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Biomarker Tests for Molecularly Targeted Therapies – They Key to …

Biomarker Tests for Molecularly Targeted Therapies — The Key to Unlocking Precision Medicine

As the promise and the pitfalls of precision medicine gain increasing attention,1,2 enthusiasm about the field has been heightened by a rapid reduction in the cost of high-throughput genomic sequencing and a dramatic increase in the identification of potential molecular targets for therapy. Biomarker tests for molecularly targeted therapies can help physicians to select the most effective therapy for a patient’s condition and avoid treatments that could be ineffective or harmful. If precision medicine is to reach its potential, such biomarker tests will have to be developed in a timely fashion.

Some observers, however, have expressed concern that these rapid developments have caused genomic data to accumulate at a rate that exceeds our ability to adequately capture, fully analyze, and properly interpret them. The medical armamentarium available to physicians seeking to tailor therapies to their patients’ conditions is expanding in parallel. Annual spending on molecularly targeted therapies for oncology in the United States now exceeds $10 billion, outpacing spending on conventional chemotherapies. In 2015 alone, the Food and Drug Administration approved 18 new agents for cancer, nearly all of which were based on the principles of precision medicine.

The degree to which physicians will be able to apply genomic information in selecting therapy that improves clinical care remains to be seen and will probably vary over the near term.3,4 The processes of identifying and validating biomarker tests and of developing and evaluating targeted therapies are complex. Potentially useful tests have not been adopted into clinical practice rapidly, in part because we lack common evidentiary standards for regulatory, clinical, coverage, and reimbursement decisions. Furthermore, clinical implementation will require the consistent collection and sharing of data on biomarker tests, treatments, and patient outcomes.5

The Institute of Medicine (IOM) has convened several expert committees over the past few years to consider a range of issues related to biomarkers, biomarker testing, genomics, and related disciplines. These efforts have highlighted the need for a systematic examination of all the challenges and opportunities associated with biomarker assays for molecularly targeted therapies. Most recently, the IOM assembled a Committee on Policy Issues in the Clinical Development and Use of Biomarkers for Molecularly Targeted Therapies (on which the authors served) to study and make recommendations about relevant regulatory, reimbursement, and clinical practice issues. The committee’s report (, released in March, provides 10 specific but wide-ranging recommendations based on the premise that properly validated and implemented biomarker tests and targeted therapies hold considerable promise for enhancing the quality of patient care and improving meaningful clinical outcomes (see IOM Committee Recommendations for Advancing Appropriate Use of Biomarker Tests for Molecularly Targeted Therapies).

First and foremost, the committee calls for the development of common standards for assessing the utility of biomarker tests in the selection of targeted therapies and improvement of patient outcomes. Such standards would inform regulatory oversight of test development and approval, appropriate clinical adoption and utilization, and decisions about coverage and reimbursement. Interoperability and integration of electronic health records and laboratory information systems, ideally by means of a national database for health care providers and patients, would enhance the sustainable implementation and continuous evaluation of such tests. The committee further recommends that equitable access to biomarker tests and targeted therapies be ensured through patient and provider education, simplified and informative labeling, and supportive reimbursement policies.

The committee’s recommendations are meant to guide both the development of evidence supporting initial clinical application of biomarker tests and the ongoing assessment of their benefit. Given that the apparent value or benefit of biomarkers for a molecularly targeted therapy may vary considerably, a primary goal of the committee’s recommendations is to increase patients’ access to appropriate, accurate, reliable tests that can direct personalized or precision therapy.

The committee pursued its work against the backdrop of President Barack Obama’s Precision Medicine Initiative, which aims to empower clinicians, patients, and investigators to work together toward more personalized care and improved clinical outcomes and includes the development of a large patient cohort from which both clinical and “omics” data would be collected. Relevant congressional actions include the 21st Century Cures bill in the House of Representatives and companion bills in the Senate. In addition, President Obama has asked Vice President Joe Biden to take charge of a new Cancer Moonshot Initiative aimed at developing a large, interoperable, and fully integrated database to accelerate cancer discovery and innovation and at improving the delivery of such advances to patients and health care providers.

If it is developed and maintained in a rigorous, evidence-based fashion with well-designed and well-executed studies, precision medicine could rapidly advance the care of patients with cancer and other diseases by tailoring treatment to individual patients’ conditions and improving clinical outcomes and quality of life, while reducing costs by averting the use of ineffective or harmful therapies. However, precision medicine comes with the methodologic challenges associated with small target populations, as well as the reimbursement challenges associated with an increasingly value-sensitive health care delivery environment. Moreover, there is potential for the unintended consequence of intensifying disparities in access to advanced health care services, including biomarker testing and molecularly targeted therapies.

