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> > 2. There are regulatory obstacles for businesses. > As someone in the biotech space, this is by far the biggest factor. When you are dealing with humans,

> > 2. There are regulatory obstacles for businesses. > As someone in the biotech space, this is by far the biggest factor. When you are dealing with humans, crashes and bugs mean deaths. Deaths mean increased regulation, often under the mistaken assumption that more rules would prevent engineers from making bugs. Modern testing and build systems might, but regulators aren't keen to change their testing systems, many of which were encoded by legislation decades ago. For example, adaptive clinical trials have been known to be theoretically superior to the Phase I/II/III design for 15 years, yet are still in limbo[1] at the FDA; their proponents are still banned from trying them out. Facebook does not need a Federal Software Assocation to sign off on its new unit testing framework. There is plenty of basic biomedical research left to be done on animals, and this is far less regulated. In the U.S., rats and mice are effectively exempt from animal welfare laws. NIH imposes some fairly regulations for funding recipients (i.e., universities), but in my experience, it's not very difficult to get a project with legitimate scientific value approved. If you can cure diabetes, it's not unreasonable to ask you to prove it in an animal model first. My understanding is that approved treatments in humans often lag 10 years or so behind what's known to work in animal models, but until we can cure most major illnesses in rats and mice, we can't blame the slow progress in treatments on the difficulty of translating therapies from the lab to the clinic.

ramanujan 14y ago
approved treatments in humans often lag 10 years or so behind what's known to work in animal models The reason for this is regulation and IRB. I direct you to Banting and Best (which I also linked below): http://www.nobelprize.org/educational/medicine/insulin/discovery-insulin.html http://www.nobelprize.org/educational/medicine/insulin/disco... Early in 1921, Banting took his idea to Professor John Macleod at the University of Toronto, who was a leading figure in the study of diabetes in Canada. Banting and Best began their experiments by removing the pancreas from a dog. ... By giving the diabetic dog a few injections a day, Banting and Best could keep it healthy and free of symptoms. The team was eager to start testing on humans. But on whom should they test? Banting and Best began by injecting themselves with the extract. They felt weak and dizzy, but they were not harmed. In January 1922 in Toronto, Canada, a 14-year-old boy, Leonard Thompson, was chosen as the first person with diabetes to receive insulin. The test was a success. Leonard, who before the insulin shots was near death, rapidly regained his strength and appetite. The team now expanded their testing to other volunteer diabetics, who reacted just as positively as Leonard to the insulin extract. The news of the successful treatment of diabetes with insulin rapidly spread outside of Toronto, and in 1923 the Nobel Committee decided to award Banting and Macleod the Nobel Prize in Physiology or Medicine. Two years from idea to animal trials to safety trials (self-experimentation) to human trials to Nobel Prize. That was when pharma moved at the speed of software; that is what a landscape free for innovation can produce. What if we tried that today? You mean, just rely on the judgment of the experts involved and the verbal consent of the patients? You mean, just allow the doctors to come up with whatever dose they felt warranted and patients to take whatever dose they feel comfortable with? You mean, resist having some kind of ostensibly judicious central authority approve all such decisions, and rely on the distributed judgments of all consenting participants involved? Yes. The typical response is that this is a recipe for anarchy. But history shows that it is a recipe for Nobel Prizes, and it is not like 1920s America was much like Somalia. Would there be risk? Sure. Some people will not be helped and others might even harmed by new and unproven treatments. That's the price if we're serious about rapid progress, or really any progress. There must always be a first human trial; why not as soon as possible if people really are dying? Needless to say, this kind of boldness won't fly in the modern US. Outside of the internet, the country has become just too risk averse, too wealthy to pay the price of progress. Our task as hackers then is to create at least one spot on this earth where patients can take whatever treatments they want, where entrepreneurs/technologists can invent whatever drugs/devices they want, and where no regulator has the power to intercede between these two consenting parties. And where we can go from idea to human trials as fast as the patient pleases.
