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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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August 13, 2009

Animal Testing: A View From the Labs

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Posted by Derek

Why do we test drugs on animals, anyway? This question showed up in the comments section from a lay reader. It's definitely a fair thing to ask, and you'd expect that we in the business would have a good answer. So here it is: because for all we know about biochemistry, about physiology and about biology in general, living systems are still far too complex for us to model. We're more ignorant than we seem to be. The only way we can find out what will happen if we give a new compound to a living creature is to give it to some of them and watch carefully.

That sounds primitive, and I suppose it is. We don't do it in a primitive manner, though. We watch with all the tools of our trade - remote-control physiological radio transmitters, motion-sensing software hooked up to video cameras, sensitive mass spectrometry analysis of blood, of urine, and whatever else, painstaking microscopic inspection of tissue samples, whatever we can bring to bear. But in the end, it all comes down to dosing animals and waiting to see what happens. That principle hasn't changed in decades, just the technology we use to do it.

No isolated enzymes can yet serve as a model for what can happen in a single real cell. And no culture of cells can recapitulate what goes on in a real organism. The signaling, the feedback loops, the interconnectedness of these systems is (so far) too much for us to handle. We keep discovering new pathways all the time, things that no model would have included because we didn't even know that they were there. The end is not yet in sight, occasional newspaper headlines to the contrary.

We do use all those things as filters before a compound even sees its first rodent. In a target-driven approach, which is the great majority of the industry, if a compound doesn't work on an isolated protein, it doesn't go on to the cell assay. If it doesn't work on the cells, it doesn't go on to animals. (And if it kills cells, it most certainly doesn't go on to the animals, unless it's some blunderbuss oncology agent of the old school). The great majority of compounds made in this business have never been given to so much as one mouse, and never will.

So what are we looking for when we finally do dose animals? We're waiting to see if the compound has the effect we're hoping for, first off. Does it lower blood pressure, slow or stop the growth of tumors, or cure viral infections? Doing these things requires having sick animals, of course. But we also give the drug candidates to healthy ones, at higher doses and for longer periods of time, in order to see what else the compounds might do that we don't expect. Most of those effects are bad - I'd casually estimate 99% of the time, anyway - and many of them will stop a drug candidate from ever being developed. The more severe the toxic effect, the greater the chance that it's based on some fundamental mechanism that will be common to all animals. In some cases we can identify what's causing the trouble, once we've seen it, and once in a great while we can use that information to argue that we can keep going, that humans wouldn't be at the same risk. But this is very rare - we generally don't know enough to make a persuasive case. If your compound kills mice or kills rats, your compound is dead, too.

I've lost count of the number of compounds I've worked on that have been pulled due to toxicity concerns; suffice it to say that it's a very common thing. Every time it's been something different, and it's often not for any of the reasons I feared beforehand. I've often said here that if you don't hold your breath when your drug candidate goes into its first two-week tox testing, then you haven't been doing this stuff long enough.

Here's the problem: giving new chemicals to animals to see if they get sick (and making animals sick so that we can see if they get better) are not things that are directly compatible with trying to keep animals from suffering. Ideally, we would want to do neither of those things. Fortunately, several factors all line up in the same direction to keep things moving toward that.

For one thing, animal testing is quite expensive. Only human testing is costlier. In this case, ethical concerns and capitalist principles manage to line up very well indeed. Doing assays in vitro is almost invariably faster and cheaper, so whenever we can confidently replace a direct animal observation with an assay on a dish, plate, or chip, we do. All that equipment I mentioned above has also cut down on the number of animals needed, and that trend is expected to continue as our measurements become more sensitive.

So things are lined up in the right direction. Any company that found a reliable way to eliminate any significant part of its animal testing would immediately find itself in a better competitive position.

And for the existing tests, it's also fortunate that unhappy animals give poor data. We want to observe them under the most normal conditions possible, not with stress hormones running through their systems, and a great deal of time and trouble (and money) goes toward that end. (In this case, it's scientific principles that line up with ethical ones). Diseased animals are clearly going to be in worse shape than normal ones, but in these situation, too, we try to minimize all the other factors so we're getting as clear a read as possible on changes in the disease itself.

So that's my answer: we use animals because we have (as yet) no alternative. And our animal assays prove that to us over and over by surprising us with things we didn't know, and that we would have had no other opportunity to learn. We'd very much like to be able to do things differently, since "differently" would surely mean "faster and more cheaply". None of us enjoy it when our compounds sicken healthy animals, or have no effect on sick ones. Just the wasted time and effort alone is enough to make any drug discoverer think so. There are billions of dollars waiting to be picked up by anyone who finds a better way.

Comments (82) + TrackBacks (0) | Category: Animal Testing | Pharma 101


COMMENTS

1. darwin on August 13, 2009 7:56 AM writes...

Well said Derek. Perfect example is cardiac physiology and potential API effects on one or more ion channels and their complex interactions. One can conduct in vitro receptor binding or other in vitro or ex vivo assays all day long, but until you test the compound in vivo, no one can have full confidence regarding arrythmogenic potential.

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2. Sili on August 13, 2009 10:05 AM writes...

Hear! Hear!

Very fair and balanced (in the real sense).

