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Drug Development

Spray-Painted For Success

I do a lot of talking around here about how the general public doesn’t really have a good idea of what goes on inside a drug company. But a conversation with a colleague has put me to thinking that this might be largely our own fault.
Consider the public face that our industry projects. Look at the press releases and the advertisements – what’s the impression that you get? That there is a defined process for discovering drugs, for one thing, and what’s more, that we are the master of it. Now, I know that we don’t always send out that message. There are attempts to tell people about how many compounds have to be made, how many projects end up failing. But for the most part, we don’t press-release that stuff.
No, the press releases are for the investors, and for them, we want to project that we’re productive, confident, resourceful. . .in short, that we’ve got things under control. The last thing Wall Street wants to hear about is that you don’t always know which drug targets are the right ones to work on, that you’re not quite sure of the best way to prosecute them, and that (despite continuing efforts) these conditions look to obtain for quite a while to come.
And this attitude is one of the things that seeps out into the general public consciousness. That, I think, is why you get people who are convinced that we could cure a lot of these diseases, but that we just don’t – you know, for all sorts of evil and profitable reasons. They’ve bought into our hype. If we haven’t cured the common cold, that must be because we make a lot more money selling people stuff for it, not because antiviral drug development is flippin’ difficult. (Especially for something like the common cold, but that’s another story).
Now, to some extent, there is a defined process for discovering drugs – well, several defined processes. It’s just that it doesn’t work all that well, not on the absolute scale. No one could look at clinical failure rates of around 90% and say that we’ve got everything covered. Weirdly, that’s one of the things that gives me hope for the industry, that even small improvements would make a big difference. What if only 80% of all the compounds we took into the clinic crashed and burned? That would be great! It would double our success rate!
But when I mention that 90% problem to people outside the drug industry, they usually have no idea. All they hear about are the successes. Perhaps it would do us some good to mention the failures once in a while?

29 comments on “Spray-Painted For Success”

  1. CMCguy says:

    Derek I think you are right and there is a natural tendency to over emphasize the successes without education on the difficult and frequent misses in the process(es). Although sure most listeners would be turned off quickly if tried to go in depth since most of us do not have your talent for communication. Certainly attempting to present an (inflated) image to not upset stockholders can be overdone while then burying all the risks is Safe harbor statements.
    There is likewise often inclination to not address errors and misdeeds that occur in Pharma in a straightforward manner and this paints a negative picture that obscures the complexity of the efforts and the fact that the majority of people doing it have main purpose to help sick people. Unfortunately some of this is driven by the legal/regulatory environment with ludicrous decision like Levine vs Wyeth where “failures’ get publicized beyond norm.

  2. Joe says:

    I think it would do some good to be able to put the vast difficulty of getting a drug to market into a 60-90 second story.
    The Pharma industry employs 100,000s of people and yet almost all of them don’t really know the whole story behind drug development, let alone share their knowledge with family and friends.
    Someone complained to me the other day about “me-too” drugs and how all pharma cares about is easy money.
    I asked them, “So is there something wrong with developing a drug similar to one millions of people use everyday, but with less side effects?”
    Similarly, my own brother (a very intelligent highly educated individual) has told me that it costs a few cents per pill to manufacture all these drugs and that the pricing is outrageous.
    People need a basic understanding of how this industry works, since some of their lives depend on it.

  3. Old Timer says:

    This is an excerpt from a Science article this week where Steven Chu says “Wall Street often punishes a company for deciding to invest in research.” So of course we have to do a lot of convincing.

  4. Nick K says:

    My experience is that a lot of people think doctors discover new drugs. Most people have never heard of Med Chem.

