Right to Try Act

[Ten oz]

 In my opinion it both leaves vulnerable to exploitation. For the false hope of being cured many terminally ill patients would probably pay anything. This also turns people in to test subjects pharmaceutical companies will use to increase shareholder value. Perhaps my fears are wrong. Is this ethical?

Quote

 

Washington (CNN)President Donald Trump signed the "Right to Try Act" Wednesday, a measure aimed at helping terminally ill patients access drug treatments that are yet to be fully approved by the Food and Drug Administration.

Trump, at a White House ceremony surrounded by patients and families who will be affected by the legislation, said his administration "worked hard on this" but said repeatedly he didn't understand why it hadn't been done before.

The bill will give terminally ill patients the right to seek drug treatments that remain in clinical trials and "have passed Phase 1 of the Food and Drug Administration's approval process" but have not been fully approved by the FDA. Some opponents of the bill argue that the legislation won't change much but could have a detrimental effect on how the FDA safeguards public health.

https://www.cnn.com/2018/05/30/politics/right-to-try-donald-trump/index.html

 

 

[Phi for All]

So far, NOTHING this administration has done has been to benefit normal people. Everything has a hidden investment agenda for the extremist business people who seem to be aiming for 100% private ownership of everything. 

This is exploiting desperate people. This is like extending credit in a friendly game of poker to someone who has been losing steadily, using the justification that he has a right to earn his money back. It's a scam, imo. Why have an FDA if you're going to approve unproven treatments?

[StringJunky]

Phase 1 results just tells if the product is toxic.... it makes no clinical sense to give a patient this at this point. It tells you nothing about efficacy. Phase 2 would make more sense because this is where testing for efficacy start and even then the notes section of this phase states: .."determines whether drug can have any efficacy; at this point, the drug is not presumed to have any therapeutic effect whatsoever".  It looks very dangerous to test and hope, on a wing and a prayer, to cure in the field just on phase 1 results. This just shows how thick this administration is.

https://en.wikipedia.org/wiki/Phases_of_clinical_research

Edited May 30, 2018 by StringJunky

[Phi for All]

8 minutes ago, StringJunky said:

It looks very dangerous to test and hope, on a wing and a prayer, to cure in the field just on phase 1 results.

Especially when you can be assured there will be ZERO liability because the patients knew going in that the treatments are a risk.

[StringJunky]

2 minutes ago, Phi for All said:

Especially when you can be assured there will be ZERO liability because the patients knew going in that the treatments are a risk.

Free guinea pigs. It will probably save hundreds of millions of dollars of testing for each novel drug. I think the total is around $1B and 10-15 years before a drug reaches the shelves normally.

Edited May 30, 2018 by StringJunky

[Ten oz]

36 minutes ago, Phi for All said:

Especially when you can be assured there will be ZERO liability because the patients knew going in that the treatments are a risk.

When my grandmother past I would have paid anything to anyone for a chance at just a few more hours. This has a dangerous potential. Even knowing better I might still give up everything I have if it were my wife who was sick and I thought there was a 0.1% chance of success. 

[CharonY]

53 minutes ago, StringJunky said:

Free guinea pigs. It will probably save hundreds of millions of dollars of testing for each novel drug. I think the total is around $1B and 10-15 years before a drug reaches the shelves normally.

The law is problematic, but not for these specific concerns, but rather because it is not quite clear what changes it would actually bring. There are no provision to provide patients with the drugs nor is it made clear who is going to pay for it. There is no clear pathway that would make it easier or cheaper for companies to conduct trials (i.e. there is no indication that the Feds would pay for it, nor is it clear that people could pay out of pocket, nor are companies compelled to accept them). The biggest risk are probably smaller companies (or subsidaries from larger ones) that could close down when things blow up in their face. I suspect that many pharms would rather not provide medication to terminally ill patients outside of trials (for which they have to pay anyway). Additional deaths can skew the results and make a drug appear less valuable than it might be.

Otoh the FDA already has provisions for compassionate access to drugs still in trials (or even investigative drugs). All it really does is muddy the water regarding FDA regulations. In the long run that could seriously impact FDA's mission (which I suspect is the main political goal).

