I thought I’d dedicate an entire post to a certain statistic which has been repeatedly misused and misunderstood by animal rights groups.
92% of drugs that test successfully in animals fail during human trials
You will find animal rights organizations, such as PETA and PCRM, all using this statistic. Often claiming that this shows that “animal research doesn’t work”.
The statistic is from the FDA (Food and Drug Administration), used to illustrate inefficiencies in drug development. However the actual statistic is much broader, it should be:
92% of drugs fail during human trials
Now it is true that they have passed animal testing to get to human (clinical) trials, but it also means that they have passed non-animal pre-clinical tests, such as in vitro. Consider:
92% of drugs that have successfully passed in vitro tests, fail during human trials
Misleading? Yes. So the next obvious question:
Why do drugs fail at the clinical stage?
Drugs fail clinical trials for two reasons – they don’t work well (lacking efficacy) or they are potentially dangerous. Drugs may fail at different stages of clinical trials – so sometimes a relatively rare, but potentially dangerous side effect turns up late into human trials when many thousands of humans are being used (late in clinical stages many more humans than other animals may have tested the drug – as more people/animals are tested, more side effects are discovered); equally some drugs may simply be ineffective in humans, or ineffective in enough humans (no one wants to release a drug that only works in, say, 30% of people – unless that 30% is a particular and selectable demographic e.g. children), this is bound to be the case since animals are not perfect models for humans, just as humans are not perfect models for other humans (thus why some people get adverse drug reactions and not others).
According to the FDA report, which suggests various improvements to the drug development process, the top area where improvements could be made is to improve the animal models (not remove, but use and improve – they also accept the good track record of animals for finding dangerous chemicals in toxicology tests), with the increase in genetically modified animals allowing us to create better animal models, hopefully we will see that 92% statistic drop.
It is worth highlighting that the FDA says many drugs are failing clinical trials at late stages, meaning that problems with drugs are not becoming clear until they are tested in many people – so it is a mystery as to why the animal rights groups try and put the blame solely on the shoulders of animal research.
What about the benefits of animal safety tests?
Well why DO we use animal safety tests? The 92% statistic ignores all the benefits of safety tests, so:
You have 1000 drugs entering animal safety tests
900 of them fail, of which, say, 20 might actually be safe in humans (false positive).
Of the remaining 100, 92 fail human tests
[The above stats are made up for illustration purposes. Approx 90% of drugs fail at the animal testing stage, and false positives aren't (cannot legally or safely be) measured]
Therefore:
90.5% of dangerous drugs have been kept out of clinical trials thanks to animal safety tests**
(However 92% of drugs have still failed clinical trials)
**[[Dangerous Drugs removed by animal safety tests]] / [[Total number of dangerous drugs]] = [[880/972]]
We can see that the lower statistic makes no mention of the benefits of animal safety tests made clear by the top statistic.
It is worth noting that around 90% of drugs are removed at every stage of safety tests, i.e. 90% are removed at non-animal pre-clinical safety tests, 90% at animal stages, and 90% during human clinical trials.
Check back on the website for more AR debunking!
Cheers
Tom
Thanks for publishing this. PETA et al love to use the Big Lie propaganda technique. Unfortunately that means we can expect them to keep repeating these misleading arguments regardless of how often they’re debunked.
Was it Mark Twain that talked about “Lies, damn lies, and statistics?”
“There are many ways of producing ‘irrefutable’ facts in support of any argument, using different kinds of animals: one just has to choose the right one. For example:
“Do we want to show that Amanita phalloides is an excellent edible toadstool? Then we have only to feed it to the rabbit….
“Do we want to discourage people from eating parsley? Let us give it to the parrot which will probably be found lying stone-dead under its perch the next morning.
“Should we wish to rule out penicillin as a therapeutic drug, we have only to give it to the guinea-pig which will be dead in a couple of days….
“If we wish to convince the consumers of tinned food that botulin poison is harmless let us give it to the cat and it will lick its lips. Let us give it instead to the cat’s traditional prey, the mouse, and it will die as if struck by lightning….
“If we need to show that Vitamin C is useless we withhold it from the diet of the most readily available animal: the dog, the rat, the mouse, the hamster…they will continue to thrive because their bodies produce Vitamin C of their own accord. But let us not eliminate it from the diet of guinea-pigs, primates, or humans or they will die of scurvy….
