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An Open-Source Cancer Pitch, Deconstructed

I’m confused. Read this and see if you end up the same way. TechCrunch has the story of Isaac Yonemoto, who’s crowdsourcing a project around a potential oncology compound. It’s a derivative of sibiromycin, a compound I hadn’t come across, but it seems that it was first studied in Russia, and then at Maryland. Yonemoto’s own work on the compound is in this paper from 2012, which looks reasonable. (Here’s more). And the crowdfunding pitch is also reasonable, in lay-audience terms:

The drug candidate 9DS was developed at the University of Maryland. The last work done on the drug showed that it had activity against cancer competitive with leading cancer drugs such as taxol. Moreover, 9DS is also likely to have lower side effects than most chemotherapies, since a related compound, SJG-136, seems to have low side effects in early clinical trials.
Project Marilyn involves: production of more 9DS, and submitting 9DS to a xenograft study (‘curing cancer in mice’). This is the next step in drug development and an important one on the way to doing clinical (human) studies. The process we’re seeking to fund should take approximately 6 months. If we recieve more funding, we will add stretch goals, such as further preclinical experiments on 9DS, development 9DS analogs, or other exciting anti-cancer ideas.

But here’s where things begin to swerve off into different territory. Yonemoto isn’t just talking about some preclinical spadework on yet another oncology compound (which is what the project actually is, as far as I can tell). He’s pitching it in broader terms:

. . .Some drugs can cost upwards of $100,000 a year, bankrupting patients. This level of expense is simply unacceptable, especially since 1/3 of people will get cancer in their lifetime.
One solution to this problem is to develop unpatented drugs – pharmaceutical companies will have to sell them at a reasonable price. To those who believe that drugs cannot be made without patents we remind them:
When Salk and Sabin cured polio, they didn’t patent the vaccine. It’s time to develop a patent-free anticancer drug for the 21st century.
The software industry and the open-source movement have shown that patenting is not necessary for innovation. Releasing without a patent means the drugs will be cheaper and it will be easier to build on the work to make improved drugs or drug combinations. Releasing without a patent means expanded access to drugs in countries that can’t afford extensive licensing and export agreements.

OK, let’s take this one apart, piece by piece, in good old classic blogging style. Yes, some oncology drugs are indeed very expensive. This is more of a problem for insurance companies and governments, since they’re paying nearly all of these costs, but the topic of drug prices in oncology has come up around here many times, and will do so again. It’s especially worrisome for me that companies are already up close to the what-the-market-will-possibly-bear price with things that are not exactly transformative therapies (what pricing structure will those have?)
But are unpatented drugs the solution? It seems to me that pharmaceutical companies will not “have to sell them at a reasonable price”. Rather, unpatented compounds will simply not become drugs. Yonemoto, like so many others who have not actually done drug development, is skipping over the longest, most difficult, and most expensive parts of the process. Readers of the crowdsourcing proposal might be forgiven if they don’t pick up on this, but getting a compound to work in some mouse xenograft models does not turn it into a drug. Preparing a compound to go into human trials takes a lot more than that: a reliable scale-up route to the compound itself, toxicology studies, more detailed pharmacokinetic studies, formulation studies. This can’t be done by a handful of people: a handful of people don’t have the resources and expertise. And that’s just setting the stage for the real thing: clinical trials in humans. That crowdsourcing proposal skates over it, big-time, but the truth is that the great majority of money in drug development is spent in the clinic. The amount of money Yonemoto is raising, which is appropriate for the studies he’s planning, is a roundoff error in the calculations for a decent clinical campaign.
So who’s going to do all that? A drug company. Are they going to take that on with an unpatented compound that they do not own? They are not. Another thing that a lay reader won’t get from reading Yonemoto’s proposal is that the failure rate for new oncology compounds in the clinic is at least 90%, and probably more like 95. If you are going to spend all that money developing compounds that don’t make it, you will need to make some money when one of them finally does. If a compound has no chance of ever doing that, no one’s even going to go down that road to start with.
Now we get to the Salk/Sabin patent example. There are plenty of persistent myths about the polio vaccine story (this book review at Technology Review is a good intro to the subject). Jonas Salk created one of the most enduring myths when he famously told Edward R. Murrow in an interview that “There is no patent. Would you patent the sun?”. But the idea of patenting his injected, killed-virus vaccine had already been looked into, and lawyers had determined that any application would be invalidated by prior art. (Salk himself, in his late work on a possible HIV vaccine, did indeed file patent applications).
Sabin’s oral attenuated-virus vaccine, on the other hand, was indeed deliberately never patented. But this does not shed much light on the patenting of drugs for cancer. The Sabin polio vaccine protected all comers after a single dose. The public health implications of a polio vaccine were obvious and immediate: polio was everywhere, and anyone could get it. But Yonemoto’s 9SDS is not in that category: cancer is not a single disease like polio, and is not open to a single cure. Even if a sibiromycin derivative makes it to market (and they’ve been the subject of research for quite a while now), it will do what almost every other cancer drug does: help some people, to a degree, for a while. The exceptions are rare: patients who have a tumor type that is completely dependent on a particular mechanism, and that doesn’t mutate away from that phenotype quickly enough. Most cancer patients aren’t that fortunate.
So here’s the rough part of cancer drug discovery: cancer, broadly speaking, is indeed a big public health issue. But we’re not going to wipe it out the way the polio and smallpox vaccines wiped out their homogeneous diseases. Cancer isn’t caused by a human-specific infectious agent that we can eliminate from the world. It crops up over and over again as our cells divide, in thousands of forms, and fighting it is going to take tremendous diagnostic skill and an array of hundreds of different therapies, most of which we haven’t discovered yet. And money. Lots of money.
So when Yonemoto says that “The software industry and the open-source movement have shown that patenting is not necessary for innovation”, he’s comparing apples and iguanas. Drug discovery is not like coding, unfortunately: you’re not going to have one person from San Jose pop up and add a chlorine atom to the molecule while another guy pulls an all-nighter in St. Louis and figures out the i.v. formulation for the rat tox experiments. The pitch on Indysci.org, which is really about doing some preliminary experiments, makes it sound like the opening trumpet of a drug discovery revolution and that it’s going to lead to “releasing” a drug. That’s disingenuous, to say the least. I wish Yonemoto luck, actually, but I think he’s going to be running into some very high-density reality pretty soon.
Update: Yonemoto has added this to the comments section, and I appreciate him coming by:
“Thanks Derek! You’ve basically crystallized all of my insecurities about the future of open-source drugs. But that’s okay. I think there are business models wherein you can get this to work, even under the relatively onerous contemporary FDA burden. To answer a few questions. I think sibiromycin is not a bad candidate for several reasons: 1. (I’m not sure I buy this one but) it’s a NP derived and NP derived tends to do well. 2. A molecule with a similar mechanism has made it into phase III and phase I/II show only mild hepatotoxicity and water retention, which are prophylactically treatable with common drugs. 3. There is reportedly no bone marrow suppression in these compounds, and importantly it appears to be immune-neutral, which would make PBDs excellent therapies to run alongside immune-recruitment drugs.”

