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Well, this is interesting. US Gov’t to dabble in drug discovery?

It looks like the NIH is going to start screening for new drugs.  Here’s a quick and dirty primer on how drug discovery works (via me):

There are two different paths to discovering a drug.  In the first path, a database of gene sequences are scanned for a potential “target”.  The target gene codes for a protein or receptor that is implicated in a disease state.  Biologists make the protein and use robots to test a library of potential “ligands”, drug compounds, against the target.  These libraries consist of hundreds of thousands and possibly millions of compounds.  When  a compound interacts with the target and elicits the right response, it is called a hit.  The hits are passed to a project team of biologists, chemists and drug designers who examine the hits, select the most promising ones, ie, the ones that look like they won’t be toxic or too hard to work with and which provide places for modification.  The team then engages in a years long struggle of iterations.  The drug designers propose modifications, the chemists make the modifications the designers suggest (or not, as the case may be.  Convincing a chemist to make a drug is the most challenging aspect of the whole endeavor, IMHO.) and the biologists test the new compounds and say “hotter” or “colder”.

There is a lot of other stuff going on in the background.  There are structural biologists who can sometimes crystallize the protein in question and make it a lot easier for the chemist and designers to see what the hell they’re doing.  Also, there are groups that test the compounds for properties other than how effective they are against the target.  Those things include toxicity, mutagenicity (how likely they are to cause cancer and birth defects), bioavailability (how easily they get into your system through the gut, stomach or blood-brain barrier), solubility (how easily they dissolve), metabolism (how your liver breaks them down and into what byproducts) and cardiotoxicity (does it make your heart spazz out).  Note that this list is not exhaustive.  The FDA is very strict about what goes into your body and drug discovery takes these regulations very seriously.

Once the potential new drug is ready, it gets passed to a development group for scale up and clinical trials.  This whole process takes a long, long, LONG time and there are many failures along the way.  It is also extremely expensive.

The other path is to bypass the gene target identification route and simply test a bunch of compounds, that are already sitting around, against a desired endpoint.  This is known as a phenotypic screen or high content screening.  In this case, the drug company does not know what the target is, well, not at first.  Instead, the tests that are conducted against cells and a desired outcome is noted.  After the phenotypic screen finds hits, it is sometimes possible to deconvolute the pathway that the compound affected and identify the targets.  In this scheme, the discovery process presumably starts out with drug compounds in the library that are already known to have desirable or promising safety profiles because they might have been worked on before for different projects but they weren’t active enough against the target they were made for.  But that doesn’t mean they can’t be used for something else.

The last pathway is what I think is going on with this new initiative at the NIH or at least that’s the way I interpret it.

There’s a lot of factual data in the NYTimes article about what the drug industry is up against.  It remains to be seen whether this new initiative will be good or bad for the industry or the public.  I can imagine many possible scenarios as to how it might turn out and some worry or encourage me more than others.

In any case, go read it and when you’re done, I’ll try to answer any questions you might have in a broad, general way.  I can’t speak for my industry or company and wouldn’t want to anyway.  But general information I can do.


Here’s a weird comment from the same article:

Great. So now taxpayers will be liable when there’s a problem. I hope there’s some kind of handoff program to private industry at some point in the program to avoid problems like that.

Soooo, let me get this straight.  The ability to sue is still of utmost importance.  Did I get that right?  Because, from where I sit, the class action lawsuits are part of the problem.  Everyone complains about not reining in the big finance guys but ambulance chasers looking for big bucks who glom onto adverse drug reaction reports like blood sucking ticks are all ticketyboo?  It’s *not* ok to curb the lawyers?  I mean, presumably, the government would not be interested in deliberate negligence and injury brought on by a joint venture, right?

Just curious.

Another commenter who doesn’t quite get how the industry works or didn’t check the graphs on the side of the page (they are pretty accurate):

Its about time. Our drug companies have lost focus on what is really important. All they concentrate on is profit and the FDA is complicit in its approval process. New drug application fees should be abolished also. One drug turns into 5 or 6 all with patents and huge costs are passed on to the US consumer. We do not need over half of these meds for they really do not benefit anyone other than the profits of big pharma. Do we actually need dozens of antidepressants or drugs for male impotence?