Before such biomarker tests become part of standard care, it is essential to establish that such tests are accurate and reliable (have analytic validity), are associated with the disease and outcome of interest (clinical validity), and actually lead to improved patient outcomes as compared with standard treatment (clinical utility). This process starts with the establishment of the reliability, accuracy, and precision of the test based on rigorous laboratory studies. Molecularly targeted agents should be administered only if a specific biomarker that predicts the effectiveness of the therapy is known to be present on the basis of a validated assay. When the effectiveness and safety of a therapy depends on the status of a biomarker, the test becomes as important as the treatment for optimal patient care.5

There is also a need for consensus on the evidence required to adequately establish clinical utility for initial use; the assessment of utility may change over time, as evidence accumulates and new tests and treatments are developed. The line between clinical research and clinical care is likely to be blurred in the era of precision medicine. We believe it will be critical for health systems and individual providers to share in the responsibility for data capture and integration until there is sufficient evidence to determine whether a given test has actual clinical utility. Payers will also have to share in the responsibility for coverage and reimbursement as the evidence is refined.

Finally, everyone involved will have to work to ensure that patients have fair and equitable access to promising as well as established biomarker tests for molecularly targeted therapies. A national initiative involving not only clinicians and laboratory scientists but also experts in informatics could continuously capture, catalogue, and annotate data on biomarkers and targeted therapies and make them available to regulators, providers, payers, and patients who want to take a more active role in shared decision making. We believe these steps will enable precision medicine to fulfill its potential for improving patient care and clinical outcomes.

BY: Gary H. Lyman, M.D., M.P.H., and Harold L. Moses, M.D.

June 1, 2016DOI: 10.1056/NEJMp1604033


Biomarkers triple clinical trial success rate

By Melissa Fassbender , 26-May-2016

A recent study of clinical drug development success rates found that biomarker-enabled drug programs are three times more likely to reach approval.

The new Report from Amplion, BIO, and BioMedTracker examined approximately 10,000 clinical trials by therapeutic area as well as three categories: rare diseases, chronic high prevalence diseases, and programs using selection biomarkers.

In order to quantify the benefit of using selection biomarkers in drug development, the researchers combined Amplion’s BiomarkerBase with BioMedTracker’s clinical transition records.

According to the report, the Likelihood of Approval (LOA) of a new drug increased from 1 in 10 to 1 in 4 when using biomarkers.

While the researchers were expecting biomarkers to improve LOA, John Audette, Amplion’s founder and president, and one of the report’s authors, told us the scale to which biomarkers had an impact was a surprise.

I think we all knew intuitively that using biomarkers to select responsive patient populations would yield more successes, but the finding that biomarker-enabled drug programs are three times more likely to reach approval was definitely a surprise,” Audette said.

Improving trial success rates

In the study, researchers focused on biomarkers that are used to identify patients who are most likely to respond to a developmental drug, which in turn increases the chance that a therapeutic benefit will be demonstrated.

It also means that you exclude patients who are unlikely to respond, and both of these dynamics increase success rates,” explained Audette. Biomarkers can also be used to indicate whether drugs have the desired effect, which can also increase success rates.

Patient selection biomarkers are the key enabling factor to precision medicine, and they are fundamentally changing drug development and dosing strategies,” added Audette.

The focus on precision medicine is causing a paradigm shift in drug development in which companies that originally focused on developing blockbuster drugs are now embracing programs with narrower indications, shorter development timelines, and reduced costs.

Audette uses a baseball analogy to explain the benefits, describing the new dynamic as less home runs and more singles and doubles. He added, “and of course patients benefit because they aren’t prescribed drugs that aren’t going to provide them any benefit.

BluePen Biomarkers announces collaboration with the University of Pennsylvania

PHILADELPHIA, PA – The University of Pennsylvania has co-founded and structured BluePen Biomarkers in collaboration with BluePrint Bio, Inc. and Emerald Logic, Inc. to conduct biomarker research and identification. BluePen is creating a comprehensive biomarker measurement and discovery pipeline for the acceleration of personalized medicine.

BluePen will collaborate with Ian Blair, PhD, the A.N. Richards Professor of Systems Pharmacology and Translational Therapeutics and Director of Center for Cancer Pharmacology in the Perelman School of Medicine at the University of Pennsylvania.

“This is innovation at its core — a results-focused collaboration of academics, private industry, and research partners around the world dedicated to improving upon existing knowledge of biomarkers through a ‘big science’ approach,” said Michael Poisel, the Penn Center for Innovation’s Director of PCI Ventures.

