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.
Even without full GMP compliance, FDA expects manufacturers to document processes for ensuring the safety and quality of the
investigational drug as part of an IND filing. This involves providing sufficient chemistry, manufacturing, and control (CMC)
information to describe the composition, manufacture and control of the investigational drug product. FDA emphasizes that
it still retains authority to terminate a study, seize an investigational drug, or halt its production if the manufacturer
does not provide sufficient risk information in the IND or fails to "establish and maintain appropriate standards of identity,
strength, quality, and purity as needed for subject safety."
FDA provides additional guidance for manufacturers about how to ensure the quality and safety of clinical test products (available
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
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.
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
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.