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Derek Lowe The 2002 Model

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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: Twitter: Dereklowe

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August 19, 2013

Is The FDA the Problem?

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Posted by Derek

A reader sends along this account of some speakers at last year's investment symposium from Agora Financial. One of the speakers was Juan Enriquez, and I thought that readers here might be interested in his perspective.

First, the facts. According to Enriquez:

Today, it costs 100,000 times less than it once did to create a three-dimensional map of a disease-causing protein

There are about 300 times more of these disease proteins in databases now than in times past

The number of drug-like chemicals per researcher has increased 800 times

The cost to test a drug versus a protein has decreased ten-fold

The technology to conduct these tests has gotten much quicker
Now here’s Enriquez’s simple question:

"Given all these advances, why haven’t we cured cancer yet? Why haven’t we cured Alzheimer’s? Why haven’t we cured Parkinson’s?"

The answer likely lies in the bloated process and downright hostile-to-innovation climate for FDA drug approvals in this day and age...

According to Enriquez, this climate has gotten so bad that major pharmaceuticals companies have begun shifting their primary focus from R&D of new drugs to increased marketing of existing drugs — and mergers and acquisitions.

I have a problem with this point of view, assuming that it's been reported correctly. I'll interpret this as makes-a-good-speech exaggeration, but Enriquez himself has most certainly been around enough to realize that the advances that he speaks of are not, by themselves, enough to lead to a shower of new therapies. That's a theme that has come up on this site several times, as well it might. I continue to think that if you could climb in a time machine and go back to, say, 1980 with these kinds of numbers (genomes sequenced, genes annotated, proteins with solved structures, biochemical pathways identified, etc.), that everyone would assume that we'd be further along, medically, than we really are by now. Surely that sort of detailed knowledge would have solved some of the major problems? More specifically, I become more sure every year that drug discovery groups of that era might be especially taken aback at how the new era of target-based molecular-biology-driven drug research has ended up working out: as a much harder proposition than many might have thought.

So it's a little disturbing to see the line taken above. In effect, it's saying that yes, all these advances have been enough to release a flood of new therapies, which means that there must be something holding them back (in this case, apparently, the FDA). The thing is, the FDA probably has slowed things down - in fact, I'd say it almost certainly has. That's part of their job, insofar as the slowdowns are in the cause of safety.

And now we enter the arguing zone. On the one side, you have the reducio ad absurdum argument that yes, we'd have a lot more things figured out if we could just go directly into humans with our drug candidates instead of into mice, so why don't we just? (That's certainly true, as far as it goes. We would surely kill off a fair number of people doing things that way, as the price of progress, but (more) progress there would almost certainly be. But no one - no one outside of North Korea, anyway - is seriously proposing this style of drug discovery. Someone who agrees with Enriquez's position would regard it as a ridiculous misperception of what they're calling for, designed to make them look stupid and heartless.

But I think that Enriquez's speech, as reported, is the ad absurdum in the other direction. The idea that the FDA is the whole problem is also an oversimplification. In most of these areas, the explosion of knowledge laid out above has not yet let to an explosion of understanding. You'd get the idea that there was this big region of unexplored stuff, and now we've pretty much explored it, so we should really be ready to get things done. But the reality, as I see it, as that there was this big region of unexplored stuff, and we set into to explore it, and found out that it was far bigger than we'd even dreamed. It's easy to get your scale of measurement wrong. It's quite similar to the way that humanity didn't realize just how large the Earth was, then how small it was compared to the solar system (and how off-center), and how non-special our sun was in the immensity of the galaxy, not to mention how many other galaxies there are and how far away they lie. Biology and biochemistry aren't quite on that scale of immensity, but they're plenty big enough.

Now, when I mentioned that we'd surely have killed off more people by doing drug research by the more direct routes, the reply is that we've been killing people off by moving too slowly as well. That's a valid argument. But under the current system, we choose to have people die passively, through mechanisms of disease that are already operating, while under the full-speed-ahead approaches, we might lower that number by instead killing off some others in a more active manner. It's typically human of us to choose the former strategy. The big questions are how many people would die in each category as we moved up and down the range between the two extremes, and what level of each casualty count we'd find "acceptable".

So while it's not crazy to say that we should be less risk-averse, I think it is silly to say that the FDA is the only (or even main) thing holding us back. I think that this has a tendency to bring on both unnecessary anger directed at the agency, and raise unfulfillable hopes in regards to what the industry can do in the near term. Neither of those seem useful to me.

