Research
The Challenging Economics of Vaccine Development in the Age of COVID-19, and What Can Be Done About It
Vu, Jonathan, Ben Kaplan, Shomesh E. Chaudhuri, Monique Mansoura, and Andrew W. Lo (2020), The Challenging Economics of Vaccine Development in the Age of COVID-19, and What Can Be Done About It, DIA Global Forum 12 (5).
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The recent destructive outbreak of the novel coronavirus, SARS-CoV-2, that emerged from Wuhan, China, and rapidly spread to Europe and North America, demonstrates beyond doubt that emerging infectious diseases (EIDs) are a clear and present danger to the world and its economy. Uncontrolled outbreaks of EIDs can devastate populations around the globe, both in terms of lives lost and economic value destroyed. Emerging and re-emerging strains of infectious disease have become more diverse over time, and outbreaks have become more frequent. In 2006, Larry Brilliant stated that 90 percent of the epidemiologists in his confidence agreed that there would be a large pandemic—in which 1 billion people would sicken, 165 million would die, and the global economy would lose $1-3 trillion—within two generations. In 2020, this remarkable statement is playing out with each passing day.
Venture Philanthropy: A Case Study of the Cystic Fibrosis Foundation
Kim, Esther, and Andrew W. Lo (2019), Venture Philanthropy: A Case Study of the Cystic Fibrosis Foundation, April 23.
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Advances in biomedical research have created significant opportunities to bring to market a new generation of therapeutics. However, early-stage assets often face a dearth of funding, as they have a high risk of failure and significant development costs. Historically, this has been particularly true for assets intended to treat rare diseases, where market sizes are often too small to attract much attention and funding. Venture philanthropy (VP) — which, for the purpose of this paper, is defined as a model in which nonprofit, mission-driven organizations fund initiatives to advance their objectives and potentially achieve returns that can be reinvested toward their mission — offers an alternative to traditional funding sources like venture capital or the public markets. Here we highlight the Cystic Fibrosis (CF) Foundation, widely considered to be the leading VP organization in biotech, which facilitated the development of Kalydeco, the first disease-modifying therapy approved to treat cystic fibrosis. We evaluate the CF Foundation’s example, including its agreement structures and strategy, explore the challenges that other nonprofits may have in adopting this strategy, and draw lessons from the CF Foundation for other applications of VP financing.
Machine-Learning and Stochastic Tumor Growth Models for Predicting Outcomes in Patients With Advanced Non–Small-Cell Lung Cancer
Siah, Kien Wei, Sean Khozin, Chi Heem Wong, and Andrew W. Lo (2019), Machine-Learning and Stochastic Tumor Growth Models for Predicting Outcomes in Patients With Advanced Non–Small-Cell Lung Cancer, JCO Clinical Cancer Informatics 3, 1–11.
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The prediction of clinical outcomes for patients with cancer is central to precision medicine and the design of clinical trials. We developed and validated machine-learning models for three important clinical end points in patients with advanced non–small-cell lung cancer (NSCLC)—objective response (OR), progression free survival (PFS), and overall survival (OS)—using routinely collected patient and disease variables. We aggregated patient-level data from 17 randomized clinical trials recently submitted to the US Food and Drug Administration evaluating molecularly targeted therapy and immunotherapy in patients with advanced NSCLC. To our knowledge, this is one of the largest studies of NSCLC to consider biomarker and inhibitor therapy as candidate predictive variables. We developed a stochastic tumor growth model to predict tumor response and explored the performance of a range of machine-learning algorithms and survival models. Models were evaluated on out-of-sample data using the standard area under the receiver operating characteristic curve and concordance index (C-index) performance metrics. Our models achieved promising out-of-sample predictive performances of 0.79 area under the receiver operating characteristic curve (95% CI, 0.77 to 0.81), 0.67 C-index (95% CI, 0.66 to 0.69), and 0.73 C-index (95% CI, 0.72 to 0.74) for OR, PFS, and OS, respectively. The calibration plots for PFS and OS suggested good agreement between actual and predicted survival probabilities. In addition, the Kaplan-Meier survival curves showed that the difference in survival between the low- and high-risk groups was significant (log-rank test P, .001) for both PFS and OS. Biomarker status was the strongest predictor of OR, PFS, and OS in patients with advanced NSCLC treated with immune checkpoint inhibitors and targeted therapies. However, single biomarkers have limited predictive value, especially for programmed death-ligand 1 immunotherapy. To advance beyond the results achieved in this study, more comprehensive data on composite multiomic signatures is required.
