Andrew W Lo

Massachusetts Institute of Technology | MIT · MIT Sloan School of Management

Gene therapy is a new class of medical treatment that alters part of a patient’s genome through the replacement, deletion, or insertion of genetic material. While still in its infancy, gene therapy has demonstrated immense potential to treat and even cure previously intractable diseases. Nevertheless, existing gene therapy prices are high, raising...

We review macro-finance models featuring nonlinear dynamics that have recently been developed in the literature, including models with funding liquidity constraints, market liquidity frictions, and bank run frictions, and discuss the empirical evidence and challenges of this class of models. We also construct an illustrative model featuring financi...

Background We consider two key challenges that early-stage biotechnology firms face in developing a sustainable financing strategy and a sustainable business model: developing a valuation model for drug compounds, and choosing an appropriate operating model and corporate structure. We use the specific example of Unravel Biosciences—a therapeutics p...

The measurement of financial risk premia, the amount that a risky asset will outperform a risk-free one, is an important problem in asset pricing. The noisiness and non-stationarity of asset returns makes the estimation of risk premia using machine learning (ML) techniques challenging. In this work, we develop ML models that solve the problems asso...

Background: The statistical significance of clinical trial outcomes is generally interpreted quantitatively according to the same threshold of 2.5% (in one-sided tests) to control the false-positive rate or type I error, regardless of the burden of disease or patient preferences. The clinical significance of trial outcomes-including patient prefer...

A fixed one-sided significance level of 5% is commonly used to interpret the statistical significance of randomized clinical trial (RCT) outcomes. While it is necessary to reduce the false positive rate, the threshold used could be chosen quantitatively and transparently to specifically reflect patient preferences regarding benefit-risk tradeoffs a...

The COVID-19 pandemic has raised awareness about the global imperative to develop and stockpile vaccines against future outbreaks of emerging infectious diseases. Prior to the pandemic, vaccine development for emerging infectious diseases was stagnant, largely due to the lack of financial incentive for pharmaceutical firms to undertake the necessar...

We review the recent literature on financing biomedical innovation, with a specific focus on the drug development process and how it may be enhanced to improve outcomes. We begin by laying out stylized facts about the structure of the drug development process and its associated costs and risks, and we present evidence that the rate of discovery for...

Objective: Provide US FDA and amyotrophic lateral sclerosis (ALS) society with a systematic, transparent, and quantitative framework to evaluate the efficacy of the ALS therapeutic candidate AMX0035 in its phase 2 trial, which showed statistically significant effects (p-value 3%) in slowing the rate of ALS progression on a relatively small sample s...

Despite its success in financial markets and other domains, collective intelligence seems to fall short in many critical contexts, including infrequent but repeated financial crises, political polarization and deadlock, and various forms of bias and discrimination. We propose an evolutionary framework that provides fundamental insights into the rol...

We perform an event study analysis that quantifies the market reaction to clinical trial result announcements for 13,807 trials from 2000 to 2020, one of the largest event studies of clinical trials to date. We first determine the specific dates in the clinical trial process on which the greatest impact on the stock prices of their sponsor companie...

Use of robust, quantitative tools to measure patient perspectives within product development and regulatory review processes offers the opportunity for medical device researchers, regulators, and other stakeholders to evaluate what matters most to patients and support the development of products that can best meet patient needs. The medical device...

The opioid epidemic in the U.S. has resulted in significant costs in human lives as well as to the health care system, employers, and insurers. While there is great motivation and urgency to address the opioid crisis, there are currently few non-opioid pain management medications in the development pipeline. The growing regulatory pressures and sti...

We study the relationships between the real-time psychophysiological activity of professional traders, their financial transactions, and market fluctuations. We collected multiple physiological signals such as heart rate, blood volume pulse, and electrodermal activity of 55 traders at a leading global financial institution during their normal worki...

Following the approval by the FDA of two COVID-19 vaccines, which are administered in two doses three to four weeks apart, we simulate the effects of various vaccine distribution policies on the cumulative number of infections and deaths in the United States in the presence of shocks to the supply of vaccines. Our forecasts suggest that allocating...

Background With multimorbidity becoming the norm rather than the exception, the management of multiple chronic diseases is a major challenge facing healthcare systems worldwide. Methods Using a large, nationally representative database of electronic medical records from the United Kingdom spanning the years 2005–2016 and consisting over 4.5 millio...

Background: We estimate the probability of successful development and duration of clinical trials for medications to treat neuropathic and nociceptive pain. We also consider the effect of the perceived abuse potential of the medication on these variables. Methods: This study uses the Citeline database to compute the probabilities of success, dur...

Introduction: Machine learning models are increasingly applied to predict the drug development outcomes based on intermediary clinical trial results. A key challenge to this task is to address various forms of bias in the historical drug approval data. Objective: We aimed to identify and mitigate the bias in drug approval predictions and quantif...

In this work, the authors develop a data-driven peer grouping system using artificial intelligence (AI) tools to capture market perception and, in turn, group companies into clusters at various levels of granularity. In addition, they develop a continuous measure of similarity between companies; use this measure to group companies into clusters and...

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Using a novel dataset of 653,455 individual brokerage accounts belonging to 298,556 households, we document the frequency, timing, and duration of panic sales, which we define as a decline of 90% of a household account’s equity assets over the course of one month, of which 50% or more is due to trades. We find that a disproportionate number of hous...

