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How might we take advantage of the Orphan Drugs grant opportunities with the FDA?

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#1 YOLF

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Posted 19 January 2015 - 01:22 AM


An orphan product is one that wouldn't be commercially viable. Obviously, most diseases are age related, so using funding from this could be used to reverse the age of kidneys or something like that. Does anyone have any leads or background that might be applicable here?



#2 niner

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Posted 19 January 2015 - 02:14 AM

An orphan drug has to treat a disease that only affects a small number of people.  I don't know how they feel about obvious off-label application.  I suspect they wouldn't look kindly on it.



#3 YOLF

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Posted 19 January 2015 - 02:52 AM

Off label application is becoming virtually non-existent with the current business models and the evolution of the provider network where understudied indications for a drug result in the drug not being Rx'd as anything not studied becomes a risk the business would rather not make. This, IMO is to substantiate and study off label use to expand the number of applications a drug is useful for. If an indication has been removed due to risk aversion, then in that sense, the drug is an orphan. Most supplements might also qualify as orphans as well.



#4 niner

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Posted 19 January 2015 - 03:15 AM

Off label application is becoming virtually non-existent with the current business models and the evolution of the provider network where understudied indications for a drug result in the drug not being Rx'd as anything not studied becomes a risk the business would rather not make. This, IMO is to substantiate and study off label use to expand the number of applications a drug is useful for. If an indication has been removed due to risk aversion, then in that sense, the drug is an orphan. Most supplements might also qualify as orphans as well.

 

Is there evidence for this claim that off-label use is almost non-existent?  As far as I can tell, there is still a ton of it going on, particularly in psych and pediatric applications.  Drug reps are prevented from pushing it, and I could imagine a few highly risk-averse practices might shy away from it, but it still happens a lot.



#5 corb

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Posted 20 January 2015 - 05:32 PM

Something like this?

http://www.ncbi.nlm....pubmed/24092817

If it actually works you might get rich, hypertension is quite widespread worldwide in the old.



#6 YOLF

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Posted 25 January 2015 - 02:32 AM

 

Off label application is becoming virtually non-existent with the current business models and the evolution of the provider network where understudied indications for a drug result in the drug not being Rx'd as anything not studied becomes a risk the business would rather not make. This, IMO is to substantiate and study off label use to expand the number of applications a drug is useful for. If an indication has been removed due to risk aversion, then in that sense, the drug is an orphan. Most supplements might also qualify as orphans as well.

 

Is there evidence for this claim that off-label use is almost non-existent?  As far as I can tell, there is still a ton of it going on, particularly in psych and pediatric applications.  Drug reps are prevented from pushing it, and I could imagine a few highly risk-averse practices might shy away from it, but it still happens a lot.

 

I'm just speaking from personal experience. I've been thinking that as medicine is so network driven and decisions are consolidated, that I might need to start interviewing my doctors or getting more familiar with the available networks in my area or traveling to doctors in better networks.



#7 YOLF

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Posted 25 January 2015 - 02:44 AM

Something like this?

http://www.ncbi.nlm....pubmed/24092817

If it actually works you might get rich, hypertension is quite widespread worldwide in the old.

While it seems to challenge some notions I've had going, it looks like it could be a good candidate. Is there more info on it? How did you find it?



#8 corb

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Posted 25 January 2015 - 01:16 PM

 

Something like this?

http://www.ncbi.nlm....pubmed/24092817

If it actually works you might get rich, hypertension is quite widespread worldwide in the old.

While it seems to challenge some notions I've had going, it looks like it could be a good candidate. Is there more info on it? How did you find it?

 

 

I don't know much about it, it was referenced in another paper. Can't remember exactly what the paper was about, probably cellular senescence.
 



#9 niner

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Posted 25 January 2015 - 02:38 PM

Hypertension is in no way an orphan condition.  It's just the opposite.



#10 YOLF

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Posted 25 January 2015 - 08:29 PM

It's about orphan drugs, not the conditions.



#11 kmoody

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Posted 26 January 2015 - 04:07 PM

 

 

Off label application is becoming virtually non-existent with the current business models and the evolution of the provider network where understudied indications for a drug result in the drug not being Rx'd as anything not studied becomes a risk the business would rather not make. This, IMO is to substantiate and study off label use to expand the number of applications a drug is useful for. If an indication has been removed due to risk aversion, then in that sense, the drug is an orphan. Most supplements might also qualify as orphans as well.