Adaptive Platform Trials: Definition, Design, Conduct and Reporting Considerations
Angus, Derek C., Brian M. Alexander, Scott Berry, et. al. (2019), Adaptive Platform Trials: Definition, Design, Conduct and Reporting Considerations, Nature Reviews Drug Discovery 18 (10), 797–807.
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Researchers, clinicians, policymakers and patients are increasingly interested in questions about therapeutic interventions that are difficult or costly to answer with traditional, free-standing, parallel-group randomized controlled trials (RCTs). Examples include scenarios in which there is a desire to compare multiple interventions, to generate separate effect estimates across subgroups of patients with distinct but related conditions or clinical features, or to minimize downtime between trials. In response, researchers have proposed new RCT designs such as adaptive platform trials (APTs), which are able to study multiple interventions in a disease or condition in a perpetual manner, with interventions entering and leaving the platform on the basis of a predefined decision algorithm. APTs offer innovations that could reshape clinical trials, and several APTs are now funded in various disease areas. With the aim of facilitating the use of APTs, here we review common features and issues that arise with such trials, and offer recommendations to promote best practices in their design, conduct, oversight and reporting.
Ram, Archana, and Andrew W. Lo (2018), Is Smaller Better? A Proposal to Use Bacteria for Neuroscientific Modeling, Frontiers in Computational Neuroscience 12 (7).
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Bacteria are easily characterizable model organisms with an impressively complicated set of abilities. Among them is quorum sensing, a cell-cell signaling system that may have a common evolutionary origin with eukaryotic cell-cell signaling. The two systems are behaviorally similar, but quorum sensing in bacteria is more easily studied in depth than cell-cell signaling in eukaryotes. Because of this comparative ease of study, bacterial dynamics are also more suited to direct interpretation than eukaryotic dynamics, e.g., those of the neuron. Here we review literature on neuron-like qualities of bacterial colonies and biofilms, including ion-based and hormonal signaling, and a phenomenon similar to the graded action potential. This suggests that bacteria could be used to help create more accurate and detailed biological models in neuroscientific research. More speculatively, bacterial systems may be considered an analog for neurons in biologically based computational research, allowing models to better harness the tremendous ability of biological organisms to process information and make decisions.
Brennan, Thomas J., Andrew W. Lo, and Ruixun Zhang (2018), Variety Is the Spice of Life: Irrational Behavior as Adaptation to Stochastic Environments, Quarterly Journal of Finance 8 (3), 55–108.
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The debate between rational models of behavior and their systematic deviations, often referred to as “irrational behavior”, has attracted an enormous amount of research. Here, we reconcile the debate by proposing an evolutionary explanation for irrational behavior. In the context of a simple binary choice model, we show that irrational behaviors are necessary for evolution in stochastic environments. Furthermore, there is an optimal degree of irrationality in the population depending on the degree of environmental randomness. In this process, mutation provides the important link between rational and irrational behaviors, and hence the variety in evolution. Our results yield widespread implications for financial markets, corporate behavior, and disciplines beyond finance.
Robust Ranking and Portfolio Optimization
Nguyen, Tri-Dung, and Andrew W. Lo (2012), Robust Ranking and Portfolio Optimization, European Journal of Operational Research 221 (2), 407–416.
