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Those Australian Students And Their Daraprim

OK, enough people have emailed me the press coverage of the students in Sydney making daraprim, which is the drug that Martin Shkreli’s former firm has famously jacked up the price of. From what I can see, a lot of the news stories on this are missing the point.

Daraprim is not hard to make in the lab. A lot of pharmaceuticals are not hard to make in the lab. The Sydney students have not achieved some sort of breakthrough workaround – they’re following perfectly reasonable organic synthesis procedures. Any competent organic chemist should be able to go over to their hood and do the same thing, and the Sydney professors involved know this, of course, as well as anyone. The people who don’t know this are the news reporters. So when the Sydney Morning Herald says that the students have “taken down” Martin Shkreli, the newspaper is spouting nonsense. This was a perfectly reasonable organic chemistry teaching exercise that’s being completely overblown in the headlines.

Here are the other things that the news stories are missing:

1. The price of a drug does not depend on the price of its ingredients, or the cost of its synthesis. We try to get that cost down as low as possible, of course, because why waste money, but it’s not the determining factor for small molecule drugs. This shouldn’t be a surprise: different models of cars (for example), at different prices, get their steel and aluminum from the same places, and contain comparable amounts of each. If you want to know what the price of a drug really does depend on, read Jack Scannell.

2. Daraprim’s ridiculous price is completely a regulatory failure. Well, that and a failure of human nature, which allows the manufacturer to exploit the regulatory failure, but you know what I mean. The company is exploiting a loophole in the regulation of generic drugs that allows it to set the price wherever it wants to, and as soon as the FDA gets off its rear about the way it handles generic drug applications and approvals, the problem will start to go away. Until it does that, the problem never will. FDA regulations are completely the reason that this situation is feasible in the first place. Don’t get me wrong; the agency has a very tough job, and gets hammered from every direction as they do it, but that’s the situation here. We should also not ignore the role of whatever insurance companies that are actually meeting the insanely jacked-up asked-for price.

3. Daraprim is not some cutting-edge wonder drug. As mentioned, it’s a generic medication. It’s been around since the 1950s; it should be basically a cheap commodity by this point. And it used to be. The reason that has changed is because of the regulatory loophole stuff mentioned in the links above.

4. You cannot make daraprim in a school lab and sell it. This should go without saying, but from the tone of some of the news stories, I wonder. Again, this is because of regulatory considerations, but these I agree with and think that they’re good ideas. If you want to manufacture a drug that people are going to put in their mouths and swallow, you have to do it under all sorts of scrutiny (Good Manufacturing Practices), and you have to formulate and package it in an appropriate (and safe) manner, and if it’s a generic drug, you have to show that what you’re making is equivalent to the other brands of the same drug that are already on the market. A university lab is not a GMP production facility, and neither is my own fume hood. Thank goodness.

OK, then. Enough with the amazing Shkreli-busting headlines. All these are doing is confusing people about where drugs come from and how daraprim’s outrageous cost increase has actually happened. The general public – and many of its elected representatives – are already confused enough about these issues. No need to make things even worse.

60 comments on “Those Australian Students And Their Daraprim”

  1. Curious Wavefunction says:

    I remember making salbutamol (Ventolin) for a college chemistry project. Does that mean I somehow “took down” Sir James Black and could start selling it for pennies from my garage?

    1. Hostile Nitrile says:

      Yep. Just like when my chemistry class did some fermentation and distillation with molasses and took down Bacardi and Big Alcohol.

      1. Curious Wavefunction says:

        I suppose we could take down Avery, Griffiths, Watson, Crick and Franklin combined if we separate, crystallize and photograph DNA.

      2. David says:

        Attempting to take down “Big Alcohol”?

        You’ll fail, but the attempt sounds like a plan to me.

        -ex Australian student, where the bars are on-campus, and have been the location for tutorials 😉

  2. Oblarg says:

    Honestly, I wonder if there isn’t anything that can be done about science journalists not actually knowing any science. It’s a ubiquitous problem, and one that causes a huge amount of public harm.

