Despite the fact that some European biotechs have been touting microdosing as the next big thing, sponsors in the U.S. are still not rushing out in great numbers to give the extremely low-dose trials a whirl.

In fact, says the FDA‘s David Jacobson-Kram, associate director of pharmacology and toxicology in the Office of New Drugs, only a few companies have shown interest in the concept since the agency published its final guidance on investigational new drug (IND) applications—including microdosage—17 months ago.

“So far, we’ve only seen a handful trickling in,” he said.

Why? Jacobson-Kram says big pharma doesn’t yet have faith in microdosing, which involves human trials in a very small number of patients who receive no more than 100 micrograms and less than one percent of a standard dose of a drug under investigation.

No Faith

Based on the strength of microdosing data, regulators have agreed to allow greatly shortened preclinical programs in some cases. It’s all part of the FDA’s Critical Path Initiative, the ambitious but unfunded research agenda to help modernize science at the FDA. The European Agency for the Evaluation of Medicinal Products (EMEA) gave microdosing its blessing three years before the FDA did.

Even so, says Jacobson-Kram, pharma companies here in the U.S. worry that microdosing may be a waste of their time, as “small doses may not be extrapolatable.”

Worse, in pharma’s eyes, microdosing has the potential to slow down the time it takes a drug to get to market, though in theory it’s supposed to do the opposite by reducing the amount of animal studies needed.

No Delays, Please

“Here’s the thing,” said Jacobson-Kram, “There’s now a crisis in drug development. More and more is being spent on research and development, and fewer drugs are coming out of the pipeline. There’s a big push to fill the pipeline, so there’s a reluctance to tack on many months to the development phase. Exploratory IND studies, including microdosing, essentially delay product development.”

Another factor complicating the arena, says Jacobson-Kram, is that sponsors aren’t using microdosage the way the FDA had hoped. Specifically, he said companies were expected to use the tool when stymied on which of several different compounds with the same target was most promising. That way, sponsors could test all of those compounds in humans early on, rather than animals, and decide to advance the candidate with the most desirable pharmacokinetics.

“But we’re not seeing it used that way so much,” said Jacobson-Kram. Instead, the agency is seeing the tool used to look closely at, say, compounds that are hard to synthesize, and other specialized issues like that, he added.

My Drug? Fail?

There’s also a bit of an attitude behind the seeming lack of interest.

“Exploratory INDs are designed to weed out the losers, to get rid of the drugs that are going to fail,” Jacobson-Kram says. “No one thinks their drug is going to fail; they think it will be the next blockbuster.”

New Guidance

So microdosing remains the redheaded stepchild of “Phase 0” research for now. But that may soon change. The FDA, says Jacobson-Kram, is about a year away from releasing ICH M3 R1, a revision to the guidance on timing of nonclinical safety studies in relation to clinical trials. The point? “To try and give sponsors more options in terms of very early studies,” says Jacobson-Kram.

“The initial guidance talks about microdose, then repeated-dose trials, and pharmacological exposures,” he explained. “With the revised guidance, we’re trying to fill in the gaps. [One might, for instance,] start out with a single-dose microdose study, then the next step might be a multi-dose microdose study. We’ll make it more of a continuum, a range of options you can choose from, not a one-size-fits-all.”

Paradigm Redux

In the meantime, though, he says a certain camp of sponsors is at least talking of embracing the slower approach to drug development that is inherent in going the exploratory IND route. “In my conversations with pharma folks, they are saying we can expect a big increase in subission of exploratory INDs,” Jacobson-Kram said. “There is resistance to making the time lines more protracted and it’s new, so it’s taking people time to adapt. But they are talking of changing the paradigm back to taking more time [with each drug].”

Still A Baby

The thing to focus on now, says Jacobson-Kram, is that microdosing is still a nascent concept, and a lot could still unfold with regard to the tool.

“We’re still really early in this process. If [microdosing studies] really fulfill their promise, I think people will jump on the bandwagon and there will be buy-in,” he said. “But I think their value still has to be proved. It’s an open question: do they accurately predict pharmacokinetics at pharmacological doses? Right now there are insufficient data to know for sure. The question will only be answered by gathering data. I think this will evolve over the next five years.”

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