Showing papers on "Companion diagnostic published in 2011"

Predictive biomarkers: a paradigm shift towards personalized cancer medicine.

Abstract: Advances in our understanding of the intricate molecular mechanisms for transformation of a normal cell to a cancer cell, and the aberrant control of complementary pathways, have presented a much more complex set of challenges for the diagnostic and therapeutic disciplines than originally appreciated. The oncology field has entered an era of personalized medicine where treatment selection for each cancer patient is becoming individualized or customized. This advance reflects the molecular and genetic composition of the tumors and progress in biomarker technology, which allow us to align the most appropriate treatment according to the patient's disease. There is a worldwide acceptance that advances in our ability to identify predictive biomarkers and provide them as companion diagnostics for stratifying and subgrouping patients represents the next leap forward in improving the quality of clinical care in oncology. As such, we are progressing from a population-based empirical 'one drug fits all' treatment model, to a focused personalized approach where rational companion diagnostic tests support the drug's clinical utility by identifying the most responsive patient subgroup.

NCCN Task Force Report: Evaluating the Clinical Utility of Tumor Markers in Oncology

Abstract: The molecular analysis of biomarkers in oncology is rapidly advancing, but the incorporation of new molecular tests into clinical practice will require a greater understanding of the genetic changes that drive malignancy, the assays used to measure the resulting phenotypes and genotypes, and the regulatory processes that new molecular biomarkers must face to be accepted for clinical use. To address these issues and provide an overview of current molecular testing in 6 major malignancies, including glioma, breast cancer, colon cancer, lung cancer, prostate cancer, and acute myelogenous leukemia, an NCCN Task Force was convened on the topic of evaluating the clinical utility of tumor markers in oncology. The output of this meeting, contained within this report, describes the ways biomarkers have been developed and used; defines common terminology, including prognostic, predictive, and companion diagnostic markers, and analytic validity, clinical validity, and clinical utility; and proposes the use of a combination level of evidence score to aid in the evaluation of novel biomarker tests as they arise. The current state of regulatory oversight and anticipated changes in the regulation of molecular testing are also addressed.

Crizotinib and Testing for ALK

Abstract: Crizotinib was recently approved by the US FDA for the treatment of advanced non-small cell lung cancer (NSCLC) harboring the ALK (anaplastic lymphoma kinase) gene rearrangement. To ensure identification of patients most likely to benefit, the FDA approved crizotinib concurrently with a companion diagnostic test-the Vysis ALK Break Apart FISH Probe Kit. This kit was used in 1 of the 2 pivotal trials leading to the FDA approval of crizotinib and has become the gold standard for detecting ALK rearrangement in NSCLC. Although ALK FISH is clinically validated, the assay can be technically challenging and costly. Therefore, other diagnostic modalities are being explored, including immunohistochemistry (IHC) and reverse transcriptase-polymerase chain reaction. This article provides an overview of the diagnostic assays available for detecting ALK rearrangement. Each assay, including ALK FISH, has its strengths and weaknesses. Recent work with commercially available ALK antibodies suggests that IHC-based tests may represent a reliable and cost-effective screening strategy; however, large multicenter studies comparing IHC with FISH are needed to validate ALK IHC. While ALK FISH remains the current standard for diagnosing ALK positivity, large-scale screening of patients with newly diagnosed advanced NSCLC, as recommended by NCCN, may require development and validation of alternative screening strategies, such as combination IHC and FISH.

US FDA perspective on challenges in co-developing in vitro companion diagnostics and targeted cancer therapeutics

Abstract: Recent advances in cancer therapy are based on agents that specifically target the products of the genes mutated in cancer cells. Development of companion diagnostic tests for these agents can simplify the drug-discovery process, make clinical trials more efficient and informative, and be used to individualize the therapy of cancer patients. Companion diagnostic development has many challenges. Examples include the reluctance of drug companies to restrict the use of their drugs through biomarker tests, difficulties of developing companion diagnostics from discovery to clinical validation, and the regulatory challenges in developing effective mechanisms to synchronize reviews of therapeutics with diagnostic devices used to personalize treatment. This article addresses the various challenges in developing companion diagnostics along with the US FDA’s approach to regulation of companion diagnostic devices.

FDA approves Xalkori with companion diagnostic for a type of late-stage lung cancer

Abstract: FDA has notified healthcare professionals and patients that the antidepressant citalopram hydrobromide (Celexa, Forest Laboratories) should no longer be used at doses greater than 40 mg per day because it can cause abnormal changes in the electrical activity of the heart.

