Dr. Joan Bushwell's Chimpanzee Refuge

After being buggery-augered with no lube by the New England Journal of Medicine’s finest, it’s refreshing for us minions of Big Bad Pharma and our small company lampreys to read an article in that august journal which moves beyond Angellic knee jerk histrionics.

Alastair J.J. Wood, M.D. offers a proposal for radical changes in the drug-approval process. As Joseph j7uy5, proprietor of Corpus Callosum notes, this is a free access article and a worthwhile read.

Wood’s proposals include severe kicking of the tires for me-too drugs, follow-up on safety after a drug’s launch, demonstration of a real clinical benefit, and encouraging discovery and development of first-in-class drugs. The prospect of extended exclusivity past a drug’s patent lifetime would in theory give the pharma companies incentive to engage in these activities. This might cause some bristling among consumer activists (check out the link below to Boldrin and Levine’s treatise on the evils of intellectual property) since branded drugs are more costly than generics, and exclusivity keeps the higher preiced med out there that much longer. Keep in mind that although generics are cheaper, they do not encourage nor pay for innovation, and honestly, that’s what pharma really needs to focus on now: innovative drugs which will be a genuine benefit for unmet medical needs.

Speaking from the discovery bench monkey’s perspective, there are some notions in Wood’s article which are pant-hootworthy. I particularly like Wood’s incentives for discovery of first-in-class drugs.

I was fortunate to be part of a discovery team (medicinal & early process chemists, biochemists, biologists, pharmacologists) who brought such a first in class compound into the clinic. It’s in Phase II now, and is yielding impressive results against a disease which fits solidly into a major “unmet medical needs” category. The compound is on the FDA fast track. Keeping the safe harbor in sight, at Phase II, there’s still a long way to go and anything could happen, but I can tell you that it is a rush to think this compound could actually make it. If my horse in the race crosses the finish line, it’ll help a lot of patients. The discovery team’s names will not be emblazoned in bold Arial font on the capsule, but it’s pretty much like being authors on a pivotal publication in a well regarded journal. Booyah! So, yes, please give our upper management bosses a carrot to let us bench monkeys do even more new cool stuff in the lab.

Wood comments on the basic science underlying drug discovery and that this largely emanates from the public funded sector. His calm assessment contrasts beautifully with Angell’s near junk-science analysis. We drug discovery scientists love basic research, and when I attend bio-organic chem type conferences, I often sigh and think it must be nice to worry about where the electron is. But financially, it doesn’t make a lot of sense for us to start from scratch. In drug discovery, we’re ready to pounce and apply our expertise to a nifty target which someone has discovered (and reported in a peer reveiwed publication) or which a genomics collaborator has identified. As Wood correctly observes, the academic arena simply does not have the resources to bring a drug to the market. If one believes that drug discovery should also perform the basic science to have legitimate claim to a target and drugs resulting from it, well, then be prepared for extraordinarily expensive drugs and a much longer time to market.

With regard to genomics, Wood notes:

…the number of new drug applications submitted to the FDA has decreased during the past 10 years even though the genomic revolution should have led to an explosion in this number.

In fact, a large number of targets have been identified via genomics but they are anything but readily tractable. The low hanging fruits which gave rise to beta-blockers, ACE inhibitors and the statins have long since been plucked from the discovery tree. The genomically identified targets must be “druggable”. Among those that are, expression and purification of the proteins (if that can even be accomplished), the in vitro assay development (including miniaturization), and target validation and characterization for these fruits high in the discovery rain forest canopy are, to be direct, pretty f*cking difficult. And that’s way before we get to looking at potential liabilies of drug metabolism, crossing the blood brain barrier in the case of CNS targetted compounds, pharmacokinetics, and well, a formidable array of issues which stands between lead compound identification and clinical candidate status. Because we discovery primates have to reach that much farther, Wood’s proposals would add a little extra sweetness at the end, or at least something of a safety net to cushion a potential fall.

Wood’s ideas look pretty good to me, but the flies, cf. the Tabanus variety, in the ointment are the FDA itself and the swampy morass that is patent law. Battling these buzzing biting bureaucracies seems quixotic but maybe Dr. Wood will aim a few good swats.

Further reading:

Point: The Truth About Drug Companies by Marcia Angell for the New York Review of Books.

Counterpoint:Of Pills and Profits: In Defense of Big Pharma by Peter Huber for Commentary Magazine.

To paraphrase Mulder, the truth isout there in-between there somewhere.

