Three Important Considerations in Operationalizing Nonalcoholic Steatohepatitis (NASH) Global Trials

Nonalcoholic steatohepatitis (NASH) prevalence is expected to increase by 63% by 2030, yet there are no approved therapies to treat it, and significant challenges remain today in related clinical studies. Experts at the PPD clinical research business of Thermo Fisher Scientific discuss solutions to common challenges that arise during NASH clinical trial execution.

Patients with NASH have yet to see an approved treatment come to their pharmacy. At the same time, NASH drug developers have been hit with several setbacks in recent years.

For those navigating this space, there are many critical factors to consider. Here are three components we keep top of mind when operationalizing a global NASH clinical trial:

• Site education and rolling performance evaluation
• Vendor selection and management
• Patient recruitment strategies

Keep reading to learn how to overcome significant hurdles many drug developers face when launching and managing NASH clinical trials.

Risk Mitigation and Safe Inclusion of New Investigational Sites

When conducting any large global study, issues will invariably arise due to size alone. When enrolling a global NASH program, additional challenges must be factored in, such as:

• High screen fail rates
• Lack of investigator familiarity with the disease
• High competition for patients

This makes experienced NASH sites a foundational component of any global program. The strong relationships we have with these sites are invaluable, and we tailor strategies to maximize patient enrollment.

However, because of recruitment challenges and competition, it may also be necessary to look at new sites and regions not typically included in global programs. This may further increase risk to a study – most critically to patient safety but also to the integrity of study safety data and enrollment performance.

We help mitigate these risks with study team experience, site education strategy and ongoing performance assessments.

Training on fundamental recruitment tactics for NASH minimizes screen fail rates. Common strategies to increase efficiencies during the recruitment process include identifying:

• Pre-screened patients with Type 2 diabetes mellitus and features of metabolic syndrome
• Patients already diagnosed with NASH via liver biopsy
• Patients who have had a non-invasive FibroScan screening to qualify them as having nonalcoholic fatty liver disease (NAFLD) and will be referred for a liver biopsy if required to diagnose NASH

Once patients are successfully enrolled in the study, sites should move to focus on ongoing safety assessments. A strong contract research organization (CRO) partner will educate sites on the correct assessments to carefully check during a liver disease study. For example, consistent review of all lab work for each patient ensures warning signs are not overlooked.

At PPD, we focus on robust site training in our clinical programs to ensure safety and consistent performance from our global sites. Our SiteCoach program ensures high-quality training for new and less experienced sites. SiteCoach safely expands a study’s footprint and provides access to more patients.

Since site performance is an important element of operationalizing NASH global trials, given the high screen fail rates of NASH studies, we can perform continuous site feasibility and identification throughout a study. This involves constantly evaluating new sites for potential backup to manage risks of non-enrolling sites or sites with higher-than-expected screen fail rates.

Patient Recruitment

In addition to the right site selection, a strong patient recruitment strategy incorporates a mix of the right geographic coverage and reduced patient burden to trial participation. Some considerations for successful recruitment and retention include:

• Home health and direct-to-patient services: These services onboard and retain patients who may not live close to sites. They do, however, require careful management of logistical and regulatory components.
• Patient concierge services: To overcome recruitment challenges, we sometimes need to enroll patients who live far from a study site. Patient concierge services help reduce burden for the patient and improve patient retention through the life of the study.
• Mobile units: Because of the testing involved, technologies that enable remote participation in NASH studies have limitations. Mobile sites can overcome this by bringing the facilities needed to the patient. This is a component of the decentralized trials movement that is gaining steam and can be critical to diversifying clinical trial participant populations.
• Clear patient education: Patient burden can be high for NASH studies because of the possible need for liver biopsy. To properly inform both the patients and the sites of trial expectations, clear patient education is a necessity. This is especially true when access to new sites and regions is required and critical for any study deploying direct-to-patient treatments or assessments.

Elevate Patient Diversity to Benefit NASH Trials

An important value-add to the success of a global NASH trial is increased patient diversity across NASH studies – and coincidentally, achieving the objectives of increased patient diversity can benefit NASH studies.

The underrepresentation of diverse groups — such as racial, social, and sexual minorities — in clinical research has been a long-standing issue. Over time, the failure to achieve diversity in clinical trials has led to limited information about drug response and measures of safety and efficacy in historically under-studied populations.

To this point, there are notable differences in the presentation of NASH across racial and ethnic groups, yet the disease is mostly characterized in non-Hispanic whites. However, there is prevalent data that indicates a higher rate of NASH in Hispanic communities, such as those in South America – a region that is critical to consider for additional inclusion for any NASH study.

Thermo Fisher Scientific’s PPD clinical research business has prioritized addressing patient barriers through innovative strategies. Decentralized trial tools — like home health care, wearable technologies and e-consent forms — increase trial accessibility for patients by reducing the burden of physically visiting a study site.

Vendor Selection and Management

NASH studies typically require numerous vendors. Histologic confirmation of NASH and liver fibrosis stage remains the accepted standard for inclusion and efficacy assessment in late Phase II and III NASH clinical development, so liver biopsies are critical. Furthermore, the right choice of central pathologists and corresponding central liver histology review processes is one of the most important considerations during the central lab selection process. The use of FibroScan or other appropriate imaging methods are often part of study preselection procedures.

Two considerations can be important here:

1. Careful vendor selection and management: This ensures that sites have the right capabilities and training to work with study vendors that are key for clear assessment of study endpoints.
2. Reduced management burden on the sponsor: Because of the number of vendors often used in NASH studies, the need for careful oversight and consistent communication across the study cannot be overlooked. PPD clinical research services feature a strong vendor manager lead role to address this need. This person provides an integrated solution to streamline communication while acting as a single point of escalation and accountability. With larger clients, the vendor management lead works directly with the client’s vendor lead. However, for our smaller clients, who may not have the internal resources to interface with multiple functions across our business, we take a different approach. Our vendor lead works behind the scenes, reducing the burden on the study team, while maintaining the project lead as the single point of contact for the client.

With the right partner by your side, it’s possible to sidestep common challenges in NASH trials.

NASH research continues to move forward amid navigable challenges. With PPD’s global footprint and experience planning, staffing and executing global Phase III trials, our team can help you succeed in getting your NASH therapies approved and over to patients who need them.