That being said, those laws are already in place in many states, so one could check whether there are any indications of what may or may not have happened as a consequence.

 

Edit: I just glimpsed at the text and would need to read it in more depth, but there is one provision that states that adverse outcomes under these rules would not be used in the approval process unless it is critical for the evaluation. So at least that part of my argument does not hold. 

Edited May 30, 2018 by CharonY

[StringJunky]

2 minutes ago, CharonY said:

The law is problematic, but not for these specific concerns, but rather because it is not quite clear what changes it would actually bring. There are no provision to provide patients with the drugs nor is it made clear who is going to pay for it. There is no clear pathway that would make it easier or cheaper for companies to conduct trials (i.e. there is no indication that the Feds would pay for it, nor is it clear that people could pay out of pocket, nor are companies compelled to accept them). 

Otoh the FDA already has provisions for compassionate access to drugs still in trials (or even investigative drugs). All it really does is muddy the water regarding FDA regulations.

Right.

[iNow]

27 minutes ago, CharonY said:

the FDA already has provisions for compassionate access to drugs still in trials

This isn’t so much in response to you, just using your comment as a jumping off point. 

I’m not yet very well versed in this space, but suspect it’s still harder to gain that access than many would like. All things being equal, I support expanding access to patients and their families and would respect their personal freedom/authority to choose for themselves whether or not the risk is worth it. 

My (admittedly poorly informed) thinking here mirrors closely my thoughts on other topics like opening up asssisted suicide and compassionate euthanasia or even abortion.

Summarized: Regardless of our personal feelings, it’s not our choice to make for them.

Edited May 30, 2018 by iNow

[StringJunky]

28 minutes ago, iNow said:

This isn’t so much in response to you, just using your comment as a jumping off point. 

I’m not yet very well versed in this space, but suspect it’s still harder to gain that access than many would like. All things being equal, I support expanding access to patients and their families and would respect their personal freedom/authority to choose for themselves whether or not the risk is worth it. 

My (admittedly poorly informed) thinking here mirrors closely my thoughts on other topics like opening up asssisted suicide and compassionate euthanasia or even abortion.

Summarized: Regardless of our personal feelings, it’s not our choice to make for them.

But doctors or drug companies should not be allowed to test on the desperate without even a modicum of known efficacy at which point it's no better than offering snake oil.

[iNow]

So the question then becomes not whether we should open this up, but instead what minimum threshold of effficacy must first be met before we do. 

[StringJunky]

11 minutes ago, iNow said:

So the question then becomes not whether we should open this up, but instead what minimum threshold of effficacy must first be met before we do. 

Yes, I think so. Enough that an expert, or experts, think it's worth it, even if it's a long shot; they need to think the science is sound. At the least, there should be an independent expert  panel that can assess the risks vs possible benefit for a particular patient. The final decision should not be in the hands of the drug company or prescribing doctor. The process could be: Company registers opportunity > Patient's doctor applies > Panel decides. This is probably likely to be happening to a degree, as CharonY said.

Edited May 31, 2018 by StringJunky

[CharonY]

1 hour ago, iNow said:

I’m not yet very well versed in this space, but suspect it’s still harder to gain that access than many would like. All things being equal, I support expanding access to patients and their families and would respect their personal freedom/authority to choose for themselves whether or not the risk is worth it. 

My (admittedly poorly informed) thinking here mirrors closely my thoughts on other topics like opening up asssisted suicide and compassionate euthanasia or even abortion.

Summarized: Regardless of our personal feelings, it’s not our choice to make for them.

Just to add information: there are ways to for individuals to request access, but the regulation is that the FDA has to sign off of them. Nonetheless, quite often they are denied by manufacturers for a number of reasons including a) it may jeopardize the approval of the drug (e.g. if the terminal ill have some adverse effects not found in healthy), b) they have limited availability, c) it would disrupt their development pipeline.

