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A new FDA policy emphasizes quality control over GMP compliance in producing clinical trial supplies.
As part of its campaign to facilitate research on drugs and medical products, the US Food and Drug Administration recently issued new policies that encourage sponsors to conduct more informative and less costly early clinical trials. A new guidance on exploratory investigational new drug applications (INDs) explains how scientists in industry and academia may test small doses of a candidate compound to see if a pharmacologic effect exists before investing in the more extensive in vitro and animal tests required for conventional Phase I trials. The aim is to quickly identify those products that show some promise of efficacy, and to halt research on those that fail to hit preliminary targets.
A key element in this streamlined approach to early clinical testing is to make it easier for study sponsors to produce the small quantities of test compounds needed for early clinical trials. To this end, FDA is exempting manufacturers and research organizations from compliance with good manufacturing practices (GMPs) when producing drugs for all Phase I studies. A guidance offers advice for ensuring that test products meet quality standards and that study sponsors document production processes and procedures, particularly for sterile products and biologics. A major bottleneck in drug development is moving from the laboratory to the clinic, pointed out FDA Deputy Commissioner for Operations Janet Woodcock in announcing the new policy at the beginning of the year. These innovations aim to spur faster clinical development.
FDA also issued its long-awaited final drug labeling regulation in January after years of debate and delay (see sidebar "New labels challenge manufacturers)." Although the basic framework of the new labeling requirement is no surprise, compliance will require significant investment by manufacturers to redesign the format of professional labeling, which will significantly extend the length of most package inserts and require an overhaul of packaging lines.
New labels challenge manufacturers
When FDA officials wrapped up the first two years of its effort to modernize "GMPs for the 21st Century" in September 2004, one of the items on the list of unfinished business was the need to streamline GMPs for clinical supplies. The original 1978 GMP regulations specified that the rules applied to investigational drug products, but the regulators left the door open to future modifications. They recognized that a prime objective of setting manufacturing standards for clinical supply production is to establish a framework for the manufacturer to operate a well-documented and controlled process for reproducing a product for further testing and ultimate commercial production. The new policy reflects FDA's current belief that manufacturers can meet these objectives without fully complying with GMP requirements; this approach, according to Woodcock, fits FDA's initiative to end a "one-size-fits-all approach to manufacturing."
The new rule explains that researchers and manufacturers may adopt modified approaches for producing small quantities of test products for use in Phase I studies, which usually involve less than 80 participants (see "Current Good Manufacturing Practice Regulation and Investigational New Drugs," Federal Register, Dec. 17, 2006, found at www.fda.gov/OHRMS/DOCKETS/98/fr/06.353.pdf). This approach is appropriate, FDA explains, because investigational production does not raise many of the issues related to manufacturing products for later clinical studies or for commercial marketing. Limited production operations have no need for rules about rotating stock for drug product containers, for example, or repackaging and relabeling drug products or maintaining separate packaging and production areas. Small-scale production may involve just a few steps within a single facility, and operations may use disposable equipment and prepackaged water.
FDA specifies that the Phase I exemption policy also applies to investigational biological products subject to GMPs. Such products include recombinant therapeutics, vaccines, allergenic products, in vivo diagnostics, plasma derivative products, blood and blood products, gene therapies, and somatic cellular therapies.
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 at 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.
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 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.
The new exploratory approach permits researchers to administer low doses to very few individuals (less than 20) for a short period of time (as much as 7 days). These trials may involve very low microdoses (less than 1/100 of the dose calculated to yield a pharmacologic effect) or slightly higher doses that still have no toxic effect on the participant. Single-dose studies may collect pharmacokinetic information or data from imaging studies, although repeat dose studies may examine pharmacologic or pharmacodynamic endpoints. Even though research participants may not feel any effect from the test compound or show any obvious response, modern imaging technology and test methods will permit the researcher to detect whether a test substance hits a target organ or metabolizes in a certain way.
The IND application filed with FDA to launch an exploratory study may contain less information than for the usual application. It would briefly describe the research program and anticipated outcomes, including a rationale for selecting a test compound and for adopting a certain study plan. The guidance also notes that CMC information can be presented as a summary report that describes the product's characteristics, source, therapeutic class, dosage form, route of administration, formulation, method of preparation, manufacturer and composition. A certain amount of analytical testing is needed to demonstrate the identity, structure, purity, and potency of the candidate product and its physical and microbiological characteristics.
FDA always will require some animal testing before launching even a micro-study, Woodcock explained, but exploratory INDs will need data on fewer animals and at lower doses, reducing the number of animals involved in preclinical testing overall.
Although some skeptics regard the exploratory IND as merely a way for drug companies to cut costs while creating additional risks for patients, Woodcock maintained that this approach will save people and animals from being exposed unnecessarily to higher and more toxic doses of untested compounds. Acting commissioner Andrew Von Eschenbach added that the new policy does not allow any compromise in standards for clinical trials or laboratory testing, but offers a way to use modern diagnostic tools to gain more insight.
If an exploratory microdose study shows promising results, the manufacturer must start over. Before launching conventional Phase I studies, the sponsor must conduct additional animal and in vitro testing and file a new IND. The hope is that further testing and development will involve those compounds that appear most likely to have a positive effect on human health.
Exploratory "phase zero" studies offer a way to gain much more valuable information about whether a mechanism of action seen in preclinical studies also occur in humans and whether a compound binds to certain molecular receptors, affects a target body organ, has a desired effect on enzyme activity or has anticipated pharmacokinetic effects—all possible signs of potential therapeutic value. Such information may lead to more efficient clinical study plans and improve the success rates of the current drug development process, one of the prime goals of FDA's Critical Path initiative. Nine out of ten compounds developed in the laboratory fail in human studies, explained von Eschenbach, because test therapies often behave differently in people than in animals and test tubes. The new policy does not change FDA's rules, Woodcock noted, but advises researchers on "how they can take advantage of the inherent flexibility in the current regulation."
Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, firstname.lastname@example.org