  5. Petros says:

    Of course they think that Medic’s invnt drugs, Gleevec was almost exlusively due to Brian Druker
    But then chemists work in shops doling out pills etc (at least in the UK)

  6. Hap says:

    Telling your bosses (the investors, who at least in some cases, are the public at large) only what they want to hear is unlikely to end well, particularly when (as explicated in the firefight in “Health Care Reform…Really?” ) we are likely to have to undertake activities that will affect the pharmaceutical and health care industries substantially. If people don’t know and understand what drug companies, doctors, and hospitals can and can’t do (and maybe even afterwards, because recent history has been good at showing that people can be awfully intransigent when reality won’t give them what they want) then people are likely to demand things that can’t be delivered, and then feel unhappy and betrayed when what they want doesn’t arrive. Better to let everyone know what can and can’t be done and then let them decide what to do and how to pay for it.
    Of course, another of the things we’ve been good at is ignoring the costs of what we want and passing them on to our children. We’ve gotten so good at it that we’ve moved on to the harder task of pretending that the costs don’t exist (by frying politicians who suggest otherwise, thus ensuring that we won’t hear about the costs). That’ll turn out well.

  7. Dr. Baron von Evilsatan says:

    Naturally, the common picture is of a vast and uncaring corporate behemoth that controls all it surveys. Like all conspiracy theories, the fatal flaw is that it assumes a level of competence that has never been seen in any organisation ever to exist in all of human history.
    The problem is, though, that saying this disregards that, even though it is not actively malevolent, the pharmaceutical industry is still a vast and uncaring horde of smaller behemoths, who, given the choice between a much more ‘lifesaving’ drug and a slightly more profitable one, will only choose the former when it will lead to profit from another avenue. For evidence, you need look no further than the neglected tropical diseases. An effective cure for, say, Dengue Fever will probably do more good for more people than pretty much every other drug that will be discovered, tested, and approved for the next three years.
    The pharmaceutical industry may not be the vast conspiratory behemoth they imagine it to be, but is the truth really that far from the fantasy?
    There are far more annoying and less accurate misconceptions out there.

  8. ex-Pfizerite says:

    When I think of some of the projects I worked on I don’t think anyone would believe that the process would yield a drug at the end. We start with the crystal clear idea of selectively inhibiting a crucial pathway in an organism and we end up with a drug that extends the life of a terminally ill patient by 5 months at the end but no one would believe the meetings, the debates over ambiguous hERG readings and last but not least the tea leaf readings from commercial as to potential sale in the middle of the project. I am afraid that the only rejoinder to investors after they learn about the middle of a project is to say we muddled through in the past and we will muddle through again this time if we are given a chance.

  9. pharmagossip says:

    So true.
    Pharma ending up believing their own BS!!
    That’s also been the problem with their promo activities: eg atypical antipsychotics and the cancer “breakthroughs” that offer weeks extra life for ‘000’s of dollars!
    Suck it up!

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  11. red rabbit says:

    The “misunderstanding” of Big Pharma: when marketing campaigns cost more than R&D, and paid lobbyists induce international lawmakers to shut down the generic companies making (good, safe) drugs for the third world at a much lower price, meh, you gotta wonder how much of this “bad press” is their own doing.

  12. Pharma Giles says:

    It’s not just “outsiders” that need to understand that failure is the usual product of R&D – it’s a concept that the industry leaders need to truly understand as well. The trouble is that the background of most big pharma CEOs certainly isn’t R&D, hence the success of “business consulting” companies such as McKinsey’s (see your August 10th post) in screwing up everything they touch in the pharmaceutical industry. R&D is an art, not a science, and pharmaceutical R&D philosophy is a poor fit with the widget-making, target-driven mentality of today’s pharma middle-management, who understands the cost of everything and the value of nothing. They equate productivity only with financial success. These days, failure of a concept is regarded as the fault of the scientists behind it and has led to the modern-day culture of covering up poor results or puffing up mediocre ones. It’s a culture that has led to debacles such as Oxycontin, Vioxx and Paxil, and in corporate malfeasance resulting in billion-dollar settlements. Is it any wonder that that the public regard our industry as a criminal one?
    Our industry was handed over to the stock market (and their lawyers and accountants) back in the late eighties. Nowadays, there seems to be a gaping chasm between “corporate management” and “science” that I’m pretty sure did not exist prior to then. In the “good old days” that modern pharmaceutical professionals (who never experienced them) like to sneer at, many of the supporting R&D functions such as HR and QA tended to be staffed right up to the top by those who never cut it as scientists. They were just as useless as today’s bunch, but at least they had some degree of empathy, unlike today’s “professionals,” who have never done anything else but their own narrow roles. All of the trillions of dollars thrown at R&D, all of the swanky facilities and all of the state-of-the-art equipment have achieved very little return of late, and why? I think it’s simply because all of the unrealistic metrics and “business-led” MBA-style middle-management (all selected by their MBA-cloned superiors) within modern-day pharmaceutical companies make them such miserable places to work, and miserable scientists seldom achieve anything.

