Molecular diagnostics clinical utility strategy: a six-part framework.

The clinical utility of a molecular test rises proportional to a favorable regulatory risk/benefit assessment, and clinical utility is the driver of payer coverage decisions. Although a great deal has been written about clinical utility, debates still center on its 'definition.' We argue that the definition (an impact on clinical outcomes) is self-evident, and improved communications should focus on sequential steps in building and proving an adequate level of confidence for the diagnostic test's clinical value proposition.

Evidence of clinical utility: an unmet need in molecular diagnostics for patients with cancer.

This article defines and describes best practices for the academic and business community to generate evidence of clinical utility for cancer molecular diagnostic assays. Beyond analytical and clinical validation, successful demonstration of clinical utility involves developing sufficient evidence to demonstrate that a diagnostic test results in an improvement in patient outcomes. This discussion is complementary to theoretical frameworks described in previously published guidance and literature reports by the U.

Regulation, reimbursement, and the long road of implementation of personalized medicine--a perspective from the United States.

There is undisputed evidence that personalized medicine, that is, a more precise assessment of which medical intervention might best serve an individual patient on the basis of novel technology, such as molecular profiling, can have a significant impact on clinical outcomes. The field, however, is still new, and the demonstration of improved effectiveness compared with standard of care comes at a cost. How can we be sure that personalized medicine indeed provides a measurable clinical benefit, that we will be able to afford it, and that we can provide adequate access? The risk-benefit evaluation that accompanies each medical decision requires not only good clinical data but also an assessment of cost and infrastructure needed to provide access to technology.

Physician Awareness and Utilization of Food and Drug Administration (FDA)-Approved Labeling for Pharmacogenomic Testing Information.

We surveyed 10,303 United States physicians on where they obtain pharmacogenomic testing information. Thirty-nine percent indicated that they obtained this from drug labeling. Factors positively associated with this response included older age, postgraduate instruction, using other information sources, regulatory approval/ recommendation of testing, reliance on labeling for information, and perception that patients have benefited from testing.

On rat poison and human medicines: personalizing warfarin therapy.

Teaching old dogs new tricks is difficult, but lessons learned from such efforts can be invaluable. Warfarin is an old drug, difficult to administer and a leading cause of drug-related mortality and hospitalizations. New genetic tests for optimizing warfarin therapy have not been adopted.

Considerations for safety pharmacogenetics in clinical practice.

The focus of treating an individual patient is the identification of the individual's specific needs. The measurement of the patient's characteristics, such as blood pressure or body temperature, and also the measurement of biomarkers, such as cholesterol or hemoglobin A1C is part of the patient's health assessment. The deeper the insights into the phenotypic and molecular characteristics of the patient, the better we are positioned to treat a patient.

The future of direct-to-consumer clinical genetic tests.

In light of the meeting of the US Food and Drug Administration (FDA) in March 2011 to discuss the regulation of clinical direct-to-consumer (DTC) genetic tests, we have invited five experts to consider the best means of overseeing the ordering and interpretation of these tests. Should these tests be regulated? If so, who, if anyone, should communicate results to consumers?

Impact of proton pump inhibitors on the effectiveness of clopidogrel after coronary stent placement: the clopidogrel Medco outcomes study.

Study Objective: To investigate the potential impact of proton pump inhibitors (PPIs) on the effectiveness of clopidogrel in preventing recurrent ischemic events after percutaneous coronary intervention (PCI) with stent placement.

Design: Population-based, retrospective cohort study.

Data Source: National medical and pharmacy benefit claims database comprising approximately 19 million members.

Real-world clinical effectiveness, regulatory transparency and payer coverage: three ingredients for translating pharmacogenomics into clinical practice.

