Ethical issues raised by intergenerational monitoring in clinical trials of germline gene modification

2020 ◽  
pp. medethics-2020-106095
Author(s):  
Austen Yeager
Keyword(s):  
Clinical Trials ◽  
Trial Design ◽  
Gene Editing ◽  
Ethical Issues ◽  
Clinical Trial Design ◽  
Careful Consideration ◽  
Future Generations ◽  
Germline Gene ◽  
Gene Modification

As research involving gene editing continues to advance, we are headed in the direction of being able to modify the human germline. Should we reach a point where an argument can be made that the benefits of preventing unborn children and future generations from inheriting genetic conditions that cause tremendous suffering outweigh the risks associated with altering the human germline, the next step will be to design clinical trials using this technology in humans. These clinical trials will likely require careful follow-up and monitoring of future generations born with altered genes. This paper addresses some of the ethical issues raised by intergenerational monitoring and sets out to show that these issues can be avoided with careful consideration and clinical trial design.

scholarly journals Intergenerational monitoring in clinical trials of germline gene editing

2019 ◽  
Vol 46 (3) ◽  
pp. 183-187 ◽  
Author(s):  
Bryan Cwik
Keyword(s):  
Clinical Trials ◽  
Gene Editing ◽  
Ethical Issues ◽  
Human Subjects ◽  
Germline Gene ◽  
Ethical Challenges ◽  
Human Subjects Research ◽  
Follow Up Study

Design of clinical trials for germline gene editing stretches current accepted standards for human subjects research. Among the challenges involved is a set of issues concerning intergenerational monitoring—long-term follow-up study of subjects and their descendants. Because changes made at the germline would be heritable, germline gene editing could have adverse effects on individuals’ health that can be passed on to future generations. Determining whether germline gene editing is safe and effective for clinical use thus may require intergenerational monitoring. The aim of this paper is to identify and argue for the significance of a set of ethical issues raised by intergenerational monitoring in future clinical trials of germline gene editing. Though long-term, multigenerational follow-up study of this kind is not without precedent, intergenerational monitoring in this context raises unique ethical challenges, challenges that go beyond existing protocols and standards for human subjects research. These challenges will need to be addressed if clinical trials of germline gene editing are ever pursued.

scholarly journals INTEREST GROUP SESSION—GEROSCIENCE: METHODS FROM BENCH TO POPULATION SCIENCE TO INFORM CONSTRUCTION OF GEROSCIENCE CLINICAL TRIALS

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S745-S745
Author(s):  
Jason L Sanders ◽  
Anne B Newman
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Biological Pathway ◽  
Efficacy And Safety ◽  
Population Science ◽  
Multiple Levels ◽  
Aging Mechanisms

Abstract We are on the cusp of a revolution in aging science. It has matured to the point where geroscience trials will test interventions in humans which alter aging mechanisms to lengthen healthspan and possibly lifespan. This goal is unprecedented in clinical trial design, and it requires retooling the clinical trial toolbox. Traditionally, trials are constructed around a single disease; interventions target a narrow part of a defined biological pathway involving only one molecule, tissue, or organ; events are well known intermediate endpoints and clinically-defined hard outcomes; and follow up may be short and historically informed based on prior trials. Geroscience trials by design target aging mechanisms which, when altered, are likely to have pleiotropic effects that modify several biologic pathways; efficacy and safety signals may require integration across multiple levels of biologic organization; intermediate endpoints are not agreed upon; and follow up timelines are undefined. In this symposium, we provide guidance on the design of geroscience trials using examples that span from bench to population science. Dr. LeBrasseur will discuss screening senolytic compounds across models of age-associated decline and advancing their candidacy as interventions. Dr. Justice will detail a framework for biomarker selection in geroscience trials, focusing on a trial of metformin as an example. Dr. Sanders will illustrate how observational data can inform phenotype use in clinical trials. Dr. Levine will explain translating omics data for use in geroscience trials, focusing on epigenomics. We expect additional discussion to hasten development of well-designed geroscience trials.

scholarly journals Conceptual Framework to Support Clinical Trial Optimization and End-to-End Enrollment Workflow

2019 ◽  
pp. 1-10 ◽  
Author(s):  
Neha M. Jain ◽  
Alison Culley ◽  
Teresa Knoop ◽  
Christine Micheel ◽  
Travis Osterman ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Knowledge Representation ◽  
Conceptual Framework ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Prospective Clinical Trial ◽  
Future Trends ◽  
Current State ◽  
Evaluation Strategies

In this work, we present a conceptual framework to support clinical trial optimization and enrollment workflows and review the current state, limitations, and future trends in this space. This framework includes knowledge representation of clinical trials, clinical trial optimization, clinical trial design, enrollment workflows for prospective clinical trial matching, waitlist management, and, finally, evaluation strategies for assessing improvement.

