IBD clinical landscape

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7 Challenges for Sponsors of Biosimilar Clinical Trials

This is the second of two articles based on our new white paper on biosimilar development in Inflammatory Bowel Diseases (IBD). In our previous article, we discussed some of the common regulatory considerations for biosimilar clinical trials. In this article, we focus on some of the greatest design and operational challenges. In the highly competitive IBD landscape, understanding the unique obstacles that biosimilar development can pose can help sponsors predict potential challenges and pivot effectively.

Designing biosimilar clinical trials to support comparability and future extrapolation requires careful planning from the outset to ensure these and other criteria are met. Sponsors should consider working with a partner experienced in understanding and overcoming the challenges of these studies. Key challenges include:

  • Endpoint selection: Ulcerative colitis, Crohn’s disease, and other IBDs are multifactorial diseases with highly subjective manifestations. When determining endpoints for biosimilar trials in IBD, it is important to select endpoints that capture relevant aspects of the disease and are sensitive enough to provide clinically meaningful results.
  • Ethical considerations: Sponsors must balance the need for clinical research with the wide availability of effective treatments for IBD. Convincing patients with established treatment regimens to participate in a biosimilar clinical trial often requires providing supporting educational materials and clear messaging to ensure informed consent.
  • Study design: Availability of existing treatments also impacts study design considerations such as blinding and the use of placebo. In cases where administration routes of the biosimilar and reference biologic vary, maintaining blinding may be challenging or impossible.1 The long half-lives of many biologics can also impact the determination of an appropriate washout period for patients who have been previously treated with the reference medicine.
  • Variability: Microheterogeneity is a common characteristic of all biologic drugs.2 Sponsors must have plans for controlling variability of manufacturing processes and raw materials to ensure that the biosimilar’s product quality remains within an acceptable range, particularly as the proprietary technology used to develop the original molecule will be unknown.3 An iterative process is therefore necessary to “guide” the fingerprint of the biosimilar towards that of the original medicine.4
  • Long-term safety: Due to the shorter length of biosimilar trials compared to the real-world treatment duration of IBD, there is a need for long-term safety and immunogenicity data. Assessing long-term safety requires resource allocation and planning for additional studies or post-marketing surveillance.
  • Patient bias: The “nocebo effect” is a negative effect of a pharmacological or non-pharmacological medical treatment induced by patients’ expectations and unrelated to the physiological action of the treatment.”5 Several studies investigating a switch to IFX biosimilar have reported higher discontinuation rates in transitioned patients than in patients continuing treatment with IFX, and it has been suggested that may be influenced by a negative perception of biosimilars.6,7,8
  • Lack of clinical and scientific interest: Investigators may be hesitant to participate in clinical trials with biosimilars compared to studies involving new biological molecules or novel pathways. Such clinical trials may be of little interest to patients who already have access to the reference product as part of the standard of care. This has led to a trend towards conducting trials in countries where the reference drug is unavailable or not covered by insurance plans.

Success starts with the right partner

Designing effective IBD trials requires careful planning from the outset to ensure these and other criteria are met. Sponsors should consider working with a partner experienced in understanding and overcoming the challenges of these studies. Sponsors that understand the unique challenges that come with IBD development can set themselves up for success.

With the help of PSI’s VISIONAL™, challenges with IBD patient enrollment and site selection can be predicted and mitigating, allowing sponsors to pivot quickly saving valuable time and money. With a network of more than 3,900 global IBD sites, and an expert team, PSI specializes in delivering pivotal Phase 2 and 3 IBD trials. Download the full white paper here, or contact us to learn more.

1 Lai ZV, La Noce A. Key design considerations on comparative clinical efficacy studies for biosimilars: adalimumab as an example. RMD Open. Published online February 1, 2016. doi:10.1136/rmdopen-2015-000154

2 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

3 Caldwell B. Variability of Biologics and its Impact on Biosimilar Development. European Medical Journal. Published online September 12, 2019:22-30. doi:10.33590/emj/10312818

4 Vulto AG, Jaquez OA. The process defines the product: what really matters in biosimilar design and production?. Rheumatology (Oxford). 2017;56(suppl_4):iv14-iv29. doi:10.1093/rheumatology/kex278

5 Pouillon L, Socha M, Demoré B, et al. The nocebo effect: a clinical challenge in the era of biosimilars. Expert Review of Clinical Immunology. 2018;14(9):739-749. doi:10.1080/1744666x.2018.1512406

6 Bressler B. Is there an optimal sequence of biologic therapies for inflammatory bowel disease?. Therap Adv Gastroenterol. 2023;16:17562848231159452. Published 2023 Apr 5. doi:10.1177/17562848231159452

7 Bernard EJ, Fedorak RN, Jairath V. Systematic Review: Non-medical Switching of Infliximab to CT-P13 in Inflammatory Bowel Disease. Dig Dis Sci. 2020;65(8):2354-2372. doi:10.1007/s10620-019-06036-0

8Scherlinger M, Germain V, Labadie C, et al. Switching from originator infliximab to biosimilar CT-P13 in real-life: The weight of patient acceptance. Joint Bone Spine. 2018;85(5):561-567. doi:10.1016/j.jbspin.2017.10.003

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Demystifying Biosimilar Development Regulations

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. 