59 comments on “An Open-Source Cancer Pitch, Deconstructed”

  1. Hap says:

    The software industry and the open-source movement have shown that patenting is not necessary for innovation.

    Hasn’t history shown mostly the opposite? People did innovate before patents, and will after, but lots of (most) innovation was kept as trade secrets, which I don’t think is what he’s hoping for. Patents were there to provide the benefits of innovation to everyone (later), rather than keeping them forever in the hands of a few.
    Software companies don’t exactly seem exemplars of the patentless society either, unless their power and ability to generate money is a sign of an absence of innovation, That would then seem to be the show-killer for patent-free innovation – if no one can make money (especially in cases where the inputs are not just time and work, but involve large amounts of materiel and money) being innovative in a patent-unencumbered world, then no one’s going to do it.

  2. David Borhani says:

    Derek, “Rather, unpatented compounds will simply not become drugs.” What about Thiola, Colchicine, and other recent examples of non-patented but now wildly expensive drugs?

  3. anonao says:

    @Hap. It depends of which software company. Some have tons of patents and fight for it (Oracle, Apple), others are using open source software, but may charge for service to grow.
    It is a difficult case, and like Derek I wish him luck, finding a new cancer drug, if it works, would be great for some patients, so success is welcomed. One thing in this project is that failure can come from unrealistic expectation on money (or he needs big funders – very rich people we have experienced having a cancer or knowing someone with it?), but also for just the compound itself (like in any pharma company).

  4. johnnyboy says:

    They’re shooting for 75K in funding, and are now at almost 60K. According to Marcia Angell, that should probably be enough to get a drug to market. Finally, cancer therapy is solved !

  5. Anonymous says:

    What’s sad is that he can’t secure traditional sources of funding for this work (grants). There’s a pipeline for promising maybe drugs in academia and it goes through proving preclinical activity in academia and then securing IP protection. Then that protection is actually a prerequisite for more capital investment that is needed to push the compound forward. If he crowd sources this, he’ll need all 1 billion in the form of public donation because the traditional avenues of investment will not be interested in technology that cannot be protected.

  6. Erebus says:

    It’s fairly obvious that sibiromycin — “like taxol, but possibly with fewer side effects” — isn’t a miracle cure. It’s no polio vaccine. In quite a few respects, generally, the comparison to the polio vaccine is unwarranted. It’s a sort of apples-to-oranges comparison. Yonemoto would do better to compare sibiromycin to other natural product drugs that have served humanity since time immemorial — quinine, colchicine, morphine, etc. (Even aspirin, after its creation, wasn’t patentable in Europe.)
    With all that said, Yonemoto is trying to do a good thing, and he should be applauded and encouraged. The “problems” you list, Derek, have everything to do with an out of control, overbearing FDA bureaucracy run by a cabal of professional government apparatchiks. In running their fiefdoms and exercising their ‘authority’, these bureaucrats stifle innovation and progress at every turn. Drug development costs keep rising, clinical testing periods keep getting longer, and the sick suffer for it.
    …We’d be better off with no FDA at all. We’d be best off with 1955’s FDA.
    Yonemoto is sure gonna get a heavy dose of reality. But we need to understand that he’s the good guy here. He’s the sort of person this world needs more of. The FDA, on the other hand, is something everybody should despise.

  7. Vader says:

    “very high-density reality”
    Gonna shamelessly steal that phrase.

  8. johnnyboy says:

    @6: LOL. You forgot the following keywords in your anti-FDA rant: “jack-booted thugs”, “kafkaesque”, “government bullies”, “conspiracy”.

  9. Erebus says:

    @8-
    Does it seem reasonable to you that developing a new drug should now cost $1B and take an average of 12 years?
    Are you aware of how different the process looked during the industry’s boom years, several decades ago?