And just for the hell of it, or maybe because Wood’s recommendation of extended exclusivity might make some squirm, here’s Boldrin and Levine’s case against most any kind of intellectual property. This gives Derek Lowe a headache. I think a headache is a mild way to describe it. I’ll just take a sharpened #2 pencil and ram it into my ear, a la Lewis Black, because that would be more pleasant than no F*CKING IP PROTECTION!

Comments

  1. #1 dlamming
    August 17, 2006

    says you: “that’s what pharma really needs to focus on now: innovative drugs which will be a genuine benefit for unmet medical needs”

    of course, for those who can’t afford the drugs pharma creates… making the drugs without making them available to everyone who needs them will simply exacerbate the exisiting class divide, in which the wealthy live better and healthier lives. even now, certain of the new cancer therapy drugs are simply not given to the “poor”, because their insurance won’t cover it.

  2. #2 Bi9ll from Dover
    August 17, 2006

    One good start would be to pull the drug advertisements – especially the genre that are demanding one to ask your doctor. Anybody other than the Good Doc remember when it was the medical profession who did the prescribing after one described his symptoms? If I need a drug pusher, I can find one on the other side of the tracks.

  3. #3 JKB
    August 18, 2006

    So, yes, please give our upper management bosses a carrot to let us bench monkeys do even more new cool stuff in the lab.

    Well, any discussion of the medical-industrial complex is an attack on mom and apple pie and is perpetuated by rabid, anti-American communists and conspiracy paranoiacs so I’d just ignore the shrill negativists and proceed slogging through life as an unrewarded bench monkey.

    For God’s sake, we implore you to selflessly continue to soldier on in an industry on the edge of collapse that is not highly incentivized but staffed by dedicated people too pious and selfless for ascetic religious life. Is must be hard elbowing other Mother Theresas off the bench and I can just imagine the mental anguish involved. My advice — nudge gently, don’t throw elbows with enthusiastic abandon. If you have to, use elbow pads as I hear Mother Theresas bruise easily.

    Can you expand a bit on the evils of IP-fascism?

    As a totally irrelevant aside, I belatedly watched NOVA last night about the selfless service of the US CSH (combat surgical hospitals) deployed to Iraq. It was an eye opener — the moral dilemmas presented to the doctors assembled for that humanitarian task. Some would undoubtedly see that show in negative terms — that a moral dilemma when viewed in the light of “mission focus” is not so much a moral dilemma as self-rationalization that checklists followed are acceptable substitutions for individual judgment. But I think that type of view is probably unjustified and is agenda driven by the communists at NOVA and Frontline.

  4. #4 JKB
    August 18, 2006

    On second thought, that was maybe a little over the top. Nevermind.

  5. #5 Doc Bushwell
    August 18, 2006

    …even now, certain of the new cancer therapy drugs are simply not given to the “poor”, because their insurance won’t cover it. – dlamming.

    Like Erbitux and Avastatin? Yeah, I read the Associated Press “Spending to Death” article, too. Antibody therapies like these are incredibly expensive, and insurance companies balk at the cost if a clear benefit can’t be demonstrated. Small molecule therapeutics like Gleevec, Tarceva, and Nexavar are also costly, but as a whole, less expensive than the biologics. Duke University Med provides an analysis o the cost effectiveness of Gleevec and concludes that its price is offset by benefit, something that insurers consider. Insurers also balk at forking out tons of money for off-label use as noted in the “Spending to Death” article.

    Monoclonal antibody therapeutics are expensive to manufacture and must be given IV. Gleevec and cousins are pricey now, but as more compounds like these emerge on the market (and as patents expire), the cost of targetted small molecule therapies will drop. The biologics are not the only example of innovative medications.

    If a cheaper stand-by cytotoxic is nearly equivalent in extension of life to a biologic like Erbitux, then it makes sense to go on the “cheap” (relatively speaking), crappy side effects and all. This is why the meaningful clinical endpoints which Wood discusses are critical. If an expensive innovative med comes on the market, then it had better confer significant benefit.

    There are tough choices to make based not only on drugs produced by greedy Big Pharma, but also the general state of medical treatment and risk-benefits. An immediate member of my family chose to die from a terminal illness rather than get her bone marrow wiped out in a procedure that had a fairly low rate of success.

    Bill, I hate DTC marketing. I think it opened a Pandora’s box, or at least was one of the monsters released. Plus the ads are just stupid.

  6. #6 Doc Bushwell
    August 18, 2006

    On second thought, that was maybe a little over the top. Nevermind.

    Oh, JKB, you socialistic imp, you! Is that an apologetic tone? Christ on crixivan, are frogs raining from the sky?

