Adapting Health Technology Assessment agency standards for surrogate outcomes in early stage cancer trials: what needs to happen?

INTRODUCTION: An avalanche of early stage cancer clinical trials is coming. The majority of these solely use surrogate outcomes that have not been validated against a target outcome of interest (e.g. overall survival). Current HTA guidance on surrogate outcome validation are not methodologically or practically conducive to this scenario. AREAS COVERED: We provide a high-level overview of methods, approaches, and conceptual thinking for making better use of limited evidence within early stage cancer HTA submissions. We outline regulatory and HTA issues and emphasize how evidence transitions from one to another, what major gaps currently exist, and how these may be bridged. We summarize current methodologies and practices, their pros and cons. We outline how complementary measurements strengthen evaluations and address fallacies and biases of conventional statistical methods for surrogate outcomes validation. The value of real-world data to support some of the necessary validity components is discussed. Lastly, we address the importance of the patient voice for better understanding which surrogate outcomes may appropriately inform HTA. EXPERT OPINION: Conventional surrogate outcome validation represents a fraught and sub-optimal framework for HTA purposes, particularly for early stage cancer. Tools for optimizing use of limited evidence exist. Education of stakeholders is highly needed.

The Pathway for New Cancer Drug Access in Canada.

Cancer treatment has evolved significantly over the past decade with the emergence of a multitude of new treatments across cancer types. Alongside the pace of drug discovery, the cost of cancer drugs has also increased. In the face of this growth in development and spending, it is crucial to have an understanding of the processes and pressures new drugs navigate to get to the market in Canada. This paper is a review of the complex, multi-step regulatory and funding process undertaken by cancer drugs in Canada. It reviews the role of Health Canada, the Patented Medicine Prices Review Board, the Health Technology Assessment, the pan-Canadian Pharmaceutical Alliance, and finally, the provincial, territorial, and federal payers. Recent developments are highlighted. Strategies to minimize duplication of effort, improve timeliness, and increase efficiency are explored. The cancer drug regulatory and funding process in Canada is complex, and an understanding of the current system and ongoing evolution is essential.

Efficiently Simulating an Endograft Deployment: A Methodology for Detailed CFD Analyses.

Numerical models of endografts for the simulation of endovascular aneurysm repair are increasingly important in the improvement of device designs and patient outcomes. Nevertheless, current finite element analysis (FEA) models of complete endograft devices come at a high computational cost, requiring days of runtime, therefore restricting their applicability. In the current study, an efficient FEA model of the Anaconda™ endograft (Terumo Aortic, UK) was developed, able to yield results in just over 4 h, an order of magnitude less than similar models found in the literature. The model was used to replicate a physical device that was deployed in a 3D printed aorta and comparison of the two shapes illustrated a less than 5 mm placement error of the model in the regions of interest, consistent with other more computationally intensive models in the literature. Furthermore, the final goal of the study was to utilize the deployed fabric model in a hemodynamic analysis that would incorporate realistic fabric folds, a feature that is almost always omitted in similar simulations. By successfully exporting the deployed graft geometry into a flow analysis, it was illustrated that the inclusion of fabric wrinkles enabled clinically significant flow patterns such as flow stagnation and recirculation to be detected, paving the way for this modelling methodology to be used in future for stent design optimisation.

Analysing The Cross-Section of The Abdominal Aortic Aneurysm Neck and Its Effects on Stent Deployment.

Stent graft devices for the treatment of abdominal aortic aneurysms (AAAs) are being increasingly used worldwide. Yet, during modelling and optimization of these devices, as well as in clinical practice, vascular sections are idealized, possibly compromising the effectiveness of the intervention. In this study, we challenge the commonly used approximation of the circular cross-section of the aorta and identify the implications of this approximation to the mechanical assessment of stent grafts. Using computed tomography angiography (CTA) data from 258 AAA patients, the lumen of the aneurysmal neck was analysed. The cross-section of the aortic neck was found to be an independent variable, uncorrelated to other geometrical aspects of the region, and its shape was non-circular reaching elliptical ratios as low as 0.77. These results were used to design a finite element analysis (FEA) study for the assessment of a ring stent bundle deployed under a variety of aortic cross-sections. Results showed that the most common clinical approximations of the vascular cross-section can be a source of significant error when calculating the maximum stent strains (underestimated by up to 69%) and radial forces (overestimated by up to 13%). Nevertheless, a less frequently used average approximation was shown to yield satisfactory results (5% and 2% of divergence respectively).

Evaluation of a New Approach for Modeling Full Ring Stent Bundles with the Inclusion of Manufacturing Strains.

