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Biomarker Standards to Play Key Role in NCI s Five-Year Clinical Trials Overhaul

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The US National Cancer Institute has initiated a "standards-setting process" for handling biomarker data that is part of a larger, five-year, $112.9 million effort to restructure the institute's clinical trials enterprise, according to a report submitted last week by the multi-institutional Clinical Trials Working Group to the NCI's National Cancer Advisory Board.

This biomarker-handling process is one of several initiatives under the broader goal of establishing "Prioritization/Scientific Quality Initiatives." Of the four broad goals the CTWG was set up to attack, this one is the most immediately relevant to pharmacogenomics, and is described in the text of the report as "potentially the most important." The institute hopes its biomarker standards initiative will allow it to more easily compare the data from different trials and laboratories, including large data sets from multiple trials. The initiative is also intended to reduce duplication in defining assay methods and data requirements, and to ease the process of data submission for US Food and Drug Administration approval.

The CTWG presented its recommendations to the NCAB in mid-February, and the advisory board accepted them last week, the NCI said in a statement. In all, the working group's efforts resulted in 22 initiatives for the improvement of clinical trials within the NCI.

Ultimately, the effort will complement the NCI's ongoing collaboration with the FDA through the Interagency Oncology Task Force, which was established in 2003, in defining "relevant issues" and in establishing policies and procedures for validating biomarkers as drug development endpoints, said the report [see sidebar].

With the recent release of its Voluntary Genomic Data Submissions guidance, the FDA has been closing in on a system to define biomarkers as "exploratory," "probable valid," and "known valid," in an effort to establish them in the diagnostic arena as clues to drug response and disease susceptibility; and in drug development as surrogate endpoint and stratification tools.

"One could imagine taking some cancer biomarkers that are close to being validated for patient use and for drug-development use, and doing some prospective studies that would … put the nail in it, and clarify the relationship between the marker and outcome," Larry Lesko, director of the Office of Clinical Pharmacology and Biopharmaceuticals at the FDA's Center for Drug Evaluation and Research, told Pharmacogenomics Reporter.

By the end of the first two years of the plan, the NCI hopes to establish and publicize standards for "procedure-specific" categories, quality control, validation, documentation, and other areas, the report said. The institute will require the use of these biomarker standards for all correlative clinical trials unless investigators can present a compelling case not to use them, while novel scientific methods will need an accompanying rationale.

Funding for the correlative-science standards portion of the plan will come from approximately about 5 percent of the total that the report estimates the NCI will spend on clinical trials management restructuring plan. Not including that amount, the entire Prioritization/Scientific Quality Initiatives goal is budgeted at about $2 million for implementation. The broader clinical trials restructuring program has a total budget of $112.9 million over the five-year period.

As it goes about revamping its approach to clinical trials, the NCI will also investigate the "costs and benefits" of developing a list of clinical trial labs and imaging cores meeting its standards, said the report. Should the list take shape, NCI studies would only use facilities from the list, according to an NCI spokesperson.

The NCI will enlist experts in imaging, molecular analysis, pathology, immunohistochemistry, and other fields to help it establish standards for assays and imaging procedures for NCI-funded correlative-science clinical trials. The institute expects these experts to include scientists from the US National Institute of Standards and Technology, as well as the pharmaceutical and biotechnology industries.

Oncology Task Force is at the Intersection of the NIH Roadmap and FDA's Critical Path

Under the Interagency Oncology Task Force, NCI scientists can spend one to three years learning about drug development from FDA reviewers and researchers in order to augment their own cancer research, according to a February statement by Les Crawford, acting commissioner of the FDA.

"We like to focus on something that's in the NIH Roadmap [for Medical Research initiative] and in our Critical Path Initiative, namely, translational medicine," Larry Lesko, director of the Office of Clinical Pharmacology and Biopharmaceuticals at the FDA's Center for Drug Evaluation and Research, told Pharmacogenomics Reporter.

"That's one thing in common with NCI," said Lesko. "What they've turned their attention to in the Roadmap is translating biomarkers that are discovered into meaningful classifiers for clinical use, and that's where FDA is very good, because that's where we lived," he said. "We focus on biomarkers as predictors of something, whether it's survival, prognosis, or dose. So, by merging the two organizations with this shared interest, that's where I think the new collaboration is going to focus."

There is not yet a final list of technologies for which standards are necessary, so the NCI will begin the effort by building one. As it defines what standards each assay or procedure must meet, the institute will borrow heavily from existing guidelines, such as those from the Clinical Laboratory Improvement Amendments and the College of American Pathology. The CTWG report directs the NCI to update its own standards "at least annually" with changes made by those organizations to their own requirements, as well as with changes dictated by technological advances.

The Four Goals of the NCI Plan

The report describes the Prioritization/Scientific Quality goal as the improvement of "prioritization and scientific quality by developing an open and transparent process for the design and prioritization of clinical trials that are science-driven and meet the needs of patient care."

The other three main CTWG goals were: to improve coordination and cooperation among the system's components; to improve standardization of tools and procedures for trial design, data capture, data sharing, and administrative functions; and to improve operational efficiency by increasing patient accrual and reducing operational barriers.

The entire plan is envisioned to be in place in five years.

The Clinical Trials Working Group was set up by Andrew Eschenbach, NCI director, at the beginning of 2004 to help the National Cancer Advisory Board decide how to better structure clinical trials to make better use of molecular medicine, according to the recent CTWG report. The working group includes academic experts, oncologists, representatives from pharma and biotech, cancer patient advocates, members of the NCI itself, members of the FDA, and representatives from the Centers for Medicare and Medicaid Services.

The complete CTWG report is available here.

— Chris Womack ([email protected])

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