
Why Drugs That Work in Mice Don't Work in Humans - apsec112
https://thelri.org/blog-and-news/why-drugs-that-work-in-mice-dont-work-in-humans/
======
dalbasal
_" Only 14% of drugs that are tested on humans succeed in demonstrating
effectiveness[1], and all of these are drugs that have been found efficacious
in animals, so successful animal studies are very far from a guarantee by
themselves."_

Regardless of the reason, this seems fine/workable. Animal studies are a step
in the funnel. I assume the step from petri dish to mouse is similar.

I wonder how many false _negatives_ get produced. Drugs which would have
worked on humans, but don't on mice, for similar reasons.

~~~
ramraj07
14% is bad when you consider that the NEXT step after preclinical experiments
is basically clinical trials (and Phase I is not to test efficacy ) which
effectively costs several hundred millions of dollars or more.

And the pharmas would just add the cost of 86% failed trials to the other meds
that do pass, so they effectively pass the cost of their bad decisions to us.

I worked in a lab that studies antibody therapeutics for almost a decade and
can go on a tirade of all the shitty decisions companies seem to make in
candidate identification, but fundamentally I really believe that this number
won't be this low if the people making the decisions in pharma companies know
what they're doing but then the CEO of gsk used to sell lipsticks so who am I
to talk right?

~~~
fredophile
I've always assumed that the reason for the low rate of success at that stage
was just a result of things that work on rats not working on humans. Your post
is suggesting that there is some evidence available before testing on people
that would help increase this rate but gets ignored. I haven't seen anyone
express this view before and would like to learn more about it. Would you
please elaborate on what kind of information isn't being used for decision
making but should be?

~~~
busyant
I am not the parent, but I worked at a few biotech startups.

My impression is that you are _mostly_ correct (a lot of animal models for
disease don't accurately reflect the analogous state in humans).

However, I was privy to a situation similar to that described by the person to
whom you replied.

* A start-up that I worked at developed a "candidate drug" to treat a condition (I don't want to get too detailed).

* The drug was good at ameliorating the disease in our simple models, but we also had a strong suspicion that the drug would be toxic in humans, higher animals.

* A decision was made that we would determine if the drug was toxic in three different species of large animal (I think we chose some type of monkey, dogs and I don't remember).

* Our "go/no-go" decision was: If the drug was NON-toxic in at least 2 of the 3 animal species, we would move to clinical (human) trials.

* 6 months later, we got the results: drug was NON-toxic in 1 of the 3 species.

* This looks like "no-go", right?

* Wrong. Board of directors put pressure on the CEO and senior management ("We put 8 figures of our hard-earned $ into round B and you promised us clinical trials over a year ago.").

* CEO folded like an accordion and got everyone to agree that we should proceed w/ Phase I trials (small n of humans tested, primarily to determine toxicity and maximum tolerated dose) despite the results of the animal studies.

* Phase 1 trial starts. Everyone gets sick (maybe 10 patients) after about 5 days of taking the drug. Trial is halted.

* We go back to square 1.

CEO should have never folded under the pressure because it was a waste of
money, time, and it put people at risk.

I've only seen this once (going to trial with a risky drug), so I think it is
a rare event.

edit2: Ironically, this is an example of a situation where the animal-studies
CORRECTLY predicted what would happen in humans.

~~~
DanBC
Imagine a similar situation but where people died: Who's corporately
responsible for that decision? The company, or the individual directors? How
about the NEDs?

~~~
busyant
> Imagine a similar situation but where people died: Who's corporately
> responsible for that decision?

No idea. Thankfully, all patients stopped the drug and the toxicity went away.

I remember having a company-wide meeting where they showed us a result from
the Phase I trial. It was a graph of time on the x-axis and the concentration
of an important molecule in each patient's bloodstream on the y-axis. Every
patient had the concentration of that molecule drop to dangerously low levels
after about 5 days on the drug, and I'm thinking, "Is this a surprise to
anyone here?"

------
leemailll
Model animals are used in researches mostly due to two reasons: cost, which is
always a big hurdle for academic studies; and reproduction, especially for
inbred mice. The use of inbred mice often is because the behavior and activity
of the mice is well-characterized, high availability, and genetically more
consistent. However, the second part nowadays is often challenged and they are
not that consistently genetically as researches show. For drug development,
the very first step is to create an animal model, however, this one also is
difficult, since more often than not one cannot generate animal model
replicates all symptoms, this could mean a model without the actual cause. I
think this is also a reason why genetic studies of diseases nowadays is still
a hot field, from there one can make an animal model and test whether that
gene is the real cause in more confidence.