  10. Canman says:

    So what happens if he doesn’t get the money for the xenografts… Are we then better off? Probably not. Might as well get this “drop in the bucket” amount of money and see what happens. If there really is potential in this compound, then let’s go in baby steps and see how far we can go. Perhaps it may kickstart interest in crowd sourcing for other drug discovery efforts and ideas.

  11. @#2,
    Those drugs (Thiola, colchicine) aren’t patented, but they do have data exclusivity/orphan approval protection from the FDA, so you end up with the same thing as a patent; only one company can sell the drug.
    Mike

  12. CMCguy says:

    #6 Erebus do you serious believe “We’d be better off with no FDA at all. We’d be best off with 1955’s FDA”? While I agree the FDA has become excessively bureaucratic, more controlled by politics than science, and often can be more a hindrance to drug development in the end they have a required and extremely tough job in protecting the public. Although doubtful is really the case perhaps the Industry needs to return to the 50s as well since today Pharma and Biotechs seem less skilled in discovery and development plus not prone to cutting corners where it suited them,

  13. a moderate says:

    I actually think the FDA does a great job. And I am a small government kind of thinker.
    I would perhaps allow a somewhat relaxed safety requirement in some indications for drugs with questionable safety, say in cancer. If patients are informed and willing to take greater risk in the face of a very serious disease like cancer, I think they should be granted more decision making power here – obviously this means they are responsible should there be untoward effects of those drugs.
    But otherwise, I am actually a fan of the FDA. Try having a job where only failures are visible and successes are invisible.

  14. annon 2 says:

    Gotta sometimes think and work out of the box. But you might not meet anyone from FDA there.

  15. ab says:

    Maybe I’m wrong here, but clinical trials are only *really* expensive for drugs that don’t work that great, right. You need a lot of people taking a lot of drug over a long period of time in order to get the statistical power to show convincingly that your drug is doing something marginally good. On the other hand, show me a drug that *cures* non-small cell lung cancer in 95% of patients after a single dose in a 20-person P1 trial, and I’ll show you a very short and cheap path to approval.
    It is noteowrthy that sibiromycin is not said drug.

  16. PorkPieHat says:

    Dude, he’s just trying to get an edge in the PR world that is crowdsourcing. You’ve taken this a bit too seriously. Its great to deconstruct this and all, but at the end of the day, he’s just another peacock strutting his stuff, like the rest of us. More power to him.

  17. Erebus says:

    As per Hansen and Chien — writing in Issues in Pharmaceutical Economics, Lexington Books; 1979 — the average cost of releasing a drug between 1963 to 1975 was $119M. (All figures adjusted for inflation.) A different study (DiMasi et al., 1991,) which examined the period from 1970-1982 found that costs nearly doubled to an average of $231M. The Office of Technology Assessment re-examined and confirmed these studies in 1993, and claimed that rising labor costs and larger trial sizes were responsible for the cost increase.
    …Fast-forward to today, and we’re at over $1 billion dollars and ~12-13 years per drug? Surely the system is badly broken, as the costs associated with drug development appear to double every decade, and clinical trials just keep getting longer. Furthermore, I believe that it would be difficult to argue that the untold billions that have been spent on the drug approval process are well-spent. If the drug approval process were shorter, cheaper, and more streamlined, we’d have cheaper drugs. We’d also have more innovative drugs. A lot of the problems with the USA’s medical system, and with the pharmaceutical industry, would be resolved if the FDA’s grip was loosened, and its power diminished. Removing it entirely is better than the alternative; I’m fairly confident that this alternative would lead to a pharmaceutical industry where even the largest companies cannot afford to take risks on drug development, and where innovation is kept to an absolute minimum. Aren’t we already starting to see this come to pass?

  18. OneManManyHats says:

    @17 Erebus
    I’m curious if they are accounting for the “low-hanging fruit” consideration. I’m not in the field of drug discovery, but it seems to me that you’re going to have a natural progression starting from easy-to-hit, cheap targets going towards very finicky, and accordingly expensive targets.
    By that train of thought, the numbers you present would make sense. During that early golden age, there were plenty of easy drugs to make with relatively low cost overhead. As we’ve exhausted those options, we have to work harder and harder to find useful drugs, giving a lower and lower ROI per drug.
    Of course, I could be completely off base.

  19. Anonymous academic says:

    @17: “If the drug approval process were shorter, cheaper, and more streamlined, we’d have cheaper drugs. We’d also have more innovative drugs.”
    We’d also have more drugs that didn’t actually do what they claimed, or have severe side effects that could have been identified with more careful testing. There is already a serious problem with pharma companies aggressively marketing psychiatric drugs (some of them quite debilitating) for unapproved conditions, for which they’ve rightly been fined billions of dollars – and you think reducing FDA oversight is the solution to all our problems?

  20. Hap says:

    Having cheaper drugs that don’t work (or that people don’t know whether they work) isn’t really a win.
    I would also imagine that the desire for blockbusters and the willingness to be less than honest in the pursuit of said goal (Vioxx, etc.) has probably led to increases in trial requirements. Smaller trials depend on trust, because there’s not enough data to tell, and, well, that bridge was burned. Irrevocably.
    Finally, longer-term administration of drugs means they have to be tested for longer times, to see what they do; the shift to drugs for indications that require taking drugs forever would raise the cost of trials on its own.
    Then of course, there’s the biotech funding fiesta. Good news: biotechs could run trials on their own, without needing a big daddy pharma, and so you could have more competition (because smaller ompanies could bring drugs to market on their own, and make the money on their own), and those that sold might get more money, depending on supply. Of course, that would probably also mean that every day could be Sketchy Biotech Day.