The past decade of pharmacogenomics was driven by the sequencing of the human genome to create ever denser maps of genetic variations for studying the diversity across individuals. Today, genotyping technology is available at a fraction of the cost of what it was 10 years ago and many pharmacogenomic variations have been studied in detail. Still, we are only starting to gain an understanding of how pharmacogenomic-guided drug therapy affects clinical outcomes: real-world studies that demonstrate the clinical effectiveness and address the economic implications of pharmacogenomics are needed to help decide when and how to implement pharmacogenomics in clinical practice, how to regulate pharmacogenomic testing and how the healthcare system will integrate this new science into an environment of rapidly increasing cost.

Back to the future: why randomized controlled trials cannot be the answer to pharmacogenomics and personalized medicine.

Randomized controlled trials are the gold standard for determining the efficacy of therapeutic interventions. However, medical practice has not evolved around the concept of randomized trials, but around the idea of careful observations, (anecdotal) case studies and the evaluation of retrospective data. Interventions discovered by these means and taken forward into clinical practice became standard practice as they continued to be superior when compared with prior or alternative types of treatment.

Payer perspectives on pharmacogenomics testing and drug development.

A series of questions about hypothetical drugs and pharmacogenomic tests was posed to a panel of representatives from the health plan, government and employer sectors in order to elicit suggestions for input on data or study design considerations important for coverage determination. The panel suggested seven areas for drug developers to strongly consider. These areas were to include comparative information on new tests versus usual care, assess the negative predictive value of new tests, measure and report on cost offsets, balance relative risk improvement with absolute risk, consider the policy implications of the products or tests, report percentage responders in addition to group mean improvements, and to include specific pharmacogenomic information in US FDA approved labels.

4th US FDA-Drug Information Association pharmacogenomics workshop, held 10-12 December, 2007.

The 4th US FDA/Industry workshop, in a series on Pharmacogenomics, was on 'Biomarkers and Pharmacogenomics in Drug Development and Regulatory Decision Making' and was held on December 10-12, 2007 in Bethesda, MD, USA, with clear objectives to continue the dialogue that began in 2002 for enabling the use of biomarkers and pharmacogenomics in drug development and regulatory decision-making. This brief commentary will highlight the major topics and outcomes discussed at this meeting that was jointly sponsored by the FDA, The Pharmacogenomics Working Group (PWG), The Pharmaceutical Research and Manufacturers of America (PhRMA), The Biotechnology Industry Organization (BIO) and The Drug Information Association (DIA).

Considerations for a business model for the effective integration of novel biomarkers into drug development.

It is 10 years since the introduction of trastuzumab into the US market, and we are still waiting for a validation of the business case for biomarker-driven drug development. While many reasons for the lack of duplication of this model may exist, the need for accelerated innovation in drug development paired with the opportunity of integrating biomarker-driven research into drug development programs may lead to new and creative ways of fostering the cooperation between drug developers and test manufacturers. The rapid increase in knowledge about biomarkers and our understanding of disease and disease mechanisms open unprecedented prospects to make not only better, more informed decisions regarding patient care, but also strategic decisions during drug development.

The balance of reproducibility, sensitivity, and specificity of lists of differentially expressed genes in microarray studies.

Background: Reproducibility is a fundamental requirement in scientific experiments. Some recent publications have claimed that microarrays are unreliable because lists of differentially expressed genes (DEGs) are not reproducible in similar experiments. Meanwhile, new statistical methods for identifying DEGs continue to appear in the scientific literature.

Pharmacogenomic biomarker information in drug labels approved by the United States food and drug administration: prevalence of related drug use.

Study Objectives: To review the labels of United States Food and Drug Administration (FDA)-approved drugs to identify those that contain pharmacogenomic biomarker information, and to collect prevalence information on the use of those drugs for which pharmacogenomic information is included in the drug labeling.

Design: Retrospective analysis.

Data Sources: The Physicians' Desk Reference Web site, Drugs@FDA Web site, and manufacturers' Web sites were used to identify drug labels containing pharmacogenomic information, and the prescription claims database of a large pharmacy benefits manager (insuring > 55 million individuals in the United States) was used to obtain drug utilization data.

