Publications
SCRAM: A Platform for Securely Measuring Cyber Risk
2020We develop a new cryptographic platform called SCRAM (Secure Cyber Risk Aggregation and Measurement) that allows multiple entities to compute aggregate cyber-risk measures without requiring any entity to disclose its own sensitive data on cyberattacks, penetrations, and losses. Using the SCRAM platform, we present results from two computations in a pilot study with six large private-sector companies: (1) benchmarks of the adoption rates of 171 critical security measures and (2) links between monetary losses from 49 security incidents and the specific sub-control failures implicated in each incident. These results provide insight into problematic cyber-risk-control areas that need additional scrutiny and/or investment, but in a completely anonymized and privacy-preserving way.
An Empirical Evaluation of Tax-Loss-Harvesting Alpha
2020Advances in financial technology have made tax-loss harvesting more feasible for retail investors than such strategies were in the past. We evaluated the magnitude of this “tax alpha” with the use of historical data from the CRSP monthly database for the 500 securities with the largest market capitalizations from 1926 to 2018. Given long-term and short-term capital gains tax rates of 15% and 35%, respectively, we found that a tax-loss-harvesting strategy yielded a before-transaction-cost tax alpha of 1.08% per year for our sample period. When the strategy was constrained by the “wash sale rule,” the tax alpha decreased from 1.08% per year to 0.82% per year.
The Challenging Economics of Vaccine Development in the Age of COVID-19, and What Can Be Done About It
2020The 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.
Bayesian Adaptive Clinical Trials for Anti‐Infective Therapeutics During Epidemic Outbreaks
2020In 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.
Fair and Responsible Drug Pricing: A Case Study of Radius Health and Abaloparatide
2020The healthcare industry in the United States (U.S.) is a complex ecosystem with many different stakeholders. Unlike the universal single-payer healthcare systems of many European countries,the accessibility of prescription drugs in the U.S. is largely determined by contract negotiations between health plans and drug manufacturers about formulary placement. These negotiations can sometimes result in higher out-of-pocket costs for the patient, since the current structure of the U.S. healthcare system creates a perverse incentive for many health plans to elicit higher rebates from drug manufacturers in exchange for formulary placement of brand-name drugs, thereby increasing patients’ out-of-pocket costs.
Estimating Probabilities of Success of Vaccine and Other Anti-Infective Therapeutic Development Programs
2020A key driver in biopharmaceutical investment decisions is the probability of success of a drug development program. We estimate the probabilities of success (PoS) of clinical trials for vaccines and other anti-infective therapeutics using 43,414 unique triplets of clinical trial, drug, and disease between January 1, 2000, and January 7, 2020, yielding 2,544 vaccine programs and 6,829 non-vaccine programs targeting infectious diseases. The overall estimated PoS for an industry-sponsored vaccine program is 39.6%, and 16.3% for an industry-sponsored anti-infective therapeutic. Among industry-sponsored vaccines programs, only 12 out of 27 disease categories have seen at least one approval, with the most successful being against monkeypox (100%), rotavirus (78.7%), and Japanese encephalitis (67.6%). The three infectious diseases with the highest PoS for industry-sponsored nonvaccine therapeutics are smallpox (100%), CMV (31.8%), and onychomycosis (29.8%). Nonindustry- sponsored vaccine and non-vaccine development programs have lower overall PoSs: 6.8% and 8.2%, respectively. Viruses involved in recent outbreaks—MERS, SARS, Ebola, Zika—have had a combined total of only 45 non-vaccine development programs initiated over the past two decades, and no approved therapy to date (Note: our data was obtained just before the COVID-19 outbreak and do not contain information about the programs targeting this disease.) These estimates offer guidance both to biopharma investors as well as to policymakers seeking to identify areas most likely to be undeserved by private-sector engagement and in need of public-sector support.
Funding Long Shots
2019We define long shots as investment projects with four features: (1) low probabilities of success; (2) long gestation lags before any cash flows are realized; (3) large required up-front investments; and (4) very large payoffs (relative to initial investment) in the unlikely event of success. Funding long shots is becoming increasingly difficult—even for high-risk investment vehicles like hedge funds and venture funds—despite the fact that some of society’s biggest challenges such as cancer, Alzheimer’s disease, global warming, and fossil-fuel depletion depend critically on the ability to undertake such investments. We investigate the possibility of improving financing for long shots by pooling them into a single portfolio that can be financed via securitized debt, and examine the conditions under which such funding mechanisms are likely to be effective.
