Exploring Novel Clinical Trial Designs for Gene-Based Therapies Proceedings of a Workshop (2020) / Chapter Skim
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2 Developing First-in-Human Gene Therapy Clinical Trials
2 Developing First-in-Human Gene Therapy Clinical Trials
Pages 11-22
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From page 11... ...
(Finkel) • Robust natural history datasets with frequent visits to the research team; standardized measures; high-quality, patient level data; and complete follow-up are needed to develop treat ments for patients with rare diseases who could benefit from gene therapy.
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From page 12... ...
Jonathan Kimmelman, the director of the biomedical ethics unit at McGill University, provided an overview of the ethical dimensions and recurrent challenges associated with early-phase research and first-in-human trials. USING NATURAL HISTORY STUDIES IN CLINICAL DEVELOPMENT When developing a clinical trial in a pediatric population, sponsors should carefully consider the study population and whether it includes newborns, infants, children, or adolescents, Finkel said.
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From page 13... ...
Transitioning to the topic of early-stage research and how those findings can help prepare for clinical trials, Finkel touched on the importance of animal models. Shortly after the SMN genes were identified by Judith 1For a more thorough review of genetic changes in Duchenne muscular dystrophy and the implications for therapy, see Gao and McNally (2015)
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From page 14... ...
in order to predict the disease course in untreated and treated patients. Natural history studies of SMA patients were valuable because they showed that age is an important variable with regard to the change in motor function, Finkel said, and there was significant functional variability among the ambulant patient population (Mercuri et al., 2016)
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From page 15... ...
There are different types of natural history data available on SMA patients, Kaufmann said. She and her colleagues at AveXis used patient registries and associated medical charts to get an initial understanding of the course of the disease, she said, noting that these data sources do have significant limitations, particularly missing data or limited time course data.
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From page 16... ...
The NeuroNEXT natural history study also provided more data on changes in motor function and electrophysiological measures that were fit for use in clinical trials (Kolb et al., 2017)
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From page 17... ...
Finally, she reiterated how important the altruistic participation of patients and families in natural history studies is for the development of efficient gene therapy clinical trials. ETHICAL DIMENSIONS OF FIRST-IN HUMAN GENE TRANSFER TRIALS Kimmelman provided a high-level overview of research ethics and discussed those concepts within the context of gene therapy clinical trials.
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From page 18... ...
Claims of therapeutic benefit in firstin-human clinical trials should be met with skepticism, Kimmelman said. A second reason it does not make sense to call early-phase clinical studies therapeutic, he said, is that there is not strong evidence to suggest that participation in an early-phase clinical trial will provide any therapeutic benefit, given that most early-phase research studies fail to find evidence of efficacy and safety.
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From page 19... ...
"I think the more we partner with patients, the more we have strong patient groups who can provide that kind of information to parents and patients, the better off we are," she said. Data Collection and Patient Stratification Speakers were asked whether they believed clinical trial data collection was robust enough to be able to understand which patients are most likely to benefit (or not benefit)
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From page 20... ...
Tools and Approaches Useful for Clinical Trial Readiness Speakers were asked by a workshop participant if they could identify tools or models that they have found useful in their work, specifically for determining the minimal effective dose of a gene therapy. High answered that large animal models are very useful in predicting therapeutic doses, efficacy, and safety.
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From page 21... ...
Speakers were asked if it might be possible to use the results from one trial in a rare disease to shorten the development time for a similar disease, say all retinal diseases, rather than starting from zero for each disease. High responded that timelines for clinical development have shortened over the 30 years that gene therapy clinical trials have been run, and she said that FDA's draft guidance documents issued in 20184 should help further shorten timelines.
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