Why Do We Use Animals In Toxicological Studies, Instead Of Humans?
JACC Bones Transl Sci. 2019 November; 4(7): 845–854.
Limitations of Animal Studies for Predicting Toxicity in Clinical Trials
Is information technology Time to Rethink Our Electric current Approach?
Received 2019 Oct xiv; Accustomed 2019 Oct 14.
Summary
Brute testing is used in pharmaceutical and industrial research to predict human toxicity, and nevertheless analysis suggests that beast models are poor predictors of drug safety in humans. The cost of creature inquiry is loftier—in dollars, delays in drug approval, and in the loss of potentially beneficial drugs for human apply. Human subjects accept been harmed in the clinical testing of drugs that were accounted rubber past animal studies. Increasingly, investigators are questioning the scientific merit of animal research. This review discusses issues in using animals to predict human toxicity in pharmaceutical evolution. Role one focuses on scientific concerns over the validity of creature enquiry. Part two will discuss alternatives to animal inquiry and their validation and use in production of human pharmaceuticals.
Key Words: animate being research, drug development, toxicity, translational inquiry
Abbreviations and Acronyms: FDA, U.Due south. Nutrient and Drug Assistants; LR, likelihood ratio; NLR, negative likelihood ratio; NPV, negative predictive value; PLR, positive likelihood ratio; PPV, positive predictive value
Graphical abstract
In that location is no dubiousness that the use of animals in science and medicine has significantly benefitted homo beings (Tabular array 1). However, many investigators are increasingly concerned that animal experimentation may be based on a scientifically flawed premise and that it retains its acceptability only because clear alternatives take not been identified. Dramatically rising costs and extremely high failure rates in drug evolution have led many to re-evaluate the value of animal studies. This review focuses on questions regarding the scientific validity of nonhuman animate being models (hereafter referred to but every bit "animal enquiry") in predicting homo toxicity in preclinical pharmaceutical testing.
Table i
Fauna Uses in Science, Medicine, and Research
| Predictive models for human being diseases and their processes |
| Predictive models for testing drugs and other chemicals for man toxicity and efficacy |
| "Spare parts"— eastward.g., pig-derived aortic valve prostheses |
| Bioreactors or factories— east.g., production of monoclonal antibodies |
| Sources of tissue to report physiological principles |
| Educational "material" to educate and train biology and medical students and others |
| Subjects in research to do good other animals |
| Subjects of research to gain basic knowledge for its own sake |
Historical Perspective
In the United States, the use of animals to examination human pharmaceuticals dates to 1937, when a liquid formulation of a sulfa antibiotic dissolved in ethylene glycol resulted in the deaths of 107 adults and children. The incident resulted in passage of the 1938 U.S. Federal Nutrient, Drug, and Cosmetic Act, mandating animal toxicity testing (1,ii). In 1946, linguistic communication was incorporated into the Nuremberg code (three) and after the Helsinki Proclamation (4) requiring homo experiments to be "designed and based on the results of creature experimentation [writer's italics] and a knowledge of the natural history of the disease." The statement was written by Andrew Ivy, a potent proponent of animal inquiry, but was not based on scientific show that such a requirement would improve rubber or efficacy of human drug evolution (3).
Today, the U.Due south. Food and Drug Administration (FDA) by and large requires preclinical testing of any new drug or biological therapeutic "for pharmacologic activeness and acute toxicity in animals" prior to inbound human being clinical trials (5). In certain cases, such every bit emergency treatment for hazardous exposure, the FDA may even corroborate in-homo use based solely on animal testing under "The Brute Efficacy Rule" (6).
Despite the securely rooted supposition that creature models accurately predict man toxicity (vii, 8, 9), fifty-fifty cursory examination of the concordance of creature and human being trials raises concerns. A 2006 review of 76 animal studies, for case, plant that approximately 20% were contradicted in humans and only 37% were ever replicated in humans (ten). A review of 221 brute experiments found agreement in human studies just fifty% of the time—substantially randomly (11). Review of 37 chemicals studied in the U.S. National Toxicology Program concluded that toxicities other than carcinogenesis were non reproducible between rats and mice, between sexes, or compared with historic control animals. Average positive predictive value (PPV) from mouse to rat was 55.3% and 44.8% for long-term and short-term studies, respectively. Combining organ, length of exposure, and sex, PPV between mice and rats hovered around l%, which is no greater than random risk (12). An analysis of 2,366 drugs concluded that "results from tests on animals (specifically rat, mouse and rabbit models) are highly inconsistent predictors of toxic responses in humans, and are little meliorate than what would result merely past gamble—or tossing a coin—in providing a basis to decide whether a compound should proceed to testing in humans" (13). Similar results were found for nonhuman primates and dogs (fourteen). Indeed, we need get no further than the failure rates in drug development to accept serious questions about whether animal testing accurately predicts toxicity in human trials.
