
Why Are So Few Blockbuster Drugs Invented Today? - forrest_t
http://www.nytimes.com/2014/11/16/magazine/why-are-there-so-few-new-drugs-invented-today.html?_r=0
======
WalterBright
Sam Peltzman's book "Regulation of Pharmaceutical Innovation" shows, with
statistics, that the 1962 FDA requirements that drugs be proved to be
effective has resulted in a dramatic slowdown of new and effective drugs,
caused by the high cost of proving effectiveness.

He also shows that the ineffective drugs prevented from coming to the market
are far outweighed by the effective ones that are delayed or never developed
at all.

~~~
rayiner
Approaching the question from an analytical perspective, there's a very
concrete, market-economic based reason for putting the brakes on such
development:

1) The information asymmetry between the public and drug developers is
absolutely astronomical. This undermines any free-market attempt to keep bad
drugs out of the market. Moreover, nobody with the resources to prove drugs
ineffective has the incentive to do so.

2) The predicative power of the science is pitiful. 90% of drugs that make it
to Phase I trials do not make it through Phase III.[1] In other words,
companies have no idea whether drugs will work until they actually test them
on people. Indeed, there is a decent amount of evidence showing that many
drugs that pass Phase III trials don't work.

The cost of proving efficacy through human trials is unavoidable. The question
isn't whether or not to conduct trials, the question is whether you do those
trials as part of the approval process, or by selling drugs that don't work to
the public at large. The inherent information asymmetry involved makes the
latter a less than compelling proposition.

[1]
[http://pipeline.corante.com/archives/2014/01/10/a_new_look_a...](http://pipeline.corante.com/archives/2014/01/10/a_new_look_at_clinical_attrition.php)

~~~
refurb
As for your first point, I think there are two factors that run counter to it.

1) The FDA already regulates what companies can say about their drugs. If
there is no evidence your drug is effective, the FDA could certainly stop you
from saying there is.

2) Without efficacy data, insurance companies won't pay much. To be honest, I
would bet insurance companies wouldn't cover such drugs at all. It would be
entirely on the patient to cover the costs.

Taking my second point further, if you can't charge a premium for your drug, I
doubt pharma companies would even develop drugs they can't prove are
efficacious. Gathering efficacy data takes a lot of money, but so does safety
data. If you can save 50% on clinical trial costs, but only charge 10% the
price, it's a losing proposition.

------
rayiner
> They found that for every billion dollars spent on research and development
> since 1950, the number of new drugs approved has fallen by half roughly
> every nine years, meaning a total decline by a factor of 80. They called
> this Eroom’s Law, because it resembled an inversion of Moore’s Law

It's not an inversion of Moore's law, it's totally consistent with it. Every
time you shrink transistor size by half, you spend exponentially more capital
on the new fabs: [http://www.futrfab.com/wp-content/uploads/2012/04/Small-
Volu...](http://www.futrfab.com/wp-content/uploads/2012/04/Small-Volume-
Technology-Fabrication_new.pdf) (Figure 2).

~~~
Alex3917
The idea that all the easy to discover drugs have been found isn't really
accurate. What's actually happening is that the FDA has signaled that they are
going to do slightly more to make sure drugs targeting the general public are
reasonably safe and actually plausibly work, and so the drug manufacturers
have basically just given up in trying to pass even this minimal bar. This is
why they are all targeting rare diseases, not because they are inherently more
profitable to treat, but because the FDA bar for safety and efficacy is lower.

~~~
Dwolb
I disagree. Traditional drug firms have proven they're unable to adequately
innovate with internal R&D due to large bureaucratic overhead. Additionally,
old blockbuster drug patents are rapidly expiring and these firms have nothing
new to offer except for small iterations on the old drug (e.g. a small change
in chemistry which offers no to very little additional benefit to the patient
while securing a new patent for the firm). In short, competition is increasing
and they're unable to make huge leaps forward in technology to stay ahead of
the competition.

Recognizing these facts, large firms have begun prospecting and betting on
start-up companies who focus on rare diseases because this is a space where
innovation has very little bureaucratic overhead and there is very little
competition. Also, this is also a space in which the market size is small and
where barriers to entry are high, reducing the threat of future competition.

In fact, if big companies believe they have bought a company with a promising
drug, they would prefer higher hurdles for FDA certification to reduce
potential competition.

~~~
jonlucc
I think this prospecting will create a problem though. If big pharma
increasingly prefer to purchase startup biotech companies that have an asset
at whatever phase the pharma is looking for, then the only people developing
new drugs will be small startups. It reduces the opportunity for assets built
for one target to be worked up in another area (e.g. an autoimmune drug to be
tried in models of ALS). It also discourages non-risky scientists, as the jobs
will increasingly be in volatile companies that leave you wondering if your
company card will work when you check into a hotel at a conference.

~~~
Dwolb
Agreed. It is a problem but you have to wonder if the market will be self-
correcting. If there are no companies left to prospect, what will fill the
gap? Maybe the major question is how long will a prospecting strategy last?