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3. SciChick on August 13, 2009 10:17 AM writes...

Derek, what's you take on microdosing? I realize there has not been enough data points to demonstrate whether this paradigm would work, but in the end, if this is feasible, one can imagine the dramatic reduction in animals that are consumed in the early phase preclinical development.

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4. BioGuy on August 13, 2009 10:42 AM writes...

All of what you say is true, Derek, however your colleagues are also reluctant to try new methods to reduce animal studies. Case in point. A company I work with, VaxDesign, has an in vitro system that replicates the human immune response to vaccines, immunosuppressants, and other agents. Lots of data. But companies have been extremely slow to adopt this new technology. People do not like change. They like their animal models and are resistant to new methods that could reduce the need for animal tests.

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5. Anonymous on August 13, 2009 12:00 PM writes...

BioGuy-I don't know anything about your model but I'd assume that companies are not using because regulating agencies we always have in the back of our minds...what data is acceptable to the regulating agencies. It takes a lot of data to get guidance from the regulatory agencies on new techniques. I'd suggest that your company partner with academia to increase the data out there and fuel the spread of the technology...but again, I don't know anything about your company...perhaps it is already headed down this path. I want to assure you though...that at least where I work no one is closing their minds to new ideas. New ideas are brought in everyday and their utility is discussed thoroughly.

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6. Anonymous on August 13, 2009 12:04 PM writes...

addition to previous comment. I know you said there is lots of data on this technique. It probably requires obscene amounts of data. Example...for all of the guidance ICH and USP provide us on residual solvents in our drugs-there are still some common solvents for which they provide no guidance because there is not enough data.

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7. Hap on August 13, 2009 12:05 PM writes...

I think the FDA wants a whole lot of data that the nonanimal tests give results correlating to those obtained from animal tests before it approves drugs or clinical data based on them - so drug companies aren't willing to spend lots of money (and the less fungible resource of time) to test whether the nonanimal tests give the same results.

This is something that would be best done by NIH - the test developers don't have the cash, and drug companies aren't going to spend their valuable time and money on a shared benefit. Alternatively, the drug companies would have to validate the alternative tests cooperatively. Probably why they haven't been validated yet.

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8. barry on August 13, 2009 12:16 PM writes...

re: microdosing
At one time, I held out huge hope for microdosing to preview the fate of a potential drug in man. Alas, it has grave flaws. No drug distributes to exactly one physiological compartment. A small compartment--that would be utterly negigible at therapeutic dose levels--can totally dominate the pharmacokinetics of a microdose. The data coming back can't be trusted.

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9. MTK on August 13, 2009 1:19 PM writes...

Excellent explanation, Derek.

Unfortunately for the really hard-core animal rights folks it won't mean anything. Their belief is based on the concept of "specieism", which is analogous to racism or sexism. The sin in their minds is that we consider some individuals to be of less worth than other individuals solely based on the species of that individual. So any animal testing no matter what the rationale is wrong. The only way to avoid specieism would be to test on humans. And just because other species practice specieism does not justify us practicing specieism. No more so than a group of racists would make it OK for us to be racists.

Good luck dealing with some of these arguments.

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10. Cloud on August 13, 2009 1:21 PM writes...

This is indeed a very good post.

If I'm feeling lazy, I tell people we have to test in animals because of Donald Rumsfeld's famous "unknown unknowns". There is so much that we don't even know we don't know....

I've also tried pointing out that the alternative is testing in humans without toxicity data to help us set a safe dose, etc. Usually, that works.

Sometimes, though, it is a lost cause to try to argue with people. One time, someone threw back at me that the smallpox vaccine had been developed without animal testing. Well, yes. Instead, Jenner tested his ideas on a human child of lower socioeconomic status (he injected his gardener's son with cowpox and then smallpox). Luckily, Jenner was right and the boy didn't get smallpox. But what if he'd been wrong?

I explained all of this, and the person thought that this was better than animal testing.

Personally, I'd rather we use animals, even cute ones, than children. Apparently, not everyone agrees with me. That scares me.

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11. Riaan on August 13, 2009 2:09 PM writes...

thank you Derek, did not expect you to post a response so soon after my comment.

I have to admit that I may be one of those people who argue the specieism point - as pointed out by another commentor.

What checks and balances are in place to guard against abuse? If this is like any other business I imagine that corners are cut sometimes, people cheat sometimes, big promises are made but what actually happens is a different matter.

And also how many frivolous "comfort" drugs are being developed and tested? Eating too much fat - take this, those lines around your eyes bothering you - we've got a cure for that!

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12. BOB on August 13, 2009 2:57 PM writes...

So you would rather live in a world without modern medicine than in one where animals are tested?

In order to live up to these principles you would need to live like Theodore Kaczynski. After all it isn't only medicines that harm the animal world. Do you put gas in your car? Do you live in a house, if so it was stolen from weaker species. What gives you the right to do that?

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13. Alig on August 13, 2009 3:37 PM writes...

I used to work for a big pharma company. They had a board for the ethical treatment of animals that set out the guidelines for what procedures could be performed and how the animals were treated. It was serious business. You obeyed those rules the same as OSHA, GMP and FDA guidelines.
Also justification always had to be given to use a higher species. Most experiments are done in rodents.

