Ellen G. Feigal, MD, Jeffrey Cossman, MD, and Raymond L. Woosley, MD, PhD
Feigal is director, medical devices and imaging, Cossman, is chief scientific officer,
and Woosley is president and CEO, Critical Path Institute, Tucson, Ariz.

The Critical Path Institute was formed to implement and advance findings by the FDA to accelerate and increase innovation in drug development.

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Submissions to the FDA of Biologic License Applications (BLA) and New Molecular Entities (NME) Drug Applications.
Modernizing the medical product development toolkit to take advantage of recent scientific and technological advances must occur to accelerate the development of more effective and safer medical products. The research and development costs for medical products continues to rise; however, the number of new molecular entities submitted to the US Food and Drug Administration (FDA) has markedly declined, success rates for moving from the first-in-human studies to regulatory approval and clinical application has declined, and post-market safety remains a concern. The reasons are complex, and there is not a single solution. Technologies including molecular imaging, gene expression profiling, and genetic tests are emerging as critical tools to change this landscape.

The high cost and long delays of medical product development are symptomatic of a failure to exploit the new medical science. Addressing this problem is a necessary part of the solution. The Critical Path Institute (C-Path) was formed to be a catalyst for changing how future medical products are developed. In this article, we cite examples of unique public-private partnerships convened by C-Path using these technologies to inform drug development, patient selection, dosing, and evaluation of efficacy and safety.

Tools for personalized medicine will require a linkage of diagnostics to inform therapeutic decisions. However, diagnostics are poor stepchildren to blockbuster drugs and are usually developed independently of their companion therapeutic. Pharmaceutical industry blockbusters are focused on common conditions and chronic use for which people need to take medications over an extended period of time. Most important, diagnostics are not co-developed along with the therapeutic and typically emerge as an afterthought for approved drugs.

What is C-Path's mission?
The urgency to change course was outlined by the FDA in a March 2004 white paper, now called C-Path. The FDA called attention to the startling decline in the number of new molecular entities submitted to them for approval and cited the lack of innovation in drug development (See chart above). This decrease is occurring despite a 250% increase in expenditures for medical research and development. Notably, there is a 90% failure in the transition from first-in-human early clinical phase development of products into the marketplace and a persisting 3% per year post-marketing removal from the marketplace of medical products deemed to be unsafe. The drug pipeline and development roadblock differs from the problems in devices.

C-Path is an independent, community funded, non-profit/tax exempt organization founded in July 2005 as a key component of the statewide Arizona Biosciences Roadmap to expand and advance the biomedical research enterprise, and dedicated to implementing the FDA's C-Path. The initiative was co-founded with staffing commitments from the University of Arizona, SRI International, and the FDA. A memorandum of understanding was established between C-Path and the FDA that identified C-Path as neutral ground to help create novel programs to enable the pharmaceutical, device, and biotechnology industry to safely accelerate and coordinate development of more effective treatments and diagnostics.

Surprisingly, the problem is not due to lack of discovery of new candidate therapies. The major factor in the bottleneck is the time-consuming and inefficient process for preclinical and clinical testing of new medical products. C-Path's mission is to accelerate the development of safe and effective medical product solutions through efficient partnerships and transparent communication among industry, regulatory agencies, and research scientists. C-Path evaluates the tools of medical product development and focuses on improving the process by testing and validating the methods. C-Path's goal is to enable the FDA to issue more informative and more reliable guidance documents to help guide the industry to more rapid development of effective and safe medical products.

C-Path programs and projects
C-Path has aligned its programs and prioritized its projects with those identified in the FDA opportunities list [US Food and Drug Administration Critical Path Opportunities List, US Food and Drug Administration, (Mar 2006)]. The list identifies areas that are current roadblocks in the regulatory process and medical product development. The 76 projects listed were distilled from extensive discussions over the preceding two years with stakeholders in industry, healthcare, disease-oriented foundations, and patient advocacy groups, and focused on six main categories:
1. Better evaluation tools
2. Streamlining clinical trials
3. Harnessing bioinformatics
4. Modernizing manufacturing
5. Developing products to address urgent public health needs
6. Specific at-risk populations – Pediatrics

From this list of projects, C-Path has begun five initiatives. For C-Path to undertake a project, it must meet certain criteria. First and foremost, it must have an FDA champion(s) interested in and committed to the project. Two or more companies must be willing to participate and commit to conduct methodological research aimed at
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C-Path serves as neutral ground for scientists from industry, FDA, and academia to address common roadblocks in medical product development.
removing a regulatory or scientific roadblock. The projects target medical areas of unmet need such as highly lethal cancers that lack effective therapy, gene-based personalized dosing for anticoagulation, adverse drug reaction surveillance, and rare or orphan illnesses. C-Path is particularly interested in those projects in which silos of science or companies (e.g., diagnostic and therapeutic companies) with different business perspectives see the value in working together in solving a common problem. C-Path invites and convenes the participants and helps design and develop the demonstration projects, with advisory input from the FDA, and often with the Center for Medicare and Medicaid Services (CMS) for issues related to coverage and reimbursement. C-Path directs and manages the projects and works with a steering committee of the participants to ensure each project has defined goals, aims, milestones, timelines, and budgets. C-Path provides interim progress reports and summarizes the results for submission to the FDA (see chart to right).