------
Balgair
Ok, so I work with a lot of immunologists and micro-bio people. The short
answer is that science is hard. The slightly longer answer is that science is
a lot about luck and sweat. Penicillin was mostly discovered by accident, as
with Viagra and many other blockbusters. This is the more observational side
of science, not the predictive side. The smart-insulin that was described is
firmly in the predictive side, the sweat side. Luck is a factor of having a
lot of scientists looking at a lot of things. Sweat is one scientist looking
at one thing. Both are valid, but one takes a lot less time.

And that is the issue, time. Why not so many recently? The time involved is
much higher. The low hanging fruit of the tree of science has mostly been
picked at this point (At least I hope so). The blockbusters are then higher up
and take considerably more effort to reach. Smart insulin needs nuclear
magnetic resonance imaging, a lot of modeling and p-chem, trial after trial to
verify results, a lot of post-doc and grad students, data processing and
computer scientists, and the resources of a lab and a half. Penicillin was a
petri dish that wasn't properly sterilized.

Science takes time, and as humans, we go for the easiest science first. We
should not sacrifice safety for speed.

~~~
jonlucc
> Science takes time, and as humans, we go for the easiest science first. We
> should not sacrifice safety for speed.

I agree, but it is also a function of money. Pharmaceutical companies often
rely on basic research from academia to get pointed in the right direction. As
that decreases, there are fewer academics discovering fewer new pathways that
pharma can target drugs for.

Additionally, funding is aimed at investigators who are likely to succeed. It
is common for a lab to essentially work one grant ahead of funding in order to
be sure to deliver.

~~~
Balgair
> Funding is aimed at investigators who are likely to succeed.

You have no idea. Friends at other universities have a very high end
microscope 'core' that can be used all that apply as a shared cost and time
device. Orientation went great, 'yeah, its awesome to use, you get great data,
blah blah blah'. When she came to the lab however, she found that only 2
professors' labs could use the core, as they had outbid all the other
professors for the time, for then next 15 years. Its a small thing, but it
speaks to the incredible gains that go to the 'winners' and the scraps that
are given to 'losers.'

------
colordrops
D.R.A.C.O. is a broad spectrum antiviral developed at MIT, but currently
languishing without almost any funding. It theoretically can cure almost any
virus, and has been successful in vitro and in mice. The mechanism should work
in humans, and yet no one wants to fund it. It's completely baffling to me
that no one is aware of this, and that it's not being fast-tracked and funded
by governments around the world:

[http://en.wikipedia.org/wiki/DRACO_(antiviral)](http://en.wikipedia.org/wiki/DRACO_\(antiviral\))

~~~
refurb
I don't know enough about DRACO, but I would argue that pharma companies have
already kicked the tires and passed on it.

I know a few people that work in pharma business development and they scour
academic labs for anything of value. For whatever reason, they don't believe
that DRACO as value, at least right now.

In the meantime, if it's as promising as you say, academic labs shouldn't have
trouble getting funding to further develop it.

~~~
colordrops
> I don't know enough about DRACO

So what are you saying besides laying out your untested assumptions about how
the world works? There are endless reasons why research doesn't get funded,
and many of those aren't because the research is bad.

> In the meantime, if it's as promising as you say, academic labs shouldn't
> have trouble getting funding to further develop it.

What evidence do you have to back this up?

Do you have any idea on how much money is made in treatments for viral
disease? Do you know how much would be lost if all viral disease was cured?

------
mkempe
Because of government controls and bureaucratic incentives: on the one hand,
the FDA is by its nature and rules inclined to block new drugs and medical
devices; on the other hand, potential inventors are either turned off or
handicapped by the FDA rules and controls.

I've developed internal software tools for healthcare companies -- having had
to study and learn the FDA rules, and having seen what these companies go
through, I'd rather give up on engineering than work in the development of
medical devices. A sane, creative mind cannot work and flourish under
compulsion.

------
harvestmoon
Interestingly, a quite high amount of breakthrough treatments were discovered
by accident. Antibiotics, the original antidepressants, antipsychotics,
lithium, viagra and others were all found initially that way.

Which may imply that our discovery approach has benefited from happy accidents
which are hard to replicate and where the basics have been found already.

~~~
jonlucc
I think Viagra was discovered during clinical trials for hypertension. It (and
it's fellow PDE5 inhibitors) is used in cardiac care, but the market is larger
for "erectile dysfunction". There are certainly programs in big pharma to
screen known drugs (that are already deemed safe for humans) in assays aimed
at new targets.

------
pessimizer
Because medicine has only recently become a science. 150 years ago, medicine
was far more likely to hasten your death or kill you than improve your
situation, and the only medical intervention that actually sometimes delivered
results was surgery.

At some point, the claims that it made started to be tested rather than simply
taken on authority, basic knowledge was accumulated, and the low hanging fruit
was plucked. The rest of the fruit is harder to get to, or may even be largely
exhausted IMO, because the field is still operating as if all sicknesses have
the possibility to be cured by a magic potion (taken orally or injected.) Now,
most announced discoveries are simply false, and the largest selling drugs
either useless or intoxicants (statins, SSRIs, Xanax, Adderall, etc.)

I'm pleased about research on parasites and gut flora, though. It's being
reduced to poop pills in its media coverage, but it's not the standard magic
potion bit.

