The Path to Collaboration
by Sarah Fister Gale
October 2007
The Critical Path Initiative’s early projects are validating the concept of better drug development through public and private partnerships.
Photography by Charles Ledford
The U.S. Food and Drug Administration’s (FDA) Critical Path Initiative (CPI) has kicked into high gear since the publication of the Critical Path Opportunities List in March 2006. Early projects already underway promise to build a foundation of information-sharing that will shave time from the drug development process and improve success rates. These projects focus on the development of centralized databases and cross-disciplinary efforts to identify key biomarkers and other clinical phase tools, and they signal a changing attitude among stakeholders in the pharmaceutical world.
In a world where trade secrets determine billion dollar profits, the CPI has been a catalyst for industry stakeholders, researchers and government agencies to find ways to set aside secrecy in order to work together toward common goals. It’s a development that offers hope to consumers and developers that this slow-moving industry might find ways to improve its drug development process and bring solutions to market sooner.
Spurring Change
The CPI is the FDA’s plan to facilitate a national effort to modernize the scientific process through which potential human drugs, biological products and medical devices are transformed from discovery into a medical product. Launched in March 2004—with the release of the FDA report entitled Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products — CPI outlines scientific reasons for the decrease in the number of innovative medical products submitted to the FDA for approval. According to the report, recent data shows that the financial investment required to launch a new drug rose 55 percent during the previous five years, and that pharmaceutical, biotechnology and medical device productivity was declining at the same time that the costs to develop a small number of treatments were rising. The current costs of bringing a new medicine to market, estimated to be as high as US $800 million, are a major barrier to investment in innovative, higher risk drugs or in therapies for uncommon diseases or diseases that predominantly afflict underserved populations.
The FDA report lit a fire under an industry that has struggled for years with new product development’s skyrocketing costs and shrinking success rates. The announcement of the Opportunities List signaled the next major step for the CPI, and was a positive indicator that all segments of the industry were ready to embrace and implement change.
Early Successes
The key to the successes of the early projects is the focus on pre-competitive issues that deliver common areas of value, such as safety and efficacy, says Raymond Woosley, Ph.D., president and CEO of the Critical Path Institute (C-Path) based in Tucson, Ariz., USA. C-Path was created to support CPI by developing collaborative projects in research.
Teamwork and information-sharing are both key to all areas of the CPI, according to Dr. Janet Woodcock, deputy commissioner and chief medical officer of the FDA, in Rockville, Md., USA. “One of the great tragedies that has occurred [in the pharmaceutical industry] is the lack of sharing of all the existing knowledge and databases that have been generated mostly in the private sector,” she says. “We have a lot of information and data out there but we have very little knowledge that we’ve built on.”
C-Path and similar nonprofit groups hope to create forums through which scientific information can be shared and compiled toward the goal of greater standardization of testing and validation. Woosley points to other industries that have established organizations to foster collaboration among competitors to achieve common goals, such as the food industry’s Center for Food Safety (CFS), or the semiconductor manufacturing industry’s International Sematech. “Like CFS and Sematech, C-Path brings together industry, the FDA and scientists to discuss processes, not products, in drug development.” By addressing non-competitive processes, Woosley hopes industry members can find common ground to develop better testing methods and tools to shorten the early clinical trial phase for products, and improve drug safety without compromising proprietary information.
“The work is not focused on product development, and that’s what’s very novel about this,” Woodcock says. “It is focused on infrastructure and developing a new scientific tool kit that we can all use to bring these products forward.”
Centralized Information
The proposed Reagan-Udall Institute for Applied Biomedical Research is another center developed as part of the CPI to promote cooperative projects. This public/private partnership at the FDA is meant to advance CPI goals by coordinating research activities between FDA regulators and academic and industry researchers. The creation of the Institute was sponsored by U.S. Sens. Mike Enzi (R-WY), ranking member of the Senate Health, Education, Labor and Pensions (HELP) Committee, and Edward Kennedy (D-MA).
“The Reagan-Udall Foundation is vital to bringing drug and medical device evaluation into the 21st century so that the FDA, academic institutions, and industry can work together to predict earlier and more accurately the safety and effectiveness of medical products,” Enzi says. “[The Foundation] will spur the development of new tools to better predict safety and efficacy, which in turn will increase the speed and efficiency of product development and evaluation.” Included in the Foundation’s key tasks are coordinating ongoing research activities between government agencies and academic and industry researchers, as well as identifying research priorities and coordinating programs to address these priorities. It also will act as a clearinghouse to share knowledge and information developed in these programs so that others may benefit from their findings.
