Dual Approaches, Added Challenges: Complexities of Combination Therapy Trials in IBD Part 3

Challenges in IBD Combination Therapy Research

This is the third post in a series on combination therapies in the treatment of inflammatory bowel disease (IBD). Previously, we covered the reasons for rising interest in combination therapy’s potential (Part 1) and the history of research in the field and the methodologies currently being explored (Part 2). In this post, we’ll focus on what comes next: understanding the challenges that must be overcome to advance this promising area of treatment.

Monitoring drug interactions and safety concerns

When combining drugs for any reason, researchers must be attentive to the risk of increased safety signals and adverse events (AEs). As discussed in Part 1, several trials have demonstrated similar safety for combination therapies compared to monotherapies, but data is still limited. Additional insights can be gleaned from studies of combination therapies for other therapeutic areas, including dermatologic and rheumatologic conditions.

For instance, a trial comparing the anti-TNF agent etanercept in combination with the targeted therapy abatacept or placebo found the overall frequency of AEs and serious AEs to be comparable between the groups at six months. After a year, however, patients receiving the combination therapy experienced higher frequencies of AEs, serious AEs, and drug discontinuation.ⁱ This highlights the important role that long-term follow-up and real-world evidence (RWE) will play in evaluating the overall safety of these therapies.

Patient recruitment/retention and long-term follow-up

GI trials face well-known patient recruitment challenges due to invasive procedures, significant time commitments, and lengthy lists of inclusion/exclusion criteria. Correspondingly, screen failure rates are increasing with estimates approaching 50% in UC and 70% in CD, with failure to meet minimal endoscopic or biomarker criteria for active disease as a primary cause.ⁱⁱ

It’s easy to see how challenges to enrollment and retention might be compounded with the introduction of one or more additional therapies. As the point of contact for patients, sites will play an important role in helping patients understand and manage the trial burden, but sites often lack the training and support to do so effectively.

Navigating regulatory pathways

Sponsors must also consider the complexities of the regulatory approval process for combination products. In the United States, combination therapies fall under the Food and Drug Administration’s definition of a combination product, which includes any combination of a drug and device, biologic and device, drug and biologic, or drug, device, and biologic. Depending on the components, the combination will be assigned to the Center for Biologics Evaluation and Research, Center for Drug Evaluation and Research, or Center for Devices and Radiological Health.

In the European Union, the regulations for combination therapies vary by country, which can lead to inequalities in access to these treatments.ⁱⁱⁱ In a review of access to targeted combination therapies for oncology in nine European countries, the authors note that one of the therapies is typically registered first as the “backbone therapy,” and “add-on therapies” are registered as treatments to be given in combination.^ii,iv

For sponsors of combination therapy trials, understanding how best to navigate the regulatory approval process – particularly where existing safety and effectiveness data may be used to support approvals – is paramount.

Choosing the right CRO for your GI trial

Choosing the right partner is one of the most important considerations for combination therapy trials. The ideal CRO should have the appropriate GI expertise and be able to motivate and support sites through challenging protocols effectively.

At PSI, we have the needed expertise and experience in managing complex IBD studies and can support our sponsors by successfully managing their studies and bringing them to successful completion. In the final post in our series, we’ll discuss strategies for overcoming challenges in combination therapy research to enroll patients and achieve quality data on schedule.

References

ⁱWeinblatt M, Schiff M, Goldman A, et al. Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial. Annals of the Rheumatic Diseases 2007;66:228-234.
ⁱⁱHarris MS, Wichary J, Zadnik M, Reinisch W. Competition for Clinical Trials in Inflammatory Bowel Diseases. Gastroenterology. 2019;157(6):1457-1461.e2. doi:10.1053/j.gastro.2019.08.020
ⁱⁱⁱVancoppenolle JM, Koole SN, O’Mahony JF, et al. Targeted combination therapies in oncology: Challenging regulatory frameworks designed for monotherapies in Europe. Drug Discovery Today. 2023;28(8):103620. doi:10.1016/j.drudis.2023.103620
^ivDankó D, Blay J y., Garrison LP. Challenges in the value assessment, pricing and funding of targeted combination therapies in oncology. Health Policy. 2019;123(12):1230-1236. doi:10.1016/j.healthpol.2019.07.009