One of the biggest thing that folks are wary about the bill is that it basically cuts the FDA off from that process. To be clear, there are pathways to access drugs prior to approval, it is not that they become available for the first time. However, limiting liability of the manufacturer and hiding the data from the approval process could make it more attractive for the manufacturer to agree. However many may still decline on grounds of cost and time investment, for example. 

[Ten oz]

9 hours ago, iNow said:

So the question then becomes not whether we should open this up, but instead what minimum threshold of effficacy must first be met before we do. 

Isn't that what this new law dispenses with? 

Edited May 31, 2018 by Ten oz

[iNow]

I haven’t yet read it

[CharonY]

3 hours ago, Ten oz said:

Isn't that what this new law dispenses with? 

Note that this is also possible without the law. I.e. the FDA was even able to approve individual use of investigational  drugs (i.e. which has not passed an trialsyet). What is needed is only tox study on safety using animal testing and be at a stage in which it could reasonably enter Phase I trials. The new law would only allow access after Phase I but does not need FDA review anymore, which is one of the issues with it.

[swansont]

15 hours ago, StringJunky said:

Free guinea pigs. It will probably save hundreds of millions of dollars of testing for each novel drug. I think the total is around $1B and 10-15 years before a drug reaches the shelves normally.

I think it saves zero money in testing. The people who would be getting access are probably not the targets that would normally be in trials and it wouldn't be double-blind, so the data will not be worth very much.

IOW if it's for people who haven't responded to traditional treatments the the disease has likely progressed quite far, so even if the treatment is effective, they may be too far gone to be saved. i.e. it would have helped when they were first diagnosed, but can't save them once they get extremely sick. I don't that kind of data tells you much about the intended use of the drug. 

If it's a disease that has no effective treatment (or it's not very effective), then you might learn something. But you'll still want to know how much of a placebo effect there is.

[Ten oz]

46 minutes ago, CharonY said:

Note that this is also possible without the law. I.e. the FDA was even able to approve individual use of investigational  drugs (i.e. which has not passed an trialsyet). What is needed is only tox study on safety using animal testing and be at a stage in which it could reasonably enter Phase I trials. The new law would only allow access after Phase I but does not need FDA review anymore, which is one of the issues with it.

My fear is that it opens the door to a variety of new drugs manufacturers can sell at a premium to desperate patients. Drugs which the manufacturers never honestly intend get through the FDA. Provided it isn't toxic manufacturers can sell anything as a possible, yet to be tested, cure for anything. Lots of opportunity to exploit people.  What is to stop a someone from selling something that doesn't do anything as a cancer treatment? Provided they claim they were developing it for cancer and it wasn't toxic they be good to go. No requirement that the company has any evidence based reason to believe it will help. 

[CharonY]

1 hour ago, Ten oz said:

My fear is that it opens the door to a variety of new drugs manufacturers can sell at a premium to desperate patients. Drugs which the manufacturers never honestly intend get through the FDA. Provided it isn't toxic manufacturers can sell anything as a possible, yet to be tested, cure for anything. Lots of opportunity to exploit people.  What is to stop a someone from selling something that doesn't do anything as a cancer treatment? Provided they claim they were developing it for cancer and it wasn't toxic they be good to go. No requirement that the company has any evidence based reason to believe it will help. 

This is mostly an issue with smaller, sketchy companies or startup  that use it to leverage funding in the short-term. It would not be a sustainable model. The provision does say that it has to go through Phase I  which costs a few millions in investment. It would need to be quite an elaborate scam just to recuperate that cost. 

[Ten oz]

15 minutes ago, CharonY said:

It would not be a sustainable model.

Get rich schemes are seldom built around sustainable models.

 

*"Seldom" is an overstatement. Rather they often are not sustainable. Many individuals have made millions and walked away rich leaving their companies bankrupt. 

Edited May 31, 2018 by Ten oz
Overstatement

[CharonY]

1 hour ago, Ten oz said:

Get rich schemes are seldom built around sustainable models.

 

*"Seldom" is an overstatement. Rather they often are not sustainable. Many individuals have made millions and walked away rich leaving their companies bankrupt. 

