Considerations When Designing Studies for Elderly Populations

by Mark Bush, Ph.D.

The aging of the American population has resulted in an increased interest in developing drugs for elderly patients.  A key principle of drug development is that drugs should be evaluated in all age groups for which they will have significant utility. As such, FDA has issued guidelines for the development of drugs that are likely to be used in elderly patients.  These guidelines are similar to those for pediatric patients.  One key difference is that older subjects can typically offer their own consent.

Safety and Tolerability

A key aspect of drug development is characterizing the safety and tolerability profile of a drug in the target patient populations. The elderly population is often at greater risk of adverse events than younger patients. When studying the elderly population, it is important to ensure that enrolled patients reflect the target population being studied rather than an idealized group with an atypically low risk of adverse events (AEs). This does not mean that all elderly subjects are acceptable candidates for a clinical study simply because they are elderly.  It can be quite reasonable to restrict enrollment of elderly subjects with unstable medical conditions. For example, it is common to exclude patients with recent cardiovascular events. In contrast, enrolling patients with prior cardiovascular events may be acceptable if they have been stable for a certain period of time.

Researchers may be anxious about enrolling older participants in drug studies due to increased risk of adverse events or mortality. However, there is nothing magical about a particular age. A healthy 75-year-old may not be impacted by a particular drug as much as an ill 50-year-old or someone of any other age. Instead, it is the physiology of the participant that counts.  Careful consideration of inclusion and exclusion criteria will help ensure that the study population is reasonably representative, while also being clinically stable.

Pharmacokinetic Changes

The natural aging process is associated with multiple factors that can alter the pharmacokinetic (PK) behavior of drugs.  These changes include altered body fat, altered total body water, declining renal function, drug-drug interactions, and drug-disease interactions.When a drug is intended for use in the elderly, it is important to understand how these factors can alter the key PK processes (absorption, distribution, metabolism, and excretion) and, as a result, a drug’s safety, tolerability, and efficacy profile.

PK changes are more common as we age than pharmacodynamic (PD) changes.  As a result, studies should focus on identifying factors associated with clinically relevant changes in a drug’s PK profile. Frequently, a population PK (popPK) assessment can be used to screen for identifying factors in the elderly population associated with meaningful alterations in PK.

Differences in the safety, tolerability, or efficacy profile in elderly subjects may actually be the result of altered PK.  For example, reduced renal function may be associated with increased drug concentrations and a resultant increase in adverse events.  Alternatively, a drug-drug interaction may cause decreased drug exposure and an associated loss of efficacy.  Using popPK as a screening tool can frequently provide insight into factors that necessitate dosage adjustments in the elderly population to maintain the appropriate balance between efficacy, safety, and tolerability.

Pharmacodynamics/Efficacy

Assessing PD changes in elderly patients can be much more challenging than assessing PK changes. Many drugs have poor dose-response information available from the general population. This can make it quite difficult to confirm altered dose-response in elderly patients.  Certain endpoints are more amenable to PK/PD assessment, such as blood pressure, heart rate and blood glucose. In these cases, robust dose-response information may be available allowing for a more informative comparison with elderly patients.  Other PD endpoints, such as depression and anxiety, are not as easily quantified.  As such, it may be difficult to detect differences in dose-response in elderly subjects.  As discussed previously, when PD differences are detected in elderly patients it is important to remember that these differences may be related to PK alterations rather than true differences in pharmacologic response.   A thorough evaluation of PK changes may provide important insight into the root cause for PD changes.

Dedicated Studies in Elderly Subjects

When a drug is to be used in a broad population (young and elderly), it may be optimal to include younger and older subjects in the same trial. This approach allows for within-study comparisons of the different age groups. However, dedicated studies in elderly subjects will likely be needed for drugs targeted specifically to elderly subjects.

Given the physiologic changes associated with aging, studies will frequently be performed to evaluate the effects of renal impairment, hepatic status, concomitant illness and concomitant medications, all of which are more likely among elderly participants. When studying the effects of these factors in elderly subjects, we are looking for relatively large effects or differences that are clinically relevant (not simply statistically significant).  Large effects in terms of drug/disease and drug/drug interactions may be detected using a pop PK approach.   Frequently, popPK can also be used to screen for high-risk drug interactions with drugs that are more likely to be used in an elderly population (e.g., digoxin and warfarin).

Dedicated PK studies can be the best approach for detecting clinically relevant alterations in PK for drugs having a narrow therapeutic index (~2-fold range between efficacious and toxic concentrations), drugs with a high likelihood of concomitant disease or concomitant drug interactions.

 

Are you designing a study aimed at the elderly population? Contact us today to speak with one of our senior consultants.