Cancer and Leukemia Group B Pathology Committee Guidelines for Tissue Microarray Construction Representing Multicenter Prospective Clinical Trial Tissues

Abstract: Practice-changing evidence requires confirmation, preferably in multi-institutional clinical trials. The collection of tissue within such trials has enabled biomarker studies and evaluation of companion diagnostic tests. Tissue microarrays (TMAs) have become a standard approach in many cooperative oncology groups. A principal goal is to maximize the number of assays with this precious tissue. However, production strategies for these arrays have not been standardized, possibly decreasing the value of the study. In this article, members of the Cancer and Leukemia Group B Pathology Committee relay our experiences as array facility directors and propose guidelines regarding the production of high-quality TMAs for cooperative group studies. We also discuss statistical issues arising from having a proportion of patients available for TMAs and the possibility that patients with TMAs fail to represent the greater study population.

Assays and biomarkers for lrrk2

Abstract: Biomarkers for screening subjects for Parkinson's disease and providing companion diagnostic tools for therapies using LRRK2 modulators, and assays for screening compounds and compositions for modulation of LRRK2 activity.

Barriers to overcome for transition of breath tests from research to routine clinical practice.

Abstract: Over the last decade noninvasive diagnostic phenotype [13C]-breath tests using suitably labeled 13C substrates as well as breath tests using endogenous/exogenous volatile organic compounds in breath have been extensively researched. Despite the potential benefits of these companion diagnostic tests and stand-alone diagnostic tests for patient/disease stratification and market segmentation to personalize medicine, the clinical and commercial development of these diagnostic tests will need to overcome a number of regulatory, financial and scientific hurdles prior to their acceptance into routine clinical practice.

Methods for assessment and treatment of mood disorders via single nucleotide polymorphisms analysis

Abstract: Described herein are assays, kits and methods for treating mood disorders by testing for one or more polymorphisms in a specific group of genes and for analyzing the results of polymorphism testing; the genes included may converge in one or more signaling pathways, and may be epigenetic. The genes are included based on the relationships of the proteins encoded by the genes in the context of particular signaling pathways and provide a diagnostically relevant nexus. Also described herein are methods of presenting the data collected by the screen, including methods of delivering interpretive comments and/or treatment guidance based on the results of the genetic screening either individually or based on the genetic composition of particular clusters of genes which may be related to each other. Importantly, drugs which modulate these genetic disturbances are described for targeted therapeutic use based upon companion diagnostic method.

Larger companies dominate cancer companion diagnostic approvals.

Abstract: Two novel cancer drugs and their companion diagnostics to predict treatment response were given a go-ahead to market in quick succession. On August 17, the US Food and Drug Administration (FDA) approved Roche/Genentech’s Zelboraf (vemurafenib) and multiplex PCR-based diagnostic for the BRAF V600E gene for individuals with advanced melanoma harboring the mutation. Approval of Pfizer’s drug Xalkori (crizotinib) for non-small cell lung cancer (NSCLC) patients with tumors containing anaplastic lymphoma kinase (ALK) gene structural variants, together with a fluorescent in situ hybridization (FISH) test for detecting rearrangements of the ALK gene, followed nine days later. Both Basel-based Roche and New York–based Pfizer claim the companion diagnostics used to screen tissue samples for the drugs’ target mutations—by narrowing patient populations to likely responders— sped clinical trials and accelerated FDA approval. But other companies considering the approach remain uncertain about the economic feasibility of co-developing medicines with companion diagnostics, as a study published last month attests (Nat. Rev. Drug. Discov. 10, 1–17, 2011). The first generation of targeted therapeutics included anticancer drugs Herceptin (trastuzumab), which was approved in 1998 with Glostrup (HercepTest), Denmark-based DAKO’s immunohistochemistry companion diagnostic for HER2 protein overexpression, and Gleevec (imatinib), which was initially approved for chronic myeloid leukemia without a companion diagnostic but added a c-KIT immunoassay to its label when approved for patients with gastrointestinal stromal tumors. These products have since turned into blockbusters for Roche and Basel-based Novartis, respectively. Sometimes, companies have found themselves with a drug-diagnostic pairing, even if they hadn’t planned on it. In the case of Thousand Oaks–based Amgen’s colorectal cancer treatment Vectibix (panitumumab), oncologists have increasingly adopted homebrew tests for the KRAS mutation, after it became clear certain variants of the encoded GTPase (G12A, G12N, G12V, G12C, G12S and G13D) predict a lack of drug response. Such testing has likely lowered Vectibix revenues as Amgen’s pricing of the drug has not increased to reflect the narrower population. Although Herceptin’s combined diagnostic and drug approval was a landmark, it did not open the floodgates to companion diagnostic approvals. Indeed, the risk, expense and complexity of taking both a drug and a diagnostic through regulatory oversight has deterred many smaller companies from developing such an approach, according to Kathleen Glaub, president of Plexxikon, in Berkeley, California. “Adding companion diagnostics makes the whole process nearly twice as expensive and twice as complex,” she says.