~~~
Balgair
For those that are interested, the Animal Welfare Act of 1966 (an the many
amendments to it) specifically spell out the animals that can be used for
research and testing. There aren't that many of them, hence why rats and mice
are so popular, as they are some of the few animals that can be used for
testing. The AWA is structured such that all animals are covered by default,
and only a few species are specifically excepted. It's an expansive law that
also covers herding, meat processing, cosmetics, hunting, etc.

In general, the AWA is very restrictive in terms of animal testing for
scientific research. Getting exceptions to use an animal for research is very
intensive and highly regulated, taking years to get the approval. Getting
approval for studies that may involve studying intentional pain, harm, etc to
an animal can take up to a decade for approval, and with much study and
research on other possible methods. Internal Review Boards (IRBs) are required
to include local lay people, clergy, other non-scientists, etc in order to
approve a study. Vivariums are also highly regulated and frequently inspected.

The US, at least nowadays, takes the welfare of animals extremely seriously
with stiff fines and real consequences for breaches and lapses in protocol.

[https://www.aphis.usda.gov/animal_welfare/downloads/AC_BlueB...](https://www.aphis.usda.gov/animal_welfare/downloads/AC_BlueBook_AWA_FINAL_2017_508comp.pdf)

[https://en.wikipedia.org/wiki/Animal_Welfare_Act_of_1966](https://en.wikipedia.org/wiki/Animal_Welfare_Act_of_1966)

~~~
mattkrause
While I agree that animal research is well-regulated in the US, many of the
details in your comment aren't quite right.

The Animal Welfare Act specifies the minimum standards of care for research
and exhibition of _most_ species of mammals. Birds, rats, and mice aren't
covered by the AWA, nor are "cold-blooded" animals. These are covered by other
regulations from the Office of Laboratory Animal Welfare (OLAW; for federally-
funded projects) or AAALAC (private funding). Farm animals are also not
included, unless they are being exhibited or used for research.

The AWA requires research institutes to form an Institutional Animal Care and
Use Committee (IACUCs), which includes scientists as well as clergy and
members of the community. This is usually different from the Institutional
Review Board (IRB), which regulates research involving human subjects. The
idea is admittedly similar though.

The AWA does not limit the species involved in research. In theory, you could
propose to set up a grizzly bear colony or something and the University of
California has (had?) a hyena colony for a while. The IACUC is responsible for
making sure that animals receive the care required by the AWA, OLAW, and other
standards, so they might turn you down if suitable resources are not available
or other, more humane approaches could be used (e.g., use a species that is
less affected by captivity).

~~~
Balgair
Thank you for the clarifications!

------
dtech
Except for maybe the last paragraph, this is not new information to basically
anyone performing studies. The problem is we don't have any ethically and
scientifically better alternatives.

~~~
rajadigopula
There is an alternate. To wake up from the ignorant direction the so called
studies are taking the human kind to. And stop calling it science. Dr. B.M.
Hedge suggested long ago that all the studies done on animals or humans are
wrong and inefficient in so many fronts. His words - According to ayurveda,
human body can be classified into around 200 types based on the K/P/H balance
of a body. A medicine that works for one may be totally neutral for another.
So, you read a paper that claims it got awesome results on a random blindfold
study, the question Dr. Hedge asks is what type of the 200 human body types is
it efficient? Apparently there is a body type that gives neutral or negative
results (ignoring side effects). Talk about working it on animals first! (-ve
downvotes welcome)

~~~
fifnir
Here's a nice smackdown which I don't have the time or knowledge to offer
myself:

"He abandons [Dr. B.M. Hegde] all rational thinking and embraces fantastical
belief systems. The sad thing is I personally know many people delaying cancer
treatment being swayed by his speeches and ending up with incurable metastasis
later."

