Comorbidities are associated with a lack of representation in randomized controlled trials. As a result, it’s often unclear whether trial findings and subsequent treatment recommendations apply to those with comorbidities.
“Since comorbidities are common in many patient populations, failing to account for them could lead to trial results that are not representative of the broader population,” said Lynsey Psimas PhD, director of pharma business development at Pearson Assessments. “By acknowledging comorbidities and including diverse participants in clinical trials, researchers can improve the generalizability of their findings.”
Comorbidities can impact how a participant responds to a treatment, exacerbate side effects or interact with investigational drugs, which could lead to adverse events or alter the effectiveness of treatment. Understanding and accounting for comorbidities enables researchers to assess the effectiveness of treatments across patient populations.
Rigid protocols are hurting, not helping
Disability exclusion is systemic. Ethical and scientific reasons are often used as the basis for excluding those with disabilities, including cognitive and intellectual disabilities, from clinical trials. But this can have a serious impact on trial outcomes.
When clinical trial populations have a lower prevalence of comorbidities and multi-morbidities than the general population, it limits the generalizability of trial findings. Eligibility criteria in studies have become a growing problem, with some data showing that exclusion criteria increased almost 60% over a 10-year period. In the rare disease space, patient pools for trials are limited and excluding those with comorbidities may not be an option. Researchers must account for them.
In trials testing those with neurogenetic disorders for example, motor or language disabilities can impact testing performance. Julie Eisengart PhD, associate professor and director of the Neurodevelopmental Program in Rare Disease at the University of Minnesota, warns that tests given in standardized form risk missing the capabilities of the people with neurodegenerative and neurogenetic disorders due to the sensory disabilities associated with their conditions.
“The testing room and the testing approach have to adapt to the needs of the affected individual,” Eisengart said. “Otherwise what happens is that their skill level is missed or lost just because the test wasn’t designed or administered in a way that makes room for those differences.”
Conducting comprehensive patient screenings, designing trials that are inclusive of individuals with common comorbidities relevant to the target population, prioritizing adaptive trial design and ensuring transparent reporting of comorbidities and their impact on clinical trial outcomes are essential for researchers to prepare for the impact of comorbidities.
Adaptive approaches are needed
When researchers use emerging information to make real-time adjustments to factors like patient populations, sample sizes and statistical methods, trials are more efficient and have higher odds of successful outcomes.
Adaptive trials have been called “more efficient, informative and ethical” than trials with fixed designs. This approach to clinical trial design can also increase the likelihood that those with comorbidities are represented—but adaptive trials are underutilized.
Eisengart eschews a one-size-fits-all approach to conducting assessments. She collaborates with families to understand a child’s particular presentation by providing appropriate materials and taking a flexible approach to testing.
“It’s a matter of really understanding the disease,” she said. “Just because somebody has experience, for example, in testing individuals with ADHD or testing autistic individuals, doesn’t mean that (the same adaptive approach will apply to every testing situation). Having that mindset…to be prepared to be flexible and less rigid about this standardization so these skill capabilities are not lost.”
Oft-cited barriers to implementing adaptive clinical trial designs include a lack of familiarity with adaptive approaches, increased technical expertise, greater costs for statistical planning and concerns about whether regulatory agencies will accept results from adaptive trial designs. Utilizing clinical outcome assessments (COAs) could help.
COAs provide objective measures of treatment effectiveness and patient-reported outcomes and should include outcome measures that are sensitive to changes in health status due to comorbidities, according to Psimas. Incorporating COAs that are adaptable and sensitive to the presence of comorbidities can enhance clinical trials and ultimately improve our understanding of treatment efficacy.
Clinical trial results need to be generalizable to real-world populations. Researchers must be aware of the impacts of comorbidities on clinical trials to understand competing risks, drug-drug, drug-disease and disease-disease interactions and take adaptive approaches to account for them in clinical trials.
For more information on acknowledging comorbidities in clinical trial designs for successful outcomes, watch the webinar, Navigating Pediatric Neurogenetic Clinical Trials: Understanding the Essential Psychometrics.
