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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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February 15, 2012

Eschenbach Says Market, Then Test

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Posted by Derek

Ex-Intel chief Andy Grove's idea to reform clinical trials didn't get much of a reception around here, although (in the end) I was more receptive to the idea than many people were (the comments to the posts here followed similar lines).

So it's quite interesting to see former FDA commissioner Andy Eschenbach making what sounds like a very similar pitch in the Wall Street Journal. It's near the end of an op-ed about reforming the FDA, and it goes like this:

Breakthrough technologies deserve a breakthrough in the wa the FDA evaluates them. Take regenerative medicine. If a company can grow cells that repair the retina in a lab, patients shouldn't have to wait years while the FDA asks the company to complete laborious clinical trials proving efficacy. Instead, after proof of concept and safety testing, the product could be approved for marketing with every eligible patient entered in a registry so the company and the FDA can establish efficacy through post-market studies.

There are several ways to look at that idea. One is to translate it into less editorial language and propose that "Patients (and their insurance companies) should be able to pay to try therapies before they're proven to have worked, as long as that proof is forthcoming". That's not prima facie a crazy idea, but it's subject to the same sorts of objections as Grove's earlier proposal. The post-marketing data will likely be of lower quality than a properly run clinical trial, and it will be harder to use it to establish efficacy. On the other hand, useful therapies would get into the hands of patients faster than happens now, and the expense of drug development would (presumably) go down. But useless therapies would also get into the hands of patients faster than happens now, too, and that's something that we're not currently equipped to deal with.

Any such scheme is going to have to deal with the legal aspect. People don't currently feel as if they're enrolled in a clinical trial when a new drug is offered for sale (although perhaps they should), and it's going to take some doing to make clear that an investigative therapy is just that. Will patients sue, or try to sue, if it doesn't work? If it goes further than that and causes actual harm? I'm thinking of Lilly's gamma-secretase inhibitor that actually seemed to make Alzheimer's worse - how do we handle things like that?

What about the insurers? Will they be happy to have the costs of a Phase III trial offloaded onto them? Not likely. There's also the question of what therapies will get to hop onto this conveyor belt: how much proof-of-concept will be needed? Will that be for the insurers to decide, what investigational drugs they're willing to pay for, so that data can be obtained?

And about that data - it would be of great importance to establish, up front, just what sort of endpoint is being sought. Clear criteria would need to be established (both positive and negative) so that a regulatory decision could be reached in a reasonable time frame. Otherwise, I fear that there are any number of entrepreneurial types who would gladly stretch things out, as long as someone else is paying, in the hopes of finally seeing something useful. No one will - or should - pay for extending fishing expeditions.

Even after all these objections, I can still see some merit in the whole idea. But the question is, after you take all the objections into account (and there are surely more), how much merit is left over? It's not as clear-cut a case as Eschenbach (or Grove) would have a person believe. . .

Some early reactions to Eschenbach's proposal are here and here. There are, I should note, a few other aspects to his op-ed that will be subject of another post.

Update: John LaMattina has similar views.

Comments (30) + TrackBacks (0) | Category: Clinical Trials


COMMENTS

1. PPedroso on February 15, 2012 9:43 AM writes...

For all the reasons already metioned by Derek I add the issue of drugs whose development is halted in Phase III for safety reasons (take torcetrapib for instance). In an approach as the one described due to the less control of the patient population probably those side effects would be more difficult to detect than in the controlled environment of Clinical trials and a large segment of the pouplation would suffer from them.
This seems a good idea to apply to certain specifi and controlled areas, like the regenerative medicine, mentioned in the excerpt.

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2. Cellbio on February 15, 2012 9:55 AM writes...

Several good concerns already mentioned. I'dd add the challenge of the placebo effect, which in some settings is quite significant. Can't really charge for placebo so no blinded stuides, which too often blow apart our well formed beliefs of the benefit of drugs (or supplements for that matter, recent omega 3 data).

The greater concern for me is how this could be actively misused. In many instances now it is hard to recruit patients to trials. I fear the marketing influence of pharma would race to get drug candidates into this system to lock up patients, hoping of course that everything works out, but really motivated to block competitors. In the end, I think this influence could do more harm to true innovators, the little guys, than it would help.

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3. Biotechtranslated on February 15, 2012 10:37 AM writes...