I’ve seen many good drugs taken off the market because of unexpected side effects.  It happens to all of the companies in the industry.  I’ve also seen drugs that the industry has spent billions of dollars and years to develop go before the FDA and get shot down.  There goes a huge investment.  It’s hard to justify taking that kind of risk with shareholders’ money, especially when money making drugs are going off patent and there’s nothing in the pipeline that can get approved.  If the FDA and the pharmaceutical companies are colluding with each other, you would expect a whole lot more drugs getting approved and the numbers simply don’t bear that out.  Sooo, I would safely ignore this commenter as dreadfully uninformed.

43 Responses

  1. My mistake was taking Biology for Non-Science Majors. I’ve never caught up since. Is it too late to sign up for Real Biology 101?

    [Edited to add] This is a serious question. I should never have taken the non-science track in my early college years. But, I was brainwashed by my mother who hates all sciences.

    • I’m the wrong person to ask. Biology has always been easy for me.

      All you have to remember is that genes are made from DNA that is stored in the nucleus. The DNA is transcribed to RNA, which is able to leave the nucleus. The RNA is translated into amino acids on the ribosomes, which are like little protein assembly units located on the endoplasmic reticulum. The proteins that come off the ribosomes are sometimes encapsulated into packets on the golgi apparatus.

      Here’s a more in depth primer on the process: http://staff.jccc.net/pdecell/proteinsynthesis/translation/steps.html

      • I flunked biology sophomore year (high school). But, Aced it in the makeup class. Found out later that summer that my original teacher ran off with the principal to Arizona after the last class of the semester. I’ve always wondered if I really flunked or if she was distracted.

        In any case, it was a pretty serious blow.

        • Biology now is nothing like the biology we took in high school many years ago.

          So, really, you can start fresh! 😉

      • (remembering) There had to be something wrong at that school because I also flunked geometry. And I’ve never made anything less than an A in my college math classes. (maybe I didn’t show my work?)

        • Seriously, I wouldn’t beat myself up over it if I were you. It’s really just DNA=>mRNA=>tRNA=>amino acids x amino acids linked together like the individual cars on a train with the same linking system => folded protein that does something cool and groovy in the cell.

          You might have had a bad teacher or it could be that the intersection of molecular biology with traditional biology was just too weird to be described well back then. We know a lot more about how this stuff works now.

      • OK — now you are freaking me out.

        THAT’s the school where I took the “Biology for Non-Science Majors” class!! It’s my county Junior College site.

        • Like I said, it’s totally a different science now than it was back then. You wouldn’t recognize it.

          • Wow. What did you guys do before the human genome project?

          • Um.
            Phenotypic screening.
            (ok, stop laughing)

          • So, looking for mold spores in a pot of cooked corn, then.

          • Something like that.
            Before we had the gene databases, we weren’t able to identify the specific targets. While using target information has been very useful, it can also be too specific. There are many potential targets along a biological pathway. For example, if we are studying a particular kind of cancer, there may be many potential targets from cell signalling to replication to programmed cell death and the target that is behaving badly maybe any one of a number of proteins and receptors in that pathway. If you only focus on changing the behavior of one particular target, you may end up upsetting a whole cellular ecosystem and trigger other proteins in the pathway to compensate.
            In phenotypic screening, all you’re looking for is the endpoint. Does the tumor cell grow or not grow? If you’re still interested at a latter point in time, you can break down the pathway under study into its component parts and figure out where the drug is acting but this is not strictly necessary. If the drug is safe and effective and doesn’t cause upregulation of other compensatory cellular mechanisms, then there’s really not a whole lot more you can ask for. You’re done! Move to the next pathway.

  2. Does the NIH patent its discoveries?

    • Good question. Who gets the patent? I guess it would depend on a lot of things. Like, whose compounds are getting screened? For what purpose? How much discovery goes on after the hits are handed over to the pharmaceutical companies? Screening is very early in the process. The drug companies will presumably still spend a lot of money doing the grunt work. The final product may look very different from the initial hit.
      I don’t know how these things are worked out. It’s not my area. Ideally, it would be a win-win for both government and the drug companies. Maybe the patent is shared? I don’t know the answer to this question but I’m cautiously optimistic.

  3. RD in your opinion is the main point that drug development has slowed to a dangerous pace really valid? Is it bean counters who have caused this or have the drug companies hit some science based barrier that must be overcome before they can pick the pace back up?

