Over the past decade there has been a steady increase in the number of published systematic reviews and many funding bodies, including the UK Medical Research Council, now require a systematic review of the existing clinical trials before they will consider funding a new trial. However, systematic reviews of animal experiments are rare.
About one in every 1000 MEDLINE records about human research is tagged as a meta-analysis compared with one in 10 000 records about animal research

Roberts I, Kwan I, Evans P, Haig S. Does animal experimentation inform human healthcare? Observations from a systematic review of international animal experiments on fluid resuscitation. BMj 2002; 324:474-76

A second important observation from the systematic review of animal experiments by Horn and colleagues' was that the methodological quality of the included animal studies was poor. It seems natural to insist that animal research should be subject to the same rigorous scientific methods used in clinical trials in human beings, yet such a point is sometimes viewed as controversial.

McMahon A. Study control, violators, inclusion criteria and defining explanatory and pragmatic trials. Star Med 2002; 21: 1365-76)

1. Sacred cows & Golden geese, C. Ray Greek, MD and Jean swingle Greek, DVM. Continuum 2000.
2. Specious Science, C. Ray Greek, MD and Jean swingle Greek, DVM. Continuum 2002.
3. Pietro Croce, Vivisection or Science?: An Investigation into Testing Drugs and Safeguarding Health, Zed Books.

The extent to which inadequate concealment of allocation might introduce bias in animal experiments is uncertain. However, it is easy to imagine how bias could arise. For example, weaker animals may be easier to catch than healthy animals, and this could result in systematic differences between the intervention and control groups on baseline prognostic factors.

"The fundamental problem in drug discovery for cancer is that the model systems are not predictive at all." says Alan Oliff, executive director for cancer research at Merck Research Laboratories in West Point, Pennsylvania.

Pharmaceutical companies often test drug candidates in animals carrying transplanted human tumors, a model called a xenograft. But not only have very few of the drugs that showed anticancer activity in xenografts made it into the clinic, a recent study conducted at the National Cancer Institute (NCI) also suggests that the xenograft models miss effective drugs.

Researchers blamed the failures on the fact that the drugs were being tested against mouse, not human, tumors, and beginning in 1975, NCI researchers came up with the xenograft models, in which investigators implant human tumors underneath the skin of mice with faulty immune systems. Because the animals can't reject the foreign tissue, the tumors usually grow unchecked, unless stopped by an effective drug. But the results of xenograft screening turned out to be not much better than those obtained with the original models, mainly because the xenograft tumors don't behave like naturally occurring tumors in humans-they don't spread to other tissues, for example. Thus, drugs tested in the xenografts appeared effective but worked poorly in humans.

"We had basically discovered compounds that were good mouse drugs rather than good human drugs," says Sausville.

The xenograft models may also have missed effective drugs. When Jacqueline Plowman's team at NCI tested 12 anticancer agents currently used in patients against 48 human cancer cell lines transplanted individually into mice, they found that 30 of the tumors did not show a significant response-defined as shrinking by at least 50% to any of the drugs.

So far, the results from these mouse models [transgenic mice] have been mixed, however. One mutant mouse strain, for example, lacks a working APC gene, a tumor suppressor that leads to colon cancer when lost or inactivated. This mouse seems to do well at re-creating the early signs of colon cancer. But in the later stages of the disease, the type of mutations in the tumors begin to diverge from those in human colon cancer, and the disease manifests itself differenrly as well. It spares the liver, for example, unlike the human cancer.
Other new mouse models have fared even worse. Take the one in which the retinoblastoma (RB) tumor-suppressor gene was knocked out. In humans, loss of RB leads to a cancer in the retina of the eye. But when the gene is inactivated in mice, the rodents get pituitary gland tumors. And BRCA1 knock-outs, which are supposed to simulate human breast and ovarian cancer-don’t get tumors at all.

“one might expect that these animals would also mimic human symptoms, not just the genetic mutations,” says molecular biologist Tyler Jacks of the Massachusetts Institute of Technology. “In fact, that is usually the exception, not the rule.”