About 12% of pharmaceuticals pass preclinical testing to enter clinical trials (15). Of those, only 60% successfully complete phase I trials (16). Overall, approximately 89% of novel drugs fail human clinical trials, with approximately one-half of those failures due to unanticipated human toxicity (Figure 1) (17). If animal tests accurately predict human toxicity, then why are toxicity-related failure rates in human clinical trials then high?
Failures in Translational Enquiry: Preclinical and Clinical Trials
Percentages of drugs that neglect in preclinical trials (due to drug toxicity or failure of efficacy in fauna testing) and in clinical trials (due drug toxicity or failure of efficacy in human testing) are shown in columns ane and 2. The tertiary column demonstrates what would happen if animal and man toxicity were closely correlated and therefore drugs with man toxicity were eliminated at the preclinical testing stage by brute toxicity testing (one-half of all drug failures in clinical trials are due to toxicity issues despite safety in animals). Success rates of clinical trials increase from 11.seven% overall to approximately 56%.
The Price of Wrong Decisions
Two critical "wrong" decisions regarding animate being tests of human being pharmaceuticals are ane) falsely identifying a toxic drug as "safe" and 2) falsely labeling a potentially useful therapeutic amanuensis as toxic.
When a human being-toxic drug is identified equally "safe" past animal testing, the nearly likely effect by far is that the drug will fail in clinical testing, frequently due to unacceptable adverse human being effects, and sometimes significantly harming volunteer research subjects in the process. Drugs that survive clinical trials and reach market approval may still be recalled later due to toxicity identified just after months or years of in-human use. Vioxx (Merck, Kenilworth, New Jersey) was plant after release to significantly increase the risk of cardiovascular morbidity and mortality, costing Merck more than $viii.v billion in legal settlements solitary (18). An estimated 88,000 people suffered eye attacks later on taking Vioxx and 38,000 died (19).
Of 578 discontinued and withdrawn drugs in Europe and the The states, almost one-half were withdrawn or discontinued in post-approval actions due toxicity (20). Van Meer et al. (21) found that of 93 post-marketing serious adverse outcomes, just 19% were identified in preclinical animal studies. In the get-go decade of the 21st century, approximately one-third of FDA-approved drugs were after cited for safety or toxicity issues. or a combination of both, including human cardiovascular toxicity and brain harm, afterwards remaining on the market for a median of 4.2 years (22,23). The well-nigh common toxicity types associated with drug withdrawals in the The states and Europe are hepatic (21%), cardiovascular (sixteen%), hematological (11%), neurological (9%), and carcinogenicity (8%) (Figure 2) (xx).
Toxicity Failures in Pharmaceutical Development
Poly peptide-based biologics (e.g., monoclonal antibodies), fusion proteins, and recombinant proteins now account for nearly development stage and marketed biopharmaceuticals (15). These nowadays a particular challenge in predicting human toxicity, due to their propensity to provoke production of antidrug antibodies. Safety concerns include cross reactivity, potentially exaggerated pharmacology, and tedious recovery from toxicity, among others (15,24)—and immunogenic responses in animals do non predict immunogenicity in humans (15,25, 26, 27).
There are many notable examples of cases in which beast trials did not predict severe man toxicity. Isuprel for treatment of asthma caused over 3,500 deaths in U.k. solitary, despite condom in rats, guinea pigs, dog, and monkeys, all of which had received doses far exceeding those administered in humans (ii,28). Thalidomide acquired devastating phocomelia in an estimated 20,000 to 30,000 infants before it was withdrawn. However, creature tests failed to reveal meaning teratogenicity in 10 strains of rats; 11 breeds of rabbit; 2 breeds of domestic dog; iii strains of hamsters; viii species of primates; and various cats, armadillos, republic of guinea pigs, swine, and ferrets (29). An antibody to care for human autoimmune disease, TGN1412, was given at one/500th the dose constitute safe in animate being testing to 6 human volunteers in a stage I trial (30,31), rendering them all critically sick inside minutes and leaving them all with long-term complications (32, 33, 34). BIA-102474-101, a drug developed for a range of disorders from anxiety to Parkinsonism, caused deep brain hemorrhage and necrosis in all 5 human volunteers during a phase I clinical trial after it was administered in doses that were i/500th of the safe dose for dogs. One volunteer died (35). Fialuridine, for treatment of hepatitis B, acquired the deaths of five volunteers during stage II clinical trials despite being safe in mice, rats, dogs, monkeys, and woodchucks in doses that were hundreds of times college. Ii other volunteers only survived after receiving liver transplants (32).
