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Peter Hanlon1, Elaine Butterly1, Jim Lewsey1
1Institute of Health and Wellbeing, University of Glasgow, 1 Lilybank Gardens, Glasgow, G12 8RZ, UK.
Background:
Frailty is common in clinical practice, but trials rarely report on participant frailty. Consequently, clinicians and guideline-developers assume frailty is largely absent from trials and have questioned the relevance of trial findings to frail people. Therefore, we examined frailty in phase 3/4 industry-sponsored clinical trials of pharmacological interventions for three exemplar conditions: type 2 diabetes mellitus (T2DM), rheumatoid arthritis (RA), and chronic obstructive pulmonary disease (COPD).
Methods:
We constructed a 40-item frailty index (FI) in 19 clinical trials (7 T2DM, 8 RA, 4 COPD, mean age 42-65 years) using individual-level participant data. Participants with a FI > 0.24 were considered 'frail'. Baseline disease severity was assessed using HbA1c for T2DM, Disease Activity Score-28 (DAS28) for RA, and % predicted FEV1 for COPD. Using generalised gamma regression, we modelled FI on age, sex, and disease severity. In negative binomial regression, we modelled serious adverse event rates on FI and combined results for each index condition in a random-effects meta-analysis.
Results:
All trials included frail participants: prevalence 7-21% in T2DM trials, 33-73% in RA trials, and 15-22% in COPD trials. The 99th centile of the FI ranged between 0.35 and 0.45. Female sex was associated with higher FI in all trials. Increased disease severity was associated with higher FI in RA and COPD, but not T2DM. Frailty was associated with age in T2DM and RA trials, but not in COPD. Across all trials, and after adjusting for age, sex, and disease severity, higher FI predicted increased risk of serious adverse events; the pooled incidence rate ratios (per 0.1-point increase in FI scale) were 1.46 (95% CI 1.21-1.75), 1.45 (1.13-1.87), and 1.99 (1.43-2.76) for T2DM, RA, and COPD, respectively.
Conclusion:
The upper limit of frailty in trials is lower than has been described in the general population. However, mild to moderate frailty was common, suggesting trial data may be harnessed to inform disease management in people living with frailty. Participants with higher FI experienced more serious adverse events, suggesting screening for frailty in trial participants would enable identification of those that merit closer monitoring. Frailty is identifiable and prevalent among middle-aged and older participants in phase 3/4 drug trials and has clinically important safety implications.
Insights
Frailty is common in clinical trials, even in middle-aged adults. Higher frailty scores predict more serious adverse events, indicating a need for frailty screening in trial participants.
Area of Science:
- Gerontology
- Clinical Pharmacology
- Public Health
Background:
- Frailty is prevalent in clinical practice but underreported in clinical trials.
- This underreporting leads to assumptions of frailty absence and questions trial relevance for frail populations.
- Industry-sponsored phase 3/4 trials for type 2 diabetes mellitus (T2DM), rheumatoid arthritis (RA), and chronic obstructive pulmonary disease (COPD) were examined.
Purpose of the Study:
- To investigate the prevalence and characteristics of frailty in participants of phase 3/4 clinical trials.
- To assess the association between frailty and serious adverse events in trial participants.
- To determine the clinical implications of frailty in drug trials for T2DM, RA, and COPD.
Main Methods:
- A 40-item frailty index (FI) was constructed using individual participant data from 19 clinical trials (7 T2DM, 8 RA, 4 COPD).
- Frailty was defined as FI > 0.24. Disease severity was assessed using HbA1c (T2DM), DAS28 (RA), and % predicted FEV1 (COPD).
- Frailty index was modeled on age, sex, and disease severity; serious adverse event rates were modeled on FI using regression and meta-analysis.
Main Results:
- Frail participants were present in all trials, with prevalence ranging from 7-21% (T2DM), 33-73% (RA), and 15-22% (COPD).
- Female sex and increased disease severity (RA, COPD) were associated with higher FI; age was associated with FI in T2DM and RA.
- Higher FI independently predicted increased risk of serious adverse events across all conditions (pooled incidence rate ratios 1.46-1.99 per 0.1-point FI increase).
Conclusions:
- Mild to moderate frailty is common in phase 3/4 drug trials, despite upper limits being lower than in the general population.
- Frailty screening in trials can identify participants needing closer monitoring due to higher risks of adverse events.
- Frailty is identifiable and clinically significant in middle-aged and older trial participants, with important safety implications.
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