We present the design of a higher throughput “heart on a chip” which utilizes a semi-automated fabrication technique to process sub millimeter sized thin film cantilevers of soft elastomers. Anisotropic cardiac microtissues which recapitulate the laminar architecture of the heart ventricle are engineered on these cantilevers. Deflection of these cantilevers, termed Muscular Thin Films (MTFs), during muscle contraction allows calculation of diastolic and systolic stresses generated by the engineered tissues. We also present the design of a reusable one channel fluidic microdevice completely built out of autoclavable materials which incorporates various features required for an optical cardiac contractility assay: metallic base which fits on a heating element for temperature control, transparent top for recording cantilever deformation and embedded electrodes for electrical field stimulation of the tissue. We employ the microdevice to test the positive inotropic effect of isoproterenol on cardiac contractility at dosages ranging from 1 nM to 100 μM. The higher throughput fluidic heart on a chip has applications in testing of cardiac tissues built from rare or expensive cell sources and for integration with other organ mimics. These advances will help alleviate translational barriers for commercial adoption of these technologies by improving the throughput and reproducibility of readout, standardization of the platform and scalability of manufacture.

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Microfluidic heart on a chip for higher throughput pharmacological studies

This companion article to Sox and Greenfield's report describes better research methods for CER. It addresses the fundamental limitations of traditional randomized, controlled trials for meeting CE...

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Rethinking Randomized Clinical Trials for Comparative Effectiveness Research: The Need for Transformational Change

The Health Insurance Portability and Accountability Act of 1996 (HIPAA) presents an important challenge to the healthcare system in its evolution from a cottage industry to a new, yet-to-be determined form. To guide the system rationally requires clinical research on a massive scale. Will HIPAA stimulate an advance in medical research so that we have evidence to guide our medical decisions and policies, or will it lead to Draconian restrictions that push the healthcare system toward a less rational, less informed approach?

Medical practice evolved in the 20th century from an almost purely anecdote-based apprenticeship system to a system in which doctors were trained by learning the mechanisms of disease and serving apprenticeships in which they learned the “tools of the trade.” Records were kept on paper and, although classification of disorders has been critical to all areas of scientific study, attention to nomenclature has been largely unsystematic in medicine. In parallel, a complex array of computerized systems has been developed for the business side of medicine, with little connection to the actual delivery of care. The dissociation between clinical and billing systems reflects the incorrect idea, basic in medical training, that doctors, armed with knowledge of disease mechanisms, can practice medicine by using deductive reasoning with little need for empirical decision support.

Most recently, the Internet and supporting information systems have revolutionized the nonmedical world. Compare the functioning of the banking industry versus that of the healthcare industry. Almost anyone with a bank account can withdraw funds or pay bills from anywhere on Earth via computer. Making sensitive information about people’s finances available is possible because of common nomenclature and data standards adopted by the finance industry. In contrast, the medical community is a haphazard mix of paper- and computer-based systems with multiple nomenclatures that do not allow the …

Health Insurance Portability and Accountability Act (HIPAA) Must There Be a Trade-Off Between Privacy and Quality of Health Care, or Can We Advance Both?

