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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, 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.

Moreover, it is just more stressful to deal with a regulatory climate where any error is assumed to have happened because you were an evil corner-cutting capitalist who didn't allocate enough for safety. This kind of Monday morning quarterbacking is unfortunately usually done by people who've never shipped a drug or device in their lives, like most politicians, journalists, or federal regulators. Twitter, unlike Genzyme[2], is not fined millions of dollars by the FDA when its site is down.

Finally, you have to guess what the law is. There is so much "discretion" [3,4] afforded to regulatory agencies that the threat of fines and seizures over bizarre interpretations of the law by a Carmen Ortiz-style ambitious regulator is never far from your mind. Example [5]:

  [Newsweek:] What exactly would constitute a “medical   
  claim?” Would pointing people to medical research papers 
  [qualify]?

  [FDA]: It depends. There are rules as to how one can do   
  that … Those rules are actually worked out pretty well, 
  and they just would need to make sure they’re staying 
  within the rules.

  [Newsweek:] Are those rules on the Web?

  [FDA]: I don’t know where the policy is. I would have to 
  get it for you. It’s an agencywide policy. I would have to 
  find it for you. And it won’t be that easy for people to 
  follow it…
Another example [6]:

  The agency has urged hospitals to allow vendors to guide 
  them on security of sophisticated devices. But the vendors 
  sometimes tell hospitals that they cannot update FDA-
  approved systems, leaving those systems open to potential 
  attacks. In fact, the agency encourages such updates.

  “A lot of people are very confused about FDA’s position on 
  this,” said John Murray Jr., a software compliance expert 
  at the agency.
And one more [7]:

  In United States v. Park, the Supreme Court held that a 
  responsible corporate official can be convicted of a 
  misdemeanor based on his or her position of responsibility 
  and authority to prevent and correct violations of the 
  Food Drug and Cosmetic Act (FDCA). Thus, evidence that an 
  individual participated in the alleged violations or even 
  had knowledge of them is not necessary.  
Think about that: criminal penalties for violations of laws that "won't be that easy for people to follow", where knowledge or participation in the alleged violations is not necessary. And the law is not static. The FDA also can and does write "guidances" outside of the legislative process which will make your business model illegal overnight or vastly more expensive due to unanticipated regulatory costs. Google does not need to guess what the DNS protocol is or will be in 2013.

For just a taste of how all this plays out, look at the FDA's ongoing attempt to regulate[8] mobile health apps. Who knows what the rules will be, what they will cost, or what the fines are? Look at the FDA's attempt to deny[5] people access to their genome without a prescription. Look at the fact that they issued a record 10000+ 483s in 2011[9], which threaten a business with civil or criminal penalties. Look at the fact that they used these 483s to shut down Teva and Sandoz and Hospira and Bedford at the same time[10], causing a massive shortage of injectables which they blamed on industry profit seeking and used to gain[11] yet more regulation, more power, more budget.

Look, finally, how they claim in an official court filing against family farms producing raw milk that you have "No Generalized Right to Bodily and Physical Health" [12], where they approvingly cite the case of Cowan vs. US, where a terminal cancer patient was denied access to experimental medication, denied the right to opt-out of the FDA:

  There is No Generalized Right to Bodily and Physical   
  Health.

  Plaintiffs’ assertion of a “fundamental right to their own 
  bodily and physical health, which includes what foods they 
  do and do not choose to consume for themselves and their 
  families” is similarly unavailing because plaintiffs do 
  not have a fundamental right to obtain any food they wish. 
  In addition, courts have consistently refused to 
  extrapolate a generalized right to “bodily and physical 
  health” from the Supreme Court’s narrow substantive due 
  process precedents regarding abortion, intimate relations, 
  and the refusal of lifesaving medical treatment. 

  See Glucksberg, 521 U.S. at 721 (warning that the fact 
  “[t]hat many of the rights and liberties protected by the 
  Due Process Clause sound in personal autonomy does not 
  warrant the sweeping conclusion that any and all 
  important, intimate, and personal decisions are so 
  protected”); see also Cowan v. United States, 5 F. Supp. 
  2d 1235, 1242 (N.D. Okla. 1998) (rejecting a claim that 
  the plaintiff had the fundamental “right to take whatever 
  treatment he wishes due to his terminal condition 
  regardless of whether the FDA approves the treatment”).
I know it sounds surreal, but they are arguing here that you only control your own body with respect to abortion, intimate relations, and euthanasia. Everything else is controlled by the FDA, yea even unto your death from cancer.