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14. Jose on August 13, 2009 3:38 PM writes...

What about the cyanobacteria? Who still stand up for them and all their brethren? And what about Periplaneta americana?

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15. BioGuy on August 13, 2009 4:03 PM writes...

Anonymous - yes of course the replacement of animal studies for regulatory purposes is not even close. Yet many animals are used for research purposes that are not part of a regulatory package. Also, you can submit in vitro data as a supplement in a regulatory application. The goal in the near term is to reduce the number of animals used in research. If an in vitro test correctly predicts human responses to vaccines, then why would you continue to use animals for that same test? Europe gives lip service to this idea but then runs everything through ECVAM which will not validate proprietary assays. The result is that many technologies that could reduce animal research use will never become validated.

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16. Riaan on August 13, 2009 4:04 PM writes...

@Bob I prefer to live in a world where harm is not done to others. If it is possible to get closer to that ideal - then do what you can to get closer to it. Just becaue it is hard is no excuse.

Does the fact that somewhere there is a guy bigger and more ruthless than you mean that he can do what he wants with you?

No, as a society we have values that determine what is acceptable for us to do. These eco-nut ideas are simply a new societal value that may (or may not) form part of the future social norm.

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17. Hap on August 13, 2009 4:33 PM writes...

As a supplement to testing, in vitro wouldn't seem to be much good - you have to spend extra time and money doing something that you have already done another way, or you have to risk having to redo many of the tests. Only when the in vitro assays well-validated and accepted by the regulatory agencies would they actually be useful as replacements for tests in animals.

What am I missing here?

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18. Larry on August 13, 2009 5:15 PM writes...

Great blog. That makes total sense. My question is then at what point is risk allowed assumed okay over reward. At what point do we take humans that have been on "compounds" for awhile and test them. I remember as a teenager I was blood tested once a month for the perscription I was taking, I dont know why but it seems logical ... getting something put in lets see how it affects the body regularyly.
One last thing is there a time when we use something like specific chiropractic and compare it to more and more "compounds" once they make it to the human "models?"

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19. Kismet on August 13, 2009 7:23 PM writes...

Riaan, sure you *prefer* to live in that world, but it is not the real world (at least not now as pointed out by Derek).
Either we use animals or people will suffer from our neglect of preclinical research. Even if you argue the speciesism point, you'd have to actually deem other species to be not just equal, but *more* important than humans, if you want us to forgo animal testing.
And don't forget that animal testing can also benefit other animals.

But please elaborate about 'frivolous "comfort" drugs'? Mitigating the damage that obesity does to our society and economy certainly is a worthwhile goal (and, no, obesity is not just a matter of laziness, although it often is).

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20. Bored on August 13, 2009 8:08 PM writes...

You know, what is so bad about specieism? We've become hypersensitive to having labels applied to us. If the animal "rights" wacko's truly believed in what they said, they would all practice Jainism.

There is no privileged frame of reference, physically or morally. We are "geocentrists" by the fact that we live on this particular speck of rock and metal. That humans currently OWN the planet is evolution's gift to us. (Or, depending on your persuasion, God's gift to us, or God's gift to us through evolution.)

Makes me want to have a shirt made that says: "Practicing Specieist."

A little courage in the face of these nuts is in order.

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21. Morten G on August 14, 2009 6:03 AM writes...

@Riaan
I think you're taking your argument to the wrong place. You can't get untested pharmaceutical drugs but if you want to live without pharmaceuticals then you have plenty of opportunity. But Derek and most people who read this blog is in the business of providing people with proven methods. Animals have weak and diffuse concepts of self and future and that's why we evaluate that where no other method is available it is better to test something in an animal before doing it in a human.
Personally I think that as long as fear and harm is equal or less than what the animal would experience in nature then we are on moral quite solid ground.

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22. Phlogiston on August 14, 2009 6:43 AM writes...

Great post. It really captures all the saliant points about animal testing in pharma. I think the biggest contribution of the early animal rights movement has been the awarness towards reducing suffering of lab animals. As pointed out in the post, happy animals make sense scientifically, morally, and financially. I can't think of any scientist who enjoys animal testing, bur we all recognize that we are vastly ignorant of biological systems, hence it is unavoidable. One could be quntitative about it and say that developing medicines which treat a painful condition or saves lives reduces the overall amount of suffering in the world for both the animals and humans who will take these drugs. For all the reasons Derek ellaborated upon, if someone did come up with a validated method which either reduced or mostly eliminated testing, every company who cares about making money would be using it. I know Derek's post will do little to change some of the extremist's minds (perhaps if they had better science education they might understand a bit more), but I do hold out hope that more moderate people will listen. One of the comments mentioned the testing a development of "lifestyle" drugs on animals, like ones for baldness, obesity, male bedroom problems, etc..., but I believe that even in those cases, most of them were designed for other reasons (high blood pressure, depression, etc). I'm not a big fan of these drugs, but I don't believe testing on humans is a very good alternative. This claim that all animals are morally equivalent is stupid. I have little sympathy for a mouse eating my cereal, much as a lion has little sympathy for a gazelle. Besides, where does one draw the line? Is a spider equivalent to a mouse or human?