That may be true, but again, a multi-million dollar investment with the hopes to scam people is rather risky. In fact, I would argue that if you have the financial backing to do Phase I (plus all the additional investment prior to that), you already got more money than you could likely get out of that kind of scheme. I.e. while there is room for abuse, the get rich part does not strike me as the most likely scenario.

[Ten oz]

13 minutes ago, CharonY said:

That may be true, but again, a multi-million dollar investment with the hopes to scam people is rather risky. In fact, I would argue that if you have the financial backing to do Phase I (plus all the additional investment prior to that), you already got more money than you could likely get out of that kind of scheme. I.e. while there is room for abuse, the get rich part does not strike me as the most likely scenario.

The whole business wouldn't need to exist just to scam people. That is more of a worst case. If a company has already invested millions in a product why not re-coup some money and let desperate patients buy it. Maybe the company gets lucky and the drug helps some people or maybe the company knows it won't help but already has so much sunk it the research they just want some of the money back.

70% of drugs move past phase 1 but then only 33% move past Phase 2 and just 30% again past Phase 3. That means the overwhelming majority of drugs that get past Phase 1 ultimately go no where. Now companies can re-coup costs on their research by selling them to desperate people. 

https://www.fda.gov/ForPatients/Approvals/Drugs/ucm405622.htm

 

You seem to be implying companies wouldn't do this because it would bad for them in the long run. Let's not forget what Alan Greenspan (former Fed Chair 87'-06') said post collapse in 2008 about such:

Quote

“Those of us who have looked to the self-interest of lending institutions to protect shareholders’ equity, myself included, are in a state of shocked disbelief,” 

"I made a mistake in presuming that the self-interests of organisations, specifically banks and others, were such that they were best capable of protecting their own shareholders and their equity in the firms,"

https://www.nytimes.com/2008/10/24/business/economy/24panel.html

 

[CharonY]

3 hours ago, Ten oz said:

If a company has already invested millions in a product why not re-coup some money and let desperate patients buy it.

That is more in line what I was suggesting earlier.  A means to leverage funds rather than a "get rich scheme". 

 

As a side note, I found a few papers that reviewed cases in states which already have right to try laws. As of 2017 there has not been a documented case where access was granted under these laws which were not already under the FDA's Expanded Access Program (some of which, such as Texas, have provisions that would prohibit manufacturers to charge patients). I.e. there is no indication that in practice these laws were little more than feel good laws with little to no actual impact.

The bigger issue is, as I stated before, the intention to limit FDA's influence and, (perhaps to a lesser degree) potential endangerment of patients as the individualized oversight by the FDA is missing. 

Also between 2010 and 2014 5000 requests were made, so the pool for a given medication might be fairly low.

Some more of the provisions of the federal act:

- drug has to pass phase I trials

- physician has to certify that no other options are feasible and patients is unable to participate in regular trial

- access requires prescriber, manufacturer and patient's informed consent (i.e. FDA as check is eliminated)

- FDA cannot use data on negative outcomes to delay or deny approval, unless the results are critical for safety reasons (a bit vague on that end)

- manufacturers are protected from liability 

- does not create any form of entitlement for the patients

 

There are many concerns including, but  not limited to:

- safety

- possible diversion of patients and resources away from "proper" trials 

- the fact that expanded access under the FDA already works (almost all requests are approved, but FDA does provide safety suggestions that are helpful to the patients)

-manufacturer's generally are already protected from liability under expanded access (historically there is a lack of legal action against them in those cases)

- manufacturer would still need to divert resources and if they are indeed on track to regular approval, there is little incentive to do so (which is why I mentioned small and sketchy companies)

 

The overall opinion in the public health community seems to range from, useless and inconsequential, a threat FDA's mission to potentially endangering. The the latter is mostly speculative at this point. 

3 hours ago, Ten oz said:

You seem to be implying companies wouldn't do this because it would bad for them in the long run.

Nope, it would even be bad in the short run. Here is the thing, unless they went to phase II they won't know that it won't work. If it is already there and shown to be inefficient, they would have hard time to find buyers.

