Clinical trials fail for various reasons, including inadequate basic science, flawed study design, suboptimal dosing, poor study operations, slow enrollment, high dropout rates, and unproven clinical or commercial value.1 However, assessing the feasibility of a study’s design before it starts can mitigate or avoid many of the risks unique to neuroscience studies. To make sure neuroscience trials are feasible, sponsors can focus on the following factors:
1. Patient needs
Feasibility in neuroscience trials is uniquely challenging due to the complexity of the central nervous system, limited biomarkers, and difficulties in patient recruitment and outcomes measurement. These challenges are compounded by the subjective nature of many symptoms and the long study durations often required to demonstrate efficacy.
Mounting evidence suggests that diagnosing and treating neurodegenerative disorders early is paramount for better prognosis. As a result, many neuroscience trials target newly diagnosed patients or those with early-stage disease. However, understanding the patient’s disease progression journey is critical to adapting protocols.
Recently, we worked with a sponsor to optimize a trial protocol for testing a disease-modifying drug in early-stage Parkinson’s disease (PD) patients. We conducted workshops on recruitment and retention in newly diagnosed PD and analyzed the study’s eligibility criteria and diagnostic testing schedule. We concluded that the trial’s permitted age range was too narrow, which would lead to a low number of patients screened, and there were too many invasive assessments. Early-stage patients are at the start of a long process. They are often unfamiliar with standard tests to stage and monitor PD progression, such as dopamine transporter imaging with single-photon emission computed tomography (DaT-SPECT). We advised the sponsor to support the sites’ recruitment efforts by providing a clinical enrollment manager (CEM) to perform chart reviews. After filing two protocol amendments (with the age range adjusted) and adding a CEM, the sponsor initiated the trial and met enrollment targets.
Sponsors must do more than just review comparable studies to estimate median enrollment times because patient burden is a critical factor, and it varies by study. For example, suppose an amyotrophic lateral sclerosis (ALS) or pediatric Duchenne Muscular Dystrophy (DMD) study requires seven lumbar punctures. In that case, that may limit the number of patients and families who choose to participate. In addition, if there are cultural reasons why a study may enroll more slowly in one country versus another, sponsors must examine those and account for this in the trial’s timeline. Moreover, if just a handful of sites are capable or interested in conducting a study, travel will be a significant issue for most patients not near those few sites, thus slowing enrollment.
Questions to answer include: What are the benefits of this study for patients and their families? What would motivate them to enroll and remain in this study versus seeking other treatment options, if available? How will the trial’s burdens mentally, physically, emotionally, and financially affect them? How can the trial design reduce barriers and support participation?
Feasibility in neuroscience trials is uniquely challenging due to the complexity of the central nervous system, limited biomarkers, and difficulties in patient recruitment and outcomes measurement. These challenges are compounded by the subjective nature of many symptoms and the long study durations often required to demonstrate efficacy.
2. Disease studied
The relative importance of recruitment and retention strategies can vary significantly based on the specific neuroscience indication. In some cases, the challenge of finding and enrolling suitable participants may outweigh the difficulties of keeping them in the study. Maintaining participant engagement throughout the trial may be the more pressing concern in other situations, particularly when data needs to be collected over an extended period.
For example, in psychiatric conditions, sponsors are dealing with the complexities of a person’s mental health, not just their physical health, and these challenges can impact long-term study participation. Most clinical trials in psychiatry report drop-out rates of more than 20%.2 Therefore, in these studies, retaining participants throughout the trial is a top feasibility consideration. Children and adults with attention deficit hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) have challenges with social interactions and communication; thus, site visits and assessments must be adapted accordingly. Patients with depression may struggle to regularly attend site visits, complete assessments, and follow a protocol due to changes in mood, decreased interest, difficulty concentrating, or fatigue. However, trial protocols can include flexible scheduling, personalized support and reminders (via an app or phone call), and careful monitoring of mood changes to address those risks. Staff who are empathetic and trained in crisis management are essential.
Neurodegenerative conditions, such as Parkinson’s disease (PD) and multiple sclerosis (MS), impact mobility. Successful recruitment and retention may hinge on transportation logistics. When someone cannot move or travel without assistance, they need the help of a loved one or a professional caregiver to enroll in a trial. Family caregivers may have full-time jobs and children to care for, and sponsors must consider strategies to make participation easy for them. Critical questions include: Can patients, their caregivers, and their families get to the sites? Is there easy access to all the areas within a site where they will undergo assessments? What type of support will be most helpful for the specific patient population of a trial?
Sponsors can recruit participants faster, help them stay in studies, and collect high-quality data by accommodating specific needs in neurodegenerative and psychiatric conditions. However, they must consider the patient’s condition and caregiver circles in feasibility assessments to plan proactively for a successful trial.
3. Site fatigue
Site fatigue is a significant challenge in clinical trials.3 This is especially true in major depressive disorder (MDD) due to the complex nature of the rating scales and assessments used to measure outcomes. At Parexel, we see a dramatic surge in MDD trials due to interest in the potential of psychoplastogens, fast-acting small molecules such as psychedelics and ketamine. These agents can produce long-lasting effects on the neural circuits associated with MDD-related maladaptive behaviors. The intense competition for MDD sites and patients has increasingly led sponsors and clinical research organizations (CROs) to adopt a site management organization (SMO) model to complement the traditional site selection process. SMOs can help identify the sites, investigators, and sub-investigators equipped to handle MDD trials and tailor support to each site's needs.
Once optimal sites are identified, it is crucial to minimize their administrative burden. A significant pain point for sites is the extensive feasibility questionnaires they receive from sponsors and CROs. These surveys can contain up to 200 questions and are often required regardless of recent completions, leading to questionnaire fatigue. Parexel’s recent experience and direct site feedback have revealed that many sites no longer open surveys.
