A Perspective on the Coming Regulatory Shift to Approval of Drugs to Treat Aging

At some point, regulatory bodies that oversee the development of new medicine will accept that therapies can target causative mechanisms of aging in order to slow or reverse the progression of aging, and that there are viable ways to assess new treatments that treat aging. There is growing pressure from the academic community and longevity-focused biotech industry for the ability to run clinical trials to treat aging, rather than to treat one specific age-related disease.

While inevitable, this change will take some years to come to pass, and likely require greater consensus in the research community on reasonable approaches to measure biological age. The scientific community is making good progress towards the adoption of improved epigenetic clocks as as a consensus means of measuring biological age in a natural environment, but it becomes challenging to stand by any of these clocks when any one causative mechanism of aging is slowed or reversed via therapy. The clock may over-represent or under-represent the contributions of that mechanism to degenerative aging, and there is no real way to find out without calibrating the clock against that specific therapy in lengthy animal studies.

In the meanwhile, companies developing therapies that target the mechanisms of aging choose one specific age-related condition for clinical trials and regulatory approval. They move ahead assuming that widespread off-label use will likely follow approval for any one age-related disease, providing further pressure for the regulatory edifice will shift to allow a more defined path towards treatment of aging as a medical condition in all older individuals.

Challenges in developing Geroscience trials

Multiple clinical conditions and pathophysiological processes have long been considered as inescapable and unmodifiable consequences of the aging process. However, these perceptions are changing. Over the past few decades, research focusing on the interplay between the fundamental processes of aging and the biology of co-morbidities has given rise to the concept of Geroscience, the goal of which is to develop new biologically-based therapeutic and preventive approaches that target fundamental aging processes; thus, to decrease age-related multi-morbidities as a group and improve healthspan.

The beneficial effect of using Gerotherapeutic drugs to modulate the fundamental molecular, cellular, and/or genetic mechanisms of aging has been demonstrated in animal models, and offers exciting preventive and even curative therapeutic translational opportunities in humans. However, Geroscience trials face numerous methodological challenges in their study design regarding demonstrating clinical effectiveness successfully in humans. One critical challenge is that the usual design of therapeutic clinical trials is centered on disease-specific diagnosis and physiopathology, whereas Geroscience trials aim to target mechanisms of aging in order to delay or prevent the onset or reduce the progression of multiple age-related diseases, geriatric syndromes, and potentially alleviate or treat such conditions.

The European Medicine Agency (EMA) and the Food and Drug Agency (FDA) have high concordance (91-98%) in decisions on marketing approvals, but the arrival of gerotherapeutic drugs will challenge both agencies to define the terms of marketing approval in the context of Geroscience. Being an emergent discipline, Geroscience will challenge some of the established protocols for fast approval of new drugs and biomarkers needed to meet the challenges of an aging society. In general, FDA or EMA approve drugs for treating diseases; however, aging by itself is not currently considered as a "disease", but as the major risk factor for multiple morbidities.

Basic scientists, clinicians, and drug agency officials already interact so that the concept behind Geroscience is understood and shared. A scale for evaluating FDA-approved drugs for their Gerotherapeutic potential has been proposed. In this context, it is important to highlight that the design of the TAME (Targeting Aging with MEtformin) trial has been approved by the FDA; TAME aims to delay mortality and the onset of several age-related diseases (e.g., myocardial infarction, stroke, cancer, dementia) and conditions (e.g., major decline in mobility or cognitive function) rather than targeting a single disease. The TAME trial may serve as a proof of concept that proves to the medical agencies that aging can be a therapeutic indication in itself. This result would favor conditions for defining new marketing approval, type of approval, and approved indication for new or already approved drugs and will be incentive for pharmaceutical companies to invest in research on Geroscience.

Designing a disease-centric trial remains the only way to date to gain approval from the FDA or EMA, each of which still adheres to the "one disease, one drug" model. The regulatory constraints required for a new drug to be brought to patients and the extent to which the patients benefit from it must also be taken into consideration when designing a trial. However, targeting a single pathology in a clinical trial is not without risk either. Diagnostic criteria change over time, in particular with the emergence of biomarkers, not-withstanding that most diseases of ageing are of complex etiology, resulting from (still poorly understood) interactions between non-modifiable factors (including age, sex, and genetic predisposition) and modifiable factors, related to environmental and other exposures, lifestyle factors, etc. Moreover, it should be emphasized that some Gerotherapeutic drugs could have a very modest and difficult to demonstrate effect in organs evaluated separately, but have a clinically significant overall effect due to their action on the whole organism, and the alternative also exists that a study using a composite score might fail to capture substantial changes within just one domain if not statistically powered for that endpoint alone. A trial centered on only one function or disease is the current conventional approach but is probably not appropriate for certain molecules such as metformin, for which effects are pleiotropic, acting on multiple organs and through multiple biological mechanisms.