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.