BluePen will measure and integrate genomic, proteomic, metabolomic, and lipidomic biomarkers, alongside clinical data, demographics, and other phenotypic data, providing its customers and collaborators with access to a comprehensive ‘multi-omics’ discoveryplatform. With this collaborative venture, Penn’s goal is to radically improve and accelerate the discovery of relevant biomarkers, without bias toward single genes, single modalities, or inappropriate mathematical assumptions.

“Our fundamental conviction is that any intervention that has a predictable biologic outcome will have a detectable biomarker signature,” said Blair. “The challenge is to detect the signature. BluePen’s comprehensive multi-omics platform married to Emerald Logic’s bio-inspired signal processing analytic approach provides a powerful solution.”

Matthew Nunez, CEO of BluePen has focused on the creation of a network of collaborative clinical and research institutions that can contribute biofluid samples and patient data, further augmenting the value of the platform.

“Our goal at BluePen is to help bridge biologic discoveries to clinical purpose,” he stated. “We have been working with researchers in oncology, inflammatory diseases, neurological disorders, and a variety of other areas of interest, to identify and validate discoveries that can mitigate human suffering while decreasing treatment costs.”

“The BluePen Biomarkers partnerships illustrate how creative collaboration enables discoveries in academic research to translate into medical advances,” said Dawn Bonnell, PhD, vice provost for research at the University of Pennsylvania.


About The Penn Center for Innovation

The Penn Center for Innovation (PCI) translates Penn discoveries and ideas into new products and businesses for the benefit of society by facilitating connections with the private sector. Whether the end result is a technology license, an R&D alliance, the formation of a new venture, or an integrated combination of these activities, PCI serves as a dedicated one-stop shop for commercial partnering with Penn.

About PCI Ventures

PCI Ventures is a division of the Penn Center for Innovation (PCI) and provides entrepreneurial support products and services for faculty, staff, and students at the University of Pennsylvania who have an interest in starting a new venture. Over the last six years, PCI Ventures has built numerous operating companies through its support programs, including UPstart, UPadvisors, AppitUP, and DevelUPmed.

About Blueprint Bio

Blueprint was founded to generate and transform intellectual property into commercial and social value, fulfilling the personalized medicine model. By identifying, protecting and offering new biological discoveries to existing clinical, pharmaceutical and diagnostic companies, Blueprint Bio is creating a validated marketplace for biomarkers signatures in personalized medicine. In order to de-risk and accelerate biomarker discovery, Blueprint is actively collaborating with the researchers and companies who are generating biologic patient data from ‘omics devices such as mass spectrometers and sequencing machines, among other assay methods, at an unprecedented rate. Blueprint is based in California, with additional offices at the University of Pennsylvania and the Mayo Clinic.

About Emerald Logic

Emerald Logic has created the world’s only integrated ‘omics precision analytics platform. The company’s mission is to make personalized medicine a reality, in order to reduce patient suffering, treatment costs, and drug development risk. Emerald’s bio-inspired signal processing technology is proven to solve problems impossible for other methods, by modeling the underlying biology of disease regardless of the number or complexity of available biomarkers, lab assessments, clinical history, and demographics. The company’s body of work includes diagnostics and prognostics for a wide variety of cancers, inflammatory diseases, neurological disorders, cardiac health, and addiction. The company’s customers include major pharma, renowned clinics, and world-class research institutions.


The promise of precision medicine

blog-precision-medicinePresident Obama recently announced that the US government will invest $215 million in research funding intended to drive patient-powered research and further the cause of personalized medicine. In the announcement it was stated that, “Through collaborative public and private efforts, the Precision Medicine Initiative will leverage advances in genomics, emerging methods for managing and analyzing large data sets while protecting privacy, and health information technology to accelerate biomedical discoveries.”

We are at the forefront of a new medical research paradigm that is focused on the individual rather than the collective. This approach to research and patient care will form the basis of the BluePrint Global Health Foundation’s strategy to combat the current challenge of unmet medical needs.

Two of BluePrint Global Health Foundation’s members, Matt Nunez and Patrick Lilley, each run companies that are making large strides towards keeping the personalized medicine promise. Patrick Lilley is the CEO of Emerald Logic, a leader in the field of computational biology. This company has proven to solve some of the largest problems with the immense data generated by clinical trials by identifying and defining non-linear relationships and effects of biological factors that lead to drug development success.

Matt Nunez, the founder of BluePrint Global Health Foundation, is the founder and CEO of BluePrint Bio, a company that is discovering, validating, protecting, publishing and commercializing new solutions for the global health market. In many cases, a discovery that may not warrant for-profit commercialization but can solve an unmet global medical need can and will be developed through our nonprofit foundation.

It is gratifying to see that the administration is providing resources and further credibility to the model of personalized medicine. We fully intend to be very active in this effort.