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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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June 10, 2014

Right To Try: Here We Go

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Posted by Derek

At what point should an experimental drug be made available for anyone to try it? The usual answer is "Unless you're enrolled in a clinical trial, then not until it's no longer an experimental drug". There's always compassionate use, but that's a hard topic to deal with, and one that has a different answer for every drug. Otherwise, the regulatory position is that volunteers take unproven drugs, and paying patients take the ones that have been through testing and review.

Colorado would like to try something different. They've passed a "Right To Try" law, which allow a therapy to be prescribed after it's passed Phase I and is under active investigation in Phase II. (Arizona, Louisiana, and Missouri are heading in the same direction). Insurance companies are not required to pay for these, it should be noted, nor are drug companies required to offer access. But if there are willing patients and a willing company, they can work together. The patient has to be suffering from a terminal illness, and has to have exhausted all approved therapies (if any).

As my fellow science-blogger David Kroll notes, though, this doesn't seem to add much past what was already allowed by the FDA:

I submit that this seemingly well-meaning but meaningless Colorado act does nothing but create a sense of false hope for similar families. The act does nothing more than assuage the concerns of lawmakers that they haven’t done enough to help their constituents. Instead, they’ve done a disservice.

At Science-Based Medicine there are similar thoughts from oncologist David Gorski. He goes into the details of the law that's under consideration in Arizona, and worries that it has such broad definitions that it opens the door to unscrupulous operators. I've worried about that as well. The Arizona law also allows the companies (at their discretion) to charge for providing the drugs (Colorado's allows for at-cost charging). The fear is that some unscrupulous operators could run the lightest, breeziest "Phase I" trial they possibly could, and then settle down into a long, lucrative spell of milking desperate patients while their "Phase II' trials creep along bit by bit. I realize that that's not a very nice thing to assume about people, but as a character in The War of the Worlds says about a similar predatory proposal, there are those who would do it cheerful. In fact, we already have evidence of people working in just this fashion.

These arguments have come up around here before, when Andy Grove (ex-Intel) proposed changing the structure of clinical trials (more here), and when Andy Eschenbach (ex-FDA) proposed something similar himself. Balancing these things is very hard indeed, and anyone who says it isn't either hasn't thought about the situation enough or is eager to sell you something. We've come to Chesterton's Gate again:

There exists in such a case a certain institution or law; let us say, for the sake of simplicity, a fence or gate erected across a road. The more modern type of reformer goes gaily up to it and says, “I don’t see the use of this; let us clear it away.” To which the more intelligent type of reformer will do well to answer: “If you don’t see the use of it, I certainly won’t let you clear it away. Go away and think. Then, when you can come back and tell me that you do see the use of it, I may allow you to destroy it.

Gorski (in that Science-Based Medicine link above) has many other good points, but there's one more that I'd like to emphasize. Some of these laws seem to be based on the idea that there are all sorts of wonderful cures out there that for some reason are tied up in sloth and red tape. It isn't so. Clearing out bureaucratic obstacles, while no picnic, is still a lot easier than discovering drugs. And allowing patients access after a Phase I does not offer very good odds, considering that almost all clinical failures take place later than that. Plenty of tox gets discovered later than that, too - only the fast and nasty stuff gets picked up in Phase I.

So overall, I think that these laws offer, for the most part, chances for people to feel good about themselves for voting for them, and chances for patients to get their hopes up, likely for no reason. Even with that, I don't see them doing much harm compared to the existing regulatory regime, except for the provisions that offer companies the chance to charge money. Those give the added bonus of opening the door to unscrupulous quacks, some of whom might have very creative ideas of what "at cost" might mean.