  21. steve says:

    #15, you’re only partly right. For drugs treating acute conditions, if they work well you only need a small trial. But for drugs treating chronic conditions (e.g., diabetes) or for vaccines you need long, expensive trials with many patients in order to identify potential risks over time.

  22. steve says:

    I should add that what’s driving a lot of this is an aging population and the fact that many of the disease now needing treatment are chronic ones. Like most issues that don’t get resolved quickly, this is complex and not likely to be subject to simple solutions. On the other hand, the current system is simply unsustainable and will eventually lead to the US having to adopt a single-payer system like the rest of the world.

  23. Erebus says:

    I just don’t think that suffocating the industry with bureaucracy is the answer. I believe that:
    -The FDA isn’t the ultimate arbiter of truth, and they’re far from infallible. (I’d perhaps add: In attempting to become infallible, they’re harming our industry.)
    -Even without an FDA, pharmaceutical companies would run clinical trials, and they would test for safety and efficacy. (I’d argue that their directors should possibly be held criminally negligent in the event of another Vioxx-esque scandal. There are also fraud/advertising laws. The industry can be regulated without the FDA, and without very many new laws.)
    -The mile-deep red-tape is doing a great deal to stifle innovation. Is it low-hanging fruit? Or is it that people like Yonemoto have literally _zero_ chance of success, thanks to the ‘oversight’ that’s currently in place? I can’t say. I’m inclined to believe the latter. We’d certainly have a much larger, more vibrant industry were there fewer restrictions in place.
    …Again, as things stand, only a few very large companies can afford to develop new drugs from pre-clinical through approval — and these companies are becoming increasingly risk-averse, as development costs keep rising…

  24. Mat Todd says:

    There’s just too much interesting stuff to discuss here, but it’s really great you raised this interesting campaign here, Derek. Possible, practical solutions to just these questions were discussed at the first Open Source Pharma meeting back in July, and we’re working on writing the meeting up properly. Essentially (and on the clear understanding that these arguments, as you say, depend on the disease we’re talking about): yes, it’s no surprise that a company on its own will probably not take an unpatented compound through clinical trials. Money is still needed, and that money needs to come from elsewhere. People shudder at the idea of such money coming from the public purse. The difference if it’s done *genuinely openly* is that everyone can see exactly how good the data are, and discrete parts of the pipeline can be funded by different actors. It’s not about just public vs. private funding and which is better at dealing with risk. It’s squarely about the openness: funding and operating the process completely differently (with different sources of money) because all the data are fully available, all the time and may be acted on by anyone with the means or inclination. Open source is far removed from what is usually meant by the fairly vague term “open innovation”.
    Yes, there’s no precedent.
    The intention of Salk aside, it’s true, is it not, that there was no patent, and yet the medicine was a successful public good?

  25. Hap says:

    The poroblem with heavier penalties for individual malfeasance in trials is that, in general, the shifts to lower regulation have come at the behest of large companies who also do not want to go to the hole for their actions. A world where regulation is a step function would be different than the one we seem to have.

  26. Mica says:

    Actually, I worked with a person who was told (by then Dean of his Medical School) in 1960’s that patenting research that could save lives was immoral (100’s of thousands of lives, and bringing millions of then dollars–just to clarify). Such were times. Method (drug and assay that went with it) still ended up being developed by a pharmaceutical company… and the person received some generous non-restricted research support (quite substantial and some of it was still used 30+ years later).

  27. anon the II says:

    The last time I looked, the US had about 300 million people out of the 9 billion or so people in the world. So the FDA is only protecting about 1 in 30. If the FDA is such a problem, then why aren’t they developing all those drugs in other countries where they’re allowed to be innovative. If an obvious “cancer cure” is developed in another country, I’m sure the FDA will not crush it’s approval in the US. I’m gonna call BS on the FDA bashing. And please, don’t start trotting out the “laetrilesque” examples.

  28. Christophe Verlinde says:

    Without a strict FDA there would be rampant cheating and scamming because society ALWAYS has types who have no qualms over making bucks at the expense of the unlucky patients who will suffer from unacceptable side effects. Just ask yourself the question ” why is pharma against FULL disclosure of ALL the data relating to trials?” Because they are in the grip of the stockholders who want big time yields. And thanks to the 401K plans almost any employe is a stockholder.
    In the nineties a trip to the museum of “Questionable medical devices” in St-Paul, MN, was an eyeopener. E.g. xrays to remove unwanted hair, radium-laced toothpaste to get “healthy rosy” gums, Indian anti-worm pills which actually contained worm cysts – “see, you did’nt even know you had worms”, radio-active mini suppositories to put in your penis to fight syphilis, pain-killing elixir with alcohol and morphine for teething babies, …
    It is only reasonable to assume that without strict FDA control there will be types out there at every step of drug development who want to cut corners. We have to face reality.

