A common concern in the community is that the FDA, the EMA, and other bodies, such as WHO, do not classify aging as a disease and that this poses a problem for developing therapies that target aging. However, this is not really as serious an issue as some people would suggest; today, we will have a look at why that is.
Why this will not stop progress
Aging is a variety of distinct processes, damages, and errors; therefore, simply treating aging in clinical terms is not a viable endpoint. For a clinical trial to be conducted, it requires a verifiable indication, and aging is too general for the FDA and EMA to classify it as a disease.
It also is not a major challenge for damage repair-based approaches, such as those proposed by SENS and the Hallmarks of Aging, as these approaches are not focused on an all-in-one therapy with the indication of “aging”. They are based on a strategy of dividing damages into manageable groups and developing a suite of rejuvenation therapies that addresses each of them.
No single therapy will reverse or halt all of the aging processes when used alone, nor will it prevent all age-related diseases that accompany them. So, to have aging as an indication in any clinical trial would be pointless for any damage repair therapy.
Researchers are free to target aging processes
That said, researchers are very well aware that the processes of aging, which lead to the familiar diseases of aging, are a problem, and this is where the focus lies. There has been considerable effort to classify these processes and precursors of pathology as diseases themselves.
A prime example is the inclusion of sarcopenia (frailty and muscle loss) in the World Health Organization International Classification of Diseases (ICD) a few years ago thanks to lobbying by members of our community. Adding more general codes to the ICD that include these aging processes and precursors is an ideal solution, as it could potentially make it easier to organize trials and develop drugs that target the aging processes.
Back in June 2018, the World Health Organization released the new International Classification of Diseases (ICD-11). The previous version, ICD-10, was published in 1983, and the new ICD-11 will likely be the standard for years to come. The new ICD-11 now includes the extension code “Ageing-Related” (XT9T) for age-related diseases, and this should go a long way towards making focusing on aging easier for future drugs and therapies. Again, this is thanks to work by members of our community, who have spent countless hours researching and pushing for change.
Most aging hallmarks are very clearly linked to specific age-related diseases, such as beta-amyloid protein and malformed tau in Alzheimer’s, lysosomal aggregates in foam cells in atherosclerosis, and alpha-synuclein in Parkinson’s disease. Companies are perfectly welcome to target these aging processes directly, and indeed more and more researchers and big institutions are doing just that in order to treat age-related diseases.
Therefore, not classifying aging itself as a disease poses few barriers to developing therapies that address aging; it’s simply a case of working within the existing framework. UNITY Biotechnology is a prime example; this company is targeting senescent cells and applying its method to multiple age-related diseases; as everyone gets senescent cells, these therapies will be broadly applicable once they become available, and off-label use is likely to expand rapidly.
Also, rejuvenation therapies could, at first, be licensed as treatments for genetic disorders, even though the root cause of the pathology underlying those diseases is not aging. An example of this is the inherited mitochondrial disorders, known as mitochondriopathies, many of which are caused by mutations in the mitochondrial DNA (mtDNA). While these mutations are inherited and are not the result of age-related, deleterious damage to the mtDNA, the same repair-based approach can be applied: the allotopic expression of the protein in the nucleus, as proposed by MitoSENS, could potentially be used to repair the mtDNA allowing normal cellular function to resume.
The majority of damage repair therapies, if not all, could be developed as therapies for diseases with accepted indications and verifiable endpoints, which should satisfy bodies such as the FDA and EMA. Therefore, whether regulatory agencies perceive aging as a disease or not is of no consequence to the development of rejuvenation biotechnologies that address the aging processes.
This does not mean regulatory changes are not needed
Even though classifying aging as a disease is unnecessary, significant reform in the regulatory system is still needed in order to encourage investors and companies to put the time and money into researching and developing rejuvenation therapies.
One area in need of reform is the establishment of aging biomarkers, which indicate the repair or removal of age-related damage, as acceptable endpoints for rejuvenation therapies. Studies that use these biomarkers would also need to include long-term follow-up studies to ascertain the effects of a therapy over a longer period of time.
This would deviate from regulators’ normal requirements that therapies have to prove an effect on hard outcomes to be approved. In an ideal situation, patients should get rejuvenation therapies long before they are in immediate danger and once diseases have manifested, but this makes trials more time consuming and more costly to run.
However, back in February 2018, the FDA published a new guidance document detailing how early-stage Alzheimer’s patients might be identified, which, if accepted, would represent a significant change in policy and a step in the right direction. The document suggests that the results of imaging tests or suitable biomarkers could be enough to consider Stage 1 Alzheimer’s patients as suitable subjects for clinical trials.
This is a positive move as it means that therapies can be tested on people in the very early stages of Alzheimer’s rather than on those who have already suffered considerable if not irreparable damage to the brain, damage that no therapy could hope to address alone. This could mean that these early-stage patients could enroll in a clinical trial and take a therapy that could potentially prevent the disease from ever progressing further or reaching the point where cognitive decline begins.
In the case of repair-based therapies, it would then be a case of demonstrating that the early stages of Alzheimer’s disease were improved via the removal or repair of the underlying age-related damage, and suitable biomarkers would show this.
Moving with the times
Another area where regulatory bodies have struggled is keeping up with the rapid march of technology and medicine. Technologies such as gene therapies have struggled to gain traction due to an antiquated regulatory framework struggling to cope with them. Thankfully, this is also being acknowledged, and the regenerative medicine advanced therapies (RMAT) framework published earlier this year seeks to address this issue and make large-scale changes to how its regenerative medicine policy framework operates as a whole.
According to new FDA regulations, a drug is eligible for designation as an RMAT if:
- The drug is a regenerative medicine therapy, which is defined as a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products, except for those regulated solely under Section 361 of the Public Health Service Act and part 1271 of Title 21, Code of Federal Regulations;
- The drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and
- Preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition.
Aging not being classified as a disease by the FDA, EMA, etc. is not a major issue; the real need is for policy changes that make developing drugs and therapies that target the aging processes easier and more financially viable. It is good that changes are being made to current frameworks and that progress will almost certainly continue in these areas.
Meanwhile, we can continue to support the development of repair-based approaches to aging knowing that such therapies, if they work, will be approved even in the current regulatory landscape.