After four years of laying a foundation for new efforts to streamline clinical testing and drug development, leaders of the
Food and Drug Administration 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). In fact, she and her colleagues are
looking to institutionalize CPI as an ongoing FDA program, she noted at a September workshop sponsored by the Drug Information
Association (DIA).
The vision is to replicate the massive investment in research and in devising more flexible regulatory approaches that stemmed
the AIDS epidemic 20 years ago. That effort produced new surrogate markers and accelerated approval processes to spur development
of new treatments, recalled Mark Harrington of the Treatment Action Group. Yet this achievement was an exception, Harrington
noted at the DIA workshop, and did not extend to new drugs for other infectious diseases.
FDA's Critical Path white paper of 2004 was a "wake up call" to the need for new approaches to translate the explosion in
biomedical research and genetic discovery into new therapies for patients. Then FDA commissioner Mark McClellan, now with
the Brookings Institution, championed the Critical Path as a way to reverse the slowdown in drug development, along with rising
R&D costs that made many new medicines unaffordable to patients.
Since then, FDA has formed numerous public–private partnerships (PPPs) 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. McClellan is optimistic that the new Reagan-Udall Institute will overcome Congressional concerns
and spur more public–private collaborations in these areas. Search for biomarkers
The key to more efficient and informative clinical research is to identify and confirm new markers able to indicate response
to a test compound. Biomarkers are commonly accepted as measures for a drug's toxicity in animals and for early impact on
organs. Several CPI collaboratives, such as the Predictive Safety Testing Consortium formed by the Critical Path Institute
in Arizona, are examining possible biomarkers that outperform conventional tests. For example, the consortium's nephrotoxity
working group, which includes 16 pharma companies, regulators, and academic experts, is identifying biomarkers able to monitor
certain kidney pathologies in animal toxicology studies, along with a process for regulators to review resulting safety data
as bridging tools.
Jill Wechsler
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The Alzheimer's Disease Neuroimaging Initiative organized by the National Institute on Aging (NIA) at the National Institutes
of Health (NIH), a consortium of pharma companies, academics, and patient groups, is examining methods for correlating imaging
and biomarker data with cognitive and clinical results and is getting results from initial studies. The Cancer Vaccine Consortium
(CVC) has 70 members working to harmonize and reduce variability in assays for cellular immune response to support development
of more reliable biomarkers.
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 FDG-PET scan project
has launched a number of studies to measure whether to assess scans as predictive measures of tumor response in cancer patients.
Similarly, studies are evaluating whether certain MRIs measuring tumor blood flow can predict response to therapy.
And the MARVEL (Marker Validation for Erlotinib in Lung Cancer) study will test 1200 lung cancer patients for the presence
or absence of a gene-influenced receptor (EGFR) that can affect response to different chemotherapy drugs. The aim is to determine
whether patients with EGFR-positive lung cancer respond better to Genentech's Tarceva (erlotinib), and if receptor-negative
patients do better on Eli Lilly's Alimta (pemetrexed).
Establishing these and other partnerships has taken months of negotiations involving data standards, information sharing,
access to results, and protection of proprietary information. The experience gained over the past few years should clarify
policies and approaches for dealing with conflicts of interest and intellectual property protections and smooth the path to
new collaborations.
Transforming trials
The CPI initiative also aims to modernize today's costly, inefficient clinical research process. In addition to low success
rates in bringing new drugs to market, public complaints about data suppression, disregard for patient welfare, and a "profits-over-
patients" attitude has roiled the clinical research enterprise. Such complaints have drawn Congressional scrutiny and reduced
public trust in biomedical study methods, along with confidence in FDA's role as a reliable gatekeeper for appropriate research
activity.
Investigator sites find themselves operating in an "ugly environment," said Ken Getz, from Tufts University's Center for the
Study of Drug Development at the DIA workshop. Sites have to deal with protracted contract negotiations, burdensome protocols,
difficulties recruiting subjects, high staff turnover, lengthy informed consent forms, disparate systems for data collections,
and rising operating costs.
The good news is that this inefficient system offers abundant opportunities for improvement, a task 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 seeks 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 clinical trial monitoring
and serious adverse event reporting. 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 results being posted on
Web sites.
NIH's Clinical Research Policy Analysis and Coordination program (CRpac) similarly seeks to improve the conduct of clinical
research by clarifying federal research policies and improving oversight of research activities. Philip Budashewitz of NIH's
Office of Biotechnology Activities prefers to regard the clinical research enterprise as an "industry in transition" rather
than an "industry in trouble." To better coordinate policies for reporting adverse events from multisite trials, CRpac plans
to establish an electronic adverse event (AE) submission system with a federal-wide AE reporting portal. Another project is
developing clearer policies for collecting human specimens.
Tackling disease
The proof of the pudding is whether better biomarkers and clinical trial methods will yield new treatments for disease. One
Critical Path project is focusing on methods to identify therapeutic targets and novel endpoints that may accelerate clinical
research on treatments for polycystic kidney disease.
Efforts to develop biomarkers for detecting liver damage from drugs, moreover, could help Novartis gain market approval for
its Cox-2 inhibitor Prexige. The drug is highly effective but "has an Achilles heel" of severe hepatoxicity in certain patients,
explained Timothy Wright, head of translational science at Novartis, at the 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 support approval. Novartis plans to run an additional clinical trial utilizing a genetic
marker, but FDA would need strong evidence that the test process can sufficiently reduce chances of a rare catastrophic event.
FDA's Analgesic Clinical Trials Project (ACTP) aims to generate interest in R&D on novel pain killers by developing new efficacy
endpoints and evaluating innovative study 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 reanalyze
data from a number of failed analgesic trials to assess ways to maintain study sensitivity and to explore high placebo responses
rates. A broader PPP will expand the scope and funding for the project to also address analgesic use in preventing chronic
postsurgical pain.
A related safety-oriented initiative headed by Rappaport's group is assessing whether exposure of children to sedatives and
anesthetics is linked to long-term neurocognitive and behavioral deficits or structural brain changes. The SAFEKIDS (Safety
of Key Inhaled and Intravenous Drugs in Pediatrics) 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 to improve clinical practice.
Jill Wechsler is the Washington editor of Applied Clinical Trials. jwechsler@advanstar.com