According to Biocentury, a Colorado company is already planning to offer access through this program:

Neuralstem Inc. (NYSE-M:CUR) plans to take advantage of Colorado's right-to-try law to offer patients access to an experimental, unapproved human neural stem cell (hNSC) therapy (NSI-566) to treat amyotrophic lateral sclerosis. President and CEO Richard Garr told BioCentury the company will not apply for an IND or other permission from FDA, noting that "the Colorado right-to-try law allows a company to prescribe for a fatal disease a therapy that has passed a Phase I safety trial and is being actively pursued in a Phase II trial." Garr said Neuralstem's hNSC ALS therapy meets these criteria, and the company plans to start a Phase III trial next year.
Neuralstem is in the process of training surgeons and identifying a hospital and neurologists in Colorado to administer the hNSC therapy. The therapy will be administered with the identical procedure, cells and training as a clinical trial, but without FDA oversight and without "the artificial limitations built around a trial," said Garr. "The whole point of right-to-try is it sits parallel to the clinical trial process, it is not instead of clinical trials." Neuralstem has not determined whether it will charge Colorado patients.

I know nothing about Neuralstem or their therapy, so I'll defer comment until I learn more. Looks like we're going to see how this works, whether we're ready for it or not.

Comments (25) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Regulatory Affairs


COMMENTS

1. Larry O on June 10, 2014 9:08 AM writes...

I agree with you on all points but if I had ALS I would jump at a 10% chance rather then face a certain and painful death. The key is drug companies should not make any profit from RTT.

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2. Bruce Cleaver on June 10, 2014 9:51 AM writes...

"So overall, I think that these laws offer, for the most part, chances for people to feel good about themselves for voting for them"

Just so.

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3. rob on June 10, 2014 10:15 AM writes...

You should also look at the UK's Early Access to Medicines Scheme and the EMA's Adaptive Licensing pilot project

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4. Anonymous on June 10, 2014 1:26 PM writes...

Maurice Saatchi is introducing a bill of comparable thrust in the House of Lords.

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5. david young md on June 10, 2014 4:05 PM writes...

There is a companion issue here. What about expanded access to drugs that are already on the market? Herceptin is available for both HER2 overexpressed breast cancer and HER2 overexpressed gastric cancer. But TDM1 (ado-trastuzumab Emtansine) is approved only for breast cancer. Can I use TDMI (or, perhaps Pertuzumab) for my gastric cancer patient? Afterall, these are drugs where the safety information is already well defined. Or, can I get Herceptin for my HER-2 positive adenocarcinoma of the esophagus (where it is not approved) even though a tumor arising just a few centimeters south (and for all intents and purposes the same cancer) would have the drug approved for and paid for?

In terms of investigational drugs, I think that one has to be very careful who might benefit from an early stage investigational drugs. For some people, who cannot be put on study, certain investigation drugs make perfect sense. A lot don't. What about the poor guy who might benefit from an investigational drug for prostate cancer, but he cannot get on trial because he had a bladder cancer resected 3 years before? Or a woman who could use an investigational drug for her breast cancer, but she cannot get on trial because she has Gilbert's condition and her bilirubin is too high. Or she has a creatinine of 2 These cases make sense.

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6. watcher on June 10, 2014 4:07 PM writes...

Oh My. And who then pays the law suits if something goes unknowingly wrong----the state of Colorado?

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7. Shane on June 10, 2014 4:07 PM writes...

The Arizona referral also only allows drug companies to charge for costs, so there could be no "long, lucrative spell of milking desperate patients..." In the future, it would be wise to read what you are writing about.

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8. Casual Observer on June 10, 2014 4:33 PM writes...

@7: As the original post says of the at-cost provision,

"Those give the added bonus of opening the door to unscrupulous quacks, some of whom might have very creative ideas of what "at cost" might mean."

In the future, it would be wise to read what you are writing about.

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9. Anon on June 10, 2014 4:57 PM writes...

I'm going to be the bad guy and say it.
We REALLY don't need physicians trying to be heroes and throwing everything at the wall to hope something sticks. I really do think this will lead to clinicians trying to "discover" new indications and disregarding other factors (patient quality of life, costs, etc). I really hope I don't see Dr. Oz prescribing cure alls next week with the typical correlative "evidence."

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10. Josh on June 10, 2014 5:01 PM writes...

Shouldn't your criticism be directed at the FDA?

