After spending 4 years laying a foundation that will streamline clinical testing and drug development, FDA leaders are poised to move the agency's Critical Path Initiative (CPI) from concept to implementation. Despite public concerns about drug safety, dangerous imports, and rising pharmaceutical costs, CPI has not fallen by the wayside.
After spending 4 years laying a foundation that will streamline clinical testing and drug development, FDA leaders are poised to move the agency's Critical Path Initiative (CPI) from concept to implementation. Despite public concerns about drug safety, dangerous imports, and rising pharmaceutical costs, CPI has not fallen by the wayside, reports Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER).
FDA's CPI white paper of 2004 announced the need for new ways to translate the rapid expansion in biomedical and genetic research into new therapies for patients. Then-FDA commissioner Mark McClellan, now with the Brookings Institution, championed CPI as a way to reverse both the slowdown in drug development and rising costs of research and development (R&D) that make many new medications unaffordable to patients.
The goal of CPI is to replicate the massive investment in research and the flexible regulatory approaches that stemmed the AIDS epidemic 20 years ago. The effort produced new surrogate markers and accelerated approval processes that galvanized the development of new treatments, as Mark Harrington of the Treatment Action Group recalled at a September workshop sponsored by the Drug Information Association (DIA). This achievement was an exception, Harrington said, and did not extend to similar encouragement of new drugs for other infectious diseases.
In the last 4 years, FDA has formed numerous public-private partnerships with industry, academia, patient groups, and other government agencies to tackle many of the 76 projects described on the CPI "wish list" published in 2006. These partnerships are developing new biomarkers, disease models, methods for genomic data analysis, and data-tracking systems, such as FDA's emerging Sentinel network.
Several CPI collaborative groups, such as the Predictive Safety Testing Consortium formed by the Critical Path Institute in Arizona, are examining potential biomarkers that outperform conventional tests. For example, the consortium's nephrotoxity working group, which includes academic experts, regulators, and 16 pharmaceutical companies, is identifying biomarkers that can be used to monitor certain kidney pathologies in animal toxicology studies; this group is also establishing a process by which regulators can review resulting safety data as bridging tools.
Organized by the National Institute on Aging (NIA) at the National Institutes of Health (NIH), the Alzheimer's Disease Neuroimaging Initiative, a consortium of academics, pharmaceutical companies, and patient groups, is examining methods for correlating imaging and biomarker data with information derived from cognitive and clinical tests. Initial studies show promising results.
The National Cancer Institute (NCI) is sponsoring several biomarker validation projects under the Oncology Biomarkers Qualification Initiative formed in 2006 by NCI, FDA, and the Centers for Medicare and Medicaid Services (CMS). The fluorodeoxyglucose-positron-emission tomography (FDG-PET scan) project has launched several studies to explore whether scan assessments can be used as predictive measures of tumor response in patients with cancer. Similarly, studies are assessing whether certain magnetic resonance imaging (MRI) scans measuring tumor blood flow can predict response to therapy. The Marker Validation for Erlotinib in Lung Cancer (MARVEL) study will test 1,200 patients with lung cancer for the presence of a gene-influenced receptor (eGFR) that can affect response to different chemotherapy drugs. The goal is to assess whether patients with eGFR-positive lung cancer respond better to erlotinib and whether receptor-negative patients respond better to pemetrexed.
TRANSFORMING CLINICAL TRIALS
The CPI also seeks to modernize today's costly, inefficient clinical research process, with its low success rates in getting new drugs to market. The clinical research enterprise has drawn public complaints about disregard for patient welfare, data suppression, and a "profits-over-patients" attitude. Such complaints have prompted congressional scrutiny and contributed to dwindling public trust in biomedical study methods.
The inefficiencies in the existing research system offer numerous opportunities for improvement; this task has been taken on by the Clinical Trials Transformation Initiative (CTTI). This group was established last year as a partnership of FDA and Duke University's Translational Medicine Institute, in collaboration with industry, academia, patient advocates, and other government agencies. The group is working to establish national standards for research functions, new review models for multisite trials, accreditation programs for investigators and sites, and improved data-management systems. Initial projects will address the monitoring of clinical trials and reporting of serious adverse events. CTTI also is considering a project to clarify best practices for oncology data management and an initiative to improve public understanding of the growing volume of clinical trial data and trial results posted at websites.
NIH's Clinical Research Policy Analysis and Coordination program (CRpac) seeks to improve conduct of clinical research by clarifying federal research policies and strengthening oversight of research activities. To better coordinate policies for reporting adverse events from multisite trials, CRpac plans to establish an electronic adverse event submission system with a reporting portal that encompasses the federal system.
The underlying question is whether better biomarkers and clinical trial methods will yield new treatments for disease.
Efforts to develop biomarkers for detecting liver damage from drugs, for example, might help Novartis gain market approval for its cyclo-oxygenase-2 (COX-2) inhibitor lumiracoxib. The drug is effective but "has an Achilles heel" of severe hepatotoxicity in certain patients, said Timothy Wright, head of translational science at Novartis, at September's DIA workshop. Last year, FDA rejected the drug, calling for additional safety data, and Wright hopes that identifying a genetic marker for patients most likely to develop liver damage from the drug could lead to clinical trials that would support its approval.
FDA's Analgesic Clinical Trials Project (ACTP) seeks to encourage an R&D focus on novel painkillers by developing new efficacy end points and evaluating innovative designs likely to improve the success rate of clinical studies for these products. Bob Rappaport, director of CDER's Division of Anesthesia, Analgesia and Rheumatology Products, heads an initiative to re-analyze data from a number of failed analgesic trials to assess ways to maintain study sensitivity and to explore high placebo response rates. A broader range of public-private partnerships would expand the scope and funding for the project, enabling it to address analgesic use in preventing chronic postsurgical pain.
Rappaport's group heads a related safety-oriented initiative that is assessing whether children's exposure to sedatives and anesthetics is linked to long-term neurocognitive and behavioral deficits or structural brain changes. The Safety of Key Inhaled and Intravenous Drugs in Pediatrics (SAFEKIDS) partnership has designed a $40 million research program with 12 possible studies to assess long-term developmental outcomes and neurotoxic effects. The aim is to identify tools that all stakeholders can use to develop safer drugs and improve clinical practice.