Human-Based Scientific Research


Anytime human-based research is mentioned, those with a vested interest in animal-based research immediately accuse me of being a Nazi and or wanting to use prisoners for research. While this polemic may work for some who are not critical thinkers, most people ignore the accuser and are at least willing to listen to the facts. Here are the facts.

Two things are more or less completely accepted by the pharmaceutical industry (the industry that actually knows whether animals are predictive because their animal-based products are taken by humans). 1. Animal models are not predictive for humans. 2. Only human-based research and testing will predict human response.

If you doubt that the pharmaceutical industry and scientists accept the fact that animal models are not predictive, consider the following.

On January 12, 2006, then U.S. Secretary of Health and Human Services Mike Leavitt said:

Currently, 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 animal studies. (1)

Björquist et al. in Drug Discovery World 2007:

Furthermore, the compound attrition rate is negatively affected by the inability to predict toxicity and efficacy in humans. These shortcomings are in turn caused by the use of experimental pre-clinical [animal] model systems that have a limited human clinical relevance . . . (2)

Kola and Landis wrote in Nature Reviews Drug Discovery 2004:

The major causes of attrition in the clinic in 2000 were lack of efficacy (accounting for approximately 30% of failures) and safety (toxicology and clinical safety accounting for a further approximately 30%). The lack of efficacy might be contributing more significantly to therapeutic areas in which animal models of efficacy are notoriously unpredictive. (3)

The executive director for cancer research at Merck Research Laboratory 1997:

The fundamental problem in drug discovery for cancer is that the [animal] model systems are not predictive at all. (4)

Littman and Williams of Pfizer 2005:

For the large number of compounds with unprecedented mechanisms of action entering Phase II there are two reasons for failure due to lack of efficacy. These are inadequate pharmacology (not rigorously testing the drug target) and the lack of predictability of animal models, particularly in some therapeutic areas such as oncology and the neurosciences. (5)

Nature Biotechnology 2010: “The low predictive value of mouse cancer models for human disease is a major challenge for cancer research” (6). Usha Sankar in The Scientist 2005:

Traditionally, compounds [new drugs] are tested in two animal species – typically, the rat and the dog. But the process is far from ideal. Animal studies can be time-consuming, require large quantities of product, and still fail to predict a safety problem that can ultimately halt development . . . Rats and humans are 90% identical at the genetic level, notes Howard Jacob, cofounder of Wauwatosa, Wisconsin-based PhysioGenix. However, the majority of the drugs shown to be safe in animals end up failing in clinical trials. "There is only 10% predictive power, since 90% of drugs fail in the human trials" in the traditional toxicology tests involving rats, says Jacob. (7)

Jonas et al. in Ann N Y Acad Sci 2001: “Agents claimed to be neuroprotective in animal stroke models have all failed in human trials” (8). Chabner and Roberts 2005: “Fewer than 10% of new drugs entering clinical trials in the period from 1970 to 1990 achieved FDA approval for marketing, and animal models seemed unreliable in predicting clinical success . . .” (9). Spedding et al writing in Nature Reviews Drug Discovery 2005:

Animal models often cannot be transposed to Phase I and Phase II clinical testing, and Phase I/II clinical testing is often not transposable to Phase III trials and the general population. (10)

An editorial in Nature Reviews Drug Discovery 2005:

Clearly, one part of the problem [of drug research] is poorly predictive animal models, particularly for some disease areas and drug classes with a novel mechanism of action, a topic we continue to cover in our ongoing 'Model Organisms' series. But arguably the best 'models' for drug discovery are human subjects and as the need to have proof of concept or mechanism for a drug before moving on to larger, more costly clinical trials has never been greater, more big-pharma companies are now embarking on programmes in experimental or translational medicine. (11)

The above is not a recent epiphany on the part of scientists. Of 22 drugs tested on animals and shown to be therapeutic in spinal cord injury by 1988, none were effective in humans (13). Heywood in 1981:

In a survey of the toxicological profiles of 50 compounds in rodent and non-rodent species, sensitive criteria of toxicity were found to be the simple characteristics, such as clinical observation of the living animal, growth and organ weight analysis, liver and kidney function tests and histological examination of selected tissues. There was poor correlation of target organ toxicity across the species . . . It is more relevant to ask how often the same target systems can be identified for the rodent and non-rodent species. The best correlations were never greater than 20%, even when considering hepatotoxicity . . . It must be accepted that simple extrapolation across species is unrealistic. (12)

If you doubt that this lack of predictability is a problem consider the following.

