A framework for applying unfamiliar trial designs in studies of rare diseases

Gupta, Samir; Faughnan, Marie E.; Tomlinson, George; Bayoumi, Ahmed M.

doi:10.1016/j.jclinepi.2010.12.019

Cited by 96 publications

(103 citation statements)

References 48 publications

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“…42,43 Several modified trial designs have been proposed to accommodate small samples. 44 However, with the exception of n-of-1 trials and RCT, randomized controlled trial; −, addressing this aspect is a weakness of this design; −/+, design has variable or moderate ability to address this aspect; +, addressing this aspect is a strength of this design.…”

Section: Study Designs: Generating Evidence To Evaluate Effectivenessmentioning

confidence: 99%

“…44 In both n-of-1 (single participant) and crossover trials, participants receive two treatments in random order with a washout period in between, such that each participant acts as his or her own control; 43,44,50 variations of these designs may incorporate more than two treatment periods, which can help to mitigate potential bias due to carryover and period effects. 44 n-of-1 trials are explicitly oriented toward supporting individual treatment decisions. 51 Multiple n-of-1 trials can also be combined to provide population-level effect estimates, although there are some challenges with the approach when the sample is small.…”

Section: Study Designs: Generating Evidence To Evaluate Effectivenessmentioning

confidence: 99%

“…51 Multiple n-of-1 trials can also be combined to provide population-level effect estimates, although there are some challenges with the approach when the sample is small. 44,50 Although both n-of-1 and crossover designs are susceptible to carryover and period effects, these approaches are ideal designs for investigating heterogeneity in treatment effects across participants ( Table 2). A drawback of n-of-1 and crossover trials is their reliance on short-term outcomes with rapid response to the intervention.…”

Section: Study Designs: Generating Evidence To Evaluate Effectivenessmentioning

confidence: 99%

See 2 more Smart Citations

Translating rare-disease therapies into improved care for patients and families: what are the right outcomes, designs, and engagement approaches in health-systems research?

Potter

Khangura

Tingley

et al. 2016

Genetics in Medicine

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Section: Study Designs: Generating Evidence To Evaluate Effectivenessmentioning

confidence: 99%

Section: Study Designs: Generating Evidence To Evaluate Effectivenessmentioning

confidence: 99%

Section: Study Designs: Generating Evidence To Evaluate Effectivenessmentioning

confidence: 99%

See 1 more Smart Citation

Translating rare-disease therapies into improved care for patients and families: what are the right outcomes, designs, and engagement approaches in health-systems research?

Potter

Khangura

Tingley

et al. 2016

Genetics in Medicine

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“…96 However, a paucity of IBC patients is still a barrier. A solution may be a national or international clinical trial, which has been a recent trend in oncology.…”

Section: A Clinical Trial Design To Study the Effect Of Tipifarnib Ormentioning

confidence: 99%

Tipifarnib and farnesyltransferase inhibitors in the treatment of inflammatory breast cancer: is the story over? A review

Dehghan-Paz¹,

Il’yasova²,

Golen³

et al. 2013

ODRR

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Inflammatory breast cancer (IBC) is a rare but aggressive form of breast cancer with unique clinicopathological features and poor prognosis. Its epidemiology is distinct from noninflammatory locally advanced breast cancer (LABC), which points to different etiology. With the advent of multimodality treatment for LABC, the outcomes for women with IBC have improved, but remain significantly inferior to outcomes for noninflammatory LABC. This review focuses on new research in epidemiology and molecular pathways characteristic for IBC. One of the critical carcinogenic events apparently driving the development and progression of IBC is activation of the RhoC protein, which is a part of the Ras oncogene superfamily. These proteins, like other Ras proteins, require posttranslational prenylation for their activation and transfer to cell membranes. Farnesylation is a common type of prenlyation that can be blocked with a new class of drugs -farnesyltransferase inhibitors. The most advanced farnesyltransferase inhibitor in development, tipifarnib, has been evaluated in Phase II clinical trials as monotherapy and in combination with antihormonal agents and trastuzumab in metastatic and locally advanced breast cancer. A few tumor responses have been observed in these trials, but not enough to warrant a Phase III trial. Potential combinations of tipifarnib with other novel agents targeting enzymes downstream to RhoC are reviewed. Some of these drugs, such as imatinib and crizotinib, are already commercially available. Others like perifosine and anti-vascular endothelial growth factor 3 antibody are currently under development. Innovative trial designs to address this rare type of cancer are discussed.