“To sum up, one has only to know how to choose the proper animal species to obtain the desired results… This is a kind of science which one can knead like dough. The trouble comes in believing that with dough one can produce health for human beings.”
(Professor Pietro Croce in VIVISECTION OR SCIENCE – A CHOICE TO MAKE, 1991. From 1952 to 1982 Croce was head of the laboratory of microbiological, pathological anatomy and chemical analysis at the research Hospital L. Sacco of Milan, Italy.)
http://www.pnc.com.au/~cafmr/online/research/drug2a.html
Fortunately animals are not picked at random. Scientists use the most appropriate model – that is the animal which is physiologically the most similar for whatever you’re specifically trying to model. So if you wanted to look at the heart then pigs would be a particularly good model. Cats eyes work in a very similar way to humans eyes.
Since antibiotics will kill the intestinal flora of guinea pigs you’d be unlikely to use them as a test for such drugs.
Ahh yes, the beloved coprophragy of guinea pigs & rabbits.
Okay, so you would choose the animal most similar (within the specific species that are actually practical to test upon). Assuming that this is similar enough to be instructive–can you separate one body system from the others? Another quote:
“There are five basic stages in which a drug has an effect when taken internally. These are: absorption into the bloodstream, distribution to the site of action, mechanism of action, metabolism, and excretion. Considering that people of different sexes, ages, health and genetic make-up may react quite differently; it is obvious that other species often react very differently. Even a minor change, repeated at each stage, can accumulate, resulting in a major change of effect. One of the most important factors is the speed and pattern of metabolism, or the way in which a drug is broken down by the body. (21) Scientific reports show that variation in drug metabolism between species is the rule rather than the exception. (22,23)
“Toxic drug effects not predicted by animal testing may be seen in people if their metabolism is slower, with the potentially dangerous result from longer exposure. The anti-inflammatory drugs phenylbutazone and oxyphenbutazone, which have been responsible for an estimated 10,000 deaths worldwide, (24) takes 72 hours for people to metabolise. However, phenylbutazone is metabolised by rhesus monkeys, dogs, rats and rabbits in eight, six, six, and three hours, respectively. (23) Oxyphenbutazone takes only half an hour for dogs to metabolise. (25)”
21. Robert Sharpe, The Cruel Deception – The Use of Animals in Medical Research, Thorsons Publishing Group, Wellingborough, Northamptonshire, 1988, p. 92.
22. Gerhardt Zbinden, Advances in Pharmacology, 1963, vol. 2, pp. 1-111.
23. R. Levine, Pharmacology: Drug Actions & Reactions, Little, Brown and Co., 1978.
24. Sidney Wolf (director of the Ralph Nader Health Research Group) in Lancet, 11 Feb. 1984, p. 353.
25. T. Koppanyi & M.A. Avery in Clinical Pharmacology & Therapeutics, 1966, vol. 7, pp. 250-270.
In his analysis, Bryan argues that – because drugs exhibit different rates of absorption, metabolism and excretion, no real predictive validity exists for animal models. He notes that oxyphenbutazone, a non-steroidal pain killer, has a much longer 1/2 life (duration of action) in humans than it does in animals, and that this accounts for “an estimated 10,000 deaths worldwide…” First off, Bryan should get his facts right (something he might do by reading articles less than 30 years old). The pyrazole analgesics like oxyphenbutazone have risks for humans – not because they last long – but because they engage in so-called drug-drug interactions (where one drug causes another to be more toxic than it would otherwise be). In other words, if an individual takes oxyphenbutazone alone, it works fine – precisely as the animal model predicted. If one subverts Doctor instructions and takes it along with other drugs, problems arise. This is not an issue with the validity of the predictive value of the animal model; it’s a problem with patient compliance.
But let’s return to his criticism: drug actions cannot be predicted well from animal models. Really? This suggests that animals (unlike humans) should not receive any pain relief when administered analgesics like oxyphenbutazone. Oops… someone should tell that to the many veterinary practitioners who use pyrazole analgesics to great effect! See, it turns out that – since compliance is not a problem in animals being treated by vets, the drug works great! So, actually, drug action is pretty similar in humans and animals.