- Someone 14y ago
  http://en.wikipedia.org/wiki/Thalidomide#Development http://en.wikipedia.org/wiki/Thalidomide#Development: "Thalidomide was developed in 1954 by the CIBA pharmaceutical company, marketed under at least 37 names worldwide. It was prescribed as a sedative, tranquilizer, and antiemetic for morning sickness.[9] Thalidomide, launched by Grünenthal on 1 October 1957" So, slightly more than two years, but it points to the problem: the judgment of the experts may be awfully wrong. Also: it is true that the Western World is more and more risk averse, but we are more permissive in allowing trials on patients who would die soon, anyway. I doubt it would be two years from idea to Nobel prize, but http://en.wikipedia.org/wiki/FDA_Fast_Track_Development_Program http://en.wikipedia.org/wiki/FDA_Fast_Track_Development_Prog... states a goal of 60 days for review, and states that that goal generally is reached.
  - ramanujan 14y ago
    So, a few points (I didn't downvote you). 1) First, FDA fast-tracks many bad things. Hundreds of millions of people were irradiated by scanners that FDA waved on through because a fellow .gov agency (TSA) sponsored them. So: even the risk-averse can't trust a single centralized regulator to be "risk-averse" rather than "pro-government". We need multiple regulators (see my posts elsewhere in the thread), where you can use things approved by the slower/expensive/safest one while I can use items approved by the faster/cheaper/riskier ones. http://arstechnica.com/science/2010/11/fda-sidesteps-safety-concerns-over-tsa-body-scanners/ http://arstechnica.com/science/2010/11/fda-sidesteps-safety-... Dr. Holdren passed the letter on to the Food and Drug Administration for review. But, in the FDA's response, the agency gave the issues little more than a data-driven brush off. They cite five studies in response to the professors' request for independent verification of the safety of these X-rays; however, three are more than a decade old, and none of them deal specifically with the low-energy X-rays the professors are concerned about. The letter also doesn't mention the FDA's own classification of X-rays as carcinogens in 2005. 2) Second, the formal IND fast-track program you mention is very political to get into (on the device side there's something similar called Pathway to Innovation). Moreover, FDA doesn't count days like you and I count days. It's like an NFL game which is 60 minutes but actually takes three hours; every time they email you back, it stops their clock. And they can email you back to ask for data that takes months to gather. This is from a device consultant but the principle is the same for drugs: http://www.myraqa.com/blog/how_long_is_90_days http://www.myraqa.com/blog/how_long_is_90_days By law, FDA must respond to your 510(k) within 90 days, and typically they do. The thing you have to understand is that FDA measures 90 days about the same way the NFL measures the 60 minutes in a football game. It's not unusual for the clock to spend more time stopped than running. 3) Third, regarding thalidomide, as you probably know there were three major catastrophes that increased FDA power (1906 publication of the Jungle which birthed proto-FDA, 1938 elixir of sulfalinamide, and 1962 thalidomide) and another major catastrophe in the early 90s that reduced FDA power (FDA delays on AZT and slowdown of AIDS drugs). Thalidomide in particular is to the FDA what 9/11 is to the TSA, it's the justification for everything they do. If you get into the history books you'll see that Frances Kelsey never actually suspected teratogenic effects; she suspected neurological issues. Moreover, thalidomide was actually a very efficacious drug for morning sickness, it was just unsafe. Yet the 1962 revision to the FD&C act added efficacy testing on top of safety testing. That's weird. The thing is, toxicological/safety testing, even aggressive safety testing is "only" in the tens of millions, not billions. It's efficacy testing (and then comparative effectiveness) that really piles on the dollars. If the lesson of thalidomide was that we should do aggressive safety testing, then no one got the message, because Kefauver & Harris' 1962 amendments to FD&C meant we ended up spending several hundred billion dollars on efficacy instead. Perhaps then the lesson from thalidomide might be that pregnant mothers should be much more risk-averse in what drugs they take. It's not really a lesson that says "we need to delay all drugs more", because due to pharmacogenomics some side effects are only going to be apparent when you introduce them into humans on a large scale anyway. Moreover, risk can't be eliminated, and different people will have different risk profiles. What if a 70 year old man with terminal cancer wants to take an experimental, non-FDA approved drug? Do you sue like the FDA did in Cowan vs. US to prevent him from doing so? For that matter, what if a 25 year old pregnant woman wants to take a new drug? Do we prevent her from doing so? Maybe we should, but we currently don't stop pregnant women from drinking alcohol or smoking cigarettes. One has to think very carefully about whether every tragedy means one must ban or mandate something with a federal law.

