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  1. Regulatory Science in Action

Comparative Clinical Studies for Assessing the Safety and Immunogenicity of Biosimilars

CDER scientists have conducted a meta-analysis to assess the value of comparative clinical studies for supporting a demonstration of biosimilarity.1

Background and Scientific Challenge

Derived mostly from a variety of natural sources, biological products (“biologics”) tend to be large, complex molecules. Many therapeutic biological products are proteins manufactured using clonal cell lines, for example, monoclonal antibodies and fusion proteins. Through their ability to target diseases precisely, these medicines have led to profound improvements in the treatment of certain types of cancer and other chronic diseases. 

Developing biologics is a challenging undertaking and the processes used for their manufacturing are complicated. As a result, the time and costs to produce these therapeutics can make patient access difficult. The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) established an abbreviated licensure pathway for biologics shown to be biosimilar to or interchangeable with an FDA-approved reference product. The BPCI Act requires that a biosimilar biological product (“biosimilar”) must meet two key criteria: it must be demonstrated to be highly similar to the reference product and have no clinically meaningful differences in terms of safety, purity, and potency (i.e., safety and effectiveness) compared to the reference product. To this end, analytical similarity studies and clinical studies comparing the proposed biosimilar to the reference product are typically conducted to demonstrate biosimilarity. Historically, the clinical development programs for approved biosimilars have generally included both a pharmacokinetic (PK) similarity study to compare the time course of medication exposure in healthy subjects, when appropriate, and a separate comparative clinical study (CCS) (also called a comparative efficacy study) in patients to address any remaining uncertainty about whether the proposed biosimilar has any clinically meaningful differences from the reference product.

How can this research advance drug development? 

In the past, clinical development of biosimilars generally has included comparative clinical studies to support a demonstration of no clinical meaningful differences between the proposed biosimilar and the reference product. This research shows the potential of using the data from the pharmacokinetic similarity studies in lieu of comparative clinical studies, thereby reducing the regulatory burden of biosimilar development.  

Comparative clinical studies in which the proposed biosimilar and reference product are compared, often in hundreds of patients, are expensive for developers. There is a growing recognition that these studies are of limited sensitivity for detecting differences between products, and that analytical studies comparing structural and functional attributes, including biological activities essential to the reference product’s mechanism of action, provide much greater detection capabilities to evaluate product attributes that can impact safety and efficacy. Because comparative efficacy studies also provide descriptive assessments of safety and immunogenicity, the extent to which safety and immunogenicity can be evaluated using PK similarity studies was evaluated by CDER scientists, particularly for monoclonal antibodies and fusion proteins. Both of these studies provide data on adverse events and immunogenicity, including the production of anti-drug antibodies which may have the potential to harm the patient or lead to reduced efficacy of the biologic medication. 

Determining the added value of comparative clinical studies for assessing the relative safety and immunogenicity of biosimilars

CDER scientists have recently examined marketing applications for certain biosimilars (monoclonal antibodies or fusion proteins) to compare how much information the data from CCS added to that collected from PK studies about the relative immunogenicity and safety of the biosimilar product. They performed a meta-analysis based on a random effects model of data submitted by sponsors in support of applications for 35 proposed biosimilars that had been subsequently approved. Data from the submitted PK studies and comparative clinical studies were analyzed to develop separate estimates of the risks for different categories of adverse events, and a risk difference (i.e., risk as determined from PK studies minus the risk determined from comparative clinical studies) was calculated. The CDER scientists also determined the risk difference for appearance of anti-drug antibodies and neutralizing antibodies in the patient’s blood. (Anti-drug antibodies (ADAs) are antibodies that bind to the biologic and may elicit adverse effects; neutralizing antibodies are ADAs that directly interfere with the biologic’s interaction with its target.)

The key findings of CDER’s meta-analysis were as follows:

  • In an analysis of data submitted in support of 35 biosimilars, CDER scientists did not find statistically significant risk differences for anti-drug antibodies or neutralizing antibodies across all studied biosimilars (Figure 1), regardless of whether the estimates were derived from pharmacokinetic studies or comparative clinical studies.
  • The estimated risks of patients experiencing any adverse event, serious adverse events, adverse events leading to discontinuation, and death were lower in the pharmacokinetic studies compared with the comparative clinical studies, but overall differences were small and were statistically significant only for serious adverse events.