Decision Making for a Companion Diagnostic in an Oncology Clinical Development Program

Abstract: The decision to incorporate the specific evaluation of a candidate companion diagnostic (CDx) in a clinical development plan (CDP) is often difficult and is exacerbated by the lack of relevant decision tools. In this article, we discuss a novel method to assess the probability of technical success (PTS) of a CDP that adequately evaluates a CDx compared with a CDP that doesn’t. We propose splitting the PTS into subjective (biological uncertainty) and quantitative (clinical uncertainty) components, assessing each separately, and then combining them in a decision theoretical manner to obtain an overall success probability of a CDP with and without a CDx.

Late-breaking news: FDA seeks input on proposed policy for diagnostic tests used with targeted drug therapies

Abstract: FDA has issued a new draft guidance to facilitate the development and review of companion diagnostics ? tests used to help healthcare professionals determine whether a patient with a particular disease or condition should receive a particular drug therapy or how much of the drug to give. The draft document is intended to provide companies with guidance on the agency's policy for reviewing a companion diagnostic and the corresponding therapy.

Protein biomarkers of recurrent breast cancer

Abstract: This patent application discloses and describes proteins found to be differentially expressed between primary tumor breast cancer cells that did not give rise to recurrent breast cancer disease after initial diagnosis and primary breast cancer cells that did give rise to recurrent breast cancer disease after initial diagnosis. These proteins can be used either individually or in specific combinations in diagnostic and prognostic protein assays on various biological samples from breast cancer patients to indicate the likelihood that a breast cancer patient's cancer will recur after initial diagnosis and treatment. Determination of differential expression of these proteins can also be useful for indicating additional therapies to combat the likelihood of recurrent breast cancer. The full length intact proteins can be assayed or peptides derived from these proteins can be assayed as reporters for these proteins. These proteins can also be identified as "companion diagnostic" proteins, wherein the differentially expressed proteins that arc used as diagnostic and prognostic indicators can also be used as targets for therapeutic intervention of breast cancer. Also disclosed and described herein are isotope labeled versions of peptides from the proteins.

FDA seeks input on proposed policy for diagnostic tests used with targeted drug therapies

Abstract: FDA has issued a new draft guidance to facilitate the development and review of companion diagnostics ? tests used to help healthcare professionals determine whether a patient with a particular disease or condition should receive a particular drug therapy or how much of the drug to give. The draft document is intended to provide companies with guidance on the agency's policy for reviewing a companion diagnostic and the corresponding therapy.

Personalized medicine: are payers the weak link?

Abstract: there is no codevelopment of tests. Tests are developed post hoc as a way of personalizing a drug, such as in the examples of abacavir and warfarin [8]. Despite the success stories, pharmaco genomics has had limited impact on clinical practice to date. The list of FDA/EMA-approved companion diagnostics is still relatively short, perhaps a dozen or so. There are significant clinical, financial and ethical barriers to the successful implementation of pharmacogenomics. Scientifically, the process of biomarker discovery and validation has been disappointingly slow. Additionally, regulatory and reimbursement issues have been problematic, particularly with respect to companion diagnostics, but also drugs that lack clinically effective diagnostics. To illustrate this point, gefitinib only works in approximately 10% of patients with advanced non-small-cell lung cancer. In June 2009, the FDA partially withdrew the drug, no longer allowing its prescription to new non-small-cell lung cancer patients, as no useful EGF receptor (EGFR) biomarker test is (yet) commercialized in the USA to pinpoint positive responders. As a result, gefitinib has encountered considerable market access issues, as payers are quite reluctant to reimburse. Even with FDA/EMA-approved biomarker tests lingering questions persist regarding their clinical effectiveness. A case in point is warfarin, which illustrates the acute translational gap that exists between knowledge and application. Tests suggest patients deficient in a certain enzyme activity (CYP2C9) may require a lower warfarin dose or more frequent monitoring and may be at risk of bleeding episodes. Since 2007, the FDA has been recommending genotyping for all patients being prescribed warfarin. In spite of this, in April 2009, the Centers for Medicare and Medicaid Services (CMS) decided not to routinely pay for genetic tests intended to help doctors determine Pharmacogenomics explores the ways in which genetic variations can be used to predict whether an individual patient will benefit from a drug, have a bad response or no response at all. Accordingly, therapies may be tailored to certain genetic characteristics of individual patients or subpopulations, drawing on data gathered from a variety of sources, including tests for biomarkers [1]. Knowledge of genetic variance can guide the selection of appropriate drugs or dosing tailored to an individual’s specific circumstances. This, in turn, may reduce the chance of adverse events, maximize the probability of better health outcomes and diminish costs [2,3]. In some instances, tests select which patients should or should not take a particular medication. For example, a test is used in conjunction with the breast cancer biologic trastuzumab to detect patients whose tumors overexpress HER2 protein [4,5]. In other cases, tests are used to predict the probability of adverse events associated with the use of a particular drug [6]. For example, there is a test which links hypersensitivity reactions to the HIV/AIDS drug abacavir to a specific genotype. Furthermore, there are tests which suggest ways to modify dosing in patients with an innately poor ability to metabolize a certain drug. In the case of warfarin, for instance, tests detect variations in the way individuals metabolize the blood-thinning agent. This may help to optimize dosing. Some personalized medicines are developed pharmacogenomically, concurrently with companion diagnostics. Trastuzumab was codeveloped with a pharmacogenomics test, which was US FDA/EMA approved and recommended prior to prescribing. There are also instances, such as the cancer biologic cetuximab, when a drug was codeveloped with a test but testing is not recommended by any regulatory authority prior to prescribing [7]. However, in most cases, at present “...in order to achieve widespread favorable reimbursement and clinical uptake for genetic tests and targeted therapies, manufacturers will need to bring more, and better, clinical evidence to the market place...”

