IBD

nurse holding the hand of an older man

Fast Start-Up & Beating Enrollment Milestones on a Phase II UC Study

At a Glance

When a small biotech approached PSI to run a complex UC study, the sponsor’s concerns were clear: streamline initial set-up, avoid complex vendor management, and overcome multiple operational challenges. PSI was up to the challenge, helping the sponsor achieve 50% enrollment five weeks before their goal and complete enrollment more than five months ahead of schedule.

Ventyx Graph

Phase 2 study in UC - Achieved 50% enrollment five weeks before their goal

Sponsor Challenges

Clinical trials are inherently uncertain, and this study highlighted the inevitability of unforeseen challenges more than most. Along with the impact of the COVID-19 pandemic, this sponsor encountered challenges such as poor performance of a central lab, issues with their IP supplies vendor, medical staff turnover, site activation delays due to equipment set-up, and the greatest challenge of all, a major study redesign and update post startup following FDA feedback.

PSI Strategy

1) Identifying the Perfect Geomix and Ensuring Fast Startup

To ensure fast site startup in the US, PSI identified the central IRB sites with both the right experience and the shortest contract finalization timelines from our database of more than 4,000 global sites. Our Site Qualification Specialists also confirmed sites were properly equipped to use study equipment before the Site Initiation Visit to avoid slowdown during activation. Using VISIONAL™, PSI’s proprietary data-driven feasibility and enrollment forecasting tool, the team identified the best country mix and site profile by collating historical enrollment rates in the given patient population from both internal and external data sources.

2) Invested in Communication

Communication with sites was crucial to enroll patients ahead of schedule. The Study Coordinator organized meetings with each site to discuss the study and each site’s immediate next steps. During the startup process, our CRAs began in-depth training and coaching with all relevant site staff on topics such as best practices for patient consent conversations, raising site awareness, study-specific tasks, and developing a site-specific patient flow to understand the referral process. PSI also developed site-facing enrollment boosting materials and contacted sites weekly to maintain investigator motivation, track screening and enrollment, and investigate any challenges with low enrollment.

3) Next-Level Site Support

Dedicated to building site relationships and understanding the dynamics of each site at the local level, PSI’s Site Support Specialists ensured that each site was supported and had the resources necessary to enroll patients effectively and maximize protocol compliance. The team developed and maintained communication pathways between the combination of physicians/departments, lab specialists, and nurses to facilitate the smooth flow of referrals, and utilized a suite of proprietary PSI tools to ensure sites understood individual stakeholder responsibilities and key study strategies.

Results

With the help of our CRAs, site support specialists, and other team members, PSI closed screening due to high volume even while sites had additional patients. We achieved 50% of the enrollment goal five weeks before the sponsor’s goal and completed enrollment more than five months ahead of schedule. The team also worked closely with investigators to ensure activation timelines were met, helping us achieve the first site activation in just 3.5 months.

“You have met and exceeded my hopes and expectations. I have seen so many challenges, and together we work through them. Speaking for myself and the entire team, we are grateful for this partnership and proud of what we have all accomplished together.”

Learn how PSI can support your hemophilia study at the resources below or contact us today

About Us

For 25 years, we have built trusted relationships with biotech sponsors, with 90% of our customers being repeat and referral. 

GI Experience

As the need for clinical trials in Crohn’s disease and ulcerative colitis grows, partnering with the right CRO matters more than ever. 100% of PSI’s GI and IBD studies have enrolled on time or ahead of schedule.

White Paper

Are Your CRO’s Site Relationships Helping or Harming Your Clinical Trial? Solid site relationships are the backbone of successful clinical trials. Without happy, supported sites, enrollment simply cannot happen predictably or within budgetary constraints 

Fast Start-Up & Beating Enrollment Milestones on a Phase II UC Study Read More »

medical staff running in a hallway

Putting the Focus Back on Site Relationships in Clinical Trials

Are Your CRO’s Site Relationships Helping or Harming Your Clinical Trial?

Solid site relationships are the backbone of successful clinical trials. Without happy, supported sites, enrollment simply cannot happen predictably or within budgetary constraints. Yet fostering deep site relationships is often overlooked because many CROs are simply unable or unwilling to put in the effort, resources, and time necessary to do so.