More than 500,000 outpatient children annually suffer adverse side effects from commonly prescribed medications. Children under the age of 5 are often the ones affected (14). Approximately the same number of children who are already in the hospital suffer adverse effects. Approximately 700,000 outpatients must visit the emergency room each year due to adverse drug reactions (15). 15% of hospital admissions are caused by adverse drug reactions (ADRs). ADRs fourth leading cause of death. 6.7% hospitalized patients suffer severe ADRs.

From 1976 to 1985, 209 new drugs were approved for use in the United States (US) after extensive animal testing. Of these 209, 198 were followed for side effects and effectiveness by the Food and Drug Administration (FDA). One hundred and two of the 198 new medications or 52% were either withdrawn or relabelled secondary to severe unpredicted side effects (16).

Legal drugs kill approximately 100,000/yr; more than all illegal drugs combined. This costs society over $136 billion in health care expenses. Furthermore, most drugs are effective in only 30–60% of patients. (17) 51% of drugs released have label changes because of major safety issues discovered after marketing (16). 20% of drugs get new black box warnings after marketing (18). 3% to 4% of drugs are ultimately withdrawn for safety reasons (19).

(Please do not consider the above a jab at the pharmaceutical industry. They know all this and are working hard on developing better testing methods that will make their products safer. The advent of the pharmaceutical age in the early 1900s revolutionized the practice of medicine and society is better off because of companies that make medications.)

Could involving humans in the drug testing and development process solve the above problems? Littman and Williams of Pfizer writing about using humans as models for other humans in Nature Reviews Drug Discovery 2005:

Humans are the ultimate ‘model’ because of the uncertain validity and efficacy of novel targets and drug candidates that emerge from genomics, combinatorial chemistry and highthroughput screening and the use of poorly predictive preclinical models . . . In the new paradigm, studies in humans increase confidence in the relevance of novel drug targets and largely replace the animal efficacy models that are often poorly predictive of the efficacy of novel agents with unprecedented mechanisms of action . . . (5)

In a 1996 edition of the journal Trends in Neurosciences:

For several neuropsychiatric disorders there is a lack of generally accepted animal models . . . For example, the lack of an effect in traditional behavioral pharmacology in animals might exclude the prospect of a molecule suitable for the treatment of subjectively reported syndromes, such as anxiety or thought disorders, in the more complex human brain. There is an increasing awareness that more efficient and sensitive strategies must be applied in the search for useful medicines. One such strategy is to find methods to test more molecules in early exploratory studies in humans. (20)

Humans are already, and will continue to be, very involved in testing new drugs. According to New Scientist: “Fifty million people around the world are guinea pigs in clinical trials testing experimental drugs right now (21).” Most participants do so because of the money they make.

One way humans are safely taking part in testing new drugs is through a revolutionary new technology called microdosing where very small doses of a drug are given directly to humans. Lappin and Garner in Nature Reviews Drug Discovery 2003:

A new method of obtaining human metabolism data known as microdosing has been developed which will permit smarter candidate selection by taking investigational drugs into humans earlier. Microdosing depends on the availability of two ultrasensitive ‘big-physics’ techniques: positron emission tomography (PET) can provide pharmacodynamic information, whereas accelerator mass spectrometry (AMS) provides pharmacokinetic information. Microdosing allows safer human studies as well as reducing the use of animals in preclinical toxicology. (22)

Of course, intact humans are not the only method of human-based research. Human cells are available and should be used instead of cells from animals. Human cells can be obtained at surgery or even from a trip to the physician’s office. DNA from human cells can be obtained by swabbing the inside of a person’s cheek. Biopsies are also a good source of obtaining specific types of cells. Referring to the results when using human cells, Palfreyman, Charles and Blander state: “they are clearly superior to those obtained from animals” (23).

