Discussion and conclusion
The review showed that frailty has been increasingly and successfully applied into clinical drug trials, especially trials in patients with cardiovascular disease and cancer. In most of the studies in the review, frailty was assessed retrospectively. Only a few studies prospectively designed frailty assessment and subgroup analysis by frailty status.
There was heterogeneity in the effect of frailty, depending on the diseases and the treatment types. The effect of frailty on the treatment efficacy was not consistent among the studies in this review. While several trials like ADVANCE, SPRINT, ASPREE showed some reduced effects of the treatment in frail patients, most of the trials showed that the benefits of the treatment are not affected by frailty status. Some even showed that the benefits of the treatment were more significant in frailer patients (DAPA HF, DELIVER). There is a need to balance the benefits of medications with the risks of adverse effects. Frail patients are often perceived to be more vulnerable to the adverse effects of medications, and their poor health may make them more likely to experience adverse effects that could negatively impact the outcome of the trials. Additionally, frail patients are often taking multiple medications, which can increase the risk of drug interactions and further increase the risk of adverse effects. Our review suggests that frailty should not be assumed to attenuate the treatment effect, and it is important to include frailty assessment in future RCTs.
One of the most significant challenges of conducting frailty assessments in clinical drug trials is the lack of a standardized definition of frailty. There is currently no universally accepted definition of frailty, leading to confusion among researchers and a lack of comparability between studies. Moreover, frailty exists on a spectrum, and it can be difficult to determine at what point a patient is considered ”frail.” This lack of standardization makes it challenging for researchers to design clinical drug trials that include frail patients, as it is difficult to determine what criteria should be used to identify patients who are appropriate for inclusion in the study. This review raised a question on the best methods to evaluate frailty. The FI and Fried’s frailty phenotype were applied in most of the trials in this review. The Frailty Index is one convenient method of quantifying frailty and has excellent predictive value for adverse health outcomes in older people.37,38 The Frailty Index is based on the conceptualisation of frailty as an accumulation of deficits throughout life. It is constructed as the proportion of deficits present in an individual out of the total number of age-related health variables considered, with a value obtained from 0 to 1. This index can be established from almost any sets of health-related variables and is a feasible way to identify frailty in older hospitalised patients. The FI is good for baseline measurement in clinical trials. In the studies in this review, the deficit accumulation approach (FI) has been predominantly used compared to Fried’s frailty phenotype. On the other hand, Fried’s frailty phenotype may be more suitable if the investigators aim for repeated measurement of frailty from baseline to follow up and with an intention to improve frailty. The frailty phenotypic type may be changed based on the intervention targeted at frailty.
How frailty was treated in statistical regression models was not consistent among the studies. The FI was treated as an ordinal variable (with different levels of frailty) or binary variable (frail/non-frail) using cut-offs in some studies, and as a continuous in some other studies. The cut-point to define frailty was FI > 0.21 was consistently applied to define frailty in most of the studies. Similarly, with Fried’s frailty phenotype, some studies categorized participants into two groups of frail/non-frail, while other studies categorized participants into three groups of fit, prefrail and frail when conducting statistical analyses.
This review suggests that screening for frailty in participants in clinical drug trials would enable the identification of those that merit closer monitoring for adverse events. Trial data may be harnessed to inform disease management in people living with frailty. Overall, frailty has become an important consideration in clinical drug trials in older people. Including frail older adults in drug trials provides valuable information on the safety and efficacy of treatments, and allows researchers to examine the effect of drugs in different frailty subgroups. As such, frailty should continue to be used as a criterion for inclusion in clinical drug trials, to ensure that older adults of all frailty levels are appropriately represented in research. There may be significant challenges to conducting frailty assessments in clinical drug trials. Researchers must select appropriate assessment tools and overcome recruitment barriers to effectively assess frailty and ensure the success of clinical drug trials. The development of practical and efficient frailty assessment tools and increased efforts to recruit older adults with frailty can enhance the quality and relevance of clinical drug trials and improve the development of safe and effective treatments in older populations.
Conflict of interest: The authors have no conflicts of interest to declare.
Funding information: This paper received no funding.