[https://www.quora.com/Do-you-agree-with-the-controversial-
vi...](https://www.quora.com/Do-you-agree-with-the-controversial-views-of-Dr-
B-M-Hegde-when-it-comes-to-medicine-and-doctors)

~~~
rajadigopula
Understood. May be the modern world needs another wim hof to become a subject
to the existing science - validity though current limited existing medical
tools to prove/validate that humans can get access to autonomous nervous
system and heal themselves (which was thought to be impossible in modern
days). The approach Dr. hedge took is not registering with the rest of the
world according to the comments above. May be he should have proven his claims
subjecting to the existing methods just to give that level of confidence who
trusts it like wim hof did.

~~~
pcnix
It's not about giving confidence to people, the existing methods are part of
the fundamental idea of the scientific method. Dr. Hegde's claim of body types
doesn't really mean anything until there's evidence to back it up. And modern
medical trials are crafted and investigated with a wide variety of statistical
tools to determine the exact impact of a treatment method. Only if his claims
can stand up to this rigorous scrutiny can they be accepted the way existing
models are. The rest of the world will then sit up and take notice, exactly
because only then will there be something for them to take notice of.

An appeal to the ancient wisdom of Ayurveda doesn't really stand on it's own
until it's backed by solid peer reviewed science. It's really not that hard, a
well designed set of trials proving your point will have the entire world at
your feet. Modern science is extremely receptive of new ideas that way.

~~~
rajadigopula
Agree. Unfortunately, this is never going to happen. The few still practicing
Ayurveda properly come from a background where they learned it from their
ancestors within their family and practicing it for free and never allow
commercialization of their knowledge. But they can gladly share the knowledge
to people who want to learn. Food, Education and Medicine/health are the 3
things the practitioners in Indian culture believes to keep free. A few
decades ago, you want to gain education, you seek a guru and become a disciple
and he teaches for free. You got a health issue, you go to a doctor and he
treats you for free. Same with food, every town/village used to have centers
where food is served free to anyone. Although it's all gone decades ago, there
are still practitioners who treat patients for free and only take donations
and not fee. Sounds, funny but It's easy to understand the underlying wisdom,
how many studies today are funded by people with commercial interests?
Research on egg is funded by Meat industry, Research on milk is funded by
Diary industry etc. How is that turning out for everyone?

~~~
klmr
In fact, most studies are funded either by governments or via donations from
the public. _Some_ public studies are _partially_ funded by industry, but with
a big caveat: industry has _no say_ on how the studies are conducted, or even
what is being studied: industry contributions to public research are not bound
to research outcomes. And all this information is readily available, since
publicly funded research institutes publish their funding sources.

It’s true that industry is funding _some_ (publicly published) research
directly, and that _some_ research publications fail to disclose their funding
source and other conflicts of interest. But for the vast majority of
biomedical research, especially fundamental research, this simply isn’t the
case.

And it requires a complete suspension of one’s critical thinking capacities to
imagine that some vast, weird conspiracy encompasses all of public research,
to suppress the “truth” that Ayurveda works, contradicting everything we know
from modern medicine as well as basic physics and chemistry. And all that just
to make a few pharmaceutical company bosses rich? Why would I, lowly
researcher on a sub-par salary, contribute to such a conspiracy? It’s
completely irrational.

------
narrator
What about drugs that work in humans, but not in mice? Could you ever get them
into trials without animal data?

~~~
Aaargh20318
This is more worrying, how many medications did we miss because they don't
work in mice ? Do we humans only get medications that work in both humans and
at least one other species ?

~~~
ctz
The same number we missed because, as it turns out, killing people with
unknown medications is a bad thing.