ramanujan 14y ago

approved treatments in humans often lag 10 years or so behind what's known to work in animal models The reason for this is regulation and IRB. I direct you to Banting and Best (which I also linked below): http://www.nobelprize.org/educational/medicine/insulin/discovery-insulin.html http://www.nobelprize.org/educational/medicine/insulin/disco... Early in 1921, Banting took his idea to Professor John Macleod at the University of Toronto, who was a leading figure in the study of diabetes in Canada. Banting and Best began their experiments by removing the pancreas from a dog. ... By giving the diabetic dog a few injections a day, Banting and Best could keep it healthy and free of symptoms. The team was eager to start testing on humans. But on whom should they test? Banting and Best began by injecting themselves with the extract. They felt weak and dizzy, but they were not harmed. In January 1922 in Toronto, Canada, a 14-year-old boy, Leonard Thompson, was chosen as the first person with diabetes to receive insulin. The test was a success. Leonard, who before the insulin shots was near death, rapidly regained his strength and appetite. The team now expanded their testing to other volunteer diabetics, who reacted just as positively as Leonard to the insulin extract. The news of the successful treatment of diabetes with insulin rapidly spread outside of Toronto, and in 1923 the Nobel Committee decided to award Banting and Macleod the Nobel Prize in Physiology or Medicine. Two years from idea to animal trials to safety trials (self-experimentation) to human trials to Nobel Prize. That was when pharma moved at the speed of software; that is what a landscape free for innovation can produce. What if we tried that today? You mean, just rely on the judgment of the experts involved and the verbal consent of the patients? You mean, just allow the doctors to come up with whatever dose they felt warranted and patients to take whatever dose they feel comfortable with? You mean, resist having some kind of ostensibly judicious central authority approve all such decisions, and rely on the distributed judgments of all consenting participants involved? Yes. The typical response is that this is a recipe for anarchy. But history shows that it is a recipe for Nobel Prizes, and it is not like 1920s America was much like Somalia. Would there be risk? Sure. Some people will not be helped and others might even harmed by new and unproven treatments. That's the price if we're serious about rapid progress, or really any progress. There must always be a first human trial; why not as soon as possible if people really are dying? Needless to say, this kind of boldness won't fly in the modern US. Outside of the internet, the country has become just too risk averse, too wealthy to pay the price of progress. Our task as hackers then is to create at least one spot on this earth where patients can take whatever treatments they want, where entrepreneurs/technologists can invent whatever drugs/devices they want, and where no regulator has the power to intercede between these two consenting parties. And where we can go from idea to human trials as fast as the patient pleases.

Someone 14y ago
http://en.wikipedia.org/wiki/Thalidomide#Development http://en.wikipedia.org/wiki/Thalidomide#Development: "Thalidomide was developed in 1954 by the CIBA pharmaceutical company, marketed under at least 37 names worldwide. It was prescribed as a sedative, tranquilizer, and antiemetic for morning sickness.[9] Thalidomide, launched by Grünenthal on 1 October 1957" So, slightly more than two years, but it points to the problem: the judgment of the experts may be awfully wrong. Also: it is true that the Western World is more and more risk averse, but we are more permissive in allowing trials on patients who would die soon, anyway. I doubt it would be two years from idea to Nobel prize, but http://en.wikipedia.org/wiki/FDA_Fast_Track_Development_Program http://en.wikipedia.org/wiki/FDA_Fast_Track_Development_Prog... states a goal of 60 days for review, and states that that goal generally is reached.