This task has only grown more complex in recent years. While historic challenges like staffing shortages, trial complexity, and issues related to site startup have intensified, they are now joined by the need to often learn and implement unfamiliar new technologies with little support and training.

Download our new white paper to learn about:

  • Top site challenges and how sponsors can help mitigate site burdens
  • How PSI’s experienced team navigates and strengthens site relationships
  • How strengthening site relationships helped one sponsor get their enrollment back on track

About Us

For 25 years, we have built trusted relationships with biotech sponsors, with 90% of our customers being repeat and referral. 

Case Study

A sponsor of a pivotal Phase 3 prostate cancer study investigating a radiopharm product approached PSI for support based on our experience and established network of 300 global radiopharmaceutical sites. 

Global Reach

Clinical trial sponsors working in oncology, hematology, IBD, infectious diseases, multiple sclerosis, and many rare diseases rely on PSI’s guidance and experience. 

Putting the Focus Back on Site Relationships in Clinical Trials Read More »

Iv drip with gray overcast sky in the background

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

About Us

For 25 years, we have built trusted relationships with biotech sponsors, with 90% of our customers being repeat and referral. 

GI Experience

We match theory to practice, making sure that our teams know what’s going on right now with IBD around the globe.

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 »

blurred female scientist using a dropper and test tube

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.

Comparability

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 

Extrapolation

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 »

pair of gloved hands drawing up medicine from a vial with a needle

Similar But Different: Regulatory and Operational Considerations for Biosimilar Clinical Development in IBD  

The rise of IBD biosimilars and what comes next

Biosimilars present untapped potential for expanding patient access and improving treatment options in Inflammatory Bowel Disease (IBD) and other therapeutic areas, but these trials also bring unique challenges and regulatory considerations.

In this white paper, you’ll learn how biosimilars have transformed the treatment landscape for IBD in the past decade, their current therapeutic uses in Crohn’s disease and ulcerative colitis, and global regulatory considerations for running biosimilar clinical trials in IBD.

Download our new white paper to learn about:

  • IBD epidemiology and current biosimilar treatment methods
  • Regulatory considerations and other challenges for biosimilar trials
  • Future opportunities for biosimilar therapeutics

Similar But Different: Regulatory and Operational Considerations for Biosimilar Clinical Development in IBD   Read More »

meeting

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 »

IBD patient enrollment

Top 4 Sponsor Challenges in IBD Patient Enrollment

The number of IBD clinical studies grows each year; however, the number of patients enrolling in these studies has not increased proportionally. Instead, patient enrollment rates for IBD trials in recent years have shown a significant decline: from 1998 to 2018, the average recruitment rate in moderate-to-severe UC decreased from 0.32 to 0.13 patients per site per month, while the average recruitment rate in moderate-to-severe CD decreased from 0.65 to 0 to 0.10 patients per site per month.i

In PSI’s white paper Inflammatory Bowel Disease: Current Status and Future Perspectives, Senior Medical Advisor Maxim Kosov breaks down recent trends in IBD clinical research, including insights into patient recruitment and retention. Read on to discover the top four challenges to consider when enrolling IBD patients for your next trial.

1. Availability of Existing Treatments

The success of FDA-approved treatments, particularly vedolizumab in 2014, ustekinumab in 2016, and tofacitinib in 2018, often leads to a decreased patient enrollment rate in placebo-controlled randomized controlled trials. When the currently approved drug provides effective treatment with minimal side effects, patients will often opt for this method instead of enrolling in a study where they may receive a placebo drug. This is often a leading factor contributing to slow enrollment.

2. Competition Between Trials

When it comes to site choices and geomix, many sponsors and their partners approach larger academic centers first, assuming that these sites will have more experienced staff and equipment. One study found patients followed at academic centers are almost twice as likely to have participated in randomized clinical trials. However, the study also found over half of enrolled patients were followed in private practice settings.2 Focusing on large institutions leads to higher competition rates. For instance, as of October 2022, in the University of California San Francisco alone, there were 29 active IBD clinical trials, and 9 of them were enrolling.ii

3. Country and Site Selection

Additional factors may influence low enrollment potential, including site choice and geomix. When choosing the right geomix of sites, sponsors must consider the incidence of the disease, treatment standards, and availability of the medications. The incidence of IBD is increasing in Asia, Africa, and Latin America, driving interest in shifting clinical trials to these regions.iii Additional factors to consider when selecting sites include the health insurance environment (the likelihood that insurance companies will approve less efficient generic medications over specialty ones) and the presence of preferred study sites (sites with whom the CRO has a long history of cooperation and appropriately trained study teams).