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23. Alig on August 14, 2009 7:04 AM writes...

Did you see the story last week of the old lady who was repeatedly warned against feeding bears from her porch? They found two bears eating her. I couldn't believe what happened next, the cops shot the bears. They didn't read the bears their rights or assigned them attorneys, they just shot them. PETA should be out there protesting against those police officers.

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24. Bored on August 14, 2009 7:27 AM writes...

#23 Alig

That was natural selection at work as well. The woman's genes predisposing her to feed bears are now out of the gene pool, and the bear's genes predisposing them to eat stupid humans are, unfortunately, also eliminated.

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25. Alastair on August 14, 2009 7:31 AM writes...

One thing that's often overlooked is pest control. I can't remember the exact figures, but in the UK a quick search suggests that about 5 times as many rats are killed by pest controllers as are used in drug research. And how many animals are killed for food? Humans use animals in many ways, drug discovery is one where at the moment we don't have another option.

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26. ARPhilo on August 14, 2009 7:43 AM writes...

How about humane pest control, not killing animals for food, AND not using them for research? The idea that all modern medicine would halt without nonhuman animal testing is a complete farce. I do believe that some scientists actually believe this because it is so ingrained in them throughout education. We are all brainwashed in school. I know I really believed that animal research was helping at some time in my life, before researching things further and seeing the deceit running rampant.

It's time to break free from that though and realize that although some methods can not tell us how something will act in a complex system, nonhuman animal testing does not tell us how things will react in the human system! Sure, sometimes there is a correlation, but pointing out a few successes in a mass of failures (causing suffering and death of humans who had things tested upon them after other animals) does not defend such a primitive practice.

Nonhuman animal research is outdated, inaccurate, inhumane, and most of all- DANGEROUS. Nonhuman animal testing does not predict human response enough for us to depend upon it. The sooner scientists realize this, the sooner we can see more medical progress without the torture of nonhuman animals being involved.

To those of you "proud" to be speciesists, that's sad. It reminds me of many other "proud" -ists in other movements. Go ahead and wear your shirts. It will only make the opposition to you look better.

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27. MarkySparky on August 14, 2009 8:10 AM writes...

#26/7 ARPhilo,

Congratulations, you hit the homerun of animal testing crankery in one post:

1. Positing an conspiracy of educators to promote animal testing, and relating your own Road to Damascus conversion;
2. Demonstrating a complete lack of understanding of the terms "complex system" and "human system";
3. Admitting that in vitro techniques are of limited utility, then demanding perfectly predictive data from 100% of animal tests;
4. Using the word "torture" means you either have never dealt with an IACUC, or your ideological definition makes "torture" so broad as to be meaningless.

Bonus points for the veiled Godwin in that last bit.

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28. Bored on August 14, 2009 8:59 AM writes...

#28 MarkySparky

Ah, but you miss the point. #27 ARPhilo is speaking from the point of view of a privileged frame of reference. Not all of us are so fortunate. Damn! I wish I could always have the moral high ground too...

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29. Alig on August 14, 2009 9:06 AM writes...

Also testing in small groups of humans doesn't always predict what happens in large populations, so we should just skip the small studies and immediately dose thousands of people so we don't wate our time.

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30. Bored on August 14, 2009 9:40 AM writes...

Alig, you don't take it far enough. Let's do away with drug testing altogether. Let's do away with Pharma! Let's do away with any type of health care of any kind. The animals don't have doctors or drugs, why should we? It isn't fair that humans can fight disease when polar bears can't. It is outright speciesist of us!

The alternative is to create medical schools for dinoflagellates. Of course, the dinoflagellates might have to do drug testing on us one day...

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31. MarkySparky on August 14, 2009 9:46 AM writes...

#31 Bored

What about veterinarians, veterinary small molecule drugs, and veterinary biologics?

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32. Sili on August 14, 2009 9:54 AM writes...

Some people seem to focus a bit too much on the negative (I do too all the time).

The important thing isn't to convince the ALF &c nuts of our good faith. It's the public we need to relate to. Move the Overton window if you like.

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33. MTK on August 14, 2009 9:57 AM writes...

Alig,

I was thinking along the same lines.

The animal rights folks argue that testing in animals isn't very accurate and therefore useless, but they're missing the point. All of the testing in vitro, in animals, and clinical is not about absolute assuredness, but rather risk management. At each step of the way, if something is observed that indicates that the compound does not have enough therapeutic value relative to other effects, it is terminated, because the risk to move forward is too large. Which is exactly why tests are first done in small numbers before moving onto larger numbers.

And ARPhilo, "pointing out a few successes in a mass of failures", fails to capture that in all probability nearly all the compounds that failed to get past animal testing would have caused massive suffering in humans had that step been omitted. So I would deem most of those very successful.

Finally, I don't quite understand why the pharma companies are the subject of all the rage? It would seem to me that Pharma should be third on the list. Should not the protests and acts of rage be directed toward the regulatory bodies which require animal studies? Pharma is doing what's required of them. If one wants to eliminate the animal testing, you have to eliminate the requirement of it for IND or NDA submission first. Second in line would be the legal system. PETA or others should ask Congress to pass a law indemnifying researchers from civil litagation arising from adverse effects seen in clinical trials that were missed due to the absence of animal testing. Changing the regulatory and legal landscape would be vastly more effective than the current strategy and tactics. Somehow I don't see it happening, however.