When animal tests falsely identify a safe chemical every bit "toxic," the nigh sure outcome is abandonment of further evolution. Undoubtedly many potentially benign drugs have failed animal testing and been lost to patients, even though they would have been both safe and effective (36,37). Because a drug that shows toxicity in brute models is unlikely to ever undergo human being testing, the magnitude of this type of "error" is unknown. Still, many highly beneficial drugs would have failed animal testing and would never have been brought to market, except that they were developed before animate being testing was required (38). Examples include penicillin (fatal to guinea pigs) (39), paracetamol (toxic in dogs and cats) (40), and aspirin (embryo toxicity in rats and rhesus monkeys) (41).
Lack of animate being tests has also caused deleterious delays in critical drug approvals. Compassionate human employ of ganciclovir demonstrated efficacy and safe in treating acquired immunodeficiency syndrome–related cytomegalovirus retinitis in more human being patients than would generally be required for a stage I clinical trial, just the FDA refused to license it due to lack of beast studies. Ganciclovir had too been used safely in over 300 patients nether compassionate use to care for cytomegalovirus colitis—more would mostly be required in a phase II clinical trial—but the FDA delayed clinical trials for more than a twelvemonth due to lack of animal studies. The drug was finally canonical after a 4-twelvemonth delay (42).
Time and dollars
Rodent testing in cancer therapeutics adds an estimated 4 to 5 years to drug development and costs $two to $four million. For industrial toxicity testing, information technology takes virtually 10 years and $three 1000000 to complete all required animal studies to annals a unmarried pesticide (43). Compared with the costs of in vitro testing, beast tests range from 1.5× to >30× as expensive (44,45).
No comprehensive reviews of the total overall cost of animal testing in pharmaceutical evolution appear to be. In part, this may exist because fifty-fifty the total number of animals or of such studies is unknown. The 2002 amendments to the Animal Welfare Act exempted mice, rats, fish, and birds used in animal research from required reporting to the U.S. Department of Agriculture (46). These are the iv nigh mutual types of animals used, and they account for >90% of all U.S. animal subjects and 81% of European animal subjects (45,47).
Costs of animal toxicity tests can be estimated from other industries, however, and are eye-opening. According to the Organisation for Economical Development, which determines animal testing guidelines and methodology for government, industry, and contained laboratories in its several dozen member countries, the average cost of a single, ii-generation reproductive brute toxicity study worldwide is €318,295 and for Europe lone is €285,842 (45), or roughly $349,890 and $314,215, respectively.
Contract inquiry organizations account for almost of the animal testing done in the The states and Europe. Statista, a global information portal for market and economic sector statistics, estimates the global markets for animal testing in 2018 at $7.4 billion for drug discovery, $11.2 billion for preclinical development and safe, $58.v billion for clinical development, and $ii.3 billion for primal laboratory testing (48). Keen (49) estimates that annual U.S. biomedical and agricultural research and development investments involving animal enquiry exceed $26 billion.
Reproducibility and Interspecies Reliability of Animal Tests
Reproducibility of animal studies within species, fifty-fifty when carried out nether rigorous protocols, is questionable. Using a database of more than than 800,000 animal toxicity studies performed for 350 chemicals under rigorous guidelines, a reviewer found toxicity was repeatable merely 70% of the fourth dimension in the same species (45). Another reviewer found that results for a single chemical often differed with animal model, strain, dose, and delivery route. About 26% of chemicals demonstrated contradictory results on repeat testing in the same species. Furthermore, discordant results sometimes ranged over 3 orders of magnitude within the same species (50).