• C-Path successfully created a consortium including thirteen of the world's top pharmaceutical companies to share methods, data, and strategies to better predict the safety of new marketed drugs. The focus is on developing preclinical predictors of toxicity to the liver, kidney, vascular system, and carcinogenicity. C-Path's consortium was announced by the Secretary of Health and Human Services (HHS), Michael Leavitt, on March 16, 2006, as the first project on the Critical Path Opportunity List to be initiated. C-Path's partners include Merck, Johnson&Johnson, Pfizer, Novartis, GlaxoSmithKline, Schering, Roche, AstraZeneca, Boehringer-Ingelheim, Amgen, Sanofi-Aventis, Bristol-Myers Squibb, and Abbott.

• C-Path is forming an industry consortium of diagnostic and pharmaceutical companies to develop a strategy for greater clinical benefit in patients with lung cancer so that the right treatments will be given to the right patients, e.g., those most likely to benefit. A critical component of this project is the consortium's development of a process for sharing and standardizing biomarker assays, DNA samples, and tissue specimens.

• C-Path has organized an approach to solving an unmet worldwide need for the prevention of strokes and death due to embolism. C-Path is working with academic and industry partners to spearhead a large-scale clinical trial using a genetic test to accurately determine the correct individual dose of the anticoagulant, warfarin. To ensure the study results will be applicable in a real-world clinical setting, the study will use inexpensive point of care diagnostic technologies that can provide results in less than an hour. Determining the best dose of warfarin for individual patients will substantially reduce the life-threatening consequences of hemorrhage or thrombosis, which are estimated at $1 billion annually in related medical costs in the US alone.

• C-Path has developed a mechanism to track marketed drugs for early evidence of adverse events, long before a larger population has been exposed. This uses a novel, statewide demonstration project with pharmacies using electronic patient registries that can be linked to an electronic Arizona Health Query database as an independent post-marketing safety active surveillance.

• C-Path is helping create "electronic medical registries" for rare and orphan diseases that can be templates for all diseases and facilitate the development of new drugs for the illnesses. C-Path is particularly interested in developing electronic tools for accelerating information flow between patients, clinicians, researchers, and companies in rare diseases and orphan product development. Regionally, Arizona has an emerging critical mass of interest from foundations, clinicians, and the research community in three diseases that fit into this category: 1)Niemann-Pick type C; 2) Valley Fever (coccidiodomycosis); and 3) Adrenocortical carcinoma. C-Path is currently in discussions with the National Library of Medicine, the Office of Rare Diseases, NIH, and the Office of Orphan Products, FDA, with the goal of establishing an inter-agency collaboration with disease-based foundations.

How does C-Path operate?
In order to retain its collaborative relationship with the FDA and industry scientists, C-Path maintains its neutrality by accepting only public support. It has received pledges for unrestricted support of more than $10 million over a five-year period to seed the Institute's programs. Sources of financial support for C-Path include both the public sector and private foundation contributions from sources in the state of Arizona, as well as the FDA and the Agency for Healthcare Research on Quality. We anticipate that core funding for C-Path will continue to include unrestricted charitable contributions, interest return on endowments and federal grant monies and appropriations. C-Path will also manage projects supported by industry consortia in order to execute specific projects identified as high priority by FDA, NIH, and/or CMS.

What are the goals?
The goals of each of the projects will include the development of an evidence database that can form the basis for the FDA to write guidance documents that will guide companies in medical product development and inform FDA decisions for medical product approval and labeling.

C-Path has developed partnerships with universities and professional organizations to conduct educational programs to train scientists in the new critical path methods of medical product development. The Drug Information Association and C-Path jointly sponsor conferences on Critical Path topics. The American College of Clinical Pharmacology and the Arizona Center for Education and Research on Therapeutics have begun a collaborative educational program on optimal management of warfarin anticoagulation. C-Path and George Washington University have an internship program for students to gain experience in pharmacological sciences at the FDA.

Examples of expected outcomes of current projects are as follows:

• New, effective diagnostic products validated by prospective clinical trials.
• A template for the evaluation and reporting of diagnostic-based clinical trial results suitable for review and approval by the FDA and worldwide by governmental regulatory agencies.
• Predictive tests for cancer treatment response to match the right drug to the right patient.
• A genetic test to precisely determine warfarin dose.
• An efficient method to rapidly identify early evidence of uncommon adverse drug reactions.
• Incorporate critical path innovations in the development of treatments for neglected diseases.

Although it is still early in C-Path's existence, the commercial sector, including competing companies, and FDA have already demonstrated their willingness to work together on C-Path's neutral ground. The medical product development problems being addressed by C-Path and its network of complex collaborative interactions are enormous and will require an ongoing commitment.

This article was published in Drug Discovery & Development magazine: Vol. 9, No. 9, September, 2007, pp. 28-40.