Introduction

Older individuals are often underrepresented in randomized clinical trials (RCTs).[1–3] They are frequently excluded as a result of direct and indirect exclusion criteria based on the presence of comorbidities and polypharmacy.[4] For instance, Van de Water et al. previously demonstrated that due to exclusion criteria based on age, comorbidities and medical history only a maximum of 12% of older breast cancer patients would have been suitable to enter breast cancer trials.[5] The consequence is that participants enrolled in clinical trials often do not represent the older patients in general medical practice and thus threaten the external validity of RCTs in the older patient population.[6, 7]

Compared to younger patients, older patients are very heterogenic with respect to frailty, mobility, functional capacity, and cognitive function. These different domains can be systematically assessed by using geriatric assessments.[8] To critically interpret the outcome in RCTs and to allow clinicians to judge to which older patients the outcomes can be applied, it is important to know which older adults have been enrolled in the trials. In scientific literature, patient characteristics are usually described in the population descriptives or in the in- and exclusion criteria section. It is currently unknown how patient characteristics with respect to physical, mental and social functioning or frailty are reported in RCTs specifically designed for older adults.

Therefore, the aim of this systematic review is to study what proportion of RCTs specifically designed for older adults report on somatic status, physical and mental functioning, social environment and frailty in the patient characteristics.

Methods

Results

The analysis in the present review started with 1369 articles. Of these 1369 articles, some articles described more than one RCT (adding a total of 24 RCTs), articles were further excluded because there was no RCT design after second review (n = 11) or no full-text was available (n = 1). After all the articles with a mean age <60 years or the articles were no mean age was available were removed. We ended up with 300 articles specifically designed for older people included for this analysis. (Fig 1) A full database of all 300 included publications, including authors, titles and journal of publication can be assessed (S1 Appendix).

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Fig 1. Flow chart for inclusion of studies.

PRISMA flow chart of the result from the performed search strategy and selection process.

https://doi.org/10.1371/journal.pone.0174053.g001

Table 1 shows a description of the main trial characteristics of these 300 trials. The median number of participants per trial was 114 (IQR 47–288), the median of the reported mean age of the participants in the trials was 66 (IQR 63–70) and the median percentage of men included in the trials is 60 (IQR 45–72). Most of the trials were classified into WHO disease categories circulatory (25%), neoplasms (19%), musculoskeletal (9%), nervous (8%) and digestive (6%).

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Table 1. Main trial characteristics of the 300 included RCTs.

https://doi.org/10.1371/journal.pone.0174053.t001

Fig 2 shows the proportion of RCTs that reported on geriatric assessments in the patient characteristics. In 102 trials (34%) somatic status, physical and mental functioning, social environment or frailty were reported in the patient characteristics. In 73 trials (24%) these geriatric domains were reported in the in-, or exclusion criteria, and in 83 trials (28%) geriatric domains were reported in the population descriptives. In total of the 300 trials somatic status was reported 23 times (8%), physical functioning 67 times (22%), mental functioning 41 times (14%), social environment 20 times (7%) and frailty was only reported 2 times (1%). (Fig 3)

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Fig 2. Proportion of RCT’s in older patients that report on geriatric assessments in the patient characteristics.

Showing the proportion of trials reporting geriatric assessments in the population descriptives or in- and exclusion criteria.

https://doi.org/10.1371/journal.pone.0174053.g002

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Fig 3. Proportion of RCT’s in older patients that report on different geriatric assessments*.

Showing the distribution of different geriatric measurements and expressed as percentage of the total trials (n = 300). *Some articles reporting more than one domain: 14 articles reporting two geriatric domains, eight articles reporting three geriatric domains and only one article reports four geriatric domains.

https://doi.org/10.1371/journal.pone.0174053.g003

When selecting trials with a reported mean age of 70 years and older (n = 78), 46% of the trials report geriatric assessments in the patient characteristics. When selecting trials with a reported mean age of 80 years and older (n = 13), 85% of all trials report on geriatric assessments in the patients characteristics (Fig 2).