The issue around insurance companies will be the biggest stumbling block. How much resistance do payers have now to paying for off-label use? And these are for drugs that have proven efficacy in other indications. A drug that has ZERO efficacy data (at least Phase III type data) is going to have the insurance companies running for the hills.

And the issues around cost sharing will be another one. If you want insurance companies to fund your clinical trials, you better make it cheap. So let's say you charge $3000/yr for an experimental cancer drug. You collect the data and wow, you've got a real hit on your hands. What do you do? Raise the price to $30,000/yr? Do you think the general public will understand why you did that or think that it's fair?

This idea is not without merit, but I think it creates a number of serious problems that need to be addressed before it could ever be viable.

Mike

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4. DLIB on February 15, 2012 10:52 AM writes...

The points each of you raise are major issues and many are orthogonal to each other...you guys have successfully gutted the merits of the idea.

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5. johnnyboy on February 15, 2012 10:59 AM writes...

I salute Derek's and the previous commenters' open-mindedness to a new idea. It is an open-mindedness that I do not share, because I find that idea to be complete and utter rubbish, and dangerous to boot. To me, this proposal is drug approval viewed through the warped lens of a dogmatic free-marketeer, for whom the best solution to get everything out and let the marketplace of patients figure it out. In theory, perhaps, with time, it would be found out that a particular drug is utter sh*te, or actually killing people. How long would that take, and how many patients would be harmed (not being helped = being harmed) in the process ? Registry data would not only be weaker than clinical trial data, it would also take much longer to collect and properly analyze, and be immensely more open to Big Pharma manipulation.

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6. PPedroso on February 15, 2012 11:07 AM writes...

@5 JohnnyBoy,

but do you recognize that the way things are being done nowadays constitute a big obstacle (or at least a delaying issue) to the development of new drugs? And that some kind of an alternative, more fast solution must be discovered and implemented?

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7. MIMD on February 15, 2012 11:28 AM writes...

Instead, after proof of concept and safety testing, the product could be approved for marketing with every eligible patient entered in a registry so the company and the FDA can establish efficacy through post-market studies.

This could only work if assuming robust informed consent is obtained from each and every patient, knowing that "proof of safety" in limited trials is no guarantee of anything.

It is not a good assumption to make.

For example, our Government and HHS is now providing incentive funding for what FDA CDRH head Jeff Shuren MD JD admits is a medical device, but from which the FDA refrains from regulating or testing. Instead, a very weak "certification" program run by HHS appointees has been set up to simply test if the device "works" in in-vitro settings.

The device is known as electronic medical records.

Buyers and users are thus buying and using at their own risk. That's fine, but the patients these devices are used upon are not given the opportunity for informed consent, even though the FDA, IOM and others admit they are neither proven efficacious nor safe.

Such is the post-rational world.

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8. RespiSci on February 15, 2012 11:31 AM writes...

...after proof of concept and safety testing.....hmmm....If I understand correctly, the drug will still undergo the long term toxicology tests (repro/carci etc) and then this drug will be manufactured for sale without having determined the optimal dose and formulation for manufacture? Or shall we just manufacture a wide array of doses and formulations for the patients to self-test as well? Any CMC experts want to weigh in on how the actual mechanics of such a proposal would work?

And how will efficacy be determined? By the number of thumbs up LIKE hits on a facebook page?

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9. cynical1 on February 15, 2012 11:37 AM writes...

Well Mr. Groves, here's our brandy dandy new multi-kinase inhibitor. We want to try it out on your osteoarthritis because our marketing group thinks that it will make a whole lot more money in that indication rather than the very rare cancer that our scientists thought it might be really appropriate for. The first group of young unemployed chemists we tried it on in our Phase I trial didn't die so you should be just fine. But then again, those guys have been exposed to so much toxic crap in their careers that nothing bothers them anymore. Ok Andy, open up and swallow two of them because you're so much smarter than the rest of us. Take two of them twice a day and give us a call and tell us how you feel in a month or two. One other thing, we don't know anything about drug interactions so you may want to lay off that crack pipe you've obviously been smoking.

Privatization of the industry and/or IP reforms are the only way it's going to survive. Get used to what's on the pharmacy shelfs.

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10. johnnyboy on February 15, 2012 12:25 PM writes...