The FDA should not allow quackery to reign inside or outside of clinical trials. These bills allow the FDA to stop access through Right to Try by shutting down the corresponding quack trials.

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11. Robert R. Fenichel on June 10, 2014 5:46 PM writes...

There are at least two potential problems with schemes like this, in addition to those already mentioned by Derek Lowe & by other posters.
First, this sort of end-run access may make it more difficult to recruit for the randomized trials that are needed to determine whether the product really works. This problem may be especially severe when the product is believed by many patients and docs to be a sure bet, on the basis of some mixture of mechanistic surmise, promotional quackery by Oz & his ilk, and wishful thinking.
Second, especially in the case of diseases whose natural history is complex, so that unblinded, non-randomized data are essentially uninformative, the same surmise, quackery, & wishful thinking are likely to convince some patients & docs that the product is a winner, before ** and even after ** good data are available to show that the product is useless. When manufacturers and/or FDA try to kill products that have developed this sort of constituency (for example, look at the history of guanethidine in reflex sympathetic dystrophy), litigation and Congressional inquiries can arise.

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12. Robert R. Fenichel on June 10, 2014 5:46 PM writes...

There are at least two potential problems with schemes like this, in addition to those already mentioned by Derek Lowe & by other posters.
First, this sort of end-run access may make it more difficult to recruit for the randomized trials that are needed to determine whether the product really works. This problem may be especially severe when the product is believed by many patients and docs to be a sure bet, on the basis of some mixture of mechanistic surmise, promotional quackery by Oz & his ilk, and wishful thinking.
Second, especially in the case of diseases whose natural history is complex, so that unblinded, non-randomized data are essentially uninformative, the same surmise, quackery, & wishful thinking are likely to convince some patients & docs that the product is a winner, before ** and even after ** good data are available to show that the product is useless. When manufacturers and/or FDA try to kill products that have developed this sort of constituency (for example, look at the history of guanethidine in reflex sympathetic dystrophy), litigation and Congressional inquiries can arise.

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13. Shane on June 10, 2014 6:09 PM writes...

@8.Again, before you comment, do yourself a favor and read the legislation. There is no latitude in the statutory definitions to open the door to "unscrupulous quacks."

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14. Li Zhi on June 10, 2014 7:47 PM writes...

I fail to see how any drug developer in their right mind would allow some random assortment of patients access while the drug was still under the critical eye of the FDA. Who decides which patient 'qualifies'? Who maintains the obviously necessary records? What are the risks to the approval process when the FDA asks for these anecdotal pseudo-data? What is the FDA's legal obligation with regard to these 'data'? If it isn't spelled out in black and white, then can you say "years of litigation"? (it isn't spelled out in black and white). As a side note, apparently some here believe the dominant costs of a drug is either processing or raw materials. Otherwise, I would expect them not to be so foolish as to presume 'cost' can be anything other than arbitrary. For those so misguided, please google "$600 hammer" (it was actually $435). Cost of non-production items is never "per unit" and can be wildly manipulated and must be arbitrary to a large extent. To think otherwise is just a failure of understanding/imagination. Far better would be (imho) to set caps on the indirect costs while fully capturing real RMC, storage and transportation along with processing scaled to reasonable production volume.

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15. Insilicoconsulting on June 10, 2014 11:00 PM writes...

I am always amazed at the moral outrage expressed in this forum when new ideas are tried out for people in the "terminal" phase. That too after phase I, " do no harm" and some indication of efficacy.

This is not the same as seeing what sticks!

It's not as if these acts are for slimming cures. Does no one believe in market forces anymore? Companies that try to sell snake oil will eventually die out. Sooner rather than later.

I am cynical about politicians too but negating everything they do when the intellectuals here cannot suggest any alternatives for "hard" problems is a bit lame.

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16. Anonymous on June 11, 2014 1:55 AM writes...

There is a difference between doing what's right (giving access to the terminally ill) and doing it right (putting in the right safeguards, checks and balances) to make it work in practice. It just takes a bit of creative thinking. Remember when we used to use that?