So that leaves mostly those that are still hopeful and also note that again, under the current rules folks can already request them and it does include investigational drugs. About 30% of them were, in fact approved later. 

You also forget that actually providing and administrating investigational drugs is a significant expense, which includes production and, depending on the treatment, also administration and supervision. Considering that on average per drug only ~12 request were made between 2010 and 2014, each treatment would need to be at a tremendous cost to be anywhere near profitable. Perhaps more importantly, it does divert resources from the actual trials which are run on a tight timeline and budget. That is one of the main reasons (aside from negative outcomes) why manufacturers usually limit access to their drugs, rather than expanding it.

Under certain circumstances it could be more likely to happen (i.e. if the production cost is very low). Overall, I would think that it would be difficult not to run at a loss.

Edited May 31, 2018 by CharonY

[Ten oz]

15 hours ago, CharonY said:

As a side note, I found a few papers that reviewed cases in states which already have right to try laws. As of 2017 there has not been a documented case where access was granted under these laws which were not already under the FDA's Expanded Access Program (some of which, such as Texas, have provisions that would prohibit manufacturers to charge patients). I.e. there is no indication that in practice these laws were little more than feel good laws with little to no actual impact.

The bigger issue is, as I stated before, the intention to limit FDA's influence and, (perhaps to a lesser degree) potential endangerment of patients as the individualized oversight by the FDA is missing. 

Also between 2010 and 2014 5000 requests were made, so the pool for a given medication might be fairly low.

Some more of the provisions of the federal act:

- drug has to pass phase I trials

- physician has to certify that no other options are feasible and patients is unable to participate in regular trial

- access requires prescriber, manufacturer and patient's informed consent (i.e. FDA as check is eliminated)

- FDA cannot use data on negative outcomes to delay or deny approval, unless the results are critical for safety reasons (a bit vague on that end)

- manufacturers are protected from liability 

- does not create any form of entitlement for the patients

There are many concerns including, but  not limited to:

- safety

- possible diversion of patients and resources away from "proper" trials 

- the fact that expanded access under the FDA already works (almost all requests are approved, but FDA does provide safety suggestions that are helpful to the patients)

-manufacturer's generally are already protected from liability under expanded access (historically there is a lack of legal action against them in those cases)

- manufacturer would still need to divert resources and if they are indeed on track to regular approval, there is little incentive to do so (which is why I mentioned small and sketchy companies)

The overall opinion in the public health community seems to range from, useless and inconsequential, a threat FDA's mission to potentially endangering. The the latter is mostly speculative at this point. 

Yes, various states have their own versions of a Right to Try law. Different states have their own various Abortion, Marijuana, Death Penalty, Gun, gambling, Alcohol use, and etc, etc, etc, laws. To varying degrees lack of a clear federal policies in nearly all case greatly impacts those  State laws and individuals exploiting them. Marijuana might be legal in CO but federal law prevents companies in CO access to banking because banks are federally insurances and monitored. Lack financing or ability to sell or contract services across State lines greatly restricts Marijuana operators abilities to run a business.  Meanwhile if we look at something like Guns local laws appear to be futile. Washington DC may have strong Gun laws but they are undercut by the fact people can take a 5 min drive into VA, buy whatever they want, and then just drive back. 

You referenced that the pool was low from 2010-present and then reference provisions in the new law. I feel this blurs the lines a bit. The Law Congress passed on May 22nd 2018 wasn't in place in 2010. The numbers you listed reflect how it was and not how it will be. The new law specifically "limits the liability of drug sponsors, manufacturers, prescribers, or dispensers that provide or decline to provide an eligible investigational drug to an eligible patient". Is limiting the liability of manufacturers, doctors, and so on a good idea? Do you feel your numbers imply access was too limited or that it was where it should be?

One only needs to look at the Opioid epidemic, 19,000 deaths from prescription opoiods in 2016, to see a clear example of where the discretion of manufacturers, prescribers, dispensers, and etc contributed to a massive problem. The public health community has dropped the ball before. The U.S. is already awash in prescription drugs. In 2017 Pharmaceutical companies spent $280 million dollars lobbying the Govt.

https://www.opensecrets.org/lobby/indusclient.php?id=h04&year=2017

 

15 hours ago, CharonY said:

Nope, it would even be bad in the short run. Here is the thing, unless they went to phase II they won't know that it won't work. If it is already there and shown to be inefficient, they would have hard time to find buyers.

