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A Roadblock to Personalized Cancer Care?

There’s a major roadblock to creating personalized cancer care.

Doctors need a way to target treatments to patients most likely to benefit and avoid treating those who will not. Tumor biomarker tests can help do this.

The problem, according to a new commentary paper, is that, unlike drugs or other therapies, cancer biomarker tests are undervalued by doctors and patients. The authors say that inconsistent regulatory rules, inadequate payment and underfunded tumor biomarker research has left us in a vicious cycle that prevents development and testing of reliable biomarker tests that could be used to personalize clinical care of patients with cancer.

“Right now biomarkers are not valued nearly to the extent that we see with therapeutics. But if a tumor biomarker test is being used to decide whether a patient should receive a certain treatment, then it is as critical for patient care as a therapeutic agent. A bad test is as dangerous as a bad drug,” says Daniel F. Hayes, M.D., clinical director of the breast oncology program at the University of Michigan Comprehensive Cancer Center.

Hayes led a blue-ribbon panel of experts from universities, corporations, insurance and advocacy organizations to outline the issues in a commentary published recently in Science Translational Medicine.

Tumor biomarker tests look at the genetic or molecular make-up of a tumor to determine whether the cancer is likely to progress, and if so, if it is likely to respond to treatment. If the test is good, it can help doctors decide when a patient can safely skip further therapy, or it can be used to direct which drug might be most likely to help. The result: “personalized medicine,” which means patients get treatments that benefit them specifically and they avoid treatments – including their costs and side effects – that are not likely to make a difference for them.

The regulatory process, the research funding, the reimbursement, even the standards for journal publications for tumor biomarker tests are all meager compared to the robust support for drug development, the authors say.

This creates a vicious cycle in which researchers and drug companies don’t invest in tumor biomarker research, tests are not fully evaluated in clinical trials, and tests with uncertain value in terms of predicting the success of treatment are published. This in turn means that few of these tests are included in evidence-based care guidelines, leaving health care professionals unsure of whether or how to use the test, and third-party payers unsure of how much to pay for them.

The authors outline five recommendations and suggest that all five must be addressed to break the vicious cycle:

  1. Reform regulatory review of tumor biomarker tests
  2. Increase reimbursement for tumor biomarker tests that are proven to help determine which therapies will or are working
  3. Increase investment for tumor biomarker research so it’s comparable to new drug research
  4. Increase the rigor for peer review of tumor biomarker publications
  5. Include only proven biomarker tests in evidence-based care guidelines

“These recommendations are not about creating more regulation; they are about creating an even playing field that allows tumor biomarker tests to be developed and proven clinically relevant. We want to stimulate innovation yet hold investigators and clinicians to the highest scientific standards – as we now do for therapeutics,” Hayes says. “We need to change the way we value tumor biomarkers in this country.”

Study: Breaking a Vicious Cycle [Science Translational Medicine]

Source: University of Michigan Health System

NextBio Announces Translational Medicine Partnership with Sanofi

NextBio recently announced a multi-year collaboration with Sanofi (NYSE:SNY) aimed at using NextBio Clinical to incorporate patient omics and clinical data into Sanofi’s drug research and development, as part of Sanofi’s Translational Medicine for Patients (TM4P) program.

Third-generation Device Significantly Improves Capture of Circulating Tumor Cells

A new system for isolating rare circulating tumor cells (CTCs) – living solid tumor cells found at low levels in the bloodstream – shows significant improvement over previously developed devices and does not require prior identification of tumor-specific target molecules. Developed at the Massachusetts General Hospital (MGH) Center for Engineering in Medicine and the MGH Cancer Center, the device rapidly delivers a population of unlabeled tumor cells that can be analyzed with both standard clinical diagnostic cytopathology and advanced genetic and molecular technology. The MGH team’s report has been published in Science Translational Medicine.