The only solution here is for hackers to carve out a jurisdiction in which the FDA has no say, where patients are free to be early adopters and startups are free to push the technological envelope. Patients in this zone will need to be mature and understand that these are version 1.0s, and may not help or even actually harm them. But every drug or device or surgery needs someone to be first, and a few brave risk takers could both benefit their own health and push humanity forward. After all, we have thousands of people dying for futile risks in various foreign wars.

So, the limiting reagent is not money, or expertise, or motivation, or smarts. raganwald, you and most of HN are plenty smart enough. It's about the freedom for companies to innovate, for patients to take risks. We need a jurisdiction (a seastead? Singapore? Estonia?) that enables us to push the technological frontier. Everything else will fall into place once we can't be punished for innovating.

[1] http://jnci.oxfordjournals.org/content/104/18/1347.extract#

[2] http://www.fiercepharma.com/story/genzyme-submits-175m-fine-...

[3] http://www.ivdtechnology.com/article/letters-labcorp-show-fd...

[4] http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2011/03/...

[5] http://www.thedailybeast.com/newsweek/blogs/the-human-condit...

[6] http://articles.washingtonpost.com/2012-12-25/news/36015727_...

[7] http://www.gatewayfda.com/fda-regulations/under-park-doctrin...

[8] http://m.spectrum.ieee.org/biomedical/devices/the-fda-takes-...

[9] http://blog.fdazilla.com/2011/11/fda-issues-483-every-50-min...

[10] http://www.forbes.com/sites/aroy/2012/06/15/how-margaret-ham...

[11] http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050796....

[12] http://www.organicpastures.com/pdfs/FDA%20dismissal%20docume...




This is why I think that this revolution will be led by hacker/patients and not business men / politicians. I am not trying to be dramatic but I will literally die for this cause because I spent my entire life sick, in bed, shitting blood and trying what everyone else wanted me to.

3 months of doing it my way and I never knew life could be this good, so while I agree that the regulatory climate makes this difficult; I dont care. I will never take such a risky attitude toward others and risk their health or wellbeing because I do not have this right but I also will not use this as an excuse to do nothing when I know I can help.


From experience, a business can make a difference in how the FDA polices a segment of the industry. You need scientists, who really know the domain (and, perhaps, have some contacts at the FDA), who can try to set the bar with FDA.

Of course, that's out of the realm of most start-ups, unless you are starting from a research facility where someone might already know the ropes. That said, my employer (which was once a tiny start-up that grew from a research lab) has directly worked with the FDA to define the regulations around our particular domain.


what does "doing it my way" in this context mean? What did you try and how did you research it?

Have looked into this kind of thing myself before and am interested in how you went about your project and if there's a community around that kind of thing.


Their way == Prednazone, Asacol / 6MP

My Way = Macrobiotics, Stress Control, Acupuncture etc...

Yes, there are many communities; I mostly used trial and error but the difference is how I measured what worked. I kept a food diary that allowed me use actual nutrient stats etc... to find patterns in my trigger foods.


I'm very glad this worked for you. I don't have Crohn's, but I also have an auto immune disease called Ankylosing Spondylitis. For many immune conditions there seems to be an environmental trigger, or something that makes it worse. There is quite abit of research that many of our conditions are caused by interactions with the bacteria in our gut and our immune response to certain food. I saw your other posts about working on tools to help people track these things, I commend you. There is a large body of people who could potentially benefit from this work. Not just people with Crohn's, but many autoimmune conditions. Keep on trucking and I wish you luck.


To the best of your knowledge, would it be illegal (notwithstanding any copyright claims) to produce an interface that would make FDA compliance easier?

