Thus, many FDA initiatives support strategies to provide more information about a drug early in the development process so
that later trials are more likely to show efficacy and safety. For example, FDA issued a draft guidance on exploratory investigational
new drug (IND) studies in April 2005 encouraging "early into man" Phase 1 trials. Using this approach, sponsors give very
small doses to small patient populations to determine early on if a drug shows any effect.
Model-based drug development is a continuing theme among clinical research statisticians who are developing methods to use
Bayesian statistical models to better predict clinical trial outcomes. This involves developing models of disease as influenced
by a drug to establish the proper dose response needed to show efficacy, explains CDER scientific advisor Donald Stanski.
Researchers can simulate early trials and then obtain feedback from FDA that can help define uncertainties and safety concerns.
Getting the dose right early, Stanski explains, can support decisions to fail a drug early—but with confidence—and thus reduce
Phase III failures.
Robert Temple, director of CDER's office of medical policy, has long been an advocate of clinical trial enrichment approaches
to improve the research process. This involves selecting clinical trial participants who are more likely to respond to a drug,
or less likely to experience safety problems. This approach may indicate safety and efficacy more quickly and efficiently,
although it may result in narrower labeling.
Perhaps the most visible sign of FDA's interest in improving performance in Phase III can be seen in the agency's new ideas
about how to respond to Phase II research.
Traditionally, the agency meets with companies after Phase II is complete to discuss the data and the company's strategies
for moving forward. But by that time, argues Lesko, it is hard to have much impact on Phase III. "It's too late," he says.
"The trial is already designed, the sites are lined up, the dosage forms are made."
To correct the situation, the agency has created a Critical Path initiative to hold informal end-of-Phase IIa meetings—at
which FDA uses disease state computer models, virtual clinical trials, in-house data, and other tools to dig deep into the
question of how companies should proceed. The meetings are voluntary—at least for now; a draft concept paper was issued several
years ago, and a draft guidance is in the works.
Promoting Public–Private Partnerships
Because FDA lacks resources to fund research, the agency seeks to spur examination of Critical Path opportunities through
joint projects with pharma companies and research organizations, either individually or in groups.
Much of the work is expected to take place under CRADAs. In a typical CRADA, a manufacturer or group of companies supplies
the funding and resources, including data on drug characteristics, research results, or innovative manufacturing approaches.
FDA offers advice on study designs and agrees to evaluate results and use them to support a regulatory test or standard. Academic
or nonprofit organizations offer research facilities and a neutral party to manage funding and protect proprietary information.
Establishing consortia takes a long time, Woodcock says. To identify and qualify a new biomarker, for example, may involve
evaluating assays from several partners, each anxious to guard its intellectual property. Members of a consortium get an early
look at how it is performing. But the goal, says Woodcock, is to improve FDA standards and develop predictive evaluation tools.
"That's what FDA gets out of this," she says.
FDA plans to work with the consortia being established to develop new predictive tools. If the science is done right, says
Woodcock, the tools will be incorporated into FDA standards, as was done in the past for stability data and animal toxicology
An early example of such efforts is a collaboration with the National Cancer Institute (NCI), which was launched in 2003 by
McClellan and von Eschenbach, when he headed NCI. Now, as the head of FDA, von Eschenbach is promoting expanded FDA collaboration
with NIH entities.
As a first step, both FDA and NCI have assigned scientists at both agencies to temporarily swap positions so they become better
acquainted with the opportunities and challenges of their colleagues. The group also is working on clinical trial automation
and development of standard clinical trial data reporting forms to permit electronic submission of NCI trial data to FDA.
NCI recently said it would use the e-signature model developed by pharma for cancer trials.