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34. cynical1 on August 14, 2009 10:22 AM writes...

As a vegetarian medicinal chemist, I feel the inclination to put in my two cents. Actually, contrary to the post above, nonhuman testing does tell us something about how it will react in a human system. If 9/10 rats die after two weeks of dosing, it is almost assured to cause gross toxicity in humans as well. If 0/10 rats die, one hopes for the best in humans. It is archaic but not outdated.

I wonder how many animal rights activists have taken prescription or over the counter drugs. If they refuse all drug treatments and would willingly die of an easily cured bacterial infection, then I applaud their convictions. However, anything less would be hypocritical. I don't eat animals because it is completely unnecessary for me to survive. However, I could have easily died from a perforated ulcer if I didn't treat my ulcers (brought on by being a medicinal chemist).

With that said, I also would suggest that the industry has refused basic common sense in early stage research. How many compounds optimized for a 7TM receptor, ion channel, nuclear receptor ect. have never even seen a simple cytotox screen before they go into an in vivo tox study? Anti-infectives aside, how much effort would it be to dose your compounds against an immortalized cell line (CHOs, MT4s, Jurkat, ect.). If I had a scaffold that showed cytotox at 1 or even 10 uM, I'd be looking for a new scaffold. No, it's not perfect but it is easy and a pretty cost effective way to prioritize hits from a screen at a minimum. When I suggested it at my last employer, they looked at me like I had two heads (and they already had the screens up for the antiviral assays). But I have to ask myself how many drug candidates that failed for toxicity reasons would have passed that quick and dirty test.

Just my two cents......

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35. Bored on August 14, 2009 10:29 AM writes...

MarkySparky,

Maybe my comments got lost in sarcasm. I was saying, "Where are the animal doctors who are animals? The drugs invented by animals?"

Your point is excellent, though. Humans, by and large, take pretty good care of animals today. (I thus invite some PETA freak to send us a link to some chicken slaughter house.)

Can you pass the honey mustard?

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36. stuff on August 14, 2009 10:32 AM writes...

I have a poster on the wall here that puts the numbers in context.

In their lifetime each human (I suspect this is for N. America or Europe) is responsible for:
* Eating 600 chickens, 30 sheep, 30 pigs and 5 cows.
* 8 mice or rats killed in public health actions; and
* 3 mice and 1 rat used in experiments.

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37. Pfizerite on August 14, 2009 1:37 PM writes...

I am always in awe of the people who are willing to be the first patient dosed with a new oncology compound and I am always afraid when the first dose is administered in a clinic.

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38. AR on August 14, 2009 5:10 PM writes...

ARPhilo-

To your point that animals are not predictive to humans - that's simply not true. While not 100% for small molecules like the kind Derek and the chemists here discuss most target organs have 80% correlation between animals and humans. The exception is liver - animals are only 50% correlative. That's one reason why liver issues do often come up during clinical trials.

Without animal testing you would see a lot more incidents like this one from the 1930's when 2,4-dinitrophenol was marketed as a diet pill and elicited this famous quote:

'The drug eliminated not only the fat, but also the patient'.


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39. anonymous on August 17, 2009 12:25 AM writes...

I remember when I first started managing preclinical studies for my company, reading about why we test in animals. In modern times, I was told, the use of animals was due to the unethical tests in humans during WW2.

To quote a bit of the wikipedia page on human subject research (http://en.wikipedia.org/wiki/Human_subject_research, yes it's wikipedia, but hey, it's a start):

During the second World War, Nazi human experimentation occurred in Germany...

The result of these proceedings was the Nuremberg Code. It includes the following guidelines, among others, for researchers:

Informed consent is essential.
Research should be based on prior animal work.
The risks should be justified by the anticipated benefits.
Research must be conducted by qualified scientists.
Physical and mental suffering must be avoided.
Research in which death or disabling injury is expected should not be conducted.

Animal ethics committees are also mandatory for any CRO/academic institution doing preclinical animal work.

It isn't as simple as some protestors would believe.

Thanks for an excellent post, Derek. Love your blog. Laughed hard at the "How a real drug industry project meeting goes" post. Have been called cynical for showing the post to my VP of Research. Heh.

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40. Paul on August 17, 2009 4:19 AM writes...

The high failure rate of drug candidated in clinicl trials (and before that in pre-clinical testing) strikes me as an excellent example of the Anna Karenina principle that "Happy families are all alike; every unhappy family is unhappy in its own way.".

Perhaps this would be a good way to explain it to the general public.

AR above notes that "The exception is liver - animals are only 50% correlative. That's one reason why liver issues do often come up during clinical trials" but of course with the liver a big problem is that even humans are often not predictive for other humans, lots of drugs fail due to idiosyncratic hepatotoxicity that isn't picked up until Phase III clinical trials or even post-marketing surveillance when they are detected in a tiny percentage of those taking the drug.

Anyway since we've had the AR folk here I'll also suggest a response, if you are a scientist concerned about the facts not getting out there why not write a piece foe www.speakingofresearch.com or www.animalresearch.info who are always keen to help scientists get the truth out there.