    1. Nunya says:

      I once applied for a science journalism internship – with a PhD in science with lots of writing experience – I was told my chances were very low because I didn’t have a science journalism degree. Apparently it’s better to know about writing but not much about science rather than the other way around. When I applied for a science journalism degree, the “science” was based on one class. So yeah… it’s gonna continue to be a problem.

      1. anon says:

        It wasn’t the degree you were missing. It’s the number of followers on Twitter and your “network” you were missing to get the job.

      2. Allan says:

        Vacancy: Lecturer/Senior lecturer in Science Communication, Victoria University of Wellington
        The Science in Society invites applications for the position of Lecturer or Senior Lecturer in Science Communication. The successful candidate will have a PhD in an appropriate humanities or social science discipline, relevant publications in refereed journals and books, teaching experience at undergraduate level, and experience supervising postgraduates. We welcome applicants who are highly effective teachers and communicators, and whose research in the field of science communication and public engagement with science lends itself to interdisciplinary collaboration.
        Applications close 26 October

        1. anon says:

          “…PhD in an appropriate humanities or social science discipline” ??!?

          1. ffs says:

            Things that are also science: anthropology, psychology, sociology. But nice of you to forget about them being sciences that are just as mis-reported (if not more) than chemistry, biology, physics, etc.

      3. Carmen says:

        Nunya- I’m sorry you got such a shortsighted response. Speaking as someone who earned a PhD before going into science journalism, I can tell you that some people out there just don’t know how to avail themselves of your skill set. But that’s not true of everyone. You mentioned having writing experience and I can’t speak to yours, but editors are looking for very specific kinds of writing samples, ones that show the ability to tell a compelling story in addition to providing context for a discovery. And yeah, as anon said, a network and a Twitter presence is essential because this field is super hard to break into. Hope you find what you’re looking for.

        1. DH says:

          With typical science journalism so bad, *why* is the field “super hard to break into”?

      4. Carmen says:

        Should add that I didn’t get a science journalism degree. People doing the hiring like them- and why not? the people come out of the programs with a defined set of skills and connections (and they’ve mastered those writing samples). that just means you have to hustle a little harder to break in. But folks with PhDs are no stranger to that. Good luck.

    2. Dr CNS says:

      Oblard,
      It depends on who is the readership. If non-scientists want to spend their time reading these sources… be my guest. It’s your time, and I don’t see major negative consequences.

      The danger I see is that these type of reports are becoming part of the narrative *within* the scientific community. In particular, there is a growing trend with major journals publishing commentaries written by “science communicators” to articles by other folks that make me uncomfortable… It feels as though the people reading the full papers cannot comprehend them, and need a cartoon and a few dumbed down statements to get it…

      1. JIA says:

        If non-scientists want to spend their time reading these sources… be my guest. It’s your time, and I don’t see major negative consequences.

        Hi Dr CNS, I have to disagree with you here. My congresspersons and senators are non-scientists and it very much matters what they understand about the pharma industry, or where drugs come from. In fact Congress just passed a $6B “21st Century Cures” bill that changes the FDA approval process regarding new indications for existing medicines. But the bill didn’t address the generic drug regulatory loop hole that Derek has described so well — perhaps because Congress doesn’t understand that loophole? I sure wish they did! Better science reporting might help.

        1. Dr CNS says:

          Points well taken, JIA and UudonRock!

          I am also puzzled by this legislation being rushed at this time. I was hoping Derek will write about that. I hope he will. A ton of money for research, and I fear a large part of it will be pissed away.

          I also, as a scientist, know first hand that one spends more time communicating new ideas to stakeholders than actually doing the science. I was fortunate that my last employer, before letting me go, gave me the opportunity to develop the communication angle – basically because my ideas were going nowhere within the organization! (not that they ever went anywhere after that 🙂

          In my experience, the onus of communicating in a way that is understood is on the speaker, and not so much on the listener. That is a bit unfair, as I don’t think, for example, I am “entitled” to understanding some things that are just outside what my older brain can take. And I don’t blame other for my own shortcomings. In addition, it becomes a downward spiral, as people do not develop the ability to understand messages that are not “optimized” for the lower bottom of the audience.

