"People treat phases as natural law," says Gombar. "But in fact, they're nowhere in the regs. There are definitions. But nowhere
did anyone ever say, 'You have to do Phase I, then you have to do Phase II.' It was just a convenient categorization. I want
to purge the world of Phase I, II, and III. It's one of my goals in life."
What is wrong with traditional phased development? For one thing, it's inefficient. That's partly because traditional blinded
study design prevents researchers from ignoring signals that might emerge early in the process; partly because the phase structure
works against overlapping research; and partly because the gaps between phases tend to be unstructured and unproductive.
But there are larger problems with traditional phased research. Because completion of each phase becomes a regulatory hurdle,
there's an emphasis on simply getting through the phases. And that means companies don't always learn as much about their
products as they should.
FDA, of course, has been working on the efficiency and effectiveness of clinical trials from its own perspective. During conversations
with the likes of Janet Woodcock and Larry Lesko, from FDA's Center for Drug Evaluation and Research, the Wyeth team heard
some terminology that struck a responsive chord: "At some point in that conversation, they started talking about Learn and
Confirm," remembers Gombar. "We hadn't seen it before, but thought, 'Wow, that's sweet. It's instantly understandable.' It
started to grow roots with us very quickly."
It turned out that the terminology wasn't unique to FDA. It actually came from the work of the late Lewis Sheiner, MD, a professor
at the University of California, San Francisco School of Medicine, who introduced the concept in a 1997 article published
in the journal Clinical Pharmacology & Therapeutics.
The article elegantly breaks drug development into two goals: learning things one needs to know about the drug, and confirming
that knowledge with testing in a representative patient population. But the two goals often fall into conflict, Sheiner argues.
"Learning and confirming are quite distinct activities, implying different goals, different study designs, and different analysis
modes. The understandable focus of commercial drug development on confirmation," Sheiner wrote, "as this immediately precedes
and justifies regulatory approval, has led, in my view, to a parallel intellectual focus that slights learning. The predictable
result...is that clinical drug development is often inefficient and inadequate."
Missing Dose-Response Curve
Inadequate in what? Gombar is quick to point to a vital, elementary set of information that often fails to emerge from clinical
research: The dose-response curve. "I'm an old pharmacologist by training," Gombar says. " In the lab, I would never ever,
ever, if I'm doing a dose-response curve on a new drug, pick three doses and study it. Yet, how are 99 percent of Phase II
studies done? Three doses and a placebo. When you have no idea what dosage you should even be using.
"We're not talking rocket science. I don't want you to do something that no one in the world has never ever done before. I
want to know what the dose-response curve looks like. Before I go to Phase III or what we now call 'confirm,' you damned well
better show me what the dose-response curve looks like."
Sheiner in his article goes beyond the dose-response curve. He talks about the "dose-response surface," a three-dimensional
plot that represents not just averages, but differences in individual patients, their prognoses, and their personal responses
to medications. And part of the power of the Learn and Confirm model is that it focuses the researcher on learning sources
of variability early in development.