The Role of Minimal Residual Disease Testing in Myeloma Treatment Selection and Drug Development: Current Value and Future Applications.

Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next-generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10 to 10 cells.

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.

Comparative effectiveness review: prostate cancer antigen 3 testing for the diagnosis and management of prostate cancer.

Purpose: We compared the effectiveness of PCA3 (prostate cancer antigen 3) and select comparators for improving initial or repeat biopsy decision making in men at risk for prostate cancer, or treatment choices in men with prostate cancer.

Materials And Methods: MEDLINE®, EMBASE®, Cochrane Database and gray literature were searched from January 1990 through May 2012. Included studies were matched, and measured PCA3 and comparator(s) within a cohort.

A perspective on challenges and issues in biomarker development and drug and biomarker codevelopment.

A workshop sponsored by the National Cancer Institute and the US Food and Drug Administration addressed past lessons learned and ongoing challenges faced in biomarker development and drug and biomarker codevelopment. Participants agreed that critical decision points in the product life cycle depend on the level of understanding of the biology of the target and its interaction with the drug, the preanalytical and analytical factors affecting biomarker assay performance, and the clinical disease process. The more known about the biology and the greater the strength of association between an analytical signal and clinical result, the more efficient and less risky the development process will be.

Biomarkers for pharmacogenetic and pharmacogenomic studies: special issues in analytical performance.

The use of in vitro tests to detect and measure biomarkers will be central to the realization of personalized medicine. The importance of proper biomarker test development processes cannot be overemphasized; whether the test is being used as part of drug development or ultimately for use as a companion diagnostic, if the test result is to be meaningful, the test analytical performance must be well characterized and reliable. This article will outline important design issues and special analytical validation issues to consider when developing and assessing an in vitro diagnostic test system for use in pharmacogenetic and pharmacogenomic studies.

Biomarkers for pharmacogenetic and pharmacogenomic studies: Locking down analytical performance.

The use of in vitro tests to detect and measure biomarkers provides promising avenues for development of new and better drugs, and will be central to the realization of personalized medicine. The importance of proper biomarker test assessment cannot be overemphasized. Whether the test is being used as part of drug development or ultimately used as a companion diagnostic, if the test result is to be meaningful, the test analytical performance must be well characterized.

Search for shortcuts on the critical path to market: US FDA perspectives from the diagnostic side.

The US FDA has been regulating medical devices (including laboratory tests) since 1976. Premarket review is well defined and may include requirements for both analytical and clinical information. In 2004, the US FDA initiated the Critical Path initiative to help foster development of new medical products.

The US Food and Drug Administration perspective on cancer biomarker development.

Despite the intense interest in biomarker development for cancer management, few biomarker assays for diagnostic uses have been submitted to the US Food and Drug Administration (FDA). What challenges must researchers overcome to bring cancer-detection technologies to the market and, therefore, into clinical use?

Point-of-care biosensor systems for cancer diagnostics/prognostics.

With the growing number of fatalities resulting from the 100 or so cancer-related diseases, new enabling tools are required to provide extensive molecular profiles of patients to guide the clinician in making viable diagnosis and prognosis. Unfortunately with cancer-related diseases, there is not one molecular marker that can provide sufficient information to assist the clinician in making effective prognoses or even diagnoses. Indeed, large panels of markers must typically be evaluated that cut across several different classes (mutations in certain gene fragments--DNA; over/under-expression of gene activity as monitored by messenger RNAs; the amount of proteins present in serum or circulating tumor cells).

FDA perspectives on potential microarray-based clinical diagnostics.

The US Food and Drug Administration (FDA) encourages the development of new technologies such as microarrays which may improve and streamline assessments of safety and the effectiveness of medical products for the benefit of public health. The FDA anticipates that these new technologies may offer the potential for more effective approaches to medical treatment and disease prevention and management. This paper discusses issues associated with the translation of nucleic acid microarray-based devices from basic research and target discovery to in vitro clinical diagnostic use, which the Office of In Vitro Diagnostic Device Evaluation and Safety in the Center for Devices and Radiological Health foresees will be important for assurance of safety and effectiveness of these types of devices.

