Including the very elderly in clinical trials


The demography of Western civilisation is changing. In Europe and North America, prolonged life expectancy, combined with low fertility rates and decelerating inward immigration, is projected to increase both the total number of very elderly people and the proportion of the population that is very elderly over the next 50 years, resulting in considerable economic and social challenges [1]. For example, the number of people aged over 85 in England and Wales is projected to rise from approximately 1.3 million in 2010 (2.4% of the population) to 5 million in 2060 (7% of the population) [2].

In part, improved longevity has resulted from the development of medicines to treat co-morbidities that are prevalent among the elderly, such as hypertension, cardiac failure and cancer. Indeed, the over 60s – 20% of the population – consume approximately 60% of the drugs prescribed in the UK. With increasing age, people may develop multiple co-morbidities for which they are prescribed further medications; approximately 20% of people aged over 70 take more than five medications [3]. Such polypharmacy increases the likelihood of adverse drug reactions, which may become compounded by the limited physiological reserve of this population [4]. Eighty percent of adverse drug reactions in the elderly are potentially avoidable, with considerable implications for reducing both the cost of contingent hospital admission and the mortality and morbidity associated with such events [5].

A number of strategies have been developed to reduce adverse drug reactions, but these ignore a fundamental problem when prescribing for the elderly, namely that there is a dearth of evidence for drug effects, side-effects and interactions from clinical trials that specifically include elderly patients. A number of factors lead researchers and companies either to exclude the elderly from clinical trials altogether, or to limit their involvement based on a rigid set of exclusion criteria that do not reflect the patient population to which the licensed drug will eventually be prescribed [6]. As a result, drug prescription is based on data extrapolated from trials on younger, fitter patients, and the elderly recipient is effectively being administered a drug whose age-specific effects have not been scientifically assessed and which may precipitate an avoidable adverse drug reaction.

Cynically, it could be argued that the factors commonly advanced to justify exclusion of the elderly from clinical trials are less concerned with the elimination of confounding variables from results than with the financial and logistical factors influencing research involving the elderly. There are genuine methodological problems when including the elderly, relating, for example, to ethical approval, consent, compliance, polypharmacy, co-morbidity, functional decline and all-cause mortality, that may indeed result in equivocal trial outcomes, but these are not insurmountable, and would be balanced by improved validation of the drug’s administration to its target population [7].

Although there has been a general improvement in the conduct of randomised trials over the last 20 years, exclusion of the elderly from clinical trials in all specialties (including anaesthesia) remains common. Between 1990 and 2002, Le Quintrec et al. [8] noted both the scarcity of randomised controlled trials in general medical journals that involved very elderly patients, and the paucity of research into certain diseases common to this age group, echoing the findings of previous studies [9]. The exclusion of elderly patients from clinical trials of anaesthesia has not been reported, but brief analysis of the 16 clinical drug trials published in Anaesthesia during 2009 that could have potentially recruited very elderly patients (> 80 years) reveals that none specifically included such patients (although three involved them anyway), whereas five specifically excluded the elderly, with the remaining eight not excluding but not involving them. However, parallels may be inferred from studies conducted in other drug-intensive specialties, such as oncology: analysing data from 28 766 US cancer patients in 55 trials between 1995 and 2002, Talarico et al. [10] found an enrolment rate of 9% among the over-75s, despite this age group representing 31% of the US cancer population.

How can this inequality be addressed? Recent guidance published by PREDICT (‘Increasing the Participation of the Elderly In Clinical Trials’) [11], a European Union-funded pan-European consortium, echoes previous advice from the American Geriatrics Society, and calls for a number of measures, including the promotion of inclusion of the elderly by national regulators, sponsors and ethics committees, improved practicability (for example, adaptation of trial information and research facilities) and greater relevance of outcome measures to the elderly population (for example, quality of life assessment).

Applied to drug trials in anaesthesia, there has to be a greater acceptance that the involvement of elderly patients makes clinical and financial sense. There is a wealth of drug research that needs to be repeated involving the very elderly with co-morbidities, with the aim of improving peri-operative outcomes and reducing adverse drug reactions in this population. Importantly, anaesthetists who advise research ethics committees should encourage applicants not to exclude the elderly automatically without good justification; furthermore, the default position of anaesthetic researchers should move towards inclusion of the elderly, taking steps to consider, for example, problems with consent or age-specific outcome measures (such as mobility, return to place of pre-operative residence, peri-operative cognitive state assessment) before ethical approval is sought. Similarly, journal editors might consider asking authors to justify any exclusion of the elderly as a potential weakness of a study, if appropriate.

Exclusion of the elderly from clinical trials is both morally and scientifically reprehensible. Prescribing effectively untested drugs that may not be beneficial, and that may in fact cause harm, violates the principles of beneficence and non-maleficence. Furthermore, exclusion is inherently ageist in a way that the profession should find as unacceptable as the exclusion of research subjects on grounds of race or gender (as has previously happened [12]). As the population ages, it is incumbent on anaesthetists to lead by example and insist on the inclusion of elderly patients in clinical trials.

Competing interests

SW represented the Age Anaesthesia Association at the launch of the PREDICT European Charter for Older People in Clinical Trials in February 2010 (BMA House, London). No external funding declared.