Enabling Precision Medicine The Role of Genetics in Clinical Drug Development: Proceedings of a Workshop (2017) / Chapter Skim
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5 Finding Innovative Ways to Integrate Genetic Research into the Drug Development Process
5 Finding Innovative Ways to Integrate Genetic Research into the Drug Development Process
Pages 69-82
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From page 69... ...
• The basket trial approach could be applied to treatments of rare genetic diseases with shared molecular etiologies through use of disease-specific assays to identify a predictive biomarker in patient cells. Rare disease organizations have essential exper tise and thus play a key role in carrying out shared molecular etiology basket trials.
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From page 70... ...
"P. J." Brooks, program director in the Division of Clinical Innovation at the National Center for Advancing Translational Sciences at NIH, described applying the basket trial approach to shared molecular etiologies in rare genetic diseases.
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From page 71... ...
In general, it takes 5 to 7 years to advance a therapeutic hypothesis to first-in-human proof-ofconcept trials, he said, adding that if the cost of drug development is to be significantly lessened, this early phase would need to be radically shortened. This would be a significant challenge, he said, but there are potential solutions to be leveraged through precision medicine approaches, such as selecting targets based on a deep understanding of human genetics and human biology and the concept of programmable therapeutics to test in proof-of-concept trials.
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From page 72... ...
As an example of this approach, Plenge cited a recent study that assessed whether heterozygous carriers of pathogenic mutations in the gene encoding lipoprotein lipase had increased odds of coronary artery disease (Khera et al., 2017)
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From page 73... ...
GROUPING RARE DISEASE PATIENTS BY SHARED MOLECULAR ETIOLOGY TO ACCELERATE CLINICAL TRIALS Another potential approach to streamlining genetics-enabled drug development and decreasing the amount of time required to bring new medicines to market was presented by Brooks. NCATS was established at NIH in 2011 to "catalyze the generation of innovative methods and technologies that will enhance the development, testing, and implementation of diagnostics and therapeutics across a wide range of human diseases and conditions."2 In contrast to many other NIH institutes and centers, 2 See https://ncats.nih.gov/about/center (accessed April 26, 2017)
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From page 74... ...
As of March 2017, there were almost 6,000 disease phenotypes with a known molecular basis, but only approximately 500 approved therapies.3 A fundamental change is needed in the way that treatments are developed for these rare diseases, Brooks said, and this is a gap that NCATS aims to help address with a program called SaME Therapeutics (Targeting Shared Molecular Etiologies Underlying Multiple Diseases to Accelerate Translation)
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From page 75... ...
As such, it is important that trials of p remature stop codon read-through compounds include multiple diseases, as it may not be possible to predict the potential clinical effects in each situation. Shared Molecular Etiology-Driven Trials It may be possible to apply the basket trial approach, which has been effective in genetically enabled oncology trials, to SMEs in rare genetic diseases, Brooks said.
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From page 76... ...
Participants were referred to the Collaborative Innovation Awards of the NCATS Clinical and Translational Science Award (CTSA) program.4 These awards were designed to stimulate collaboration with investigators from at least three different CTSA sites, and although it is a broad funding opportunity, the program has a vested interest in supporting clinical trials of drugs targeting SMEs underlying rare diseases.
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From page 77... ...
CTTI Patient Groups and Clinical Trials Project In October 2015, the CTTI PGCT Project put forth recommendations that outlined best approaches for engaging patient groups across the research and development continuum and for managing sponsor–patient group relationships to ensure that the needs of all stakeholders are met and to improve the overall quality of clinical trials. As a follow-on to these recommendations, the PGCT commenced a second stage of the project to develop a model for assessing the economic value of conducting patient engagement in drug development programs, Leventhal said.
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. Leventhal shared a case study wherein the model was populated with the anticipated probabilities of success and failure for a drug development program and the ensuing NPV and ENPV was calculated (see Figure 5-2)
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. Presented by David Leventhal, National Academies of Sciences, Engineering, and Medicine workshop presentation, March 8, 2017.
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ENPV modeling can account for important drivers of value in a clear and well-accepted summary metric, he said, adding that for engagement activities resulting in the avoidance of an amendment or an improved patient trial experience, the benefits in cost and ENPV vastly outweigh the resources spent on engagement. Therefore, ENPV modeling and similar approaches can support sponsor decisions to increase patient engagement throughout development.
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From page 81... ...
studies.9 • Patients in Global Product Development Initiative -- Soliciting input from patients about ongoing clinical development programs, including how to measure impact, identify gaps, and implement improvements. During the discussion session, a workshop participant suggested that biopharmaceutical companies involve experienced patient advocates in external stakeholder meetings and foster conversations among stake olders h to better understand the patient perspective.
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