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41. Belen on August 17, 2009 11:15 AM writes...

Maybe the animal rights activists would be kind enough to let us test on them instead?

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42. Jonadab the Unsightly One on August 17, 2009 8:00 PM writes...

Well, in the movies the scientist always takes the drug candidate himself, usually before it's ready, frequently without permission, and almost always with comical results. I suppose you could try that approach...

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43. Jonadab the Unsightly One on August 17, 2009 8:41 PM writes...

The "specieism" argument is fundamentally ridiculous. If you really believed that without reservation, it would be unethical for you to consume plants (much less animals) as food; you would manufacture our own food using solar power. (Let me know how that works out for you.) Other things that would be unethical under such a belief system include wooden furniture, wool blankets and cotton clothing (not to mention plant-based dyes), antibiotics, and the cultivation of plants for ornamental purposes (not just flowers, but grass lawns as well). It's a fundamentally untenable position.

That doesn't mean it's right to treat animals badly and harm them unnecessarily. We should treat them as well as we can. But the idea that all species must be treated equally with humans is simply not viable.

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44. anonymous on August 18, 2009 1:28 AM writes...

Ha, Jonadab's post #42 reminded me of one of our CMC managers tasting a suspension of our oral drug during a formulation trial. Guess you could call that semi-informed, and the first-in-human trial?!

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45. Petros on August 18, 2009 7:05 AM writes...

I remember our research director dabbing his finger in a pot of our development compound to check the taste wasn't awful (it had been very clean in tox by then). He had seen an old project, for a cromoglycate me-too, founder on the awful taste of the drug.

And in the 19th century it was not uncommon for chemists to taste their compounds, the statements are in their papers

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46. unethical ethicist on August 18, 2009 8:53 PM writes...

Nuremberg Code later became the Declaration of Helsinki ... and it's now GCP?

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47. Jose on August 18, 2009 9:42 PM writes...

Sterling-Winthrop had box for "taste" on new compound submission cards until the early 80's.

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48. Anonymous on August 19, 2009 5:49 AM writes...

Have heard many tales of folks tasting promising candidates (particularly inhaled/intranasals as they are difficult to 'mask')!

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49. Nadia on October 19, 2009 5:01 PM writes...

Im a student of Science. Ok, so im not that academically achieved yet, but my future is set in stone. I want to work in Bio-Medical Science. Which means, one day i may too have to swerve to test on animals. Im divided in my views. I believe yes it has proven to be worthwhile thus far. It has gained us knowledge and cures for many diseases. Yet, how would i ever be able to look in the animals eyes and inflict pain and suffering? How can you, as a human being with thoughts and emotions, block all this out, and do your job?

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50. James Howson on October 20, 2009 3:56 AM writes...

I think that animal testing is appaling in every way. these animals die because of sick people like you

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51. BioMan with Dog on October 20, 2009 7:34 AM writes...

It's all well and good. You got married, bought a house, have 2 young healthy kids and 2 dogs, your parents are on vacation and all is perfect. Someone ask you about animal testing, you think on your two dogs (could be Labrador and Husky) and arguments flow all the way, you are ready to fight.
It's all wrong and bad. You got married, bought a house, one of your kids just born has severe birth defects, sedative Thalidomide (check on the web for effects) was not tested on animals. One of your parents is in hospital diagnosed with cancer. Someone ask you about animal testing, you would sacrifice both of your dog just that your kid is healthy and that cure can be found for cancer.
I'm not against or for animal testing.

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52. Omar on October 21, 2009 5:12 AM writes...

Animal testing?

For cosmetics? No thank you.

For fundamental research? No thank you.

For arms testing? No thank you.

Toxicology test for anything else than medicine? No thank you.

For pharmaceutical, psychological and medical purposes etc? Mmmm now it get's interesting. Because then it is supposedly directly saving lifes right? Now we get a lot of arguments like "if you don't condone animal testing then stop taking medicine" (excuse me, what kind of logic is that? Sometimes I do need medicine, but as a consumer I want drugs to be developed without animal testing and I will make sure my voice is heard. But it does not follow suit that until such medicine exists, I am forced to shut up and refuse any medicine).

Lets look at the latter form of animal testing. Is there a lot of animal testing (for instance in psycological tests) where the animals do not suffer? Fortunately yes. So lets disregard all those tests and drill down to the ones where animals are really suffering. Badly. The kind of tests that are often wrongly placed into the "mild category". But lets not start discussion either.

I am sure we can all agree that a lot of experiments are very painful and stressful. I am sure that we can all agree that those "really hard-core animal rights folks" often did find horrible conditions when they unlawfully broke into laboratories, outdated sedatives etc. Lets be honest, there *are* enough reported cases of animal cruelty and neglect. But lets not even go there.

Lets focus on the pain inflicted to animals as a direct cause of the nature of the experimentation. And lets not pretend that *all* of these tests are directly to save lives. Because we don't need another paracetamol. That's all driven by companies' selling figures right?

So we're left with the very painful and stressful experiments that are really performed to save human (and/or animal) lives. Is it worth it? As a Christian and as a person I would say no. (would I accept a life-saving medicine for a dying dear one that has been tested on animals? Of course! But would I wish for that drug to have been developed without in vivo tests? Yes of course!).