------
Amorymeltzer
My go-to example is Vitamin C: it's an essential nutrient for humans, but
mice, like most other animals, are capable of simply producing it. That's
usually a good starting point for the "they're really different" conversation.

~~~
anitil
For the curious:
[https://en.wikipedia.org/wiki/L-gulonolactone_oxidase#Conseq...](https://en.wikipedia.org/wiki/L-gulonolactone_oxidase#Consequences_of_loss)

I couldn't really make sense of the two proposed theories, other than one
suggested perhaps it was an advantageous adaption in the presence of malaria.

------
syntaxing
I wonder if it's possible to use machine learning to speed up this process.
Rather than doing computational biology, can we use a hybrid system? For
instance, can we test this on mice and then feed some sort of parameter into a
model to see the probability it working on humans rather than testing it
directly on humans. I'm sure this won't be a perfect model but I wonder if it
can raise the 14% to 20% while using less resources.

~~~
aaavl2821
ML (or anything really) that could predict which molecules would work in
humans without testing them in humans would probably be on of the most
important advances in medicine ever, and would massively lower drug costs and
open up new areas for drug research

Phase 2 failure -- ie stuff failing in humans after working in mice -- is the
biggest cost driver in drug dev. You spend $50-100M+ to get there and 35% of
things fail. If you could eliminate you'd cut a massive chunk of the cost and
risk of drug dev

However I don't think ML is the thing to study if you want to create ML to
predict whether drugs will work in people. There is not enough data about how
the human body works to develop a good model. Better to work in biology to
develop good models of disease, or in developing tools to better measure the
molecular biology of the living human body. It's unclear if predicting drug
effectiveness with ML will be possible in our generation

For more near term applications of ML in drug discovery and development see
here:
[https://www.getrevue.co/profile/nathanbenaich/issues/6-impac...](https://www.getrevue.co/profile/nathanbenaich/issues/6-impactful-
applications-of-ai-to-the-life-sciences-new-essay-150757)

------
ggm
I'm not arguing for pigs over mice but I ask since transgenic pigs are often
said to be future potentially viable transplant sources would not trials in
pigs be a better model?

(Ethical nightmares)

~~~
interfixus
We are closer related to rodents than to pigs. Whether this is an argument for
one thing or for another or for nothing at all, I really have no idea.

~~~
klmr
This isn’t quite true. The issue is that rodents evolve a lot quicker due to
effective population size and generation time. As a consequence, the genetic
divergence between rodents and humans is in fact greater than that between
humans and pigs (see e.g.
[https://europepmc.org/abstract/pmc/pmc1142312](https://europepmc.org/abstract/pmc/pmc1142312)),
even though pigs branched off earlier than rodents.

~~~
interfixus
Had a vague that something like that might be in play. I obviously have some
reading up to do. My assumption was, that our branch would, until quite
recently, have been rapid breeders too. And the pigs' one as well.

------
nonbel
How many of these drugs actually do work in mice? Every study that comes out
on the topic shows at least 50% and often closer to 90% of preclinical
research does not replicate or even is not replicable in principle.

~~~
hjk05
Research and drug development are pretty different leagues. A research paper
might be 3 researchers with 20 mice. When your looking at preclinical trials
it’s more like 300 people and 5000 mice per trial and god knows how many
trials before something goes through.

The reproducibility crisis is happening in academia. There isn’t that much
room for uncertainty when it comes to industrial drug development. You won’t
find drugs making it all the way to market only for “another group” to be
incapable of reproducing the effect.

~~~
nonbel
> "When your looking at preclinical trials it’s more like 300 people and 5000
> mice per trial and god knows how many trials before something goes through."

This is sampling to a foregone conclusion. It is guaranteed to yield
unreproducible effects.

> "You won’t find drugs making it all the way to market only for “another
> group” to be incapable of reproducing the effect."

I doubt this from the description above.

------
danieltillett
While mice are not humans (who would have known), we could do a lot better by
moving away from using inbred mice.

More positively we could make a lot more use of domestic pets in research. If
we started to treat more pets as research subjects we could really do a lot of
great research.