scholarly journals Edaravone in Amyotrophic Lateral Sclerosis’Lessons from the Clinical Development Program and the Importance of a Strategic Clinical Trial Design

US Neurology ◽  
2018 ◽  
Vol 14 (1) ◽  
pp. 47 ◽  
Author(s):  
Said R Beydoun ◽  
Jeffrey Rosenfeld
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Trial Design ◽  
Development Program ◽  
Clinical Trial Design ◽  
Clinical Development ◽  
Disease Heterogeneity ◽  
Clinical Development Program ◽  
Lateral Sclerosis

Edaravone significantly slows progression of amyotrophic lateral sclerosis (ALS), and is the first therapy to receive approval by the Food and Drug Administration (FDA) for the disease in 22 years. Approval of edaravone has marked a new chapter in pharmaceutical development since the key trial included a novel strategic clinical design involving cohort enrichment. In addition, approval was based on clinical trials that had a relatively small patient number and were performed outside of the US. Edaravone was developed through a series of clinical trials in Japan where it was determined that a well-defined subgroup of patients was required to reveal a treatment effect within the study period. Amyotrophic lateral sclerosis is associated with wide-ranging disease heterogeneity (both within the spectrum of ALS phenotypes as well as in the rate of progression). The patient cohort enrichment strategy aimed to address this heterogeneity and should now be considered as a viable, and perhaps preferred, trial design for future studies. Future research incorporating relevant biomarkers may help to better elucidate edaravone’s mechanism of action, pharmacodynamics, and subsequently ALS phenotypes that may preferentially benefit from treatment. In this review, we discuss the edaravone clinical development program, outline the strategic clinical trial design, and highlight important lessons for future trials.

Clinical Trial Design and Statistics

2018 ◽  
Author(s):  
Julie Ann Sosa
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Data Analysis ◽  
Trial Design ◽  
New Technologies ◽  
Drug Application ◽  
Clinical Trial Design ◽  
Double Blind Study ◽  
Type I ◽  
End Points

A clinical trial is a planned experiment designed to prospectively measure the efficacy or effectiveness of an intervention by comparing outcomes in a group of subjects treated with the test intervention with those observed in one or more comparable group(s) of subjects receiving another intervention.  Historically, the gold standard for a clinical trial has been a prospective, randomized, double-blind study, but it is sometimes impractical or unethical to conduct such in clinical medicine and surgery. Conventional outcomes have traditionally been clinical end points; with the rise of new technologies, however, they are increasingly being supplemented and/or replaced by surrogate end points, such as serum biomarkers. Because patients are involved, safety considerations and ethical principles must be incorporated into all phases of clinical trial design, conduct, data analysis, and presentation. This review covers the history of clinical trials, clinical trial phases, ethical issues, implementing the study, basic biostatistics for data analysis, and other resources. Figures show drug development and clinical trial process, and type I and II error. Tables list Food and Drug Administration new drug application types, and types of missing data in clinical trials. This review contains 2 highly rendered figures, 2 tables, and 38 references

A novel, hybrid, single- and multi-site clinical trial design for CLN3 disease, an ultra-rare lysosomal storage disorder

2019 ◽  
Vol 16 (5) ◽  
pp. 555-560 ◽  
Author(s):  
Heather R Adams ◽  
Sara Defendorf ◽  
Amy Vierhile ◽  
Jonathan W Mink ◽  
Frederick J Marshall ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Rare Diseases ◽  
Trial Design ◽  
Neurodegenerative Disorder ◽  
Clinical Trial Design ◽  
Trial Participation ◽  
Local Participation ◽  
Cln3 Disease ◽  
Study Participants

Background Travel burden often substantially limits the ability of individuals to participate in clinical trials. Wide geographic dispersion of individuals with rare diseases poses an additional key challenge in the conduct of clinical trials for rare diseases. Novel technologies and methods can improve access to research by connecting participants in their homes and local communities to a distant research site. For clinical trials, however, understanding of factors important for transition from traditional multi-center trial models to local participation models is limited. We sought to test a novel, hybrid, single- and multi-site clinical trial design in the context of a trial for Juvenile Neuronal Ceroid Lipofuscinosis (CLN3 disease), a very rare pediatric neurodegenerative disorder. Methods We created a “hub and spoke” model for implementing a 22-week crossover clinical trial of mycophenolate compared with placebo, with two 8-week study arms. A single central site, the “hub,” conducted screening, consent, drug dispensing, and tolerability and efficacy assessments. Each participant identified a clinician to serve as a collaborating “spoke” site to perform local safety monitoring. Study participants traveled to the hub at the beginning and end of each study arm, and to their individual spoke site in the intervening weeks. Results A total of 18 spoke sites were established for 19 enrolled study participants. One potential participant was unable to identify a collaborating local site and was thus unable to participate. Study start-up required a median 6.7 months (interquartile range = 4.6–9.2 months). Only 33.3% (n = 6 of 18) of spoke site investigators had prior clinical trial experience, thus close collaboration with respect to study startup, training, and oversight was an important requirement. All but one participant completed all study visits; no study visits were missed due to travel requirements. Conclusions This study represents a step toward local trial participation for patients with rare diseases. Even in the context of close oversight, local participation models may be best suited for studies of compounds with well-understood side-effect profiles, for those with straightforward modes of administration, or for studies requiring extended follow-up periods.