But if we're left with these tests, would it not be fair to:

* increase the budget for research for alternatives to animal testing drastically?

* share information globally so the every same experiments aren't conducted unnecessarily more than once?

* lawfully enforce and thoroughly verify that real, proper, trained vetinary care is always applied?

* lawfully enforce and thoroughly verify that real, honest living conditions are provided?

* giving more publicity to what happens in these secretive laboratories, so the general public has more insight in what happens and (hopefully) can apply more pressure to look for disbanding animal testing all together.

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53. Omar on October 22, 2009 9:18 AM writes...

Anonymous wrote "Animal ethics committees are also mandatory for any CRO/academic institution doing preclinical animal work." Yeah and we all know how those committees operate right?

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54. Omar on October 23, 2009 9:44 AM writes...

The writer of this article talks about happy animals yielding better results. My gut-feeling tells me that lab animals are not happy by definitio. For those of you who dismiss gut-feelings and emotions as valuable parameters (which I think is ridiculous) I point to Jeffrey Mogil's studies and relevant following studies. Interesting note (from a cruelty perspective is that for this study In this study, the scientists injected acetic acid into one or both of each pair of same-sex adult mice they were studying, causing them to writhe in pain, and allowed them to observe each other). Talking about CRUELTY.

Furthermore I 'd like to point to the following very interesting paper: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2642860/

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55. Ace Shorty on October 28, 2009 4:26 PM writes...

they may not be like u nd me but, it isn't fair. the "rat or ur child" dnt sit bac nd watch innocent animals get harmed bc of wat we need! volunteer 4 wat is rite! dnt test on animals their bodies dnt react the same way ours do, so eter way we'll ris ka humans life, why risk an ania=mals 2?

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56. cleo on October 30, 2009 6:13 PM writes...

they should stop this from happening the horrer for the poor animals. they shouldn't have to put up with this.I know that childeren would come first out of animals but their like childeren to me .thats what they should be to every one els too.apart of the famliy

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57. Jenna on November 2, 2009 1:25 PM writes...

yes,yes, very good indeed, i totally agree with this, and besides, you would rather have animals tested than risk something bad happening to yourself for instance. thank you, and goodbye.

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58. cjniy on November 6, 2009 10:30 PM writes...

Is there any real hell in this earth? I would say yes, there are hells all over the world. The kings or the masters in these hells are human beings---- maybe that is why human beings were driven out of the Garden of Eden.
According to the report which was worked out by a British animal protection organization, we know the cruel fact that exists in the Wickham Laboratories. There are lots of rabbits locked in the small cases which are absolutely smaller than the rabbits’ bodies. And according to the investigators’ photos, we could see several little white mice had been left in the case on a corner of the lab, they were waiting for the coming of Death but they could not do anything to stop it. All these things are done by human beings, the only race in this world thought they have something names humanity. I believe that the lanyard">http://www.ybuw.com/Lanyards/">lanyard the staff wear are bloody. And according to the photos, we could see the innocent eyes of those rabbits and mice. They do not what will happen to them, they do not know how to escape from these cases, and they might only have the feeling of pain and have to suffer these things in silence.
What are those examines for? Maybe some of them are taken for testing the anti-wrinkle cosmetics that only female human beings would use. Why should they suffer pain for the lady they have not known? And we could imagine that how many blood or life would be devoted for one simple bottle of anti-wrinkle cream. And I think that is not the most horrible lab, or we should call it a hell, in this world. The worst ones are located in China, in these hells they pick up bear galls from bears alive and keep them in the little cases in the dark rooms. And in Japan, people even eat the dolphins alive as what they called sashimi. Face to the earth like this, even God would close his eyes and turn his back to us, I think.

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59. cjniya on November 15, 2009 6:38 PM writes...

Is there any real hell in this earth? I would say yes, there are hells all over the world. The kings or the masters in these hells are human beings---- maybe that is why human beings were driven out of the Garden of Eden.
According to the report which was worked out by a British animal protection organization, we know the cruel fact that exists in the Wickham Laboratories. There are lots of rabbits locked in the small cases which are absolutely smaller than the rabbits’ bodies. And according to the investigators’ photos, we could see several little white mice had been left in the case on a corner of the lab, they were waiting for the coming of Death but they could not do anything to stop it. All these things are done by human beings, the only race in this world thought they have something names humanity. I believe that even the wristbands the staff use for party are bloody. And according to the photos, we could see the innocent eyes of those rabbits and mice. They do not what will happen to them, they do not know how to escape from these cases, and they might only have the feeling of pain and have to suffer these things in silence.
What are those examines for? Maybe some of them are taken for testing the anti-wrinkle cosmetics that only female human beings would use. Why should they suffer pain for the lady they have not known? And we could imagine that how many blood or life would be devoted for one simple bottle of anti-wrinkle cream. And I think that is not the most horrible lab, or we should call it a hell, in this world. The worst ones are located in China, in these hells they pick up bear galls from bears alive and keep them in the little cases in the dark rooms. And in Japan, people even eat the dolphins alive as what they called sashimi. Face to the earth like this, even God would close his eyes and turn his back to us, I think.