4. Screen Failure Rates

Over the past decade, screen failure rates in IBD trials have grown, approaching 50% in UC and 70% in CD, primarily due to failure to meet minimal endoscopic or biomarker criteria for active disease and a growing list of exclusionary concomitant medications. In PSI studies, we’ve seen a screen-out rate of 26-48% in UC and up to 64% in CD.

Some general recommendations to minimize screen failure and aid in patient enrollment rates include higher drug-to-placebo rates (such as a ratio of 2:1 or 3:1 rather than 1:1), broader use of patient-reported outcomes as the primary study endpoint, and optimization of study visits’ duration and complexity (including fewer procedures and endoscopies). Additional options for trial design include adding a long-term open-label extension for patients responding to therapy, and more involvement from the patient’s primary GI physicians at local hospitals and private practices. Primary care doctors see patients at the earlier stages of the disease course. There is a better chance that such patients are more likely to meet eligibility criteria than those admitted to larger hospitals or academic institutions, where the disease is often more severe and potential complications more frequent.

global map of PSI IBD sites with teal dots as markers
PSI has built and nurtured a database of 3,900+ sites in more than 50 countries across the globe to identify the ideal geomix for your study.

Conclusion

IBD patient recruitment and retention depends on the study protocol criteria and complexity, which must be scientifically sound to achieve the goals of the study as well as being attractive to patients. PSI provides a thorough review of the protocol by internal therapeutic area experts and harnesses the power of AI and machine-learning through our INTELIA platform, combined with strong site relationships around the globe, to ensure your study meets enrollment goals. If you’d like to learn more about PSI can support your global Phase 2 and 3 IBD trials, click here.  

i Harris, M. S., Wichary, J., Zadnik, M., & Reinisch, W. (2019). Competition for clinical trials in inflammatory bowel diseases. Gastroenterology, 157(6), 1457–1461. https://doi.org/10.1053/j.gastro.2019.08.020

ii Heyman, M., Terdiman, J., Lewin, S., Verstraete, S. G., & Mahadevan, U. (2022, November 7). UCSF inflammatory bowel disease clinical trials – San Francisco Bay Area. UCSF Clinical Trials. Retrieved November 21, 2022, from https://clinicaltrials.ucsf.edu/inflammatory-bowel-disease

iii Ng, S. C., Shi, H. Y., Hamidi, N., Underwood, F. E., Tang, W., Benchimol, E. I., Panaccione, R., Ghosh, S., Wu, J. C., Chan, F. K., Sung, J. J., & Kaplan, G. G. (2017). Worldwide incidence and prevalence of inflammatory bowel disease in the 21st Century: A systematic review of population-based studies. The Lancet, 390(10114), 2769–2778. https://doi.org/10.1016/s0140-6736(17)32448-0

Top 4 Sponsor Challenges in IBD Patient Enrollment Read More »

IBD

Inflammatory Bowel Disease: Current Status and Future Perspectives

In today’s crowded IBD clinical trial landscape, it can be difficult to complete your study as quickly and efficiently as possible. Being aware of the unique challenges that come with IBD trials can help you prepare and pivot more effectively when complications arise. In this white paper, Dr. Maxim Kosov, Senior Medical Advisor at PSI, breaks down recent trends in IBD clinical research, including insights into patient recruitment and retention.

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. Download our new white paper to learn about:

  • IBD epidemiology, patient risk factors, and cost drivers
  • Current diagnostic and treatment methods
  • Common clinical trial challenges and methods for patient enrollment and retention

View a sneak peek below

 

Executive Summary 

Inflammatory bowel disease (IBD) is an umbrella term that covers several clinical conditions, with two of them being the most common: Ulcerative Colitis (UC), which is limited to the colonic mucosa; and Crohn’s Disease (CD), which potentially affects any segment of the gastrointestinal tract from the mouth to the anus.

