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Attention turns to its ederly population and their lack of participation in clinical research.
It's official. Europe is getting too old. Even the European Commission admits it. In its annual report of the European Union for 2009, it notes that its own expert bodies during the year "added further evidence to the argument that the social and economic consequences of change require closer attention. The...tentative 'worst case' scenario for the decades ahead suggested the current economic and financial crisis would result in severe falls in living standards owing to persistent lower growth and a permanent increase in age-related expenditure as a proportion of GDP."
Peter O' Donnell
The clinical trials community is also responding. A workshop organized by the geriatric medicines working party of the European Forum for Good Clinical Practice made a chilly start to the new year in Brussels even chillier, with its own assessment of whether Europe is a ready to cope with the challenge of an aging population for medical research.
The answer so far is not very satisfactory, suggested Jean-Marc Husson of Eudipharm, the cochair of the meeting. In his view, older people remain, in effect, another "orphan population" in respect to medicines, because data from older people rarely features in most current marketing authorization applications—and trials in the elderly are rarely carried out for anything other than degenerative diseases and bone disorders.
So far, only the European Commission and a few European countries—notably The Netherlands—are starting to respond by urging clinical trials in the aging population, in particular with an EU-funded project known as Predict, involving a group of geriatricians from the UK, Spain, The Netherlands, Italy, Poland, Lithuania, Romania, Israel, and the Czech € 750,000 funding from the EU's research program, focuses on increasing the participation of elderly in clinical trials.
The basic rationale of Predict is the fairly evident observation that while the elderly account for high drug consumption, they are underrepresented in clinical trials. And since it is essential to demonstrate the efficacy and safety of drugs for Europe's increasingly aging population, clinical trials need to take into account the relevant issues of this population, such as changed metabolism, multiple chronic conditions, and polypharmacy.
So Predict has set itself the task of investigating the reasons for the exclusion of the elderly in clinical trials—and, more ambitiously, of providing solutions for this problem. Its systematic literature review is examining the conditions that constitute barriers and promoters of clinical trials, its questionnaires are quizzing professionals who work with the elderly, and its focus groups area penetrating the thinking of older people and carers, particularly patients with heart failure, depression, diabetes, stroke or cancer. Meanwhile, it is working toward creating some sort of charter for the rights of older people in clinical trials.
Among its findings to date are the paradox that while heart failure is the most common cause of hospital admission in older people, trials for antihypertensives tend to focus on a much younger age group. According to Predict, 44% of patients with their first diagnosis of hypertension are aged 70 or above, but the mean age of patients in trials is 63.5 years, and trial participants have fewer cardiovascular risk factors, co-morbidities, and cardiovascular diseases than the general population. In fact only recently has evidence from trials been available, for the first time, for people over age 80.
The study's own surveys reveal almost unanimous agreement that difficulties arise for both prescribers and patients because of under-representation of older people in clinical trials for the medicines they commonly use. There is also wide agreement that there is no justification for exclusion from trials on age grounds alone, and that people with physical or mental health co-morbidities should not be excluded in protocols.
Research is needed specifically on older people as opposed to broad population studies. In addition, simple chronological age should not be used as a defining feature, since that fails to take into account the wide differences among the older population.
At the same time, some caution is recognized as necessary: Only those capable of giving informed consent should be invited to participate, and carers or family are not adequate proxies for that. And in Europe, with its checkered history still fresh in the memory of many, further sensitivities are necessary, because populations who have experienced political oppression in their lifetime can display concern at the possibility of being required to take part rather than being invited.
Pierre Baeyens of Belgium, the European president of the International Association of Gerontology and Geriatrics, pointed to another paradox. Although guidelines on studies in geriatrics have existed at international level—through ICH—since 1994, little notice has been taken of them. The guidelines, he noted, emphasize the need for special consideration for people over age 65, because of co-morbidity, concomitant drug-therapy, and the consequent risk of drug interaction. But, he went on, his review of 10 recently authorized new medicines revealed that they were tested in only very few, and rather active, older people, just over age 65.
Meanwhile, the ICH steering committee endorsed the concept of a question and answer document as a complement to its guideline. This proposed refinements such as taking account of the number and age distribution of expected elderly participants in a given indication and the criteria for selection, with special efforts to include those now classed as "very elderly." It also urged clinical study protocols that set out to evaluate specified risks and benefits of the drug in the elderly, including common co-morbidities and concomitant therapies.
As a consequence, the latest draft of the international rules now recommend using more than the minimum 100 geriatric patients required until now, and including patients aged at least 75, and patients with concomitant therapies and co-morbidities.
In parallel, suggested modifications to current practice are being formulated in Europe. For instance, to reflect the fact that what is now considered geriatric medicine is dealing with a much older age group than was the case until a generation or so ago, support is growing for replacing 65 with 80 in guidelines. To respond to the predominance of women in the elderly population (currently there are three women for each man at the age of 80), a majority of trial recruits should be women. Adequate representation should be ensured for frail people, such as those suffering significant weight loss or who can no longer get up easily out of a chair. And recruits should also be taking several medicines a day.
The European Medicines Agency was asked in 2006 for an opinion on the adequacy of guidance on the elderly regarding medicinal products for human use. Its review of existing European guidance documents and of a sample of recent European marketing authorizations revealed reasonable compliance with the established international norms. But it also raised questions about the adequacy of those norms, and there is support for updating the ICH guideline.
Husson is enthusiastic about taking account of the specific characteristics of elderly people during drug development, and also during daily use of authorized products. He underlined the stratification of ages in relation to co-morbidity and multiple therapies: in France people over age 65 take an average of 3.5 different drugs, and those over 75 take eight. Special attention should also be given to the analgesics, anti-inflammatories, anti-hypertensives, and anti-diabetics that are commonly used in elderly populations, he cautioned.
An industry perspective from Dr. Solange Corriol-Rohou of AstraZeneca, underlined the need to ensure that the population in the clinical trial program is representative of the target patient population. This can mean including patients across the entire spectrum of the geriatric population.
The risks of generalizing about the elderly were echoed by Professor Anthea Tinker, Professor of Social Gerontology at King's College, London. The lack of research on older people (especially very old) is practically and ethically unacceptable, especially when the results of studies are then applied to older people, she said. Any presumptions that older people are vulnerable and cannot take part in research should be discarded.
In addition to Predict, other age-related projects that the EU is funding include Tolerage (examining normalization of immune reactivity in old age, with backing of €7.7 million), Resolve (understanding nonregenerative repair to resolve chronic inflammation and achieve healthy aging, with a budget of €10.6 million), Mark-Age (a European study to establish biomarkers of human aging, with €11.9 million), and Why We Age (a road map for European research on molecular aspects of healthy aging, and has €490,000 in funding).
Beatrice Lucaroni of the Commission's research department likes to flourish the possibilities of funding for projects in the field of human development and aging research—some €2.5 billion over the last four years. Old people like to say that youth is wasted on the young. With so much attention now turning to trials in the elderly, it is unlikely that money is going to be wasted on the old.
Peter O' Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium