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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: Twitter: Dereklowe

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March 26, 2010

Diminishing Returns

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Posted by Derek

As we slowly attack the major causes of disease, and necessarily pick the low-lying fruit in doing so, it can get harder and harder to see the effects of the latest advances. Nowhere, I'd say, is that more true than for cardiovascular disease, which is now arguably the most well-served therapeutic area of them all. It's not that there aren't things to do (or do better) - it's that showing the benefit of them is no easy task.

Robert Fortner has a good overview of the problem here. The size of the trials needed in this area is daunting, but they have to be that size to show the incremental improvements that we're down to now. He also talks about oncology, but that one's a bit of a different situation, to my mind. There's plenty of room to show a dramatic effect in a lot of oncology trials, it's just that we don't know how to cause one. In cardiovascular, on the other hand, the space in which to show something amazing has flat-out decreased. This is a feature, by the way, not a bug. . .

Comments (40) + TrackBacks (0) | Category: Cancer | Cardiovascular Disease | Clinical Trials | Drug Industry History


1. darwin on March 26, 2010 10:57 AM writes...

might be oversimplified but if quality of life were as objectively quantified as surviability, wouldn't the rules of the game change?

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2. PharmaHeretic on March 26, 2010 12:12 PM writes...

I was not aware that we had effective drugs for treating arteriosclerosis, congestive heart failure and reducing ischemic and re-perfusion injury in MI and stroke.

Just because you cannot do it, does not mean it can't be done. Many famous and well funded "scientists" could not achieve what the wright bothers achieved in 1903. Same for the discovery of controlled nuclear fission (lise meitner ultimately succeeded where others had failed).

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3. davesnyd on March 26, 2010 12:39 PM writes...

The size of the trials needed in this area is daunting, but they have to be that size to show the incremental improvements that we're down to now.

So-- how much of "it is so expensive to bring a drug to market" is because of the real costs of clinical tests?

Or, how much of it is because everyone is looking for the next cardiac/lipid blockbuster and so they are forced, by need, into doing huge trials to get a statistically significant 0.4% improvement that they can then tout in their marketing?

Or, put another way, if you were looking to serve a smaller market, but one with little or no viable therapeutic options now, and could do phase III with, say, 200 people instead of 20,000; would you provide more net good, still make significant profits, but have lower cost-to-market?

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4. retread on March 26, 2010 1:16 PM writes...

There are plenty of diseases out there with no effective therapy. Is it because I'm a neurologist that so many seem to involve the nervous system? Anything really helping Alzheimer's disease, amyotrophic lateral sclerosis (ALS), reversing the deficits in multiple sclerosis, curing glioblastoma multiforme, reversing the deficits after a completed stroke, Duchenne muscular dystrophy (or any hereditary muscular dystrophy) etc. etc. will be screamingly obvious without a large clinical trial. Patients and their families with any of the above would love to worry about diminishing returns of the latest drug.

There was only one trial of the Salk vaccine for polio. Similarly, the effects of L-DOPA were very easy to see and very convincing immediately.

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5. fred on March 26, 2010 1:59 PM writes...

Retread and PharmaHeritic are right: the NEED is there; the WILL-- maybe not.

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6. cynical1 on March 26, 2010 3:12 PM writes...

Let me applaud and echo Retread and PharmaHeritic's comments. From personal experience, I have seen one major pharmaceutical company run itself into the ground by only working in areas where the unmet medical need was minimal and the hurdles to improve on safety and efficacy enormous. (Ironically, the only ray of sunshine in their pipeline is a phase III lupus drug they in-licensed.) This strategy was brought down from the marketing groups alone and the R&D management would parrot whatever line of twaddle they were fed. "Not enough patients." "Too risky" "Only proven mechanisms" "We only want blockbusters." They wouldn't have known a blockbuster if someone had dropped a pallet of it on their heads. Staff who openly argued with that strategy were punished and/or layed off. The downfall of our industry is neither surprising nor unexpected. And the people who were piloting the Titantic are still in charge and clueless that they've hit the iceberg. Good riddance to bad rubbish.

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7. Skeptic on March 26, 2010 4:01 PM writes...

The consumer isn't screaming for innovation...they are however screaming for LOWER PRICES. They don't give a damn where it comes from either. So who is in the med chems corner:

Taxpayer: Nope
Consumer: Nope
Fractional Reserve Bankers: Nope
Whatever chemistry society: Nope
Doctors and Pharmacists: Nope

There you go. All you have is your naive belief in "my skills will save me"...Ha!

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8. milkshake on March 26, 2010 4:12 PM writes...

I am rather tired of the "all low hanging fruit was picked" argument. I bet all these "easy" targets got easy only in retrospect, after the breakthrough drug and additional me-too follow-ons got on the market.
The problem is 1) management bonus schemes and managements long-term irresponsibility for its actions 2) obsession with target-driven drug design

I would rather like to see more primary screening done in animal models and cell cultures, even without the detailed mechanistic understanding. Thats how the drugs were historically discovered. The mechanism of action of Tylenol was only elucidated few years ago. (Now, try to find funding or even secure an approval for a drug that acts through unknown target).

My complaint is that projects nowadays start with identification of a protein or receptor that is supposed to play a role in some pathology, then proceed to develop a ligand and perturb the function of the target. More often than not the outcome is that the biology does not work as intended in vivo, or does not work at all.

Its like putting the cart before the horse - working out some molecular biology solution first and then be on a lookout for a problem that could be fixed with what you had developed.

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9. Nick K on March 26, 2010 6:09 PM writes...

Thank you, Milkshake. A concise and well-argued diagnosis of Big Pharma's malaise. I couldn't agree more. The current, dogmatic approach you describe virtually precludes any breakthroughs by serendipity.

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10. Dave R on March 26, 2010 6:24 PM writes...

Hear hear milkshake. Exactly right!

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11. MIMD on March 26, 2010 6:39 PM writes...

The low hanging fruit, let alone anything higher, can't be picked when the midgets have laid off all the giants whose shoulders they might have stood on.

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12. anon on March 26, 2010 9:22 PM writes...

Milkshake (as usual) and sceptic both make astute points.
"The consumer isn't screaming for innovation...they are however screaming for LOWER PRICES."

In general, true. No one wants to actually PAY for something they may have to take everyday. Human nature. But, I am a consumer, too, and I understand that if a drug really improves the quality of life I WANT IT. The difference is that I understand the blood, sweat, and tears (and rat poop) that go into getting something from the round bottom to the pharmacy shelves.

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13. Anonymous on March 26, 2010 10:18 PM writes...

Agree with Milkshake@8 about over-emphasis on target-driven drug design and desire for more cell-based screening.

However there is often a lot of resistance from many of those who began screening in the 1990s and some medicinal chemists to de-emphasizing the target-based approach. As ahistorical as this view may be, it is argued that a cell assay is a black box in which the molecular target is unknown.

How might such resistance be overcome?

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14. Fred on March 26, 2010 10:34 PM writes...

Milkshake is absolutely correct. Essentially biotech killed it. Once the "money" threw down with the biologists we became lost in the maze of omics this and combi that. Somebody count the dollars.

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15. AR on March 27, 2010 6:40 AM writes...

Yup, I have to side with those who decry reverse-chemical genetics and reductionist approaches to complex biology. Any measurement of biology using various probe/over-expression/under-expression techniques, starting with the recent sirtuin-tagged debacle to the 1990’s favored knockout mice have rarely produced clinical robust targets. There are a few exceptions, but over use of genetics-based approaches seems to merely document skewed biology, or worse, provide incorrect biology.

Going back to the black-boxed cell won’t provide all the answers considering the in vitro grown cell has a separate set of issues, too, but it will start with the more ‘normal’ complexity necessary to drive correct biology.