The amount and type of clinical evidence that is necessary to establish biosimilarity, and the role of comparative clinical studies, has been an important question for regulatory authorities since the biosimilar pathway was established. In the Journal of Clinical Pharmacology, the CDER scientists present analyses supporting a conclusion that pharmacokinetic similarity studies, as currently designed, provide similar information to descriptively evaluate immunogenicity and safety as comparative clinical studies. The data from this study, along with other research findings, are part of the overall scientific evidence supporting FDA’s updated recommendations for assessing the need for comparative clinical studies to support a demonstration of biosimilarity.

Figure 1

Figure 1. Left panel: Risk differences for anti-drug antibodies (proportion of patients exhibiting anti-drug antibodies in PK studies minus the proportion in CCS studies). Right panel: risk differences for neutralizing antibodies (proportion of patients exhibiting anti-drug antibodies in PK studies minus the proportion in CCS studies) from data in applications for various biosimilars. The diamond shapes indicate the overall risk differences

Figure 1. Left panel: Risk differences for anti-drug antibodies (proportion of patients exhibiting anti-drug antibodies in PK studies minus the proportion in CCS studies). Right panel: risk differences for neutralizing antibodies (proportion of patients exhibiting anti-drug antibodies in PK studies minus the proportion in CCS studies) from data in applications for various biosimilars. The diamond shapes indicate the overall risk differences and the width of the 95% confidence intervals for these estimates based on a random effects model. Abbreviations: IV = intravenous administration of the drug; SC = subcutaneous administration; LC = non small cell lung cancer; BC = breast cancer; RA = rheumatoid arthritis; PSO = psoriasis; NHL = non-Hodgkin lymphoma; RRMS = relaps remitting multiple sclerosis; OP = osteoporosis.

The amount and type clinical evidence that is necessary to establish biosimilarity, and the role of comparative clinical studies, has been an important question for regulatory authorities since the biosimilar pathway was established, and this topic was discussed most recently in a public workshop in the fall of 2023. In the Journal of Clinical Pharmacology, the CDER scientists of the study described here concluded that pharmacokinetic similarity studies as currently designed provide useful information to descriptively evaluate immunogenicity and safety, and comparative clinical studies do not appear to be more definitive. They suggest that this finding should be considered when determining whether the information obtained in CCS, given their additional cost and duration, outweighs the benefits of a more abbreviated biosimilar development program.

References

  1. Ji P, Schrieber SJ, Glaser R, Chen J, Shukla C, Doddapaneni S, Chandrahas S. A Meta-Analysis of the Safety and Immunogenicity of Pharmacokinetic Similarity Studies and Comparative Clinical Studies. J Clin Pharmacol. 2025 Apr;65(4):499-507.
  2. Chen BK, Yang YT, Bennett CL. Why biologics and biosimilars remain so expensive: Despite two wins for biosimilars, the supreme court's recent rulings do not solve fundamental barriers to competition. Drugs. 2018;78(17):1777‐1781.
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Glossary

comparative clinical study: in the context of biosimilarity, a study in which patients are randomly assigned to the proposed biosimilar or its reference product and evaluate primary efficacy endpoints and descriptive comparisons of safety and immunogenicity.

fusion proteins: a type of biologic in which different proteins or parts of proteins are joined.

meta-analysis: a quantitative analysis of data from multiple studies addressing a common research question.

monoclonal antibodies: are therapeutic proteins that recognize specific targets of a disease. They are produced by a clonal cell line.

pharmacokinetic study: in the context of biosimilarity, a study in which blood levels of the proposed biosimilar and the reference product are compared over time. The study can be conducted in healthy volunteers or in an appropriate patient population when a healthy volunteer study is inappropriate.

random effects model: a statistical model where some of the predictive factors are also estimated from the data. These models are often used when dealing with data that are grouped in some way (e.g., data from patients in a given trial or data from a certain biosimilar).

statistically significant: in the present context, meaning that the estimated values for the risk difference is within its 95% confidence interval.

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