    The medical-industrial complex is not a sacred cow, and I am not above criticizing practices therein. Neither am I not defending double digit profit margins, but profitable in some way the drug companies must be. Here’s a thoughtful analysis on Wood’s proposals. You might want to go over and bitchslap the kindly country psychiatrist for his temerity in suggesting that “the potential for big profits is the only thing that justifies the large investments and great risks that are taken by pharmaceutical companies” even though what he says is, well, true.

    Being the self-righteous sanctimonious bench moneky that I am, I have something to confess to you, JKB. I would like to work on a target that would Really Help Poor People. Let me roll up the sacred sleeves of my labcoat and tell you about it.

    See, I’d set up a not-for-profit pharma (then slap myself silly on the back for doing so) and get to work on my fantasy project: inhibitors of the dengue and West Nile viral NS3 protease. There’s a lot of nice work on these proteases out of academic labs, and looking at the substrate specificities and structures of the proteins, one can envision synthesizing potent inhibitors against these proteases. The inhibitors would likely be peptidomimetics which means optimizing their pharmacokinetic properties will be a bitch, and their production won’t be cheap. But hey, as a worthy non-profit, I’m sure I can gather donations to fund the work. My scientists don’t mind working long hours for a pittance because we’re Doing Good, better than that tart Mother Theresa. Since these drugs are meant for diseases in poor countries, maybe I can perform clinical trials on the cheap, too, because regulations are nice and lax in those troublesome countries where dengue fever is endemic.

    Snarkiness aside, I honestly wish I could work on these proteases, but the market drivers of Big and Small Pharam in the US and Western Europe pretty much negate that. Hey, if things keep warming up, and cases of dengue fever break out in Crawford, TX, maybe then I’ll get my chance! OneWorld Health looks like pretty cool nonprofit for this dengue viral protease stuff. Check out that little graphic as to where they get their lead molecules: academia and…wait for it…industry.

    So what are the alternatives for the lumbering sauropods of Big Pharma, now poised under the asteroid’s expanding shadow? Socialized drug discovery and development? Excuse me while I sharpen another #2 pencil.

    Actually, here’s an alternative: preventative medicine. Exercise, eat well, keep your weight down, get enough sleep, learn to meditate, and otherwise do those lifestyle things to avoid Rx meds altogether. Oh, and don’t get cancer, rheumatoid arthritis or a psychiatric/CNS illness.

  7. #7 JKB
    August 18, 2006

    Oh, JKB, you socialistic imp, you! Is that an apologetic tone? Christ on crixivan, are frogs raining from the sky?

    First-off, I must warn you that you’ll rot in hell for all eternity if you continue on with that profanity, and secondly,

    No, I really wasn’t apologizing as much as after posting I discovered that I was working from an antiquated version of Strunk & White. My edition indicated that if you run into the phrase “…Angellic knee jerk histrionics…” it’s recommended to start invoking the blessed Mother Theresa profusely. Then to my chagrin, I noted that I was using an obsolete reference from like six versions ago. It’s not apology as much as sheepish embarrassment.

    I mentioned before that I’m not a scientist, but I do have a passing familiarity with reading irrelevant stuff, mostly science-fiction and conspiracy pulp. Initially, I thought the article was some boring scientific article, but thought what the heck, let me go through and read it – I read The Gulag Archipelago by bleeping the Russian names so I figured I could do the same with medical terms. …And surprisingly, it turned out to be more of an economics missive that postulated protectionist policies for one of the most profitable industries in the US.

    My newspeak alarm went off when I read the phrase, “Economic Darwinism”, and had an accompanying slide where all the solutions involve “extending periods of exclusivity”. Why, what can that possibly mean?

    That is certainly an odd turn of the phrase — Economic Darwinism that hinges on governmental protection of IP? Hmm, I sense some Disney IP-envy from Big Phrma and could almost hear the unoiled wheels turning — How could our high powered brains be beaten to the punch by those simple dunderheads in Orlando? Oh well, all is not lost — use the precedent and flow with it — that’s what counts at this point.

    I like your alternative to Big Phrma, and I’m not against industries per se — only ones that are driving the country broke when they attach the vacuum to the national treasury because cashing checks is slow.

    And really, to tell the truth people think I’m just trolling, but I’m really not. I really do believe some of the stuff that seems too odd by a half.

    You think that extending life is a good thing, but I think it’s unsustainable and at a current population count of 6.5B we’ve got bunches of spares.

    The combination of extended life expectancy, free-markets, consumption and pollution are a concern to me in the general sense of thinking what the viability of survival is if I consider jackasses like Inhofe or Stevens. They’re a match to the tinder that free-markets produce without regard for more than the next quarter.