Both UC and CD are chronic, lifelong inflammatory diseases with a pattern of flare-ups and remission. While we have learned a lot about the predisposing factors, clinical symptoms, pathways, pathology, and genetics, the exact cause of these diseases remains unknown. The number of clinical trials aimed at the discovery of novel therapeutic options is increasing annually. But with more trials comes increasing complexity and challenges.

As a result, while we have come a long way in developing options to treat the symptoms of the diseases, we do not yet have a definitive treatment or cure. These diseases remain highly debilitating and, while no longer fatal in industrialized countries with the current state of medicine, continue to have a negative impact on the overall quality of life for the patient. This white paper will discuss UC and CD’s respective epidemiology and risk factors, current diagnostic and treatment approaches, and considerations for designing effective clinical trials.

Discover the Latest IBD Insights in our Latest Whitepaper

ABOUT THE AUTHOR

Maxim Kosov, MD, PH.D.
PSI SENIOR MEDICAL ADVISOR

Maxim Kosov, MD, Ph.D., is a Senior Medical Advisor at PSI CRO AG (USA). He graduated from Pediatric Medical Academy in Saint-Petersburg, Russia, in 1993 and worked as an intensive care physician in neonatal intensive care units of several major hospitals. He completed an international fellowship in neonatology at Albany Medical College, NY, USA, in 1996. In parallel with clinical work, Maxim was an Assistant Professor of the Faculty of Anesthesiology and Intensive Care at Saint-Peterburg Pediatric Medical Academy.

He joined PSI in 2004 and acted as a Medical Monitor in more than 60 clinical trials in various indications. He is the author/co-author of more than 50 publications and presented his research works at numerous international meetings and congresses, including annual European Respiratory Society (ERS) meetings in Berlin (2002), Stockholm (2002), and Drug Information Association (DIA) Congress in Hamburg (2016). He is a member of ASCO.

ABOUT PSI CRO

PSI CRO is a privately-owned, full-service clinical research organization (CRO) operating globally. PSI’s global reach supports clinical trials across multiple countries and continents and specializes in the planning and execution of global pivotal registration clinical trials. With an exceptionally high repeat and referral business rate combined with minimal staff turnover, PSI is committed to being the best CRO in the world as measured by its employees, customers, investigators, and vendors.

Global headquarters are based Switzerland at 113a Baarerstrasse, Zug 6300. www.psi-cro.com

Inflammatory Bowel Disease: Current Status and Future Perspectives Read More »

How to Boost Patient Enrollment in a Global IBD Trial

For one of the largest-ever global IBD trials, we knew our sponsor’s success depended on identifying the right sites and keeping them engaged.

Details:

Therapeutic Area: IBD

Geography: 40 countries

Sites: 400

Patients: 800 (planned)

Current Status:

  • Patient enrollment on schedule
  • PSI is on track to enroll 500 patients by year-end

How to Engage Investigators & Patients in the Highly Competitive IBD Landscape

After a large pharmaceutical company delivered enrollment 60 days ahead of schedule for a Phase 2 inflammatory bowel disease (IBD) study with PSI CRO, the sponsor faced a new challenge: one of the largest-ever IBD programs in the same indication. Competition for IBD patients is fierce, and we knew success depended on not only identifying the right sites but also keeping them engaged throughout the duration.

The sponsor engaged PSI to manage 400 sites and enroll 800 patients across 40 countries. With the length and size of the study, many sites went silent after the initial excitement. The onset of the COVID-19 pandemic introduced a whole new set of extraordinary challenges, which was especially noticeable during the summer months – already a typically slow period, but also when many countries implemented additional restrictions to slow the spread of new variants that made enrollment even more difficult.

To re-energize the study team and keep enrollment on track, the sponsor introduced a new incentive campaign with PSI modeled after the Summer Olympics to foster a sense of friendly competition.

3 Steps to Empower Your Sites

  1. Create a compelling, inclusive campaign to motivate sites

PSI divided the study teams to stand for their respective countries and introduced the following scoring system:

  • Gold medal: Awarded for every subject randomization
  • Silver medal: Awarded for every subject screening
  • Bronze medal: Awarded for every subject rescreening

The project team developed creative materials and branding to engage the teams during the campaign and made sure that countries of all sizes stayed visible within the competition thanks to an averaged rating system.