          IMHO, part of the problem is the energy that it takes to communicate well within an attention span that gets shorter every generation… You have to be very disciplined… And there is no app for that in the app store…

          Not sure what the solution is… but this is killing real science.

      2. UudonRock says:

        I had the great pleasure of meeting Bassam Shakhashiri in 2012 while he was the president of the ACS. He gave a dissertation on the topic of science education followed by a call for scientific communication. The later focused on the idea of scientists communicating to non-scientists on a level that could be understood. There is a serious lack of that in every regard throughout media, as well as academic and industrial research. A better dialogue is exceptionally important to cultivate, but most people are more likely to believe political spin on any topic of societal relevance than empirical data. One seriously slanted documentary can cause more damage to scientific understanding of the non-scientific community than all the poorly written articles in the world. Vaxxed comes to mind. Fortunately that was halted but there are still parents who think MMR vaccine causes autism. You can’t convince everyone. “Truth” is subjective. In addition when the media calls out a demonized pile of unmentionable semi-organic sludge like Martin Shkreli, the layman does not care about the finer details. How does one even begin to approach the situation and tell them that this is not as good as they think? Communicating science has never been easy, and it is damaging when the accepted practice is to allow those with minimal to no understanding attempt to be the bridge between the lab and the world outside. It is also difficult for scientists concerned with research or publication to dumb it down for a broader audience. There should be a reasonable middle ground of higher caliber scientific journalism that can accomplish this, but will it sell papers?

    3. Noni Mausa says:

      As a retired journalist with a strong interest in sciencey stuff, I can say that your average journos are in the business of ALWAYS writing about topics they don’t have the time to thoroughly research. That was my downfall at a rural weekly, where my interest in science was forever trumped by my ignorance of football, hockey, baseball, and all other sports save snooker.

      I enjoyed writing technical articles where the subtleties of the topic were carefully laid out, but often my intent was crippled by a 300-400 word limit, plus an editor with a razor sharp machete, plus a readership who, frankly, couldn’t parse a chain of reasoning with a hand-drawn map and a native guide.

      That was a decade ago — the time constraints, slashed workforce, and high wordage demand have made it even harder since then to put out good coverage.

      I can see how tempting it is for a worn out writer to jump on the Shkreli-haters’ bandwagon. The chance to make your equally tired and frustrated readers laugh for a change must be irresistible. And any readers in a position to understand or research the topic will find their own way to the less-satisfying but more useful truth of the matter.

  3. provocateur says:

    Technically FDA approval is only needed if your compound is being engaged in interstate commerce (where the feds have jurisdiction). If you can make and sell your compound entirely within an individual US state, you may be fine. I have heard though this is likely to be interpreted in a very strict way, so that literally every part of your product, the compound, the vial, the label, the ink on the label, needs to originate from your state. It would be an interesting (dangerous?) thought exercise to see if this could actually be done and in which state.

    1. provoked provocateur says:

      3D drug printer? Or would that have to be made in-state too?

    2. Kent G. Budge says:

      Unlikely. Even if you manufacture completely from stuff originating in your state, your sales will affect the interstate market. That was sufficient in Wickard v. Filburn.

      Hey, I’m not defending SCOTUS’ decision there. I’m just sayin’.

      1. Fenichel says:

        To my knowledge, the only pharmaceutical legally marketed in the US without FDA regulation in recent times was a scorpion antivenom that was made in, and shipped only within, Arizona starting about 35 years ago. I’ve been told that it has in the past few years been brought under the FDA umbrella, so now there may be none.

        1. tangent says:

          Now where else but here would I ever learn about that! I love (a subset of) the commenters here. Thanks.

    3. Emjeff says:

      This is a theoretical concept,one that could never be met in practice. There is no way you would find everything you would need for a product to be manufactured in a single state, so it’s not a viable loophole.