PPV, NPV, and LR
Sensitivity reflects how likely a positive test is to detect all subjects with a condition, and specificity reflects how likely a negative test is to exclude all subjects without the condition (Figure iii). PPV reflects how oft a positive test actually identifies a subject with the condition, and the power of the negative predictive value (NPV) of a test reflects the proportion of subjects with negative tests that really do not accept the status. Whereas sensitivity, specificity, PPV, and NPV are ofttimes used to describe the accuracy of tests, they are non sufficient to inform usa how much "value" to attribute to whatever given examination. For case, suppose a positive toxicity test in mice for a group of drugs ever predicts human being toxicity (sensitivity = 100%), just it too indicates human being toxicity when it is not present—in fact the examination results always indicate that the drug is toxic. Such a test would have almost no use in determining human toxicity despite being 100% sensitive. A useful toxicity exam is 1 that also indicates accurately when toxicity in animals is not nowadays in humans or has high specificity. Furthermore, we want to know how ofttimes the test accurately indicates man toxicity, compared with how accurately it indicates human being nontoxicity.
Computing LR
The likelihood that a test showing toxicity in a mouse predicts toxicity in the rat (positive likelihood ratio [PLR]) or that a test showing no toxicity in a mouse predicts nontoxicity in a rat (negative likelihood ratio [NLR]). M+R+ = toxicity nowadays in both mouse and rat; M+R− = toxicity present in mouse but non in rat; Thou−R+ = toxicity not present in mouse, just present in rat; and M−R− = toxicity not nowadays in mouse and likewise not present in rat.
Sensitivity, specificity, PPV, and NPV are all strongly affected by the prevalence of the condition they test for and are therefore of limited value in assessing the reliability of a test when the prevalence of the condition is unknown. Lower prevalence increases the likelihood of fake positive results, and higher prevalence increases the likelihood of false negative results. Once a drug tests positive for toxicity in animals, information technology is rarely tested against humans, and the prevalence of the real status the exam is being used to "detect"—human toxicity—remains unknown.
Nonetheless, the "value" of using a given test to ameliorate the post-test probability of ruling in or ruling out a condition can be calculated using likelihood ratios even if the prevalence of the condition is unknown, so long as the sensitivity and specificity of the test are known. LR are indicators of whether the results of a given test will "add weight" over the pre-examination probabilities (i.eastward., prevalence rate) of the condition in deciding what the probability is that a condition is actually present or absent.
At that place are 2 types of LR: the positive likelihood ratio (PLR) indicates how much more likely it is that a condition exists later on a positive examination result, when compared with its pre-exam probability. The negative likelihood ratio (NLR) indicates how much the probability that a condition exists decreases compared with its pre-test probability, given a negative examination result. The modify in post-test probability from pre-test probability is calculated past multiplying the pre-test probability (prevalence) by the PLR or NLR. If the change in post-test probability from the pre-test probability is minor (i.e., LR, the multiplier, is small), then the test is unlikely to help determine the presence or absenteeism of a condition over but knowing its prevalence. LR of <ane.0 actually indicate a negative shift in post-exam probabilities. In other words, if a PLR is <1.0, and then for whatever field of study that has a positive test result, the probability that they have the condition decreases compared with the pre-exam probability. For an NLR of <one.0, for any subject with a negative exam, the probability that they do not have the condition also decreases compared with the pre-test probability. For an LR of 1.0, there is no change from pre-test probabilities (pre-test probabilities are simply multiplied by 1), and the test also was not useful. For LR >ane.0, the probability of the condition being nowadays increases in the face of a positive examination, and the probability of the condition being absent increases in the presence of a negative test. For LR from i.0 to 10, these changes are relatively small-scale (meaning the exam will not add much), but for LR >ten, the changes increase exponentially and are considered meaning (51, 52, 53, 54).
Using LR to calculate the probability that a test volition improve detection of a condition or ruling it out is complex; information technology requires knowing the sensitivity and specificity of a examination and pre-examination probabilities, conversion of probabilities to odds and back again, and then using a log tabular array (i.eastward., a Fagan'due south nomogram) or log calculator to determine how much a test is likely to better (or subtract) the chances of detecting the condition (53).
LR are increasingly being used to express translatability of animal toxicity testing (52, 53, 54, 55). Bailey et al. (14) establish that the presence of toxicity in a species sometimes added evidentiary weight to the run a risk of toxicity in another, only the reverse was not true: negative toxicity tests in animals did non significantly increase the probability that a toxic exam would also be negative in humans, and a lack of toxicity in any species would not reliably point a likely lack of toxicity in any other species, including comparisons of primate to human toxicity tests (xiv). Furthermore, even in the presence of brute toxicity, LRs were extremely inconsistent and varied considerably for different classes of drugs (thirteen,52). Like findings have been reported in multiple analyses and reviews in other studies (52,54, 55, 56).