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The portfolio optimization problem has attracted researchers from many disciplines to resolve the issue of poor out-of-sample performance due to estimation errors in the expected returns. A practical method for portfolio construction is to use assets’ ordering information, expressed in the form of preferences over the stocks, instead of the exact expected returns. Due to the fact that the ranking itself is often described with uncertainty, we introduce a generic robust ranking model and apply it to portfolio optimization. In this problem, there are n objects whose ranking is in a discrete uncertainty set. We want to find a weight vector that maximizes some generic objective function for the worst realization of the ranking. This robust ranking problem is a mixed integer minimax problem and is very difficult to solve in general. To solve this robust ranking problem, we apply the constraint generation method, where constraints are efficiently generated by solving a network flow problem. For empirical tests, we use post-earnings-announcement drifts to obtain ranking uncertainty sets for the stocks in the DJIA index. We demonstrate that our robust portfolios produce smaller risk compared to their non-robust counterparts.
Wong, Chi Heem, Kien Wei Siah, and Andrew W. Lo (2019), What Are the Chances of Getting a Cancer Drug Approved?, DIA Global Forum, May.
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Billions of dollars are spent annually on cancer drug development, yet effective treatments for many types of cancer remain as elusive as ever. Recently, the MIT Laboratory for Financial Engineering announced the launch of Project ALPHA (Analytics for Life-sciences Professionals and Healthcare Advocates), a large-scale estimation of clinical trial probabilities of success (PoS) for a variety of drug development programs, where a single program is defined as the set of all clinical trials corresponding to a unique drug-indication pair. In that study, we found that only 3.4 percent of all cancer drug development programs from 2000 to 2015 moved from phase 1 to regulatory approval, despite the fact that oncology accounted for 42 percent of all drug development programs in that dataset.
Vu, Jonathan T., Benjamin K. Kaplan, Shomesh E. Chaudhuri, Monique K. Mansoura, and Andrew W. Lo (2022), Financing Vaccines for Global Health Security, Journal Of Investment Management 20 (2), 1-17.
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Recent outbreaks of infectious pathogens such as Zika, Ebola, and COVID-19 have under-scored the need for the dependable availability of vaccines against emerging infectious diseases (EIDs). Prior to the COVID-19 pandemic, the cost and risk of R&D programs and uniquely unpredictable demand for EID vaccines discouraged many potential vaccine developers, and government and nonprofit agencies have struggled to provide timely or sufficient incentives for their development and sustained supply. However, the economic climate has changed significantly post-pandemic. To explore this contrast, we analyze the pre-pandemic economic returns of a portfolio of EID vaccine assets, and find that, under realistic financing assumptions, the expected returns are significantly negative, implying that the private sector is unlikely to address this need without public-sector intervention. However, in a post-pandemic policy landscape, the financing deficit for this portfolio can be closed, and we analyze several potential solutions, including enhanced public–private partnerships and subscription models in which governments would pay annual fees to obtain access to a portfolio of stockpiled vaccines in the event of an outbreak.
Bayesian Adaptive Clinical Trials for Anti‐Infective Therapeutics During Epidemic Outbreaks
Chaudhuri, Shomesh, Andrew W. Lo, Xiao, Danyang, and Xu, Qingyang (2020), Bayesian Adaptive Clinical Trials for Anti‐Infective Therapeutics During Epidemic Outbreaks, Harvard Data Science Review.
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In the midst of epidemics such as COVID-19, therapeutic candidates are unlikely to be able to complete the usual multi-year clinical trial and regulatory approval process within the course of an outbreak. We apply a Bayesian adaptive patient-centered model—which minimizes the expected harm of false positives and false negatives—to optimize the clinical trial development path during such outbreaks. When the epidemic is more infectious and fatal, the Bayesian-optimal sample size in the clinical trial is lower and the optimal statistical significance level is higher. For COVID-19 (assuming a static Ro = 2 and initial infection percentage of 0.1%), the optimal significance level is 7.1% for a clinical trial of a non-vaccine anti-infective therapeutic clinical trial and 13.6% for that of a vaccine. For a dynamic Ro ranging from 2 to 4, the corresponding values are 14.4% and 26.4%, respectively. Our results illustrate the importance of adapting the clinical trial design and the regulatory approval process to the specific parameters and stage of the epidemic.