      At least once,to my knowledge, FDA agreed to let an MD prescribe and manufacture a drug in a single state, mostly as a way for them to save face. Remember “anti-neoplastons “? This nonsense was dreamed up by some quack inTexas, who soon had hordes of cancer sufferers coming to his clinic to be treated with this pseudo-science. When the FDA tried to shut him down, the public uproar was so great ( there’s that great science journalism again) , that the FDA backed off, with the proviso that the “drug” could not be used or shipped outside of Texas.

  4. Isidore says:

    I recall making barbituric acid in organic chemistry lab in college, decades ago. Unfortunately no Australian journalists were on hand to write glowingly how we had taken down Adolph von Baeyer.

    1. Bob Weiss says:

      Just be glad there weren’t any DEA agents around to raid the lab and brag about taking down a previously unknown “college cartel”….

  5. Ananoymous says:

    “New reporters” should be “news reporter”. Nice article, someone needed to write this for the world out there

  6. Daniel Morgret says:

    Couldn’t this still be used to put pressure on a few selected high-priced generics, including Daraprim? If there is a relatively straightforward procedure that can be reasonably expected to produce a safe product, and have a predictable yield (for dosing), someone who needs the drug could make it for their own use without bothering with the regulatory hurdles. I would have a clear conscience doing it.

  7. Kiwi Kiwi Kiwi says:

    Australians are descendants of convicts, what did you expect?

    1. hand.me.the.wobbla says:

      (and prostitutes)

      1. Sean says:

        I don’t know if US citizens can have a prescription filled in the UK but in the UK the price is –

        Net price 30-tab pack = £13.00

        If this is legal, please make people aware.

  8. me says:

    On the other hand, black/grey market drugs could potentially save lives of people unable to afford legal formulations. Given that people are already comfortable buying illegal drugs on the street and importing drugs from foreign pharmacies, the growth of this sort of thing doesn’t seem all that farfetched.

  9. Peter S. Shenkin says:

    I made mescaline in undergrad orgo chem lab, but it didn’t take down the peyote farmers.

    Well, another reason it didn’t take down the peyote farmers was that the synthesis failed: the Rosenmund reduction went too far.

    We had to pick an organic synthesis from the literature that started with materials available in the stockroom. The synthesis had to have a certain level of complexity. The stockroom had a jar of gallstones. The literature synthesis started with gallstones. The first operation was grinding the gallstones in a mortar. That was harder than it sounds. But not as hard as keeping the Rosenmund reduction under control. 🙁

    1. Barry says:

      surely those should have been oak gall, not gallstones?

  10. Long Ago and Far Away says:

    Any chance this can get posted verbatim on Reddit, for all the ill-informed people over there? And maybe also posted in, say, the NYT?

  11. anon says:

    No need to read Jack Scannell. The price of a drug depends on what the market will bear.

  12. pragmatist says:

    “They synthesised the end-product last week. Dr Williamson tested its purity in a spectrograph at university.

    “It’s one of the most beautiful spectrographs I’ve ever seen, actually,” she said.”

    What’s a spectrograph?

    1. anon says:

      It’s a terrific device for tremendous chemistry.

    2. Nick K says:

      Who needs mass spec or NMR when you have a spectrograph? Everyone knows that!

    3. Down under says:

      It’s a tlc in Australian.

  13. Steven Aston says:

    Thanks for writing this, Derek. I’m not a chemist but I know most of the issues involved with this and was getting very tired explaining this to people so now I can just link them to this helpful column!

  14. Rock says:

    Speaking of making things worse, flipping through the Nov 21st issue of C&E News I happen to see a “by the numbers” blurb stating that in 2015, Medicare and Medicaid paid out $457 billion for prescription drugs. I realized immediately that this was nonsense and started digging myself. The 457 billion dollar number is the total prescription drug sales in the US in 2015. If that was the government share, the entire US federal budget would be going to healthcare. I asked them for a prominent retraction.