    Did I miss your notes on IP? Because superficially it would seem that getting cheaper drugs to the poor through generics would be a morally right thing. Of course! I see where my logic fails: the generics have driven Big Phrma out of business and profitability. Damn them. Damn all socialists and IP hatas!

    To the same hell you’ll be spending that eternity for your profanities.

  8. #8 qetzal
    August 19, 2006

    So, what are your solutions, JKB?

  9. #9 JKB
    August 19, 2006

    So, what are your solutions, JKB?

    Socialized medicine with fixed cap profits on a variety of predatory industries. You have to restrict grazing on the commons if there’s any chance for responsible stewardship.

    Fixed cap profits have not chased people away from government contracts and although not as attractive as the ability to mark up a product 570,000% (Xanax 1Mg) and have the gaul to seek further exclusivity under — should I say, dubious promises. I think the caps would be good enough, although one would have to endure the onslaught of Phrma’s marketing postulation that the quality of America’s health-care would suffer greatly (and Americans, blessed as they are, do not deserve the mediocrity that pervades the rest of the world.)

    A pollyannish view to be sure, but that would be my ill-conceived solution — one that broadens affordable health-care to the dregs of American culture (the 40M uninsured) although admittedly, it would not be as deep.

    Additionally, I do not support the premise of IP because it exacerbates availability and withholds communally generated products from wider use.

    The first people that trot out the argument that science is a multi-generational endeavor that relies on standing on the shoulders of previous giants, conveniently forget those giants when they submit a claim that their “invention” deserves IP protection due to unique nature of their own work.

    I think if they can prove that they did it in the absence of previous scientists and teachers (that worked unselfishly for the greater good but mostly for the pleasure of AHA and the enlightenment of others) they may have a point. i.e. prove that what you developed was done without calculus, without computers, without optics, without textbooks, even without abacuses.

    Additionally, prove that the conditions of your work product were provided without reliance on America’s trailer trash protecting your borders, and your freedoms you may have a case. For example, I think the development of unique science in south Beirut may be under that rubble we see on TV and consequently stunted.

    Stability is infrastructure that costs something, so while there were some that were feeding their brains into encephalitic proportions by attending private schools, others were digging ditches at minimum wages to keep danger at bay so that free-markets, freedom of movement and communication could be had by the folks back home. Still other dregs were paving the roads and running the power stations that provided necessary energy. To me, claiming IP is the same as claiming class stature and distinction. (Hmm, I guess those nuns didn’t knock every bit of utilitarianism out of my skull…)

    But you know, to claim that an individual, uniquely can claim ownership of a process for personal gain while ignoring both the science giants and the little people that provided the conditions is convenient rationalization for self-delusion. Thankfully, the world is full of sycophant so the delusion can be fed interminably.

    Having said that, I do have co-workers, friends and acquaintances that make claim to IP. They know my views but we still remain friends(?) although I routinely make it clear that I think they’re lower than dirt. They view it as disturbing but recognize that I am poorly motivated to do anything about it. That makes it possible to have us a beer and go see a disturbing foreign movie together.

    That was probably over the top, but like a rabbit in snare, I only know the forward, and fast-forward.

    Whaju expect the work-product of anger, depression and envy to be?

  10. #10 qetzal
    August 19, 2006

    Socialized medicine with fixed cap profits on a variety of predatory industries. You have to restrict grazing on the commons if there’s any chance for responsible stewardship.

    [snip]

    A pollyannish view to be sure, but that would be my ill-conceived solution — one that broadens affordable health-care to the dregs of American culture (the 40M uninsured) although admittedly, it would not be as deep.

    I don’t see how a cap on pharma profits will make healthcare that much more affordable. The Public Citizen report you link says pharma profits were 17% of revenues in 2002. If that were capped to 3% (Fortune 500 median, per the same report), drug prices would only be about 14% lower.

    Of course, that assumes expenses and revenues are the same under a profit cap. No doubt that’s wrong, but I still don’t think profit caps alone will dramatically reduce drug prices.

    Perhaps your real objection is simply that you think 17% profit on drugs is morally offensive. If so, why not just say so?

    Fixed cap profits have not chased people away from government contracts and although not as attractive as the ability to mark up a product 570,000% (Xanax 1Mg)….

    If you truly believe that figure has any relevance at all, you are exceedingly ignorant about drug costs. However, I suspect you know it’s a gross and deliberate mischaracterization. I suspect you quote it anyway so you can paint pharma in the worst light possible, regardless of accuracy.

    Figuring the mark-up on Xanax based on the cost of the active ingedient is a bit like figuring the mark-up on a Lincoln based on what it costs to make the engine. A more realistic comparison is branded Xanax versus generic alprazolam. According to one on-line pharmacy, 100 pills @ 1 mg each costs ~ $160 versus ~ $16. That difference is more than enough for rational discussion, assuming you care about that.