Examples: - a website that republishes FDA information in a far easier to grok manner (assuming they are as impenetrable as most government websites I've had the misfortune to require using) - a choose-your-own-adventure formatted application made in Twine that would allow you to explicitly follow the known rules - an application that alerts drug/device developers of guidance updates


Good question. Broadly speaking, the whole regulatory space (not just FDA, but all other agencies) is indeed a massive business opportunity. There are basically two ways to operate here:

  Option 1: reduce costs of complying with FDA. 
  Option 2: reduce the power of FDA.
Option 1 means automation of form submissions, NLP/data mining on past enforcement actions, search engines for FDA.gov like FDAZilla, reproducible research templates for regulatory filings, that kind of thing. That helps, but only up to a point, as the FDA themselves is not very tech savvy and will look askance at any attempt to significantly streamline the process. From their perspective: streamlining means regulators will do more work in a shorter amount of time for no increase in pay, which they don't want to do, and which may well be perceived by them as aggressive behavior on your part (moving too fast). They think in terms of years to clearance, not days or weeks.

So then there is Option 2: reduce FDA power. I've come to believe that the second strategy is much more effective in the long run. So what does that entail?

1) Regulator review sites. Something that might be surprisingly effective would be a site that named and shamed individual regulators, kind of like TheFunded.com for regulators. With some good SEO this might be the single most effective thing one can do. It would be incredibly popular and could branch out into SEC, EPA, and other agencies.

2) Regulatory review sites. Relatedly, with all other domains (movies, music, books, etc.) there is a thriving system of competitive, third party reviews and star ratings. Yelp, Amazon, Metacritic, Rotten Tomatoes, even Google PageRank are all review methodologies that are intentionally robust to the decisions of a single regulator. Figure out how to get 2000 cardiologists worldwide to do public internet reviews of heart drug/devices rather than a hand-picked FDA panel of 15, and you can show under very conservative assumptions that the resulting rank-ordering of products will be far more accurate.

3) Filing in other countries first. For example, within medical device companies, it's well known now that you get your CE Mark in Europe first[1,2,3], and then think about the US. You can get some revenue and the CE Mark process is far more consistent than the US.

4) Otherwise enhancing regulatory competition. Imagine if Harvard, the Mayo Clinic, and Cedars-Sinai could suddenly clear drugs and devices like the FDA. The FDA already contracts with scientists from there to run their expert panels, as they don't have the expertise in house. The CE Mark strategy above is this in embryo, but it's only two jurisdictions (EU and US). I'm not sure how you'd pull this off, but the basic idea is to use other "name brands" in medicine to help set up regulatory competition.

5) Software-based regulatory arbitrage. With modern information technology, it may be possible to locate software-based components of a device/drug overseas in fast market access countries[4] like Singapore, Hong Kong, or Israel.

6) Medical tourism and/or medical cruise ships. Figuring out ways to do internet marketing of offshore medical tourism to Americans, with transparent prices and treatments proven in other countries (even if not FDA approved) will be a big deal over the next 10-20 years as the US medical system enters crisis from all the aging seniors. All you need is a relatively small but high profile group of people voting with their dollars to seek treatment or move operations overseas to start provoking real change. Nothing within the system will do that now.

These are the sorts of ideas, many informational, that I think will have a much bigger impact than methods to streamline compliance.

[1] http://thehill.com/blogs/healthwatch/medical-devices-and-pre...

[2] http://www.nytimes.com/2011/02/10/business/10device.html?pag...

[3] http://www.medicaldevices.org/system/files/FDA%20impact%20US...

[4] www.emergogroup.com/files/fast-access-markets-slides.pdf


> 4) Imagine if Harvard, the Mayo Clinic, and Cedars-Sinai could suddenly clear drugs and devices like the FDA.

none of those entities have sovereign immunity!


Right, but if there were a private system similar to the one in which Underwriters Laboratories operates, that'd be preferable. I'm not sure how to get there from here, which is why I said "I'm not sure how you'd pull this off".

For example, it might be feasible to get Cedars-Sinai to partner with (say) Singapore's HSA and do some kind of fast track approval process intended to compete with FDA's slow approval. Here Singapore's name brand would be enough for the Asian market while Cedars' brand would establish to American medical tourists that the product/device/service had been vetted.


Something like this already exists, albeit in an early stage: http://www.legitscript.com/products/IBUPROFEN (see the product search input on the left-hand side)


We need the FDA to regulate drugs and medical devices. There's too much potential for quackery. I don't think removing the FDA is going to find a cure for diabetes. It's a fundamental research problem at this stage. Stem cells are showing some potential as a future cure. See the article below.

http://www.medicalnewstoday.com/articles/252759.php

We need more funding for medical research. PhDs should not be low-paid labor. Too many smart people drop out of research careers due to the low salaries. We should be paying medical researchers similar incomes to engineers at Silicon Valley tech firms.

