March 14, 2006 | How did Speedel, a small Swiss biopharma company, shave off a third of the development timeline and budget for a renin inhibitor for heart disease? How did it confidently pick the best of three compounds to put into clinical trials? One word: microdosing.
Now microdosing has new federal backing. Last month, in January, three years after a similar blessing at the EMEA, the FDA published a final guidance on exploratory investigational new drug (IND) applications. A catchier term is "Phase 0." The FDA defines one such tool as "microdose studies," or human trials in perhaps six patients who receive no more than 100 micrograms and less than one percent of a standard dose of a drug under investigation. Based on the strength of microdosing data, regulators are will allow radically shortened preclinical programs in some cases.
The FDA's David Jacobson-Kram, associate director of pharmacology and toxicology in the Office of New Drugs, says that the agency hopes to encourage the issue of exploratory INDs and microdosages. "This is a tool they can use very early in development, in the lead selection phase," Jacobson-Kram says. "We view this as one of the steps on the Critical Path." He says the agency clearly stated back in February, 2005 that industry could begin using such techniques right away. "We have not been inundated" with early IND filings, Jacobson-Kram notes.
That may be because a parallel road, the clinical trial authorization (CTA) track at the EMEA, is a bit more well travelled. For his part, Jacobson-Kram believes microdosing could be useful, but he's circumspect about how widely it will be adopted.
"The real advantage is that you'll be able, with fairly minimal expense and effort, to weed out those compounds that would fail because of bad bioavailability or bad pharmacokinetic properties," he says. "If you talk to people in industry, there is not a uniform consensus about the value of the tool. There are some companies that see a lot of promise. There are some that are quite sceptical."
For its part, the Critical Path may not be the dead end that many in industry presumed. In the next federal budget, President George Bush has proposed the first actual funding for the program. His proposed $10 million outlay is barely enough to fund an FDA think tank for the Critical Path in Arizona. But even a little money is significant at a time when new federal initiatives are rare.
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Microdosing, for its part, is based on techniques first used to date archaeological relics. Drugs or metabolites of drugs can also be tagged with radioactive carbon-14. When the resulting samples are processed by a high-energy particle beam, an accelerator mass spectrometer (AMS), single molecules of analytes can be detected. In the life sciences, the technology was pioneered by John Vogel at the U.S. Dept. of Energy's Lawrence Livermore lab in California, but commercialized abroad.
Brits 1, U.S. 0
Colin Garner, an engineer with academic and corporate credentials, bought an accelerator and founded Xceleron in York, England. For now, it is the world's only Good Laboratory Practice (GLP)-certified facility for AMS. One of Xceleron's early clinical trials, funded by Lilly, Hoffman-LaRoche, Schering and Servier, validated the degree to which AMS techniques would replicate known or unknown pharmacokinetic profiles of larger dosages. Studying Warfarin, Valium and other compounds still under development, Xceleron found the mass-balance curves for microdoses and ordinary doses closely overlap.
Xceleron now has a small U.S. office where Scott Tarrant is VP of business development. He reports additional interest in the weeks since the final FDA guidance on the topic. "We've seen quite a bit more interest in microdosing," says Tarrant. "You can get mass-balance information in a Phase I study instead of conducting a separate study in Phase II." The company offers solutions for both preclinical and clinical work, providing metabolite profiling, absolute bioavailability studies, and human microdosing.
Because of the minute quantity of drug, needless to say, microdose research provides no insight into a compound's efficacy or risk. Rather, the concept is to put a drug into man at doses so small as to present no safety issues-but shed light on traditional ADME-tox questions nonetheless. Ideally, AMS studies show how the human body metabolizes a drug.
Tarrant points out that drug concentrations that are too low or off target typically result in poor efficacy; while concentrations that are too high or on target too long may trigger safety issues. Xceleron can characterize the drug's pharmacokinetic profile long before it would typically be well understood in man. "With AMS, you can do absolute bioavailability studies without having to do the supporting intravenous toxicology studies," notes Tarrant. "The reason is the dose is so low."
For some, the appeal of microdosing rests on eliminating the tediously long and highly expensive research into the pharmacokinetics of a drug in the mouse, rat or dog-only to have entirely new concerns when the drug is tested in humans. But Tarrant notes AMS and microdosing may also help identify which animal models to use.
So-called Phase 0 trials, combining elements of preclinical and clinical work, remain more radical. Even Tarrant thinks it will take a while for the largest companies to adopt the Phase 0 concept. "The Phase 0 trial is the real revolutionary part, " Tarrant says. "It takes a while to change people's paradigms, and more so in Big Pharma than in biotech."
Xceleron is not the only provider of AMS and microdosing. Glaxo is buying two accelerators, one for each side of the Atlantic. And in California, 6-employee Vitalea Science hired Livermore's John Vogel and also reports robust growth. Vitalea co-founder Stephen Dueker, a nutritionist, points out that his field has long dealt with microdosages on a daily basis-microdosages of vitamins, that is.
At his company, Dueker says, a typical microdosing study might cost a few hundred thousand dollars, vs. several times that for a two-year animal project. Like a few others relatively new to drug research, he's convinced the traditional approach to preclinical work is ripe for streamlining. "Animals are very, very poor predictors of human metabolism," Dueker says. "These drugs are not being developed for the veterinary market. They're been developed for us. That's why it's hot and promising. Eventually, all first in human tests are going to be in microdoses."
In Basel, at Speedel, the company views AMS and microdosing as just one relatively ordinary ADME analytic in its arsenal. When it chose Xceleron, it was the only industrial provider of AMS and microdosages. "AMS is seen as a further development in bioanalytics with very impressive sensitivity but not an answer to all questions," says J. Chris Jensen, director of pharmacology. He notes that adding a radioactive label to a drug is not always a trivial technical challenge. But the regulatory hurdles are now no big deal, thanks to EMEA and FDA guidance, and based on existing ADME rules for radioactive tracers.
Jensen says he can only conjecture why the rest of the industry has not adopted microdosing with more enthusiasm. "Many companies were waiting for clear guidelines from both the EMEA and particularly the FDA," he muses. "Some companies prefer higher doses so that efficacy/safety parameters may be studied, which are allowed in the FDA's new exploratory IND guidelines." Jensen adds there may also be cultural forces at play. "Some companies wait for 'major' players such as Glaxo, etc. to start using/establishing the technique. And some dogs-old and young-are always adverse to new tricks."