scholarly journals Flares in patients with systemic lupus erythematosus

Rheumatology ◽  
2020 ◽  
Author(s):  
Kathleen McElhone ◽  
Janice Abbott ◽  
Margaret Hurley ◽  
Jane Burnell ◽  
Peter Lanyon ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Trial Design ◽  
Disease Duration ◽  
Clinical Trial Design ◽  
Reference Population ◽  
World Population ◽  
Future Clinical Trial ◽  
Systemic Lupus

Abstract Objective SLE is characterized by relapses and remissions. We aimed to describe the frequency, type and time to flare in a cohort of SLE patients. Methods SLE patients with one or more ‘A’ or ‘B’ BILAG-2004 systems meeting flare criteria (‘new’ or ‘worse’ items) and requiring an increase in immunosuppression were recruited from nine UK centres and assessed at baseline and monthly for 9 months. Subsequent flares were defined as: severe (any ‘A’ irrespective of number of ‘B’ flares), moderate (two or more ‘B’ without any ‘A’ flares) and mild (one ‘B’). Results Of the 100 patients, 94% were female, 61% White Caucasians, mean age (s.d.) was 40.7 years (12.7) and mean disease duration (s.d.) was 9.3 years (8.1). A total of 195 flares re-occurred in 76 patients over 781 monthly assessments (flare rate of 0.25/patient-month). There were 37 severe flares, 32 moderate flares and 126 mild flares. By 1 month, 22% had a mild/moderate/severe flare and 22% had a severe flare by 7 months. The median time to any ‘A’ or ‘B’ flare was 4 months. Severe/moderate flares tended to be in the system(s) affected at baseline, whereas mild flares could affect any system. Conclusion . In a population with active SLE we observed an ongoing rate of flares from early in the follow-up period with moderate–severe flares being due to an inability to fully control the disease. This real-world population study demonstrates the limitations of current treatments and provides a useful reference population from which to inform future clinical trial design.

Recommendations for improving clinical trial design to facilitate the study of youth-onset type 2 diabetes

2019 ◽  
Vol 17 (1) ◽  
pp. 87-98
Author(s):  
Muhammad Yazid Jalaludin ◽  
Margarita Barrientos-Pérez ◽  
Mona Hafez ◽  
Jane Lynch ◽  
Naim Shehadeh ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Clinical Trials ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Control Group ◽  
Onset Type ◽  
Therapeutic Choice ◽  
Glycemic Targets ◽  
Definition Of

Background The prevalence of type 2 diabetes is increasing in youths and differs from adult-onset type 2 diabetes in its characteristics and progression. Currently, only two drugs are approved for youth-onset type 2 diabetes and many patients are not meeting glycemic targets. Clearly, there is an urgent need to complete clinical trials in youths with type 2 diabetes to increase the therapeutic choice for these patients. However, factors such as limited patient numbers, unwillingness of patients to participate in trials, failure to meet strict inclusion and exclusion criteria, and poor clinic attendance have limited the size and number of trials in this complicated patient demographic. Recommendations This is a narrative opinion piece on the design of clinical trials in youth-onset type 2 diabetes prepared by researchers who undertake this type of study in different countries. The review addresses possible ways to enhance trial designs in youth-onset type 2 diabetes to meet regulatory requirements, while minimizing the barriers to patients’ participation. The definition of adolescence, recruitment of sufficient patient numbers, increasing flexibility in selection criteria, improving convenience of trial visits, requirements of a control group, possible endpoints, and trial compliance are all considered. The authors recommend allowing extrapolation from adult data, using multiple interventional arms within future trials, broadening inclusion criteria, and focusing on endpoints beyond glucose control, among others, in order to improve the successful completion of more trials in this population. Conclusions Improvements in trial design will enable better recruitment and retention and thereby more evidence for treatment outcomes for youth-onset type 2 diabetes.

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