Drug companies spend hundreds of millions of dollars to bring a brand-new medication to market (JAMA, March 3, 2020). They then turn around and charge patients and their insurance companies enormous prices. Once their brand name drugs lose patent protection, however, the costs drop dramatically for generic equivalents. Can we teach old drugs new tricks by developing off-label uses (not yet approved by the FDA) that are both revolutionary and affordable?
The FDA’s Drug Approval System Is Flawed:
The Food and Drug Administration has, to our way of thinking, a bizarre system of drug approval. Let’s start with the basics.
Here is how the agency describes its mandate:
“New drugs and biological products for people must be FDA approved before they are marketed in interstate commerce. This means that a company must demonstrate that its drug or biological product is safe and effective for the intended use, and that it can manufacture the product to federal quality standards.”
A drug company used to have to demonstrate that a medicine was significantly better than placebo in two clinical trials. That seems straightforward…but as you no doubt have heard, the devil is in the details. The FDA routinely approves new medications that just move the needle on a “surrogate marker.”
Take Aduhelm (aducanumab), the new drug for Alzheimer’s disease. It has not been shown to reverse memory loss, keep people functional or out of nursing homes. What it does do is lower levels of amyloid in the brain. It is thought that this sticky protein contributes to dementia, but this theory has become highly controversial. A number of researchers no longer think that lowering amyloid will actually reverse Alzheimer’s disease. Nevertheless, the drug has received FDA approval.
What About Drug Side Effects?
Remember, the FDA maintains that it only approves products that are “safe.” And yet if you watch any television, you are likely to see a variety of prescription drug commercials that list adverse reactions such as heart attacks, strokes, kidney failure and death as potential complications. So, all FDA-approved drugs are safe? Well, not exactly.
Repurposing Old Drugs for New Uses:
One of the greatest underutilized opportunities in medicine is teaching old drugs new tricks. There are a surprising number of medicines that could be used for hard-to-treat conditions at an affordable price.
How can we use old drugs in new ways? You might think that the FDA would be all in when it comes to helping companies repurpose off-patent products. Sadly, there is no system that offers pharmaceutical manufacturers and incentive to do this kind of research.
Once a drug is approved, though, a doctor can prescribe it for any purpose. The FDA does not have any power to regulate the practice of medicine. If a physician hears through the medical grapevine that sildenafil (Viagra) will stop snoring, he could prescribe it for such a purpose. (I made that up, so please do not pester your doctor for such an off-label use). The FDA could not object, however.
If a doctor thinks a beta blocker heart medicine like propranolol could calm someone down, she could prescribe it for stage fright or performance anxiety. The trouble is that the benefits and risks of the drug to treat this off-label indication are murky if there is a paucity of good research. No drug company is likely to undertake such a study if there is no pay back. Without a system to encourage innovative research, doctors are flying blind if they want to try to teach an old drug new tricks.
Minoxidil for Hair Loss:
Take minoxidil, for example. You may recognize it more easily under its brand name Rogaine. This over-the-counter topical treatment helps counteract male pattern baldness.
As a pill, minoxidil was first introduced for hard-to-treat hypertension in the 1970s. While it is effective, it can also cause some very serious side effects, including a buildup of fluid around the heart. It may also cause swelling of the feet and legs, rapid heart rate and unexpected hair growth.
This last side effect led to the development of the topical formulation, Rogaine. That is how most people have used minoxidil for the last several decades. Now, though, some dermatologists have discovered that low-dose oral minoxidil (less than 5 mg per day) seems to fight hair loss without most of the serious side effects it produces at usual oral doses (Dermatology World Insights and Inquiries, Jan. 5, 2022).
But what doctors really need are large, well-controlled clinical trials to establish both efficacy and safety. In addition, some dermatologists are prescribing minoxidil together with a unique diuretic (spironolactone) that is also available generically. This combination is being used experimentally to treat female pattern hair loss (Australian Journal of General Practice, July 2018).
Before dermatologists start prescribing this combination, however, they desperately need solid scientific evidence about both benefits and risks. Sadly, such studies are expensive and uncommon.
Because the drugs are off patent, no single company can get rich on a new indication. Thus, they have no incentive to do the research to support new ways of using these drugs.
Teaching Old Drugs New Tricks For Depression:
Hair loss is an important problem, but there are other conditions that are far more serious. Depression and neurodegenerative diseases are hard to treat. Existing drugs leave a lot to be desired.