@6 : I would like to see it better articulated what the problem is exactly. Is it that it takes a long time to get a drug approved ? This long period is a direct consequence of the high (and growing) risk aversion and litigiousness of the general population. People want drugs that work and have no side effects, and are happy to sue when they get the opposite. The FDA is there to serve the population, so it has no choice but to reflect popular sentiment, and to have high (and growing) standards for efficacy and safety. This translates into the need to gather more data before approval. Grove and Eschenbach's proposals would never, ever, ever pass the smell test of the population (as represented by consumer groups and health advocates). The different phases of drug approval are not dead wood; they are all there for a reason, and you will never succeed in cutting off one part or another of the process without significant consequences on patients down the road. It is true that the FDA could be more efficient in its handling of applications; if you believe in miracles, you might get a brave administration that would be able to increase FDA funding significantly enough for the agency to hire more people, but that would speed up approval processes maybe by a few months, at most.

If you consider that it takes too long to get a drug approved, it should be asked too long for whom. Too long for the pharma companies, which makes it more expensive and threatens the long-term future of the business ? The best way to counteract that would be to extent patent protection for 5 or 10 more years. Rather than trying to drastically cut the approval time (which will never happen, for the reasons stated above), increasing patent duration would take into account the growing length of the approval process and increasing difficulties in developing new drugs that are better than what's currently available. But before that can happen politically, the general population will have to be convinced that pharma is indeed in danger; we're definitely not there yet, and we'll have to see a couple of big pharma go out of business before that reality sinks in.

Or is the length of the approval process a problem for the patients ? Well, I know it sucks to be sick. But most diseases out there already have drug treatments, however imperfect. Before putting out new ones that may only offer nominal improvement on current drugs, you need a process to make sure that the new ones are worth it. This may be hard to accept for a patient crying out for better treatment, but in the end it's for their own good. And for diseases without current useful treatments, there are accelerated approval processes in place.

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11. CR on February 15, 2012 12:42 PM writes...

This idea, to me, seems to try and address the fact that the approval time is so long that patent life becomes, effectively, very short and companies have a harder time getting costs back. Seems to me the best way would be start patent protection after the drug is approved. The approval process takes so long that patent lives are cut short. If the patent life was started after approval I think more companies might be willing to keep things in the clinic. The life doesn't have to be 20 years post-approval; but somewhere in the 7 - 10 years post-approval would be a huge help.

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12. PPedroso on February 15, 2012 12:43 PM writes...

@11 Thanks for the complete and extense answer.

I agree with most of what you're writing. My concern relates to the way we are developing and investigating the new drugs. I do not think it is reasonable or efficient to R&D for 10 years and then just conclude that the drug has safety or efficacy issues in a Phase III study and just shut the programme. There must be a way to guarantee this on a much earlier phase and what I see is Pharma Companies neglecting their early phase research (by downsizing) and going after sub-populations that will constitute easy phase II and phase III studies with no risk whatsoever and a small impact in the society.
Of course, this is particulary relevant for unmet medical needs like cancer and neurodegenerative disorders.

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13. Hap on February 15, 2012 1:04 PM writes...

Some of the patent life issues could be dealt either with marketing exclusivity rules (start the clock at approval?) or by pausing the patent period during the FDA approval process. The problem with patent rule changes is that other countries would have to buy into them, which I don't know will happen.

Maybe there's something to the translational medicine thing - if the federal government finds out how hard making drugs is, they might be more willing to find a way for drug companies to make drugs and money, because otherwise it would be difficult for them to make them. On the other hand, we'll probably just hope that someone else makes them.

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14. TJMC on February 15, 2012 1:22 PM writes...

While the idea has been well "gutted", as #4 DLIB notes early (and others added since…), this raises a perhaps useful derivative idea. The kinds of scanning tools that this would use could supplement the “well-controlled clinical” yet slow and somewhat opaque process we now have.

For instance, some experiment now with rapidly digesting and analyzing twitter, blog and other non-traditional sources to uncover what the market is saying about products (or sentiments on stocks,etc.)
I have seen some musings about using these tools to scan for progression or evolution of differing communicable diseases (by NHS, CDC and maybe even DHS...) I often wondered why similar scanning on comments from patients on new drugs are not also used by the FDA as a "earlier warning system" of “signals” ahead of Phase IV reporting etc. Anyone know of any such plans or projects?