“This new technology allows us to follow how cancer cells change through the process of metastasis,” says Mehmet Toner, PhD, director of the BioMicroElectroMechanical Systems Resource Center in the MGH Center for Engineering in Medicine, the paper’s senior author. “Cancer loses many of its tissue characteristics during metastasis, a process we have not understood well. Now for the first time we have the ability to discover how cancer evolves through analysis of single metastatic cells, which is a big step in the war against cancer.”

The new device – called the CTC-iChip – is the third microchip-based device for capturing CTCs developed at the MGH Center for Engineering in Medicine. The first two systems relied on prior knowledge of a tumor-specific surface marker in order to sort CTCs from whole blood and required significant adjustment for each different type of cancer. The systems also required four to five hours to process a single blood sample.

The only U.S. Food & Drug Administration-cleared, commercially available device for capturing and enumerating CTCs – the CELLSEARCH® system developed by Veridex, LLC – relies on magnetic nanoparticles that bind to the same epithelial protein used in the MGH -developed microchip-based devices and cannot always find CTCs present at very low numbers. In January 2011 the MGH entered into a collaborative agreement with Veridex and its affiliate Janssen Research & Development, LLC, to establish a center of excellence in research on CTC technologies.

Combining elements of both approaches – magnetic labeling of target cells and microfluidic sorting – the CTC-iChip works by putting a blood sample through three stages. The first removes from the sample, on the basis of cell size, all blood components except for CTCs and white blood cells. The second step uses a microfluidic process developed at the MGH to align the cells in a single file, allowing for extremely precise and rapid sorting. In the third stage, magnetically labeled target cells – either CTCs tagged via the epithelial marker or white blood cells tagged on known blood-cell antigens – are sorted out. Tagging white blood cells instead of CTCs leaves behind a population of unlabeled and unaltered tumor cells and doesn’t rely on the presence of the epithelial marker or other known tumor antigens on the cell surface.

The new system was able to process blood samples at the extremely rapid rate of 10 million cells per second, handling a tube of blood in less than an hour. Both the mode of sorting out tagged CTCs, called tumor-antigen-dependent, and the technique that depletes white blood cells, called tumor-antigen-independent, recovered more than 80 percent of tumor cells from different types of cancer that had been added to blood samples. Comparison of the antigen-dependent-mode CTC-iChip with existing commercial technology for processing blood samples from patients with prostate, breast, pancreatic, colorectal and lung cancer showed the CTC-iChip to be more sensitive at detecting low levels of CTCs.

In the antigen-independent mode, the CTC-iChip successfully identified CTCs from several types of cancers that had lost or never had the epithelial marker, including triple-negative breast cancer and melanoma. CTCs isolated through this mode were put through standard cytopathological analysis, which revealed structural similarities to the original tumor, and detailed molecular genotyping of CTCs from a single patient found significant differences in gene expression patterns among individual CTCs.

“We’re only beginning to identify potential applications of the ability to analyze how tumors mutate as they spread, but this should help improve our understanding of the fundamental genetic principles of metastasis,” says Toner, the Benedict Professor of Surgery at Harvard Medical School (HMS). “We hope to develop this technology to the point where it could be used for early diagnosis, which is the ‘Holy Grail’ that all of us working on CTC technology have been striving for.”

Ravi Kapur, PhD, of the Center for Engineering in Medicine, leader of the innovation team within the MGH Circulating Tumor Cell Center, says, “The CTC-iChip provides a first-in-class device for high-efficiency, high-speed tumor cell sorting from a clinically relevant blood volume. The chip is designed for mass manufacturing, and simple automation for clinical translation.” The team is working with collaborators at Veridex and Janssen to refine the system for commercial development.

Study co-author Daniel Haber, MD, PhD, director of the MGH Cancer Center and Isselbacher/Schwartz Professor of Oncology at HMS, adds, “The study of cancer metastasis has been limited by the inability to quickly and reliably isolate tumor cells in transit in the blood. This new approach is likely to be a game changer in the field.”

Study: Inertial Focusing for Tumor Antigen–Dependent and –Independent Sorting of Rare Circulating Tumor Cells

Source: EurekAlert!