“The FDA alone cannot serve this valuable function, nor can industry or academia,” Enzi says. “Only through an institution, such as the Reagan-Udall Foundation, can we bring various parties together to serve the common goals of developing new products more quickly while ensuring that these products are safe.”
Biomarker Research
With the support of groups like C-Path, the National Cancer Institute (NCI) and the Foundation of the National Institute of Health, many CPI projects already are up and running. One of the first was the Predictive Safety Testing Consortium (PSTC), in which pharmaceutical companies share and validate each other’s safety testing methods under FDA advisement. Through PSTC, which is sponsored by C-Path, 16 member companies, represented by 160 scientists, along with 15 FDA and 20 European Medicines Agency (EMEA) representatives are sharing pre-clinical safety biomarkers in four workgroups: carcinogenicity, kidney, liver and vascular injury. Notably, the FDA scientists are acting as participants—not regulators—in the Consortium project. Each member of the Consortium already has shared internally developed pre-clinical safety biomarkers in the four pathology areas.
“They have developed a mechanism with all the appropriate intellectual property and antitrust arrangements for these companies to pool their assays and data on animal toxicogenomic tests and related tests that have been developed to better predict toxicity in the animal testing,” Woodcock says. “Until now, all of these tests and data have been sequestered away … the Consortium will make the data and the assays publicly available at the end of the testing period.” The safety biomarkers will be cross-validated by other members of the Consortium, and the data generated will be the basis for an FDA guidance to provide direction for the entire pharmaceutical industry on how to better test drugs for safety.
“Everyone loses when a drug goes down,” Woosley says. “By sharing testing methods we can agree which ones are the highest performing and those will be submitted to the FDA. It will create a pool of knowledge and a much richer panel for testing, which we can make sure everyone is using.”
Biomarker research is core to many of the early CPI projects as biomarkers can enable early decision-making and can reduce the trial-and-error processes often found in later stage drug development. “Diagnosis is the foundation of medicine, not treatment,” Woodcock says. “We have been rushing to develop treatments and we have not been rushing to figure out all the things we need to know about people before we intervene and treat them.”
Unfortunately, biomarker research carries neither the glamour nor the profits of other pharmaceutical research endeavors. Though the scientific community agrees that applying biomarkers that predict the success of therapy is likely to be an effective strategy, pharmaceutical companies rarely develop biomarkers to the point where they have been validated for clinical trials. “That’s why we think consortia are needed to develop [biomarkers] because there are many parties that will benefit from their development, not to mention the patients,” Woodcock says.
Christopher-Paul Milne, associate director for Tufts University Center for the Study of Drug Development in Boston, Mass., USA, agrees. “Biomarkers are at the heart of a lot of things we are trying to do to expedite the drug development process,” he says. “They give us an early indication that prospective compounds will do what we think they are going to do, and that can shave time from the development process.” For example, with cancer treatments, doctors often have to wait five to 10 years to judge success based on survival rates, Milne says. “If instead doctors could directly tie tumor reduction to survival, they could judge success in much less time using that biomarker.”
Each One, Teach One
As part of a Federal collaboration called the Oncology Biomarker Qualification Initiative, which includes the FDA, the NCI, and the Centers for Medicaid & Medicare Services, several cancer biomarker discovery projects are under way, including projects on FDG-PET scanning in cancer. This initiative hopes to advance the development of personalized treatment and diagnostic testing. The goal of C-Path’s Cancer Biomarkers working group is to undertake a clinical trial that will provide the FDA with evidence to guide the selection of tests that predict response to the treatment of non-small-cell lung cancer drugs that target novel proteins in cancers.
The Cancer Biomarker project is particularly important because cancer drugs have the highest failure rate in clinical development. Compounding that problem is the fact that diagnostic companies typically can’t justify the investment into biomarker research because it doesn’t result in commercial products the way other drug research does, notes C. Anthony Altar, Ph.D., director of The Biomarkers Consortium, an effort of the Foundation for the National Institutes of Health (FNIH), in Bethesda, Md., USA. “Biomarker discovery is an area of research that pharmaceutical companies don’t commonly explore,” Altar says. “However, pharmaceutical companies will benefit from being able to test proprietary compounds using the data from biomarker research.”
“If we can standardize methods to assess drugs on a level playing field it will help us more accurately predict drug dosing, safety and efficacy,” Altar says. “It’s an important mission at the NIH that the data generated from this research become rapidly available to the public so that everyone benefits from it.”