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15. braintheoryguy on February 15, 2012 1:40 PM writes...

I see another benefit to this quicker release of drugs. Drugs often demonstrate placebo effects (efficacy above baseline). Therefore many drugs WOULD have a therapeutic effect, whether the drug itself is efficacious or not.

Though this type of efficacy is misleading, it is indeed a real benefit to patients.

This placebo effect would also benefit the pharmaceutical industry. Their products would work as placebos and (perhaps) as ligands as well. Who doesn't want to sell a product that works and that the public is happy with? Ask the alternative medicine companies how it's working for them.

A win-win for everyone. Science can sort out the real story, in time.

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16. Drug Developer on February 15, 2012 1:49 PM writes...

A couple of points:

1. The FDA currently grants 5 years of "data exclusivity" for a newly-approved compound, independent of any patent considerations. That prevents any generics from being approved during that time. (Technically it prevents them from cross-referencing the originator's safety and efficacy data; they could still run their own big clinical studies, but that's not what their business model is.) So one could envision making this window a little longer to promote continued pharma R&D investment.

2. "Proving" safety is now quite often the longer and more expensive task, and getting more so each year; efficacy is often faster and cheaper. So unless FDA relaxes their requirements around safety then I don't see how Eschenbach's proposal helps at all.

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17. Anonymous on February 15, 2012 2:44 PM writes...

How would safequards since Vioxx change in this model? Would we go back to pre-2000"surprises"? Of course we do not have any way to test out similar serious effects that have such low but proven correlations without "trials" in the millions. Is that one of the reasons for Eschenbach's rationale?

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18. Hap on February 15, 2012 4:01 PM writes...

How do you market drugs without evidence that they are effective? I'm not sure that either "caveat emptor" or the supplementeer method of saying the placeboXXXXXXXXsupplement does everything under the sun while showing the FDA warning about "this product does not treat, diagnose, or cure...blah blah blah" really does pharma any good at all. Either method should make money, but if people wanted to work in a "respect optional" field, I'm sure they could find a quicker and more lucrative career path in telespamming, supplementeering, or financial management. I'm not so sure you'll get better, cheaper, or safer drugs that way, either.

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19. Mark Murcko on February 15, 2012 6:25 PM writes...

We put the concept of a "provisional approval" of a drug into "Alpha Shock" because somehow or another there will need to be a way to put compounds out into larger and more diverse trials more quickly. Of course the details will matter greatly but IMHO we all need to think hard about this. This concept will be fleshed out more in an upcoming article in the new journal, "Disruptive Science & Technology." Best wishes everyone / Mark

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20. Anonymous on February 15, 2012 7:36 PM writes...

It is my understanding that prior to the 1962 amendment to the Food and Drug act, companies’ submitted data in NDA equivalents that demonstrated that their drugs were reasonably safe. The FDA then had 90 days to say no, these drugs are not safe enough. FDA could ask for additional data or outright block the marketing of the drug. After 90 days the company could market its drug if the FDA did not say no. It is the perfect psychology for a regulator as they never had to say yes only no. Frances Kelsey was granted Distinguished Federal Civilian Service Award from JFK for just saying no to thalidomide. The 1962 law profoundly changed that approach to government regulation of drugs. Now the FDA must say yes to a drug for it to make the jump into the marketplace. In addition to significant new safety requirements, a new standard for drug efficacy was introduced in that law. After 1962, regulators had to affirmatively approve drugs on their safety and also on their efficacy. What a nightmare for a civil servant. They would actually have to put their balls on the table and say yes to a drug. They knew they would never know enough about any drug to positively rest assured of never being second guessed by the politicians. A major consequence of that change was a precipitous drop in the number of new drugs coming to market and a substantial escalation in the costs for inventing new drugs. I am still amazed that any drugs are approved by the FDA.

About 90% of the drugs (and vaccines) my spouses, child and I (I am 62) have been given/taken over the decades are from that pre-1962 era including drugs for cancer, hypertension, lipids, pain, angina, depression, ADHD, inflammation, daily aches and pains, anesthesia, and infections. These drugs work pretty damn well having saved my life on at least a couple occasions (infections), and my spouse is still alive 15 years after being treated for cancer with these old drugs. So the old system did work. Even to this day no one gets too worked up over the 3000 to 5000 patients who die in the country each year from aspirin-induced GI bleeds, not even the trial lawyers. So perhaps what is being proposed might be worth thinking more about at least for drugs that can really change medical care?

