Table 4.

Clinical trial designs that may address challenges and opportunities of enrolling participants with comorbidities.

Challenges	Opportunities	Designs
Safety concerns Compliance Heterogeneity of biology and treatment effects	Improve generalizability of trial results Personalized decision making Understand how effects differ due to the presence of a comorbidity or due to age Utilization of real-world evidence	Adaptive enrichment strategy design Group sequential design with interim analyses to evaluate excluding specific comorbid conditions based on safety. Phase IV studies Designing studies to evaluate safety or efficacy in individuals with comorbidity Pragmatic trials Expanding eligibility criteria Generalizable setting Master protocols to assess optimal treatment selection Registry-based randomized clinical trials Post-approval safety studies