Prof. Garner told Outsourcing-Pharma.com that big pharma tend to criticise microdosing studies - also know as Phase 0 trials - but it is not based on any practical data, but only on 'gut feel'.
"We are dealing with a very conservative industry and this scepticism will last until we have more data," he said.
"We could debate this back and forth but the only solution is to conduct more studies."
Garner was reacting to an earlier story published in BioPharma-Reporter.com which reported on a panel discussion held during the BIO conference in Boston last month, where industry players including pharma companies, government and medical experts debated the pros and cons of integrating Phase 0 studies into drug development strategies.
The concept of a Phase 0 study is that it is conducted as an interim step between preclinical and Phase I studies, where a small number (up to seven) of human volunteers take doses of experimental new drugs that are just 1/100 of therapeutic dose so there is no risk of toxicity.
R&D costs to develop biopharmaceuticals can be up to $1.2bn (€0.9bn), according to the latest data from the Tufts Centre, and only three out of 10 biologic drug candidates that start clinical trials make it to market.
Added to that is the high attrition rate early in the development, as one in three drugs fail in Phase I clinical testing despite extensive preclinical screening of potential candidates.
Supporters of Phase 0 studies claim they can identify compounds likely to fail earlier, or derisking drugs, preventing wasted investment of time and resources.
A proportion of these failures can be attributed to poor pharmacokinetic (PK) data leading to potential efficacy or safety issues in humans, and it these weaknesses that microdosing is designed to pick up.
Microdosing reduces costs because the microgram amounts of compounds that are required do not need to be scaled up to manufacturing levels. In addition, it means that fewer animal studies are needed to support microdosing studies compared to Phase I trials so there are ethical as well as cost advantages, which makes animal welfare groups really keen on the adoption of the technique, said Garner.
Microdosing uses accelerator mass spectroscopy (AMS) to count radioactive carbon atoms (14C) in blood, urine and or faecal samples from volunteers who have taken radiolabelled doses of test compounds.
Xceleron pioneered the concept of microdosing as the UK-based company did the first study back in 1999, said Garner.
Since then, he said, his company has examined 40 different molecules and had Phase I data for 11 of them.
"We found that 90 per cent of them showed a correlation between microdose PK and pharmacologic PK properties," he said.
The data for five of these 11 molecules was published last September in Clinical Pharmacology and Therapeutics and showed positive results for three of them, and debating data for one drug.
The Consortium for Resourcing and Evaluating AMS Microdosing (CREAM) trial, in which Garner was involved, was performed to compare the PK of warfarin, ZK253 (Schering), diazepam, midazolam, and erythromycin - when administered at a microdose or pharmacologic dose.
Each compound was chosen to represent a situation in which prediction of pharmacokinetics from either animal or in vitro studies (or both) was, or is likely to be problematic.
Good correlation between microdose and therapeutic dose PK was found for diazepam, midazolam, and development compound ZK253, the study found.
The oral microdose of erythromycin failed to provide correlative data.
The issue, Garner said, is that the results for warfarin have been debated over and over since then. According to the CREAM research, clearance was reasonably well predicted but scientists observed discrepancy in distribution, which they attributed to high-affinity, low-capacity tissued binding.
These specific results were seen by industry as a failure and therefore, some concluded that microdosing was useful for only three drugs out of five (60 per cent) while Garner and his team argue that the technique has the potential to help in early drug candidate selection in 80 per cent of the cases.
"It is strange that pharma companies accept to make decisions based on animal data, where the correlation with therapeutic data is highly variable - correlation between PK in rats and PK in humans is between 60 and 70 per cent - but find it difficult to accept data based on human testing. It clearly shows the conservative nature of the industry," said Garner.
"A Phase I trial can cost anything from $5m to $10m whereas a microdosing study usually costs around $500,000," said Garner.
"Obviously, it would be ideal to have 100 per cent correlation but the results we have so far are sufficient to 'derisk' drug candidates before sending them to the clinic. The best model for man is man."
He added that after discussing with many pharmacokinetics experts, he and his team concluded that "when we have data for 20 molecules studied at microdoses and the data correlates with pharmacologic doses, it will be enough to validate the technology".
So far, Xceleron has been working exclusively with small molecules but doesn't exclude the possibility to use the technique with biologics in the future.
"We could soon see instances of phase 0 studies for monoclonal antibodies," said Garner.
Xceleron is currently leading a European project launched last year which aims at bridging the gap between the laboratory and the clinic.
The European Microdose AMS Partnership Programme (EUMAPP) is a 30-month programme in which the EU has injected €4m in order to boost Europe's expertise in microdosing and its application of AMS to selecting new drug candidates, by demonstrating the reliability demonstrating the reliability of the microdosing approach for predicting drugs' PK when used at pharmacological doses.
Seven different biopharmaceuticals are being tested and so far two out of two drugs have shown linearity between their microdose and pharmacological PK data.
According to Garner, Europe is leading the way on microdosing. While the US Food and Drug Administration (FDA) published it guidance on microdosing studies in January last year, which it regulates under the banner of an "Exploratory IND" (Investigational New Drug) application, the European regulator, the EMEA, had already published its own document in 2003.