  29. DCRogers says:

    “This is more of a problem for insurance companies and governments, since they’re paying nearly all of these costs”
    Huh? Unless there’s a money-fairy somewhere, health-care customers are ultimately paying every cent, either through premiums, forgone wages, or taxes.
    And in the longer term, it’s a huge problem for pharma, as worst-case pricing examples barely distinguishable from extortion of the dying proliferate and torpedo any remaining good will towards the industry.
    Given the flaws of the current patent-based system, I’m willing to give alternative ideas a listen and a lot of slack.

  30. JAB says:

    So sibiromycin is a nice tractable benzodiazepine structure, so all the med chem folks will like that, but what about the known mechanism? It’s a DNA damaging agent. I would hope we’re beyond putting all of our anticancer eggs in that basket! If someone can show another mechanism, then I might be favorably inclined.
    Secondly, xenografts are fine models to test compounds in, but that’s still a pretty early stage of development. Lots and lots of compounds don’t make the transition from in vitro activity to in vivo, though I suspect that a sibiromycin analogue might be fine on ADME/PK issues.

  31. Erebus says:

    @27 – The FDA may not “crush” the approval of foreign drugs. But for various reasons, the USA is the most lucrative market for drugs in the world, and the FDA won’t approve foreign medications unless they’ve gone through the same rigorous drug approval process as other new drugs.
    I’d add that Russia, Italy, and numerous other countries have pharmacopoeias that are very different from the USA’s.
    @28- I’d rather see a small, reasonable, forward-thinking FDA than no FDA at all. But the current situation, where the industry is suffocating on red tape, where costs double every decade, where small and innovative companies are unable to survive at all… this is the worst of all possible regulatory situations.
    One could easily argue that the FDA need test only for safety, not for efficacy. The market and doctors can decide how efficacious a medicine is.

  32. anon says:

    @Erebus:
    you base your statements on assumptions that appear to be massive over-simplifications, making it hard to take you seriously.
    “I just don’t think that suffocating the industry with bureaucracy is the answer” –> ohh really? have you ever talked to a person who asserted it was the answer?
    “The FDA isn’t the ultimate arbiter of truth” –> see response above.
    “-The mile-deep red-tape is doing a great deal to stifle innovation”
    Here you assume there is mile deep red-tape, and then talk about what it is doing. for example, it is actually pretty easy to get cancer drugs into people, you just need to show reasonable potency data in animals, and not incredibly bad toxicity. since the patient population is sick and dying the FDA does allow leeway in drug profiles.
    The money for drugs is there if you actually have a promising drug. This is where the whole small biotech develops something then sells itself to a big company for an ass-ton of money model of biotech comes from. but in the end the big company gets the credit for the drug (and they are also doing alot).
    its impossible to take you seriously when you speak the way you do.

  33. Anonzy says:

    I have a question similar to #6: for instance how does tecfidera (dimethyl fumarate) which you can buy off the shelf for a few dollars a kilo get patented and become a billion dollar drug for multiple sclerosis?

  34. Hap says:

    @31: But if the FDA is reponsible for as much of the clinical trial burden as you say, then there should be enough money in the reduced populations to cover the reduced costs of clinical trials, and if the drugs are good, eventually the FDA will have to catch on. If some other country has a drug that works, there is little to stop people from going there, and likely there will be pressure (depending on the size of the population) for someone to approve it. It also would seem like a way for countries who want their own pharmaceutical industries to change the game in their favor – making drugs that work but aren’t available in the US would be a significant boost to them. There’s also lots of big drug companies who would love to change the FDA’s regulations in their favor and who could easily find drugs elsewhere and sell them if they had them. But these things don’t seem to have happened, and if it’s all about the money, there’s not necessarily a reason why they haven’t.

  35. diver dude says:

    I shall hence-forward use the phrase “high density reality” at any opportunity I can.

  36. Erebus says:

    @32-
    I’ll ignore the ad hominem remarks & the sentence-fragments taken out of context. Your post appears to claim two things:
    1. That it’s easy to get cancer drugs into people.
    This is, of course, provably false. Do you know how much it costs, and how difficult it is, to get to that approval stage? Vismodegib, a late-stage cancer drug which was truly fast-tracked, took roughly 8 years from pre-clinical through approval. You can guess how inefficient that process was, and how much it cost. I could also bring up nivolumab, which is still unapproved in the USA after 35 trials. (Though Japan has already approved it.) Other such cases abound.
    2. That the business model of “we can’t afford to develop this on our own, so we need to sell ourselves to a larger company” is a good one.
    Needless to say, I wholeheartedly disagree. As small companies are essentially forced to sell, the market is effectively distorted. This also serves to entrench existing power-structures, which preserves inefficiencies.
    @34-
    “Making drugs that work but aren’t available in the US would be a significant boost to them.”
    I wholeheartedly agree. But, in all honesty, nobody’s going to travel to Croatia or South Africa for something like sibiromycin. They’d travel for a cure, or for a significant chance at a cure — but not for something that’s comparable to existing medicines.
    That said, if current trends continue, I’m certain that they shall result in more R&D and more filings for first-approval taking place outside the USA.

  37. diver dude says:

    For an interesting alternative approach to the clinical development of low cost therapies for cancer, check out the link below
    http://www.independent.co.uk/life-style/health-and-families/health-news/cancer-drugs-trial-for-when-standard-treatment-is-not-viable-shows-incredible-signs-of-success-9804279.html
    It’s not getting a lot of airplay at the moment, but it could be very powerful (full disclosure, this guy is a friend and ex-boss of mine. I own no stock).

