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Selected Statistical Topics of Regulatory Importance
Published in Demissie Alemayehu, Birol Emir, Michael Gaffney, Interface between Regulation and Statistics in Drug Development, 2020
Demissie Alemayehu, Birol Emir, Michael Gaffney
In personalized medicine, certain molecular targeted therapies tend to involve a high cost of delivery. In such instances, use of biomarkers that predict response may be a viable alternative to gain efficiency. This is especially attractive, provided the cost associated with the use of companion diagnostics, which involves testing before giving treatment, is not in excess of the savings obtained by tailoring treatment only to the target patient population.
Molecular Pathologic Diagnostics for Personalized Medicine
Published in Il-Jin Kim, Companion Diagnostics (CDx) in Precision Medicine, 2019
With the recent successes of molecular targeted drugs, such as trastuzumab, cetuximab, and imatinib, the importance of molecular pathologic diagnosis has been increasing. Trastuzumab requires testing for the status of human epidermal growth factor receptor 2 (HER2), and cetuximab therapy can only be applied in the absence of RAS mutations.1,2 The United States Food and Drug Administration (FDA) defines companion diagnostics as a diagnostic assay required for the use of the associated drug based on clinical efficacy and safety data. Complementary diagnostics for personalized therapy is defined as a diagnostic assay that predicts a favorable outcome of the associated drug by selecting patients based on results of the assay; however, molecular targeted drugs can be applied without complementary diagnostics results. The programmed death ligand 1 (PD-L1) immunohistochemistry (IHC) 28-8 PharmDx assay (Dako, Glostrop, Denmark) was approved as the first complementary diagnostic test for nivolumab in 2015.3Companion and complementary diagnostic tests are performed using various methods, including IHC, in situ hybridization (ISH), real-time polymerase chain reaction (PCR), and next-generation sequencing (NGS).
Basket Trials at the Confirmatory Stage
Published in Zoran Antonijevic, Robert A. Beckman, Platform Trial Designs in Drug Development, 2018
In order to validate the companion diagnostic for new indications as a test that can distinguish between patients who will and will not benefit from the therapy, biomarker-negative patients must also be enrolled. It is desirable to keep the number of biomarker-negative patients as small as possible, and in some indications it may not be ethically feasible to enroll them. If the lead indication supports the biomarker hypothesis and companion diagnostic assay, we propose that a single biomarker negative cohort be made with small contributions of biomarker-negative patients from those indications for which this is ethically feasible, normally those for which the randomized design is an add-on of the experimental therapy to a base of standard of care. We propose this biomarker negative randomized sub-study be powered on the more sensitive interim endpoint.
Proteome-based pathology: the next frontier in precision medicine
Published in Expert Review of Precision Medicine and Drug Development, 2021
Michael H. Roehrl, Victor B. Roehrl, Julia Y. Wang
We are certain that a focus on proteomics and proteome-based diagnostics will have enormous impact on diagnostics, risk prediction [14–16], disease monitoring, and therapy selection in the immediate future. This will require long overdue modifications to our routine clinical practice (more fresh and frozen tissue biopsies, rather than the century-old paraffin wax embedding). There is also an education and training need: physicians must be educated about the possibilities (and limitations) of proteomics in medicine and how it complements with other molecular diagnostics. The technology is ready. Proteome-Based Diagnostics promises an unprecedented quantitative, biochemical, functional, and dynamic look at human disease. We believe that it will become the cornerstone of a new generation of companion diagnostics and that it will be a decisive element of clinical trials and drug development of the next decade.
Commonly setting biological standards in rare diseases
Published in Expert Opinion on Orphan Drugs, 2019
Daniel J. O’Connor, Jenny Buckland, Neil Almond, Jennifer Boyle, Carmen Coxon, Eleni Gaki, Javier Martin, Giada Mattiuzzo, Clive Metcalfe, Mark Page, Nicola Rose, Begona Valdazo-Gonzalez, Yuan Zhao, Christian K. Schneider
Another priority for standardization institutions is the development of standards for cancer genomics, with the presence of a genetic marker linked to the initiation of a specific therapy or personalized medicine. Companion diagnostics are increasingly required to select the appropriate patients for a therapeutic product; many of these are molecular tests for a specific genetic marker. Long-term monitoring of the patient is also usually required, in the evaluation of initial therapeutic response, the emergence of any therapeutic resistance and ultimately remission status. Such testing often requires the quantification of the genetic marker, and thus the availability of standards for consistent, accurate, and sensitive reporting, which should be independent of assay, laboratory, or geography.
Promoting the value of precision medicine to the public: the power of storytelling
Published in Expert Review of Precision Medicine and Drug Development, 2018
The Genetics Home Reference has defined ‘precision medicine’ as ‘an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person’ [1]. While the concept is sound, most physicians may find it difficult to quantitatively assess an individual’s environment and lifestyle variations, short of obvious factors, such as smoking, lack of exercise, and poor dietary habits. The field of molecular pathological epidemiology has begun to link a patient’s environment and lifestyle to his disease management [2]. In contrast, there has been much progress in determining the role of germ-line and somatic mutations for the diagnosis and prevention of specific diseases, but especially for selecting the most appropriate therapeutic treatment. ‘Companion diagnostics’ usually refers to use of specific drugs or biologics to treat patients who have demonstrated the presence of a specific somatic variance in order to improve therapeutic efficacy. The adoption of ‘companion diagnostics’ continues at a reasonable pace. As of 27 April 2018, the FDA has approved 26 companion tests linked with therapeutics for treatment of various diseases, with several more in process [3]. Medical specialists such as oncologists, rheumatologists, and others who see these patients have been the drivers for the use of these special laboratory tests.