FDA Outlines Critical Path Opportunities

The Food and Drug Administration unveiled its long-awaited Critical Path Opportunities List in March, a summary of some 76 scientific projects that agency leaders believe can increase the efficiency, predictability, and productivity of medical product research and development. At the top of the list are a number of initiatives to identify and validate new biomarkers for clinical studies and product evaluation, along with proposals to improve clinical research practices and trial design. New statistical and computational approaches may make clinical research more informative, while computer modeling promises to avoid wasted efforts and streamline development programs.

Jill Wechsler

FDA believes that new analytical and diagnostic technologies open the door to developing more accurate and predictive measures of how a test product may affect physiological or pharmacological responses. In vitro diagnostic tests could identify patients at risk for adverse events as well as those most likely to benefit from therapy. New safety biomarkers may provide early indications of a compound's toxicity and avoid wasted research efforts. And markers of drug metabolism may accelerate individualized drug dosage that can yield safer and more effective treatments.

As the most expensive aspect of drug development, a main Critical Path objective is to encourage more productive research practices. This involves moving away from long and costly empirical testing and adopting trial designs based on a better understanding of underlying disease states and drug mechanisms of action. FDA wants sponsors to conduct more "learning trials" to explore dose–response relationships and yield more information about product performance. Instead of just gathering data on how a population responds to a test product, the aim is to gain information on how variations in disease states, organ systems, and genomes can make individuals respond differently to treatment.

Wide-ranging proposals

The list of proposals for creating more efficient clinical trials ranges from fairly practical approaches, such as establishing common standards for case report forms and for collecting clinical trial data, to devising more sophisticated research models. FDA would like to see consortiums formed to clarify statistical methods and propose standards for designing non-inferiority trials and studies with enriched patient populations. Agreement is sought on rules for revising trials based on interim results and for using historical data and animal studies to better predict human response. Groups also could address how to handle studies compromised by subject attrition and missing data.

Tailored study protocols

Another important objective is to develop study protocols tailored to specific diseases or conditions. New trial designs could improve understanding of how treatment response relates to outcomes for cancer patients. More analysis on whether pathogen levels in the blood accurately correlate to infection may improve development of vaccines and antibiotics. Standardized measures of patient symptoms and pain scores would help researchers measure a variety of indicators.

New approaches to data pooling and statistical modeling also hold promise for improved decision-making in the clinical research arena. One project in the works, for example, aims to establish a large database on cardiac arrhythmic risk to address the significance of QT interval prolongation. Pooled data on historical controls could reduce the size of control groups in clinical trials, while combined adverse event data on products or diseases could avoid safety problems in research.

Computer models of human physiology also may yield information about likely long-term performance of implanted medical devices, and clinical trial simulation could improve decisions on drug dosing. FDA and sponsors have discussed establishing a public database on unsuccessful clinical trials as a way to identify patterns associated with failure and help sponsors avoid repeating past mistakes. Databases on rare diseases, including patient histories and biomarkers, could provide virtual historical control groups, identify study subjects, and improve the design of clinical programs.

Encouraging collaboration

The Opportunities List aims to spur companies and research organizations to jointly tackle these challenges. FDA recognizes that government agencies and individual sponsors cannot address this broad range of activity, and that the agency's role is to help define how partnerships may work and to evaluate results and develop policy guidances on new approaches that researchers find to be effective.

One early model is the Predictive Safety Testing Consortium, which has been established by the Critical Path (C-Path) Institute in Arizona and several major pharmaceutical companies. Industry participants have agreed to cross-test each other's preclinical laboratory test methods on different compounds to determine which approaches are most effective in detecting toxicity in kidneys, muscle, and liver. Novartis, for example, will ask other companies to assess which of several genetic and biochemical markers can best determine whether a product is likely or not likely to cause renal safety problems. James Shannon, head of Novartis pharma development, points out that existing markers can predict negative outcomes late in development, but sponsors really need tests able to indicate early on if renal cells are being attacked.

C-Path will submit resulting data to FDA, which will weigh whether the information supports agency guidance on how best to detect kidney or liver safety problems during development. The goal is to identify the most informative tests—animal, in vitro, or clinical—for predicting toxicity, explains C-Path president Ray Woosley. The ability to determine which compounds have unacceptable side effects early on can head off investment in unpromising development programs and spur efforts to find safer compounds. Data on test methods will be available to consortium members, as will rights to license any resulting technologies eligible for patent protection.

Another collaboration, the Oncology Biomarker Qualification Initiative, was formed by FDA, the National Cancer Institute (NCI), and the Centers for Medicare and Medicaid Services (CMS) to generate procedures and evidence for developing more effective cancer treatments. The group's first project is to evaluate whether PET scans can provide a marker for early drug response in non-Hodgkin's lymphoma. This initiative supports the broader goal of assessing how well molecular imaging technology reveals drug interaction with a target and if this information can be used in tumor staging and assessing patient response to treatment. The hope is to gain new tools that improve both product testing and later treatment decisions for a range of cancers.

Moving on

FDA Deputy Commissioner Janet Woodcock regards this list of research opportunities as a fluid document that will evolve over time. She expects to issue an update this summer of projects underway and those that FDA can support more directly. The agency hopes to work with industry to demonstrate the practical value of biomarkers by identifying the range of measurements that already exist. FDA participated in an Institute of Medicine workshop on cancer biomarker development in March and plans to hold a workshop on what type of evidence is needed to qualify biomarkers for different purposes. This should lead to a general biomarker qualification guidance that will describe a "fitness for use" standard that links biomarker validation to its intended use. Additional guidances on specific qualified markers will follow, possibly starting with documents on testing for liver and kidney toxicity.

Also on the agenda is draft guidance on drug-diagnostic co-development. FDA published a concept paper on this topic in April 2005, but the specifics of developing a diagnostic test to fit a new therapy have been difficult to pin down.

Many of these initiatives call for drug companies to share data on test results and best practices, something that industry generally is reluctant to do. Reaching agreement on the C-Path safety consortium involved dozens of lawyers and endless paperwork to define a precompetitive area for collaboration that avoids antitrust violations. While the participants believe that it is in the interest of industry and public health to have better markers for drug safety, such joint projects could collapse if participants don't pull their weight or wrangle over intellectual property issues, comments Shannon of Novartis. And Critical Path could lose its impetus with a shift to less supportive FDA leadership.

But industry leaders believe that the time is right for change. "We now have the science and technology to support a powerful engine for drug development," Shannon observes, "but the rules of the road say we can't drive more than 30 miles per hour." Industry collaboration under FDA leadership provides an opportunity to move away from redundant testing and wasteful procedures and allow new approaches to flourish. Biomarker development and clinical trial innovation may take more time and effort than anticipated, but even small gains may make a difference.

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Jill Wechsler is the Washington editor of Applied Clinical Trials, (301) 656-4634 jwechsler@advanstar.com