California taxes are funding one of the biggest research efforts into stem cells. So the big tech firms are contributing to the effort through their taxes.

http://www.cirm.ca.gov/


Let's go point by point.

1) Regarding diabetes and the FDA:

  I don't think removing the FDA is going to find a cure for 
  diabetes.
Well, before the FDA as such even existed, Banting and Best came up with the idea for insulin supplementation in 1921. A patient was treated by 1922. They won the Nobel Prize by 1923. Today's FDA would have made their methods completely impossible and they would have been criminally prosecuted.

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. Macleod didn't 
  think much of Banting's theories. Despite this, Banting 
  managed to convince him that his idea was worth trying.

  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.
  
Point: the FDA need not exist to make progress against diabetes. That is, federal regulation is not a necessary condition.

2) Regarding type I vs. type II errors:

  We need the FDA to regulate drugs and medical devices.   
  There's too much potential for quackery. 
So that is the key question: is the goal to allow rapid technological progress or is the goal to prevent quackery? You can of course eliminate all quackery by rejecting all new devices (high false negative rate), and many major innovations sound like quackery at the beginning. Here's another Nobel Laureate, Barry Marshall.

http://www.nobelprize.org/nobel_prizes/medicine/laureates/20...

  The extreme skepticism of my colleagues led me to believe   
  that I might never be funded to perform the crucial trial 
  of antibiotics...  I realized then that the medical 
  understanding of ulcer disease was akin to a religion. No 
  amount of logical reasoning could budge what people knew in 
  their hearts to be true. Ulcers were caused by stress, bad 
  diet, smoking, alcohol and susceptible genes. A bacterial 
  cause was preposterous.
3) Regarding researcher income:

  We should be paying medical researchers similar incomes to 
  engineers at Silicon Valley tech firms.
The thing is that the entire higher education establishment is about to crash hard with the student loan bubble. I think an alternative paradigm is to reduce the equipment costs associated with starting a bio lab, via diybio.org, biocurious.org, openpcr.org, and the like. This goes in hand with broadly reducing capital costs (regulatory + equipment). In so doing it will become easier to do biotech startups with a Valley culture, and the salaries will follow.

4) Concerning stem cells:

  California taxes are funding one of the biggest research 
  efforts into stem cells.
Nothing against CIRM, they're fantastic. But the FDA is forcing the resulting stem cell startups overseas.

http://blogs.nature.com/news/2012/10/texas-stem-cell-provide...

  Last September, Nature predicted a stem cell showdown in 
  Texas, between the FDA and a company providing unproven 
  stem cell treatments, and that seems to be happening. In a 
  severe “warning letter” posted on the agency’s website this 
  week (but dated September 24, 2012), the FDA told 
  Sugarland, Texas-based Celltex Therapeutics Corporation 
  that its stem cell products fall under FDA regulation and 
  need to be approved before use in patients.

  The letter is a challenge to new regulations that the Texas 
  Medical Board put in place in April, which had made FDA 
  approval an option, not a requirement. Those regulations 
  state that doctors injecting stem cells into patients need 
  FDA approval or the approval of a local institutional 
  review board (IRB). The warning letter makes clear that the 
  FDA expects its approval to be mandatory—effectively 
  replacing the “or” with an “and”.
http://gizmodo.com/5881492/according-to-the-fda-your-stem-ce...

  In recent court filings, the Food and Drug Administration 
  has asserted that stem cells—you know, the ones our bodies 
  produce naturally—are in fact drugs and subject to its 
  regulatory oversight. So does that make me a controlled 
  substance? The bizarre controversy revolves around the 
  FDA's attempt to regulate the Centeno-Schultz Clinic in 
  Colorado that performs a nonsurgical stem-cell therapy 
  called Regenexx-C.

5) At the end of the day

  We need the FDA
You might want to look at the FDA Alumni Association (http://fdaaa.org) or the membership list of the Alliance for a Stronger FDA (http://strengthenfda.org/members/).

Why is it in Roche's interest to lobby for a stronger FDA? Because FDA alumni are hired by large manufacturers to lobby the FDA and increase barriers to entry for startups. When you get into the details of how regulations are actually enforced, it is all about relationships/politics/press coverage and has very little to do with technical merit.