But let’s look into this further. Perhaps more sophisticated, nervous system effects of drugs won’t correspond so well between rats and humans? Actually, once again, Bryan has a problem. Cocaine, methamphetamine and morphine are drugs that humans readily abuse for their rewarding properties. Offered the opportunity, animals will voluntarily seek and take these drugs, as well. The drugs produce action in the brain that are near identical in rats and humans, hence why the rats abuse the drug, as well. And it’s not just rats… even zebrafish like the way that morphine makes them feel and will seek them out. So actually, animal models can often predict drug action pretty darned well.
What about drugs used to treat schizophrenia? Here, surely the rats will not predict humans. Oops again. Antipsychotic drugs produce remarkably similar behavioral and hormonal changes in rats and humans, and what is more, if you build a mathematical model to account for differences in drug absorption, metabolism and excretion, you can predict near perfectly how a dose of an antipsychotic drug will affect people by studying rats.
Overall, it is clear that one needs only a slightly more sophisticated understanding of pharmacology than Bryan has to offer. Pharmacological studies in rodents have revolutionized the development of drugs for humans. Though they are not perfect, all sorts of ailments, from pain to cancer to mental disorders, are now treated by drugs first predicted by studies in animals. We have a lot to thank the rats for….
You cannot criticize the validity of a source because it was published 30 years ago, unless you cite a newer source which contradicts or disproves it, which you did not. You also make some strawman arguments against Bryan, who is merely pointing out the difficulties in reaching accurate conclusions using animal experimentation, rather than claiming that “no real predictive validity exists for animal models” as you presumed.
Bryan pointed out the differences in drug absorption, metabolism, etc… between (non-human) animals and humans. Under-predicting these parameters for humans would increase the probability of drug-drug interactions you mention; the longer a drug is in your system, the greater the likely hood a patient will take another drug while the previous one lingers.
Perhaps the effort to develop a mathematical model for drug absorption, metabolism, etc… could be used to, oh I don’t know, develop a complete mathematical model of the the drug’s interaction in humans?
Hey Marc, thanks for reminding me of this. I was unable to respond because my comments mysteriously stopped being recieved. Maybe I can post my answer now. ~B
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Watch how “David” takes periodic jabs at my credibility. As for his argument, it is familiar. Big drug companies, just like any major corporation, are notorious for NEVER admitting that they did anything wrong. Drugs hurt people because patients didn’t do what they were supposed to, not because the drugs themselves are unreasonably hazardous.
My point, which David did not truly address, is that animal testing can lead to misleading results which could confuse a researcher about the drug’s effects in humans. These (potentially harmful) effects can only be assessed in hindsight by looking at the drug’s epidemiological results in humans. Thus, animal testing is not helpful, or worse. I’ll leave it up to the reader to decide, though I’ve emphasized a few noteworthy points.
~Bryan
First, a chemistry lesson:
Analgesic: drug that relieves pain without blocking the conduction of nerve impulses or markedly altering the function of the sensory apparatus.
http://www.britannica.com/EBchecked/topic/22403/analgesic#ref=ref213151
Pyrazole: any of a class of organic compounds of the heterocyclic series characterized by a ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions.
http://www.britannica.com/EBchecked/topic/484811/pyrazole#ref=ref97607
Phenylbutazone: a white or light yellow compound, C(19)-H(20)-N(2)-O(2), formerly used as an anti-inflammatory and analgesic drug in the treatment of arthritis, bursitis, and gout.
http://www.answers.com/topic/phenylbutazone
Phenylbutazone diagram:
http://en.wikipedia.org/wiki/File:Phenylbutazone.svg
The [phenylbutazone] half-life in the horse ranges from 3.5-6 hours, and like aspirin is dose-dependent. Therapeutic efficacy however, may last for more than 24 hours however, probably due to the irreversible binding of phenylbutazone to cyclooxygenase.
Other serum half-lives reported for animals are: Cattle ≈ 40 – 55 hrs; Dogs ≈ 2.5 – 6 hrs.; Swine ≈ 2 – 6 hrs.; Rabbits ≈ 3 hrs.
Uses/Indications – One manufacturer lists the following as the indications for phenylbutazone: “For the relief of inflammatory conditions associated with the musculoskeletal system in dogs and horses.” (Package Insert; Butazolidin® — Coopers). It has been used primarily for the treatment of lameness in horses and occasionally as an analgesic/anti-inflammatory, antipyrexic in dogs, cattle, and swine.