Human tissue is being used and will continue to be used even more in testing drugs. DNA chips are the future of medicine. Service writing in Science:

DNA chips A 2-3 cm wide silicon or glass chip impregnated with thousand of strands of DNA can be used to see if a new potential drug triggers a gene to act or stops it from acting. The DNA chip also allows scientists to see how the entire cell will respond to the drug simultaneously. As we understand more of how genes are involved in disease we can test potential drugs to see what effect they have on the DNA that comprises the gene. Genetic-medicine is one of the most promising fields in medicine today. (24)

There are many other ways humans are being ethically used in research. As I mentioned in my last blog, autopsies are a very good source of studying humans and the diseases that affect us. If you want me to go into more detail about any of this, email me and let me know.

The point of all of the above is simply that ethical research involving humans, populations of humans, computer models based on humans, and human tissues is taking place every day in the US and around the world. There is nothing scary about any of this unless using animals in labs is paying your mortgage.

Furthermore, it is a good thing that ethical human-based research is so prevalent. Lawrence Altman, MD medical writer for the New York Times in his book Who Goes First: The Story of Self-Experimentation in Medicine:

This deficiency [of experimentation on humans] has helped foster many misconceptions and myths about the way research is carried out and has led many people to the mistaken impression that all experiments can be - and are – done on animals. Ultimately, however, humans must become test subjects, and the leap from experimenting on animals to experimenting on humans is always a huge one . . . Significant advances were made more often in the twentieth century than in all of history, and underlying these advances is a cardinal fact: they were achieved only through experiments on humans. This uncomfortable truth makes many people squeamish . . . If those goals [curing AIDS, cancer and other diseases] are to be realized, human experimentation will continue to be mandatory since medical progress hinges on learning how humans respond to cutting-edge therapies . . . More people will come to recognize that ultimately the right animal in experiments designed to advance our knowledge of human diseases must be human. And they will realize the obvious fact that someone must be the first volunteer. p10, ix, and 316

(If all this science talk is a little too much for you but you are nonetheless interested in the subject, please try reading FAQs About the Use of Animals in Science: A handbook for the scientifically perplexed.)


1. FDA. (FDA, 2006), vol. 2010, pp. FDA News Release.

2. P. Björquist, P. Sartipy, Drug Discovery World, 17 (2007).

3. I. Kola, J. Landis, Nat Rev Drug Discov3, 711 (Aug, 2004).

4. T. Gura, Science278, 1041 (Nov 7, 1997).

5. B. H. Littman, S. A. Williams, Nat Rev Drug Discov4, 631 (Aug, 2005).

6. M.E., Nature Biotechnology28, vii (2010).

7. U. Sankar, The Scientist19, 32 (August 1, 2005).

8. S. Jonas, V. Aiyagari, D. Vieira, M. Figueroa, Ann N Y Acad Sci939, 257 (Jun, 2001).

9. B. A. Chabner, T. G. Roberts, Jr., Nat Rev Cancer5, 65 (Jan, 2005).

10. M. Spedding, T. Jay, J. Costa e Silva, L. Perret, Nat Rev Drug Discov4, 467 (Jun, 2005).

11. Editorial, Nat Rev Drug Discov4, 613 (Aug, 2005).

12. R. Heywood, Toxicol Lett8, 349 (Aug, 1981).

13. American Paraplegia Society, J Am Paraplegia Soc11, 23 (Jul-Oct, 1988).

14. F. T. Bourgeois, K. D. Mandl, C. Valim, M. W. Shannon, Pediatrics124, e744 (Oct, 2009).

15. D. S. Budnitz et al., JAMA296, 1858 (Oct 18, 2006).

16. General Accounting Office., FDA, Ed. (GAO, Washington DC, 1990).

17.  J. Lazarou, B. H. Pomeranz, P. N. Corey, JAMA279, 1200 (Apr 15, 1998).

18. K. E. Lasser et al., JAMA287, 2215 (May 1, 2002).

19. O. M. Bakke, M. Manocchia, F. de Abajo, K. I. Kaitin, L. Lasagna, Clin Pharmacol Ther58, 108 (Jul, 1995).

20. L. Farde, Trends Neurosci19, 211 (Jun, 1996).

21. P. Shetty, New Scientist, 49 (July 11, 2009).

22. G. Lappin, R. C. Garner, Nat Rev Drug Discov2, 233 (Mar, 2003).

23. M. G. Palfreyman, V. Charles, J. Blander, Drug Discovery WorldFall, 33 (2002).

24. R. F. Service, Science282, 396 (Oct 16, 1998).


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