I could go on in this vein...among other things, you might be interested in the fraction of pre-1938 drugs and pre-1976 devices that are routinely prescribed from an ostensible age of quackery.

However, the fundamental idea is not really to convince people who want the FDA that it should continue to exist, but to get a critical mass of people who don't want the FDA to create a place where it does not have power. Then you and those who agree with you can reside in the US, where the FDA has sole authority. And we can opt-out of the FDA, as both patients and entrepreneurs.

This is going to require thinking outside the confines of the United States and US politics, but the payoff will be nothing short of a revolution in the pace of biomedical innovation.


No one was arguing that point. The FDA does good things. The FDA does bad things. The question is whether the FDA is more helpful than harmful.

I for one am happy that the FDA inspects my food and medicine and holds them to a standard of safety. On the other hand they do make some medical devices and advances overly expensive to make and create a barrier to entry into the market.


Sure, I am also happy that there is some regulatory body at all, but without consistent testing criteria and regulatory standards, it simply cannot be as effective.

I worked with a programmer who had designed a watch that had an array of sensors in it with a wireless device to relay the info to your computer automatically. It would have been great for marathoners or people with heart conditions. He wouldn't even start the process of getting it approved, because he was too intimidated by the FDA. That doesn't necessarily mean he was right, but the chilling effect is clear.


I think you would be rather surprised what those standard really are. Far lower than you would expect.


I am aware of those standards. I'm also aware of how much worse it was before we had them.


Exactly, the solution is to fix those standards, not remove them. That's why I tend to not take Libertarian "certification bodies for safety, not 'regulation'" ideas seriously.


> > 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.


  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/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.


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_Prog... states a goal of 60 days for review, and states that that goal generally is reached.


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-...

  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

  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.


While I don't disagree with most of your points here, I want to know more about your opinions on efficacy testing. It is definitely a strange corner of the FDA mandate and seems most justified by their marketing restriction power---the principle that marketing medical claims should be done from a position of earned, valid authority.

But it's definitely the most expensive and difficult to test component of FDA regulation. It's also awkwardly theoretical do to the sterility and white coatedness of the testing procedures (you and I both have something to say against RCTs). But at the same time, a market inundated with false claims to efficacy would be terrible. The current mobile health market is a fair comparison---many of them are efficacious, all of them would love to claim it, but nobody knows which ones.


So, regarding efficacy testing, I think the costs/benefits have to be assessed in full context. If you go back to the time before the FDA, it was a time of incredible wonder drugs and useless patent medicines. Kind of like the Internet: the price of being able to put up a domain name in 10 minutes with no centralized check for accuracy means information proliferates and the web/market/search sorts it out.

And we kind of know what a safe-but-not-necessarily-effective market for drugs will look like: the supplement industry. Supplements are cheap, they vary in effectiveness on a per person basis, and they have undoubtedly produced some really great things (creatine, omega 3). Take a look at this awesome graphic:

http://www.informationisbeautiful.net/play/snake-oil-supplem...

The thing is, with centralized regulation for efficacy two things happen. First, many of the bubbles on that graph never appear in the first place. Second, because they never appear, they never accumulate enough evidence/market size to rise up the list. We are choking the channel if centralized regulators require our minimum viable products to be not just safe, but highly efficacious.

The best way to see this is that centralized regulation kills iteration. Talk to anyone in the drug space: they'd love to be able to change their dosing methodology (altering dosage amount, frequency, formulation) or otherwise take advantage of serendipitous post-market findings. Viagra, famously, was initially intended to medicate blood pressure[1].

But right now they can't even change the labels on their drugs without the FDA's approval, which is why the average layman gets a folded-up chemistry textbook[2] rather than a user-friendly instruction manual, let alone a website which totes up other people's experiences with the drug. To get a sense of how much that could contribute to the patient user experience, see Help Remedies[3], which can get away with better UI/UX because they're dealing in generics.

Anyway, on net, I think something like a pharmacogenomic erowid.org [4,5] is the best way to establish efficacy. That would be distributed and the data would be public and constantly updated, with sample sizes far in excess of the current FDA process. Patients would get accounts and link their genomic information with the site after buying any new drug, and input their own survey data in order to see other people's (aggregated, anonymized) experiences. This would mean that you can launch safe drugs of unproven efficacy, and then collect efficacy data at a far larger scale than we do today. But this kind of innovation will only be possible in a jurisdiction outside the FDA's thumb.

