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?

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. No matched analyses were possible. Differences in independent performance estimates between PCA3 and comparators were computed within studies. Studies were assessed for quality using QUADAS (Quality Assessment of Diagnostic Accuracy Studies) and for strength of evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. RESULTS: Among 1,556 publications identified, 34 observational studies were analyzed (24 addressed diagnostic accuracy and 13 addressed treatment decisions). Most studies were conducted in opportunistic cohorts of men referred for procedures and were not designed to answer key questions. Two study biases (partial verification and sampling) were addressed by analyses, allowing some conclusions to be drawn. PCA3 was more discriminatory than total prostate specific antigen increases (eg at an observed 50% specificity, summary sensitivities were 77% and 57%, respectively). Analyses indicated that this finding holds for initial and repeat biopsies, and that the markers were independent predictors. For all other biopsy decision making comparisons and associated health outcomes, strength of evidence was insufficient. For treatment decision making, strength of evidence was insufficient for all outcomes and comparators. CONCLUSIONS: PCA3 had a higher diagnostic accuracy than total prostate specific antigen increases, but strength of evidence was low (limited confidence in effect estimates). Strength of evidence was insufficient to conclude that PCA3 testing leads to improved health outcomes. For all other outcomes and comparators, strength of evidence was insufficient.

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. The development of a cooperative framework among regulators, product sponsors, and technology experts will be essential for realizing the revolutionary promise that microarrays hold for drug development, regulatory science, medical practice and public health.

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. General technological points, assessment of potential concerns for transitioning microarrays into clinical diagnostic use and approaches for evaluating the performance of these types of devices will be discussed.

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. This article will outline important 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: 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. Of particular importance is understanding that good analytical performance is a result of a well-coordinated analytical system specifically designed to provide quality results.:

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 10-5 to 10-6 cells. These technologies may be combined with functional imaging to detect MRD outside of bone marrow. Moreover, immune profiling methods are being developed to better understand the immune environment in myeloma and response to immunomodulatory agents while methods for molecular profiling of myeloma cells and circulating DNA in blood are also emerging. With the continued development and standardization of these methodologies, MRD has high potential for use in gaining new drug approvals in myeloma. The FDA has outlined two pathways by which MRD could be qualified as a surrogate endpoint for clinical studies directed at obtaining accelerated approval for new myeloma drugs. Most importantly, better understanding of MRD should also contribute to better treatment monitoring. Potentially, MRD status could be used as a prognostic factor for making treatment decisions and for informing timing of therapeutic interventions. Clin Cancer Res; 23(15); 3980-93. ©2017 AACR.

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. Biomarkers were seen as an important part of this new program for both traditional diagnostic purposes and to aid in drug development. The US FDA has created programs to foster use of biomarkers both for routine diagnostic and for drug development purposes. There is growing methodology to serve as road maps for efficient and scientifically sound development in this area. The US FDA has a flexible regulatory tool box to apply to biomarker development, and has the clear aim of working as a partner to bring these important medical devices quickly to the medical marketplace.

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). The classical biosensor format (dipstick approach for monitoring the presence of a single element) is viewed as a valuable tool in many bioassays, but possesses numerous limitations in cancer due primarily to the single element nature of these sensing platforms. As such, if biosensors are to become valuable tools in the arsenal of the clinician to manage cancer patients, new formats are required. This review seeks to provide an overview of the current thinking on molecular profiling for diagnosis and prognosis of cancers and also, provide insight into the current state-of-the-art in the biosensor field and new strategies that must be considered to bring this important technology into the cancer field.

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. Marker development should be driven by clinical needs, including early cancer detection, accurate pretreatment staging, and prediction of response to treatment, as well as monitoring disease progression and response to therapy. Development of a national repository that uses carefully preserved, well-annotated tissue specimens will facilitate new marker development. Reference standards will be an essential component of this process. Both hospital-based and commercial laboratories can play a role in developing biomarkers from discovery to test validation. Partnering of academe and industry should occur throughout the process of biomarker development. The National Cancer Institute is in a unique position to bring together academe, industry, and the Food and Drug Administration to (a) define clinical needs for biomarkers by tumor type, (b) establish analytic and clinical paradigms for biomarker development, (c) discuss ways in which markers from different companies might be evaluated in combination, (d) establish computational methods to combine data from multiple biomarkers, (e) share information regarding promising markers developed in National Cancer Institute-supported programs, and (f) exchange data regarding new platforms and techniques that can accelerate marker development.

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. We then discuss the methods that the Food and Drug Administration uses to assess the performance of in vitro diagnostic devices in the marketplace as a component of the total life cycle approach to medical device regulation.

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. Tumor markers may be reviewed as 510(k) submissions or as premarket approval application (PMA) submissions or may be exempt from premarket reviews. The FDA works hard to maintain an appropriate balance in its oversight activity and to ensure that its mission is focused on activities designed to promote public health.

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 (FDA) surveillance activities include monitoring adverse event reports from healthcare professionals, manufacturers, and lay users. METHODS: To gain insight into problems reported to FDA on glucose meters, we analyzed reports received over a 3-year period (2000-2002) from all sources (mandatory and voluntary) and focused on reports from users. RESULTS: The vast majority of in vitro diagnostic device (IVD) reports (84%, n = 18,959) were on glucose meters, with 333 glucose meter reports from users. Among the user reports, the most common problems were false high or low values and erratic values. Unique issues reported included purchase of incorrect glucose meter strips, calibration problems, and misunderstanding how FDA regulates glucose device performance. CONCLUSION: The FDA gains valuable insight from and encourages user reports.

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. It was also agreed that all Her2 testing must be performed on samples fixed only in 10% buffered formalin, as specified in the Food and Drug Administration-approved testing methods. Participants agreed to plan strategies to educate pathologists, clinicians, and laboratories about the need and use of such a standard. A National Committee for Clinical Laboratory Standards guideline for the use of the standard reference material will be created to facilitate this process.

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.S. Food and Drug Administration, Centers for Disease Control and Prevention, Institute of Medicine, and Center for Medical Technology Policy, among others. These reports are comprehensive and specifically clarify appropriate clinical use, adoption, and payer reimbursement for assay manufacturers, as well as Clinical Laboratory Improvement Amendments-certified laboratories, including those that develop assays (laboratory developed tests). Practical criteria and steps for establishing clinical utility are crucial to subsequent decisions for reimbursement without which high-performing molecular diagnostics will have limited availability to patients with cancer and fail to translate scientific advances into high-quality and cost-effective cancer care. See all articles in this CCR Focus section, "The Precision Medicine Conundrum: Approaches to Companion Diagnostic Co-development."

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. Rapid entry into clinical practice will only be achieved by using a rigorous scientific approach, including careful specimen collection and standardized and quality-controlled data collection. Early interaction with appropriate regulatory bodies will ensure studies are appropriately designed and biomarker test performance is well characterized.

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. This law also introduced the requirement for premarket review of new versions of old devices and of fundamentally new medical 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. General points and potential issues related to the analytical and clinical validation of these types of devices will be discussed.