By John Russell
January 20, 2010 | TUCSCON, AZ—Turning FDA’s Critical Path Initiative (CPI) into practical tools to accelerate drug discovery and development has had its challenges. But that hasn’t deterred Ray Woosley, CEO of the C-PATH Institute, whose sole mission is to foster private-public cooperation to fulfill CPI’s grand vision. Woosley is a glass-half-full realist and C-PATH is starting to justify his steady confidence.
The basic idea is to set up consortia to develop scientific consensus among drug developers and regulators around methods and tools (see “C-PATH Consortia”). Much of the time the end product is a biomarker.
Formed in 2005, the not-for-profit C-PATH has about 500 scientists drawn from its members: roughly 30 major pharmaceutical companies, six patient advocacy organizations, and representation from FDA, EMEA, NIA, NINDS, NCI, and NHLBI.
The proof, of course, is in the pudding, however slowly it’s cooked and Woosley relishes talking about C-PATH’s first concrete result: a new panel of kidney biomarkers developed by its first consortium, the Predictive Safety Testing Consortium (PRTC) and approved by FDA and EMEA in November 2008.
“They (PRTC members) said we’re currently required to measure BUN (blood urea nitrogen) and creatinine by FDA. Those tests were described in the literature 104 years ago,” recalls Woosley. “People said you know we got 23 different tests (urine proteins) that we can measure and we think they are far more sensitive.”
The companies agreed to test each other’s biomarkers and assays. “At the end of the day they had seven biomarkers that worked much better than BUN and creatinine. We submitted that to the FDA,” says Woosley. A few months later, the FDA issued the first ever biomarker qualification. “It was also the first time the FDA and the EMEA jointly reviewed science, and within the same week both declared those biomarkers qualified for use.”
Initial FDA approval was for rat, but with a case-by-case acceptance in human. Since then several NDAs have used this panel although none have been approved as yet. In the meantime, PRTC has two clinical protocols in the works to get the panel approved for human testing.
Using these markers can help move a drug into phase I quickly, and potentially monitor the drug going forward. “That is one of the other things we learned,” he says. “Don’t try to hit a home run with the FDA. Ask for small reasonable things and give them the data and let them get comfortable with it and then they will move. If you ask them for a home run on day one, they are going to push back.”
Woosley, a physician and pharmacologist, has long been interested in accelerating drug development and worked in industry and academia. Before the CPI was formally released in 2004, to great fanfare, Janet Woodcock, currently director of the FDA’s Center for Drug Evaluation and Research, and one of the CPI’s primary architects, sent a preprint to Woosley. It was soon apparent that there wasn’t any money for the CPI.
Woosley was no stranger to raising money. As dean of the University of Arizona’s College of Medicine, Woolsey had helped raise $90 million in four months for the TGen (Translational Genomics Institute) initiative. He suggested going back to the state of Arizona to ask for CPI support. They raised $11 million in four weeks and got additional support from TREO (Tucson Regional Economic Opportunities). That $11 million has established the value of C-PATH, namely to address the problem that “the critical path for drug development is not very straight and is tortuous at best,” says Woosley.
FDA and C-PATH signed an MOU in the fall of 2005. Today C-PATH has 28 staffers, a third are which are scientists. Early on it decided against accepting funding from any company—“FDA wouldn’t trust us”—and once sent back a $40,000 check. Funding for the next five years is again from Arizona plus some federal money. Most of its target projects are drawn from the CPI Opportunities List issued by FDA in 2006. It detailed 76 opportunities.
Woosley admits not all attempted projects have been successful, but the ones that have worked are “where we are were able to find a project FDA felt was important, but we then found multiple companies who cared about that problem or process. We tried once with a problem that one company cared about and the FDA suspected our motives,” says Woosley.
The guiding principles are sharing knowledge; sharing failures; collaborate on applied science; and use public-private partnerships. C-PATH would be a neutral party to catalyze change. It drafted an agreement that deals with all things legal—anti-trust, IP, and liability. “Every company signs the agreement and we enforce to ensure we don’t go beyond the safety of pre-competitive science. That allows them to share data and knowledge.”
FDA is an active participant and other regulatory bodies have followed suit. There are no payers participating nor is the Center for Medicare and Medicaid Services (CMS).
“At some point, we will want to work with the insurance companies. We tried to work with CMS. We had a great project we took to CMS and they just couldn’t handle it. We’re hoping that after health care reform is over, we can go back to them and get their involvement.”
PRO was C-PATH’s second consortium (see “C-PATH Consortia”). “I was blown away at how this is a major problem in our industry today,” says Woosley. “The old method, if you wanted to know if the drug works was to ask the doctor. People now recognize maybe we should also ask the patients. But how can you do that reliably? They’re not medically savvy, so you give them a questionnaire or a PDA or something and gather data,” says Woosley.
“The FDA would like to know that those gatherings are giving you valid data. That’s our largest consortium. We’ve got companies working in several disease areas—depression, irritable bowel syndrome, asthma, diabetes, and two forms of cancer.”
The companies participating in the asthma project are all using patient questionnaires to assess the value of the drug. Rather than seven companies using seven different questionnaires that need to be independently validated, the FDA asked essentially, “Why can’t everybody agree on one questionnaire?” “So that’s what we’re doing,’” says Woosley.
The latest C-PATH effort, CAMD, is tackling neurodegenerative diseases, including Alzheimer’s and Parkinson’s. Woosley says the concept of using disease progression models to simulate a trial has been percolating at FDA and a few big pharmas for a while. Unfortunately little pharma can’t afford it. “Once we get these databases (progression models based on placebo data) into the public they gain even more traction,” says Woosley.
C-PATH’s main mission is to get scientific consensus but what happens after that? “If you want your drug approved you send in a NDA—if you want to change the way you test the drug you just have to use it and hope the FDA will approve it. We went back to Janet and said, ‘We need for you to put your blessing on this new science.’ She said, ‘We don’t have any process, let’s think about it.”
Now, says Woosley, “There’s an ICH (International Conference on Harmonization) process being written to define the process that we’ve now been using for getting that scientific consensus approved by the FDA. We don’t use the word valid or validated. We call it qualified. Is there a scientific consensus that a certain methodology is qualified for use in supporting decision making in drug development? So a qualified biomarker is our end product.”
The pathway involves a planning phase, with small working groups, and an execution phase, both of which have FDA advisors. There follows a formal submission to the FDA, specifically the BQRT—the biomarker qualification review team (a separate group of scientists), which reviews the submission like it’s a new drug, says Woosley.
C-PATH tried to get FDA to approve disease models but it declined. “The EMEA was actually eager to. FDA has told us that they will give us some sort of indication that a disease model is ready to be used but they don’t want to call it qualified.”
There’s plenty of work ahead and Woosley is excited by the prospects. He believes that Arizona has the right take on private-public organization and will continue to support C-PATH. Moreover the list of expected submissions to FDA in 2010 is long. As the results reach a critical mass, he expects more of industry and government will take notice.
Predictive Safety Testing Consortium (PSTC) — focus on safety issues; 17 companies. A new liver panel is also well along. www.c-path.org/pstc.cfm
Patient Reported Outcome Consortia (PRO) — the largest, with 24 companies. Focus on efficacy and developing standards. www.c-path.org/PRO.cfm
Coalition Against Major Diseases (CAMD) — 16 companies. Focus on sharing clinical placebo data to permit building predictive models of disease.
This article also appeared in the January-February 2010 issue of Bio-IT World Magazine.
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