[1] http://www.mc.vanderbilt.edu/lens/article/?id=116

[2] http://dailymed.nlm.nih.gov/

[3] http://www.helpineedhelp.com

[4] http://www.pharmgkb.org/

[5] http://www.erowid.org/


To take the internet domain registration metaphor further, it also requires a centralized value authority (google) in order to be navigable. In some sense, Google's primary task is spam filtering---analogous to efficacy guarantees---which enable efficient information gathering.

I don't argue that the FDA is an efficient structure for doing efficacy testing, I just think punting the value discovery/marketing process to vague distributed processes isn't a good answer.

I think the supplement market is a great example as well. Many low value treatments saturate the market and the responsibility for making decisions is democratized and difficult. Canonical sources of efficacy information might not be needed as barriers to entry, but reputation, trust, and canonization are valuable heuristics in decision making processes and this leads to power.

If Google doesn't link you, you die.


> 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.

Well, we'd get new treatments a decade faster, but a lot of these treatments would not work and/or would kill people. But, as I said above, I don't think this would dramatically increase the speed of innovation, except for diseases where we don't have effective animal models. It's faster to run experiments on animals than people. For these diseases, removing regulations let people try treatments that worked on animals in humans faster. But the problem is really that there are many diseases we can't treat effectively in any organism, and letting people try any treatment they want in humans isn't going to fix this.

I think you are vastly overestimating what society has to gain by deregulating medicine. You'll get a one-time gain of 10 years of progress at the cost of an unknown number of lives.


First off, I am happy that we both seem to agree on a qualitative fact: there is indeed a tradeoff between what statisticians call type I and type II errors. At one extreme, you can let everything through, advance technology rapidly, and suffer some side effects (type I bias). Or you can block everything, stop technology, and suffer no side effects (type II bias). If we agree on this qualitative point, the key is whether we are currently at a Pareto optimum. Is our current system optimizing the type I vs. type II tradeoff? I have a numerical scenario below which you can critique, but first to your points.

  It's faster to run experiments on animals than people. 
I'm not gainsaying the utility of animal models. I just think the goal needs to be to get to humans as soon as the safety data is in, because people are dying.

  I think you are vastly overestimating what society has to 
  gain by deregulating medicine. You'll get a one-time gain 
  of 10 years of progress at the cost of an unknown number of 
  lives.
Well, the reason sulfalinamide/thalidomide were heavily covered in 1938/1962 respectively was that those were relatively rare events. So I would somewhat disagree that the number of lives would be unknown. But, ok, let's take as a given that some would die. On the other side of the ledger, we both agree that tens of millions of people each year are dying from cancer and heart disease. So let's consider two scenarios for a cure for condition X, which kills 1 million people per year.

In scenario I, we do it status quo and safe, with no deaths. Very generously, let us grant that a cure appears in 10 years. This is generous because a regulated market may never iterate upon the cure if it is radical/different (e.g. Barry Marshall and H. pylori).

In scenario II, we accelerate the cure in a deregulated market. The R&D phase takes 1 year and costs us 100 deaths from test pilots / early adopters; the scaling phase takes 2 years and costs us another 900 deaths from volunteers. These numbers are vastly in excess of any reasonable safety testing paradigm in a deregulated space (no one died in Banting & Best's experiments) and I cite them as extremely conservative upper bounds.

Ok. Then in scenario I, the status quo, you had

  - 0 die from testing
  - cure appears at end of 10 years
  - 10 million people die over those 10 years
  - 10 million deaths
In scenario II, you had

  - 1000 die from testing over 3 years
  - 3 million die from disease over those yeers
  - cure appears in year 3
  - no further deaths
  - 3 million + 1000 total deaths
So scenario II saves ~7 million lives. Feel free to play with the numbers, but that's the kind of calculus I think we need to engage in, one that explicitly reckons with the cost of delay. In reality, the number of deaths attributable to R&D won't be close to 1000, though it won't be zero. But there is no reasonable scenario in which R&D actually consumes anything close to as many lives as the disease itself.


