Regulatory Beat: Biotech Innovation Benefits From Streamlined Manufacturing Policy

As part of its campaign to facilitate research on drugs and medical products, the Food and Drug Administration (FDA) recently issued new policies to encourage sponsors to conduct more informative and less costly early clinical trials. A new guidance on exploratory investigational drug applications (INDs) explains how scientists in industry and academia may test very small doses of a candidate compound to detect any pharmacologic effect before investing in more extensive in vitro and animal studies required for conventional phase 1 trials. The goal is to quickly identify products that show some promise of efficacy, and to halt research on those that fail to hit preliminary targets.

Jill Wechsler

A key element in this streamlined approach to early clinical testing is to facilitate production of small quantities of test compounds needed for early clinical trials. To this end, FDA issued a new rule exempting manufacturers and research organizations from compliance with Good Manufacturing Practices (GMPs) when producing drugs for all phase 1 studies. A companion 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 lab to the clinic, said Janet Woodcock, FDA deputy commissioner for operations when she announced the new policy in January of this year. These innovations aim to establish more efficient clinical study plans and improve the success rates of the current drug development process, a primary goal of FDA's Critical Path Initiative.

MODERNIZING GMPS

The new rule reflects FDA's belief that manufacturers can establish a controlled process for reproducing a test product, even if they don't fully comply with GMP requirements. The regulation explains how researchers and manufacturers can adopt modified approaches for producing small quantities of test materials for phase 1 studies [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, according to FDA, because limited production operations have no need for rules regarding stock rotation for drug product containers or for repackaging and relabeling drug products. Small-scale production may involve just a few steps within a single facility, and operations may use disposable equipment and prepackaged water to accomplish this.

FDA specifies that the phase 1 exemption applies to investigational biological products normally subject to GMPs. These include recombinant therapeutics, vaccines, allergenic products, in vivo diagnostics, plasma derivative products, blood and blood products, gene therapies and somatic cellular therapies. The rule modification does not pertain to previously approved products now in phase 1 studies, or to phase 2 and 3 trials.

Consequently, pharma 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 biotech manufacturers to modify their operating procedures and validation requirements for producing early test products. The rule may also enable some companies to produce investigational agents in-house instead of contracting them out.

ENSURING QUALITY

Even without full GMP compliance, FDA expects manufacturers to document processes for ensuring the safety and quality of an 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 the authority to terminate a study, seize an investigational drug, or halt 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 instructions for manufacturers on how to ensure the quality and safety of clinical test products in one new guidance (available at www.fda.gov/cder/guidance/6164dft.htm) and notes that it may issue additional information to help clarify GMP requirements for producing investigational drugs for later stage clinical trials. The guidance advises researchers to establish quality control procedures that describe how they will control production components and laboratory testing. Sponsors need to keep complete records of production processes, including equipment maintenance, analytical tests, and distribution. Reagents and components should be properly labeled and organized. Additional steps should be taken to prevent contamination of investigational biologics and sterile products.

This modification of GMP requirements is "incredibly important," says Woodcock, because it will allow researchers 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. 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, who strongly support the new policy, can produce compounds in the labs "much more readily," Rosenberg said.

EARLY EXPLORATION

Streamlined approaches for producing clinical test compounds aim to encourage scientists in industry and academia to take advantage of FDA's accompanying exploratory IND policy. The other FDA guidance explains how researchers may administer very low doses of a test substance to very few individuals (less than 20) for a short period of time (up to seven days) [see www.fda.gov/cder/guidance/7086fnl.htm]. Even though study participants may not display 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 aim is to generate information on a candidate drug's mechanism of action or pharmacologic effect before investing in the full battery of preclinical and animal testing required for even a small phase 1 safety study. The policy applies to drugs and to well-characterized therapeutic biological products, but not to human cell or tissue products, blood proteins, vaccines or medical devices.

The IND application filed with FDA to launch an exploratory study may contain less information than normally submitted for routine applications. It would describe the research program and anticipated outcomes, including a rationale for test compound selection and for adopting a particular study plan. The guidance also notes that CMC information can be presented as a summary report, describing 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 necessary 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 may include data on fewer animals and at lower doses, reducing the number of animals involved in overall preclinical testing.

Although some skeptics regard the exploratory IND as merely a way for drug companies to cut costs while creating additional risks for patients, Woodcock maintains that this approach will save people and animals from unnecessary exposure to higher and more toxic doses of untested compounds.

If an exploratory microdose study indicates promising results, the manufacturer has to start over. Before launching conventional phase 1 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 be targeted to those compounds that appear most likely to have a positive effect on human health. 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 regulations."

Jill Wechsler is BioPharm International's Washington editor, 7715 Rocton Avenue, Chevy Chase, MD 20815, 301 656 4634, jwechsler@advanstar.com