Enabling Precision Medicine The Role of Genetics in Clinical Drug Development: Proceedings of a Workshop (2017) / Chapter Skim
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4 Integrating Genetics into the Drug Development Pathway for Complex Diseases
4 Integrating Genetics into the Drug Development Pathway for Complex Diseases
Pages 43-68
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From page 43... ...
• Ethnic variability in the prevalence of genetic variants is an important consideration for recruitment and enrollment strate gies for clinical trials and in prospectively accounting for the representativeness of populations studied in GWASs. (Farkouh, Williams)
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From page 44... ...
• Pharmacogenomics research holds promise for detecting associ ation between genetic variants and efficacy outcomes or safety signals, but is still in its infancy and is practically limited by several factors, including small early-phase trial populations, a lack of prospective collection of genetic and phenotypic data in EHRs, and the relatively high prevalence, and thus poor prog nostic or predictive value, in the population of putative genetic risk factors for adverse drug reactions. (Blanchard, Nelson)
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PATIENT PERSPECTIVE ON GENETICS-ENABLED DRUG DEVELOPMENT: VIEW FROM THE PRADER WILLI SYNDROME COMMUNITY Strong discussed the pathology and clinical course of Prader-Willi syndrome (PWS) and the integration of genetic information into precision drug development for PWS treatments, including the challenges of and opportunities for engaging patients and their families in precision medicine.
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. Genetics-enabled clinical trials with molecularly defined subpopulations could potentially inform drug efficacy and safety profiling for PWS treat
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To further this goal, the Foundation for Prader-Willi Research is initiating a pilot PWS Genomes project which will conduct whole-genome sequencing of individuals with PWS. Genetic data will be linked to information in the Global PWS Registry, which has now enrolled 1,000 indi viduals.1 Together, these different sources of information could inform clinical management and drug selection, serve as a source of molecularly defined populations for the enrichment and stratification of clinical trials, and help develop a better understanding of the genetic variability in drug safety and efficacy characteristics of PWS treatments.
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From page 48... ...
There is also a need for a data-sharing model where genetic information is returned to and stays with the individual, Strong emphasized, noting that it is important that patients own their genetic data, so that these data are accessible to them as they move between treatment and clinical trial settings over the course of their lifetime. Despite these challenges, there are opportunities to reach out to and engage with the PWS community, Strong said, noting the following observations: • The rare disease community is in general a "tight-knit group," and advocacy organizations are often thought of by patients as unin timidating, trusted partners.
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From page 49... ...
In summary, Strong said, genetic information has tremendous potential beyond the diagnosis of rare diseases to improve clinical trial efficiency, particularly with regard to trial design, interpreting efficacy findings, and safety. However, there are challenges to be addressed, including educating the rare disease community in ways that are informative yet accessible, reporting back genetic data to patients and families in a timely manner and usable format, and limiting the overall burden on families who are already overwhelmed by complex, chronic diseases.
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From page 50... ...
for the observed outcome coupled with the prevalence of the genetic variant in the general population meant that the pharmacogenetic risk factor had significant predictive value for the observed adverse event, Nelson said. 2 To read the full FDA alert about abacavir see https://www.fda.gov/Drugs/DrugSafety/ ucm123927.htm (accessed May 18, 2017)
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However, he continued, though successes have been realized in identifying genetic risk factors for adverse events, some of which have been incorporated into treatment guidelines (Martin et al., 2014) , two main practical limitations have prevented the majority of this pharmacogenetic evidence from making it into treatment guidelines.
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For example, GSK and others have studied the potential impact of genes on steroid treatment response in asthma patients. GSK undertook the largest pharmacogenetic study to date of patient response to inhaled corticosteroids, Nelson said, evaluating data across seven GSK clinical trials with a total of 2,672 patients.
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. • Common genetic risk factors alone generally do not accurately predict patient risk, particularly for rare serious adverse events.
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. Hypotheses could be a part of testing candidate genes associated with drug metabolism or targets, FIGURE 4-2 Routine genetic/genomic studies in clinical trials at Merck.
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profiling of patients' tumors. A "dual-consenting" informed consent approach, Blanchard explained, is used to incorporate pharmacogenomics into immediate and future clinical trials, with the goal of maintaining patient privacy and consenting choice without delaying the trial.
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First, the overall trial results were evaluated in the context of the presence or absence of two baseline risk factors among the participant population. This subcategorization of the participant population showed that the therapy was most beneficial in patients who presented with both baseline risk factors -- in short, high-risk patients responded best to the drug.
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CLOPIDOGREL PHARMACOGENETICS IN CORONARY ARTERY DISEASE: THE TAILOR-PCI TRIAL In the context of coronary artery disease (CAD) ,3 a common complex disease, Farkouh discussed the pharmacogenetic characteristics of clopidogrel, a treatment indicated for patients with CAD, and discussed the TAILOR-PCI trial, which is using genetic data to improve patient outcomes after percutaneous coronary intervention for CAD.
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. Complicating the issue, Farkouh said, is the fact that two new compounds, prasugrel and ticagrelor, have been developed and have shown in large clinical trials to be superior to clopidogrel in terms of major adverse cardiovascular events.
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; CV = cardiovascular; MI = myocardial infarction; PCI = percutaneous coronary intervention; WT = wild type. SOURCE: Michael Farkouh, National Academies of Sciences, Engineering, and Medicine workshop presentation, March 8, 2017.
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2/* 3 ticagrelor prospective genotyping arm, rather than the combined comparison of the two randomized arms.
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TAILOR-PCI is a large pragmatic study designed and conducted to address this gap. REACTION PANEL AND DISCUSSION Following the speaker presentations, reaction panelists reflected on key ideas from the session and shared their perspectives on issues pertaining to the use of genetics for safety profiling, the economic considerations related to the implementation of genetics-enabled clinical trials, and the recruitment and retention of minority patients for clinical trials.
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However, in some cases unknown genetic variants can affect drug response, and there may be adverse events that could not have
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A workshop participant mentioned that a key finding from the Clinical Trials Transformation Initiative (CTTI) is the need for a plan to identify clinically relevant patient populations at the beginning of clinical drug development.
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Case Studies in Asthma Williams shared lessons learned for recruiting diverse patient populations and retaining trial participants. The Study for Asthma henotypes and P Pharmacogenomic Interactions by Race-Ethnicity SAPPHIRE)
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On average, adherence to the inhaled corticosteroid therapy in the overall patient population was approximately 50 percent. In clinical trials in general, Williams said, adherence is not often reported, and only patients who complete the trial are evaluated.
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From page 66... ...
Rare disease advocacy groups have different levels of baseline literacy concerning genetics or clinical trials, Strong said, and accordingly their patient bases may or may not have all the information about the questions they should ask when approached about participation in a clinical trial. It is important to inform patients about what it means to participate in a clinical trial and to demystify the process, Langbaum said, so that when they are invited to participate in a study, they are prepared.
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of successful mechanisms for engaging participants in precision-medicine clinical trials for Alzheimer's disease. Colombian Alzheimer's Prevention Registry A trial for a rare, autosomal-dominant form of Alzheimer's disease is being conducted in Colombia, South America, where it is estimated that there are about 5,000 living family members of the world's largest utosomal-dominant mutation kindred.7 The Colombian Alzheimer's Prevena tion Registry was launched in anticipation of the trial and served as a preenrollment recruitment mechanism to identify potential study participants.
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The most significant barrier to registration, however, is that potential participants want to receive their APOE test results. The recruitment process for the Generation Study is similar to a funnel, Langbaum said.
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