Older people and clinical trials

Gary MillsConsultant in Anaesthesia and Intensive Care Med, Sheffield

Teaching HospitalsHon Professor of Critical Care Med and Perioperative

Medicine, Sheffield University

Summary

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

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

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

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.

Work Package 1

What evidence is there that the elderly have been excluded from clinical trials?

EC project no: HEALTH-F4-2008-201917

Methods: search strategy1 patient selection/ (29217) 2 selection bias/ (2353) 3 prejudice/ (15942) 4 under represent$.tw. (1105) 5 underrepresent$.tw. (1951) 6 represent$.ti. (13007) 7 (discriminat$ adj5 age).tw. (758) 8 (exclud$ adj25 (older or elderly)).tw. (1477) 9 exclusion criteria.tw. (3887) 10 (entry criteria adj25 (elderly or older)).tw. (24) 11 (select$ adj (older or elderly)).tw. (357) 12 (nonenrol?ment or non-enrol?ment).tw. (30) 13 enrol?ment.ti. (857) 14 (participation adj25 (elderly or older)).tw. (1183) 15 participat$.ti. (16295) 16 or/1-15 (86021)

17 exp Clinical Trials as Topic/ (196808) 18 trials.tw. (177858) 19 randomi$.tw. (206575) 20 clinical studies.tw. (36140) 21 clinical trial.tw. (42547) 22 or/17-21 (505814) 23 16 and 22 (9409)

24 exp Aged/ (1660420) 25 elderly.tw. (112175) 26 ((old or older) adj2 age$).tw. (38873) 27 ((old or older) adj2 (adult$ or patient$ or people or subject$)).tw. (81567) 28 or/24-27 (1725928)

29 23 and 28 (2481)

Clinical trials

Under-representationOlder people

Results

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.

SIMVASTATIN

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

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.

BOWEL CANCER

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.

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.

• 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

Alzheimer’s disease

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)

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.

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

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

It is justified to have an upper age limit at the protocol design stage of a clinical trial…….

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Figure 1: Justification of upper age limit 1 Because of high rates of polypharmacy 2 Because of high rates of co-morbidity 3 Because adverse events are more common 4 Because of cognitive disability 5 Because relatives might not agree or might be concerned regarding the inclusion of older family members 6 Because of high drop-out rates 7 Because of reduced life expectancy 8 Because of physical disability 9 Because it is often difficult to obtain informed consent 10 Because results in younger people (under 65 years) can be extrapolated to older people 11 On age grounds alone

If no upper age limit is stated in the protocol, clinicians recruiting patients to a trial may still be reluctant to recruit older people

because…….

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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

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

Why not take part in trials on epilepsy?

Study factors• 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.

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

Neurology in the elderly: more trials urgently needed www.thelancet.com/neurology Vol 8 November 2009 p969

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 Clin Oncol 2005: 23 3112-3124

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)

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)

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).

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)

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.

Realistic Evidence

Avoid Discrimination

Practical Safety Relevant

Outcomes Values

Multiple Languages

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.

Intensive Care Admissions

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

Are we collecting the right data?

• Appropriate outcomes• Need to be more informative than just 30 day

survival• Are we collecting the right data

Frailty and mortality on the ICU

Frailty and mortality on the ICU

Data

• We must collect the right data• Must include appropriate outcomes• This was apparent to CEPOD

Partidge JSP, Harari D, Dhesi JK. Frailty in the older surgical patient

Knee joint and primary hip replacement surgery, which ispredominantly performed on patients over theage of 65, has been found to be ‘highly costeffective’22 even for patients who have mildor moderate knee arthritis. Despite this, theyare procedures that have been categorised as‘effective interventions with a close benefit orrisk balance in mild cases’ where eligibilityis likely to be narrower than in the past.23

As a result, a number of primary care trustshave revised their policies on hip and kneereplacement to reflect a low-priority procedureclassification.24 This will disproportionatelyaffect older people.

In the new commissioning world, post April 1st

All areas• Good evidence based clinical care must include older people• We need good data to audit and explain appropriate costs

and appropriate outcomes• Research needs to include older people• Not just drug trials• Need to consider all areas of care• Surgery• Design and staffing of wards• Design of our processes must be age and carer friendly• Aftercare