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“…3,4 In these studies, patients serve as their own controls, and their responses to therapies are quantified for that individual patient. These types of trials seem to require a constant, measurable background disease variable (eg, arthritis, attention deficit hyperactivity disorder) or frequent symptom event (eg, asthma) to assess individual treatment effects.…”

Section: Article See P 984mentioning

confidence: 99%

Supraventricular Tachycardia Treatment Efficacy in Infants

Perry

2012

Circ: Arrhythmia and Electrophysiology

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I n this issue of Circulation: Arrhythmia and Electrophysiology, Sanatani et al 1 report a randomized, double-blind study of a comparison of digoxin and propranolol for chronic therapy of supraventricular tachycardia (SVT) in infants <4 months of age. The key findings in 61 patients were that there were no differences in SVT recurrence for the 2 drug treatment groups and that there were no recurrences of SVT after 4 months of therapy with either antiarrhythmic agent. Another salient point to be taken includes an expectation that perhaps 10% of infants diagnosed with SVT can be expected to require subsequent hospitalization for management of SVT recurrences. Article see p 984As is often the case with even thoughtful attempts to perform these types of clinical trials in pediatric electrophysiology, and pediatric cardiology generally, the study is underpowered to make feasible many of the desired statistical analyses between the 2 treatment groups. As a result of the relatively small numbers of patients in a given institution, multicenter studies in our field are frequently required to achieve the requisite N for these study designs. As the authors note, issues of patient enrollment, physician biases, parental consent, and inadequate follow-up plague this and other similar efforts. The history of this specific article is telling, in its attempts to clear the hurdle of peer review: it was submitted to 4 journals, critiqued by 12 reviewers, and underwent 8 revisions in response to seemingly unachievable demands for the statistical rigor of a large, randomized clinical trial. The study and its lead author became fixtures for a plea to the masses for patient enrollment at the Pediatric and Congenital Electrophysiology Society business meeting at Heart Rhythm Society for each of the past 6 years. With its key features intact, it has reached its well-deserved publication.From a practical standpoint, yes, the study is underpowered. It is still worthy of our attention and publication, even in its descriptive terms, for its effects on what we do, how we educate families, and how we lay the foundation of their expectations going forward. Personally, over the years, I have scaled back the duration of therapy for infants with SVT from 12 months to 8 months and then to 6 months. As a result of this current report, I have been stopping therapy for SVT in these non-Wolff-Parkinson-White, common SVT mechanism patients at 4 months. The data from Sanatani et al 1 have been available in review form for the better part of a year, and (anecdotally!) over that time period we have not seen an SVT recurrence. That aspect of the current article raises another value of this data: it provides us with a data set from which we can pose new questions, such as "do all infants with SVT warrant ongoing treatment, and if not, which patients?" As the authors query, do we need (or want) a placebo study for this population?This all brings us to an important consideration for the design of studies for rare (ie, low N) conditions. A valid critique of ra...

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A framework for applying unfamiliar trial designs in studies of rare diseases

Cited by 96 publications

References 48 publications

Translating rare-disease therapies into improved care for patients and families: what are the right outcomes, designs, and engagement approaches in health-systems research?

Translating rare-disease therapies into improved care for patients and families: what are the right outcomes, designs, and engagement approaches in health-systems research?

Tipifarnib and farnesyltransferase inhibitors in the treatment of inflammatory breast cancer: is the story over? A review

Supraventricular Tachycardia Treatment Efficacy in Infants

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