Also, why do people automatically think about law suits when something goes wrong? As long as participants are happy to sign away their rights to sue for another shot at life (and have been properly informed about the risks involved), there should be no problem.

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17. newnickname on June 11, 2014 9:32 AM writes...

Some random thoughts here ... A major cost in clinical trials is not the drug but the medical overhead. Do you think doctors will inject a drug into a patient for free? In many (most?) cases, the office visit and doctor's reimbursement is more than the cost of the drug. So, I ask, will the bill require doctors to administer the drugs for free or "at cost"? (The cost of maintaining a medical practice isn't cheap: in addition to the MD's cut, there are the support staff, record keeping costs, regulatory - insurance - Medicare/aid filing costs, etc. If a 10 minute office visit to get jabbed with a needle gets a $600 insurance payment, how much of that goes to the MD and how much goes to the other costs?)

I don't know the current estimate of the per patient cost for Clinical Trial recruitment, treatment, analysis, filing (FDA) and publishing data. Even for a hangnail treatment, it's got to be at least $25,000 per patient per year. (Please correct me! I'm taking a guess!)

If you skip all that technical stuff, you can just dispense all these experimental drugs from a vending machine at the mall and let patients pick what they want ... "at cost". (Don't forget that the vending machine guy gets his cut, too.) I can picture a concordance of symptoms and drug options, like finding the right windshield wiper or headlight for your specific make and model of car.

(Website still flaky and unreliable!! Please fix!!)

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18. David Borhani on June 11, 2014 9:36 AM writes...

Late to comment due to web site failure...

I agree with many of the comments, and especially the one (@14) about how this proposal will affect recruitment for trials. Shameless plug for a Letter Adam Butts and I wrote a few years ago, in response to Andy Grove: Rethinking Clinical Trials: Biology's Mysteries (Science editors came up with the title, not us!).

@5: Is HER-2 positive esophageal adenocarcinoma really the same as HER-2 positive gastric adenocarcinoma (as distinct from GIST, or MALT)? I thought esophageal and gastric epithelial cells were quite different. Is it obvious that anti-HER2 therapy would be beneficial in the face of distinct cellular background? And, see @9's comment. We already witness too many heroic attempts IMO.

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19. respisci on June 11, 2014 10:28 AM writes...

@16 Creative thinking indeed. I am sympathetic in doing what is right for terminally ill patients but I foresee situations where an in-development drug proceeding through Phase 2 or Phase 3 studies for which the patient population has been selected may now also be provided off-trial to patients not selected for the clinical trial. If one of those patients in the off-trial die or have SAE, then the Phase 2 or 3 clinical trials would be put on hold until the death is investigated. Most likely conclusion would be that the off-trial patient should never have been on the drug in the first place. There is a very real risk is in delaying development of the drug for the actual target population or prevent it from being developed at all.

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20. MedMonkey on June 11, 2014 10:30 AM writes...

@15:
"Does no one believe in market forces anymore?"

Ah, I remember when I believed in market forces, when I was a child, but discovered as I grew up that it was all made up nonsense.

If companies that sell snake oil really did go out of business, products like this (http://i.imgur.com/bvbt3Cx.jpg) wouldn't exist and companies like Boiron wouldn't make €350 million.
If quackery was driven out of medicine purely from market forces, people wouldn't still be paying hundreds of thousands of dollars to Stanislaw Burzynski for fake cancer cures. I mean, this one example is responsible for killing so many people, not just from denying people actual treatment, but from reactions to "antineoplasons" themselves! Here's a guy that kills patients, and "the market" allows not only his continuation but his sadistic profiting off the suffering of people!

More to the point, though, simply passing a Phase I trial isn't proof of safety. Phase I trials are typically only done in a dozen or so volunteers, and are done in healthy individuals. There's no chance of drug interactions, no chance of disease state/drug interaction, and a very low chance to detect anything but the most toxic or common adverse events.

Hell, drugs have come to the market and *still* not had all their adverse effects known, even after passing a Phase III trial involving many thousands of patients!
To imply that passing a Phase I trial is enough to say "do no harm" is laughable.