FDA perspectives on pharmacogenetic testing.

The field of pharmacogenetic testing is emerging as a topic of interest for many, due to its potential to improve patient care and optimize therapeutic development. The US Food and Drug Administration is interested in incorporating pharmacogenetics into development activities whenever appropriate to protect and promote public health. This article is intended to reflect the opinions of the Office of In vitro Diagnostic Device Evaluation and Safety in the Center for Devices and Radiological Health on some issues associated with developing in vitro diagnostic devices for use in pharmacogenetics.

Translational crossroads for biomarkers.

A group of investigators met at a Specialized Programs of Research Excellence Workshop to discuss key issues in the translation of biomarker discovery to the development of useful laboratory tests for cancer care. Development and approval of several new markers and technologies have provided informative examples that include more specific markers for prostate cancer, more sensitive tests for ovarian cancer, more objective analysis of tissue architecture and an earlier indication of response to treatment in breast cancer. Although there is no clear paradigm for biomarker development, several principles are clear.

Introduction to the Food and Drug Administration (FDA) regulatory process.

FDA oversight of medical devices, including in vitro diagnostic devices (IVDs or laboratory tests), in the United States was a direct result of the passage of the Medical Device Amendments of 1976. This law introduced a series of general controls for medical devices including registration and listing, requirements for production using good manufacturing practices, and requirements for post-market reporting of device failures. This produced for the first time a menu of laboratory tests on the market, a system to ensure these were produced consistently over time, and a mechanism for FDA to identify problems with device use and to work with companies to ensure corrective action.

Consumers report glucose meter problems to FDA.

Objective: Glucose meters have unquestionable clinical utility, particularly in management of diabetes mellitus. U.S.

Food and Drug Administration regulation of in vitro diagnostic devices.

The Food and Drug Administration regulates the sale and distribution of laboratory devices under a statutory and regulatory framework that is unfamiliar to most clinical laboratory scientists. In this article we briefly describe the criteria that are used to classify and review in vitro diagnostic devices. We discuss the similarities and differences between devices that are not subject to premarket review, and those that are required to undergo either a premarket application or premarket notification [510(k)] pathway.

Standard reference material for Her2 testing: report of a National Institute of Standards and Technology-sponsored Consensus Workshop.

A workshop was sponsored by the National Institute of Standards and Technology, the Cancer Diagnosis Program of the National Cancer Institute, the Food and Drug Administration, and the College of American Pathologists to address the need for a reference material for Her2 gene protein testing. It was agreed that such a standard was desirable and necessary to ensure the reliability of Her2 testing to qualify patients for trastuzumab therapy. Two standards consisting of well characterized cell lines will be produced, 1 that will be a National Institute of Standards and Technology-certifiable standard, and 1 that will be a commercially developed standard for use in all Her2 testing.

Medical applications of microarray technologies: a regulatory science perspective.

The potential medical applications of microarrays have generated much excitement, and some skepticism, within the biomedical community. Some researchers have suggested that within the decade microarrays will be routinely used in the selection, assessment, and quality control of the best drugs for pharmaceutical development, as well as for disease diagnosis and for monitoring desired and adverse outcomes of therapeutic interventions. Realizing this potential will be a challenge for the whole scientific community, as breakthroughs that show great promise at the bench often fail to meet the requirements of clinicians and regulatory scientists.

Regulatory issues in tumor marker development.

The Food and Drug Administration (FDA) has been actively involved in oversight of medical devices, including in vitro diagnostic devices (IVDs) since the passage of the Medical Device Amendments of 1976. A variety of both premarket and postmarket regulatory controls were put into place as a result of this new program. The type of oversight applied to tumor markers available for marketing in the United States depends on both the intended use of the test and the manner in which it is being commercialized-whether offered as a test kit or system or as a laboratory testing service.