  38. diver dude says:

    For an interesting alternative approach to the clinical development of low cost therapies for cancer, check out the link below
    http://www.independent.co.uk/life-style/health-and-families/health-news/cancer-drugs-trial-for-when-standard-treatment-is-not-viable-shows-incredible-signs-of-success-9804279.html
    It’s not getting a lot of airplay at the moment, but it could be very powerful (full disclosure, this guy is a friend and ex-boss of mine. I own no stock).

  39. Lane Simonian says:

    “Unpatented compounds will simply not become drugs.” Therein lies the problem (even if there are a few partial exceptions or outliers). There is basically one pathway to disease treatment in the United States and that is through pharmaceutical companies mediated by the FDA (which has probably approved too many drugs of questionable safety rather than prevented good ones from making it to the market). What are the other alternatives? The federal government sponsoring clinical trials on small molecule natural compounds (rarely), money from “charitable” disease fund-raising organization (rarely), pharmaceutical companies developing synthetic versions of natural compounds (not very often any more)? So why not “crowdsource” wealth philanthropists who either for humanitarian purposes and/or ego purposes want to put their stamp on defeating a particular disease.
    To say that some of these compounds must not be effective because otherwise they would have received funding is to ignore the reality of medical research in this country.
    Happy Birthday to the late Jonas Salk!

  40. Jumbo says:

    Just to add another dimension (or at least expand on some earlier tangential mentions), who in the world of partnering/big pharma would be interested in sibiromycin? The oncology field is rapidly moving away from cytotoxics toward cancer-type gene regulation (either direct, or of the aberrant protein sequelae). Plus, xenograft data nowadays will do nothing to entice a deep-pocketed partner. So, you spend the crowd’s money, and still face a chasm for further development, with very VERY uncertain partnering prospects. While I respect the effort, can it really be true that the NCI drug initiative would not be funding this if it was really innovative/promising?

  41. Jumbo says:

    Just to add another dimension (or at least expand on some earlier tangential mentions), who in the world of partnering/big pharma would be interested in sibiromycin? The oncology field is rapidly moving away from cytotoxics toward cancer-type gene regulation (either direct, or of the aberrant protein sequelae). Plus, xenograft data nowadays will do nothing to entice a deep-pocketed partner. So, you spend the crowd’s money, and still face a chasm for further development, with very VERY uncertain partnering prospects. While I respect the effort, can it really be true that the NCI drug initiative would not be funding this if it was really innovative/promising?

  42. Jumbo says:

    Just to add another dimension (or at least expand on some earlier tangential mentions), who in the world of partnering/big pharma would be interested in sibiromycin? The oncology field is rapidly moving away from cytotoxics toward cancer-type gene regulation (either direct, or of the aberrant protein sequelae). Plus, xenograft data nowadays will do nothing to entice a deep-pocketed partner. So, you spend the crowd’s money, and still face a chasm for further development, with very VERY uncertain partnering prospects. While I respect the effort, can it really be true that the NCI drug initiative would not be funding this if it was really innovative/promising?

  43. Hap says:

    There’s lots of people doing R+D and some trials (excluding Generex) outside the US, and they could be doing that to lower their costs and not necessarily because the FDA is blocking them. The evidence for your point would be if drug companies start doing major trials and get approvals outside the US without trying to go to the FDA (or irrelevant of them). If they are still doing FDA-grade trials elsewhere, it’s either because they need them to get approved (which means other countries balance drug production vs. risk similarly to the US, and companies can’t get the appropriate trial data other ways) or because they’re still intending to get them approved here, and the FDA isn’t dissuading them.

  44. hypnos says:

    Derek, I’m pretty sure that one could theoretically come up with a different model for the pharmaceutical industry: A group of large payers could invest (initially) a (small) fraction of their (huge!) combined budgets to hand out grants for promising drug discovery projects (including clinical phases and registration / approval). In exchange, they would receive the resulting drugs (if any) at a very low cost. I’m pretty sure that such a model would attract proposals from academic institutions, but also from small and large pharma because it would move the risk to the customer side. The payers would have a lot more influence on the kinds of drugs that get developed (which they would certainly like).
    I don’t know whether such a model would be more or less efficient. But I guess it could work.

  45. 1 says:

    “”Making drugs that work but aren’t available in the US would be a significant boost to them.” I wholeheartedly agree. But, in all honesty, nobody’s going to travel to Croatia or South Africa for something like sibiromycin.”
    But, can USA-based physicians prescribe medications that are approved in other countries? The patient can then buy them from non-USA-based online pharmacies.
    And, if a physician prescribes a medication, will a USA-based insurance company then have to pay for it? Or do USA-based insurance companies only pay for FDA-approved medications?

  46. Twelve says:

    @36. “One could easily argue that the FDA need test only for safety, not for efficacy. ”
    Well, no. Clinical trials are about determining the window between exposures required for efficacy and the safety/tolerability signals associated with that exposure. Commonly, the efficacy metric starts as a measure of target engagement, progresses to surrogate markers or endpoints later in the trials, and eventually to outcomes in PIII. At every decision point, the clinical team is anxiously weighing the apparent benefits of their candidate against the AEs, and considering dose adjustments to optimize the overall profile (Paracelsus quote).
    For oncology drugs, where the therapeutic window is sadly often close to 1 (or even less), dose adjustments are done for individual patients during the trials, based on their AEs and particularly SAEs, but it’s always in the context of what exposures are expected to yield some benefit.
    As for expecting ‘the market’ to sort this out, well,
    Ibuprofen and other NSAIDS
    encainide
    flecainide/CAST
    estrogen-progestin/WHI
    Etc.
    In the latter 3 cases, the FDA required additional trials before new efficacy claims could be put in the label of these drugs. All of the medicines above had been marketed for years under the assumption, supported by limited clinical studies, that they had definite benefits for their patients. More rigorous studies, required by the FDA, demonstrated the opposite.
    Please outline, with specific examples, what ‘streamlining’ steps should be taken on the FDA’s charter to improve the health of Americans.