 

Is there evidence for this claim that off-label use is almost non-existent?  As far as I can tell, there is still a ton of it going on, particularly in psych and pediatric applications.  Drug reps are prevented from pushing it, and I could imagine a few highly risk-averse practices might shy away from it, but it still happens a lot.

 

I'm just speaking from personal experience. I've been thinking that as medicine is so network driven and decisions are consolidated, that I might need to start interviewing my doctors or getting more familiar with the available networks in my area or traveling to doctors in better networks.

 

My two cents...

 

This is not an accurate claim. Off label application is very common. This website provides a nice overview (http://www.cancer.or...-label-drug-use) and cites a survey where 8 out of 10 doctors have prescribed off label. The largest issue is probably insurance reimbursement. Willingness to go off label with vary from doctor to doctor and the "do no harm" doctrine applies. A doctor treating someone with aggressive terminal cancer would probably be more likely to go off label and be creative since the risk of doing more harm than the cancer is low, whereas a GP might be less inclined to go off label with a generally healthy patient because there is risk of doing more harm than good if the person is generally healthy. 

 

Perhaps some of your observations are based on the idea that physicians are fundamentally trained to be pattern recognizers. If presentation includes A, B, C but not D, then diagnosis is X and prescribe Y. Some physicians (particularly research oriented ones) think out of the box, but the majority of my medical school peers and the physicians that trained us, at least, were "follow the decision tree" types -- not much room for creativity.

 

The art in this is to find or develop a drug with widespread use in aging or an age-related indication, for which you could also pursue an orphan indication. The goal being to obtain FDA approval with a smaller clinical trial (i.e. fewer patients, smaller trial, less expensive) or a shorter one (i.e. treat a form of a condition that has an early onset so the trial is shorter, then go off label for the full condition while you are conducting that longer, more expensive clinical trial). Although off-label, professional societies and influential foundations can recommend standard of care for various conditions, even if the clinical data is not yet available. So the goal is to become standard of care, whether it be on or off label.

 

As a more specific example, we are developing lysoSENS enzymes for age-related macular degeneration. However, AMD clinical trials are super long... probably need about 5-10 years to see a significant effect just because of how slowly the disease progresses. The AREDS clinical trial lasted 9 years, for example. So very expensive. However, AMD has a juvenile onset form called Stargardt's disease, which may have the same underlying pathology. A clinical trial to treat Stargardt's would be much shorter and smaller, allowing for approval at a fraction of the cost. Of course, we would want to do a proper AMD study (probably started in parallel with a Stargardt's one), but if the Stargardt's results came in within 1-2 years and the enzyme(s) were safe and effective, there may be substantial rationale for physicians to use them off label for AMD for the ~7 years before the AMD results come back. This is precisely why the embryonic stem cell companies working on AMD (Ocata Therapeutics, formerly called Advanced Cell Technologies) are doing both Stargardt and AMD clinical trials.



#12 kmoody

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Posted 26 January 2015 - 04:17 PM

On further comment... consider this in the context of aging. If you were to have a drug that cured aging tomorrow (100%, call it an immortality pill, once daily), and you started a trial, how long until you would see the effects statistically? It would take a while... even "basic" mouse studies looking at aging endpoints last 3-5 years and cost several hundreds of thousands of dollars (or more) per treatment unless a short-lived model is used. A larger sample group would get you significance faster, but at tremendous additional cost.



#13 corb

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Posted 27 January 2015 - 11:47 AM

Hypertension is in no way an orphan condition.  It's just the opposite.

 

Yes. But the drug is supposed to be effective against periaortic fibrosis, and there are rare conditions that could benefit from that.
As kmoody already said, a trial for something general like hypertension could take years, but a trial for chronic periaortitis which has an incidence of less than 1 in 100,000 people shouldn't take nearly as long or be as hard to organize.

 

I thought that was Perc's idea to begin with - finding rare disease that can benefit from a drug that has anti aging potential and using that to make a case for efficacy and safety, without jumping over all of FDA's hoops.