  13. DrugMonkey says:

    An excellent point. Drilling down to a more limited but necessary topic, it would be good to point out *where* compounds failed. Chem, bench model, animal model, large animal model and the *reasons* (bad efficacy, bad PK, side effects, etc, etc). This would go a long way in the animal rights discussions to show how many drugs never even get put in animals, to show where the USDA species experiments disqualify something that looked good in rat, etc.
    The current impression of only the drugs which fail human clinical trials permits the disingenuous argument that the animal models are bad for passing along drugs which will fail in humans. It allows the ARA nut to ignore the many compounds which were eliminated from consideration because of the animal studies.

  14. 1 says:

    There have been quite a few posts on the role of drug discovery in academia. what kind of work i.e. research would you do if you were to be in academics? Curious to see the views of a medicinal chemist.

  15. Chris says:

    There is another thing that contributes to the “90%” failure rate of drugs — Many small biotech-type companies can only afford to do ONE phase I study and ONE phase II study. That is usually the development plan that is presented to the VC’s backing the company. Unfortunately, basing the whole clinical development plan on data from mice, rats and dogs does not always produce the best dose and regimen (and patient population) for these studies. Many possibly good drugs have died and ended up as paper in boxes stored at Iron Mountain because they weren’t given a fair chance!

  16. Lucifer says:

    The problem lies in the very nature of our current system. It is still run like a zero sum world, when it is clearly not zero sum.

  17. srp says:

    I always want to know what people think is hard about their jobs. Those “bottleneck” issues give a pretty good idea of what distinguishes the successful from the unsuccessful, where the high-leverage areas for improvement are, the character of people’s workdays, etc. Some industries have a lot of “behind-the-scenes” information that conveys the difficulties (e.g. the movie business). Pharma, not so much.
    BTW, I’d love to see Derek address the deal that Billy Tauzin and the big pharma trade association made with the Obama Administration. Specifically, they agreed to pump $150 million into advertising in support of whatever bill the Democrats eventually cough up in return for a guarantee that Medicare won’t try to negotiate down their prices. It’s a little frustrating for those of us that try to defend pharma from its ideological enemies.

  18. Tom Womack says:

    I may be unusually disillusioned about this, but I tend to describe drug development as a process of making chemicals which do interesting things in the test tube but turn out to be mouse poison. I know there must be lots of examples which cure mice and kill dogs, let alone the ones which work fine in two animals and do nothing in man, but I’m a structural biologist so I never come across those except in things like this blog.
    Structure-based work seems quite reliably capable, given a few years and a few millions of dollars, of making a nanomolar protein inhibitor given a high-micromolar one, but at least the kind presented at academic conferences has not visibly during those few years asked whether the stuff is mouse poison or not.
    There are the occasional talks which start ‘we love this receptor family, there are exactly eleven of them and the assays are easy enough that it’s possible to check specificity against them all’, and there was one (from a group studying human serum antigen) which strongly recommended doing affinity tests for HSA on everything since recombinant HSA was very readily available and HSA-binding was a common drug issue, but one target protein per talk is still the most common.

  19. Karen says:

    *laughs* I found your post by following a link from The Atlantic. Your post reminds me of a bit of the situation in finance. Analysts hate unpredictability, and misgauging your earnings in either direction indicates you don’t have full control over your business. The end consequence is that corporations take any leeway they can to massage their results.