    Additionally, I do not support the premise of IP because it exacerbates availability and withholds communally generated products from wider use.

    Drugs cost money to develop. 5-7 years of animal safety testing, clinical trials, and manufacturing process development are expensive. You can hardly deny that, even if you reject specific claims like $800 million/drug.

    Moreover, all of that is mandated by government regulatory authorities (FDA, EMEA, etc.). It’s not optional.

    Someone has to pay for that. Right now, private companies do so because IP gives them a period of exclusivity when they can recoup those costs and make a profit. If you abolish IP, you’d better replace it with some other form of limited exclusivity, or else propose another way to cover development costs.

    What do you propose?

  11. #11 Joseph j7uy5
    August 19, 2006

    Part of the challenge of developing drugs entirely in the public sector, is that it would be extremely difficult to construct a system that would accomplish those goals, without cannabalizing the existing for-profit structure. There is only a finite numbre of people with the necessary skills and talents. Plus, in order for it to work optimally, it would have to operate with ocmplete freedom of access to information. How could we set up a system like that, without doing a great deal of damage to the existing system? That is a pretty big gamble: if we set up an open drug-development system and it did not work, but did damage to the existing system, we’d have a mess on our hands.

    A system that operates entirely on public funds would be open to political influence. Imagine we spent a billion dollars trying to develop something to prevent Alzheimer disease, and it did not work. Every “taxpayer’s rights” organization in the country would be hopping mad. Never mind that the basic science would probably be worth the investment.

    I know pharamceutical companies have internal politics, too, but at least they don’t have to deal with hordes of complainers who are completely uninformed.

  12. #12 JKB
    August 20, 2006

    Oh, snap but you got me.

    You asked for what my solution would be, I told you what it was.

    It is obviously uninformed, ignorant and based on, bitterness, anger, depression and envy. I previously forgot to mention bitterness but it’s dishonest to omit that because it is pretty central.

    I knew my solution wasn’t perfect, so therefore wasn’t right because only perfection is right. When I go to other countries and see people under socialized health umbrellas I am obviously seeing things through a severely distorted prism of seeing what I want to see. My lack of education leads me to draw overly simplistic conclusions and that is a general failing that isn’t likely to be reversed overnight.

    What do you propose?

    I don’t propose anything. I don’t desire a rational discussion; you exposed me again and now I must retreat to my corner and lick my wounds. Man, I have a big chuck of ass missing from where you took that bite.

  13. #13 qetzal
    August 20, 2006

    Sorry, JKB. I thought there was a chance you were interested in rationally discussing possible improvements.

    My mistake; won’t happen again.

  14. #14 JKB
    August 20, 2006

    Gosh qetzal; I must have misread you.

    …That difference is more than enough for rational discussion, assuming you care about that.

    I didn’t realize that in order to have a rational discussion I needed to comply with your standards for hyperbole. See I was talking about the principle of capped profits vs. uncapped, driven by free-markets injected with the government steroid of sanctioned monopoly, but you seemingly fixated on the large markup that I used to punctuate the point of runaway free-markets. Doh!

    I had you confused with someone that likes to assign homework and then pick at it. Aside from taking exception with my scale of hyperbole, no misspellings or punctuation corrections? Yea, that other guy woulda had plenty to say about the punctuation and misplaced commas.

    If you abolish IP, you’d better replace it with some other form of limited exclusivity, or else propose another way to cover development costs.

    What do you propose?

    I thought the original article was talking about extending IP protection not decreasing it for purposes of enhancement enticement. Are you actually arguing that it is in the realm of possibilities that IP would be curtailed in the near future because I don’t care for it? You had me going there with the talk of rational discussion.

    But here’s how I may handle it if I was despotic for a day (or a few decades): take the capped profits and distribute to your shareholders, pay your workers, etc, but excess income generated by the limited IP protection go into an controlled escrow that you can draw on for that expensive research with a few caveats. You just can’t have IP money distributed to your stockholders or give it to your scientists. (And Shhh…, if we need to, maybe we can reach into that IP escrow to meet the SS shortfall if it becomes necessary, but lets discuss that later…)

    See that way, the motivations of your scientists stay pure and they can concentrate on doing what’s necessary, not what’s sexy or pays exceedingly well. We don’t want them burdened with patents and the moral dilemmas that they bring.

    Would that work for you as a solution dearie? Because what I mainly hear from your blockquoted section above that assigns me the essay, is that IP and IP exclusivity pays the research and compliance bills; so if IP income is distributed to those two roles, the issue would be settled, right?