    • Disclaimer: Before I get started, note that these are general trends and observations about things that are happening in just about all companies in the industry. It’s not a comment on any one company. I’m not speaking for the industry and I don’t know all of the things that are going on behind the scenes so do not consider me a resource or authority. But, if you talk to researchers at any one of them, you’ll hear similar themes. In my opinion, there are several causes for the lack of new drug approvals, all of them collaborating in a perfect storm:
      1.) FDA regulations and requirements for clinical trials have gone up. I don’t think anyone would argue that too much safety is a bad thing though.
      2.) Class action lawsuits have siphoned away a lot of money that might have been spent on research or returned to the shareholders, some of whom may be us. Wyeth, which no longer exists, paid out more than $32 Billion dollars to class action lawsuits over phen-fen. (That whole lawsuit was very hinky IMHO.) In response, drug makers are very very skittish about carrying a drug candidate through if there is even the slightest chance that it could result in being pulled from the market. Compounds don’t even get into man if there’s an in vivo study that shows any potential problems no matter how small or borderline they are. Companies simply can’t take a risk of losing billions of dollars.
      3.) Too many mergers. This has had an enormous effect on the research process because the merger mania has taken place at a time when the biological sciences are going through a kind of revolution. Research that is started-stopped-restarted does not go smoothly.
      4.) Technology. We’re learning so much all of the time about how things work and developing new techniques and this just takes time. And money. And shareholders aren’t very patient so there’s a lot of rearranging of the deck chairs to make things go faster but while that might work for automobiles, you can’t rush a tissue culture.
      5.) Fads. The industry seems to careen from one to the other. First it’s high throughput screening, then it’s combinatorial chemistry, then it’s systems biology. All of these things are happening at the same time. But there is a lot of investment in a technology that still needs to work out the kinks before it is abandoned for the next big thing.
      6.) Outsourcing. I hate to sound like a broken record but sometimes, there’s just too damn much of it. For drug discovery to happen in the best of circumstances, all of the parts have to work together more or less smoothly and that can’t happen if every week, you have do deal with another bunch of contractors who are now handling some administrative task that used to be handled by an internal unit. You have to wait for them to get up to speed and for you to learn the new SOP. It’s time consuming and wasteful. Whatever money the braintrust who wrote the contract thinks he’s saving is getting eaten up by delays in getting things done.
      7.) Managerial fads. I won’t go into this because the examples are too numerous to recound and every company has their own examples of new systems that failed and were never going to work from the outset. And sometimes, VPs of research who seem to know what they’re doing and who are liked and respected are replaced by suckups who have absolutely no clue and are more interested in climbing the ladder. (happened in a previous life. It didn’t go well with the replacement)
      8,) Insufficient research personnel. I know that sounds crazy but in all my years in research, most of it was spent under a hiring freeze.That means every project team has to carefully prioritize its work and timeline and fight for FTEs. When you have to sit around for months waiting for ADMET data on your compounds, drug discovery goes nowhere. OTOH, there are quite a few people who could and should be offered a chance to retrain in another area. A more flexible staff might be able to overcome some of these bottlenecks.
      9.) Spending money in the wrong places. Might I suggest that moving research facilities from the midwest to the coasts was not the best use of money. Sure, there’s more culture in Boston and NY and San Francisco. But the prestige of having facilities located there means that the scientists have to be paid a whole lot more. And there is this thing called the internet. You can do all kinds of things with it nowadays, if you could only get your IT department to learn how to use it. If I were king of the forest, I would have a satellite office in Cambridge, where all of the hot spit is happening these days, and the major research facilities in Kalamazoo. You could pay for a lot more staff at a much lower cost of living. JMHO.

      In summary, it takes time and resources to do it well and in this era of quarter to quarter expectations from the shareholders, that just isn’t possible.

      • Forgot to mention patent expirations. You need to file patents early but the clock starts ticking immediately once they’re granted. So, that means if a drug is tied up at the FDA waiting for approval, there’s less time to recoup the investment. I have no idea of knowing how many therapeutic agents could be approvable but aren’t because there is no way to make any money off of them. Legal is not my area but I suspect that the industry passes on opportunities because of the patent issue.

      • I forgot to mention that Derek Lowe’s blog, In the Pipeline, touches on many of these issues in a more informative way but you’re likely to be over your head if you’re not familiar with how the industry works. Still, very much worth a visit if you’re interested in what the industry is up against.

  4. Do I read the post correctly? Do we need to help the pharmaceutical companies to overcharge us? Somehow in Europe and Canada, similar drugs cost a fraction of what they cost in the US (personal knowledge).