  15. Peter Kenny says:

    University of Sydney’s Open Source Malaria Program must bear some of responsibility for the press coverage of this story. Presumably the faculty members had the opportunity to see (and provide feedback on) the story prior to publication. Something that those who use the term ‘open source’ in the context of drug discovery don’t seem to grasp is that pharmaceutical products are open source in that the regulatory authorities require that you say exactly what the drug is (and how you’re manufacturing it) before you can sell it. I do believe that drug discovery (especially for diseases that affect people in developing countries) needs to be more open. However, press reports like this and the continued use of ‘open source’ in a pharmaceutical context run the risk of damaging the credibility of those who seek to make drug discovery more open.

  16. Johnny-John says:

    Peter, you might get a kick out of this then:

    “The OpenZika project will ultimately generate several billion docking results, which could make it the largest computational drug discovery project ever performed in academia. The potential challenges we foresee will be finding laboratories with sufficient funding to pursue compounds, synthesize analogs, and develop target-based assays to validate our predictions and generate SAR (Structure-Activity Relationship) data to guide the process of developing the new hits into leads and then drugs.”

    http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0005023

    1. Peter Kenny says:

      Johnny-John, The thermodynamic proxies article (my review of which is linked as the URL for this comment) may reduce the enthusiasm of laboratories for validation of the authors’ predictions.

  17. Daryl Adair says:

    Notwithstanding the reproducibility of this drug in laboratory conditions, the Sydney student episode surely allows further discussion about what is the essence of the problem, as Lowe himself emphasises: “Daraprim’s ridiculous price is completely a regulatory failure”. This is not a scientific issue; it is a policy problem and a failure of politics. So, what is the solution? In the meantime, actual people are suffering because of the enormous price of this drug.

  18. Matthew Todd says:

    Hi Derek. You know better than all of us how difficult it is to control a story, particularly when it’s picked up so widely. It’s hard to control how it’s presented (beyond the only text we had input on: http://sydney.edu.au/news-opinion/news/2016/11/30/students-make–750-drug-cheaply-with-open-source-malaria-team-.html) and how it’s received, then, later, what people do with it and the conflict-based language that is propagated. I’m fairly sure that those people directly involved, including me, have emphasized the following up front (that I’m assuming we here all agree on and understand):

    1) This is an educational project. Obviously the drug can be made by many other people, but that misses the point: these were high school students. Not college. High school. I don’t know about you, but I wasn’t doing anything as complicated as this when I was in high school (benzoic acid crystallization, anyone?). The teachers also showed considerable initiative in taking the time out to get involved with this science project at the outset. We’re all busy, but they wanted to give their students real research to do, i.e. where one is not confident of the outcome because there is no previous cohort who did the same thing. The students and their teachers are right to be congratulated (as Martin Shkreli has now done), and I assume it is this overwhelming positive that has caught the public imagination.

    2) We assumed at the start that this would be simply a matter of digging up the patent and repeating the procedures, but there was surprisingly little information in the literature about the route, and various things needed to be changed or tweaked, as you might expect. I was deeply impressed by how these students and their teachers dealt with this. You can see the workaround details because…

    3) ..it’s open source, meaning the nuts and bolts are on public display in real time and anyone could jump in. People advised the students. The public details should help reproducibility, just as you say in your post above, Derek. Certainly easier than before the project started. (Discussion: https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/374; ELN: http://malaria.ourexperiment.org/daraprim_synthesis)

    4) Any higher-level comments about drug pricing have (I’m fairly sure) been limited to *the price increase of this particular drug* not *the whole of pharma*. We (here, in our medchem soc-med bubble) all know that the cost of a medicine is not the material in itself (you already mentioned Jack’s excellent piece (http://www.forbes.com/sites/matthewherper/2015/10/13/four-reasons-drugs-are-expensive-of-which-two-are-false/#1161512548a5)). I’m fairly sure that people on the outside of the medchem bubble do not know that, at all. The significance of the picture that emerged, of one of the students holding $100K of drug, is that it brings that single idea to the public: the material is cheap, so why is the drug now so expensive? There’s the point – people don’t know why. This example can shift the discussion to that more interesting place.