  47. DrSnowboard says:

    My feeling is we would do well to remember the point of the FDA (as I understand it) – patient safety. Already in oncology trials there is a lower standard as patients are terminal, although my personal feeling is quality of life should be considered more. De-regulate further and you are soon below the grate and looking at snake-oil and polywater due to positive results in someone’s grandma.

  48. CMCguy says:

    Erebus even with the legitimate flaws pointed out in the FDA I think you are weighting too much blame their way. The FDA is an easy target but not alone is being responsible for the extreme increase in drug development cost, included the arrogance and inefficiencies within Pharma/Biotech that have little to do with FDA. I see the FDA as largely underfunding and under-resourced to perform their mission much less frequent new mandated burdens which results in endemic problems which I would direct on Exec and Legislative Branches. I would actually wish for the Agency and Developers to work in close collaboration to become more of a partner than barrier but with Marcia Angell (have to wash my mouth out now) and others COI dogma that will never happen. You really do want to go back in time if hold to “one could easily argue that the FDA need test only for safety, not for efficacy. The market and doctors can decide how efficacious a medicine is”. I believe this was the mode that played for at least a good portion the last century (1940s-1990s?), which might have been the Golden Age and did successfully produce many medicines probably created more sludge than want to remember. More significantly I would presume the current legal/tort system, which is a factor that already weighs very heavy now IMO, would have even greater impact on the process if operated without establishing efficacy.

  49. yonemoto says:

    Thanks Derek! You’ve basically crystallized all of my insecurities about the future of open-source drugs. But that’s okay. I think there are business models wherein you can get this to work, even under the relatively onerous contemporary FDA burden.
    To answer a few questions. I think sibiromycin is not a bad candidate for several reasons: 1. (I’m not sure I buy this one but) it’s a NP derived and NP derived tends to do well. 2. A molecule with a similar mechanism has made it into phase III and phase I/II show only mild hepatotoxicity and water retention, which are prophylactically treatable with common drugs. 3. There is reportedly no bone marrow suppression in these compounds, and importantly it appears to be immune-neutral, which would make PBDs excellent therapies to run alongside immune-recruitment drugs.

  50. anon says:

    I think a powerful, transformative idea has been neglected in this discussion. Without fundamentally changing the clinical trial process, it does not seem likely that a watershed moment will occur.
    Doing the same thing over and over and expecting a different result is the definition of what?
    Why not create a different regulatory framework for those patients who are truly terminal, perhaps those with a month or two (or less) of life expectancy?
    Why has government ever put patients in the circumstance whereby doctors and clergy have essentially offered them last rites while still refusing to allow these patients the option to seek unapproved treatments. It is unconscionable. Government never possessed such moral or legal authority. Why not extend a more all-encompassing version of the Right to Try Law?
    Any imminently terminal patient should be allowed to access any drug of their choosing without a placebo arm. No regulatory filing would be required. All such individual reports would be instantly recorded on a government website as registered medical documents.
    Such clinical trials could be conducted in a matter of weeks. Speed-trialing would be the new form for these clinical trials. A clinical trial’s endpoint might be weekly (or hourly) progression free survival. A pharmaceutical company would be allowed to work back in randomized clinical trials to less immediately terminal patients (perhaps 6 months or less life expectancy) and then file for approval.
    Developing pharmaceuticals in this way could dramatically change the nature of drug development. Companies could have results within weeks, the financial risk of development would be enormously reduced etc.
    There have been recent reports of the development of highly effective cancer drugs. These reports have also noted that it might require years for phase 1 clinical trials to start.
    There are tens of thousands of terminal patients right this second who are offered no real options for their illness. For many the only choice offered is palliative.
    Why not fundamentally change the way clinical trials are conducted for terminally ill patients
    in order that a different outcome becomes possible?

  51. Erebus says:

    @46 – I realize that there’ll be problems with ineffective and dangerous drugs if the regulatory burden is loosened. But we have problems with them in any case. Vioxx, for instance, was approved. A few of those glitazones were also approved. That they were restricted or pulled from the market post hoc is illustrative of my point. Let’s loosen restrictions, get drugs to the people who need ’em more quickly and cheaply, and see what happens. I’m entirely confident that there’ll be more good than bad, and that the bad will eventually be restricted or removed from the market. Doctors and patients will then have more power to decide how they want to treat the illnesses they face.
    I wholeheartedly believe that the “drug approval process” that we currently have is among the worst of all possible regulatory situations. The problems our industry has got with the patent system pale utterly in comparison to the problems we have with the FDA.
    @48 – Our large drug corporations are arrogant? Perhaps. But perhaps they’re arrogant because they know that they’re the only entities with sufficiently deep pockets to develop drugs. The status quo suits them just fine, I’d imagine; they’re effectively protected from real competition. As I said earlier, the fact that it costs $1B+ (and Matt Herper at Forbes pegged it at $5B last year) to develop a drug, means that existing corporations and structures are entrenched and unassailable by smaller competition. If a small-fry company looks like it has something, real or imaginary, it’ll be devoured — it will not be able to develop its drug on its own. Does this not contribute to the arrogance of large corporations? And how much of this is due to our absurdly risk-averse drug approval process? Just about all of it, I’d say. If legitimate competition from small, fast-moving, and innovative entities were possible — as is the case in almost every other industry — they might be more humble. They might not exist. There’d certainly be more value in this industry to go around.
    Post #50 is right on.

