Drug safety evaluation in geriatrics

By

Prof. Satish Sharma, Dean, School of Pharmacy

Background Elderly population is increasing worldwide.

In India, the size of the elderly population is fast growing, from

5.6 per cent in 1961 it is projected to rise to 12.4 per cent of

the population by the year 2026.

With an increasing share of population in this age group, it is

natural to expect an increase in the problems associated with

them as well

It is estimated that one out of two elderly in India suffers from

at least one chronic disease which requires life-long

medication. It is reported that use of medications has

increased significantly among the elderly in the last decade

Background Conducted studies have revealed a high prevalence of irrational

use of drugs among Indian elderly

Polypharmacy is common among elderly patients

In spontaneous reporting studies there is a higher probability of

lack of identification and under-reporting of ADRs due to various

reported factors

Avoidable adverse drug events (ADEs) are the serious

consequences of inappropriate drug prescribing

Premarketing drug trials often exclude geriatric patients and

approved doses may not be appropriate for older adults

Medication use by older people

Prescription medications

Over-the-counter medications

Herbal medications

Herbal medicines may interact

with prescribed drug therapies

and lead to adverse events

dietary supplements

Medication use by older people

Caring for older people

Need for adequate representation of geriatric patients

Geriatric patients can respond differently from younger

patients to drug therapy, and such differences can be

greater in patients 75 years and older:

The geriatric population has age-related physiological

changes that can affect the pharmacokinetics of the drug and

the pharmacodynamic response to the drug, both of which

can influence the drug-response and the dose response

relationship

Geriatric patients are more prone to adverse effects since

they often have comorbidities and are taking concomitant

therapies that could interact with the investigational drug

Factors to be considered for adequate representation of geriatric patients

It is very important to ensure, to the extent possible, that the

population included in the clinical development program is

representative of the target patient population.

As stated in the current ICH E7 guidance, estimates of the

prevalence of the disease to be treated by age or examination of

the age distribution of usage for other drugs of the same class or

for the same indication should be provided by the applicant

In the marketing application, depending on the numbers of

patients, data should be presented for various age groups (for

example <65, 65-74, 75-84, and > 85) to assess the consistency

of the treatment effect and safety profile

Consideration for special population in the planning of the clinical development program

Geriatric patients often have co-morbidities and concomitant

therapies that could interact with the investigational drug and

make patients more likely to have undesirable effects and

interactions.

Therefore, it is important to assess the safety and efficacy of a

drug in such patients and to design a study with

inclusion/exclusion criteria that allow their participation.

There may exist a reluctance to include vulnerable geriatric

patients at high risk of adverse outcomes (so-called “frail”

geriatric patients). However, care in randomization should allow

the appropriate attribution of findings either to the investigational

drug or to other factors

Clinical development program for safety and efficacy of a drug

An appropriate representation of the geriatric population

(including patients with concomitant therapies and co-

morbidities) should be enrolled in the clinical development

program to adequately characterize efficacy and safety in the

geriatric population and allow for comparisons with the

nongeriatric population. This information would ordinarily be

expected in a marketing application

It is preferable to include both nongeriatric and geriatric patients

in the same study(ies), which can facilitate observation of age-

related differences

In some cases, a separate study in the geriatric population can

be preferable

Clinical development program for safety and efficacy of a drug

Clinical development program for safety and efficacy of a drug

Every effort should be made to include geriatric patients using

concomitant therapies and with co-morbidities in the

premarketing clinical development program.

In some cases, enrollment of these patients can be challenging

and it could be appropriate to collect data postmarketing

Where enrollment of geriatric patients has been insufficient

despite the efforts of the applicant, a specific plan to collect data

postmarketing should be discussed during development and

presented in the marketing application.

Information relevant to the geriatric patient population, including

any limitations, should be reflected in the product labeling.

Special consideration in the planning of the

clinical studies

Depending on the mechanism of action of the drug and/or the

characteristics of the disease, certain specific adverse events

and age-related efficacy endpoints should be actively sought in

the geriatric population, e.g., effects on cognitive function,

balance and falls, urinary incontinence or retention, weight loss,

and sarcopenia

This may require specific testing, e.g., for cognitive function.

Applicants should also refer to disease specific guidance for

specific recommendations concerning the evaluation of both

efficacy and safety in geriatric patients

Special consideration in the planning of the

clinical studies

The pharmacokinetics in geriatric patients (over the entire

spectrum of the geriatric patient population) should be evaluated

to identify age-related differences that are not explained by other

factors such as reduced renal function or weight differences

The potential influence of impaired renal/hepatic function, as well

as potential drug interactions, is often assessed in studies with

nongeriatric subjects

Population pharmacokinetic analysis could provide the requested

data if a sufficient number of patients in different age ranges

(including patients >65 and >75 years) are included in the clinical

trials

Quality measures of drug prescribing

Avoidance of inappropriate medications

Appropriate use of indicated medications

Monitoring for side effects and drug levels

Avoidance of drug-drug interactions

Involvement of the patient and integration of patient values

Quality measures of drug prescribing

Educational interventions,

Peer comparison feedback,

Computerized order entry and decision support

Multidisciplinary team care led by physicians, clinical

pharmacists, and combinations of these approaches

Polypharmacy

Polypharmacy is defined simply as the use of multiple

medications by a patient.

The issue of polypharmacy is of particular concern in older

people who, compared with younger individuals, tend to have

more disease conditions for which therapies are prescribed

The use of greater numbers of drug therapies has been

independently associated with an increased risk for an adverse

drug event (ADE), irrespective of age, and increased risk of

hospital admission

Polypharmacy

Impact of polypharmacy

Older individuals are at greater risk for ADEs due to metabolic

changes and decreased drug clearance associated with aging;

this risk is compounded by increasing numbers of drugs used.

Polypharmacy increases the potential for drug-drug interactions

and for prescription of potentially inappropriate medications

Polypharmacy was an independent risk factor for hip fractures in

older adults in one case-control study, although the number of

drugs may have been an indicator of higher likelihood of

exposure to specific types of drugs associated with falls (eg,

central nervous system [CNS]-active drugs