Parametric multistate survival models: Flexible modelling allowing transition‐specific distributions with application to estimating clinically useful measures of effect differences

Crowther, Michael J.; Lambert, Paul C.

doi:10.1002/sim.7448

Cited by 118 publications

(152 citation statements)

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“…Patient-level data from a retrospective chart review study designed to describe the A multistate survival model using data from the natural history study was developed using methods detailed by Crowther and Lambert [26] to inform the transitions between the five 'alive' health states. Six parametric distributions were tested: exponential, generalised gamma, Gompertz, log-logistic, log-normal and Weibull.…”

Section: Clinical Datamentioning

confidence: 99%

An Economic Evaluation of Voretigene Neparvovec for the Treatment of Biallelic RPE65-Mediated Inherited Retinal Dystrophies in the UK

et al. 2020

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Introduction: Voretigene neparvovec (VN) is a gene therapy and the first approved pharmacological treatment for biallelic RPE65-mediated inherited retinal dystrophies (IRD), a rare condition that starts in early life and causes vision to progressively deteriorate towards complete blindness. In a phase III trial, treatment with VN significantly improved functional vision and visual function, and in October 2019 the National Institute for Health and Care Excellence (NICE) Highly Specialised Technologies Enhanced Digital Features To view enhanced digital features for this article go to https://doi.org/10.6084/ m9.figshare.11637108.

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Section: Clinical Datamentioning

confidence: 99%

An Economic Evaluation of Voretigene Neparvovec for the Treatment of Biallelic RPE65-Mediated Inherited Retinal Dystrophies in the UK

et al. 2020

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“…A parametric multistate survival model was estimated on the basis of observed health state transitions to derive the annual transition probability of disease progression for patients who received SC (eTable 4 in the Supplement provides details). 20 By construct, the multistate survival model allows progression from less to more severe health states but restricts patients from regressing to less visually impaired states, consistent with disease progression. Estimations were conducted using the msset and predictms commands in Stata, IC version 15 (StataCorp).…”

Section: Natural History Model Of Vision Lossmentioning

confidence: 99%

Cost-effectiveness of Voretigene Neparvovec-rzyl vs Standard Care forRPE65-Mediated Inherited Retinal Disease

Johnson¹,

Buessing²,

O'Connell³

et al. 2019

JAMA Ophthalmol

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IMPORTANCE Voretigene neparvovec-rzyl, the first gene therapy approved by the US Food and Drug Administration, was approved for the treatment for RPE65-mediated inherited retinal disease (IRD) in December 2017. This gene therapy is associated with high up-front costs and high efficacy, although of unknown duration, and its cost-effectiveness has not been assessed with RPE65 IRD-specific, longitudinal, patient-observation-level data. OBJECTIVE To assess the incremental cost-effectiveness ratio (ICER) of voretigene neparvovec-rzyl compared with standard care for RPE65-mediated inherited retinal disease. DESIGN, SETTING, AND PARTICIPANTS In this economic analysis, a health state transition model based on visual acuity and field with a lifetime horizon was developed to estimate the cost-effectiveness of voretigene neparvovec-rzyl. The model was populated with data from a clinical trial of voretigene neparvovec-rzyl to evaluate treatment outcome and a natural history study of RPE65-mediated IRD to examine disease progression. Direct costs were derived from the literature. Indirect costs, including educational attainment, productivity, caregiver burden, and governmental programs, were estimated using published literature and data analysis of public national surveys. A health utility vignette study specific to RPE65-mediated IRD was used for health utility inputs. The cost-effectiveness study described in this article was conducted from September 15, 2017, to August 23, 2018. EXPOSURES Bilateral voretigene neparvovec-rzyl therapy or standard care. MAIN OUTCOMES AND MEASURES Incremental cost-effectiveness ratio. RESULTS The model population included 70 patients with RPE65-mediated IRD, with a mean age of 15 years; 42 of 70 patients (60%) were female. In the base case, voretigene neparvovec-rzyl compared with standard care was associated with lower total costs ($2.2 million vs $2.8 million) and higher quality-adjusted life-years (18.1 vs 8.6). Voretigene neparvovec-rzyl remains cost-effective if at least 8.8% of the long-term treatment effect continues after year 3 when including indirect costs and 43.3% when excluding indirect costs, assuming a cost threshold of $150 000 per quality-adjusted life-year. CONCLUSIONS AND RELEVANCE Results of this study suggest that voretigene neparvovec-rzyl is cost-effective compared with standard care when using a lifetime horizon, excluding indirect costs, and using a threshold of $150 000 per quality-adjusted life-year.

