Identifying frailty in trials: an analysis of individual participant data from trials of novel pharmacological interventions

Abstract

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.

Frailty in people with rheumatoid arthritis: a systematic review of observational studies

“…Despite these limitations in comparing frailty prevalence between studies, the estimates reported in this review indicate that frailty is common in people with rheumatoid arthritis compared to the general population. This is consistent with previous observations that frailty, identified using a frailty index, was common in phase 3-4 randomised controlled trials of people with rheumatoid arthritis 41 . As in this review, frailty in these trials was strongly associated with greater disease activity.…”

The degree of frailty as a translational measure of health in aging

“…Despite this, excluding patients who live with higher degrees of frailty from clinical trials is a common, if derided, practice 98,99,[132][133][134] . Nevertheless, people living with mild to moderate frailty find their way into trials and bring with them a higher risk of adverse outcomes 135 . In consequence, it has been recommended that people who live with frailty merit closer monitoring 135 , and that trials in chronic diseases in which frailty is common should determine which treatments frailer patients might tolerate best 136 .…”

Observed and expected serious adverse event rates in randomised clinical trials for hypertension: an observational study comparing trials that do and do not focus on older people

“… 4 We previously showed, in an individual-level participant data analysis, that frailty is associated with increased risk of serious adverse events in trials. 13 Furthermore, frailty in participants in cardiovascular trials is associated with adverse cardiovascular outcomes independently of traditional risk factors. 26 While frailty has been shown to be present in participants of trials for hypertension in older people, 8 , 9 frailty in these trial participants is thought to be less severe than frailty in people in the community.…”

“…All these characteristics are more common in older age, associated with poor health outcomes, and often underrepresented within trials. [12][13][14][15][16] Previous studies assessing trial representativeness have tended to apply trial exclusion criteria to population samples derived from routine healthcare data or disease registries, concluding that many people living with long term conditions would be ineligible for trials. 5,6,10,17 However, such an approach does not directly assess the health outcomes in trial participants compared with those…”

“…All these characteristics are more common in older age, associated with poor health outcomes, and often under-represented within trials. 12 , 13 , 14 , 15 , 16 …”