As a biologist I have to ask this question: how much of reverse chemical genetics approach was pushed by pharma med chemists who always chose the simple in vitro binding/inhibition/reporter type assay results over the usually inconclusive whole cell screening approach?

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16. Cellbio on March 27, 2010 12:46 PM writes...

Agree with Milkshake, and, anon 13, tried to overcome resistance. Ran a cell based screening program in primary immune cells, screened whole libraries, diversity sets, focused collections, and could show greater specificity than existing drugs and "target" focused medchem leads with clear SAR that would support compound selection. The biological profile was derived from multiple measures, and more stringent than target-based efforts biochemical counter-screening in terms of maintaining the pharmacology signature. Yet, still not able to overcome the target bias. Convinced some, but the folks that interface with the FDA were uncomfortable with the uncertainty of exposing humans to an agent that might impact a target whose function in critical human biology would not become apparent until the first exposure to meaningful doses. This kind of argument is hard to overcome, because it anticipates the most severe outcome and anticipates species selectivity. Actually had the head of R&D invoke the possibility of the target expressed in one or two cells that might be critical for regulating heart function, and we'd never know until the dosed individual crashed to the floor.

In contrast, people remain comfortable exposing humans to drugs whose pharmacology is poorly understood, as long as they can draw a simple cartoon and invoke a target and pathway. This is intellectually vacant, as imposing a paradigm and failing to measure additional aspects of a compounds impact does not equate to selective biology. But at least you can tell the FDA the "target" is not expressed in liver, so we don't expect liver tox. I saw this method of project management become the default for advancing against internal metrics and securing bonus etc. Actually had people refuse our offers to profile their leads. They would rather fail in GLP tox or Phase 1.

I gave up and left for start ups where I could pick the team I work with.

Milkshake, I hope we get a chance to work together.

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17. milkshake on March 27, 2010 2:39 PM writes...

We will see about that.
You got gmail.

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18. done that on March 27, 2010 2:46 PM writes...

For 8, Sorry, but Milkshake is melting:

Many of the highly researched therapeutic and disease areas with the greatest unmet need today do not have suitable, accepted, in vivo models or even half-way decent cell based systems that project outcome for successfully treating human disease. They are not like a drug for blood pressure which can be modelled nicely preclinically with one dose, or antibacterials which can be tested predictably in plates for activity. This is one of the big contributers as to why productivity for new drug approvals are down as the bulk of theapeutic areas that are still unmet don't have good pharmacological models applicable to human disease and treatment.

Another perspective applied to practitioners is that today's discovery medicinal chemists are so accustomed to only making mg quantities of new molecules, that they often balk at requests for provision of larger quantities (tens of grams) when biologists are interested and willing to conduct in vivo studies.

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19. milkshake on March 27, 2010 3:08 PM writes...

One can have useful model in engineered animal like zebrafish. And even with mice one does not need 10g of material, 500mg is plenty for the initial screening in mice. And cell cultures need very little.

The main complaint against in vivo testing is that it is so low-throughput.

I am not saying that everything must be tested in animals first, only that more projects should start with a realistic model of the pathology, and sometimes it would be helpful to try to find a provisional chemical series that do something useful in the model - even if you don't know the actual target of these series. That could be elucidated later, finally followed by HTS with the identified pure protein and with new series (to see whether the mechanism still holds) etc.

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20. Anonymous on March 27, 2010 9:24 PM writes...

good day for ARCA Biopharma today.You will never know the future.So stop trying.As the Hindu holy book Bhagwat Gita says 'Do your dharma or in this case research.Do not worry about the consequences'.

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21. Skeptic on March 27, 2010 11:12 PM writes...

Productivity is a problem only because there has been a growing number of leetches sucking the chemists (and other scientists) dry.

Those sickening TV ads don't say "Go see your chemist". Those swank charity events for [pick your disease] wouldn't work if the chemists replaced the celebrities. The chemistry lobby well doesn't even exist. The guru's on TV proclaiming "this potion will make you live forever" are not representatives of some chemistry society.

