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Older people and clinical trials

Older people and clinical trials . Gary Mills Consultant in Anaesthesia and Intensive Care Med, Sheffield Teaching Hospitals Hon Professor of Critical Care Med and Perioperative Medicine, Sheffield University. Summary. The extent of the problem Exclusion from clinical trials PREDICT

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Older people and clinical trials

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  1. Older people and clinical trials Gary Mills Consultant in Anaesthesia and Intensive Care Med, Sheffield Teaching Hospitals Hon Professor of Critical Care Med and Perioperative Medicine, Sheffield University

  2. Summary • The extent of the problem • Exclusion from clinical trials • PREDICT • Charter • Perioperative period • Critical care and older people

  3. Administration on Aging. A Profile of Older Americans: 2007. Washington, DC: United States Department of Health and Human Services. 2007

  4. Numbers of different medications in use in a study of 700 >75 year olds Looked in survivors over a 5 years period Average number of medications increased from 6.3 to 7.5 > 5 medications: increased from 54-67% >10 medications increased from 19-28% Polypharmacy is common Polypharmacy is increasing

  5. These issues led to the 9 EU nation “increasing the PaRticipation of ElDerly In Clinical Trials PREDICT” project • WP 1: Is there evidence of exclusion of older people in clinical trials and is this the case in current trials? • WP 2: The opinions of professional across Europe? • WP 3: How do patients and carers feel about exclusion/inclusion of older people? • WP4: Combining the information above into a Charter to promote appropriate inclusion of older people in clinical trials.

  6. Work Package 1 EC project no: HEALTH-F4-2008-201917 What evidence is there that the elderly have been excluded from clinical trials?

  7. Methods: search strategy

  8. Results

  9. SIMVASTATIN Age distribution in patients receiving simvastatin (black - trial population, grey - consumer population, white - consumer with adverse reaction population). Martin K, Begaud B, Latry P, Miremont-Salame G, Fourrier A, Moore N. Differences between clinical trials and postmarketing use. Br J Clin Pharmacol 2004; 57(1):86-92.

  10. CANCER Cancer Research UK. UK Bowel Cancer incidence statistics. 2007.

  11. BOWEL CANCER Trimble EL, Carter CL, Cain D, Freidlin B, Ungerleider RS, Friedman MA. Representation of older patients in cancer treatment trials. Cancer 1994; 74(Suppl 7):2208-2214.

  12. Colorectal cancer • Incidence (Cancer Research UK 2007) • 60% new cases aged 70+ • 44% new cases aged 75+ • Chemotherapy in advanced disease • systematic review 1992-2001(Jennens et al. 2006) • 94 trials including 29,148 patients • median age 62.2 years • Australia cancer registry • median age 70.2 years Jennens et al. Increasing underrepresentation of elderly patients with advanced colorectal or non-small-cell lung cancer in chemotherapy trials. Intern Med J 2006; 36:216-220.

  13. Alzheimer’s disease The most common form of dementia Over 7 million people in Europe Projected 16.5 million by 2050 Brookmeyer et al. Forecasting the global burden of Alzheimer's disease. Alzheimer's and Dementia 2007; 3(3):186-191.

  14. Alzheimer’s disease • Age specific incidence rates (Kukull 2002) 65-69 2.8 (1.0, 8.2) 70-74 4.4 (2.6, 7.4) 75-79 7.8 (5.2, 11.6) 80-84 27.5 (21.2, 35.7) 85-89 41.9 (30.5, 57.6) 90+ 56.1 (34.7, 91.2) • Cochrane review cholinesterase inhibitors (Birks 2006) Mean age in RCTs 74.1 years

  15. Other conditions • Older people have been under-represented in clinical trials • Heart failure (Badano 2003, Costantino 2009) • Alzheimer’s disease • Cancer (Jennens 2006, Trimble 2004, Stewart 2007) • Cardiovascular disease (Bartlett 2001) • Hypertension (Uijen 2007) • Parkinson’s disease (Mitchell 1997) • Depression (Giron 2005)

  16. WP 1 Conclusions • under-representation of older people in trials of treatments in a range of conditions. • little work has been published on the application of potential methods to improve trial participation in older people.

