Older People In Clinical Trials Research Articles

Aspirin Use in Older People Highlights the Need for Improved Inclusion of Older People in Clinical Trials.

Aspirin Use in Older People Highlights the Need for Improved Inclusion of Older People in Clinical Trials.

Effect of gut microbiome modulation on muscle function and cognition: the PROMOTe randomised controlled trial

Studies suggest that inducing gut microbiota changes may alter both muscle physiology and cognitive behaviour. Gut microbiota may play a role in both anabolic resistance of older muscle, and cognition. In this placebo controlled double blinded randomised controlled trial of 36 twin pairs (72 individuals), aged ≥60, each twin pair are block randomised to receive either placebo or prebiotic daily for 12 weeks. Resistance exercise and branched chain amino acid (BCAA) supplementation is prescribed to all participants. Outcomes are physical function and cognition. The trial is carried out remotely using video visits, online questionnaires and cognitive testing, and posting of equipment and biological samples. The prebiotic supplement is well tolerated and results in a changed gut microbiome [e.g., increased relative Bifidobacterium abundance]. There is no significant difference between prebiotic and placebo for the primary outcome of chair rise time (β = 0.579; 95% CI −1.080-2.239 p = 0.494). The prebiotic improves cognition (factor score versus placebo (β = −0.482; 95% CI,−0.813, −0.141; p = 0.014)). Our results demonstrate that cheap and readily available gut microbiome interventions may improve cognition in our ageing population. We illustrate the feasibility of remotely delivered trials for older people, which could reduce under-representation of older people in clinical trials. ClinicalTrials.gov registration: NCT04309292.

Пожилые пациенты в рандомизированных клинических исследованиях: этические аспекты

Considering patients of elderly and senile age, pronounced discrimination continues to be observed, expressed in their insufficient inclusion or non-inclusion in randomized clinical trials. As a result, the clinical recommendations based on the results of such studies cannot be fully applicable to this category of patients. The problems of inclusion/non-inclusion of older people in clinical trials are numerous. The reasons for their occurrence and solutions affect, among other things, the ethical sphere. Compliance with basic ethical principles such as respect for persons, beneficence and justice should underlie the decision to include a patient in a study. In general, when evaluating these ethical principles from the point of view of the well-being of the entire population of elderly and senile patients, it is necessary to rethink the principles according to which this category of patients was excluded from clinical trials.

Inclusion of Older People Reflective of Real-World Clinical Practice in Cardiovascular Drug Trials.

BackgroundUnderrepresentation of older people in clinical trials remains. This study aimed to examine the inclusion of older people and associated safety and efficacy reports from clinical trials of new molecular entities for cardiovascular disease indications since commencement of the US Food and Drug Administration Drug Trial Snapshot (DTS) Program. The DTS provides concise information on participants included in clinical trials supporting US Food and Drug Administration approval of new drugs.Methods and ResultsA cross‐sectional analysis between January 1, 2015 and April 30, 2019 of DTS data including approval date, indication, number of trials and participants, age distribution, efficacy, and safety statements was conducted. Participation‐to‐prevalence ratio (PPR) was used to describe representation of older participants in trials relative to disease population. Efficacy and safety statements regarding age were compared with drug prescribing information. A total of 72 079 participants from 10 DTS reports were identified and 39 625 (55.0%) were aged ≥65 years old. Overall, 63.6% of cardiovascular disease DTS reports were representative of people aged ≥65 years old for specific cardiovascular disease conditions. Underrepresentation was observed in 4 DTS: 2 for heart failure (PPR 0.48 and 0.62), 1 for pulmonary arterial hypertension (PPR 0.72), and 1 for venous thromboembolism (PPR 0.38). Participants in clinical trials for new drugs for the treatment of atrial fibrillation (PPR 0.99 and 1.21) and hypercholesterolemia (PPR 0.84 and 0.97) were reflective of the older population for these diseases. An increased risk of adverse events in older participants was reported in 40% DTS safety statements but no differences were reported in the drug product information.ConclusionsDespite the fact that >60% of cardiovascular disease trial participants for new molecular entities included in the DTS program were representative of the older population in real‐world clinical practice, concerns remain for conditions including heart failure or venous thromboembolism. Drug product information safety statements regarding age differences in adverse events were not reflective of trial findings. An increased directive is needed to facilitate the generation of real‐world evidence and appropriate reporting within drug product information for these potentially at‐risk patient populations.