Marketing, insurance hucksters, pharmacists, executives, doctors, etc...all elbowing out productive scientists for a greater share of the pie.

And what do they really bring to the table in terms of added value?

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22. DrZZ on March 28, 2010 9:31 AM writes...

Its like putting the cart before the horse - working out some molecular biology solution first and then be on a lookout for a problem that could be fixed with what you had developed.

As opposed to more empirical approaches where you pick some model system and when you find something that works in that model you go on the lookout for a clinical population that your model is relevant to. And how do you do that. Probably by looking for the molecular mechanisms that drive the model and see if those mechanisms apply to the clinical situation. Wherever you start, if you don't have good evidence on how your tools relate to the ultimate goal, you are going to run into significant challenges. The most important thing isn't the tools you pick, it's how well you plan for the particular challenges that apply to the approach and problem you choose to work on.

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23. done that on March 28, 2010 2:19 PM writes...


You are one of those ulitmate dreamers who can come up with wild schemes that will lose a company much money on technicals adventures, or make sure of financial failure if in a small biotech.

Efforts at trying to come up with models in zebrafish are not in use in Pharma because,they are are simply not practical. How do you administer an oral compound? How does one monitor "normal" physiology?

Further, mice cannot be used to construct models for many human disease states. The idea that this is ubiquitous to all human conditions is over-done-hype. Analogous to the hype that combinatorial chemistry will be used to find development candidates faster, increasing the flow of new drugs to the market. In both areas, after more than 10 years, where's the meat? Don't be so naive in always taking in the hype...a great way to lose a lot of money if you'd take seriously every highly touted concept promoted in the biotech world.

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24. Cellbio on March 28, 2010 2:42 PM writes...

DrZZ, I agree that, if this is a fair interpretation, using animal models to explore mechanisms is the best practice, and add that use for "efficacy" is pointless. The utility of this approach is limited by the uncertainty of knowing what mechanism is relevant to human disease, or perhaps to say it more precisely, to any particular human.

In my experience, the mechanisms are most often clarified when clinical utility is demonstrated, or perhaps more often refuted with clinical failure. This fuels the me-too approach as the path is clear. However, I will add that the molecular mechanistic explanations simplify the pharmacology of a compound, and it is likely that many drugs, gleevac for sure, statins also, are efficacious because of polypharmacy. This aspect can be better fit into drug discovery by restoring, and upgrading, cellular pharmacology approaches, and as said above, turning animal pharmacology into mechanistic measures, not clinical surrogates. My opinion anyway.

Having working signal transduction and molecular biology for nearly 30 years, yikes, I think our ability to overestimate our understanding of molecular mechanisms in human pathophysiology should not be underestimated.

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25. DrZZ on March 28, 2010 3:43 PM writes...

Having working signal transduction and molecular biology for nearly 30 years, yikes, I think our ability to overestimate our understanding of molecular mechanisms in human pathophysiology should not be underestimated.

I agree completely, but empirical models are no one size fits all magic bullet to route around that lack of understanding. Whatever tools or models you use, it is unlikely you will be very successful if you don't understand their limitations and while there are major gaps in understanding molecular mechanisms, there are major gaps in understanding how cell culture and animal models relate to actual clinical utility as well.

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26. milkshake on March 28, 2010 5:05 PM writes...

I worked for three companies that did target-driven rational drug design with varying degree of success. What bothered me was that the biochemical assays that were used as a primary screen did not reflect well the activity in cell (not only because of the penetration/distribution/cell metabolism issues - but simply because some of the protein assays were quite artificial, with incomplete sequence protein being expressed and being part of an artificial reporter system that was designed to work well for HTS.)

Now, the some of these hits could be elaborated to work in cell, but some did not for reasons that were nebulous, but we tended to trust the cell data more. Then we went through many rounds of potency/selectivity/CYPs and DMPK optimization, to get a sensible compound with unbound levels in plasma that were sustained for some time above effective concentrations, and then you look again for animal model for markers of inhibition of the target in vivo. Then, if there were no unexpected snags like hypotension shock or pronounced organ tox in animals we went for efficacy studies in vivo.