Next-Generation Circulating Tumor Cell Test Demonstrates High Efficiency and Accuracy in New Study

Veridex, LLC (Veridex) recently announced that the first study of the company’s next-generation circulating tumor cell (CTC) technology, developed in collaboration with researchers at Massachusetts General Hospital (MGH), has been published in Science Translational Medicine. The collaboration, initially announced in January 2011, has led to the development of a next-generation CTC (or “liquid biopsy”) technology that offers enhanced specificity and sensitivity and enables more extensive characterization of captured cells.

The new technology tests for CTCs from the blood of cancer patients using advanced microfluidic separation techniques integrated with innovative magnetic sorting to isolate a broad spectrum of rare circulating cancer cells. This technology will allow physicians to get information about a patient’s cancer at the time treatment is being administered, one of the key components to enabling personalized medicine.

Results from the in vitro study showed the integrated system enabled the processing of large blood volumes with high throughput and efficiency, and also allowed for the ability to isolate CTCs from both epithelial and non-epithelial cancers.

In the study, the technology was used to identify the presence of CTCs in patients with cancers of the lung, prostate, pancreas, breast, as well as melanoma.

“Veridex is proud to have introduced CELLSEARCH®, the first and only FDA-cleared CTC test, and we’re excited to work with the team at Massachusetts General Hospital on our next-generation test,” said Nicholas C. Dracopoli , Ph.D., Vice President and Head of Oncology Biomarkers, Janssen Research & Development, LLC. “Together, Veridex and the MGH team bring more than 25 years of experience in rare cell technology to this project. We’re encouraged by the positive results from this study and the potential role this technology may play in helping to advance physicians’ ability to monitor their patients and develop more personalized treatment approaches.”

“These results show the possibility of its use for patients in ‘real time’ as they are receiving treatment. We hope that this next-generation CTC technology will become an everyday tool for doctors treating patients with cancer,” said Mehmet Toner , Ph.D., director of the BioMicroElectroMechanical Systems Resource Center in the Massachusetts General Hospital.

How It Works

The system used two modes of immunomagnetic sorting to isolate CTCs: a positive selection mode to identify and tag target CTCs based on expression of the epithelial surface marker EpCAM (“epithelial cell adhesion molecule”), and a negative selection mode, in which the blood sample is depleted of leukocytes by tagging them with specific antibodies. The test’s ability to isolate CTCs in this manner allows for RNA-based, single cell molecular characterization and expression analysis of CTCs. It will also allow for the test to be used in a broader range of cancers, including cells undergoing epithelial-mesenchymal transition (EMT) and cancer stem cells.

The technology integrates three sequential processes in a single automated system to capture clinically significant CTCs. First, after whole blood samples have been labeled with magnetic beads, the system separates nucleated cells, including CTCs and white blood cells, from red blood cells and platelets with minimal cell loss. Next, the system aligns nucleated cells in a single file within a sorting channel. Finally, the magnetically tagged cells are deflected into a collection channel for identification. These three integrated functions replace the need for separate cell lysis (break down), centrifugation and sorting steps.

About Circulating Tumor Cells

Circulating tumor cells are cancer cells that have detached from the tumor and are found at extremely low levels in the bloodstream. The value of capturing and counting CTCs is evolving as more research data is gathered about the utility of these markers in monitoring disease progression and potentially guiding personalized cancer therapy.

Study: Inertial Focusing for Tumor Antigen–Dependent and –Independent Sorting of Rare Circulating Tumor Cells

Source: PR Newswire

ASU Scholars Advocate Innovation in Regulatory, Payment Pathways for Personalized Medicine

Two innovative programs designed to improve the availability of emerging medical technologies that can help patients receive more effective, efficient and personalized health care are advanced in a commentary written by a team of scientists and policy experts, including seven from Arizona State University, and published today in Science Translational Medicine.

The March 13 article, “Regulatory and Reimbursement Innovation,” explores the benefits of coverage with evidence development (CED) and parallel review for the regulation and reimbursement of molecular diagnostics. Molecular diagnostics include tests that aid in better prediction, diagnosis, prognosis and treatment of disease through the use of DNA, RNA and proteins.