To make this work, it is really necessary to put the MDs back in charge of pharma, and I mean really in charge. Drug companies who wish to take this kind of approach must kick out all the sales and marketing folks, because they would be such a corrupting influence here and the experiment could not tolerate their influence even a little. This would have to be strictly a science-based, biomedicine-driven endeavor, so the CEO must also be an MD, no exceptions. As for pricing and profits in the case of this kind of experiment, all monies paid for the medicines would have to be returned with interest, all profits and incentive compensation disgorged even by past employees should the drug eventually prove to be ineffective, again without exceptions. Safety is a trickier matter. Pre-agreed upon compensation schedule would need to be implemented and the trial lawyers would need to be barred from initiating any legal proceedings on behalf of injured patients. All participating patients would have to sign a hold harmless agreement upon getting any scrip filled for these experimental meds. With these safeguards in place maybe, just maybe this concept would work and the kinds of drugs like those from the pre-1962 era that so profoundly impacted our lives, might again materialize in the future.

Anyone buying this?

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21. Biotechtranslated on February 15, 2012 8:56 PM writes...

@20,

That's a great bit of history of how the FDA has evolved over time. Very interesting!

However, I have to take exception to your comment about how all these pre-1962 drugs seemed to be just fine. You're running under the assumption that once the FDA didn't say "no" to these drugs and they were marketed, no one looked at them again. This isn't true. Almost every drug that is currently marketed (either approved yesterday or approved 60 years ago) undergoes post-marketing surveillance either in a formal fashion (through adverse event reporting to the FDA) or in an informal fashion (through interested researchers who are testing a hypothesis). So all these wonderful pre-1962 drugs you speak of have actually been worked over with a fine-tooth comb for the last 50 years.

There are plenty of drugs that were approved pre-1962 that have been pulled of the market or whose use has been seriously curtailed (propoxyphene, barbiturates, etc) due to issues that came up after approval.

And you mention the 3000 to 5000 patients who die from aspirin-induced GI bleeds. Don't think for a minute that the FDA doesn't take it into consideration when issuing guidelines for use. Aspirin is a very valuable therapy and is very widely used. It's risks (including GI bleeds) are know and balanced with it's benefits (and cost!)

Mike

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22. hibob on February 16, 2012 3:53 AM writes...

Imagine if someone at Intel came up to Grove back in the day and said "Great News! Our latest testing regime shows the new 90 nm Pentium CPUs work better than having no CPU in the socket 40% of the time; they're also better than putting a placebo in the socket almost 30% of the time. For the 65nm die shrink, we think you should just skip functional testing of new CPUs until post marketing."

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23. Morten G on February 16, 2012 6:26 AM writes...

@11 CR +1

Also statistics is a pretty advanced science. There must be better ways than going "Okay, our drug must be better than so and so on these parameters for it to be actually doing something." (Unless you are testing it head to head with an existing drug). Yes, I know that post-hoc t-testing will always find something http://xkcd.com/882/ but there are better tools, significance of distributions of things like QOL etc.

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24. LJStewartTweeet on February 16, 2012 2:06 PM writes...

Derek. Your Blog is fantastic ! It covers nicely the most important issues questions / challenges that are presented by Andy Grove and now Andy Eschenbach. The Andy’s are talking about changing the economics of drug discovery / development through a complete reorganization of the FDA, and I agree with both Andy’s.

It’s not so crazy to agree with them. Here’s why.

When 9 out of 10 (90%) of the Phase 2 clinical trial projects fail in the pharmaceutical industry (1), we all have to be willing to consider massive change in thinking about how to reset the safety / efficacy equation.

Let’s consider Traumatic Brain Injury (TBI) and Posttraumatic Stress Disorder (PTSD).

A TBI sufferer is defined as anyone having a blow to the head and afterwards has either lost consciousness or has been dazed and confused. According to the Centers for Disease Control and Prevention (CDC), there are an estimated 1.5-1.7 million new TBIs each year in the United States (2; 3). Approximately, 75-80% of the civilian TBI patients (~1.1 million) are treated and released from an emergency room (ER) (4), having apparently sustained a concussion defined as a mild TBI (mTBI), though it is unclear how to define a “mild” TBI, many of which may have long lasting effects. The other TBI sufferers are not so fortunate; where ~52,000 TBI victims die each year in the US, and another ~235,000 are hospitalized for extended periods of time (5).
These statistics make TBI the leading cause of death and disability in the United States and a contributing factor to a third (30.5%) of all injury-related deaths (3; 6).