  52. diver dude says:

    #50 there is a draft law under consideration in the UK at this moment that would permit this approach. There is considerable unease amongst lawmakers and the medical fraternity about how to ensure appropriate safeguards for vulnerable patients are put in place.

  53. anon says:

    “27. anon the II on October 28, 2014 12:00 PM writes…
    The last time I looked, the US had about 300 million people out of the 9 billion or so people in the world. So the FDA is only protecting about 1 in 30. If the FDA is such a problem, then why aren’t they developing all those drugs in other countries where they’re allowed to be innovative. If an obvious “cancer cure” is developed in another country, I’m sure the FDA will not crush it’s approval in the US. I’m gonna call BS on the FDA bashing. And please, don’t start trotting out the “laetrilesque” examples”.
    How about metformin? You may not remember all the hand-wringing from the FDA about cancer that kept it off the US market for what, 20 years? It is now the most widely prescribed and probably safest diabetes drug despite the incompetence of the FDA.

  54. john says:

    Mixed feelings. I don’t think open source drug discovery is a bad thing, and the fact that it’s any alternative to the current system of drug development and approval is refreshing. There are details to work out, for sure, but organized open soruce drug discovery is basically at it’s infancy. Under the current scheme, yes, drug companies are by and large the only entities capable of seeing drugs through clinical trials, but as discussed above, the current system is also kind of broken. Between patents, FDA approval, and the US healthcare/insurance system, it’s a pretty complex problem.
    Using crowdfunding is also a pretty neat way to fund science, too. So long as you can package the science as something the public should be interest in, I’m sure there’ll be no shortage of people looking to “support a good cause.”
    However, I think the packaging here certainly borders on disengenuous. Gargantuan chunks of the discovery process are left out after the proposed animal testing of just one compound (or MAYBE two or three if they have funds to make more!), and the process is described as if all of the open source kinks have been worked out. Worst case scenario, this perpetuates the notion that “drug discovery is so easy, of course THEY wouldn’t develop this because it won’t make them money. But it’s so good that now people will do it open source!” without addressing the real complexities/costs of drug development, or hurdles that open source must overcome.

  55. Lyle Langley says:

    @33, Anonzy…
    “I have a question similar to #6: for instance how does tecfidera (dimethyl fumarate) which you can buy off the shelf for a few dollars a kilo get patented and become a billion dollar drug for multiple sclerosis?”
    It’s called a method-of-use patent. It was noticed that it was used in Germany (I believe) for psoriasis and then it was tested in MS and then patented for that method. There is no composition of matter patent. As for the pricing, it is priced that way because they can.

  56. anon says:

    That is very exciting news about the UK moving towards protecting the rights of terminally ill patients.
    Under ideal Right to Try conditions (which would include mandatory immediate reporting of patient outcomes, very relaxed restrictions on accessing treatments chosen by patients and the legalization of a medicinal chemistry industry that could provide pharmaceutical-similar grade medicines if patent holding companies were unwilling to release their products), it would not be unreasonable to expect that a cure for metastatic illness would emerge within days.
    A casual glance of the cancer breakthroughs that have been announced even in the last few weeks provide some credibility to this claim.
    Reducing the time required for drugs to pass through the clinical trial process by a few orders of magnitude would without question revolutionize medicine.
    The main problem has been that one nation created a regulatory model in which the same process of failure was repeated and a different result was somehow expected in the future. To ensure catastrophic failure, every other nation cloned
    this flawed regulatory model. The complete absence of innovative experiments in regulatory procedures around the world demonstrates a profound lack of independent thought.
    How could universalist ethical and legal arguments have ever swayed the world to embrace the same flawed model? (What other social structure in our community enjoys such near unanimous approval?) Even more surprising is how a nation born and founded on the ethos of radical freedom could have ever allowed the freedom of their most vulnerable citizens to be usurped.

  57. Anonymous says:

    #56 well its under discussion. I am not sure how likely it is to make it into law. It is called the Medical Innovation Bill sponsored by Lord Saatchi (sometimes the House of Lords has its uses, arcane though they be). If you google it the full text of the current version of the bill can be downloaded as a pdf.

  58. anon says:

    Is the full text of the bill only 3 pages?
    I thought such a bill would include hundreds of pages of small set footnotes painstakingly defining ever word.
    It is not clear to me whether or not this bill only applies to rare illnesses or all terminal illnesses. It is surprising that the patient rights groups did not advance the idea that choice of treatment for terminally ill patients
    is an inalienable human right that is
    not within the legal authority for government to either grant or deny.
    This bill is a start, though to really get breakthrough changes it might have to be redrafted elsewhere. Mandatory immediate reporting of outcomes of each registered patient treated under the law should have been included.
    This would quickly create a positive information feedback cycle resulting in transformative change.
    It is truly hard to imagine why this was not done decades ago. It is an easy win for politicians advancing it.

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