  20. Anne says:

    Honestly? My layperson’s perception of the big pharmaceutical companies is that they’re looking to pad the ol’ bottom line. There’s a reason why they’re such good investments, right? They aren’t spending their days looking for *new* cures and treatments — that kind of thing goes on in universities and research hospitals. Big Pharma is constantly working to repackage the drugs that make them the $$$ — combining existing cholesterol-lowering drugs into a single package, or making time-release products, in order to have a newest-and-greatest to market to doctors and the public, and to beat out the going-generic timeclock. Oh, and if they make something that does damage to people, like the statins (ask me about the side effects that have done permanent damage to my dad)? They keep it quiet for as long as they can.
    I have already told my docs that I will do whatever I possibly can to avoid the pharmaceutical slippery slope — a pill to take care of Problem A, and then another one to counteract the side effects of the first one, and so on, and so on — change my diet, change my lifestyle, whatever. No. pills. Until there is absolutely no other choice. And maybe not even then.
    The saddest, most depressing thing I have seen in recent years is watching my dad and my stepmom grimly go through the morning ritual of downing their assortments of overpriced pharmaceuticals.

  21. mark b says:

    Excellent insights. Can i offer some tangents? As a healthcare marketer, I’ve often been amused at the gap between the persona medical professionals often like to project – academic distance, unimpeachability, the armor of science – and the sometimes (often?) seat of the pants nature that diagnosis can often come down to. Clear statements of fact, or empathy, can be agonizingly hard to come by.
    Yet, as much as I’d like to think it’s health professionals or scientists who project this flimsy aura (here comes the tangent), I’m reminded of my first house purchase and finding that the uber-confident, ever-so-helpful, I’m-on-your-side realtor wasn’t: Upon finding misrepresentations about work done on the house, her response to my pleas for help was: I can’t help you, I’m paid by the seller.

  22. grow on trees?? says:

    @Anne–Overpriced? You just complained in your post about the side effects your dad has experienced. If you want cheaper drugs then many other people will have side effects too because people demand safe products and it costs money to test them. Consider penicillin, or aspirin for Pete’s sake. Plenty of people have had side effects from them but there was no direct to consumer adversing to highlight it when they were discovered. There is a risk-reward each time you use any product.
    With respect to price, if a product costs alot to manufacture, should it not be avaialbe? Would you complain the same way about a Mercedes because you think it costs too much? I would love a Mercedes but don’t demand they lower their price because I can’t afford one.
    Also, your cheap drugs were oftentimes discovered here in the States. When the patent ran out, overseas companies (OUTSOURCING) make it for literally a fraction of the cost because all the work has been done for them already. I’ll bet all the “buy American” people would never hesitiate to take pills made in China or India because they cost less.
    Sorry for the rant, just sick of the criticism by people who just don’t freaking get it.

  23. z says:

    Anne, #20, said, “They [big pharma] aren’t spending their days looking for *new* cures and treatments — that kind of thing goes on in universities and research hospitals.” Many of the readers of this blog would take issue with this, because they work for big pharma, and they have spent their whole careers looking for *new* cures and treatments. It’s not easy, and most attempts are unsuccessful, but we try as hard as we can and as best as we know how. Derek has written several posts about where new drugs come from, and, for the most part, they do *not* come from universities and research hospitals, they come from the pharmaceutical industry.
    Regarding the bottom line: We live in a capitalist society, and this is a business, so it must make money. That is a simple fact of the reality of the system. If we can improve our existing drugs, why shouldn’t we do it?
    “I have already told my docs that I will do whatever I possibly can to avoid the pharmaceutical slippery slope…change my diet, change my lifestyle, whatever.” And you certainly should do these things. This is good. Drugs are not magic pills that let people ignore any responsibility for their health (even though some people may use them this way). But the fact remains that diet and lifestyle cannot fix everything, and many conditions require medication. All drugs involve a risk-benefit analysis. Yes, there are potential side-effects, but the potential health benefits outweigh them, so people take the drugs.
    “Overpriced pharmaceuticals.” Drug pricing covers a lot more than the physical cost to manufacture a drug. It is estimated that every new drug on the market is the product of close to one billion dollars in research and development. This is money spent up-front, before a product is launched. Then there is only a limited period of exclusivity before generic companies jump in take the profits away (their development costs are practically nonexistent, because we already did all the hard work).