Epigenetic-based companion diagnostics.

Abstract: In current medical practice, when a patient is diagnosed with cancer the treating physician generally follows a standard protocol, assigning the treatment that gives a favorable response in the largest proportion of patients. However, in many individual instances this approach may not be the most effective solution and, typically, treatment is only initiated or altered once the cancer has actually started progressing. During this process, patients will lose treatment time waiting to start chemotherapy or will endure severe side effects associated with toxic chemotherapeutic treatments. While some patients are undertreated because current diagnostic methods cannot provide accurate enough information regarding the aggressiveness or drug response of their disease, others with nonaggressive forms of cancer are overtreated and unnecessarily undergo the side effects associated with chemotherapeutic treatment. Epigenetic markers have been widely investigated and are considered key regulators of cellular transcription. Histone modifications and DNA methylation have been demonstrated to play key roles in maintaining stem-cell-like states, cellular differentiation and cancer. In particular, DNA methylation is a frequent, abundant and stable cancer mark, with an inherent role in oncogenesis and tumor progression. In this article, the potential of DNA methylation as a companion diagnostic is assessed, illustrated by exploring some development paths. Epigenetic silencing of MGMT is a key example of how biomarker development, biological pathways and clinical utility come together, serving as a hallmark of epigenetic companion diagnostics.

[Companion diagnostics: significances and issues in its clinical application].

Abstract: Studies on the biological significance of human genome sequence variations revealed their association with diversity in patient's individual response to a particular drug. Based on it, pharmacogenomic tests have been developed and could be used as an indication of pharmacological responses to a therapeutic intervention to select appropriate patients to be treated with a particular drug, and adjust dosage to have maximum efficacy while minimizing adverse events. Companion diagnostic tests are used in a specific context that provides information that enables better decision-making about the development and use of a potential drug therapy. It is a key tool in personalized medicine and a solution to develop individualized drugs. However, in development and clinical application of such tests, there are problems in biological, technical and clinical aspects. Of primary importance is coordination among government, industry and academic professionals, to make standards and evidences for system development and application and to guide society including public and care providers, hence providing health care service with good quality.

Models of partnership between the pharmaceutical and diagnostics industries around companion diagnostics for cancer and beyond

Abstract: An increase of targeted anticancer therapies has led to the beginning of a new era of cancer treatment, partly by replacing classical chemotherapies, partly supplementing these. Whereas for some substances only clinical experiences are relevant for treatment decisions, for some major cancer groups predictive markers are known that indicate probable tumor responses. To identify the latter, a need for companion diagnostics is given, often already existing as successful cooperation between pharmaceutical and diagnostic industries. This editorial focuses on the impact of companion diagnostic tests in personalized anticancer medicine, reporting recent advances in identifying and characterizing tumor subgroups responding to selected drugs. The most successful targeted therapies are directed against the EGFR/Her-2/neu receptors with regard to their downstream molecules in major cancer groups, including breast, gastric, lung and colorectal carcinomas. The development of biomarkers provides great opportunities to identify subpopulations with differential drug responses. On the one hand patients themselves are gaining major advantages of personalized and better tolerable cancer treatment, on the other hand, owing to very focused targeted therapies, these developments make possible cost-intensive targeted drug investigations and trials, especially in a situation of limited healthcare budgets.