    • Yes, you are the only person in America with personal knowledge of the cost discrepancy between the US and Canada.
      How would you propose bringing the cost of drugs down? You can’t complain if you don’t have any suggestions.

  5. ahhh, Packers just won it by 7-

    • BTW, This is a Steelers only blog. Thou shalt root for the Steelers and only the Steelers.

      • LOL.

      • This is not a laughing matter. Do you think it’s funny???
        Steelers. Repeat after me: “GO STEELERS”

        Good, now no more lip.

        • butttttt, but I want Steelers V. Packers….

          And considering the Packers beat the Jets 9-0 earlier this season, I am guessing the Steelers seem a bit scarier at the moment

          (okay, I shall now end my lip)

        • Now look what you did, RD, that was a total wipeout!

          The Eagles were a complete fail, so I’m glad the Steelers won.

  6. From the nyts article:
    Whether the government can succeed where private industry has failed is uncertain, officials acknowledge, but they say doing nothing is not an option.

    For any company to suceed it has to make money. The fed gov doesn’t have to make a profit or even break even. IMHO: The fed gov should step in where business can’t.

    But this is disturbing:
    drug companies have typically spent twice as much on marketing as on research

    Like to see that change.

  7. There shouldn’t be any privitization of medicine in that case, since private companies are not able to control so many important factors. Creating medicine should be part of public policy. Healthcare policies must move beyond insurance policies.

    • The public sector and regulation sucks too.

    • Ok, fine. Who is going to discover medicine for you then?
      Just curious. Because a lot of scientists don’t enter the working world until they are in they’re almost 30, after college, grad school and their post doc. Sooo, this is not the easiest field to learn and practice. There’s got to be a good living in it, I mean, better than delivering mail or processing passports, or no one will want to do it. We can make more money becoming quants on Wall Street and you can get your new medicines from India where they may be more interested in a whole host of diseases that are of no interest to us here.
      Just because YOU might want us all to work for the government, doesn’t mean WE do. Pay us a decent salary comensurate with our years of education and experience and give us a comfortable middle class life style where we can make enough money to own a house, retire, and send our kids to college and, fine, I’m there. Otherwise, maybe you can come up with a different plan that shows that you actually value what we do. Because somebody’s has to pay and if I can’t pay my mortgage, I’m quitting the business, selling my house, buying a cheap house in Pittsburgh and going to work in my cousin’s gyro shop. The job is too demanding to not be properly compensated.

      • I value what you do. Being science impaired just like my math impairment, I admire and am grateful for people with your talents. But jobs have been moving out of the country for thirty years. Whole industries have disappeared and I value the people who worked in those industries too. Being highly educated doesn’t make you more special or above what has happened to the uneducated and more and more, educated masses. Everyone is getting screwed by corporations that have one purpose and that is to satisfy the stock holders by making more and more profit every year.
        We have deregulated industry to the point that we are all surfs if we are not lords. Blame your company if you are getting screwed and join the rest of the employees union of the displaced.

  8. And yet Lilly’s Cymbalta was approved in April when a girl in my study on it hung herself in January. All the studies on it that were being done out of house were stopped then and a lot of people dropped out of my study. It paid 4500 and it was the worse drug I ever took. You could see it destroy people in front of your eyes.

    • Clinical is not my area. However, I knew the guy who invented Effexor. I’ve heard a lot of horror stories about effexor and yet, the chemist used to get letters, tons of them, from people all around the world who thanked him for saving their lives and bringing them out of darkness and despair. That’s a drug discoverer’s dream scenario, to have done something to help people.
      If you work in the area, you know that there are many different neurotransmitters at work in depression and they work in a complex way with each other with feedback mechanisms and upregulation that we are only beginning to discover. It wasn’t until last year that we found out how Prozac works and that’s been on the market for decades.
      So, I don’t know anything about Cymbalta but there’s a reason why we conduct clinical trials. Some depressed people, especially teenagers, need more supervision than others when they begin a drug regimen. But you know this.

  9. ADRs are incredibly important. Adverse reactions from medications are one of the top ten leading causes of death. The money lost annually is at least the equivalent if not more than the cost drug companies put into research.


    Part of the reason that some may feel “collusion” has occured is because of statements by FDA members themselves.


    While I would agree that we should not knee jerk in regards to pulling a drug off the market I haven’t seen that as the case. Drugs like Propoxyphene were on the market for years before the drug was pulled and it was only pulled after it became clear that benefits outweighed the risk.