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“…Here, we used standard parametric models including exponential, piecewise exponential, and Weibull distributions to extrapolate beyond the observation period. A more flexible parametric framework for parametric analyses of time‐to‐event data and an extension to multistate models have been suggested recently, which could potentially be applied for extrapolation purposes in sample size reviews and, of course, also in the final analysis. This will be considered in future research.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

Blinded sample size reestimation in event‐driven clinical trials: Methods and an application in multiple sclerosis

Friede

Pohlmann

Schmidli

2019

Pharmaceutical Statistics

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Motivated by a recently completed trial in secondary progressive multiple sclerosis, we developed blinded sample size reestimation procedures for clinical trials with time-to-event endpoint and assessed their properties in simulation studies. Assuming independent right-censoring and proportional hazards for the two treatment groups, we considered event-driven designs with fixed number of events, which guarantees the power to be at a desired level under a certain alternative. We develop reestimation procedures based on parametric models and show that these maintain the expected duration of the trial at a target length in flexible follow-up designs across a range of nuisance parameter values by adjusting the number of patients recruited into the trial based on blinded nuisance parameter estimates. Furthermore, we provide convincing evidence from a simulation study that such procedures proposed do not inflate the type I error rate in any practically relevant way, thereby satisfying the standards set by relevant international guidelines. Inspired by practical application of these procedures, we outline a number of extensions including methods for extrapolating the observed survival curve beyond the interim time point, application of reestimation procedures to interval censored data, and situations in which a confirmation of event is required leading to a certain lag time. KEYWORDSadaptive design, internal pilot study, multiple sclerosis, parametric models, sample size | INTRODUCTIONThe idea of using data from the first stage of a two-stage design to estimate a nuisance parameter and to adjust the sample size of the second stage accordingly in order to maintain the power of a hypothesis test based on all data goes back a long way and was described by Stein in the 1940s. 1 In contrast to Stein's proposal that used the variance estimate from the first stage data in the test statistic of the final analysis, it is common practice to use the data of both design stages to estimate the nuisance parameters in the final analysis. In their seminal paper, Wittes and Brittain 2 referred to the latter as the internal pilot study design. The advantages and disadvantages of both approaches were, for example, investigated by Proschan and Wittes, 3 considering sample size reestimation based on unblinded nuisance parameter estimates. Already, from the early paper by Wittes and Brittain, 1 it was clear that the approach using naively a nuisance parameter estimate based on data aggregated across both design stages inflates the type I error rate above the nominal level and various ways of adjusting for this in the final analysis have been proposed over the years. [4][5][6][7][8] Blinded procedures, which use interim data pooled across treatment code and therefore do not require breaking the treatment code at interim, were found to be equally effective in adjusting the sample size, 9 but with much smaller,

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Parametric multistate survival models: Flexible modelling allowing transition‐specific distributions with application to estimating clinically useful measures of effect differences

Cited by 118 publications

References 30 publications

An Economic Evaluation of Voretigene Neparvovec for the Treatment of Biallelic RPE65-Mediated Inherited Retinal Dystrophies in the UK

An Economic Evaluation of Voretigene Neparvovec for the Treatment of Biallelic RPE65-Mediated Inherited Retinal Dystrophies in the UK

Cost-effectiveness of Voretigene Neparvovec-rzyl vs Standard Care forRPE65-Mediated Inherited Retinal Disease

Blinded sample size reestimation in event‐driven clinical trials: Methods and an application in multiple sclerosis

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