Statistical methodology for evaluation of time-to-event surrogate and true endpoints in small-sample meta-analysis of clinical trials

Clinical trials can be lengthy and costly, with new treatments taking more than a decade to become available to the patients who need them. It is therefore of great interest to improve efficiency in this process, such as replacing the primary endpoint of a clinical trial with an alternative endpoint that can be measured with greater ease, reduced cost or reduced observation periods. Such replacement endpoints are called surrogate endpoints, and there has been a vast amount of research conducted to establish statistical methodology that can reliably assess whether such endpoints are appropriate for future use. The aims of this research are therefore threefold; to identify appropriate methodology that can be used in the assessment of time-to-event surrogate and true endpoints; to examine the identified methods via simulation studies for the setting of small sample sizes, across a variety of scenarios, and in particular for surrogate endpoints that capture information on both an intermediate disease status and the long-term clinical outcome of interest; and finally to develop improved methodology that can advance the surrogacy evaluation process for these settings. The findings of the research build on the existing surrogate endpoint literature by demonstrating that the most commonly used approaches for evaluation of time-to-event surrogate and true endpoints can have potential limitations. As a result of this finding, and based on the identified strengths and weaknesses of the examined statistical approaches under the settings of interest, a novel methodology for the evaluation of time-to-event surrogate and true endpoints is proposed and evaluated. This method provides an alternative option for the evaluation of surrogate endpoints, and is recommended for further use

Assessment of the information theory approach to evaluating time-to-event surrogate and true endpoints in a meta-analytic setting

In many disease areas, commonly used long‐term clinical endpoints are becoming increasingly difficult to implement due to long follow‐up times and/or increased costs. Shorter‐term surrogate endpoints are urgently needed to expedite drug development, the evaluation of which requires robust and reliable statistical methodology to drive meaningful clinical conclusions about the strength of relationship with the true long‐term endpoint. This paper uses a simulation study to explore one such previously proposed method, based on information theory, for evaluation of time to event surrogate and long‐term endpoints, including the first examination within a meta‐analytic setting of multiple clinical trials with such endpoints. The performance of the information theory method is examined for various scenarios including different dependence structures, surrogate endpoints, censoring mechanisms, treatment effects, trial and sample sizes, and for surrogate and true endpoints with a natural time‐ordering. Results allow us to conclude that, contrary to some findings in the literature, the approach provides estimates of surrogacy that may be substantially lower than the true relationship between surrogate and true endpoints, and rarely reach a level that would enable confidence in the strength of a given surrogate endpoint. As a result, care is needed in the assessment of time to event surrogate and true endpoints based only on this methodology

Safety and efficacy of vismodegib in relapsed/refractory acute myeloid leukaemia: results of a phase Ib trial

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149232/1/bjh15571_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149232/2/bjh15571.pd

Correction to: Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study

Following publication of the original article [1], it was reported that the legend for Fig. 1 was incomplete. The complete figure legend is:https://deepblue.lib.umich.edu/bitstream/2027.42/148648/1/12885_2019_Article_5568.pd

A model for predicting effect of treatment on progression-free survival using MRD as a surrogate end point in CLL

Our objective was to evaluate minimal residual disease (MRD) at the end of induction treatment with chemoimmunotherapy as a surrogate end point for progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) based on 3 randomized, phase 3 clinical trials (ClinicalTrials.gov identifiers NCT00281918, NCT00769522, and NCT02053610). MRD was measured in peripheral blood (PB) from treatment-naïve patients in the CLL8, CLL10, and CLL11 clinical trials, and quantified by 4-color flow cytometry or allele-specific oligonucleotide real-time quantitative polymerase chain reaction. A meta-regression model was developed to predict treatment effect on PFS using treatment effect on PB-MRD. PB-MRD levels were measured in 393, 337, and 474 patients from CLL8, CLL10, and CLL11, respectively. The model demonstrated a statistically significant relationship between treatment effect on PB-MRD and treatment effect on PFS. As the difference between treatment arms in PB-MRD response rates increased, a reduction in the risk of progression or death was observed; for each unit increase in the (log) ratio of MRD2 rates between arms, the log of the PFS hazard ratio decreased by 20.188 (95% confidence interval, 20.321 to 20.055; P 5 .008). External model validation on the REACH trial and sensitivity analyses confirm the robustness and applicability of the surrogacy model. Our surrogacy model supports use of PB-MRD as a primary end point in randomized clinical trials of chemoimmunotherapy in CLL. Additional CLL trial data are required to establish a more precise quantitative relationship between MRD and PFS, and to support general applicability of MRD surrogacy for PFS across diverse patient characteristics, treatment regimens, and different treatment mechanisms of action

Health-related quality of life and symptoms in patients with rituximab-refractory indolent non-Hodgkin lymphoma treated in the phase III GADOLIN study with obinutuzumab plus bendamustine versus bendamustine alone

