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.