Full disclosure - I've met Enriquez, three years ago at SciFoo. I'd be glad to give him a spot to amplify and extend his remarks if he'd like one.

Comments (40) + TrackBacks (0) | Category: Drug Development | Drug Industry History | Regulatory Affairs


1. Anonymous on August 19, 2013 9:05 AM writes...

FDA is certainly not the problem, they are merely responding to the requirement for greater safety and efficacy caused by new innovations raising the bar.

The main problem is in our misguided expectation that getting more data more cheaply corresponds to greater R&D productivity in terms of new patient benefits delivered per R&D spend.

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2. Anonymous on August 19, 2013 9:08 AM writes...

It's not about how many assays one can run or how many compounds one can make. It's all about how much we understand the human body. Can you recall how many drugs (and illegal drugs) were discovered based on adrenaline?

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3. Kent G. on August 19, 2013 9:23 AM writes...

I think this is a nice illustration of the distinction between data, information, and knowledge. Enriquez seems to have discovered that transforming data into information, and information into knowledge, is not straightforward. Welcome to the party.

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4. Anonymous on August 19, 2013 9:31 AM writes...

@3: ...and knowledge to understanding, and understanding to ideas, and ideas to working solutions.

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5. Bernard Munos on August 19, 2013 9:33 AM writes...

The loss of innovation culture in the industry can hardly be blamed on FDA. Poor leadership is a far more likely culprit. The CEOs who shifted "their primary focus from R&D of new drugs to increased marketing of existing drugs — and mergers and acquisitions" are the same folks who brought us six sigma, the industrialization of R&D, and the process culture that supplanted the innovation culture that made the industry great. Talk about a legacy... Thankfully, a number of companies have reacted against this nonsense, and taken steps to revive innovation. This is starting to show through more and better drugs.

FDA is doing its bit too, with breakthrough designations and an embrace of innovative therapies that must be acknowledged. To claim that it is responsible for the industry's woes is simply unfair. Management blunders must be acknowledged, and reversed.

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6. johnnyboy on August 19, 2013 9:56 AM writes...

No no no no. Enriquez is a business and finance guy, and like all business guys, he seems to be completely invested into the catechism that regulation is public enemy #1, and if only we could get rid of regulation what a wonderful world this would be (for business guys).
If FDA was really the problem, there would be a glut of NDAs but not many getting approved. That is not where the blockage is or has been. The real problem, as pointed out by others, is that, to paraphrase Barbie, Biology is Hard. Many, many thousands of times harder than any hotshot with a HBS degree could possibly fathom.

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7. Kelvin on August 19, 2013 9:57 AM writes...

@Bernard: I couldn't agree with you more.

The main barrier to innovation is that leaders need to be comfortable with uncertainty, and giving up their need to control things they cannot control.

Innovation requires a particular mindset to think big and different, start small, fail fast and often, and learn in the process. It means being willing to "let go" and explore the outliers, rather than establishing processes to avoid them and maintain the illusion of control.

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8. a. nonymaus on August 19, 2013 10:59 AM writes...

We may also be running into a lack of druggable targets for diseases that are seen as potentially profitable. Take Parkinson's disease, for example. When symptoms appear, it's because vast swaths of the CNS dopaminergic neurons are already dead. Short of a breakthrough from the labs of V. Frankenstein, H. West, or others active in the field of reanimation, I don't see dead neurons as a druggable target.
If you want to see things that are amenable to drug treatment and aren't already solved, start working on TB or protozoal diseases or something.

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9. pgwu on August 19, 2013 10:59 AM writes...

Many in this business seems to be going bottom fishing to de-risk, in effect, kicking the can down the road. FDA is just an easy target to pick for blames. Not saying there are no bureaucracies.

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10. Lola on August 19, 2013 11:20 AM writes...

@2 anonymous: one of the best comments I have read here. People should learn more about adrenaline and the discoveries it inspired, and how those programs developed and evolved. The stories of the antihistamine class and especially the H2 antagonists are particulary interesting; pay close attention to the timelines...

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11. No on August 19, 2013 11:24 AM writes...

FDA is not preventing anyone from curing cancer. They are preventing people (like Mr. Enriquez, I presume) from making money back on their investments into cancer treatments. Too bad. Prove your stuff has some benefit before you profit on it, especially since you're really only selling hope to desperate and unlucky people.

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12. Bernard Munos on August 19, 2013 12:20 PM writes...