A number of studies have reviewed LR of specific drug toxicity tests for which both brute and human data are available. In a review of 2,366 drugs, including data from 3 of the most common animal enquiry species—rat, mouse, and rabbit—PLRs were by and large high (i.e., in that location is a likelihood that positive toxicity tests in animals would show toxicity in humans). But median NLRs were very low—1.12 (rabbit), i.39 (mouse), and 1.82 (rat); in other words, they were of little or no value in excluding man toxicity (13). The investigators too examined canine models and found that PPV and PLR for human toxicity were not correlated with 1 another: NLR were low, indicating that the dog provided little evidentiary weight to ruling out toxicity in humans (52). Afterwards analysis of 3,000 drugs establish that tests inferring no toxicity in whatever 1 species, including nonhuman primates, have no evidentiary weight with regard to toxicity in whatsoever other species (xiv). In a comparison study reported by pharmaceutical companies of 150 drugs associated with adverse events or toxicity in humans (55), LR could not exist determined due to a lack of specificity reporting on the tests. Paglialunga et al. (56) examined translatability of respiratory safety pharmacology studies from animate being models to humans and found that PPV and PLR were so low that animal tests provided little value in predicting human being toxicity.
Growing Scientific Criticism
Equally early every bit 1962, scientists questioned the supposition that brute models reliably predicted human responses. Lichtfield (57) examined 6 drugs studied in animate being models and establish that rats and dogs demonstrated PPVs (for human response) of 0.49 and 0.55, respectively, essentially random hazard. He opined that the differences between species in specific drug responses were so hitting that one could actually use the results of drug toxicity tests alone to identify whether an entity was a rat, rather than a dog or a human, and concluded in that location was no ground for predicting adverse human furnishings for the 6 drugs from beast studies. A 1990 assay of the toxicities of 24 drugs abandoned during human clinical trials demonstrated that 16 had no creature model toxicity correlation (58).
In 1981, the Council on Scientific Affairs of the American Medical Association stated, "The Council's consultants hold that to identify carcinogenicity in brute tests does non per se predict either risk or event in human experience. . . . the Council is concerned nearly the hundred[southward] of millions of dollars that are spent each year (both in the public and individual sectors) for the carcinogenicity testing of chemical substances. The concern is particularly grave in view of the questionable scientific value of the tests when used to predict the man experience" (59).
The 2019 West Coast Regional Safety Pharmacology Society Meeting discussed concerns nearly the lack of concordance between animal and homo safe studies, including lack of canine and man concordance for proarrhythmia risks of new cardiovascular drugs and the failure of animate being research to predict drug-related risks in the human fundamental nervous and respiratory systems (60,61).
Regulatory and research leaders are increasingly taking notice of the issue. In 2006, Michael Levitt, and then U.South. Secretary of Health and Homo Services, stated, "nine out of ten experimental drugs fail in clinical studies because we cannot accurately predict how they will behave in people based on laboratory and animate being studies" (62,63). A landmark review and report by the Institute of Medicine in 2011 concluded that the employ of chimpanzees in biomedical research is unnecessary (64). Although the reasons for information technology are complex, in 2015, the National Institutes of Health announced they would be ending all chimpanzee research (65). Andrew Wheeler, ambassador of the U.Southward. Ecology Protection Bureau, pledged in September 2019 to phase out all toxicity testing in mammals over the next 16 years (66).
Is the Scientific Premise Behind Beast Models Valid?
Many concerns regarding reliability of animal models in predicting human toxicity are not based on the scientific underpinnings of interspecies translation, but rather call out collateral, potentially correctable issues, such as technical competence in executing beast enquiry, the soundness of animal enquiry report design, and publication bias (Table 2) (67, 68, 69, 70, 71). Indeed, Knight (72) could observe no review of animal research studies that rated a bulk of the experiments as having "good" methodological quality. An obvious solution would be correction of these problems to ameliorate translation rates of beast research. Despite widespread efforts to improve the quality of methodology in animal studies, however, studies examining whether such measures consistently ameliorate the reliability of animal models in predicting man toxicity have yet to be published, although a number of studies practice demonstrate continued issues with predicting human efficacy (73).
