continues to demonstrate flexibility in biosimilar development while upholding regulatory and scientific standards. For example, PD and biomarkers eliminated the need for a CCS for some less complex biosimilars. Likewise, FDA recently declared that if the comparative analytical assessment for a proposed biosimilar or interchangeable insulin supported a demonstration that the products were highly similar, ”a comparative clinical immunogenicity study generally would be unnecessary to support a demonstration of biosimilarity or interchangeability.”

It may be many more years before technological advances, structure-function-clinical performance understanding, and global experience with biosimilars completely align to eliminate the necessity for CCS data. Until then, revisiting the current role of the CCS in light of knowledge and data gathered over the first ten years of US biosimilar experience should be considered in order to further advance the goals of expanded market access to critical biological treatments in the next decade.

References available upon request.