  1. Invest time into building close relationships with the site teams

To be truly patient-centric, a CRO needs to first be site-centric. Our mission is to make the site’s life in clinical trials as trouble-free as possible. It’s not easy, because clinical trial protocols are typically overcomplicated by all sorts of requirements that add work to the site staff already exhausted by routine medical practice. That’s why we are focused on building site support processes, working closely with the site staff to prevent and fix any signs of screening and enrollment delays.

PSI works carefully with each investigator to increase the percentage of patients entering the study, providing training and resources so the site teams understand the best moment to screen patients for the study and that screen failure patients could be reassessed. The project team provides extra support to sites and patients with personal protective equipment, implements additional procedures for direct shipment of the drug to patients’ homes, identifies a big network of local labs to minimize trips during the pandemic, and arranges comfortable and safe conditions for patients’ travel or travel reimbursement.

  1. Build on a long-standing partnership

With the same leadership team in place since 2015 for the program, including the same Global PM and Co-Manager from the Phase 2 Study, the PSI teams draw on their experience from previous studies for this client during the competition. PSI Country Managers and Clinical Operations colleagues are also engaged to help the project teams come together to meet a common goal. It’s great to have a stable global team on such a complex project.

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5 IBD Clinical Development Trends to Watch From ECCO 2022

Last month, I had the honor of representing PSI CRO at the European Crohn’s and Colitis Organization (ECCO) 2022 Congress. Now in its seventeenth year, this is the biggest event for all those working at the forefront of inflammatory bowel disease (IBD) clinical research, with nearly 6,000 attendees representing more than 100 countries.

This year’s theme was “Navigating the Oceans of IBD,” focusing on what it takes to transform the latest science into practical approaches. The numerous sessions discussing novel treatments made it clear that IBD is an exciting therapy area with many new treatments on the horizon. While new therapies will offer more choice for patients and the potential for more personalized treatment in IBD, studies testing the efficacy and safety of novel combinations will be required. In addition, presenters highlighted the need for head-to-head comparative trials to help guide treatment decisions. I’ve identified five IBD clinical development trends to watch as you plan your next study.

#1: The potential of JAK inhibitors for improving the efficacy of ulcerative colitis (UC) therapy

The latest data on Janus kinase (JAK) inhibitors demonstrates that these therapies have a rapid onset of action, are associated with durable efficacy, and achieve stringent composite endpoints encompassing both endoscopic and histologic assessments with a favorable benefit-risk profile. The key to clinical efficacy for these therapies is selectivity. With a highly selective agent, we can suppress JAK1 with a higher dose while remaining below the threshold of JAK2 activation. Selectivity brings us to a different level of clinical efficacy, and greater JAK1 selectivity over JAK2 could potentially translate into a more favorable benefit-risk profile.

We started to see it with tofacitinib, a pan-JAK inhibitor. With selective JAK inhibition, we now see striking deltas in all endpoints, including rapid efficacy and superior mucosal healing. Efficacy must be balanced with safety. For example, consider the increased risk of herpes zoster related to certain JAK inhibitors. Filgotinib and upadacitinib, selective JAK1 inhibitors, show a much lower incidence of herpes zoster than tofacitinib, a JAK pan-inhibitor. However, even with selective JAK inhibitors, the incidence of herpes zoster is higher than with placebo.

As a systemic inflammatory disease, IBD can affect other organs, and more than 40% of patients with IBD have at least one extra-intestinal manifestation. Selective JAK inhibitors may also make an impact here. One study found that a 45-mg induction dose of upadacitinib resolved more extra-intestinal manifestations at eight weeks than placebo (40% versus 33%) with an even more striking difference in resolution of peripheral or axial arthropathies (55% versus 42%). Similar effects were observed in a maintenance phase.

#2: Tailoring each clinical trial to the drug’s individual safety profile

Patients’ top concerns when choosing treatment include the achievement of long-term remission; route/frequency of administration; and such safety considerations as risk of infections (particularly of herpes zoster and tuberculosis), cardiac toxicity, and lymphoma risk (the last one is most relevant to biologics and small molecules). Some of these safety concerns, such as the risk of serious infections, vaccination status prior to initiation, and liver function, are universal and relevant to all drugs. Some are drug-specific; for instance, viral reactivation and non-melanoma skin cancer for tofacitinib and filgotinib.

