Ted Agres, Deputy Managing Editor, Washington Times

Illustration: Roger Schillerstrom 
The US Food and Drug Administration (FDA) has announced new rules intended to accelerate the drug development pipeline by making preclinical and early-stage clinical trials easier and less costly to conduct. The new FDA regulations offer guidance for researchers in industry and academia on how to conduct very early clinical studies more efficiently and to produce small quantities of drugs safely and cost effectively.

"These changes will enable US medical researchers to evaluate much more efficiently the promise of scientific advances discovered in their laboratories," said Acting FDA Commissioner Andrew von Eschenbach in announcing the new rules in January. "The FDA is committed to facilitating the rapid translation and the development of that knowledge into the development of new drugs or treatments."

Until now, researchers conducting very early studies have had to follow the same current good manufacturing practices (cGMP) as companies mass-producing products for broad- scale distribution. "These requirements are so burdensome for early phase 1 studies that many leading medical research institutions have not been able to conduct these studies of discoveries made in their laboratories," said Janet Woodcock, FDA deputy commissioner for operations.

Because of cGMP and other requirements, preparing a single new experimental drug for human testing costs sponsors between $500,000 to $1 million, according to the FDA. Even then, nine out of 10 such experimental drugs fail in clinical trials, in part because laboratory and animal studies are not the best predictors of how the new drugs will perform in people. Lipitor, for instance, Pfizer's blockbuster drug for reducing cholesterol, showed lackluster results in early animal studies. It wasn't until the drug was tested in a small group of healthy human volunteers—at the behest of a research scientist—that its effectiveness became evident.

The new FDA guidance encourages researchers to take advantage of "existing flexibility" in the amount of data needed for submission with an investigational new drug (IND) application. New drug sponsors "often provide more supporting information in INDs than is required by regulations," the FDA notes in its "Guidance for Industry, Investigators, and Reviewers: Exploratory IND Studies." As a result, limited, early phase 1 studies "are often supported by a more extensive preclinical database than is needed for those studies alone." This has made the discovery process more time intensive and costlier than necessary.

Here's why: New drug candidates are usually selected using in vitro testing to examine binding to receptors, effects on enzyme activities, toxic effects, and other pharmacologic properties. While these tests usually require only small amounts of the drug, greater quantities are needed for in vivo animal testing, usually in rats and dogs, to determined safety and efficacy.

"These early tests are usually resource intensive, requiring significant investment in product synthesis, animal use, laboratory analyses, and time," the FDA guidance states. "Many resources are invested in, and thus wasted on, candidate products that subsequently are found to have unacceptable profiles when evaluated in humans." And because animal testing does not always predict performance in humans, potentially effective candidates may not be developed.

Under the new guidance, researchers are encouraged to conduct low-risk, exploratory IND studies in small groups of healthy human volunteers prior to seeking approval for phase 1 trials. These exploratory IND studies would use microdose applications of drug candidates for short time periods (typically up to seven days) to obtain pharmacokinetics information and to explore the drug's biodistribution characteristics.

In a separate guidance, the FDA also outlined less onerous requirements for producing small quantities of the investigational new drugs to be used in these exploratory IND and screening studies. Under "Guidance for Industry INDs—Approaches to Complying with cGMP During Phase 1," sponsors would be given greater leeway in producing, storing, and administering small quantities of experimental drugs, which often take place in research laboratory and academic settings.

Together, these two new recommendations "will help more researchers conduct earlier, more-informed studies of promising treatments so patients have more rapid access to safer and more effective drugs," said Health and Human Services secretary Michael Leavitt.

As expected, industry reaction has been favorable. "Too many times, promising treatments fall through the cracks because the process involved with experimental clinical studies can be arduous and full of red tape," said Billy Tauzin, president of Pharmaceutical Research and Manufacturers of America (PhRMA), Washington, D.C. "The modernization of such studies, as called for in the FDA's new guidance, is critical for cutting the red tape and also ensures that FDA's rigorous safety standards are not compromised."

In addition to encouraging greater use of exploratory IND studies to improve clinical success rates, the FDA this year will emphasize pharmacogenomic data initiatives and continue to push industry to implement postmarketing surveillance programs to address drug safety issues, states the Tufts University Center for the Study of Drug Development (CSDD). "As drug development becomes more complex and expensive, developers tend to concentrate available resources on fewer projects," said Tufts CSDD director Kenneth Kaitin. "Fewer development projects, in turn, lead to fewer new drug approvals."

According to the CSDD "Outlook 2006" report released in January, only 58 new drugs in 2002-2004 received FDA marketing approval, a 47% drop from the peak of 110 new drugs in 1996-1998. The report predicts that drug developers will increase their reliance on licensing, outsourcing strategies, and co-development agreements between large and small companies to boost R&D productivity. In addition to concerns over safety, other challenges facing the industry include public anxiety over the lack of vaccines to fight potential pandemics as well as ever-rising drug prices.

Turning the situation around "will require the industry, working with regulators, to embrace strategies and technologies that will enhance development of more complex drugs of high therapeutic value while improving assessments of product safety and effectiveness," Kaitin said. "It's a tall order, but it can be done."