This is quite a typical "screening funnel " and it contains a long chain of ifs. When you use this approach it takes only one link of the chain to be slightly unrealistic and you go off the rails, optimizing your compounds based on irrelevant criteria while throwing away good ones.

So yeah, eventually you need to know your target. But pathologies like type II diabetes or glaucoma or Alzheimer may have more than one target driving the disease, with feedbacks mechanism that are hard to figure out, so we might as well take an existing compound - ideally an approved drug with off target activity in our assay - and try to optimize it in vivo even if we have to put up with low throughput and mixed SAR and unclear mechanism of action for awhile. Only then you try to figure out the responsible protein.

Also, I should mention that money lost by small biotech companies going belly up for pursuing an untested methodology platform is negligible in comparison with the money wasted by big pharma in the blockbuster heard mentality. Medchem and biology part of drug discovery is not that expensive compared to a phase III failure.

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27. Cellbio on March 28, 2010 5:28 PM writes...

Agree with you ZZ. The only way I know how a cell assay I develop relates to clinical trials is to have clinical trial data...very empirical. Also agree with the one-size fits all comment. Unfortunately, this mentality is not prevalent in Pharma, and development proceeds much the same way for all projects, with obvious variance, including an overemphasis today in the utility of biochemical screening and funneling strategies. I believe this approach is not bad per se, but runs off the rails when the pharmacology probed in cells and animals is restricted to the biology related to the biochemical hypothesis. This funneling becomes more than a manner of triaging work, and puts real limits to the scope of questions that can be probed.

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28. Nick K on March 28, 2010 6:16 PM writes...

I've always wondered how many great drugs are sitting undiscovered in compound collections because senior management was too wedded to mechanistic approaches and failed to test them in disease models...

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29. Anonymous on March 28, 2010 7:09 PM writes...

In Milkshake's defense (not that he needs it), we need more ultimate dreamers. Without risk, there is no innovation. Once we go from risk-taking mode to safe self-preservation mode, we become slugs.

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30. Pharmachick on March 29, 2010 2:49 AM writes...

Couple of things spring to mind here (sorry for being late to the party ... my timezone is somewhat off):

1) davesnyd has got a point (kindof) ... but the way I would put it is that "Why bother doing a trial of 200K participants to effect a 0.04% improvement, when you could find a REAL outcome variable and do a trial of old school proportions e.g. 60 % improvement with 800 people". (I would venture to contend that the esteemed Dr. Black himself; would likely approve of such approaches ... i.e. strive to cure not dampen symptoms) ...

2) I wonder if all this low-hanging fruit argument is somewhat true and not-true:
true because you can no longer do a Phase III in 500 people and get approved for "every person in the known universe" ...BUT...
"not true" in the terms that "low hanging fruit" now applies to symptoms/disease that are still "obvious" [and also, on that note: obviously genetically or developmentally 'abnormal'] but since the rest of the obvious ones are either solved or put in the "too hard" basket .. obvious is becoming rather harder to solve.

just another 0.02 for the current LHF argument

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31. LondonChemist on March 29, 2010 2:54 AM writes...

How about a quick survey: what areas of human health problems are NOT effectively met by current treatments?
I'll start with chronic pain (especially neuroapthic) and TB. Debabtable about malaria.
Any other thoughts?

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32. Pharmachick on March 29, 2010 3:12 AM writes...

Sure London Chemist,
good idea ... but the sheer number of diseases/syndromes we could all add within a few minutes would be mind-boggling.

To whit, within 1 minute I can come up with ...

"pretty much all tropical diseases" including (but not limited to):

trypanosomiasis etc

Also, in the non-tropical-disease field:
Canavan's disease
Wilson's Disease
Cystic Fibrosis
malignant melanoma

Okay I'm done. Bet you there are so many more out there... Y'all need to remember that Drug Disc & Dev. is a crossroads of input and output.. for some of these diseases the patient population is small enough that big Pharma says "Meh" ... for others the etiology is unknown, too hard, not sufficeintly understood etc.