For the ~1.64 million soldier warriors who served in Iraq (Operation Iraqi Freedom, OIF) and Afghanistan (Operation Enduring Freedom, OEF), Traumatic Brain Injury (TBI), Depression and Posttraumatic Stress Disorder (PTSD) are major ongoing medical concerns as the “signature” wounds of war (7). An estimated ~100,000 (~8%) of the US soldiers who were deployed to Iraq or Afghanistan since 2001 have suffered TBIs 8, many of which were sustained in close proximity to blast explosions (9; 10; 11).

Furthermore, Posttraumatic Stress Disorder (PTSD) is strongly associated with military brain injury wherein ~44% of concussed warriors also suffer from PTSD (12).

Aggregate estimates can vary, but there are between 3.2-5.3 million Americans currently living with TBI-related disabilities (13; 14). In 2000, the medical costs of TBI in the US, together with indirect costs such as lost productivity totaled an estimated $76.5 billion (15). In 2012, the aggregate costs of TBI and PTSD could be north of $100 billion.

Despite the tremendous unmet medical need in TBI and PTSD, proportionally very little is being done to develop drug therapies for TBI and PTSD. A search of ClinicalTrials.gov web site (February 6, 2012) found that there are only 14 active Industry sponsored (Pharma or Biotech) clinical trials ongoing for TBI in the US, and only 4 ongoing industry sponsored clinical trials in PTSD. For TBI, the ProTECT III clinical trial together with one industry sponsored Progesterone “SyNAPSe” trial for TBI 16 are the only two late stage therapeutic clinical trials ongoing in TBI. The molecules being tested for PTSD have been known for many years, and include Ketamine (17; 18) and Propanolol (19; 20).
These are important studies, but much more is needed to address TBI and PTSD.

We need to imagine a clinical trial system and FDA change, where 100’s of safe molecules (remember, safety is what Andy Eschenbach is talking about) can be tried with TBI and PTSD patients over the next 10 years in order to have any hope of finding efficacious treatments.

It’s time for change.

How many safe drug candidate molecules (past Phase I) exist with CNS activity (penetration of the Blood Brain Barrier), but with no clear therapeutic efficacy for their original intended clinical use? Could such molecules be found to work for a different indication such as Alzheimer’s Disease, TBI or PTSD? Would Pharma cos. consider making their failed, but safe molecules (passed Phase I) available to the community to be freely used for study?

Consider the February 9, 2012 publication in Science Express on the discovery by Case Western Reserve researchers that Bexarotene (Targretin), could reverse the behavioral deficits of Alzheimer’s Disease (AD) in a mouse model and also reduce the amount of amyloid (Aβ) plaque in brain (21; 22). Targretin is a brain barrier permeant RXR nuclear hormone receptor agonist, which is already FDA approved for treatment of cutaneous T-cell lymphoma (CTCL, a type of skin cancer).

If we had molecules approved on measures of safety then I bet the world could find effective drug treatments to match diseases a lot faster than current mode of operation, and at much reduced cost.

Sincerely.

References
1. Paul, S. M., Mytelka, D. S., Dunwiddie, C. T., Persinger, C. C., Munos, B. H., Lindborg, S. R. & Schacht, A. L. (2010). How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nat Rev Drug Discov 9, 203-14.
2. Daneshvar, D. H., Riley, D. O., Nowinski, C. J., McKee, A. C., Stern, R. A. & Cantu, R. C. (2011). Long-term consequences: effects on normal development profile after concussion. Phys Med Rehabil Clin N Am 22, 683-700, ix.
3. Coronado, V. G., Xu, L., Basavaraju, S. V., McGuire, L. C., Wald, M. M., Faul, M. D., Guzman, B. R. & Hemphill, J. D. (2011). Surveillance for traumatic brain injury-related deaths--United States, 1997-2007. MMWR Surveill Summ 60, 1-32.
4. CDC. (2003). Report to Congress on Mild Traumatic Brain Injury in the United States : Steps to Prevent a Serious Public Health Problem. National Center for Injury Prevention and Control.
5. Selassie, A. W., Zaloshnja, E., Langlois, J. A., Miller, T., Jones, P. & Steiner, C. (2008). Incidence of long-term disability following traumatic brain injury hospitalization, United States, 2003. J Head Trauma Rehabil 23, 123-31.
6. Faul, M. D., Xu, L., Wald, M. M. & Coronado, V. G. (2010). Traumatic Brain Injury In The United States: Emergency Department Visits, Hospitalizations and Deaths 2002 – 2006 US Department of Health and Human Services
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25. Anthony Bishop on February 16, 2012 10:48 PM writes...