You want an alternative solution to this "hard" problem? The system as it exists without this law deals with this problem. There are already provisions for "compassionate use" of investigational drugs, especially for terminal illnesses like cancer. This law does nothing but give false hope to dying patients and create potential loopholes for shady businessmen to sell inadequately tested drugs to desperate patients.

How's that for "moral outrage"?

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21. Anonymous on June 11, 2014 10:52 AM writes...

Shane writes (#13):

@8.Again, before you comment, do yourself a favor and read the legislation. There is no latitude in the statutory definitions to open the door to "unscrupulous quacks."

The AZ bill (available here) states:

36-1312.B. A manufacturer may (2) Require an eligible patient to pay the costs of or associated with the manufacture of the investigational drug, biological product or device.

Nowhere does the bill define what costs can or can't be considered "associated with" manufacture. Imagine an unscrupulous one-drug company that treats one patient per year in a trial, while offering RTT access to 999 patients. What stops them from claiming that 99.9% of their total annual costs are associated with manufacture?

More generally, I agree with Derek. These laws aren't going do much of anything to increase access to drugs in legitimate development. There's little reason for a developer to provide access, and many reasons not to.

Unless they're written better, the only substantial effect of these laws will indeed be to provide loopholes for unscrupulous operators.

(It's also amusing to note that the AZ bill defines an investigational drug as one that has completed "phase one of a clinical trial." Presumably they meant "a phase one clinical trial.")

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22. david e young md on June 11, 2014 12:11 PM writes...

To clarify a point that someone else made.

For oncologists who given an experimental treatment off study (compassionate care) we have generally acquired the investigational drug free of charge and provide the drug free of charge. We still pay for iv tubing, iv fluids and the nurses time for administering the drug and do not pass these costs on to the patient. These costs are very minimal (5 dollars for a bad of saline and 3 dollars for the iv tubing and the nurse is there anyway giving other patients chemotherapy) and the "good will" of giving patients access to compassionate investigational drugs is probably worth more than the few dollars we lose in giving free iv fluids. We do bill Medicare / Insurance for the evaluation and management of seeing the patient and do get paid for that, at least in most cases. But there is never a circumstance where a physician will make lots of money by giving investigational drugs in the office. Remember, we do not and cannot charge for drugs that we get for free.

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23. Courthouse on June 12, 2014 9:24 AM writes...

This should be done under a "good will" free format. Clinical trials are there for a reason - they protect the patient, and more importantly capture priceless information that is vital to discovering what really works. My concern is that just trying stuff to see if it works in a non-clinical study gives a binary answer - works (kind of), or not. A compassionate use study within a Phase I study will put the absolutely essential (even if minimal) safe guards in place and also capture some usable clinical information.

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24. newnickname on June 13, 2014 7:23 AM writes...

@22, david young: Official clinical trials can pay rather well. I've read that some MDs double, 3x or more-x their non-Clin Trial income by participating (depending on the trial and the number of patients they treat).

But back to a Compassionate Use law, you do say that you don't charge for a free drug and even comp the tubing and needle, but you also say "We do bill Medicare / Insurance for the evaluation and management of seeing the patient and do get paid for that, at least in most cases." That insurance payment pays you, your staff, the rent, the electric bill and so on so keeps you alive and in business and you can easily write off a bag of saline. DrugCo has no such guaranteed payment. It's not clear (to me) what a drug company can charge as the "cost" of the actual Compassionate Use drug: a portion of CEO perks? repaving the shipping and receiving driveway? receptionist salary? chemist salaries? journal subscriptions?

Or, in the case of Pipeline, server maintenance? :-)

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25. clinicaltrialist on June 20, 2014 11:55 PM writes...

Folks, most people don't realize that 1) FDA has no jurisdiction over drugs that are not shipped across state lines and 2) a physician can prescribe any drug, including unapproved drug, to any patient - the prohibition is on the company from selling the drug but an MD can order the drug from a compounding pharmacy or Sigma and treat the patient with it

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