That broad information-sharing is another core function of the early CPI opportunities because it will lead to standardization of test methods, and break down the existing silos around isolated critical data that can be used industry wide in the drug development process. To support the goal of sharing information, one of the first projects to come out of the CPI was the Federal Investigator Registry of Biomedical Information Research Data (FIREBIRD). FIREBIRD automates the Form 1572 registration process, which is a key activity in the regulatory data submission process and compliance requirement for investigators participating in clinical trials, says Dr. Ken Buetow, associate director of bioinformatics and information technology at the NCI, in Rockville, Md., USA. “FIREBIRD is part of a much larger effort to build an electronic infrastructure to support the complete lifecycle of clinical research, from early trials to regulatory submissions,” Buetow says. “We are creating a 21st century infrastructure to support 21st century medical development.”
FIREBIRD is the first step toward this goal and will function as the global investigator registry for commonly referenced data and a secure database to store, query and structure submission information. It will enable investigators to register online with NCI and other sponsors, including pharmaceutical companies, and it will automate the existing FDA Form 1572 registration process, allowing investigators to centrally maintain and manage all 1572 registrations. “Automating the 1572 registration gives regulators a uniform place to investigate research, and it gives industry and academia a one-stop shop for maintaining information,” Buetow says.
FIREBIRD was an early CPI project for several reasons. “It was doable, it was not controversial and it will be extremely beneficial,” Buetow says. It also was a long time in coming. “The pharmaceutical industry hasn’t used computer technology for global information-sharing the way other sections of the business community have,” he says. “This transition is key to the future biomedical research.”
Stepping Up
One of the reasons it has taken so long to create a centralized repository for data is that there was no clear indication of whose responsibility it was to develop and maintain it. “The pharmaceutical companies couldn’t do it because of antitrust issues, the FDA is financially strapped, and academia is a separate community,” Buetow says. “FIREBIRD required a partnership among all of them, and it took the visionary leadership of the NCI and the FDA to make it happen. If you want infrastructure you need stakeholders.”
The benefits of FIREBIRD, Buetow says, are threefold. It is a forum for those who want to identify themselves as investigators available to do trials; it facilitates people’s awareness of Institutional Review Boards (IRBs) and Clinical Laboratory Improvement Amendments (CLIA) certified labs; and it eliminates much of the paper from the regulatory system. “It removes redundancies, and reduces steps from the process,” he says. “That is a critical component of CPI.”
FIREBIRD completed its first technical pilot to assess the technology specifications of the tool and the first operational pilot to assess its effectiveness. In the operational pilot program, 49 sponsors and 112 investigators ran parallel trials using the FIREBIRD infrastructure, and the group currently has the authorization to move 100,000 investigations into the tool, according to Buetow. The pilot was a great success, he says, with important lessons learned. “The biggest challenge for the academic setting was the movement of the tool to the desktop, and the need for legally enforceable digital signatures and security,” he says.
To meet this need, the NCI implemented Secure Access for Everyone (SAFE) as an Identity Assurance Infrastructure, which delivers electronic authentication and legally enforceable digital signing capabilities to all investigators, clinical research assistants and sponsors participating in the clinical trial activities.
Forward Thinking
Buetow predicts the commercial version of FIREBIRD should be up and running within a year. The next information infrastructure module, Janus, is underway. Janus is a standards-based clinical data repository that utilizes the open source data model. Created by the FDA in partnership with IBM, the repository provides a data collection and analysis warehouse for clinical trial data submitted for protocols as well as clinical outcomes data. All of this information is then submitted in Investigational New Drug (IND) applications to the FDA. Depending on the particular trial, the IND holder may be NCI, a pharmaceutical or biotechnology company, a NCI Cooperative Group or an academic institution funded by NCI. “We’ve already completed the technical pilot for Janus and are gearing up for the operational pilot,” Buetow says. “It’s the next step in creating a suite of interactions in an electronic context to facilitate collaborative processes for clinical research.”
The pharmaceutical industry is hopeful that great strides will be made as a result of these early projects, but there is still much research to be done, Woosley says. “Fifteen years and a billion dollars is too much to develop a drug,” he adds. “We need to strive for personalized medicine in a reasonable amount of time.” By identifying pre-competitive areas to promote discussion and research, key stakeholders across the industry are finding ways to work together for everyone’s benefit. “By sharing our successes and mistakes, we can agree on the best paths to achieve these goals,” Woosley says.
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