You get it. Innovation cannot thrive upon law and order. Sooner or later, HR folks will need to come to grips with this. Innovators (the real ones) are rebels at heart. They are not interested in growing and nurturing existing markets beccause they want to obliterate and replace them with something better. They don't want competitive advantage from greater efficiency, because they want to change the game. They don't want to optimize, they want to disrupt and dominate the new markets they are creating. The most damaging legacy of the process-minded CEOs who brought us the innovation crisis has been to purge disrupters from the ranks of pharma. Yes, they are tough to manage, but every innovative company needs them, and must create a climate that allows them to thrive. Ideally the CEO should double as Chief Innovation Officer, and those who do have many grateful shareholders to thank them. Think Art Levinson, Roy Vagelos, George Yancopoulos (Regeneron), John Martin (Gilead) to name a few; but also Besos, Jobs, Gates or Branson outside pharma.

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13. Kelvin on August 19, 2013 12:27 PM writes...

@Bernard: Absolutely spot on, and you can count me as one of those purged rebels and trouble makers! :-)

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14. annon2 on August 19, 2013 12:40 PM writes...

Over the years, I've observed that FDA typically tries to be helpful, for example giving advice in a general way within a given treatment approach and/or disease area based on other information they've seen without giving enough details to compromise confidentiality integrity.

If providing safety with adequate chance of efficacy to warrant patient exposure in larger numbers means FDA is the problem, then yes FDA is the problem. Personally, when experiening the types of things that some scientists and clinicians would be willing to do, I've grown more appreciative of FDA's role of oversight & review.

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15. MoMo on August 19, 2013 12:41 PM writes...

Correct assessment Bernard. Meanwhile the teat suckers and saprophytes looking to cash in on Innovators and rebels are looking hungry- all because they let the MBAs run the shop and burn it to the ground. Using the FDA as an excuse instead of pointing the finger at themselves is a form of denial, its its only a matter of time before these finance guys have their cars repossessed, their houses in foreclosure and their wives run off with Yoga instructors half their age.

The same things that happened to all the good scientists that were cast out since the 2008 Pharma purge.

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16. zmil on August 19, 2013 12:46 PM writes...

The obvious response is that the speedier advances of the past were due to picking low hanging fruit, and now all the targets are super hard. But I'm wondering if there's a way to test this hypothesis; can we control for the relative difficulty of drug targets from each era in some way?

One approach that occurs to me is to look at emerging infectious diseases, and compare the speed at which we're currently able to develop treatments vs the speed of development of treatments to infectious diseases in the past. Presumably, since they're "emerging" they wouldn't be subject to the same selection bias as diseases we've been trying to cure for ages, like cancers and whatnot. Thus the percentage of low hanging fruit should look more like the percentage of low hanging fruit in the infectious disease field from, say, half a century ago.

One specific example is the speed with which effective treatments for AIDS were developed. It's really quite extraordinary: HIV was first identified in 1983, and the first truly effective treatment, the first generation of HAART, came around 96. But of course one would want to see how the entire field of EID has done over, say, the last 10, 20 years.

The obvious problem I see is that trends in that field might not apply in other areas, since antimicrobials are rather distinct in many ways from other drugs. But maybe there are other potential natural experiments of the same sort?

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17. annonie on August 19, 2013 1:02 PM writes...

As said earlier under another topic, we don't know nearly as much as we think we know about disease and it's underlying biochemistry and biology. The assumptions here are that imporved technology such as cheaper technology, access to more compounds, faster high-throughput screening, more gene sequences etc is what makes a drug. While these are steps along the way of the technical processes toward discover of a new drug, none really get down to the understanding of basic biology and what biochemical processes may underly given disease states. THAT is today's biggest problem in a nut-shell, full stop.

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18. Anonymous on August 19, 2013 1:04 PM writes...

#5 Bernard; #7 Kevin. An eloquent summary in your brief discussions

Bernard..."The loss of innovation culture in the industry can hardly be blamed on FDA. Poor leadership is a far more likely culprit.
Kevin..."The main barrier to innovation is that leaders need to be comfortable with uncertainty, and giving up their need to control things they cannot control. Innovation requires a particular mindset to think big and different, start small, fail fast and often, and learn in the process. It means being willing to "let go" and explore the outliers, rather than establishing processes to avoid them and maintain the illusion of control".