F. Hoffmann-La Roche Lt

A phase Ib study to assess the efficacy and safety of vismodegib in combination with ruxolitinib in patients with intermediate- or high-risk myelofibrosis

Background: The JAK inhibitor (JAKi) ruxolitinib is standard treatment for myelofibrosis (MF), but some patients are unresponsive. Pre-clinical and clinical data suggest that addition of a Hedgehog pathway inhibitor (HPI) to ruxolitinib might improve response. Vismodegib is an HPI approved for treatment of locally advanced and metastatic basal cell carcinoma. The MYLIE study assessed the safety and efficacy of combining ruxolitinib with vismodegib in ruxolitinib-naive patients with MF and characterized the pharmacokinetics (PK) of vismodegib in this setting.Methods: In this phase Ib study, ten patients with intermediate-or high-risk primary or secondary MF received open-label vismodegib (150 mg/day orally) and ruxolitinib (15 or 20 mg orally twice daily, depending on baseline platelet count) for up to 48 weeks, or until withdrawal or discontinuation. PK samples were collected throughout the study for comparison with other patient populations. Efficacy outcomes at week 24 included spleen response (>= 35% reduction in volume by imaging) and improvement in bone marrow fibrosis by central and investigator assessment, symptom response (>= 50% reduction in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom score), and anemia response (per International Working Group for Myeloproliferative Neoplasms Research and Treatment revised response criteria).Results: As of November 17, 2017, eight patients had completed 48 weeks of treatment with vismodegib and ruxolitinib; two discontinued treatment early. At week 24 (+/- 1 week), three patients experienced a spleen response by central review and no patients showed a 1-grade improvement in bone marrow fibrosis by central review. Five patients experienced symptom response at week 24, and no patients experienced an anemia response. The most common adverse events were muscle spasm (100% of patients), alopecia (70%), dysgeusia (50%), thrombocytopenia (50%), and nausea (40%); these events were predominantly grade 1/2. Three patients experienced a total of six serious adverse events.Conclusions: The combination of vismodegib and ruxolitinib was tolerable and no new safety signals were seen, but there was no evidence that the addition of vismodegib to ruxolitinib improved any of the efficacy outcome measures assessed. Further evaluation of this combination will not be pursued

Les sciences de gouvernement

Depuis le début du XIXe siècle, ce n'est plus le secret qui légitime les « arts de gouvernement > en Europe. C'est la science. Élections, colonies, propagande, état civil, hygiène, risques naturels : les territoires de cette revendication, promue nouveau Graal de la raison bureaucratique, ont donné naissance à des savoirs de plus en plus professionnalisés. Ce sont d'eux que viennent en droite ligne les « expertises » qui aujourd'hui encore trament l'administration du politique. S'intéresser, comme y invite cet ouvrage, à ces savoirs mais aussi à ces figures, revues, théories ou disciplines aujourd'hui sans sépulture, ce n'est pas céder à une passion érudite. C'est oeuvrer à une histoire sociale : celle des registres de scientificité dont s'est continûment enorgueillie la conduite du pouvoir politique. C'est se donner les moyens d'interroger les instruments de connaissance et de légitimation par lesquels se font puis se défont les modèles d'action gouvernementale, ceux qui ont accompagné l'extension des interventions de l'État. Car ces « sciences de gouvernement », qu'elles soient oubliées ou toujours actuelles, décriées ou pourvues de titres académiques, n'ont cessé d'apporter de la majesté au politique. Un éclat d'objectivité dont se targuent toujours les pratiques du gouvernement de la Cité

Les sciences de gouvernement

Depuis le début du XIXe siècle, ce n'est plus le secret qui légitime les « arts de gouvernement > en Europe. C'est la science. Élections, colonies, propagande, état civil, hygiène, risques naturels : les territoires de cette revendication, promue nouveau Graal de la raison bureaucratique, ont donné naissance à des savoirs de plus en plus professionnalisés. Ce sont d'eux que viennent en droite ligne les « expertises » qui aujourd'hui encore trament l'administration du politique. S'intéresser, comme y invite cet ouvrage, à ces savoirs mais aussi à ces figures, revues, théories ou disciplines aujourd'hui sans sépulture, ce n'est pas céder à une passion érudite. C'est oeuvrer à une histoire sociale : celle des registres de scientificité dont s'est continûment enorgueillie la conduite du pouvoir politique. C'est se donner les moyens d'interroger les instruments de connaissance et de légitimation par lesquels se font puis se défont les modèles d'action gouvernementale, ceux qui ont accompagné l'extension des interventions de l'État. Car ces « sciences de gouvernement », qu'elles soient oubliées ou toujours actuelles, décriées ou pourvues de titres académiques, n'ont cessé d'apporter de la majesté au politique. Un éclat d'objectivité dont se targuent toujours les pratiques du gouvernement de la Cité