Certain safety-related inclusion criteria for clinical trials with small molecules should therefore be universal: pregnancy test, vaccination (including herpes zoster), infections (screening for viral hepatitis), blood test (lymphocytes, neutrophils, hemoglobin), ECG, tuberculosis screening, and skin assessment (risk of skin cancer). However, each study protocol’s design must also consider the individual safety profile of the drug.

#3: The need for additional research into long-term effects

Additional research is needed into the IBD therapies’ potential for long-term effects, such as progressive multifocal leukoencephalopathy (PML), which is associated with certain inflammatory disorders. PML is a rare, opportunistic viral infection of the brain caused by the John Cunningham virus (JCV), typically in immunocompromised individuals. The seroprevalence of JCV antibodies ranges between 35% and 90% in the adult population as a latent or persistent infection. PML is also seen in inflammatory disorders such as systemic lupus erythematosus (SLE), sarcoidosis, polymyositis, and myasthenia gravis. Most cases were seen in multiple sclerosis with natalizumab. Patients with IBD are also considered at risk and need to be monitored for PML.

#4: An increased understanding and treatment options for patients who don’t respond to anti-TNF therapies

A significant number of patients fail to respond to anti-tumor necrosis factor (anti-TNF) therapy. New data suggests that interleukin 23 (IL-23) may be a key driver of molecular resistance to anti-TNF therapy, and blocking IL-23 may restore the balance between pro- and anti-inflammatory responses in the inflamed gut. There are several treatment options for such patients, but there have been no attempts to compare efficacy of different drugs until recently.

Two studies were presented at the congress that addressed this gap. The first one compared tofacitinib with vedolizumab in adults with symptomatic UC with prior exposure to at least one anti-TNF treatment. Both groups met the primary endpoint of corticosteroid-free clinical remission at 16 weeks (45% for the tofacitinib group and 40% for the vedolizumab group); however, the endoscopic improvement at week 16 showed the superiority of tofacitinib with a 24% rate versus 7% in vedolizumab patients.

The second study compared vedolizumab to ustekinumab after at least one anti-TNF treatment failure in subjects with Crohn’s disease. The study’s main objective was to compare the short- and long-term treatment survival rates with efficacy and safety as secondary objectives. The study showed a statistically significant higher five-year survival rate with ustekinumab, with the safety profile being similar for both drugs.

#5: New approaches to defining treatment goals in both UC and Crohn’s disease studies

In all international guidelines, treatment goals include endoscopic parameters (normal mucosa or Mayo endoscopic score 0-1). Most recent clinical trials include endoscopic subscore 0-1 and both central reading and histology during initial trial. Mucosal healing can now also include histologic improvement, as seen in the ustekinumab program.

The upadacitinib program looked at the composite endpoint endoscopic-histological score and histologic remission defined as a Geboes score of less than 2.0, which means the absence of neutrophils both in the epithelium and the lamina propria. The Geboes score is a six-grade classification scoring system to assess inflammation in UC. The most stringent definition is Geboes score 0-1: no eosinophils, no neutrophils in lamina propria, no neutrophils in the epithelium, no erosion, and no ulceration. Achieving histologic remission may be correlated with improved patient outcomes: decreased risk of clinical relapse, decreased corticosteroids use, lower risk for colectomy, and lower risk of hospitalization. Increased mucosal inflammation in UC may be associated with an increased risk for colorectal cancer.

Another study compared endoscopic healing at one year with different biologics. The best endoscopic healing for ileal involvement was seen with the infliximab biosimilar (37% of patients) and the lowest rate with ustekinumab (23%) and vedolizumab (19%). In the case of colonic involvement, the lowest rate of endoscopic healing was observed with ustekinumab (29%) and vedolizumab (31%), and the highest for adalimumab (62%).

Final thoughts

As the need for clinical trials in Crohn’s disease and ulcerative colitis grows, CRO collaboration matters more than ever. At PSI CRO, we’re committed to keeping abreast of the latest scientific advances and partnering with the companies doing the most exciting work in the IBD space. Learn more about our IBD expertise here and how we can support your next study.

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