    Likewise Seldane enjoyed a large time on the market and it was pulled only after a safer alternative became available.


    I get where you are coming from that companies want a return on their investment and they aren’t going to invest if they are worried that any returns will be lost by liability claims. I will agree that it seems unfair to penalize drug companies when clinical trials are completed and more adverse reactions surface when clinical trials are such a small portion of the population it doesn’t seem fair to punish the company unless you can out and out prove it was caused by malfeasance and a determination to hide effects. So I would agree with you that we should look at that aspect.

    Anyway, I do find it interesting that alot of the ADR reporting seems to be on older medications and particularly pain meds.

    • This was caught in the filter because of the number of links.

    • Selvage is a notorious example. But what about the COX2 inhibitors? If you have severe rheumatoid arthritis, your choices are very limited now.

      • Damn you autocomplete! As I was saying, seldane is a notorious example. But there are other drugs that were probably salvageable.
        Nevertheless, if the intention is to downplay the re that lawsuits play in the discovery of new drugs, it just isn’t working. A drug company is not going to take any risks anymore. So, the examine their portfolio. Womens’ health therapeutics? Nope. Antibiotics? Not bloody likely. Cardiovascular? Not a chance. So, those things don’t get made. Too risky and expensive.
        That’s what happens. Don’t blame us. We’re only taking cues from the public. The drug must be as close to perfect as possible or the company gets sued within an inch of its life whether there was deliberate negligence or not. And all of us who work for the industry are charged with filing adverse drug reports whenever we hear about them, even if the reaction was unexpected and positive. We have 48 hours to file a report, from anyone. Our friends, our families, someone we overhear in the DMV lane.
        Whenever a drug gets pulled from the market after an unexpected event, we all get the chills, even when it’s not our company. That could be us. Years of research and billions of dollars down the drain.
        In this atmosphere, aspirin and acetaminophen would never have gotten approval. They’re too dangerous.
        Let that sink in for a sec and you’ll know what we’re up against.

        • The American public is spoiled. We are used to so much success that we expect everything to be perfect from the get go. That demand is killing our future.

          The quest for perfection is the standard but people must realize that getting it on the first try is difficult to impossible.

  10. I didn’t want to log in to NYT, RD — but I was able to see the first page. The lede was interesting because, your blog must have been the one to draw attention to this subject.

    “The Obama administration has become so concerned about the slowing pace of new drugs coming out of the pharmaceutical industry that officials have decided to start a billion-dollar government drug development center to help create medicines.”


    I wonder if this means you will be working for them now? Also — your industry. Wow. I bet when you were in school it was nothing like that…

    Just. Wow.

    That fourth paragraph was interesting. Also what is a robotic screener? I’d rather have a human working on stuff you know? But, call me old fashioned.


    • I suspect we will be interacting at some point but I don’t know how and I don’t have any secret information. And even if I did, I’d have to kill you afterwards.
      As for the robotic screener, you definitely don’t want to do this job by hand.
      Here’s the idea:
      Your company has a compound room with millions of chemical compounds in tiny vials. You want to know which compound has druglike properties against a protein or cell system.
      So, you get a robot that dispenses protein or cells into thousands and thousands of tiny wells. Note that this is the same protein or cell system for each well. Usually, the biologists will also add stuff to the wells called reagents or antibodies or indicators.
      Then you program the robot to go to your compound library and choose thousands of compounds to dispense into the wells where the protein or cells are. When those druglike compounds interact with the protein or cells in the right way, something will happen with the indicators and the well of interest will give a signal which is recorded by the robot. The high throughput screening group collects the data as to which wells gave signals and analyzes the intensity of the signal. Then they analyze which compound caused the signal to go off. Then the analyze which compounds in the wells gave the strongest signals.
      This is all done with robots and computers and special statistical software and because we’re talking about potentially millions of compounds, you definitely do not want to and can’t do it by hand.

  11. sorry no sympathy for big pharma from me- not until they stop spending millions (billions?) on advertising to the lay public on TV. It must pay or they wouldn’t be doing it. That money should be put into research and development. And as for the drop in new drugs in the pipeline- that just means the easy pickings are gone.

    And the problem with the NIH going into drug company screening territory isn’t that hey are doing it but what will happen to the level of R-01 funding because of it. R-01’s are where the real breakthroughs come and the funding for those is already much to low for real innovation.

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