Patients' preferences and existential perspective: what to consider and how should patient's expectations be guided?

With an ageing population, surgical procedures in older patients are becoming increasingly more common. This can pose clinical and ethical dilemmas, during which clinicians need to make complex decisions. In this paper we discuss the importance of assessing mental capacity to assess if the older patient can make his or her own decisions relating to surgery. We also discuss the importance of understanding ethical principles, in order that clinicians can better guide patient's decision-making. In addition, we look at ageism, frailty, and co-morbidities, and their influence on clinician's decisions regarding surgery in older patients. Further to this, we look at the influence of evidence-based medicine on treatment options, and the under representation of older people in clinical trials and the importance of this. Finally, we consider the importance of considered decisions regarding resuscitation, when considering surgical intervention in older patients. We conclude that patient-centred individualised care, considering patients expectations, wishes, and priorities is vital, whilst aiming to improve or maintain quality of life, and minimise risks when able.

A survey of geriatric expertise in medicines evaluation at national regulatory agencies in Europe: There is still room for improvement!

We investigated geriatric medicine input in national regulatory medicine licensing agencies across Europe, focusing on changes occurred since a previous survey published in 2011. A questionnaire was mailed to 22 national regulatory agencies in 2014. Four reminders followed: 16/22 (73%) answered. Currently only one agency (6%), i.e. the Swedish Medicines Authority, has a specific committee to evaluate medicines for older people, while previously, 2/21 agencies (10%) had a specific committee to assess medicines used by older people. The Swedish and Dutch regulatory agencies (13%) have binding policy on how to assess medicines for older people. On the other hand, nine national agencies (56%) follow external policies for the evaluation of geriatric medicines. Six agencies (38%) follow a policy concerning the inclusion of older people in clinical trials. Eight agencies (50%) have at least one geriatrician on their medical advisory boards, although this position is permanent at only three of them. Twelve agencies (75%) have access to ad-hoc geriatric advice. Compared to the previous survey, 6/21 agencies (28%) had a geriatrician on their medical advisory boards and 10/21 (48%) agencies provided for ad-hoc input of geriatricians into advisory board discussions. Finally, three regulatory authorities (19%), involve geriatricians in research on drug prescription in older people. This survey demonstrates that, despite some improvement from the previous investigation, there is still a need for promoting a greater involvement of geriatric expertise in medicines evaluation across Europe.

Participation of older people in preauthorization trials of recently approved medicines.

To investigate the inclusion of older people in clinical trials of recently authorized medicines, evaluating adherence to the 20-year-old International Conference of Harmonisation (ICH) guideline on geriatrics (E7). Observational. European public assessment reports, published clinical trials, World Health Organization International Clinical Trials Registry Platform. Individuals aged 65 and older and 75 and older. Number and proportion of randomized participants and all exclusion criteria of studies involving diseases characteristically associated with aging (venous thromboembolism, osteoporosis, atrial fibrillation) and diseases not unique to older adults (type 2 diabetes mellitus, depression, bipolar disorder, epilepsy). In 114 Phase II and III trials of 12 medicines, 43.1% of participants were aged 65 and older, and 16.1% were aged 75 and older. In trials involving diseases characteristically associated with ageing, 57% were aged 65 and older; 22% were aged 75 and older. In trials involving diseases not unique to old age, 9% were aged 65 and older, and 1% were aged 75 and older. Upper age limits were applied in 30.7% of the trials; the frequency did not differ between larger (sample size ≥ 500) and smaller trials (P = .36), although it was significantly lower in trials involving diseases characteristically associated with aging (18.0%) than in trials of diseases not unique to old age (45.3%; P = .002). Age-sensitive exclusion criteria, based on comorbidity (75.4%), concomitant medication (71.9%), and other criteria correlated with age (60.5%) were applied more frequently in larger trials (P < .02). Studies of diseases not uniquely associated with old age included an unacceptably low proportion of older people, contrary to the recommendations of the ICH E7 guideline. Although the proportion of older participants in trials of diseases characteristically associated with aging was appropriate for certain medicines, the use of age-sensitive exclusion criteria limits the representativeness of the trial population for daily practice.

