Why the exclusion of older people from clinical research must stopBMJ 2012; 344 doi: https://doi.org/10.1136/bmj.e3445 (Published 21 May 2012) Cite this as: BMJ 2012;344:e3445
Exclusion of older people from clinical research, and of under-recruitment to clinical trials, is widespread.1 This problem has stark consequences, according to an expert committee of the European Medicines Agency (EMA). “The drugs we are using in older people have not been properly evaluated.”
While the paucity of clinical trials on young children is well documented and frequently discussed, the same cannot be said of a similar shortfall at the upper end of the age spectrum. In fact older people are proportionately under-represented or even absent from most drug trials. This matters because just as children are not physiologically identical to adults, neither are very elderly people equivalent to those decades their junior.
Recognising this, and mindful that the older generation (those over 80) are the fastest growing sector of the population, the EMA recently held a workshop at its headquarters in London to consider what might be done.
One group active in this field is PREDICT (Increasing the Participation of the Elderly in Clinical Trials), a consortium funded by the European Union to study the participation of elderly people in clinical trials and propose ways of boosting recruitment. The group began by checking that the under-representation is real. It reviewed trials completed during the past 10 years in six conditions: heart failure, hypertension, coronary heart disease, depression, Alzheimer’s disease, and colorectal cancer.2
Antonoio Cherubini is a professor of geriatrics at Perugia University and a member of the EMA’s geriatric expert group. “The PREDICT study confirmed that in every condition there was a wide gap between the real clinical practice population and the patients who were included in clinical trials,” he said. Both age and sex were out of kilter.
The group then checked to see if this distortion is continuing. Using a World Health Organization database of current clinical trials in heart failure the PREDICT consortium identified the same pattern. “Exclusion of older patients at the level of eligibility criteria is still very common,” according to Cherubini. Exclusion of patients with comorbidity and cognitive impairment also tends to keep older people out of trials. “We’re now working on oncological disease, and the situation we’re finding is exactly the same.”
James Goodwin, head of research at Age UK, told the London audience at the EMA workshop: “I regard this as absolutely scandalous. This kind of age bias leads to uncertainty about risks and benefits in new treatments for older people, and delays in bringing them new treatments.” There was, he added, a general prejudice against the old in our society. He cited a study of activity in one stroke unit in which 26% of patients under 75 received magnetic resonance imaging compared with only 4% above that age.3
But ageism aside, why does he think that older people find themselves so often excluded from clinical trials? Goodwin identified several reasons, including resistance to change, a perceived absence of models from which to garner expertise, and a lack of adequate resources.
When PREDICT organised a survey of health professionals and older patients, it found that both groups were conscious of factors that tended to militate against inclusion. Health professionals often felt under no special obligation to recruit elderly people; patients were discouraged by a dislike of randomisation, concerns about the consent procedure, and practicalities such as transport.
One delegate at the London meeting also blamed research ethics committee rules. “Ethics committees don’t let us phone patients,” he complained. “The only way we can contact them is to let GPs write, and no more than twice. Then they get a four or five page information sheet that worries them by saying things like ‘There’s a small risk of death.’” These things, he suggested, were barriers to recruitment. “What is really unethical at the moment is that patients are not going into trials because of the barriers.”
Cherubini agreed. “We cannot necessarily use the same consent form for a 90 year old person as for a 40 year old one,” he said. “We need simplified explanations.”
This is only one of a stack of ideas put forward by the PREDICT consortium to boost the recruitment of elderly patients. Trial organisers will need to make all sorts of changes to commissioning and ethical arrangements, to the recruitment process, and to the conduct of trials, Cherubini suggested. He advocated simplified protocols, fewer exclusion criteria, more training for research staff, more emphasis to patients on the benefits of participation, easier physical access to research institutions, the possibility of home visits, more frequent follow-up and contact . . . The list goes on.
Formal studies on improving the participation of older people are thin on the ground. Direct contact with patients, involving their general practitioners, and providing more information seem to help, said Cherubini. “But while a lot of opinions have been expressed about strategies, we don’t have a formal evaluation of which interventions are most effective.”
The European Organisation for Research and Treatment of Cancer (EORTC) is another body that has taken a close and critical look at clinical trials in older people.4 The obstacles it identified include aspects of trial methodology such as upper age limits and the definition of appropriate endpoints, and inadequacies of the regulatory framework. It perceived only a limited interest in change on the part of the drug industry.
So what to do? “Do we just have to lift the upper age limit of clinical trials, or do we need specific trials for elderly people?” wondered Ulrich Wedding of the University of Jena in Germany and a member of EORTC’s cancer in the elderly task force. “And what are the appropriate endpoints for elderly cancer patients?” Classic endpoints, he said, are often inadequate. There’s a need for more emphasis on quality of life measures and the preservation of functional capacity. “If you ask older cancer patients themselves what is most important they will often say it is to maintain their independence. We haven’t addressed this endpoint so far in clinical trials.”
PREDICT asked more than 500 health professionals how to increase the recruitment of older patients. Among their suggestions were a specific requirement to undertake such recruitment and, equally realistically, that any financial reward they were receiving should be adjusted to recognise the extra work involved.
Questioning the patients themselves revealed that their willingness to take part would be boosted if, among other things, follow-up evaluations were done at home, participation was encouraged by their own doctors, appointments could be scheduled to meet their needs, and transport costs reimbursed.
Goodwin put forward what he called some “golden principles” for boosting involvement. These included the use of older people’s existing networks when recruiting and the creation of a more user friendly climate. In an effort to stimulate interest and encourage clinicians to take the problem seriously, PREDICT has compiled a charter for the rights of older people in clinical trials (box).5
Charter for the rights of older people in clinical trials5
Older people have the right to access evidence based treatments
Inclusion of older people in clinical trials should be promoted and discrimination prevented
Clinical trials should be made as practicable as possible for older people
Older people should be safe in clinical trials
Outcome measures should be relevant to older people
The values of older people participating in clinical trials should be respected
Role of manufacturers
Given that drug manufacturers hold the purse strings for many trials, their interest in the matter—or lack of it—is a key consideration. In spite of some appearances to the contrary, there are people in the industry who favour change. The European Federation of Pharmaceutical Industries and Associations has surveyed 15 of its members. To judge by what Brigitte Stemper of Bayer told the meeting about the key findings, the industry’s position might be described as cautiously sympathetic.
In most circumstances manufacturers claim that they would favour including a representative group of older people in large trials. But she added: “In certain conditions it might make sense to have a completely separate trial, though that is a secondary option.” Registry data are also useful, she said, but this too is a secondary option. Data from randomised controlled trials remain the preferred alternative.
Many of the manufacturers’ thoughts seem to echo those of the academics at the meeting. The choice of appropriate endpoints, for example. Are standard endpoints always relevant in older patients? “One thing emerging more and more,” said Stemper, “is the need to focus on quality of life measures and on activities of daily living,”
Another industry representative, Philippe Guillet, Sanofi-Aventis’s head of healthcare technologies for ageing, also regretted the general exclusion of the oldest patients from pre-authorisation clinical trials. “We need to include them . . . and to take into account their specific characteristics,” he said. “We need to shift from the paradigm of product centred innovation to patient centred innovation. We need to understand the unmet needs of the older population to ensure that whatever we look for in the preclinical animal models is translatable into relevant measures in clinical studies.”
Practical help on some of these issues will soon be available in the form of a 30 page document, Geriatric Research Guidelines, to be published by the Brussels based European Forum for Good Clinical Practice. A draft version6 is already available on the web and will be finalised at an open meeting to be held on 11 June at University College London.
According to one of its authors, Florian von Raison, “The document provides recommendations on various ethical aspects of clinical trials performed in older people, and who may belong to a vulnerable patient population. This will contribute to the protection of all older patients in clinical trials, and to a better inclusion rate.”
In the end it was Cherubini who issued a call to action on bringing more old people into clinical trials. “It’s time to move from research to implementation,” he declared. The geriatric community will need little persuading of this; whether the rest will be quite so eager to follow their lead is more questionable.
Cite this as: BMJ 2012;344:e3445
Competing interests: The author has completed the ICMJE unified disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declares no support from any organisation for the submitted work; no financial relationships with any organisation that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Commissioned; not externally peer reviewed.