  17. Equipoise and balance • Too little information • Concerns about risks of placebo • Desire to be in treatment arm • Too much commitment • Extra blood tests • Too much information • Concerns regarding risk of treatment • Desire to be in placebo arm • Not serious enough a condition

  18. Future needs • Studies on how to help patients enter studies • Time • Simpler, clearer explanation • Better study design • Appropriate recognition by funding bodies • Studies on how to keep patients in studies • Carers

  19. Figure 2: Reluctance to recruit 1 Of their high rates of co-morbidity 2 Of their high rates of polypharmacy 3 Of cognitive disability 4 Adverse events rates may be higher 5 It requires more time for patient recruitment and/or assessments 6 Of physical disability 7 Of the difficulty in recruiting older people 8 Of their short life expectancy 9 Older people are more likely not to comply with trial requirements 10 Older people may be more likely to refuse consent 11 Of lack of interest from older people in participating

  20. Conclusions • Over 70% agree that not having enough older people in clinical trials resulted in difficulties for older patients • 87% believe that excluding people on age grounds alone was unjustified. • Country differences: Czech, Lithuanian and Romanian professionals felt that exclusions based on comorbidity were justified

  21. Why not take part in trials on epilepsy? Study factors Patient factors Elderly people might be unaware of the importance or availability of clinical trials the complex consent procedures required for participation can deter older individuals some elderly patients might have cognitive impairment, which can make it difficult (but not impossible) to obtain informed consent Families or carers might be unwilling to allow participation transportation and mobility problems can be a hindrance • comorbidities that increase the risk of unexpected events • taking multiple medications • increases the potential for drug–drug interactions. • age-related changes in body composition and physiology • elderly patients’ pharmacodynamics might be different from those of younger patients, leading to a • perception that, in very elderly patients, extra years of life are not worthwhile • use of drugs or procedures shown to be beneficial in younger patients might be futile. Neurology in the elderly: more trials urgently needed www.thelancet.com/neurology Vol 8 November 2009 p969

  22. In oncology • Age: Only ¼ of eligible older patients enrolled • Physicians perceptions • Protocol eligibility criteria: with restrictions on comorbid conditions, functional status to optimise treatment tolerability • Lack of social support • Need for extra time and resources to enroll patients Systematic Review (31 eligible papers) of Barriers to the Recruitment of Older Patients With Cancer Onto Clinical Trials C A Townsley, R. Selby, LL Siu. J ClinOncol 2005: 23 3112-3124

  23. Opinions of patients and carers • “A body at 40 years old reacts in a certain way to a drug, at 60 years old, the body has another reaction and at 80 years old or above, another one. Drug intake depends on the body and age.” (Pilot Group, Romania). • Older persons have to participate in clinical trials since they are affected from more than one disease at the same time”. (Diabetes Group, Italy)

  24. Exclusion • “Please don’t treat us as though, you know, “It’s time you’re gone.” (Carers Group, UK) • “It looks like that the best thing is that older persons rapidly die. After a certain age, adult and young people start to neglect or leave us aside. This is unfair!” (Depression Group, Italy)

  25. Involvement • “However, I would like to know if what we are saying here today is not going to end up in a trash bin?” (Pilot Group, Poland). • “You take part in it, but you don’t even know how this investigation is developing. You don’t know if it’s going somewhere or not.” (Stroke Carers Group, Spain).

  26. The future • “When you are in research it is not yet certain that the medicine is beneficial or not and therefore it is in the stage of research. In the short run the profit is not mine personally, in the long run the profit is to the general population." (Pilot Group, Israel) • “We all should support research because it helps others.” (Pilot Group, Czech Rep.) • “It is not so important for us: it is more important to attempt for the grandchildren, for the future generations.” (Hypertension Group, Lithuania)

  27. How the Charter developed • The results of WP1, 2 and 3 were combined into a European Charter. • designed to improve the participation of older people in clinical trials. • This was then discussed before a large expert audience (BMA House, in London, UK in 2010). • Comments and suggestions from the panels and the audience were incorporated into the the Charter.

  28. Realistic Evidence • Avoid Discrimination • Practical • Safety • Relevant Outcomes • Values

  29. Multiple Languages

  30. Help with how to run clinical trials will be aided by • “Medical research for and with older people in Europe proposed guidance for ethical aspects” • (http://archive-be.com/page/76183/2012-07-06/http://www.efgcp.be/%5Cdownloads%5CEFGCP%20Geriatric%20Research%20Guidelines%20Feb.2012%20for%20public%20consultation.pdf), • which is being produced by the European Forum for Good Clinical Practice.

  31. Intensive Care Admissions

  32. Elective and Emergency Surgery admissions to Critical Care • Study of 88504 patients • Unit mortality of 7.6% and a hospital mortality of 11.8%. • pre-existing chronic renal (OR 1.40), • respiratory (OR 1.20) • cardiac failure (OR 1.29), • acute kidney injury (OR 1.88) • Age OR 1.42 per 10 years of age

  33. Are we collecting the right data? • Appropriate outcomes • Need to be more informative than just 30 day survival • Are we collecting the right data

  34. Frailty and mortality on the ICU

  35. Frailty and mortality on the ICU

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