Good luck!

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33. Anonymous on March 29, 2010 7:26 AM writes...

"I would venture to contend that the esteemed Dr. Black himself; would likely approve of such approaches ... i.e. strive to cure not dampen symptoms"

I'm not so sure given that he invented one of the biggest ever symptomatic dampeners in cimetidine.

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34. Anonymous on March 29, 2010 7:49 AM writes...

None of this is really news - you don't see many big pharma with cardiovascular research groups any more and the reason is obvious. The patients simply won't pay for relatively small improvements in outcomes. While it is easy to blame the companies (and god knows they've screwed up in all sorts of ways) fundamentally the industry has a problem with affordability. Most diesases are simply not homogeneous enough to give us a large enough group of patients to treat - as companies who have invested heavily in oncology are rapidly discovering. As most countries have a cost/benefit ceiling for therapies we can't simply pursuit smaller and smaller patient populations. Where maybe we might have a chance, for example Alzheimer's, we're getting our patients to late in the disease process to really have much of a chance - but if we wanted to treat earlier we'd be faced with very large long term trials on ostensibly healthy individuals to show any kind of positive outcome.

So I think there is a good case for arguing that the current sytem of funding for drug research is broken. Essentialy companies have to try and recover too much money over too short a time (when they are successful) coupled to a very high risk of failure in the R&D phase anyway.

Until intellectual protection is extended to a more sensible term on drug discoveries I don't see any way out of this bind. I'd prefer to see a long patent extension granted on first approval for new entities.

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35. current bind on March 29, 2010 9:43 AM writes...


Longer patent extensions are not a fix for the lack of success in the last decade in making new drugs. This is just a way for Pharma to continue with their current inefficient ways based on the model which gave many blockbuster successes of the 70's to mid 90's. It only slows down the train toward pharmaceutical downsizing, consolidation, forcing companies to work differently, to design different business models, to accept that the profits of the past are a thing of the past.

There will still be a drug industry, but it will be different in the future. R&D will not be able to look like it did in the 90's or even like it does now. Where it goes is not clear, except that there will be fewer people in big pharma doing discovery while still spending a lot of money since so many phase 3 trials require long studies with hundreds of subjects.

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36. Anonymous on March 29, 2010 10:17 AM writes...

"It only slows down the train "

Nope - it would turn some disease areas into reasonable investment opportunities. You can always babble on about needing to change business models but there is no doubt that research into some of the neurodegenerative diseases in particular would be hugely boosted if it were possible to imagine running longer time clinical trials and still generate a meaningful financial return. The current sytem which only delivers short term financial returns for the innovator companies is part of the problem. The shift to biologicals at the moment is largely driven by the (mistaken) belief that protection from generic medicines is going to be more straightforward for this class of drugs. It has very little to do with target doability or development costs.

In your model "current bind" we will still have large long phase 3 trials but you've not explained who exactly is going to pay for them. Since we can't increase population numbers for many of these diseases nor reduce development costs, the only lever is to increase the time over which the investment is recouped.

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37. doctorpat on March 29, 2010 7:14 PM writes...

The consumer isn't screaming for innovation...they are however screaming for LOWER PRICES.

I for one would happily pay a lot more for a warfarin substitute that didn't have all the other problems with eating rat poison. I suspect that only the consumers who have good medicine for their particular problem are ignoring the need for innovation.

My best hope is that India and China get sufficient commercial protection (at least for domestic companies) that they can start doing serious research in a way that avoids the traps the western system has gotten caught in. (And do mass trials at third/second world prices)

Don't get me wrong, they'll get caught in their own traps. But having multiple cultures of research and development can only increase the chances of some group finding a way around each trap.

Of course it might lead to a vast (illegal) drug trade in stuff that the FDA hasn't approved yet. But that doesn't concern me at all.

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38. milkshake on March 29, 2010 8:18 PM w