The U.S. Food and Drug Administration (FDA) requires certain diagnostic tests to provide reasonable assurances of safety and effectiveness before they can be marketed. The Centers for Medicare and Medicaid Services (CMS) determines whether such products are “reasonable and necessary” before they can be covered by Medicare. The FDA and CMS currently are reviewing CED and parallel review for more widespread use, according to the article.

One of the co-authors, ASU Regents’ Professor Gary Marchant, Faculty Director of the Center for Law, Science & Innovation (LSI) at ASU’s Sandra Day O’Connor College of Law, said these tests are expected to improve health outcomes by giving providers optimal treatment choices for their patients.

“It’s a new paradigm of health care,” said Marchant, who founded LSI’s Program on Personalized Medicine, Law & Policy, the nation’s first law-school program that fosters the discipline’s study through collaborative, multidisciplinary evaluation of critical issues. “And it’s a critical time for both of these innovative programs, because agencies of the federal government are actively considering expanding them.

“These tests produce complex algorithms that can help your physician direct your health care, where you should go for treatment and what medications can – and cannot – help you,” he said. “People are dying unnecessarily, and we need to get these diagnostics out more quickly and with better data.”

Regulatory and reimbursement roadblocks hinder the tests’ development and slow their integration into routine care decisions, according to lead author, LSI Research Director Rachel Lindor. A graduate of the law school’s J.D. program who is now completing her M.D. degree at Mayo Medical School, Lindor began researching these issues during an externship in 2011 at the U.S. Department of Health and Human Services.

An LSI-hosted workshop in April 2012, “Potential Solutions to Regulatory and Reimbursement Barrier for Molecular Diagnostics: Parallel Review and Coverage with Evidence Development,” followed. It drew notable experts from government, industry and academia to brainstorm solutions to these barriers; their input led to the now-published article.

“Overall, the group seemed to agree that both of these policies were good in theory, but there were pieces of each that made people skeptical they would actually work,” Lindor said. “We came up with a few changes at the workshop that we thought would make them more attractive for developers who may have products coming up through the pipeline.”

Parallel review enables developers to meet with both CMS and FDA early in a product’s review process, in order to clarify the agencies’ evidentiary expectations and reduce inefficiencies. CED allows CMS to temporarily cover new products not yet supported by sufficient evidence to meet its “reasonable and necessary” coverage threshold while additional data are evaluated.

“Our recommendations on CED focused on trying to streamline the process so developers wouldn’t see it as a hurdle to getting paid for their products – things like smoothing out the way that FDA and CMS work together when they review the same product and shortening the time it takes for CMS to actually start a CED,” Lindor explained. “The group was also concerned about CMS’ hints that CED may be used by local Medicare contractors, so one of our recommendations was that CMS provide some more logistics on how exactly that would work.”

Lindor said tweaks to the parallel review program could make it more amenable to diagnostic test developers and speed the tests’ access to insurers, care providers and patients.

“Our group recommended that CMS give developers some assurance that there will be some benefits to participating, which could be done by shortening the time it takes to go through the process, or by providing more flexibility about what type of payment decisions would come from the review,” Lindor said. “We also recommended that the policy be made available to a broader range of products than it’s open to now.”

Dr. Denis Cortese, Director of ASU’s Health Care Delivery and Policy Program, and a co-author of the article, said “The primary goals of these two programmatic recommendations are to more quickly and accurately determine the appropriate role for new medical technologies in medical practice and patient care.”

Another co-author, Dr. George Poste, Chief Scientist of ASU’s Complex Adaptive Systems Initiative, said molecular diagnostics have enormous potential to increase diagnostic accuracy and increase the efficacy and safety of drugs in multiple diseases.

“Current ambiguities in regulation and reimbursement policies for these new tests are a major barrier to corporate investment and R&D innovation,” Poste said.

Study: Regulatory and Reimbursement Innovation

Source: EurekAlert!