  24. Spencer says:

    Dear Derek:
    (Your name is the same as one of the MLB pitchers.)
    I totally agree with you, that sometimes pharma should broadcast a few of the most important, hyped drug candidates, and follow up with news on what happened to them (successful launch or failure). The public has no idea about pharma R&D.
    I do want to add that perhaps pharma gets too much profits. Pharma’s recent pledge to provide $80 billion to cover Medicare’s “donut hole” for seniors is a good thing in the right direction. However, this pledge is not definite. We will see what actually happens later.

  25. Gerald Fnord says:

    Someone earlier stated that drugs companies are there to help the sick. They are officially there to benefit the share-holders (the ‘public good’ section of articles of incorporation being a dead letter), and in reality to benefit their management.
    Not being explicitly evil, they don’t _mind_ benefitting the sick, but even at best they are deficient in makoto.

  26. Mutatis Mutandis says:

    I think Pharma companies radiate the belief that “there is a defined process for discovering drugs” in part because, unfortunately, our bosses and managers BELIEVE that. I know it is mind-boggling, but that’s how much of the industry is run: In the belief that by applying a chain of streamlined procedures, success is more or less guaranteed. The leadership are rarely R&D scientists, but usually marketeers and sometimes doctors (not always that much better…)
    There are, of course, many particular variants of this belief, and every pharma company seems to have its own cargo cult. I’ve seen a lot come and go over the years, some weirder than other. Some (still) believe that by screening at least a million combinatorial chemistry compounds, you must inevitably find a drug. Others (still) believe that their Bio-IT have the right tools to select smaller libraries that must inevitably contain a drug. Others put their faith in various new and unproven technologies (RNAi drugs are a favourite bet) or even in management models.
    The real secret of the industry: There is no magical recipe, and no other way of discovering new drugs, than by doing good science, trying a lot of things, and bouncing back every time you fail. Many of the people who work for “Big Pharma” put much more devotion and effort in their work than the general public tends to believe. In this industry, I have met a lot of workaholics and a significant number of idealists.
    But the problem of Big Pharma is that our managers always seem to be on a search for alternatives to doing good science. Because they don’t understand it, hence it cannot be that important. But in the long term, there are none, at least if we want to survive as an industry.

  27. I want to reinforce PharmaGiles above. Although this isn’t the focus of the post, the industry is plagued by lack of innovation, and part of the problem is the corporate model/culture that PharmaGiles describes. The board will tend to listen to and lean on whatever corporate function is most clearly and obviously linked to near-term profit-production, which in this case is commercial, so the pipeline is neglected and 5-10 years down the road, everyone is surprised that there’s nothing in the oven. This is why large pharmas can’t grow their molecules organically and have to continue buying up small biotechs for their molecules. Very few big companies have been able to avoid the sterility of big pharma and the ones that have (like Genentech) kept their eyes on the ball by keeping people with science background in key positions.

  28. The common cold is almost certainly not worth trying to cure at our current level of technology and with our current level of understanding of chemistry and biology. The investment that would have to go into such a cure it is out of all proportion with the relatively minor nuisance it causes, compared to other diseases.
    Concentrate on the serious stuff, please. I’ll suffer through carrying a handkerchief for a couple of days a couple of times a year and treat the symptoms with decongestants and cough drops. I think I spend about six bucks a year on cold remedies.
    People whine about colds a lot, but in the scheme of things they’re really not that big a deal. Heck, a cold is usually not even serious enough that you have to use up sick days at work over it, so I guess we’ll live.
    I mean, sure, if you just sort of happen to stumble upon a cure for the common cold while doing other work, hey, great. But in terms of diseases worth pouring billions of dollars and decades of research into, the cold just isn’t that high on the list, IMO.
    Obviously there’s lots of research being done into the big famous scary ones (Cancer, Alzheimer’s, AIDS, …), but there are also a lot of less terrifying but nonetheless life-altering conditions. Macular degeneration, Crohn’s, osteoarthritis, hypothyroid, hemorrhoids, ,,, there are a LOT of conditions that are more worthy of your efforts than the cold.

  29. ex-Pfizerite says:

    Jonahdah, Agouron/Pfizer actually had a project that went to the clinic to treat the common cold and the compound worked reasonably well in controlled settings since the patient had a narrow treatment window. While you might think that a cold is a nuisance to someone with COPD or asthma a cold can be very serious.

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