The Restrictive Political Anarchy of Off-Label Use is Why it Matters Whether or Not Aging is an Accepted FDA Indication

Over at the Life Extension Advocacy Foundation (LEAF), an argument is made that we shouldn’t be overly concerned about the current unwillingness of the FDA and similar regulatory bodies to recognize the treatment of aging and its causes as a valid indication. What is an indication? The outcome of the present overly burdensome regulatory process is formal approval of the use of a specific medical technology for a specific defined condition or set of symptoms. That condition or set of symptoms is known as an indication. Aging is not currently in the list of recognized conditions. The argument made by LEAF is that there are defined paths for rejuvenation therapies to be approved as treatments for specific age-related diseases. Thus treatments can be developed in principle, and from there the concept of off-label use applies.

Not classing aging as a disease is not a major problem

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. However, 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.

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. 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.

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.

The counterargument to this proposition is that off-label use at scale is not a given – it is by no means certain that a rejuvenation therapy can be approved for, say, arthritis patients, and then the floodgates immediately open for everyone and anyone to use it for any plausibly connected medical condition. Yes, off-label use, as written into law, says that physicians can prescribe approved therapies for unapproved uses. It is estimated that 20% of medical usage in the US is off-label, but this is something that has arisen slowly and organically over time. There are few good analogues in recent medical history for anything as broadly effective as a rejuvenation therapy, something that can beneficially treat hundreds of named conditions.

Why is this a problem? FDA staff see themselves as the shield that stands between unrestricted use of therapies and the public at large. They are opposed to widespread off-label use, as they see this as an end-run around their shield. This is the justification for preventing patient choice – the usual authoritarian assumption that people have no agency and are not qualified to make their own decisions or order their own affairs. When potential therapies and potential indications are first put in front of the FDA, minimizing the likelihood for off-label use is a topic that will come up. If you, for example, propose to treat only a fraction of the population of patients who have a specific condition, based on some biomarker that might be used to segregate the patient population into smaller groups than is presently the case, then the fact that this will tend to lead to significant off-label use in the rest of the patient population is one of the reasons why such designs can be rejected.

When off-label use rises to a significant level in some other way, the FDA may step in. But this is not a given. There are no hard and fast rules here. It is a political anarchy: FDA bureaucrats want to shut down that off-label use and force more clinical trials on their own terms, one named disease at a time, but there is always too much to do in any given day. On the other side of this are developers, patient advocates, and public opinion. People involved in providing therapies when the FDA has decided that they want to step in risk prosecution, fines, and jail time for their principles if the FDA decides to take a hard line. This is the case whether or not it is legal under the letter of the law to offer these technologies off-label: the FDA will squeeze the manufacturers and the distributors, not the physicians. Fighting this sort of intervention may will be ruinously expensive, a long-running legal battle with a government agency with far greater resources than any of the other players in the space.

The bottom line is that when senolytics or other early rejuvenation therapies are narrowly approved for specific age-related conditions, that will likely roll right into a sizable battle over off-label use. It seems inevitable that people will try – and why shouldn’t they? Does the law serve humanity, or does humanity serve the law? Should we all lie down and die because FDA staff are prissy about their rules? Because of the incentives and the parties involved, it just isn’t the case that approval for the first few age-related diseases will immediately enable widespread use, unless the political and public opinion battle immediately goes very poorly for the FDA. Sadly, I don’t see why it would: the leadership at the FDA has successfully shut down or held back numerous other avenues for off-label delivery of beneficial treatments over the past decades, over the objections of many well-supported advocacy organizations and the voices of suffering patients.

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