Venture Philanthropy: A Case Study of the Cystic Fibrosis Foundation
2019Advances 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.
Adaptive Platform Trials: Definition, Design, Conduct and Reporting Considerations
2019Researchers, 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.
Machine-Learning and Stochastic Tumor Growth Models for Predicting Outcomes in Patients With Advanced Non–Small-Cell Lung Cancer
2019The 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.
What Are the Chances of Getting a Cancer Drug Approved?
2019Billions 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.
Why Artificial Intelligence May Not Be As Useful or As Challenging As Artificial Stupidity
2019A commentary on the article, "Artificial Intelligence—The Revolution Hasn’t Happened Yet" by Michael I. Jordan, published by Harvard Data Science Review (July 2019).
Bridging the Valley of Death Through Financial Innovation
2019Congressional testimony prepared for the U.S. House of Representatives Financial Services Committee Hearing on Examining Private Market Exemptions as a Barrier to IPOs and Retail Investment, held on September 11, 2019. Professor Lo discusses proposed legislation intended to allow innovative companies to gain greater access to investors who are comfortable with the higher risks (and rewards) of private investments. He highlights the "Rare Disease Fund Act" sponsored by Representatives Juan Vargas (CA-51) and Scott Peters (CA-52), which proposes the development of a "megafund"—created under the full supervision of the SEC—to acquire the development rights to multiple rare disease therapeutic candidates. Such a public-private fund focused on rare diseases could serve as a viable pilot project for further development of the megafund concept. Professor Lo remarks, "With more innovative financial and business structures, and the already existing close partnership between orphan drug developers and government agencies like the National Center for Advancing Translational Sciences, we can make even greater progress in easing the burden of disease for millions of Americans."
Risk and Reward in the Orphan Drug Industry
2019Thanks to a combination of scientific advances and economic incentives, the development of therapeutics to treat rare or orphan diseases has grown dramatically in recent years. With the advent of Food and Drug Administration–approved gene therapies and the promise of gene editing, many experts believe we are at an inflection point in dealing with these afflictions. In this article, the authors propose to document this inflection point by measuring the risk and reward of investing in the orphan drug industry. They construct a stock market index of 39 publicly traded companies that specialize in developing drugs for orphan diseases and compare the financial performance of this index, which they call ORF, to the broader biopharmaceutical industry and the overall stock market from 2000 to 2015. Although the authors report that ORF underperformed other biopharma companies and the overall stock market in the early 2000s, its performance has improved over time: from 2010 to 2015, ORF returned 608%, far exceeding the 317%, 320%, and 305% returns of the S&P, NASDAQ, and NYSE ARCA Biotech indexes, respectively, and the 83% of the S&P 500. ORF does have higher volatility than the other indexes but still outperforms even on a risk-adjusted basis, with a Sharpe ratio of 1.24 versus Sharpe ratios of 1.17, 1.14, and 1.05, respectively, for the other three biotech indexes and 0.71 for the S&P 500. However, ORF has a market beta of 1.16, which suggests significant correlation to the aggregate stock market and less diversification benefits than traditional pharmaceutical investments.
Machine Learning with Statistical Imputation for Predicting Drug Approvals
2019We apply machine-learning techniques to predict drug approvals using drug-development and clinical-trial data from 2003 to 2015 involving several thousand drug-indication pairs with over 140 features across 15 disease groups. To deal with missing data, we use imputation methods that allow us to fully exploit the entire dataset, the largest of its kind. We show that our approach outperforms complete-case analysis, which typically yields biased inferences. We achieve predictive measures of 0.78, and 0.81 AUC (“area under the receiver operating characteristic curve,” the estimated probability that a classifier will rank a positive outcome higher than a negative outcome) for predicting transitions from phase 2 to approval and phase 3 to approval, respectively. Using five-year rolling windows, we document an increasing trend in the predictive power of these models, a consequence of improving data quality and quantity. The most important features for predicting success are trial outcomes, trial status, trial accrual rates, duration, prior approval for another indication, and sponsor track records. We provide estimates of the probability of success for all drugs in the current pipeline.