7 Challenges for Sponsors of Biosimilar Clinical Trials Read More »

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Demystifying Biosimilar Development Regulations: Key Considerations for Sponsors

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. https://www.ema.europa.eu/en/human-regulatory/overview/biosimilar-medicines-overview

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. https://www.ema.europa.eu/en/documents/assessment-report/inflectra-epar-public-assessment-report_en.pdf

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. https://www.ema.europa.eu/en/documents/leaflet/biosimilars-eu-information-guide-healthcare-professionals_en.pdf.

6 European Medicines Agency. Biosimilar Medicines: Overview. European Medicines Agency. April 26, 2023. Accessed July 3, 2023. https://www.ema.europa.eu/en/human-regulatory/overview/biosimilar-medicines-overview.

Demystifying Biosimilar Development Regulations: Key Considerations for Sponsors Read More »


IBD Clinical Trial Landscape: 3 Greatest Unmet Needs in IBD Clinical Development in 2023  

With the steady increase in the prevalence of inflammatory bowel disease (IBD) worldwide and the discovery of new disease pathways, there has also been a renewed interest in IBD drug development. During the ten years from 2010 to 2020, the number of clinical trials in the IBD therapeutic area almost doubled due to a combination of factors, including the continuous development of biologics, the discovery of new pathways, and, consequently, the introduction of new classes of medications such as JAK–STAT pathway inhibitors.

Our new white paper Inflammatory Bowel Disease: Current Status and Future Perspectives offers insights into recent trial and research developments that will most impact study design and operationalization for various IBD therapies and indications. In our previous post, we discussed the common challenges in IBD patient enrollment. In such a competitive landscape, it is also critical for drug developers to understand the major unmet needs in IBD management.

1. Lack of Predictive Biomarkers for Early Diagnostic Testing

There are a number of biomarkers, divided into two groups based on their application, currently used in clinical practice, but there is no single one that can help with an accurate diagnosis of IBD. The first group, aimed at diagnosis and monitoring of IBD, contains blood-based biomarkers of inflammation (C-reactive protein and erythrocyte sedimentation rate) and stool-based biomarkers (e.g., fecal calprotectin, fecal lactoferrin, fecal neopterin, and polymorphonuclear neutrophil elastase). The second group of biomarkers, aimed at the subclassification of IBD between UC and CD, includes blood-based biomarkers such as antineutrophil cytoplasmic antibodies (ANCAs), anti–outer membrane protein C (Anti-OmpC), anti–S. cerevisiae antibodies (ASCA), and anti-I2, anti-carbohydrate, and pancreatic antibodies.i These biomarkers can only be used as supporting data secondary to clinical data and endoscopic examination. Another limitation of biomarkers is their inability to predict response to therapy in patients with IBD.

2. Lack of Drugs with Minimal Side Effects

Conventional therapy methods, including 5-aminosalicylates, corticosteroids, thiopurines, anti-TNFs, and others, are generally effective in controlling symptoms, but adverse side effects such as immunosuppression, systemic fungal infections, and possible cancer development may have an overall negative impact on the disease outcome. There continues to be an unmet need for long-term treatments with minimal side effects, one of the greatest motivators for driving new IBD biologic development. For instance, all anti-TNF-α drugs in the US carry a boxed warning due to the increased risk of infections in 25–30% of patients, with limited treatment options afterwards. Etrolizumab was a potentially promising drug that was thought to close this gap, but as of November 2022, etrolizumab met its primary endpoint of inducing remission versus placebo for patients with UC in only two out of five studies and failed to meet its primary endpoint versus placebo as maintenance therapy.ii

3. Lack of Oral Drug Formulations

Based on the literature analysis and feedback from clinical trial investigators (and indirectly from the patients), the primary unmet need in management of moderate to severe IBD is lack of oral drug formulations: patients would prefer an oral formulation over the subcutaneous or intravenous administration. If the disease progresses further, requires hospitalization and IV corticosteroids, treatment options are limited with options of infliximab or cyclosporin, that in turn have significant side effects and they are at risk of toxic megacolon or bowel perforation with subsequent surgery. Prevention of this outcome is another focus of drug development – finding effective drugs for a late-stage disease.

Key Takeaways

IBD therapeutics and biologic developments have, thus far, not been able to provide substantial holistic solutions that improve a patient’s quality of life. More than that, limitations in testing, serious side effects, recalls and a lack of convenient therapeutic options have made minimal improvements upon current therapies. With the growing number of IBD studies, it is essential to consider and choose the right partner to help your IBD clinical trial stand out.

Despite the competition, PSI continues to deliver higher enrollment rates than typical across the industry due to our relationships with more than 3,900+ IBD sites around the world. Our studies are successful due to our long-term relationships with recruiting sites; we know the investigators on a personal level and they are motivated to work with us. Visit us online to learn more about our IBD therapeutic experience.

i Soubières, A. A., & Poullis, A. (2016). Emerging Biomarkers for the Diagnosis and Monitoring of Inflammatory Bowel Diseases. Inflammatory Bowel Diseases, 22(8), 2016–2022. https://doi.org/10.1097/MIB.0000000000000836 

ii M. Agrawal, B. Verstockt. (2021) Etrolizumab for ulcerative colitis: beyond what meets the eye. Lancer Gastoenterology and Hematology 7(1): P2-4. https://doi.org/10.1016/S2468-1253(21)00369-1 

IBD Clinical Trial Landscape: 3 Greatest Unmet Needs in IBD Clinical Development in 2023   Read More »