#14 Danail Bulgaria

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Posted 27 January 2015 - 12:00 PM

An orphan drug has to treat a disease that only affects a small number of people.  I don't know how they feel about obvious off-label application.  I suspect they wouldn't look kindly on it.

 

How about thinking out something for the cancer of the mouth - tongue cancer, lip cancer, cancer from salivatory glands? They affect small number of people.



#15 niner

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Posted 27 January 2015 - 03:30 PM

It's about orphan drugs, not the conditions.

 

There's no such thing as an orphan drug without a condition, and if a common condition is the likely application, I don't think that the FDA will cut you a lot of slack on it.  If there is a true orphan indication for the drug, then you might be able to get that approved under orphan status.

 

 

Hypertension is in no way an orphan condition.  It's just the opposite.

 

Yes. But the drug is supposed to be effective against periaortic fibrosis, and there are rare conditions that could benefit from that.
As kmoody already said, a trial for something general like hypertension could take years, but a trial for chronic periaortitis which has an incidence of less than 1 in 100,000 people shouldn't take nearly as long or be as hard to organize.

 

I thought that was Perc's idea to begin with - finding rare disease that can benefit from a drug that has anti aging potential and using that to make a case for efficacy and safety, without jumping over all of FDA's hoops.

 

If periaortic fibrosis is rare enough, and if it's actually effective for it (it's moderately effective in a mouse L-NAME model) then that might work.  If a disease is truly rare, then it will be harder, not easier to organize a trial, because patients are scattered all over the country, so you'll need multiple centers.  That makes it more expensive.

 

 

An orphan drug has to treat a disease that only affects a small number of people.  I don't know how they feel about obvious off-label application.  I suspect they wouldn't look kindly on it.

 

How about thinking out something for the cancer of the mouth - tongue cancer, lip cancer, cancer from salivatory glands? They affect small number of people.

 

It might be rare enoughUnder the ODA drugs, vaccines, and diagnostic agents would qualify for orphan status if they were intended to treat a disease affecting less than 200,000 American citizens.   Given the incidence rate of oral cancer, it's possible that there could be less than 200,000 people in the US at one time who have it.  Most orphan drugs that I've heard of have populations that are smaller than that.

 

Why not just find the country that has the laxest drug laws in the world, get the drug into use there, then provide it to others through medical tourism or the black market.  If it really works, everyone will want it, the profit opportunity will be obvious, and lots of deep-pocketed entities will be interested in getting it approved in the developed world.



#16 Danail Bulgaria

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Posted 27 January 2015 - 04:23 PM

Can you use a random anti - cancer drug?

 

laxest drug laws ... black market... Africa maybe?



#17 corb

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Posted 27 January 2015 - 05:34 PM

If a disease is truly rare, then it will be harder, not easier to organize a trial, because patients are scattered all over the country, so you'll need multiple centers.

 

I meant it more in the way of people would be more eager to join the trial, but I have to admit you are correct, if it's too rare it would be hard to organize a trial logistically.
 

So ideally, we need a drug that has potential in anti aging or at least lowering mortality in general, that can work on a rare condition, that is not so rare as to impede a trial which can be run by a small organization with limited resources. I am not a medical professional so I can't be sure what condition would be the best fit for a trial like that but I'm sure with drugs that have such a wide effect like TM5441 there will always be possibilities.

 

By the way I didn't say it in the first post but I think the idea is great for a particular reason - this could easily be run as a non profit as well, I'm surprised you guys haven't done something like that yet.

Remember the Ice Bucket Challenge last year? That collected money like no ones business. I mean sure not all diseases are as gruesome as ALS but I'm sure you'll be able to get funds.

When you put a disease in the public eye and when you put human faces behind the name of the disease people almost feel obligated to donate. So at least financially if it's played out right getting money for trials should be easy. And "we need money for a trial" is a great selling point, you could get money worldwide, sure not everyone will be able to take part in the trial but people from every country would love to be cured or at least their symptoms alleviated if they have the disease you have a drug for.

 

It's a bit of an underhanded way to move life extension research along but, if it works, why not?



