The complexities of clinical research in older patients
Authors: None The Lancet Healthy Longevity
Journal: The Lancet Healthy Longevity (2021)

The Food and Drug Administaration (FDA) approval of aducanumab for treatment of Alzheimer's disease has been polarising. Despite improvements in the formation of amyloid beta plaques—a hallmark of Alzheimer's disease—evidence of benefits for cognitive decline was less clear. One trial (EMERGE) showed no improvements in cognitive decline, while a second trial (ENGAGE), showed a 23% improvement compared with the placebo group. Although interpreted by Biogen, the manufacturer of aducanumab, as signalling clinical benefits, results were met with scepticism: members of an FDA advisory committee cautioned that positive effects could equally as likely have stemmed from an accelerated decline in the placebo group. Moreover, adverse effects of brain swelling and bleeding were noted, ranging from mild to severe and occurring predominantly in APOEε4 carriers. The criticism of premature approval of the drug culminated in the resignation of three FDA advisors. However, others have lauded the approval as heralding substantial progress in the field, because it fills a long-standing gap in treatments for Alzheimer's disease. This case illustrates the challenge facing the research community of striking a balance between rapidly providing much-needed treatments for desperate patients and families while ensuring drug efficacy and patient safety. The Accelerated Approval programme of the FDA, initiated in 1992, was a response to this challenge; drugs are granted quick approval by demonstrating efficacy on a surrogate marker, which is purported to predict clinical benefits, but confirmatory trials must be done after approval to confirm clinical benefits. However, this safety net appears to have many loopholes, including long delays: Biogen will have about 8 years to confirm the clinical benefits of aducanumab. The aducanumab example also highlights the complexities of clinical trial design in older patients. As older patients have unique needs, clinical trials should be designed with consideration of these needs. However, clinical trials done in older adults are notoriously plagued by design flaws, most notably the selection of inappropriate endpoints and the use of unrepresentative populations (eg, patients without many comorbidities). Another key element of clinical trial designs in older adults is the use of inclusion criteria that reflect the functional capacities of patients in the community for whom the treatments are intended. The clinical trials for aducanumab were done in patients with mild forms of Alzheimer's disease but approval was intended for use in all people with Alzheimer's, across varying severity, begging the question of whether even the promising findings of plaque clearance can necessarily be extrapolated. These strict exclusion criteria of trials are at odds with the heterogeneity of older adult populations, creating an artificial and unrepresentative sample. Although there have been efforts to move away from age-based exclusion criteria, exemplified by the NIH Policy and Guidelines on the Inclusion of Individuals Across the Lifespan as Participants in Research Involving Human Subjects, even exclusion criteria that do not explicitly reference age often inevitably exclude older people due to certain exclusionary criteria being more common in older age groups. By restricting participation on the basis of age-associated criteria, the resulting sample is far removed from real patient populations, as demonstrated in a study published in our current issue that showed lower rates of serious adverse events in clinical trials compared with in patients in the community, with the discrepancy evident even for trials that specifically recruited older participants. And finally the issue of aducanumab also reopens the debate about whether using surrogate endpoints is clinically justifiable. How will a patient's quality of life improve if plaque reductions are not paralleled by improvements in cognitive functioning? Especially for older adults, such trials must incorporate the understanding of ageing well by including outcomes such as health-related quality of life and the ability to live independently. To ensure optimal treatment for age-related diseases, the unique heterogeneity of older patient groups must be reflected in the design of clinical trials. Although the complexities of these groups can appear daunting in the pursuit of clean and controlled data, they must be addressed if clinical research is to be translated into genuinely effective clinical practice.