Demystifying Biosimilar Development Regulations: Key Considerations for Sponsors

By Maxim Kosov

Senior Director, Operations Management

Biosimilars – biological medicines highly similar to another already approved biologic – have emerged in recent years as an area of rapid development activity, especially for Inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC). While these drugs have historically faced the common misconception that they are less safe and less effective compared to the original biologic product, biosimilars undergo very rigorous and extensive testing before receiving regulatory approval, and public perceptions are starting to shift. As these drugs continue to grow in popularity with physicians and patients alike, it is crucial for sponsors to understand what these changes mean for current and future IBD development activity.

In our new white paper, Similar But Different: Regulatory and Operational Considerations for Biosimilar Clinical Development in IBD, we discuss how biosimilars have transformed the treatment landscape for IBD in the past decade, their current therapeutic uses in CD and UC, and global regulatory considerations for running biosimilar clinical trials in IBD. This post reviews some of the regulatory factors that are evaluated for biosimilar medications during the course of a trial. The list of full regulatory requirements varies by country; however, these factors are common parts of the evaluation process by many regulatory bodies.


Even licensed biologics undergo changes in relevant molecular attributes over time.1 In a study of biologics licensed for use in rheumatology, all reported changes to the production process over time, including change of cell culture supplier and modification of the protein purification procedure.2 The original medicines available today are therefore not identical but comparable to those available in previous years. 

Biosimilars must demonstrate clinical comparability with the reference drug (the original biologic) in order to receive regulatory approval. The following table outlines the properties and methods used to demonstrate comparability in a biosimilar for infliximab (IFX).3,4

Properties How was similarity determined? 
Protein structure and production quality  Detailed laboratory analysis of the structural characteristics of different batches of the drug 
Pharmacokinetic, pharmacodynamic and toxicological tests on animals  "In vitro" and "in vivo" tests on different species 
Pharmacokinetic, pharmacodynamic and toxicological tests on humans  Initial clinical trials 
Clinical efficacy and safety  Major clinical trials
Safety in everyday practice  Risk management plan , Post-marketing trials (Phase 4),  Routine reporting of side effects,  Pharmacovigilance 


The initial comparability tests are conducted in the indication and population that are considered the most sensitive to detect clinically significant differences in safety, immunogenicity, and efficacy between the original and biosimilar drug. If the biosimilar product is highly similar to the reference medicine and has comparable safety and efficacy in this therapeutic indication, safety and efficacy data may then be extrapolated to indications already approved for the reference medicine.5

Extrapolation must be supported by all the scientific evidence generated in other comparability studies. In these cases, clinical trials are often not required to be repeated for all indications; instead, changes are approved based on data from quality and in vitro comparability studies. The possibility of extrapolation is dependent on the regulatory landscape of the particular country or countries in which the clinical trial is being conducted. In the EU, which pioneered biosimilar regulation by establishing a solid framework for approval, decisions based on extrapolation are dependent on a number of criteria:5,6

  • Mechanism of action: The mechanism of action of the active substance should be mediated by the same receptor in both the initial and extrapolated indication. If the mode of action is complex, involving multiple receptors or building sites, additional studies may be needed to prove that the biosimilar and reference medication will behave similarly.
  • Study population: Comprehensive comparability studies must demonstrate that the biosimilar is highly similar to the reference medicine in a “key population” in which potential differences can be detected.
  • Clinical setting: Data from one indication may not be directly applicable to an indication within another therapeutic area where the mode of action, posology, or pharmacokinetics may be different. Additional studies may be needed in this case.
  • Safety data: A comparable safety profile for the proposed indication must be established in one therapeutic indication before extrapolation. Comparability must be shown at the structural, functional, pharmacokinetic, and pharmacodynamic levels, and efficacy must be comparable.
  • Immunogenicity data: Extrapolation of immunogenicity data always requires justification as immunogenicity is determined by more than product-related characteristics. Factors relating to patient (age, immune status), disease (comorbidities, concomitant treatments) and treatment-related factors (route of administration, length of exposure) must be considered.

Meet the challenges of your IBD trial with confidence

Understanding each country’s regulatory intricacies of biosimilar development is crucial for the success of your trial. With a network of more than 3,900 global IBD sites, and a regulatory team with local regulation expertise, PSI specializes in delivering studies on time and with quality data.

Discover the full white paper here, or contact us to learn more about running your pivotal Phase 2 and 3 IBD trials with PSI.

1 Schiestl M, Stangler T, Torella C, Cepeljnik T, Toll H, Grau R. Acceptable changes in quality attributes of glycosylated biopharmaceuticals. Nat Biotechnol. 2011;29(4):310-312. doi:10.1038/nbt.1839.

2 Schneider C. Biosimilars in rheumatology: the wind of change. Annals of the Rheumatic Diseases. 2013;72(3):315-318. doi:10.1136/annrheumdis-2012-202941

3 European Medicines Agency. Assessment report Inflectra. European Medicines Agency. June 27, 2013.

4 Krznarić Ž. Biosimilars in Inflammatory Bowel Disease: From Theory to Practice. Presented at: PSI Internal Training; June 27, 2023.

5 European Medicines Agency, European Commission. Biosimilars in the EU – Information Guide for Healthcare Professionals. European Medicines Agency. 2019.

6 European Medicines Agency. Biosimilar Medicines: Overview. European Medicines Agency. April 26, 2023. Accessed July 3, 2023.