Regulatory Beat: Critical Path Initiative Tops FDA Priority List for 2006

Andrew von Eschenbach, acting commissioner of the Food and Drug Administration (FDA), says that implementing the Critical Path Initiative is "one of my highest priorities," and is encouraging more FDA collaboration with other government agencies, academia, and industrial partners to find better ways to encourage innovation. As head of the National Cancer Institute (NCI), Von Eschenbach has supported joint projects with FDA to spur development of new cancer drugs, including efforts to qualify biomarkers for cancer detection in specific patient populations and to examine how imaging technologies can monitor the impact of therapies on cancer tumors.

Jill Wechsler

Such activities fit the framework of FDA's Critical Path report, issued in March 2004, which describes the high cost and disappointing results of the current biomedical development process. New drug approvals have flattened out in recent years, particularly for new molecular entities. This trend is even more troubling at a time when the public and private sectors combined are spending more than $100 billion on biomedical research.

Now, a number of occurrences may be creating a "perfect storm" for public-private collaboration on biomedical R&D. First, recent scientific discoveries provide unprecedented opportunities to use biomarkers, computer models, genomics, and other new technologies to develop more informative research methods. At the same time, the pharmaceutical industry faces a crisis. With pipelines drying up, revenues falling, and drug safety issues generating public hostility, manufacturers are under pressure to find more efficient ways to develop and produce safe and effective medical products. Although companies are concerned about protecting intellectual property, they realize that it is too costly to develop biomarkers and genomic tests on their own and that more cooperative efforts make sense.

Even the heightened focus on drug safety, which has pushed innovation out of the limelight for the past two years, may bolster efforts to reduce toxic side effects and limit patient exposure to inappropriate therapies. Tests able to identify patients who respond more positively to a product can lead to safer medicines; more targeted clinical studies can help avoid exposing non-responders to an experimental product.

Manufacturers are also recognizing the importance of improving the industrial model for drug manufacturing, notes FDA deputy commissioner Janet Woodcock, who heads up FDA Critical Path efforts. Talk of more industry collaboration "would have fallen on deaf ears" ten years ago, she acknowledges, because manufacturers did not realize until recently how much outdated manufacturing processes were costing them.

PROMOTING PARTNERSHIPS

Industry now recognizes the need to work with FDA in addressing these problems. FDA's experience with complex biological products gives it "unique insight into the gaps in scientific knowledge and tools needed for more efficient product review," comments Kathryn Carbone, associate director of research at the Center for Biologics Evaluation and Review (CBER). Too many products fail in development, she explained at the September PDA conference, because there is no assay for adequate product characterization or the manufacturer cannot scale up sufficiently.

Because FDA lacks resources to support research on these issues, the agency seeks to spur examination of Critical Path opportunities through joint projects with industry and research organizations, either individually or through group collaborations. In response to increased FDA urging, companies now are "stepping up to the plate," Woodcock says. For example, Novartis announced in September that it is working on three research collaborations with FDA. One examines how to apply process analytical technology (PAT) to new methods for assuring quality manufacturing. FDA and Novartis are negotiating a Cooperative Research and Development Agreement (CRADA) that calls for joint evaluation of research findings and will give FDA experience in implementing and validating proposals under its PAT guidance. Another project involves the development of preclinical biomarkers to evaluate renal toxicity. A third collaboration will assess hurdles related to developing a diagnostic kit utilizing a drug product. Novartis plans to conduct an observational study involving several compounds in its pipeline where a genomic diagnostic may prove to be of value.

BACKING BIOMARKERS

Biomarkers and diagnostics are key in the Critical Path program and are particularly important to ensure the safety and efficacy of complex biologics, notes Carbone.

Most manufacturers use their own biomarker development programs to predict animal toxicity and select drugs for development, but FDA seeks collaborative arrangements to validate biomarkers that can be used industry-wide.

For example, the Critical Path Institute (Tucson, AZ), a non-profit organization supported by FDA, SRI International, and the University of Arizona, is launching a Toxocogenomic Cross Validation Consortium that will bring manufacturers together to validate each other's safety test methods. Separately, FDA's National Center for Toxicological Research (NCTR) and Massachusetts-based BG Medicine have signed a CRADA for a Liver Toxicology Biomarker Study to identify standard tests for early-stage product development.

Internally, FDA is surveying its medical officers on what biomarkers have been submitted in applications and accepted as surrogate endpoints. FDA plans to form a group to develop guidance on biomarkers and to support Critical Path collaborations.

FDA's pharmacogenomics (PG) initiative also provides important information on how industry is using genomic data to identify drug targets and devise development programs. In March 2005, FDA established a voluntary genomic data submissions process that encourages pharma and biotech companies to share PG data with the agency outside the normal application review process. FDA has received 30 submissions for discussion by its PG review group. The European Medicines Evaluation Agency is participating in some meetings to encourage a common approach to assessing genomic submissions, which may become a topic for review by the International Conference on Harmonization.

In the near future, FDA hopes to issue a draft guidance on drug-diagnostic co-development that describes how to link a targeted drug with a test to identify individuals likely to respond to treatment. Diagnostics are crucial to the development of personalized medicines, but appropriate product development timing is a big concern, along with fear that FDA may require co-development with certain new therapies.

MODERNIZING MANUFACTURING

Although FDA's campaign to update good manufacturing practices has launched a number of projects in this area over the past two years, the Critical Path initiative aims to spur further collaboration on innovative manufacturing practices. CDER's Office of Pharmaceutical Science is establishing a CRADA with Con-formia Software of California to survey the industry on what issues most affect the selection of drug candidates for commercial manufacturing. In addition, Purdue leads a group of 11 universities in forming the National Institute for Pharmaceutical Technology & Education to address manufacturing and scientific issues that affect variability in product quality.

Although industry and academia have to take the lead in addressing these issues, FDA recognizes the need for a better toolkit to reduce the amount of uncertainty in the drug approval process. "What we need to do is fundamentally change the dynamic and to focus therapy on the people who benefit," Woodcock explains.

One sign of progress is finalization of the long-awaited Critical Path Opportunities List of research projects and collaborative efforts that FDA believes can streamline pre-clinical testing, clinical trial operations, and quality production. CBER's "wish list" includes a number of investment opportunities to improve biotech R&D:

• Develop well characterized cell banks and assays for adventitious agents

• Develop methods of pathogen inactivation for blood, plasma, and tissues

• Develop multipathogen and rapid detection methodologies

• Improve storage methods for blood and tissues

• Establish assays, standards, and reagents for the flu vaccine.

Woodcock considers the list a "call to action" for industry and academia to work together to reduce the high cost of new drug development and spur innovation.

Jill Wechsler is BioPharm International's Washington editor,7715 Rocton Avenue, Chevy Chase,MD 20815,301.656.4634, jwechsler@advanstar.com.