Integration and use of biomarkers in drug development, regulation and clinical practice: a US regulatory perspective.

The US FDA encourages the integration of biomarkers in drug development and their appropriate use in clinical practice. It is believed that this approach will help alleviate stagnation and foster innovation in the development of new medical products, and, ultimately, lead to more personalized medicine. To facilitate the use of biomarkers in drug development and clinical practice, the FDA organized workshops, issued guidances, established a voluntary submission process, developed online educational tools and, most importantly, strives to ensure the integration of this information into drug labels, for example, via the update of existing labels, or the inclusion of appropriate language in new drug labels.

Strategic paths for biomarker qualification.

Biomarkers may be qualified using different qualification processes. A passive approach for qualification has been to accept the end of discussions in the scientific literature as an indication that a biomarker has been accepted. An active approach to qualification requires development of a comprehensive process by which a consensus may be reached about the qualification of a biomarker.

Qualification of biomarkers for drug development in organ transplantation.

The drug development process is dependent upon having established end points for measuring drug efficacy and adverse effects. New drug development in organ transplantation suffers from having end points which are either outdated or which do not serve the purpose of addressing the current critical drug therapy problems. Numerous biomarkers have been examined in organ transplantation, but almost all would be classified as exploratory for drug development purposes.

Questions and answers about the Pilot Process for Biomarker Qualification at the FDA.

The FDA has developed a Pilot Process for Biomarker Qualification. Initial experience with this process has underscored the care that a long-term approach to biomarker qualification independently of development for specific drugs should have in the assembly of external industry consortia as well as the internal regulatory organization for these qualification efforts. There are complex scientific and clinical issues associated with these qualifications, and it is paramount that the expertise needed for their review be identified so that a comprehensive consensus may be reached at the end of this process.

An integrated bioinformatics infrastructure essential for advancing pharmacogenomics and personalized medicine in the context of the FDA's Critical Path Initiative.

Pharmacogenomics (PGx) is identified in the FDA Critical Path document as a major opportunity for advancing medical product development and personalized medicine. An integrated bioinformatics infrastructure for use in FDA data review is crucial to realize the benefits of PGx for public health. We have developed an integrated bioinformatics tool, called ArrayTrack, for managing, analyzing and interpreting genomic and other biomarker data (e.

Implementing the U.S. FDA guidance on pharmacogenomic data submissions.

The FDA Guidance for Industry: Pharmacogenomics Data Submissions was issued in 2005. This guidance document covers a broad area associated with how and when to submit genomic data to the FDA. Additional tasks associated with genomic data submissions include the implementation of genomic data submissions; the process for qualification of exploratory biomarkers into valid biomarkers; and technical recommendations for the generation and submission of genomic data to the FDA.

The Predictive Safety Testing Consortium: A synthesis of the goals, challenges and accomplishments of the Critical Path.

The qualification of biomarkers of drug safety requires data on many compounds and nonclinical and clinical studies. The cost and effort associated with these qualifications cannot be easily covered by a single pharmaceutical company. Intellectual property associated with safety biomarkers is also held by many different companies.

The MicroArray Quality Control (MAQC) project shows inter- and intraplatform reproducibility of gene expression measurements.

Over the last decade, the introduction of microarray technology has had a profound impact on gene expression research. The publication of studies with dissimilar or altogether contradictory results, obtained using different microarray platforms to analyze identical RNA samples, has raised concerns about the reliability of this technology. The MicroArray Quality Control (MAQC) project was initiated to address these concerns, as well as other performance and data analysis issues.

Pharmacogenomics steps toward personalized medicine.

The goal of personalized medicine is to maximize the likelihood of therapeutic efficacy and to minimize the risk of drug toxicity for an individual patient. One of the major contributors to this concept is pharmacogenomics. Marked interindividual genetic variation contributes significantly to both susceptibility to diseases, and response to drugs.