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60. Omar on November 17, 2009 11:32 AM writes...

Although I fully agree with the last 5 posts, I don't think scientists or graduates will answer to this. They just don't have the empathy for 'their animals' so I would suggest to leave the emotion out of your posts as much as possible and try to only engage in a very rational discussion. Only posts full of ranting against animal experimentation (which, again, I wholeheartedly agree with) will not provoke any reply. And lets not involve the (indeed horrible) bear farms in China or any other horrible animal abuse.

Scientists, affiliates, students, I look forward to an in-depth reply to my posts here.

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61. casyah on January 14, 2010 6:27 PM writes...

U GUYS ARE FUCKING ASSHOLES.....U CAN FIGURE A NEW WAY TO TEST PRODUCTS WITH OUT HURTING ANIMALS.......WHO CAN LOOK INTO THE ANIMALS EYES AND STILL TEST ON THEM. SO STOP FUCKING TRYING TO ACT ALL INNOCENT CUZ U GUYS DONT GIVE A SHIT.....FUCK U AND ONE DAY U WILL HEAR FROM ME Again but in person......and there is no accuse for testing on innocent animals how would u like to be tortued like that?

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62. hiiiiya on January 24, 2010 1:51 PM writes...

to be honest you lot are sick, if that was you, a member of your family, your children or whatever would you sacrafice them to find out new things?. didnt think so, i can't stop it as much as would love to. If you want to do any sort of testing how about you try sacrificing a member of your family, friends or work collegues and leave the animals to live their life. We are the same as them

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63. MTK YOU MUPPET on January 24, 2010 1:56 PM writes...

MTK,

in that respect you justifying "these people" you yourself are refering to animal rights people to be of a different species to you. so in reference to racism you are still singling out a group.

Sort it out fella

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64. mysterious on February 22, 2010 1:58 PM writes...

WHY R U ALL SUCH GEEKS! JUST TEST ON THE BLOODY ANIMALS AND STOP BEING SOOO BORING!!! GET A LIFE!!! U ONLY LIVE ONCE 4 GOD SAKE!!!

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65. sparkle candy on February 22, 2010 2:05 PM writes...

I totally agree with mysterious and think they are the only person to understand life...live fast die young!!! rock on!

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66. jay on March 9, 2010 8:14 AM writes...

animal testing is horrible and should asap! why do they do this when animals are so diff, from us!

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67. andy on April 25, 2010 2:29 PM writes...

I personally believe for it to be OK to test drugs on healthy people and animals. Drugs need to be tested in order for people to know if it is safe or not. Without doing so, many people will die because they never got the proper treatment for there illness. You need to test drugs on healthy people and animals though, because if you tested on sick humans or animals, you might not be able to tell how the drug affects them. I mean this as in if they are having diarrhea or vomiting you won't no if it is because of the drugs or their own natural sickness. Also when you test drugs on healthy beings, they are less likely to get sick and can be saved from any harm done to them. If already ill people or animals get more sick they might run the risk of death. I say it's OK to test drugs on animals though because they have similar bodily functions as people do and not to offend any body,but it is a less risky matter.

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68. Mrs. Brown on May 31, 2010 12:38 PM writes...

Why yes, let's go back to the pre-animal testing days of the 20s and 30s where not just deadly medicines like a sulfa preparation dissolved in diethylene glycol killed hundreds of people, but cosmetics were deadly as well! I'm sure the women blinded by Lash Lure dye and the women killed by Koremlu depilatory cream were happy to die in pain because no testing on animals was done prior to marketing.

That's not even to mention that pre-FDA there were no laws against promoting and selling ineffective and dangerous substances and procedures. John R. Brinkley "The Goat Gland King" made millions transplanting the testicles of young goats into the scrotums of men anxious about their performance. This went on for decades despite a large proportion of his patients dying of infection due to implanted foreign bodies. "Cancer cures" of apple cider vinegar and salt peter sold by the gallon, over the counter preperations containing large quantities of opium and cocaine, dinitrophenol the diet drug that was very effective until you dropped dead of it.

I'm happy I live in a time where the medications I need are not only tested for toxicity, but efficacy as well. Having taken an animal science class with a unit on handling lab animals, and visiting a university animal testing facility, I'm also satisfied with the treatment of test animals covered by AAALAC and believe that coverage needs to be extended to all species. Most problems I've seen come not from researchers being callous but from not having staff familiar with the proper care of non rodent species, particularly reptiles and amphibians.

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69. Kayla on June 1, 2010 12:28 PM writes...

SO when you say you guys don't have alternatives i think your wrong Like a human you can't replace a animal !!!! id rather see you test on yourself and see how it is!!!!!

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70. Rob@ cabin plans on November 17, 2010 4:53 AM writes...

I think your point is very balanced, if we have other alternative or ways not involving animal testing that would be great. This maybe horrible practice but we have to understand that to save lives, sacrifices are needed while there are no other ways yet.

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71. Anonymous on January 1, 2011 10:48 PM writes...

what are you talking about?????i dont understand one word.english man english. ohh and hey next time u post u might want to REASRCH i think that will help aalllooott

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72. Robin Bush on January 6, 2011 5:10 PM w