Is Age Just a Number? Clinical Drug Development in Older Adults
Sabina Paglialunga, PhD Director, Scientific Affairs
What Makes Older Adults So Special?
Older adults, defined as 65 years of age and up, currently represent ~17% of the general US population and is expected to rise to one-fifth of the population by 2030. Considered a ‘special population’ in the drug development, older adults may hold a greater risk of adverse drug effects due to multiple comorbidities and polypharmacy. A CDC study found that 64% of older adults have two or more chronic conditions, and an estimated 30-35% of older adults take 5 or more prescription medications, which increases the risk of drug-drug interactions. Furthermore, during clinical development safety signals in older adults may differ from younger counterparts. Special attention should be paid to signs of dizziness, delirium, osteoporosis, falls, sedation, bleeding, urinary retention, and loss of appetite.
Ageing and Drug Metabolism
Ageing can significantly affect drug metabolism. A classic example is the reduction in glomerular filtration resulting in lower kidney function typically observed with increasing age, which may require drug dose adjustment for some medications. Other physiological changes include reduced drug absorption; a decrease in muscle mass and increased adiposity can affect drug distribution; as well as lower phase I and phase II enzyme capacity can result in metabolism alterations. Add this to multiple comorbidities and polypharmacy, and there may be a significant shift to the benefit-risk assessment for a new drug in development.
These issues were highlighted in a recent FDA Workshop “Roadmap to 2030 for New Drug Evaluation in Older Adults”. The session stressed the importance of safety and efficacy data of new molecular entities in older adults at the time of NDA or BLA submission as well as major barriers facing current trials, such as stringent I/E criteria that often exclude older adults from trial participation and lack of representation in clinical studies.
Clinical Trial Participation
A 2010-2019 landscape study of drug development applications submitted to the FDA presented during the Workshop found major underrepresentation when comparing disease prevalence to clinical trial demographics. For example, heart failure is prevalent in 25% of adults 80+ years old, however this age group was only represented by 5% of clinical trial participants in heart failure drug studies. Similarly, osteoporosis is estimated in 29% of adults 80+ years old, yet clinical studies only enrolled 12% of octogenarians or older in osteoporosis drug trials. On the other hand, when considering all older adult trial participation, the outcome is not so bleak. According to a recent drug trial snapshot, last year the FDA approved 53 new drug applications (including BLA), in which 30% of trial participants were 65 years of age or older.
Chronological vs. Biological Age
The ICH E7 Q&A and FDA guidance recommend geriatric subpopulation safety and efficacy analysis of three groups; 65-74, 75-84, ≥85 years old. The EMA takes this one-step further in a recent reflection paper,emphasizing biological age and patient frailty over chronological age during drug development with a patient-centric approach. Discussed during the Workshop, the Short Physical Performance Battery is one recommended tool to characterize baseline frailty, testing gait, balance and strength in older adults.
Advantages of Enrolling Older Adults in Early Clinical Development
Increasing representation in Phase III trials, removing unnecessary I/E criteria, and coordinating with nursing homes, long-term care facilities and hospices are just a few approaches to enrich a study with this special population. However, prior to initiating studies in this vulnerable group, early clinical data in healthy older adults can provide valuable insight into PK and PD changes compared to younger adults. Armed with clinical data from older adults during Phase I studies can help de-risk programs when designing Phase II and Phase III I/E criteria.
Over the past 10 years, Celerion has completed 14 Phase I clinical studies in geriatric populations for SAD/MAD, safety & tolerability, food effect, DDI trials, enrolling more than 3000 older adult participants. In our vast database of healthy volunteers, we have a sizeable number of older adults owing to large retirement communities in Phoenix area, enriched by the “snowbird” population.
Traditional barriers to enrolling older adults in late stage clinical trials include safety concerns, trial logistics such as number of visits and intensive assessments, as well as hesitancy of this study population. The latter two can be reconciled through thoughtful study design and community partnership and awareness campaigns. Over coming safety concerns may be attained with early phase clinical studies in a healthy geriatric population to de-risk a drug program.