A very old cholesterol-lowering medication called fenofibrate (Tricor) is stimulating interest among neuroscientists. That’s because it has a unique mechanism of action in the brain.
The drug’s anti-inflammatory activity and effects on dopamine neurons make it an intriguing agent against both depression and Parkinson’s disease (Biomolecules, May 2022). Clinical trials would be both expensive and time consuming. Few drug companies would undertake such research without a big incentive, and there is no mechanism to support such an idea. Fenofibrate is not without side effects, so any research into its off-label uses would require a careful consideration of safety.
Ketamine for Depression?
Another very old drug is ketamine. I learned about it in graduate school at the University of Michigan around 1970. That’s because my mentor, Dr. Edward Domino, was the primary researcher on the first published paper involving this injectable anesthetic (Clinical Pharmacology and Therapeutics, May-June, 1965). You can learn about the unusual pros and cons of this medicine at this link.
Surprising Ketamine Side Effects and Anti-Suicide Benefits:
Ketamine has been controversial for decades. This anesthetic is now used to treat depression. What about chronic pain? Does it have a role?
Ketamine has one FDA-approved indication as an injectable anesthetic. And yet there are hundreds of ketamine “clinics” that have sprung up all around the country. They are advertising the off-label use of ketamine for depression, chronic pain, PTSD, anxiety and suicidal thoughts.
Ketamine may be a great antidepressant when all else has failed. It may also be a fabulous pain reliever when traditional analgesics fail patients in severe chronic pain. Without large, well-controlled clinical trials, however, we will not be able to make wise decisions about the pros and cons of these off-label uses.
A recent review in the journal Pharmacotherapy (July, 2022) warns:
“Considering the scientific studies reviewed in this assessment, we find that neither ketamine nor esketamine has been shown to be safe for extended clinical use to treat depression. At subanesthetic doses, ketamine is a well-documented drug of addiction and abuse. Images from animal studies demonstrate damage to neurons with even brief exposure. With extended use, the abnormal vacuoles created may exceed the self-repair capacity of the neurons and trigger apoptotic cell death.”
That’s pretty technical, but the gist of the argument is that we need good research to determine the long-term safety and effectiveness of ketamine for unapproved uses. Sadly, no drug company is likely to undertake these studies since it cannot patent ketamine or charge a hefty price.
Teaching Old Drugs New Tricks Requires Government Support!
There are many other old generic drugs that might be repurposed for challenging conditions. The tuberculosis vaccine, BCG, has been around for over a century. It may help protect against COVID-19 and some cancers.
The antidepressant fluvoxamine may also work against the coronavirus. A study published in PLOS One (Oct. 6, 2022) reports on 14 studies.
The conclusion:
“Most evidence supports that the use of antidepressant medications, mainly Fluvoxamine, may decrease the severity and improve the outcome in hospitalized patients with SARS-CoV-2…Further clinical trials should be conducted to clarify the effects of antidepressants on the severity of COVID-19.”
No drug company will likely undertake such research. Will the government? Probably not.
Government Inaction?
Maybe it’s time for the NIH to invest in innovative research on off-patent medications. If a drug proves effective for a new indication, we need policies to allow non-profit organizations to make it available at an affordable price. It’s time for both the FDA and Congress to come up with new strategies to teach old drugs new tricks!
You may find our interview with Dr. David Fajgenbaum of great interest. He has a rare and life-threatening condition called Castleman disease. He discovered an old drug called sirolimus could be taught a new trick to treat his form of Castleman disease. This is an extraordinary story of courage and innovation. Here is a link to the podcast. You can stream the audio by clicking on the white arrow inside the green circle under Dr. Fajgenbaum’s photo.
Learn More:
You can visit https://chasingmycure.com/ for more information. Dr. Fajgenbaum recently spoke to the Clinton Global Initiative. Here is a link to the YouTube: https://www.youtube.com/watch?v=3FzWOd6l15I
You may also wish to review these recent stories on his Every Cure initiative:
https://abc7ny.com/amp/every-cure-rare-disease-nonprofit-clinton/12240968/
What Do You Think?
Should Congress come up with a program to teach old drugs new tricks? How can we create incentives that will allow researchers to spend the time and money to investigate off-label opportunities? Why should we let these inexpensive and potentially breakthrough drugs languish in obscurity?