    5) Nobody should be seriously suggesting the students will sell the drug. But people (regular, non medchem people) do not know why they can’t. I was asked about this aspect several times and delineated the issues, and I hope those came through if they were mentioned. Everyone here knows that a Uni lab is not a GMP facility. Nobody outside knows that. I don’t think the stories suggested the school-derived material would end up on the market (correct me if I’m wrong) but, again, it’s hard to control people extrapolating.

    Regarding those bigger picture questions (beyond what the students actually did) some people are chiming in to say that Turing profits are for the R&D behind the development of improved medicines for toxoplasmosis. That’s commendable, if it’s true, even if one knows there are other ways to raise such funds (as you said in a previous post, Derek (http://blogs.sciencemag.org/pipeline/archives/2015/09/21/martin-shkreli-has-one-idea-and-its-a-bad-one)). But one would ultimately need to take that pledge on trust, and to trust that the set price is appropriate to prospective R&D activities combined with an x% profit margin. So let’s audit, in a few years.

    1. pragmatist says:

      Good thoughts Matt. Props all around!

    2. tangent says:

      Those are good points, but would you consider some critique of the press release you linked to on sydney.edu.au?

      The article is all about pricing, if you go by the headlines; they don’t get into any of the nice thoughts about educational value and impressive work by high school students (which I’m sure make press office people turn gray). Headlines really color the readers’ understanding of the rest.

      The top line is “make $750 drug cheaply”. This implies there’s some significance to the fact that it was done cheaply. But of course it was cheap, why wouldn’t it be — that has no relation to the “$750” it’s juxtaposed with.

      The subhead is “Synthesis of essential medicine challenges price-hike loophole”, again making the price the point of the article. How does it challenge it? The ease and cost of the synthesis don’t form any kind of decent argument against the drug’s pricing. Because they attempt too broad an argument — patented drugs are routinely priced many times above their cost of manufacture, and most of us are okay with that. Any effective challenge has to refer to the fact that the company is vulturing a generic. “Loophole” is the substantive word in all this, but this was equally a loophole before the students ever did their chemistry work.

      How much control did you have over the headlines — were these headlines your own doing, or the university press office’s? There is a /reason/ that press offices like to write the headlines most of all. The headlines control whether your story lives or dies. But to do that, they can and will undermine any good intentions you have in the text!

      Drawing eyes and emphasizing that the price is ridiculous, I recognize those are real things. I appreciate your idea that once people ask “why is it expensive then?” that they could start to learn the answer. But if you could count up the actual outcome, I think empirically you’d find that almost none of your readers got there, to understanding or effective action.

      Hey, if that’s your goal, go for it: weave the start of that context into your press release. “Daraprim, launched in 195x, increased in price 50x in 2015, because the generic now has only one maker under FDA rules.” I’m sure it can be done better so newspapers will pick it up, but please don’t tell me it’s not allowed because it doesn’t relate directly to the science.

  19. SPQR says:

    Bunch of nerdy asian kids in lab coats, thats your story right there folks!

  20. Pommie Bas*ard says:

    …Maybe the Aussies should stick to cricket. On second thoughts (recent run of 7 consecutive Test Cricket defeats, only ended by a winning a dead game with the Series already lost), maybe they should stick to Test Synthesis against naff opposition. The Aussies always were formidable flat track bullies…

  21. Doug Steinman says:

    There are some very good science writers out there. Check out The Cancer Chronicles by George Johnson. Excellent book by a “science journalist.”

  22. Garrett says:

    On the “You cannot make daraprim in a school lab and sell it” front:
    What would be the impact of a college chemistry/pharmacy program doing a limited run of a life-saving drug in a crisis? Like this:

    http://vitals.nbcnews.com/_news/2013/03/26/17431799-frustrating-zinc-shortage-endangers-tiniest-babies-doctors-say?lite

  23. Jose says:

    Garrett, the risks for any institution are simply astronimical. GMP exists for a reason, and dosing someone with ‘officially sanctioned’ but non-GMP materials is a million/billion dollar lawsuit waiting to happen.

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