Geriatric clinical pharmacology and clinical trials in the elderly

The aging process is linked to changes in the physiological function of organs and changes in body composition that alter the pharmacokinetics of drugs and pharmacodynamic responses. Comorbidity and polypharmacy in the elderly decreases tolerability of drugs, leading to greater vulnerability to adverse drug reactions than that observed in younger adults. In geriatric pharmacotherapy, the general recommendation is dose reduction and slow titration, which is based on pharmacokinetic considerations and concern for adverse drug reactions, rather than clinical trial data. Older patients are under-represented in clinical trials. In the absence of evidence, extrapolation of risk–benefit ratios from younger adults to geriatric populations is not necessarily valid. Sound evidence through prospective clinical trials is essential, and geriatric societies, governments, and patient advocacy groups should collaborate to promote the inclusion of older people in clinical trials. It is believed that all involved in clinical trials have both an obligation and an opportunity to eliminate age discrimination in clinical trial practice.

Appropriate prescribing in older people

SummaryPrescribing for older people is often complex and challenging. With age, people almost invariably develop diseases leading to the prescription of drugs and the risk of multiple prescribing increases, especially if there is strict adherence to single disease guidelines. There remains a paucity of evidence from clinical trials as to the efficacy of many drugs in patients aged over 80 years due to the gross under-representation of older people in clinical trials. Older people are also at increased risk of adverse drug events, which are an important cause of morbidity and mortality. A significant percentage of these are both predictable and potentially avoidable.In this updated review the concept of appropriate prescribing in older people is explored, including the importance of individualized care and shared decision-making. The available tools to enhance prescribing practice are examined, including those aimed at reducing inappropriate prescriptions and under prescribing. The limitations of existing tools are discussed and areas with particular promise and scope for advancement are highlighted, including the development of integrated IT systems and software engines to aid clinicians in appropriate prescribing.

Age-adjusted reference values could be used for screening healthy older people in clinical trials

Healthy adults are generally recruited for first-in-human clinical trials. However, their inclusion/exclusion criteria are not easily applied to trials for the elderly. Reference values were modified by 10–20% in screening tests to investigate the usefulness of the age-adjusted inclusion/exclusion criteria. Seven items were modified, including fasting blood sugar (FBS) and systolic blood pressure (SBP). Of the 28 screening failures, modified FBS caused 11 screening failure cases with no concomitant medication. Elevated SBP affected few concomitant medication cases in the middle-aged. Age-adjusted reference values maintained the inclusion/exclusion criteria of healthy elderly Korean participants by rendering the concomitant medication issue clinically insignificant.

Exclusion of Older People from Clinical Trials

There has been concern about under-representation of older people in clinical trials. The PREDICT study reported that older people and those with co-morbidity continue to be excluded unjustifiably from clinical trials. However, there is no information about differences of opinion on these issues between EU countries. The results of a survey of health-related professionals from nine EU countries that participated in the PREDICT study are presented in this study. The aim of the study was to identify and examine any differences of opinion between EU countries on the inclusion of older patients in clinical trials. A questionnaire using a Likert scale and free text was completed by 521 general practitioners, geriatricians, clinical researchers, ethicists, nurses and industry pharmacologists/pharmacists. The questions explored the impact of the present situation, possible reasons for under-representation and potential methods of improving participation. Countries participating were the Czech Republic, Israel, Italy, Lithuania, the Netherlands, Poland, Romania, Spain and the UK. There was agreement that exclusion from clinical trials on age grounds alone was unjustified (87%) and that under-representation of older people in trials caused difficulties for prescribers (79%) and patients (73%). There were national differences between professionals. All but the Lithuanians believed that older people were disadvantaged because of under-representation. The Czech, Lithuanian and Romanian professionals felt that it was justified to have age limits based on co-morbidity (61-83%) and polypharmacy (63-85%). Romanians also thought that having age limits on trial participation was justified because of reduced life expectancy (62%) and physical disability (58%) in older people. All but the Romanian professionals felt that the present arrangements for clinical trials were satisfactory (62%). All but the Israelis (56%) and Lithuanians (70%) agreed that regulation of clinical trials needed alteration. Although respondent selection bias cannot be excluded, the differences that emerged between countries may be the result of the political and healthcare-system differences between older and newer members of the EU. These differences may influence decision making about clinical trial regulations and practice in older people.