To combat site fatigue and make site feasibility testing more efficient, Parexel has developed the Site Alliance Neuroscience Network, a centralized internal database. We continuously curate this list of pre-qualified sites that meet our stringent criteria for neuroscience trials. We track how recently each site has submitted feasibility data, allowing them to update their information only when it changes. This respects their time and ensures we have current information, accelerating site selection and study start-up times.
Another factor contributing to fatigue at high-volume sites is the turnover rate among staff in resourcing roles (versus patient-facing roles, such as nurses).4 Often, resource officers are young graduates who find themselves in a high burnout occupation. As a result, sites lose resource staff during a trial. We advise sponsors to address that problem in two ways. First, we recommend using CEMs to assist sites by managing the workload, streamlining processes, and offering guidance to less experienced staff. Second, we recommend providing financial support to increase staffing hours or hire more experienced personnel. Supplemental funds might cover overtime, skilled temporary workers, or a division of job duties that is more sustainable and minimizes staff burnout.
4. Site performance
Prior site performance statistics can help sponsors determine whether it is feasible to meet recruitment, enrollment, and study completion deadlines.
At Parexel, we rely on a proprietary investigator intelligence platform, “Landscape,” which curates granular performance data from multiple industry sources and our internal data. It provides a comprehensive view of historical and current investigator and site capabilities and performance. The database enables contingency planning by identifying risks such as changes in the standard of care (SoC) by country, projected competition for patients in the indication, and the intensity of scientific interest in the experimental agent. These factors impact site motivation and performance. With this data, we can recommend effective, data-driven strategies to select optimal sites.
For example, we have conducted numerous trials of novel PD treatments in the last five years, including trials with a subset of patients having PD-related mild cognitive impairment (MCI). We use our Landscape database to drill down to sites capable of recruiting this subset of participants and have the protocol-required capabilities. We then assess their interest in the planned trial.
Our database is differentiated by detailed data on each site’s specialties and specific capabilities in terms of disease progression. Increasingly, trials target smaller patient subpopulations, and stratifying patients by disease progression, for example, is extraordinarily complex and requires precise diagnostic tools and skilled technicians.
Although feasibility is typically a data-driven exercise, neuroscience trials require solid personal relationships with PIs and sites in addition to analytics. These trials are complex, study visits are intense, and the field is hyper-competitive. For this reason, at Parexel, we have found that building enduring relationships in our neuroscience site network is a powerful predictor of success. We have established continuity with top sites using the same medics, solution consultants, and alliance network managers—all with neuroscience training.
Although feasibility is typically a data-driven exercise, neuroscience trials require solid personal relationships with principal investigators and sites in addition to analytics. These trials are complex, study visits are intense, and the field is hyper-competitive.
5. Rater training
Training site staff to administer neurologic and psychiatric assessments is fundamental to a successful trial. The primary and key secondary efficacy endpoint(s) of neuroscience trials are often functional rating scales that capture the severity of disease or condition, cognitive function, or symptom changes, not outcomes such as mortality and survival that can be directly measured.
The scientific validity and consistency of rating scales depend partly on the quality and consistency of the rater, who must use them to capture “minimal clinically important” differences over time.5 Neuroscience trial raters need significant training using specific rating scales regardless of how long they have been in clinical practice.6 And rater training must be standard across all clinical trial sites.
For example, during site visits, patients with cognitive impairment associated with schizophrenia (CIAS) may undergo the MATRICS Consensus Cognitive Battery (MCCB) assessment, a 90-minute test. A site visit that includes the MCCB can stretch to six hours. The MCCB is a complex, novel rating scale, and raters need extensive training to ensure it is used accurately and consistently, yielding high intra-rater reliability. Having the same well-trained rater throughout the study is crucial for people with schizophrenia because they often struggle with paranoia and have difficulty trusting others; this also prevents any inter-rater variability in the study data. Sponsors can safeguard data quality and patient well-being by prioritizing rater training and consistency in CIAS trials.
At Parexel, rater training is a core component of feasibility testing, and we discuss this topic constantly with sites in our neuroscience network.
6. FDA-mandated diversity
The FDA has mandated that clinical trials enroll more diverse patients regarding race, ethnicity, age, and gender. Diversity in neuroscience includes these factors and additional vital aspects, such as disease progression, co-morbidities, polypharmacy, body mass index (BMI), and disability. Feasibility analyses must include a sound strategy for meeting or exceeding diversity requirements, which can smooth regulatory review and support reimbursement.
Epidemiology work can reveal which diseases impact certain ethnic groups, while medical literature reviews can identify prevalence and incidence rates. Claims data help to identify investigators’ relative access to underrepresented populations and are incorporated into our evaluation of best-fit investigator sites to support representative enrollment. In 2022, we helped a sponsor prepare one of the first diversity plans for a bipolar study, and we have worked on countless others since.
Sometimes, trial sponsors may need to conduct trials at lesser-known sites to enroll diverse patients. At Parexel, we develop plans to support less experienced or well-known sites and plan community outreach activities. We start with a list of the ten top-performing sites in an indication and then identify which have expertise by stage of the disease. If the study relies on advanced diagnostic tools or biomarkers to identify patients, some sites may be unable to participate.
Feasibility testing mitigates risk
Feasibility analysis informs clinical trial sponsors about risk. Identifying and quantifying risks precisely creates an impetus for action. Suggesting that a study design “might be challenging” is not enough. High-quality feasibility testing helps sponsors optimize protocols and empowers them to make contingency plans that would have been overlooked or unidentified.
Contributing Expert