So that leaves mostly those that are still hopeful and also note that again, under the current rules folks can already request them and it does include investigational drugs. About 30% of them were, in fact approved later. 

You also forget that actually providing and administrating investigational drugs is a significant expense, which includes production and, depending on the treatment, also administration and supervision. Considering that on average per drug only ~12 request were made between 2010 and 2014, each treatment would need to be at a tremendous cost to be anywhere near profitable. Perhaps more importantly, it does divert resources from the actual trials which are run on a tight timeline and budget. That is one of the main reasons (aside from negative outcomes) why manufacturers usually limit access to their drugs, rather than expanding it.

Under certain circumstances it could be more likely to happen (i.e. if the production cost is very low). Overall, I would think that it would be difficult not to run at a loss.

If a company starts with 100 drugs at Phase 1 on average 70 make it to Phase 2. Of the 70 only 13 will end up at Phase 4 approved  (percentages listed in previously provided FDA link). This new law will enable companies to  sell up to all 70 that go to Phase 2 despite knowing that the overwhelming majority of them do not work. How would it hurt a company in the short term to push selling every drug they have at Phase 2?

[CharonY]

4 hours ago, Ten oz said:

You referenced that the pool was low from 2010-present and then reference provisions in the new law. I feel this blurs the lines a bit. The Law Congress passed on May 22nd 2018 wasn't in place in 2010.

The numbers quoted are from FDA's expanded program (as requested by patients) and as I have already noted, liability does not seem to be an issue as there have been virtually no legal challenges (an opinion share by experts). 

 

4 hours ago, Ten oz said:

If a company starts with 100 drugs at Phase 1 on average 70 make it to Phase 2. Of the 70 only 13 will end up at Phase 4 approved  (percentages listed in previously provided FDA link). This new law will enable companies to  sell up to all 70 that go to Phase 2 despite knowing that the overwhelming majority of them do not work. How would it hurt a company in the short term to push selling every drug they have at Phase 2?

There is no mechanism for that. If a drug fails Phase I it cannot be used for anything. If it passes, the manufacturer would need to invest in Phase II anyway (at a cost of ~5 x of that of Phase I). Nothing in the bill changes that. You are also probably misunderstanding the market situation of non-approved drugs. The treatment is not mass produced at this step. Rather. the manufacturers are still developing the treatment, often with modifications  based on trial results. I.e. they only have limited supply and rarely a surplus that they can push anywhere. And remember they still need sufficient supply for their trials. 

Plus. if they wanted to push it, they would now also invest into marketing. And that is not going to work out well as the actual customer pool is small. You cannot compare it to pain medication, as the only possible patients are the terminally ill, who cannot be registered in regular trials, are not too old to undergo treatment, etc. I.e. it is only a relatively small pool who may consider using an experimental drug. While marketing could raise the number of requests somewhat, there is an hard upper limit.

What you seem to suggest is that companies are going to invest millions into Phase I, then for some reason give up on Phase II before trying (or worse, while trying, losing a few more millions on the way). Note that they cannot simply pull out of trials; only drugs in approval pipelines are eligible.

Then invest more money to produce drug surplus and marketing in the hope of getting enough terminal ill patients and their doctors to sign up and make up for those investments. That sounds like a good way to lose money to me. The fact that many drugs has no bearing on it. Folks do not invest tons of money into pre-trial and early trials with the expectation that it will fail eventually.

Again, the only realistic scenario is when they already got data late in the pipeline (e.g. during Phase II) that the drug is less promising and maybe leverage some funds to make up. It would be more about cutting losses than making money, though. One potential way could be to leverage successes in order to get more buy-in from investors.

But it is hardly comparable to the opioid scenario you describe (unless you manage to suddenly create new terminal ill for a specific treatment). 

 

Edited June 1, 2018 by CharonY