Last week, the Food and Drug Administration (FDA) released two new guidance documents and a final rule intended to streamline the early clinical development of new drugs and biologics for cancer and other diseases. The documents represent strategic actions that are part of the agency's Critical Path Initiative. The Critical Path is a blueprint for updating the technologies and tools needed to optimize the process of discovery, development, and delivery of medical products. These specific guidances address major barriers in the early development of new interventions, including testing small quantities of new agents prior to undertaking full-scale clinical trials and evaluating new investigational agents in humans before demonstrating their manufacturability.

The joint NCI-FDA Interagency Oncology Task Force (IOTF), which was established in 2003 to enhance and accelerate the overall process of developing new cancer interventions, has focused extensively on these issues as part of its work to improve the overall cancer drug development process.

Today, 9 out of 10 compounds developed in the laboratory fail in human studies. "One problem is that researchers conducting very early studies were required to follow the same manufacturing procedures as those companies that mass-produce products for broad scale distribution," said Dr. Janet Woodcock, FDA deputy commissioner for Operations.

In the first guidance document, Exploratory IND Studies, FDA offers recommendations about safety testing, manufacturing, and clinical approaches that can be used in very early studies, sometimes called exploratory, or phase 0, trials. This guidance will allow researchers to develop a better understanding of parameters such as drug distribution, pharmacokinetics, and target localization of new agents prior to undertaking large-scale trials. INDs - Approaches to Complying with CGMP During Phase I, and an accompanying rule, outlines an approach for compliance with good manufacturing practice (CGMP) requirements for the manufacture of small amounts of drug product for testing prior to undertaking large phase I studies. Requirements for full-scale phase I studies will not change.

"This new guidance will allow investigators to evaluate microdoses of investigational agents in small numbers of patients, which will provide the opportunity to apply new molecular technologies, and answer questions about pharmacokinetics and potential biomarkers of efficacy and toxicity," said Dr. Anna Barker, NCI deputy director for Strategic Scientific Initiatives. "A microdose is less than 1/100th of a typical drug dose that would have a pharmacologic effect. However, it is sufficient for use in areas such as advanced imaging to assess effect at the molecular level, such as whether it is readily metabolized or is hitting its intended molecular target."

Dr. Barker added that through its intramural program, NCI has set up a new unit to do these types of trials on promising candidate drugs with a goal of speeding up safer and more effective cancer interventions to patients.

"This guidance really makes it possible to do those kinds of studies very early on, so we can screen a wider variety of individual drugs in the pipeline to better understand those we should take forward," said Dr. James Doroshow, director of NCI Division of Cancer Treatment and Diagnosis.

Dr. Steven Rosenberg, chief of NCI's Surgery Branch, added, "This will have a major impact on the ability of scientists to evaluate whether their findings will be helpful to patients."