- ramanujan 14y ago
  So, a few points (I didn't downvote you). 1) First, FDA fast-tracks many bad things. Hundreds of millions of people were irradiated by scanners that FDA waved on through because a fellow .gov agency (TSA) sponsored them. So: even the risk-averse can't trust a single centralized regulator to be "risk-averse" rather than "pro-government". We need multiple regulators (see my posts elsewhere in the thread), where you can use things approved by the slower/expensive/safest one while I can use items approved by the faster/cheaper/riskier ones. http://arstechnica.com/science/2010/11/fda-sidesteps-safety-concerns-over-tsa-body-scanners/ http://arstechnica.com/science/2010/11/fda-sidesteps-safety-... Dr. Holdren passed the letter on to the Food and Drug Administration for review. But, in the FDA's response, the agency gave the issues little more than a data-driven brush off. They cite five studies in response to the professors' request for independent verification of the safety of these X-rays; however, three are more than a decade old, and none of them deal specifically with the low-energy X-rays the professors are concerned about. The letter also doesn't mention the FDA's own classification of X-rays as carcinogens in 2005. 2) Second, the formal IND fast-track program you mention is very political to get into (on the device side there's something similar called Pathway to Innovation). Moreover, FDA doesn't count days like you and I count days. It's like an NFL game which is 60 minutes but actually takes three hours; every time they email you back, it stops their clock. And they can email you back to ask for data that takes months to gather. This is from a device consultant but the principle is the same for drugs: http://www.myraqa.com/blog/how_long_is_90_days http://www.myraqa.com/blog/how_long_is_90_days By law, FDA must respond to your 510(k) within 90 days, and typically they do. The thing you have to understand is that FDA measures 90 days about the same way the NFL measures the 60 minutes in a football game. It's not unusual for the clock to spend more time stopped than running. 3) Third, regarding thalidomide, as you probably know there were three major catastrophes that increased FDA power (1906 publication of the Jungle which birthed proto-FDA, 1938 elixir of sulfalinamide, and 1962 thalidomide) and another major catastrophe in the early 90s that reduced FDA power (FDA delays on AZT and slowdown of AIDS drugs). Thalidomide in particular is to the FDA what 9/11 is to the TSA, it's the justification for everything they do. If you get into the history books you'll see that Frances Kelsey never actually suspected teratogenic effects; she suspected neurological issues. Moreover, thalidomide was actually a very efficacious drug for morning sickness, it was just unsafe. Yet the 1962 revision to the FD&C act added efficacy testing on top of safety testing. That's weird. The thing is, toxicological/safety testing, even aggressive safety testing is "only" in the tens of millions, not billions. It's efficacy testing (and then comparative effectiveness) that really piles on the dollars. If the lesson of thalidomide was that we should do aggressive safety testing, then no one got the message, because Kefauver & Harris' 1962 amendments to FD&C meant we ended up spending several hundred billion dollars on efficacy instead. Perhaps then the lesson from thalidomide might be that pregnant mothers should be much more risk-averse in what drugs they take. It's not really a lesson that says "we need to delay all drugs more", because due to pharmacogenomics some side effects are only going to be apparent when you introduce them into humans on a large scale anyway. Moreover, risk can't be eliminated, and different people will have different risk profiles. What if a 70 year old man with terminal cancer wants to take an experimental, non-FDA approved drug? Do you sue like the FDA did in Cowan vs. US to prevent him from doing so? For that matter, what if a 25 year old pregnant woman wants to take a new drug? Do we prevent her from doing so? Maybe we should, but we currently don't stop pregnant women from drinking alcohol or smoking cigarettes. One has to think very carefully about whether every tragedy means one must ban or mandate something with a federal law.