Ring stent bundles have been used in several biomedical stent-graft devices for decades, yet in the published literature, the numerical models of these structures always present significant simplifications. In this paper, a finite element (FE) ring stent bundle has been developed and evaluated with a combination of beam and surface elements. With this approach, the shape, the global stiffness and the strains of the structure can all be well predicted at a low computational cost while the approach is suitable for application to non-symmetrical, patient-specific implant simulations. The model has been validated against analytical and experimental data showing that the manufacturing strains can be predicted to a 0.1% accuracy and the structural stiffness with 0-7% precision. The model has also been compared with a more computationally expensive FE model of higher fidelity, revealing a discrepancy of 0-5% of the strain value. Finally, it has been shown that the exclusion of the manufacturing process from the simulation, a technique used in the literature, quadruples the analysis error. This is the first model that can capture the mechanical state of a full ring stent bundle, suitable for complex implant geometry simulations, with such accuracy.

A Methodology to Quantify the Geometrical Complexity of the Abdominal Aortic Aneurysm.

The abdominal aortic aneurysm (AAA) anatomy influences the technical success of the endovascular aneurysm repair (EVAR), yet very few data regarding the aortic tree angles exist in the literature. This poses great limitations in the numerical analyses of endografts, constraining their design improvement as well as the identification of their operational limitations. In this study, a matrix Φ of 10 angles was constructed for the description of the pathological region and was implemented on a large dataset of anatomies. More specifically, computed tomography angiographies from 258 patients were analysed and 10 aortic angles were calculated per case, able to adequately describe the overall AAA shape. 9 dimensional variables (i.e. diameters and lengths) were also recorded. The median and extreme values of these variables were computed providing a detailed quantification of the geometrical landscape of the AAA. Moreover, statistical analysis showed that the identified angles presented no strong correlation with each other while no lateral or anterior/posterior symmetry of the AAA was identified. These findings suggest that endograft designers are free to construct any extreme case-studies with the values provided in a mix-and-match manner. This strategy can have a powerful effect in EVAR stent graft designing, as well as EVAR planning.

Evolution of drug reimbursement in Canada: the Pan-Canadian Pharmaceutical Alliance for new drugs.

Canada has a unique system of public drug coverage and reimbursement characterized by a centralized review agency that makes funding recommendations along with decentralized authority for delivering health care across 10 provinces and three territories. There has been a significant increase in price negotiation for new pharmaceuticals in the past 10 years, first by individual provinces and now through a collective price negotiation process called the "Pan-Canadian Pharmaceutical Alliance." As of February 2014, the Pan-Canadian Pharmaceutical Alliance has already completed 32 negotiations despite still being in a formative stage; it is anticipated that a formal process will be developed in the coming year. In this article, we describe the evolution of price negotiation in Canada and identify several opportunities for improvement of the current process, including the incorporation of economic considerations into price negotiation.

Atmospheric dynamics in the "Laboratory Biosphere" with wheat and sweet potato crops.

Laboratory Biosphere is a 40-m3 closed life system equipped with 12,000 W of high pressure sodium lamps over planting beds with 5.37 m2 of soil. Atmospheric composition changes due to photosynthetic fixation of carbon dioxide and corresponding production of oxygen or the reverse, respiration, are observed in short timeframes, e.g., hourly. To focus on inherent characteristics of the crop as distinct from its area or the volume of the chamber, we report fixation and respiration rates in mmol h-1 m-2 of planted area. An 85-day crop of USU Apogee wheat under a 16-h lighted/8-h dark regime peaked in fixation rate at about 100 mmol h-1 m-2 approximately 24 days after planting. Light intensity was about 840 micromoles m-2 s-1. Dark respiration peaked at about 31 mmol h-1 m-2 at the same time. Thereafter, both fixation and respiration declined toward zero as harvest time approached. A residual soil respiration rate of about 1.9 mmol h-1 m-2 was observed in the dark closed chamber for 100 days after the harvest. A 126-day crop of Tuskegee TU-82-155 sweet potato behaved quite differently. Under a 680 micromoles m-2 s-1, 18-h lighted/6-h dark regime, fixation during lighted hours rose to a plateau ranging from about 27 to 48 mmol h-1 m-2 after 42 days and dark respiration settled into a range of 12-23 mmol h-1 m-2. These rates continued unabated until the harvest at 126 days, suggesting that tuber biomass production might have continued at about the same rate for some time beyond the harvest time that was exercised in this experiment. In both experiments CO2 levels were allowed to range widely from a few hundred to about 3000 ppm, which permitted observation of fixation rates both at varying CO2 concentrations and at each number of days after planting. This enables plotting the fixation rate as a function of both variables. Understanding the atmospheric dynamics of individual crops will be essential for design and atmospheric management of more complex CELSS which integrate the simultaneous growth of several crops as in a sustainable remote life support system.

Airtight sealing a Mars base.

Atmospheric leakage from a Mars base would create a demand for continuous or periodic replenishment, which would in turn require extraction or mining for oxygen and other gases from local resources and attendant equipment and energy requirements for such operations. It therefore becomes a high priority to minimize leakage. This article quantifies leak rates as determined by the size of holes and discusses the implications of pressure for structural configuration. The author engineered the sealing of Biosphere 2 from which comparisons are drawn.