Clinical Trial Upgrades — A Critical Path to Innovative Consortia

Martha Brumfield, President and CEO of the Critical Path Institute (C-Path)	Diane Stephenson, Executive Director of C-Path’s Coalition Against Major Diseases

At the 2014 BIO International Convention in June, I spoke with Martha Brumfield, President and CEO of the Critical Path Institute (C-Path), and Diane Stephenson, Executive Director of C-Path’s Coalition Against Major Diseases. C-Path is a non-profit organization working with the FDA and the EMA in forming government-industry consortia that create new universal biomarkers and clinical-trial simulation software tools to improve the speed and reliability of drug development. C-Path had its origins in a 2004 FDA Report, “Innovation/Stagnation — Challenge and Opportunity on the Critical Path to New Medical Products.” The Institute’s founder, Dr. Raymond Woosley, then the Dean of the School of Medicine at the University of Arizona, approached Janet Woodcock of the FDA’s Center for Drug Evaluation and Research, and proposed building a platform to enable public/private partnerships to form around goals listed in the report; thence, the Institute. C-Path prides itself on being neutral and independent, and “lets the science dictate where our programs go,” according to Brumfield. It currently runs seven consortia focused on key therapeutic areas, each one typically made up of industry, academic scientists, government organizations, advocacy groups and patients, as well as a scientific liaison from the FDA and scientific advisor from the EMA. 

(Note: Some of the edited transcript below was quoted in “Industry Partnerships with Patient Foundations — The Best Practices, Part Three of a Four-Part Series, Life Science Leader, August 2014.)

WHAT DO THE PEOPLE IN A C-PATH CONSORTIUM ACTUALLY DO?

BRUMFIELD: They all participate in developing a consensus around the science aimed at the consortium’s objective. For example, the Predictive Safety Testing Consortium uses biomarkers to predict organ-specific toxicity in patients. Other C-Path consortia are looking for biomarkers that can be used to enrich clinical trials, for example, one of the things Diane is working on is a program in Alzheimer’s disease. And we have been successful at having the EMA endorse imaging of the hippocampus as a biomarker that can be used in a clinical trial.

DOES THE HIPPOCAMPUS CHANGE WITH ALZHEIMER’S?

STEPHENSON: Yes. Along with loss of memory, a loss of tissue in the hippocampus is one of the first changes that happen. But the good thing about having a regulatory decision is it doesn’t matter what therapeutic target or what sponsor is bringing their drug forward. If they use this tool, when they bring their drug forward and they use this way to enrich their trial, they have a much better chance of success because so many patients are heterogeneous and they can have confidence now that they’re treating the right patients, at the right time.

HOW DOES A C-PATH CONSORTIA GET STARTED?

BRUMFIELD: Ideas for new projects come to us from many directions. Sometimes the FDA may tell us they want us to focus on a particular issue. The first time was when the agency asked us to take the lead on developing patient-reported outcome instruments, and we are now doing that for seven different disease areas. When we take on a project, we broadly reach out to those who have expertise or interest in the area and invite them to join the consortium. We want everyone’s voice at the table, and we also bring in patient perspectives.

Other times, a foundation may come to us and ask us to do something. The National Multiple Sclerosis Society [NMSS] approached us to help them develop a clinical outcome assessment instrument that can be used to evaluate new drugs to treat multiple sclerosis. They recognized that current tools are archaic and don’t represent current uses for patients. NMSS came to us with a grant and asked us to stand up a consortium, and now nine companies are participating, as well as several European and in the U.S. academic centers, working together to define the key elements of an outcome assessment instrument. We have a commitment from the companies to provide individual patient-level data on 16,000 patients that we will aggregate in a database to help the consortium design the best instrument for the future. We successfully prosecuted the first set of biomarkers that the FDA, the EMA, and the PMDA (Pharmaceuticals and Medical Devices Agency) in Japan, qualified. Once you have a success, people realize, wow, this process can work. So it’s a reinforcement of the willingness to come together and collaborate.

The impetus for our very first consortium, the one that’s been looking at biomarkers to predict organ-specific toxicity, came to us from scientists within industry. One company came to us and said its own labs and those of its competitors were all doing great things with toxicity assays, but the companies must get together to validate the new assays. So we brought multiple companies together to share not only their assays, but also test the assays on their own compounds.

SO THE ALZHEIMER’S CONSORTIUM WENT THROUGH A SIMILAR PROCESS? WHAT’S THE POTENTIAL OUTCOME OF A CONSORTIUM PROJECT RELATED TO ALZHEIMER’S?

STEPHENSON: Yes, the FDA asked us to help coordinate a series of meetings with some other important advocacy organizations to talk about getting stakeholders, industry and others to bring down the regulatory barriers to combining drugs for Alzheimer’s. People are frustrated and challenged with the number of failed trials with Alzheimer’s drugs, and they are realizing that like cancer, Alzheimer’s is a complex disease. The resulting series of meetings were really transformational, and we just had two publications accepted that are essentially position papers, saying we have to think differently, the FDA wants to reform the regulatory path so companies can work together to move their drugs in parallel as combinations through the drug development process. It is an example of where the FDA is working with us to help influence and change thinking — to help pave the way for learning, from diseases like oncology, how to get the right drugs to the right patients in drug development.

As with our success getting a safety biomarker qualified by global regulatory agencies, companies now realize that if one company tried to do that on their own it would not have worked. In Alzheimer’s disease, we had companies share data from more than 24 clinical trials, and all that data was put together in a common standard so that it’s all in a single database. The information, which could never have come from one company alone, was used to build a statistical model that predicts how companies can design trials in the future more effectively.

BRUMFIELD: The other really positive aspect of that example, once the database was formed, the companies wanted external researchers to have access. So we keep a link on our website, and we’ve had more than 250 researchers come now and tap into the database. Companies see the access as beneficial to the scientific community, although not all of our consortia are comfortable doing that.

ARE YOU SHARING AND USING CLINICAL TRIALS DATA IN THE SAME WAY GSK AND OTHER COMPANIES HAVE ADVOCATED? 

BRUMFIELD: They’re focused on transparency. Their goal is, once the study is completed, if a qualified researcher wants to use the data from that study, they can request it, and use it for a clearly defined and reported purpose. But what Diane is describing is the power of aggregating 6,000 patients worth of data, so that you can find trends. So we do a lot of data aggregation, not for transparency, but because we want to learn something scientific about the disease process, such as how the biomarkers were used. So our approach is we have a research objective to create certain biomarkers or simulation tools, we understand what data we need to achieve that research objective and provide substantial evidence to the regulators, so they have the confidence to accept the biomarkers or tools, and then we collect and pool that data.

YOU ARE ALSO TARGETING SOME UNMET MEDICAL NEEDS IN THE LARGER WORLD.

BRUMFIELD: The Bill & Melinda Gates Foundation came and asked us to help coordinate a massive set of stakeholders and people from all over the world, including the World Health Organization, the Centers for Disease Control and Prevention, the National Institutes of Health and other research institutions. Company after company has been pulling out of drug development in the TB space, yet the regimen used today to treat TB is horrible. The side effects are terrible and patients sometimes have to take the drug for up to two years. The foundation said, let’s stop thinking about developing a new drug to add to a horrible regimen — let’s develop a completely new regimen! But that strategy requires testing new chemical entities in parallel. We have had a lot of discussion with the FDA about this, and it incorporated some of our suggestions in its guidance document on combination drug development for two or more investigational new drugs. What we need now is sponsors and drug developers to step up and say, “I’m ready to do this — in partnership with a competitor.”