Question: Do standard eligibility criteria get in the way of diversity?
Standard eligibility criteria often exclude patients with low mobility, cognition, communication skills, or technological proficiency. But in real life, many neurological patients are challenged in one or more of these areas.
Sometimes, companies use eligibility criteria to find the “cleanest” possible data set. They assume minimal diversity will be cheaper, faster, and easier, and they may plan to address the gaps in post-marketing trials.
Some exclusions ensure patient safety, and these won’t change, but others may be unnecessary. Patients with co-morbidities, such as high blood pressure, high cholesterol, or overweight, might minimally affect the adverse event profile of an experimental agent but will generate data that are more generalizable to real-life patients. For diseases of aging, overly strict eligibility criteria can result in studies that routinely enroll younger- and healthier-than-average participants who are not representative of the target patient population.1
Even if eligibility criteria are inclusive, selection bias is always a danger. For example, principal investigators (PIs) may prefer to offer a clinical trial opportunity to an MDD patient with a strong, supportive family network. Such patients are more likely to complete a trial successfully. However, not all MDD patients have family to lean on, and once a drug is approved, it must also work for them. Many severely depressed patients never enroll in clinical trials.
Too often, the inclusion and exclusion criteria are copied and pasted from an earlier trial. We advise sponsors to reexamine them for every new trial critically.
Standard eligibility criteria often exclude patients with low mobility, cognition, communication skills, or technological proficiency. But in real life, many neurological patients are challenged in one or more of these areas.
Question: Can site selection and partnership increase diversity?
In two ways: selecting sites that serve a diverse population and supporting them in accommodating those patients.
At Parexel, we use real-world data (RWD) to identify a mix of urban, suburban, and rural sites where a trial can be run. For a complex neuroscience trial, you need experienced sites, but you may also have to go to inexperienced sites if they have a large target population. But then, we have to train their investigators and site staff.
We recently worked with a sponsor who requested help meeting the FDA’s new diversity guidelines after initiating a Phase 3 neuroscience trial. We identified additional sites and proposed a hybrid network in which PIs from experienced sites partnered with those from less experienced ones. We also supported the sites by providing them with the resources needed for community outreach activities to spur enrollment.
Sponsors may have to accommodate some particular site burdens to get the diversity they need for their trials. For instance, site visits for patients with AD or other dementias take longer than those for other diseases. A site may only be able to see two AD patients a day for assessment visits, and site staff and trial participants may need regular breaks. These can make neuroscience trials more time-consuming and less profitable, and sponsors may need to compensate to incentivize sites.
As well as apparent disabilities, many neuroscience patients suffer from non-apparent disabilities. The Society for Clinical Research Sites (SCRS) recently added disability as a domain in their Diversity Site Assessment Tool (DSAT). Even experienced sites may need more training, and sponsors may have to provide it. Recently, we trained a site that specializes in conducting trials for ALS and other neurodegenerative diseases on how to incorporate language etiquette and site readiness that goes beyond just meeting access requirements of the Americans with Disabilities Act (ADA).
Question: Are diverse neuroscience trials more expensive?
Yes. So it’s essential to balance the budget against the needs. One sponsor may want a patient-informed trial with maximum diversity, no matter the cost, while another may have a single compound in development and a tight budget. The latter may reasonably ask, “What is the minimum diversity I need to get my drug over the line?”
We begin with a conversation about what a sponsor is willing to spend. This is critical because many strategies for boosting recruitment, engagement, and retention cost money. For example, we recently worked on a dementia trial. The protocol specified that patients report to the site in the morning for assessment, followed by a Mini-Mental State Examination (MMSE) in the afternoon. Dehydration and fatigue can exacerbate dementia and lower MMSE scores, so patients needed something to eat or drink during the visit. We advised the sponsor to help participants with transportation expenses and provide food and refreshments.
Sponsors may only be able to cover transportation and support services for some patients in a trial or only a percentage of patients’ expenses. We build the care into the budget and the recruitment projections. If patients’ costs are not sufficiently covered, we often encounter problems in retention and compliance.
It’s essential to balance the budget against the needs. One sponsor may want a patient-informed trial with maximum diversity, no matter the cost, while another may have a single compound in development and a tight budget.
Question: What other factors limit diversity in neuroscience trials?
We do not have as many or varied patients to choose from as we might. For many people, the biggest hurdle is getting themselves or a loved one diagnosed. Increasingly, scientific data suggests that early diagnosis of diseases of aging is paramount to slowing progression. Often, critical symptoms are not evident to patients or their families. Late presentation and diagnosis of neurodegenerative diseases impede early participation.
Different cultures have different views on aging and dignity. In some cultures, not seeking medical help is considered more dignified than seeking it. Dementia in Japan is treated very differently than it is in the UK or an African country. For some families, pretending not to notice or be bothered by cognitive decline is a way of showing respect and deference for elders. That, too, impedes participation.
Trust in the medical system can vary by racial and ethnic identity. If someone has never been to a hospital until their dementia diagnosis, they may not trust the results. Biomarkers raise thornier ethical issues in neuroscience than in oncology, where results are black or white. For example, in AD, the presence of a biomarker does not guarantee future disease, and there may not be any therapy to offer. Finally, whether the indication is dementia or some other degenerative condition, clinical trial personnel have to deal with legal issues like powers of attorney more frequently than in different therapeutic areas.
Trust in the medical system can vary by racial and ethnic identity. If someone has never been to a hospital until their dementia diagnosis, they may not trust the results.
Contributing Experts