Importance A critical question in health care is the extent of scientific evidence that should be required to establish that a new therapeutic agent has benefits that outweigh its risks. Estimating the costs of this evidence of efficacy provides an important perspective. Objective To estimate costs and assess scientific characteristics of pivotal efficacy trials that supported the approval of new therapeutic agents by the US Food and Drug Administration (FDA) from 2015 to 2016. Design and Setting This study identified 59 novel therapeutic drugs using the annual summary reports from the FDA Center for Drug Evaluation and Research. ClinicalTrials.gov, FDA reviews, and peer-reviewed publications that were publicly available in 2017 were used to identify 52 characteristics of each efficacy trial. Costs were calculated with a global clinical trial cost assessment tool available to contract research organizations and pharmaceutical sponsors. Main Outcomes and Measures Estimated mean cost and 95% CIs based on industry benchmark data from 60 countries. Measures of trials’ scientific characteristics included trial design (no control group, placebo, and active drug), end point (surrogate outcome, clinical scale, and clinical outcome), patient enrollment, and treatment duration. Results A total of 138 pivotal clinical trials provided the basis for approval of 59 new therapeutic agents by the FDA from 2015 to 2016, with a median estimated cost of $19.0 million (interquartile range, $12.2 million-$33.1 million). Estimated costs ranged from less than $5 million for trials without a control group for 3 orphan drugs with fewer than 15 patients each to $346.8 million (95% CI, $252.0 million-$441.5 million) for a noninferiority trial with end points assessing clinical benefit. Twenty-six of 138 trials (18.8%) were uncontrolled, with a mean estimated cost of $13.5 million (95% CI, $10.1 million-$16.9 million). Trials designed with placebo or active drug comparators had an estimated mean cost of $35.1 million (95% CI, $25.4 million-$44.8 million). Costs also varied by trial end point, treatment duration, patient enrollment, and therapeutic area. Conclusions and Relevance The highest-cost trials were those in which the new agent had to be proved to be noninferior with clinical benefit end points compared with an agent already available or those that required larger patient populations to achieve statistical power to document smaller treatment effects or accrue infrequently occurring end points.

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Estimated Costs of Pivotal Trials for Novel Therapeutic Agents Approved by the US Food and Drug Administration, 2015-2016

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) reduce anemia in cancer patients and may improve quality of life, but there are concerns that ESAs might increase mortality OBJECTIVES: Our objectives were to examine the effect of ESAs and identify factors that modify the effects of ESAs on overall survival, progression free survival, thromboembolic and cardiovascular events as well as need for transfusions and other important safety and efficacy outcomes in cancer patients SEARCH STRATEGY: We searched the Cochrane Library, Medline, Embase and conference proceedings for eligible trials Manufacturers of ESAs were contacted to identify additional trials SELECTION CRITERIA: We included randomized controlled trials comparing epoetin or darbepoetin plus red blood cell transfusions (as necessary) versus red blood cell transfusions (as necessary) alone, to prevent or treat anemia in adult or pediatric cancer patients with or without concurrent antineoplastic therapy DATA COLLECTION AND ANALYSIS: We performed a meta-analysis of randomized controlled trials comparing epoetin alpha, epoetin beta or darbepoetin alpha plus red blood cell transfusions versus transfusion alone, for prophylaxis or therapy of anemia while or after receiving anti-cancer treatment Patient-level data were obtained and analyzed by independent statisticians at two academic departments, using fixed-effects and random-effects meta-analysis Analyses were according to the intention-to-treat principle Primary endpoints were on study mortality and overall survival during the longest available follow-up, regardless of anticancer treatment, and in patients receiving chemotherapy Tests for interactions were used to identify differences in effects of ESAs on mortality across pre-specified subgroups The present review reports only the results for the primary endpoint MAIN RESULTS: A total of 13933 cancer patients from 53 trials were analyzed, 1530 patients died on-study and 4993 overall ESAs increased on study mortality (combined hazard ratio [cHR] 117; 95% CI 106-130) and worsened overall survival (cHR 106; 95% CI 100-112), with little heterogeneity between trials (I(2) 0%, p=087 and I(2) 71%, p=033, respectively) Thirty-eight trials enrolled 10441 patients receiving chemotherapy The cHR for on study mortality was 110 (95% CI 098-124) and 104; 95% CI 097-111) for overall survival There was little evidence for a difference between trials of patients receiving different cancer treatments (P for interaction=042) AUTHORS' CONCLUSIONS: ESA treatment in cancer patients increased on study mortality and worsened overall survival For patients undergoing chemotherapy the increase was less pronounced, but an adverse effect could not be excluded

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Philip W. Lemons

Papers

Reducing the costs of phase III cardiovascular clinical trials.