Table 2
Ordinarily Used Arguments Confronting Animal Inquiry
| Argument | Critique |
|---|---|
| Methodological: Animal models should be abandoned because the scientific methodology of the experiment was poor. | The quality of methodology in an individual experiment cannot exist extrapolated to the question of whether animate being experimentation as a whole is invalid, simply to whether the private experiment is yielding true results. |
| Historical: Historically, medical dependence on fauna modeling is much less robust than we are led to believe. | Historical use of animal modeling is a poor measure out of the validity of current experimentation and methods. To determine whether fauna modeling is reliable in current scientific discipline, we need to use mod scientific knowledge and examine modern methodology to determine whether animal modeling is predictive of human outcomes today. This takes into account information and methods that may or may non have been historically available. |
| Reviews: Review manufactures have determined that certain animal species have non been disquisitional in various medical developments, and therefore animal experimentation should exist abolished. | The invalidity of using certain specific animals does not necessarily rule out animal models every bit a whole. |
| Alternatives: The beingness of alternative models requires u.s. to carelessness animal research. | Whereas alternatives to fauna research exist or are developing in many areas of medical enquiry, in many instances such alternatives do not be. This argument does not address whether continued utilise of animal models is scientifically valid, regardless of alternative methods, and it does not attempt to ascertain whether certain animal models are predictably successful and others are predictably unsuccessful. |
Instead of methodologies and publication bias, an increasing number of investigators propose that the problem may prevarication with the basic premise of creature testing itself (69,74). The biological sciences take increasingly embraced theories regarding complex systems (e.g., anarchy theory and complexity theory) to explain mechanisms in evolution, the biology of cancer, the divergent backdrop of animal species, every bit well as the failures of translation of drug therapeutics from animal species to humans (75,76). Because animals and humans are classic examples of incompletely understood complex systems, some investigators propose that it may simply exist scientifically invalid to assume that toxicity of a substance in any one species can reliably predict toxicity in any other, no matter how stringent animal testing standards are fabricated (69).
Alternatives to Animal Testing
Alternatives to animal testing will be discussed in more than detail in office 2 of this review; they include in vitro tests using prison cell lines, tissue samples, use of culling organisms such equally bacteria, iii-dimensional modeling and bioprinting, in silico tests, organ-on-scrap technologies such as 3-dimensional organoids, computer modeling, and phase 0 in-human being microdosing trials (77, 78, 79, 80, 81, 82). A comprehensive report of the accuracy, LR, and costs of alternative testing methods compared with creature toxicity testing has not been published; even so, at that place is data suggesting that in vitro testing and other methods are significantly faster and less expensive than animal models (42,44). Using homo cells, tissue, or organ models to form the footing of an in vitro test may meliorate accurateness in weeding out drugs with meaning agin man effects; withal, this assumption, too, will require rigorous study.
Researchers will undoubtedly exist challenged sooner rather than later to reduce creature research every bit the result of public advancement efforts. A 2019 spending pecker passed by the U.Due south. House of Representatives includes a directive to the National Institutes of Wellness to advance the replacement of nonhuman primates in inquiry with alternative research models (83).
The FDA states that for the purposes of corrective testing, they believe "that prior to utilise of animals, consideration should be given to the use of scientifically valid alternative methods to whole-animate being testing" (84). The Interagency Analogous Commission on Validation of Alternative Methods and the National Toxicology Programme Interagency Center for the Evaluation of Alternative Toxicological Methods were established in 1997 to coordinate the development, validation, acceptance, and harmonization of culling toxicological test methods throughout the U.Southward. government (85) and take equally a part of their mission the explicit mandate to reduce or eliminate whole fauna testing. The Biennial Progress Written report of the Interagency Coordinating Commission on Validation of Alternative Methods for 2016 to 2017 details actions they have taken, including, amidst others: 1) publication of guidance documents waiving all astute dermal lethality studies for pesticides and describing a process for evaluating; 2) publication of notices reducing the number of hamsters for potency testing of certain vaccines; and 3) publication of a roadmap for integrating predictive toxicology methods into safe and risk assessments by the FDA (86). At this time, the FDA mostly still requires submission of preclinical brute information in investigational new drug applications (5).
Conclusions
Although creature toxicity testing has been the stalwart basis of "ensuring" safety of in-human being clinical testing and apply, examination of the published data raises significant questions about whether it is reliable and should be abandoned or at least significantly concise in favor of other potentially more reliable methods. Savings in time and cost for new therapeutics could exist substantial, if the safety of nonanimal preclinical testing is proven. Increasingly, scientific organizations and authorities regulatory agencies are recognizing that culling methods may replace animal testing and meliorate the flow and safety of new therapeutics to human use.
Footnotes
Dr. Van Norman has received fiscal back up from the Journal of the American College of Cardiology.
The writer attests they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more than information, visit the JACC: Basic to Translational Scienceauthor instructions folio.
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978558/
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