Contraindications/Precautions – Because phenylbutazone may mask symptoms of lameness in horses for several days following therapy, it can be used by unethical individuals to disguise lameness for “soundness” exams. States may have different standards regarding the use of phenylbutazone in track animals. Complete elimination of phenylbutazone in horses may take 2 months and it can be detected in the urine for at least 7 days following administration. [Note: this is actually another animal rights issue I discovered. I have included a separate post ("Horse Medicine") with details. ~BG]
Adverse Effects/Warnings – The primary concerns with phenylbutazone therapy in humans include its bone marrow effects (agranulocytosis, aplastic anemia), renal and cardiovascular effects (fluid retention to acute renal failure), and GI effects (dyspepsia to perforated ulcers). Other serious concerns with phenylbutazone include, hypersensitivity reactions, neurologic, dermatologic, and hepatic toxicities.
While *phenylbutazone is apparently a safer drug to use in horses and dogs than in people*, serious adverse reactions can still occur. Toxic effects that have been reported in horses include oral and GI erosions and ulcers, hypoalbuminemia, diarrhea, anorexia, and renal effects (azotemia, renal papillary necrosis). *Unlike humans, it does not appear that phenylbutazone causes much sodium and water retention in horses at usual doses*, but edema has been reported. In dogs however, phenylbutazone may cause sodium and water retention, and diminished renal blood flow. Phenylbutazone-induced blood dyscrasias have also been reported in dogs.
Drug Interactions [Note: This is a lot of very technical information, but it does not suggest that "drug-drug interactions" are the primary danger for humans taking these compounds. ~BG] – Both phenylbutazone and the active metabolite oxyphenbutazone are highly bound to plasma proteins and may displace other highly bound drugs. This mechanism may affect serum levels and duration of actions of phentoin, valproic acid, oral anticoagulants, other antiinflammatory agents, sulfonamides, and the sulfonylurea antidiabetic agents. Phenylbutazone and oxyphenbutazone can induce hepatic microsomal enzymes and increase the metabolism of drugs affected by this system (e.g., digitoxin & phenytoin). Conversely, other microsomal enzyme inducers (e.g., barbiturates, promethazine, rifampin, corticosteroids, or chlorpheniramine, diphenhydramine) may decrease the plasma half-life of phenylbutazone. Phenylbutazone may increase the plasma half-life of penicillin G or lithium. Phenylbutazone administered concurrently with hepatotoxic drugs may increase the chances of hepatotoxicity developing. Phenylbutazone may antagonize the increased renal blood flow effects caused by furosemide. Concurrent use with other NSAIDs may increase the potential for adverse reactions developing, however many clinicians routinely use phenylbutazone concomitantly with flunixin in horses.
http://www.elephantcare.org/Drugs/phenylbu.htm
Phenylbutazone may interact with other medications. Consult with your veterinarian to determine if other drugs your pet is receiving could interact with phenylbutazone. Such drugs include barbiturates, antihistamines and other non-steroidal anti-inflammatories.
A *rare problem* in animals has been a suppression of the bone marrow and the formation of blood cells caused by phenylbutazone. Affected animals may show signs of anemia, such as weakness or lethargy.
http://www.petplace.com/drug-library/phenylbutazone-butazolidin-butatron/page1.aspx
Phenylbutazone became available for use in humans for the treatment of rheumatoid arthritis and gout in 1949. However, it is no longer approved, and thus not marketed, for any human use in the United States. This is because some patients treated with phenylbutazone have experienced severe toxic reactions, and other effective, less toxic drugs are available to treat the same conditions.
*Phenylbutazone is known to induce blood dyscrasias, including aplastic anemia, leukopenia, agranulocytosis, thrombocytopenia and deaths. Hypersensitivity reactions of the serum-sickness type have also been reported. In addition, phenylbutazone is a carcinogen, as determined by the National Toxicology Program.*
For animals, phenylbutazone is currently approved only for oral and injectable use in dogs and horses. Use in horses is *limited to use in horses not intended for food*. There are currently no approved uses of phenylbutazone in food-producing animals.