Fighting Against Age Discrimination in Clinical Trials

At the American Geriatrics Society 2008 Annual Meeting, representatives of two geriatric societies, the European Union Geriatric Medicine Societies and the American Geriatrics Society, and two regulatory agencies, the U.S. Food and Drug Administration and the European Medicine Agency, conducted a roundtable discussion aimed at reviewing the participation of older people in clinical trials. This article summarizes the important issues discussed at the meeting. Historically, regulatory agencies started to promote the inclusion of older participants in clinical trials in the late 1980s. The identification of the causes of delay in including older participants in clinical trials, as well as of the ongoing bias against including older participants with multiple comorbidities, is important to help geriatricians fight against age discrimination in clinical trials. To overcome this problem, geriatrics societies and regulatory agencies must work together to propose new definitions, study designs, and technologies aimed at improving the evaluation of drugs in older people with multiple comorbidities and polypharmacy.

Factors influencing the participation of older people in clinical trials - data analysis from the MAVIS trial.

Older people are less likely to be included in clinical trials. Little is known about factors influencing older people's decisions about participating in clinical trials. To examine the views of older people about participating in clinical trials. Postal questionnaire to 801 participants who had completed the MAVIS nutrition trial, aged 65 yrs and older. Closed and open questions sought participants' views about factors important to them when deciding to take part in a trial, features of the MAVIS trial they liked and disliked and changes they would suggest. 540 (59% of MAVIS trial participants) returned the questionnaire. The most important reasons reported for taking part in the trial were helping the research team and medical knowledge, and helping other older people. Participants valued good communication with the trial staff and good organisation. Participants reported concerns about swallowing pills and taking a placebo. Participants reported that future participation in trials could be influenced by poor health status. This questionnaire surveyed older participants who had taken part in a randomised controlled trial. It did not elicit the views of people who had withdrawn or never decided to take part in the trial. Older people report altruistic reasons for taking part in trials. Simple trial designs, which minimise demands on participants and maintain good communications should be preferred. Explaining the need for older people, despite poor health, to participate in trials may help the generalisability of clinical trials.

The under-representation of older people in clinical trials: barriers and potential solutions.

Frail older people are still under-represented in clinical trials. The evidence-base for clinical decision-making in this age group is poor even though older patients are the core business of health services. We examine possible causes for the exclusion of older people from clinical trials and propose possible solutions for this unjust and inequitable situation. Some progress has been made but more needs done to ensure equality and uniformly high standards of health care for older people.

What's different about older people.

Older people can be regarded as a marginalised group within society from a number of perspectives including that of health. When it comes to the use of medication older people have suffered from a double whammy. Not only are they more at risk from the adverse effects of drugs but also their involvement in clinical trials has been limited so that rational prescribing both to maximise benefit and to reduce risk has been problematic. Their special problems have been recognised formerly by the Department of Health in its NSF for Older People [National Service Framework for Older People. Department of Health, London (2001a)], [Medicines and Older People. Implementing medicines-related aspects of the NSF for Older People. Department of Health (2001b)]. Early studies focussed on compliance, the avoidance of poly-pharmacy and the high prevalence of adverse effects of drugs and the reasons for this. Studies in long-stay patients showed dramatic differences in pharmacokinetics between such older people and young healthy volunteers. Initially such differences were ascribed to age alone and the overall message became "start low and go slow". Studies in healthy older people then revealed that age differences in drug metabolism were, as a rule, not so marked although clearance of renally excreted drugs was reduced in line with the age associated decline in renal function. Including older people in clinical trials poses challenges. Many traditional trialists do not have ready access to older people, co-morbidity and poly-pharmacy are common and most people feel reluctant to ask older people to take part in complex and potentially hazardous trials. Concern about compliance is unwarranted. Adverse events may be more serious. Thus in a younger patient postural hypotension may make a subject unsteady but in an older subject the unsteadiness may lead to a fall, the fall to a fracture, and the fracture to poor recovery. The choice of end-points is crucial. Although reduction of clinical events is clearly important, effects on quality of life become more important as natural life expectancy reduces. Although regulatory bodies state that they now evidence of effectiveness in older people before registration there are still many examples of arbitrary and illogical upper age limits in clinical trials.