My engineering services business does regulatory affairs and compliance engineering work for medical device manufacturers, in addition to embedded SW. IEC 62304 and IEC 60601-1 3rd edition, etc. I can say that the parent comment is spot on. Great summary, IMO.


There is a other point of view, if one looks at who is paying the cost of the medical research: The public.

How is medical research founding supported? In order of prominence: Tax money from NIH. State granted and enforced monopoly in the form of patents. State granted extended monopoly (after the patent is expired) which is granted by the FDA, including exclusivity to the data from testing. There is also affects from insurance and the health care system, but that one is much more complex to evaluate in this context.

A completely unregulated industry could had produced faster results, but in that case its business model should not be in an depended relationship with the government. It should not get the majority of its founding from tax money. It should not depend on state granted monopolies.

As it is now, FDA is the regulation that enforces the public right to get what it payed for. Its their money after all. If one would like that to change, one should start by removing tax money and government monopolies to be the sole critical part of medical research.


Lot of important points to engage there, and generally agree with the spirit of the comments. I think many biotech startups would instantly take a deal that gave them and their patients the ability to opt-out of FDA, in exchange for some demonstration that they aren't using public funds (e.g. committing to not use some fraction of the research literature, ineligibility for all govt grants, etc.).

Regarding patents, they are a form of artificial scarcity on the sales end. Regulation is a form of artificial scarcity on the R&D end. That's why regulatory affairs and IP are the two most important departments in any pharma company.

It's useful to think about what the pharma industry would look like with no FDA and no IP protection. It'd look a lot like food, energy drinks, or supplement manufacturers, making commodity products with marketing as the primary source of margin. Generic drug manufacturers are a good first step towards this; we'll see more of this in the near future with the pharma cliff and end of many major drug patents.

Incidentally, the intersection between regulation and IP produces some extremely bizarre behavior:

http://www.fda.gov/downloads/Drugs/.../Guidances/ucm079342.p...

  This guidance is intended to provide industry with 
  information on how the Food and Drug Administration (FDA) 
  is applying the 180-day generic drug exclusivity provisions 
  of the Federal Food, Drug, and Cosmetic Act (the Act) in 
  light of recent court decisions. The guidance
  addresses the issue of the elimination of the "successful 
  defense" requirement, which required an abbreviated new 
  application (ANDA) applicant to be sued for patent 
  infringement and to prevail in the litigation to receive 
  the 180-day period of marketing exclusivity.
How crazy is that? For many years official FDA policy was that a generic maker had to actually be sued for patent infringement - and win in the lawsuit - as the condition for receiving a 180-day monopoly!

I can get into the duct-tape upon duct-tape that led to this bizarre state of affairs, but think about how perverse it is that the FDA was telling companies to break patent law (or at least risk a civil lawsuit) as a matter of policy. That's the kind of thing you uncover when you actually look at how regulations are implemented.

Finally, regarding funding, yes, NIH spends about $31B per year, which is a lot. However, drug companies spend $4B per drug approved[1], which is an incredible amount of money when multiplied across all drugs. I'm not sure exactly how one could stop drug companies from profiting from public domain research as you propose. Are you saying that NIH should get into the business of drug development and/or not allow its funded academics to publish papers or start drug companies?

If you are saying the former, I actually happen to agree that NIH would be reasonably good at drug development, as Francis Collins has proposed, because as a fellow .gov it would be able to play hardball with the FDA in a way that no normal company could. Among other things, it wouldn't fear going out of business, and would be able to appeal to the HHS secretary if FDA retaliated against it. On the other hand, this new NIH-to-FDA pipeline would lose a lot of checks and balances; it'd sort of be like HHS as the large drug co with NIH as the scientists and FDA as the regulatory affairs, without any real check by the market other than the nationalized drug companies of other countries.

Think about how the FDA fast tracked [2] things like TSA body scanners and you'll get a sense for what its actual commitment to safety is when it's a fellow .gov that is sponsoring a drug/device.

As a final point, if you meant instead that NIH should be abolished and academics should stop publishing papers, I think we will actually see the implosion of the US higher ed research establishment over the next 5-10 years due to MOOCs and budget cuts, so that may come to pass as well.

[1] http://www.forbes.com/sites/matthewherper/2012/02/10/the-tru...

[2] http://arstechnica.com/science/2010/11/fda-sidesteps-safety-...