~~~
saagarjha
Good luck getting people to allow their pets being used for research!

~~~
danieltillett
People are really keen to allow their pets to be used in research as long as
they understand the importance. Pets are a massive resource that is just being
wasted.

~~~
BostonEnginerd
My cats are certainly not being wasted. Who else would step across my keyboard
when I’m typing?

~~~
danieltillett
You should consider yourself lucky to be able to use your cat's keyboard while
she is taking her afternoon stroll.

------
fallingfrog
This all makes sense! I’ve heard there is a similar effect for single cell
research, where a lot of the study of human cells says that they are full of
support structures and making all kinds of chemical signals that actually are
a stress response to being placed on a piece of glass rather than floating in
liquid. Kudos to these researchers for making an honest attempt to get it
right.

------
Mitchhhs
I wonder if a similar proportion of drugs that work in Humans wouldn't work in
mice. Are we missing out on a ton of potential?

------
chiefalchemist
I'm not sure how common the practice is, but I've been told (by a trusted
source) that if a med study doesn't get the desired results they just get a
new set of mice and try again.

That is, results can vary based on the mice used for reasons not understood
(but gut bacteria perhaps).

~~~
jonlucc
I work in pre-clinical pharma research, and this isn't really true in my
experience, but there are a couple caveats. At least in my experience, we
wouldn't run the same study again, but we might change the model. There are a
few models that all point to a similar indication, so we might try both. If a
treatment works in one but not the other, it's definitely seen as less strong
evidence of efficacy, unless there's some very compelling mechanistic reason.
That's not quite as crazy as it sounds, though, because translation from mouse
to human is already poorly understood, so it can be hard to know which model
will suggest positive effects in clinical trials.

~~~
VBprogrammer
I'm interested in how compounds are chosen for medical research. Do you just
start with a wide range of compounds which you are able to make and fire them
at a range of different potential medical issues? That seems staggeringly
unlikely to find something useful.

I know some drugs are extracted by isolating a compound from a traditional
remedy. That obviously makes sense.

~~~
twic
This is a huge field of research and development, with a number of different
approaches.

Almost always, though, you are starting with a particular medical problem in
mind, so the first step is to develop some kind of assay for detecting
compounds which might be useful in treating it. Ideally, this would be a
simple biochemical reaction, but it might be something involving cell culture.

For example, if you wanted to find new painkillers, you might look for
chemicals inhibiting cyclooxygenase (as ibuprofen does). You can buy kits for
doing that assay commercially [1], where you prepare a solution of the enzyme,
add your test chemical, then add a substrate which emits light when the
cyclooxygenase breaks it down, and measure the intensity of light produced.

If you wanted to find new anti-cancer drugs, you might look for drugs which
cause proliferating cells to get stuck in the metaphase step of the cell cycle
(as paclitaxel does). You would plate out some rapidly proliferating cells,
add your test chemical, wait twelve hours, then fix them, stain them with a
DNA-specific dye, and use a microscope to count the number of cells in
metaphase (which is quite distinctive [2]). This is a lot more tedious than
the cyclooxygenase assay, but we have robots that can handle liquids and
plates of cells, and operate microscopes, and process images, so it can be
highly automated, at a cost.

Then you take your assay and go hunting for molecules.

One approach is indeed just to start with a wide range of compounds. You can
get libraries of small molecules [3] [4], so you give them to your robots (or
graduate students), and put them all through your assay to find which ones
work.

You can also start with mixtures of compounds, perhaps obtained from natural
sources. For example, you could go and collect twenty species of fungus or sea
sponge, grind them up, and put the extracts of each through your assay. If
anything works, you then fractionate the extract somehow (eg by
chromatography), and put each fraction through your assay. You pick fractions
which work, fractionate them further, assay the sub-fractions, and repeat
until you have got a pure substance with some activity, which you then
characterise. Here, you can knowledge of ecology and biology to pick likely
species - for instance, fungi are a good source of antibiotics, because they
have to make antibiotics to defend themselves in their natural habitat.