Investigation by FDA and State regulatory counterparts has found phenylbutazone on farms and identified tissue residues in culled dairy cattle. In addition, USDA’s Food Safety Inspection Service has reported phenylbutazone residues in culled dairy cattle presented for slaughter for human food throughout the U.S. in the past two calendar years. This evidence indicates that the extralabel use of phenylbutazone in female dairy cattle 20 months of age or older will likely result in the presence, at slaughter, of residues that are toxic to humans, including being carcinogenic, at levels that have not been shown to be safe.
http://forum.equisearch.com/forums/p/57354/329508.aspx
Phenylbutazone (Butazolidine) was once widely employed for the treatment of arthritis but reports of aplastic anaemia, an often fatal blood disease caused by damage to the bone marrow, led to the drug’s withdrawal in some countries and to its restriction in others, notably America, France and the UK.(1)
On the basis of animal tests, phenylbutazone had seemed a safe drug with no toxic effects observed in rats even after administration of 5-10 times the dose used for people.(2) In particular, phenylbutazone’s harmful effect on the bone marrow had not been predicted,(3) and one year after marketing, researchers noted that “there have been no published reports of serious effects…on the hemopoietic (blood forming) system…in the experimental animal.”(4) Later research showed that the dangers could be identified by test-tube experiments with human bone marrow cells.(5)
It has been estimated that phenylbutazone and oxyphenbutazone, a closely related drug that also causes aplastic anaemia, have been reponsible for 10,000 deaths worldwide.(6) Oxyphenbutazone (Tanderil) was withdrawn altogether in 1985.
http://www.iaapea.com/101_page.php?id=38 (includes references)
Currie reported on the effects of phenylbutazone to the Second European Rheumatology Congress in 1951, and a year later, he administered the drug by intramuscular injection to 81 patients with rheumatoid arthritis – 77 of which had relief of their symptoms but only 24 showed any sign of improvement(4). Dr Pemberton commented in the `British Medical Journal` in 1954 “Currie`s original view that the drug has an anti-inflammatory effect was supported by early experimental work on animals, but has not been substantiated clinically”(5). Later, Brodie explained “Phenylbutazone is metabolized slowly in [hu]man[s], about 15% per day, but in mice, rabbits, dogs, guinea pigs, and horses, it disappears from the body in a few hours… It is so rapidly metabolized in rats that enormous quantities are needed to induce an anti-inflammatory effect”(6). Clinically, phenylbutazone caused such adverse reactions as agranulocytosis, and asplastic anaemia(7). Figures released by the UK Committee on Safety of Medicines in 1984, revealed that the drug was responsible for 445 deaths in a 20-year period(8).
Oxyphenbutazone was an active metabolite of phenylbutazone(9), and was subjected to animal experiments. Brodie of the American National Heart Institute at the US National Institute of Health has commented “Oxyphenbutazone should have been discarded on the spot, considering its 30 minute half-life in the dog, the half-life in [hu]man[s] is 72 hours, a difference of 150 times”(10). But the drug entered clinical use in 1965(11) and not only did it have no obvious advantage over phenylbutazone, but also had resulted in serious adverse reactions and deaths – so much so that in 1984 the UK Committee on Safety of Medicines advised the government that product licenses for oxyphenbutazone should be revoked, in view of it having caused 131 deaths in a 20-year period(12).
http://www.freewebs.com/scientific_anti_vivisectionism10/arthritis.htm (includes references)
Butazolidin (Phenylbutazone)
This NSAID is commonly used in equine medicine to reduce pain and inflammation, but in humans can produce serious phototoxicity,(11) as well as serious or fatal liver(12) or bone marrow(13) disease. Bone marrow toxicity was demonstrated in human cell cultures after the drug was released and produced more than 10,000 fatal cases of aplastic anemia.(14-16)
http://www.pcrm.org/resch/anexp/dangerous_med.html (includes references)
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* During the 3rd quarter of 2008 the FDA received 24,872 serious adverse drug reaction (ADR) reports identifying 854 different drugs. The cases described 2,778 patient deaths, 1,162 cases of disability & 20,932 cases of other kinds of serious injury in a 3-month period. Bear in mind that the ADRs *reported* to the FDA are estimated at between 1-10% of the total ADRs related to FDA-approved, marketed prescription drugs.
http://www.ismp.org/QuarterWatch/2008Q1.pdf