One of finest collection of reminiscences and honest analysis of, at times risk leadership and persistence, is contained in Vol 1 of Chronicles of Drug Discovery (1982),when scientists and science still ruled up to Phase I development. The tome contains the accounts, some scientifically turgid, others insightfully analyzing the professional and career risks taken by brave science leaders to champion their cause. The book is a frank revealation on the development of small molecule drugs and therapeutic areas encompassing Cimetidine, Clozapine, Clonidine, Atenolol, Ibuprofen, Rifampin, Cefoxitin and other standout (then) new therapies that ushered in the halcyon Era of drug development. This is an absolute must read to give perspective and credence to how strong leadership and persistence on the basic research level paid off

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19. Anonymous on August 19, 2013 1:15 PM writes...

Although I do agree that there is truth in his statement about "bloated process and downright hostile-to-innovation climate for FDA drug approvals" I think his conclusion on that being answer for lack of drug innovation is going way too far. While a significant contributing factor to assign as major cause is too reductionist (or bottom-line with faulty weighting). The FDA bureaucracy has indeed grown largely unchecked while the mission has expanded and resources inadequate or unfocused. The often mentioned high costs of Phase 3s probably is due to "extreme" FDA requirements. I am less sure about "this day and age" portion as I hope the many words and promises in recent times will help streamline demands and enable cooperation between the industry and FDA. It is too soon to tell and I remain skeptical that either side can really take positive advantage because of past antagonism, public pressures and general nature of the tasks and relationship.

I would suggest there are a number of elements that have made R&D cost so high or weakened innovation that to point only to a single item as being responsible will never capture essence of the issue. #5 BM makes an important observation about lack of leadership and change of focus from science as major issue inhibiting progress and also think others have well pointed out we have been able to increase the knowledge without understanding or effective translations. In many cases R&D became over enamored with the latest shinny new "tools", expected them to give sufficient answers all by themselves, and started to get myopic where ignored other critical aspects or continuing with older models. At the same time no one likes to talk about "Litigation" and although very hard to quantify the Torts/Legal situation has become a definite barrier at times to new drugs being developed.

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20. gwern on August 19, 2013 2:04 PM writes...

It's very easy to refute people who claim the FDA is solely the problem and who don't accept any claims about low-hanging fruit or saturation: simply ask why we do not see thousands of blockbuster drugs coming from low-regulation countries like China.

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21. Anonymous on August 19, 2013 2:09 PM writes...

@20: Well they did discover the benefits of melamine as an additive to baby milk powder in China. If only the FDA would allow such breakthroughs to pass through in the US.

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22. Bernard Munos on August 19, 2013 2:24 PM writes...


You can wear it as a badge of honor, because it is.

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23. daen on August 19, 2013 2:59 PM writes...

A slight tangent here.

I have quite a lot of sympathy for the FDA, especially the CDRH.

I came to the Bay Area three years ago since when I have mainly worked in regulatory compliance, initially for a company developing a thyroid test which wanted to go the 510(k) route to ensure that whatever happened in the IVDMIA LDT arena would allow their test to be grandfathered in once the dust had settled.

However, it didn't work out; at a meeting in SF in 2011, the 2007 draft guidance document was deemed to not be useful or complete enough to progress and was effectively shelved. Worse, a CDRH-instigated independent review of 510(k) and PMA procedures by the Institute of Medicine effectively declared the process irredeemably broken and suggested a complete overhaul. The company I worked for invested a lot of effort with an end-goal in mind which simply didn't materialize.

Now, I certainly don't blame the FDA. It's been clear that the 510(k) and PMA processes are hopelessly outdated. No-one want to go the PMA route, so you have this rather absurd situation where iPhone apps are going through 510(k) on the basis of equivalency. Really?

The solution is a comprehensive overhaul of the CDRH's remit, and to a certain extent (more pertinent to Derek's initial post) the FDA overall. I stress that I am a big fan of the FDA, but it is severely limited by the FDC Act and its amendments, very few of which, in my opinion, have materially altered the drug or medical device submissions process in a positive way.

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24. exGlaxoid on August 19, 2013 3:46 PM writes...

The problem is clearly very complex, but I see many factors. There are MUCH higher expectations of drugs now, once-a-day dosage, no side effects, no herg or P450 effects, high potency, high selectivity, cost, patentability, and more. Also, the long trial time and generic laws have lead to the idea that a drug must make tremendous profits in a short time to be worth developing.

Yet many drugs in the past were approved with major issues: aspirin, acetominophen, naproxen, tagamet, penicillin, AZT, sulfonyl ureas, valium, benedryl, seldane, etc.

Those first generation drugs are either still used or lead to second or third generation drugs that are much be