Comparison of treatment effects between animal experiments and clinical trials: systematic review

Editor—The Perel et al. study, “Comparison of treatment effects between animal experiments and clinical trials: systematic review,” is narrow in both size and scope.¹ It examines only six examples of one particular aspect of animal research. The authors themselves noted in the conclusion of the original version of this paper published on the University of Birmingham website that their sample size “was far too small to give precise statistical estimates of the extent of concordance” between human and animal studies.²

Unfortunately, small sample size was not the only constraining factor of this study. The authors were also limited by their narrow view of animal research. This paper only examined immediate preclinical testing of new drug therapies, but animal research aids medical science in many more ways. In addition to these tests, animal studies play a role in the initial development of candidate drugs, and the development and testing of medical devices (e.g. pacemakers) and surgical procedures (e.g. heart surgery). Even more vital, animal research informs clinical research by building the foundation of biological knowledge. Basic research that expands our understanding of how life systems function indicates to clinicians not only what direction to pursue but what directions are possible.

Although animal research informs clinical research, its circumstances and experimental goals differ from those of clinical research. Thus their protocols and experimental designs necessarily differ. Animal studies generally seek a mechanism of action for treatment, rather than treatment efficacy. They are usually conducted on defined, genetically homogenous subjects with near perfect compliance, as opposed to the large scale diversity of genetics and behavior of a clinical population. Some clinically necessary procedures, such as double-blinding, serve little purpose in an animal study, since rats are not susceptible to the placebo effect. Furthermore, accepted standards for animal welfare as well as many national and institutional protocols insist that sample sizes of animal studies be small. Despite these differences, the protocol used by Perel et al. to determine that the animal studies were of “poor” quality was based, for the most part, on standards meant for large clinical trials. ¹

The authors also claimed in their ‘Methods’ section that they “were unaware of the results of the animal studies when selecting the six interventions.”¹ However, the first Basic Principle of the World Medical Association Declaration of Helsinki states that clinical research “should be based on adequately performed laboratory and animal experimentation.”³ This means that for any clinical study, one may reasonably assume that animal studies showed a positive result. Otherwise, the clinicians would be ethically remiss for placing humans at risk. By only examining animal studies that advanced to human trials, the authors ignore the many other animal studies that stopped known hazards from being tested in humans.

Animal research may not be a perfect predictor of clinical results, but it is much better than going directly to human trials without any preliminary screening. Just as computer simulations and cell cultures reduce the number of animal studies that are necessary, animal studies hone the list of therapeutic possibilities further to a selection of reasonably safe expectations for clinical research. Will the authors next examine via systematic review the concordance of cell culture studies to clinical trials?

Timothy I. Musch, PhD

Kansas State University

College of Veterinary Medicine

Chair, Animal Care and Experimentation Committee, American Physiological Society

Robert G. Carroll, PhD

East Carolina University

Brody School of Medicine

Armin Just, MD PhD

University of North Carolina at Chapel Hill

Department of Cell & Molecular Physiology

Pascale H. Lane, MD

University of Nebraska Medical Center

Department of Pediatrics

William T. Talman, MD

University of Iowa College of Medicine

Department of Veterans Affairs Medical Center

Chair of the FASEB Animal Issues Committee

References

1. Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, Macleod M, et al. Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ, 2006; doi: 10.1136/bmj.39048.407928.BE (published 15 December 2006) ‹http://www.bmj.com/cgi/rapidpdf/bmj.39048.407928.BEv1›

2. Perel P, Roberts I, Sena E, Wheble P, Sandercock P, Mcleod M, Mignini L et al. Testing treatment on animals: relevance to humans. University of Birmingham Department of Public Health and Epidemiology Website. 2006 ‹http://www.pcpoh.bham.ac.uk/publichealth/nccrm/PDFs%20and%20documents/Publications/JH18_Final_Report_May_2006.pdf›

3. World Medical Association Declaration of Helsinki: Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects. U.S. Food and Drug Administration Website. 1989 ‹http://www.fda.gov/oc/health/helsinki89.html›

Competing interests:
None declared