Diagnostics & Imaging Week International Correspondent
and D&IWs

LONDON — A widespread failure to control bias in animal tests is the cause of the unprecedented attrition rates that are seen when treatments for stroke are progressed into clinical trials, according to an international group of researchers.

Many of the issues raised by this finding apply to testing using animal models of disease in general.

The researchers have accumulated data on 700 drugs that have been tested in animal models of stroke. Of these, about 500 showed positive effects.

But of almost 100 that subsequently advanced into clinical trials, only one, tissue plasminogen activator (tPa), was found to be effective in humans.

Most recently, NXY-059, being developed by AstraZeneca (London), showed no effect in a worldwide Phase III clinical trial in 3,200 patients, despite having improved outcomes by 44% in animal tests.

“So either the animal studies for NXY-059 were misleading, or the clinical trials weren’t sensitive enough, or animal experiments aren’t a good model of human disease,” said Malcolm Macleod, consultant neurologist at Stirling Royal Infirmary (Stirling, Scotland).

Macleod is leading an international research project, Collaborative Approach to Meta-analysis and Review of Animal Data in Experimental Stroke (CAMARDES), which aims to bring improvements in the design, conduct, reporting and use of animal data in the development of stroke drugs.

Speaking at the annual British Association for the Advancement of Science meeting at York University earlier this month, Macleod described how the animal data for NXY-059 was analyzed to assess if research bias had influenced outcome.

It turned out that studies which did not randomize animals said NXY-059 improved outcome by more than 50%, while those that did, estimated the effect at 20%. Similarly, studies which did not conceal treatment allocation from the researcher inducing the stroke said NXY-059 improved outcome by more than 50%; those that did estimated the effect at 25%. And studies that did not blind the assessment of outcome said NXY-059 improved that outcome by 50 percent; those which did estimated the effect at less than 30%.

The researchers have reported similar findings for other putative stroke drugs, but Macleod said the impact of poor study quality was much more pronounced in the case of NXY-059 (which was known also as Cerovive). Curiously, the 3,200 patient trial was at odds with an earlier 1,700 patient Phase III trial, which met its primary endpoint of a reduction of physical disability at 90 days post-treatment. AstraZeneca stopped development of NXY-059 when the results of the second Phase III trial were announced in November 2006.

“Another concern with the data for NXY-059 and for other interventions is that the number of animals used in individual experiments was generally too small to allow a precise estimate of outcome. In the long run this means more animals have to be used as scientists attempt to replicate the imprecise results of other studies,” noted Macleod.

Macleod estimates that over the past 20 years at least 250,000 animals have been used in the preclinical development of potential stroke drugs.

He argues that the CAMARADES findings show there is significant scope for improvements in the design, conduct, analysis and reporting of animal experiments. By minimising bias, such improvements would improve the amount of valid information gained from those animals used.

MSI completes VScan HIV testing

Medical Services International (MSI; Edmonton, Alberta) said it has completed testing with its VScan HIV test kit and the VScan Hepatitis C test kit in Europe. The company said completion of this testing will allow it to apply for European Union approval of both test kits.

MSI said EU approval will allow the company to expand its distribution network initially with 10 distributors in Europe, and it anticipates that with EU approval, it will result in the sale of up to 11 million ($2 million gross) test kits in the first year.

“It is believed based on studies completed that this will be a very active market with rapid growth potential,” MSI said. “Once approval is received, the company expects to also market the kits through an independent Internet site.”

The company’s VScan rapid test kits are single-use, disposable tests for the screening of HIV 1 and 2, hepatitis B and C, tuberculosis, malaria, Dengue fever, West Nile virus, syphilis and prostate cancer.

Biomarkers used to track Alzheimer’s progression

Prana Biotechnology (Melbourne, Australia) said it has completed patient enrollment in its Phase IIa clinical trial of PBT2 in patients with early Alzheimer’s disease.

The Phase IIa trial is a double blind, placebo-controlled study exploring the safety and tolerability of PBT2 and its effects on the mechanism and progression of the disease by investigating biomarkers of Alzheimer’s disease as well as measures of cognition. Prana said it will complete dosing of the last patient by the end of 2007, and is on track to deliver results in the first quarter of 2008.

PBT2 is the firm’s first lead compound to be selected from its drug library of Metal Protein Attenuating Compounds, which have a unique mechanism of action that may be useful against a range of neurodegenerative conditions.