#18 YOLF

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Posted 30 January 2015 - 02:19 AM

 

 

 

Off label application is becoming virtually non-existent with the current business models and the evolution of the provider network where understudied indications for a drug result in the drug not being Rx'd as anything not studied becomes a risk the business would rather not make. This, IMO is to substantiate and study off label use to expand the number of applications a drug is useful for. If an indication has been removed due to risk aversion, then in that sense, the drug is an orphan. Most supplements might also qualify as orphans as well.

 

Is there evidence for this claim that off-label use is almost non-existent?  As far as I can tell, there is still a ton of it going on, particularly in psych and pediatric applications.  Drug reps are prevented from pushing it, and I could imagine a few highly risk-averse practices might shy away from it, but it still happens a lot.

 

I'm just speaking from personal experience. I've been thinking that as medicine is so network driven and decisions are consolidated, that I might need to start interviewing my doctors or getting more familiar with the available networks in my area or traveling to doctors in better networks.

 

My two cents...

 

This is not an accurate claim. Off label application is very common. This website provides a nice overview (http://www.cancer.or...-label-drug-use) and cites a survey where 8 out of 10 doctors have prescribed off label. The largest issue is probably insurance reimbursement. Willingness to go off label with vary from doctor to doctor and the "do no harm" doctrine applies. A doctor treating someone with aggressive terminal cancer would probably be more likely to go off label and be creative since the risk of doing more harm than the cancer is low, whereas a GP might be less inclined to go off label with a generally healthy patient because there is risk of doing more harm than good if the person is generally healthy. 

 

Perhaps some of your observations are based on the idea that physicians are fundamentally trained to be pattern recognizers. If presentation includes A, B, C but not D, then diagnosis is X and prescribe Y. Some physicians (particularly research oriented ones) think out of the box, but the majority of my medical school peers and the physicians that trained us, at least, were "follow the decision tree" types -- not much room for creativity.

 

The art in this is to find or develop a drug with widespread use in aging or an age-related indication, for which you could also pursue an orphan indication. The goal being to obtain FDA approval with a smaller clinical trial (i.e. fewer patients, smaller trial, less expensive) or a shorter one (i.e. treat a form of a condition that has an early onset so the trial is shorter, then go off label for the full condition while you are conducting that longer, more expensive clinical trial). Although off-label, professional societies and influential foundations can recommend standard of care for various conditions, even if the clinical data is not yet available. So the goal is to become standard of care, whether it be on or off label.

 

As a more specific example, we are developing lysoSENS enzymes for age-related macular degeneration. However, AMD clinical trials are super long... probably need about 5-10 years to see a significant effect just because of how slowly the disease progresses. The AREDS clinical trial lasted 9 years, for example. So very expensive. However, AMD has a juvenile onset form called Stargardt's disease, which may have the same underlying pathology. A clinical trial to treat Stargardt's would be much shorter and smaller, allowing for approval at a fraction of the cost. Of course, we would want to do a proper AMD study (probably started in parallel with a Stargardt's one), but if the Stargardt's results came in within 1-2 years and the enzyme(s) were safe and effective, there may be substantial rationale for physicians to use them off label for AMD for the ~7 years before the AMD results come back. This is precisely why the embryonic stem cell companies working on AMD (Ocata Therapeutics, formerly called Advanced Cell Technologies) are doing both Stargardt and AMD clinical trials.

 

Well, it's very common for a small number of people and not available to most young people who stand to benefit from it the longest as terminal patients are usually old. The decision tree is fine if you have Canadian insurance and everything is paid for, otherwise it is more expensive to find a correct diagnosis/treatment, especially if you happen not to have the most common things a doc sees in their practice. Taking advice from a patient is also very important if they've researched well enough. They know much more about their condition than a doc can learn in 5 minutes. Though the decision tree would explain why docs make decisions from only the first few things. 

 

I'm obviously aggravated here and a little disappointed by lots of doctors visits with little to no results for things I've been seeking treatment for for years. The above should be taken with a grain of salt.

 

Anyways, decision trees and trying common diagnoses first can expose the patient to more unnecessary treatments, copays, and drug side effects than they might have suffered from a comprehensive analysis and a little more risk and some follow up monitoring/blood tests. It would probably cost the same or less to do it this way, you would think insurance companies would want to do it this way.







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