~~~
jeffreyrogers
I'm not fully sure why you've been downvoted, but I think your comment on
SSRIs is a bit misguided. I don't know enough about the others you've
mentioned (statins, Xanax, Adderall, etc.) but the evidence for the efficacy
of SSRIs is very strong and they certainly aren't intoxicating.

~~~
smaccoun
Got a link for that? Several publications have been making the news lately
showing antidepressants are really no better than placebo in general

[http://www.scientificamerican.com/article/antidepressants-
do...](http://www.scientificamerican.com/article/antidepressants-do-they-work-
or-dont-they/)

~~~
glenra
Try this:

[http://slatestarcodex.com/2014/07/07/ssris-much-more-than-
yo...](http://slatestarcodex.com/2014/07/07/ssris-much-more-than-you-wanted-
to-know/)

...which also sort of goes along with this overview of depression treatment in
general:

[http://slatestarcodex.com/2014/06/16/things-that-
sometimes-h...](http://slatestarcodex.com/2014/06/16/things-that-sometimes-
help-if-youre-depressed/)

The relevant upshot of that first link includes:

(1) Everybody agrees SSRIs are at least _somewhat_ better than placebo

(2) Placebos really are _unreasonably effective_ compared to non-treatment, so
even merely being _as_ effective as placebo is a huge benefit, not to mention
being somewhat _better_ than that.

(3) What constitutes a "clinically significant" improvement (even relative to
placebo) turns out to be kind of arbitrary. As in, a drug that misses that
arbitrary goal might still be hugely beneficial to people. (especially if you
compare it to non-treatment)

(4) Glomming all SSRIs together into one big lump to reach conclusions about
the group combines some that work pretty well with some that are known to not
work well at all, which can bring down the _average_ effectiveness of the
_group_ to below that arbitrary "clinically significant relative to placebo"
mark even though individual SSRIs might on their own be more likely to make
the cut.

------
narrator
A lot of interesting drugs are developed and marketed only overseas these
days. The Russian pharmaceutical industry has come up with a lot of
interesting ones lately.

For example:

[http://pharmstd.com/page_22.html](http://pharmstd.com/page_22.html)

~~~
aomurphy
I've seen this cited several time on HN recently, is there a better source for
this? Sorry, I imagine a lot of this stuff is in Russian only, but I would
love if you could give an article/book/post about this sort of thing.

~~~
narrator
This is their best selling drug:

[http://en.wikipedia.org/wiki/Arbidol](http://en.wikipedia.org/wiki/Arbidol)

It's marketed as an over the counter cure for Influenza and only sold in
Russia and China.

I guess the proof is in the pudding. Death rates for influenza are low by
world standards in Russian and China:

[http://www.worldlifeexpectancy.com/cause-of-
death/influenza-...](http://www.worldlifeexpectancy.com/cause-of-
death/influenza-pneumonia/by-country/)

Of course that could be a fluke and this drug is just a sugar pill because all
medicine not approved by the FDA is fake, right? We have the most expensive
medicine in the world, by far, so it must be the best!

------
jmckib
> Doing so, he knew, would require years of clinical trials in preparation for
> a new-drug application submission to the F.D.A. “That’s the only reason
> people were afraid.”

------
HarryHirsch
Derek Lowe has another theory:
[http://pipeline.corante.com/archives/2014/11/06/what_happens...](http://pipeline.corante.com/archives/2014/11/06/what_happens_after_your_first_drug_approval.php)

Your average startup brings exactly _one_ drug to market, and then is aquired
and broken up. The current system does not encourage building institutional
experience in the field, in fact it destroys it.

------
georgewfraser
Great review article on this topic in nature:
[http://diyhpl.us/~bryan/papers2/bio/Diagnosing%20the%20decli...](http://diyhpl.us/~bryan/papers2/bio/Diagnosing%20the%20decline%20in%20pharmaceutical%20research%20and%20development%20efficiency.pdf)

------
mrbill
Maybe they are, but there are hurdles in getting them to market. Here's an
example about Merck's suvorexant.

[http://www.newyorker.com/magazine/2013/12/09/the-big-
sleep-2](http://www.newyorker.com/magazine/2013/12/09/the-big-sleep-2)

------
cdoxsey
Worth a listen:
[http://www.econtalk.org/archives/2012/11/angell_on_big_p.htm...](http://www.econtalk.org/archives/2012/11/angell_on_big_p.html)

------
notastartup
I believe the biggest reason is the lack of embracing software in the process.
You still have people standing around in front of beakers and petridish. You
are using the same darn rigid rules from 18th century. This is why progress is
so slow.

Imagine if you opened up the vast knowledge of drugs and creating new drug and
testing it was as easy as writing a program, it would do wonders.

Software is not eating up the world in this slice of the market.

------
cnp
Silly that they need to invent new drugs when there are so many "blockbusters"
right here to be grown from the ground and used