Discussion

The main finding of this article is that only in 34% of all trials specifically designed for older patients report of geriatric assessment in the patient characteristics.

Our results are in line with the limited evidence that geriatric characteristics are underreported in RCTs. Benraad et al. described that geriatric characteristics are rarely taken into account in RCTs on anti-depressant drugs in late-life depression.[9] There are a number of possible explanations of the limited report of somatic, physical and mental functioning, social environment and frailty in RCTs published in 2012. First, the underreporting of somatic, physical and mental functioning, social environment and frailty might suggest that they were not taken into account at all. Second, it is possible that assessments of somatic, physical and mental functioning, social environment and frailty were included in the study protocol but were not reported in the published paper. This is also known from literature, describing that in 12% of the trials published in high-impact general medical journals the exclusion criteria were not well reported.[6] Third, the included participants in RCTs might have been implicitly selected based on protocol level, patient level or physician level. An example of protocol level is that the study protocol prescribes to visit the research facility three times a week. Older patients who have an impaired mobility or do not have a caregiver available, will be less likely to participate and are implicit selected on the functional or social domain. A form of implicit selection on patient level is a form of healthy user bias in which only the healthy older adults are willing to participate. Implicit selection on physician level is a phenomenon also described in literature, in which eighteen percent of the treating physicians stated that they had not offered their older patients a clinical trial because of comorbid conditions that might have affected their response to treatment, even though they had met the eligibility criteria for the trial.[10] In conclusion, as a result of the very limited report of somatic, physical and mental functioning, social environment and frailty, the external validity of the trial results is very limited. This might hamper the extrapolation of the trial results to individual older patients who suffer from functional impairment or frailty.

Literature describes that assessment of external validity is complex[11] but at least the characteristics of the included study population should be described in a transparent fashion[12] and therefore at least include patient and disease characteristics[13]. The included study population can be assessed by the description of the in- and exclusion criteria and patient and disease characteristics are usually found in the population descriptives. Especially in case of older adults, because of their huge heterogeneity as described previously, it is important to have a complete insight of the patient characteristics. We realise that insufficient time or funding can be one of the reasons not taking the geriatric assessment into account. However, this step has to be taken to gain better insight whether the results are applicable to older adults seen in regular practice[14, 15]. The choice of the domain assessed and instruments used depends on the patient population, the intervention and the outcome, unfortunately literature has no consensus on this point yet. From the present review we can conclude that it is currently difficult for the clinician to judge for which older adult the results of RCTs can be applied. This adds to the lack of evidence that already exists because of the very limited number of trials that specifically targets older patients.

We included only RCT's with a median age of 60 years or older. It is not expected that trials including younger adults perform geriatric assessments. Although the age of 60 years and older is chosen rather arbitrarily, it is striking that even in this sub-selection only one third of the trials reports on geriatric assessments to describe its population. Even when selecting the RCTs with a median age of 70 and older, not even half of the trials reporting on geriatric assessments. Only when selecting RCTs with a median age of 80 and older, the report on geriatric assessments 85%, however this is just representing less than one percent of all the included trials.

There are a few limitations to this systematic review. Our search was limited to a 10% random sample of the identified publications from 2012. However, since it contains a random sample, we can assume this is a representative sample, although we did not formally test this. Second, we excluded 106 articles in were no mean age was reported. The main strength of this review is that it is was currently not known how somatic status, physical and mental functioning, social environment and frailty are used and reported in RCTs. This review gains more insight in the external validity of RCTs for older adults.

Conclusion

Somatic status, physical and mental functioning, social environment and frailty are underreported even in RCTs specifically designed for older patients published in 2012. Therefore, it is unclear for clinicians to which older patients the results can be applied. We recommend systematic to transparently report these relevant characteristics of older participants included in RCTs.

Supporting information