Or you could start with some knowledge of the structure and function of the
target (from X-ray crystallography, NMR, and good old fashioned biochemistry),
and try to rationally design a molecule which will bind to and inhibit it.
Computer simulations are useful here. Combinatorial methods let you design
hundreds of molecules which might work, and then put them all through the
assay.

Or you could hope that an antibody will do the job, and inject your target
protein into some mice, wait for them to make an immune reaction to it, then
collect their blood, extract B-lymphocytes, culture them in bulk, purify
antibodies from the culture, then assay the antibodies. If something works,
split the lymphocytes into single-cell clones, and assay each clone's
antibodies one by one.

I don't work in this field, so my knowledge of these techniques is from
undergraduate study, and one relative who grinds up sponges. It's possible
some of the approaches i mention are obsolete, or were only ever speculative.

[1] [https://www.abcam.com/cyclooxygenase-cox-activity-assay-
kit-...](https://www.abcam.com/cyclooxygenase-cox-activity-assay-kit-
luminometric-ab139432.html)

[2]
[https://www.le.ac.uk/bl/phh4/roottip.htm](https://www.le.ac.uk/bl/phh4/roottip.htm)

[3] [https://www.tdi.ox.ac.uk/small-compound-
libraries](https://www.tdi.ox.ac.uk/small-compound-libraries)

[4]
[https://wiki.nci.nih.gov/display/NCIDTPdata/Compound+Sets](https://wiki.nci.nih.gov/display/NCIDTPdata/Compound+Sets)

~~~
VBprogrammer
Thanks, that was exactly the answer I was looking for but couldn't quite
figure out how to formulate the question so that Google would provide a useful
answer!

------
Amygaz
Any mice trial should use 4 different breeds: one of the academic hallmark
(black6 or balb/c) for publication purpose, one that represent your model (or
so you think) because that’s the logical thing to do, and a truly wild type
one (captured in the wild) to capture the noise.

Even this bias longevity piece needs to do that. This 4 breeds will all have
different immune system, cognitive behavior and lifestyles, which are all
central to aging.

~~~
klmr
The issue with that approach is that you’d multiply the number of sacrificed
animals by 3 (or 4, did you forget a breed?), for limited gains in insight.
Your approach would be a lot more defensible if it didn’t involve killing
vastly more animals, and a fairly large increase in research cost. These
things are always a balance, and there’s no evidence that always using your
approach would be worth it.

~~~
ennisthemennis
I agree "any mice trial" is too strong a statement, and also 4 groups is kind
of infeasible. But I do think there is not enough research on how these
particular inbred mouse strains might bias research. Even the same strain
sourced from different companies have produced different results, due to
microbiome differences [1]. It's possible that we are way "overfitting" to
these particular academic mice

[1]
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870873/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870873/)

------
AngeloAnolin
Human !== Mice

We can even argue that Human !== Human due to a million variables that
differentiates them at microcellular level.

------
dumbfoundded
Is the converse true? Are there drugs that would only work in humans but not
any animal models?

------
karosass1
Short answer: Humans are not mice

------
najarvg
Fascinating and very timely for me. I was privileged to sit through a talk by
the head of cancer immunotherapy at our institution where he was explaining
the past, present and future journey of cancer immunotherapy research and this
exact topic of mouse model applicability to human subjects came up. His TLDR
on this was that differences are likely due to - 1\. Controlled lines of mice
bred specifically to minimize confounding during pre-clinical studies 2\.
Immune response activation pathways differing from "in the wild" situations
for actual subjects 3\. The immense diversity of gut microbiota, their
temporal and inherited gene signatures and impacts on drug metabolism which
are incredibly hard to control for in experiments

Very nice to see an approachable post out there outlining a lot of these
issues.

------
AbyormPiranha
Because mice aren't humans.

------
foobaw
Because we are not mice.

~~~
dkural
Actually; we're 75% mice, genetically speaking.

