The exemption from GMPs does not extend to previously approved products now in Phase I studies, or to Phase II and III trials. Consequently, pharmaceutical and biotech companies are likely to continue manufacturing clinical supplies in GMP-compliant facilities to avoid complications with later scale-up activities. At the same time, the new policy provides an option for manufacturers that want to streamline production processes for early test products and may spur some companies to shift from contacting out to producing investigational agents in-house. FDA estimates that large manufacturers may save as much as $1500 per IND for Phase I studies caused by these modifications in operating procedures and validation requirements.

The GMP exemption is a "direct rule" that automatically goes into effect June 1, 2006 unless a third party submits "significant adverse comments" challenging the rule as inappropriate, ineffective, or unacceptable. In that case, FDA must initiate a formal notice-and-comment process that could take months, if not years.

Ensuring quality

FDA provides additional guidance for manufacturers about how to ensure the quality and safety of clinical test products (available at http://www.fda.gov/cder/guidance/6164dft.htm) and notes that it may issue additional guidance to clarify how pharmaceutical companies should meet GMP guidelines when producing investigational drugs for later clinical trials. The guidance advises researchers to establish quality control procedures that describe how they will control production components and laboratory testing. Sponsors must keep complete records of production processes, including equipment maintenance, analytical tests, and distribution. Reagents and components should be properly labeled and organized, and additional steps should be taken to prevent the contamination of investigational biologics and sterile products.

This modification of GMP requirements is "incredibly important," says Woodcock, because it will allow researchers in laboratories to produce small quantities of a test product without adhering to policies designed for large-scale production. Laboratories at academic institutions and the National Institutes of Health that don't have ready access to large production facilities stand to benefit immediately. Up until now academic researchers have been "at the mercy of the large pharmaceutical and biotech companies," commented Steven Rosenberg of the National Cancer Institute (NCI). He explained that if NCI researchers want to move a promising compound from the test tube to the clinic, they have had to find a company with GMP-compliant facilities to produce it. Now, NIH researchers can produce compounds in the laboratories "much more readily," Rosenberg said.

Early exploration

Streamlined policies for producing clinical supplies aim to encourage researchers at pharma companies as well as research organizations to take advantage of FDA's new early-into-man study paradigm described in its exploratory IND guidance (available at http://www.fda.gov/cder/guidance/7086fnl.htm). This approach aims to generate more information about a candidate drug's mechanism of action or pharmacologic effect before investing in the full battery of preclinical in vitro and animal testing required for even a small Phase I safety study.

FDA officials believe that current IND regulations provide sufficient flexibility for the agency to authorize such exploratory studies without initiating a lengthy rule-making procedure. Traditional Phase I studies, explained Woodcock, escalate doses for trial participants until they reach a toxic level. These, however, usually provide information on what dose patients can tolerate and little insight about how the compound may affect the patient.