"Will that be for the insurers to decide, what investigational drugs they're willing to pay for, so that data can be obtained?" Imagine the US Health Insurance industry having the same mandate as National Institute of Clinical Excellence in the UK............

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26. Hap on February 17, 2012 1:53 PM writes...

1) Drugs aren't just dinged in P3 for efficacy - they've also been dinged for safety (torcetrapib?). Saying that lots of "safe molecules" are going to be tested isn't really true - you don't know that and won't until they're tried on scale.

2) Nothing is perfectly safe - what you want from a drug is that its benefits be significantly greater than its costs (and that both be known) in a well-defined subset of the population. A drug is safe for someone when its expected benefits significantly outweigh its expected harm. Under this scheme, you won't know efficacy when you take a drug, and you won't necessary know the risks either (because you are part of the trial large enough to find them - you only know that there aren't any severe or acute risks associated with the drug because of P2). If you thought people were unable to judge risk/reward ratios and expectations before, I don't see how making those values impossible to determine rather than merely difficult is going to make anyone happier with pharma.

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27. John Thacker on February 18, 2012 9:55 AM writes...

Rather than simply speculate and give opinions based on anecdote, I recommend that people actually read the body of academic research on the FDA. You're not engaging with any of the scientific literature or the arguments of the opponents.

It's quite obviously the case that a dramatic slowdown in drug approvals occurred in 1962 (Peltzman (1962)), with no noticeable effect in decreasing the number or proportion of unsafe or ineffective drugs (Peltzman (1973), Grabowski and Vernon (1983)).

It's certainly true that you want a drug whose benefits is significantly greater than the costs. It's also true that you want public policy whose benefits is greater than the costs. In the case of the FDA's efficacy requirements, overwhelming academic consensus is that the costs are much greater than the benefits.

The FDA has killed *far*, *far* more people by delaying drugs and making drug development more expensive than it has saved. The unanimity of all scientific and academic studies on this topic is astounding. Please point me to any study disagreeing on this topic, as I've pointed you to dozens that all argue that the 1962 efficacy requirements kill.

All I see are anecdotal arguments, devoid of data.

Someone brings up off-label use. Under the arguments presented above, off-label use ought to be banned as well. Is that the position of most people commenting here?

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28. John Thacker on February 18, 2012 10:03 AM writes...

Here are links to some of the specific studies comparing the pre and post 1962 FDA's track record.

The case really is clear-cut. It's misleading to pretend that it's not, unless you can actually come up with a study supporting the current FDA regime. I'd be very willing to look at one.

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29. hibob on February 19, 2012 8:41 PM writes...

@John Thacker:
Could you narrow that down to some papers that cover FDA regulations and decisions from, say, the past 20 years? I'm not sure estimates of the number of NCEs that were not approved fifty years ago are the best measure for the agency and medical spending as it exists today.

Also consider:

1. keeping bad drugs off the market doesn't just prevent mortality/morbidity directly, it shifts medical spending away from paying for harmful or useless drug regimens, the associated harm caused by those regimens, and the resulting lawsuits. Those dollars can then be spent on effective care instead.

2. The drugs with the best safety and efficacy profiles are the least likely to be delayed or denied.

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30. Ken Rubenstein on February 21, 2012 10:52 AM writes...

How are doctors and patients supposed to make good risk vs benefit decisions when they know a lot about the risk, but relatively little about the benefit? No, it's muddled thinking. I really doubt that many people are being deprived of medical wonders because of the need to show they work. This plan is an invitation to medical quackery as investors and managers roll up their sleeves and sell us sophisticated snake oil.

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