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.

Comments

Great article, Reason. It's necessary to discuss the influence of the state in the society, and the best way to change the state is through democracy. We can't ignore politics.

Posted by: Nicolas Chernavsky at July 20th, 2018 9:52 PM

Hi Reason,
It is understandable why FDA doesn't want to classify aging as a disease. The definition is blurry, the implications are huge and risky.

On the other hand, if we can have results leg syndrome , why not have a syndrome for reach major cause of aging? Senecent cells inflammatory and metabolic syndrome. Extra cellular waste accumulation syndrome and such. This is a few extra steps but once you cover all the major causes you can just have a syndrome that combines all of the categories and don't call it aging. Call it chronological deteriorative syndrome. It will be more narrow but more defined.

Posted by: Cuberat at July 20th, 2018 10:36 PM

I'm just going to go by whether a treatment makes someone look younger. And if it doesn't, it's not an anti-aging treatment, it's only good medicine.

Posted by: NY2LA at July 22nd, 2018 1:18 AM

As a pragmatic I'd say the better idea will be the one that can be made to work at the end. I suspect that gives lifespan.io a big advantage because they seem to head for 100.000 readers later this year and that can be converted into political power (it's also an attractive market, btw.). I'm not even sure what the difference between a comprehensive panel of biomarkers (following the SENS or hallmarks model) and aging itself is. For me that's just semantics.

Posted by: Matthias F at July 22nd, 2018 6:38 AM

It is understandable that the FDA does not want aging to add a list of diagnoses. Aging is not a disease because nobody has healed it. It's a poisoning. Poisoning with poison, which is the same for all. The air pressure is the same on the whole planet.

Anti-aging drugs can not cure any disease associated with age, but instead prolong the length of time the patient suffers from the disease.

Medication against senility, senolytics, are largely ineffective because age is irreversible. They are only stimulants that will build up the old organism to function as a younger one. No health insurance company will start to pay for drugs that slow down aging. There is already the problem that some people are taking medication that slows down aging, because they disadvantages health care providers who have to take care of that person for a long time.

Posted by: Omasta at July 22nd, 2018 6:19 PM

Hi Omasta,
>Aging is not a disease because nobody has healed it

The same argument can be applied to Alzheimer's, schizophrenia, and AIDS, and a ton of other diseases, which don't have a cute o isnly a treatment.

I don't like to classify aging as a disease because it has many blurrily defined manifestations . Concrete damage is another thing. Senecent cells clearly cause harm. The se secrrtion phenotype can be measured with varying degrees of success. And stiffening of the artheried, cholesterol plaque, etc are measurable markers and causes of other diseases.

>Anti-aging drugs can not cure any disease associated with age, but instead prolong the length of time the patient suffers from the disease.

That is the current state of art. And all the medical advanced just help training the symptoms and not the root cause. So the effect is only supportive. But we know that receding or slowing aging is in theory possible. After all we have long lived and immortal species as example. So if there are scientific improvements eventually aging will be solved. Will it take 30, 100 or 10000 years that's another story. There is no fundamental law of nature that states that our lifespan is called at 125 years. It just happens that evolution didn't have to select for longevity when some other traits were offering more advantage.

>
>Medication against senility, senolytics, are largely ineffective because age is irreversible. They are only stimulants that will build up the old organism to function as a younger one.

If it walks like a duck, swim like a duck, and quacks like a ducks, and prolongs the healthy lifespan, then for all intents and purposes it is a 🦆 duck.

>No health insurance company will start to pay for drugs that slow down aging.
That's a different subject. They might actually prefer to pay for anti-aging drugs if it turnes out cheaper. If you live ten or twenty more hrs withouts major complaints or expensive treatments and just do dead or become too old to qualify and you have to switch providers. In fact anti aging is the only way the jelly systems can be profitable. Either that or euthanize everyone advice certain age. ( Say 45 without much investment or 65 with all the modern advanced. Above 65 you are a liability. Plain and simple.

Posted by: Cuberat at July 22nd, 2018 10:47 PM

Matthias F said: "I'm not even sure what the difference between a comprehensive panel of biomarkers (following the SENS or hallmarks model) and aging itself is."

None of them is a panel of biomarkers but a panel of treatments (or more exactly strategies to find treatments).

Posted by: Antonio at July 23rd, 2018 2:45 AM

>None of them is a panel of biomarkers but a panel of treatments

I do understand that. And both models have two columns - the damage and the treatment. The biomarkers are used to quantify the damage to proof that the treatment works. Put them in a third column and you get the complete picture. That means if SENS/hallmarks are comprehensive then an accompanying panel of biomarkers should be exactly the same as a definition of biological age.
I'm sure one can play a lot of word games around that or think about new definitions of damage classes to better fit the shortness of viable biomarkers or make those definitions fit to specific diseases and whatnot.

Posted by: Matthias F at July 23rd, 2018 4:25 AM

I don't really see any biomarker in any of them. If you identify damage with biomarker, then yes, it can be considered that they define biomarkers, but then you have only two columns, not three.

For example, I have never seen Aubrey talking about biomarkers specific to SENS, only about the need of biomarkers for aging in general, including those not much related to SENS damage like epigenetic markers. Indeed, Steve Horvath was a speaker in the Undoing Aging conference.

Posted by: Antonio at July 23rd, 2018 6:55 AM

> If you identify damage with biomarker, then yes, it can be considered that they define biomarkers, but then you have only two columns, not three.

I agree. The only thing with a perfect 1:1 correspondance between damage and biomarker is that you limit your options. Let's take for example crosslinks - you could use biopsy samples and clucosepane antibodies to determine them but your patients won't like having pieces of them cut off. You could also measure farsightedness, skin elasticity and blood pressure to get basically the same result. But high blood pressure could also be caused by senescent cells or magnesium deficiency, so there's no 1:1 correspondance there. But it's a well established indicator - you don't even need regulatory changes to treat it.

I could make a similar case for the other 6 SENS categories and have aging completely covered without using the word itself.

Posted by: Matthias F at July 23rd, 2018 7:59 AM

I think that if anti-aging therapies were to be given off-label, shown to work, and then the FDA stopped it - there could be riots!

Posted by: bmack500 at July 27th, 2018 10:50 AM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.