> Finally, regarding funding, yes, NIH spends about $31B per year, which is a lot. However, drug companies spend $4B per drug approved[1], which is an incredible amount of money when multiplied across all drugs.

I think this $4B number is the Research & Development line off a financial report. I am not an accountant but I believe this number can include tons of things that people don't normally think of as R&D but just regular cost of doing business, and what we do think of as research is often a very small percent of it. Perhaps tax laws incentivize companies to put as many expenses in this category (of like 3 categories) as possible.

On a related point, people used to quote a number like it cost $500 million to bring a new drug to market, often as a justification for patents. I remember reading an academic article that showed how the real cost was almost always 1/20 of that, but drug companies were including the construction of optional new plants that were used for existing drugs too, 20 year leases on specialty tree farms and other supplies, and huge "present value" calculations that would take $2 million spent by a university 20 years ago, use the companies cost of capital (maybe 14%), and even though the company only paid $500k for the rights a few years ago they would calcuate some number in the tens or hundreds of millions that was never paid by anyone.


  I remember reading an academic article that showed how the 
  real cost was almost always 1/20 of that
This is the Light and Warburton study. The short answer is that it's kind of like a freshman saying "I could build Facebook overnight" by wgetting Facebook's CSS/JS. But for anyone in engineering who knows what FB's backend infrastructure is like, they know it would be nontrivial to clone FB.

The best response to Light and Warburton is that if it really took only $43 million to ship a drug, then they should raise the capital and start a drug company. It would be by far the most capital-efficient and successful drug company of the last 50 years. If they have really figured out how to cut all the fat, they would be hailed throughout the industry.

But I hope to persuade you that when someone outside the industry is off by two orders of magnitude ($43M vs. $4B), it is likely that they are the ones who have missed something important. I encourage you to read Derek Lowe's more detailed critique here:

http://pipeline.corante.com/archives/2011/03/07/the_costs_of...

http://pipeline.corante.com/archives/2011/03/08/that_43_mill...


I prefer a more clean structure in which one pick one scheme and go with it. If tax money is supposed to be the major way to fund medical research, then the goal (effective treatement) and the cost (tax dollars) should be combined to get the most treatments for least amount of dollars. The current system is not cost effective, and no attempt at even trying to bring it into some form of cost effective control has even been made. Current system is to first pump tax dollar at research, then throw state monopolies and exclusive right to medical companies so they will take the tax produced research and produce products, which in effect means that the products with the most earning under least effort gets made. Treatment effectiveness just happens to get lost in the transition, and get traded for profit vs production costs. That can not be the best use of tax money, or the power of granting state monopolies.

The $31B is considered to be 1/3 of all funding for all medical research (including humans and pets/animals). In the area of core research, including those illnesses that are life threatening, then NiH stands for around 95% of the funding.

Having the government do the research, including the testing, and then let generics do the production of the devices/drugs (under somewhat high taxes) could be one way to do it. It would likely be considerable cheaper than the current system, as it would have a hard time doing worse than the current system. The ("we are not worse than the other guy") slogan might not the best, but it would be a start to get somewhere better than now.

Or, they could do the opposite, pulling out from funding medical research. The government do not fund the research for most things. Maybe those 31B$ could be better spent elsewhere and thus force pharma to be self-dependent.

In regard to academics... If Academia fund some research, then same rule again apply. Follow the money. Is it tax money, private researchers money, or institution money that funded the research. If its tax money, then the research belongs in public domain. If its the researchers private money, then its the researchers that decide of the research. If its the institution and the research is funded by private inventors, then its the institutions decision. I might not like it when research is not published to the public domain (will considered it a bit immoral), but primarily one should honor the investor with the result of the funding. If that investor is the public, it should be illegal to prevent the public access to to the result. That include universities that is state funded.


The other solution is for the U.S. to reign in all the statutory laws that have dropped the requirement of mens rea. Originally to be criminally guilty you had to have intent and action. Over the last few decades we have been progressing or law system to exclude intent making it possible to be found criminally guilty of crimes you had no intent on breaking. Including a strong default of mends rea in all laws that do not otherwise mention it would allow defendants to use the laws convoluted nature as a valid defense.

P.S. I am not a lawyer and probably completely wrong.


Thank you for this post. It should be a Wikipedia page about regulation.




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