Biomedical innovation suffers from a “funding gap” between the needs of drug development firms and the availability of funds. The requirement of large investments for drug development projects and the high pipeline risk associated with FDA approval causes this funding gap in part. In this paper, we propose a new financial instrument—the “FDA hedge”...

Probability matching, also known as the "matching law" or Herrnstein's Law, has long puzzled economists and psychologists because of its apparent inconsistency with basic self-interest. We conduct an experiment with real monetary payoffs in which each participant plays a computer game to guess the outcome of a binary lottery. In addition to finding...

The regulatory approval process for new therapies in oncology involves costly clinical trials that can span multiple years and historically have had a low probability of success. To derive estimates of the probability of success and other related risk characteristics in oncology clinical trials, we searched Informa Pharma Intelligence's Trialtrove...

Bayes’ rule is a fundamental principle that has been applied across multiple disciplines. However, few studies have addressed its origin as a cognitive strategy, or the underlying basis for generalization from a small sample. Using a simple binary choice model subject to natural selection, we derive Bayesian inference as an adaptive behavior under...

We describe a novel collaboration between academia and industry, an in-house data science and artificial intelligence challenge held by Novartis to develop machine-learning models for predicting drug-development outcomes, building upon research at MIT using data from Informa as the starting point. With over 50 cross-functional teams from 25 Novarti...

Background: With multimorbidity becoming the norm rather than the exception, the management of multiple chronic diseases is a major challenge facing healthcare systems worldwide. Methods: Using a large, nationally representative database of electronic medical records from the United Kingdom spanning the years 2005 to 2016 and consisting over 4.5 mi...

The interaction between product market competition, R&D investment, and the financing choices of R&D-intensive firms on the development of innovative products is only partially understood. We hypothesize that as competition increases, R&D-intensive firms will: i) increase R&D investment relative to existing assets in place; ii) carry more cash; and...

We represent risk factors as sums of orthogonal components capturing fluctuations with cycles of different length. The representation leads to novel spectral factor models in which systematic risk is allowed—without being forced—to vary across frequencies. Frequency-specific systematic risk is captured by a notion of spectral beta. We show that tra...

Academic institutions play a central role in the biotech industry through technology licensing and the creation of startups, but few data are available on their performance and the magnitude of their impact. Here we present a systematic study of technology licensing by one such institution, the Massachusetts Institute of Technology (MIT). Using dat...

Teaser: A portfolio-based parallel discovery strategy, coupled with an adaptive clinical trial platform, significantly reduces the financial risks of undertaking novel drug development projects for glioblastoma and expedites the drug discovery process. Development of curative treatments for glioblastoma (GBM) has been stagnant in recent decades lar...

We compare and contrast the expected duration and number of infections and deaths averted among several designs for clinical trials of COVID-19 vaccine candidates, including traditional and adaptive randomized clinical trials and human challenge trials. Using epidemiological models calibrated to the current pandemic, we simulate the time course of...

The regulatory approval process for new therapies involves costly clinical trials that can span multiple years. When valuing a candidate therapy from a financial perspective, industry sponsors may terminate a program early if clinical evidence suggests market prospects are not as favorable as originally forecasted. Intuition suggests that clinical...

We provide a critical review of macroeconomic models used for monetary policy at central banks from a finance perspective. We review the history of monetary policy modeling, survey the core monetary models used by major central banks, and construct an illustrative model for those readers who are unfamiliar with the literature. Within this framework...

We assess the potential financial impact of future gene therapies by identifying the 109 late-stage gene therapy clinical trials currently underway, estimating the prevalence and incidence of their corresponding diseases, developing novel mathematical models of the increase in quality-adjusted life years for each approved gene therapy, and simulati...

We compare and contrast the expected duration and number of infections and deaths averted among several designs for clinical trials of COVID-19 vaccine candidates, including traditional randomized clinical trials and adaptive and human challenge trials. Using epidemiological models calibrated to the current pandemic, we simulate the time course of...

Advances 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 s...

A key driver in biopharmaceutical investment decisions is the probability of success of a drug development program. We estimate the probabilities of success (PoSs) 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, yiel...

In the midst of epidemics such as COVID-19, therapeutic candidates are unlikely to be able to complete the usual multiyear 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 clini...

A 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, yield...

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...

We examine the disruptive pricing strategy of abaloparatide, an osteoporosis drug launched by Radius Health in 2017 at a list price 45% lower than its main competitor. This strategy allowed Radius to gain rapid access to this market and achieve a corresponding growth in patient volume. It now faces two challenges: the perverse incentive of Medicare...

One of the most enduring empirical regularities in equity markets is the inverse relationship between stock prices and volatility. Also known as the leverage effect, this relationship was first documented by Black, who attributed it to the effects of financial or operating leverage. This article documents that firms that had no debt (and thus no fi...

Purpose: 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), a...

Implicit in the drug-approval process is a host of decisions—target patient population, control group, primary endpoint, sample size, follow-up period, etc.—all of which determine the trade-off between Type I and Type II error. We explore the application of Bayesian decision analysis (BDA) to minimize the expected cost of drug approval, where the r...

2019 Portfolio Management Research. All rights reserved. Thanks 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 expert...

Rare-disease drug development is both scientifically and commercially challenging. This case study highlights Agilis Biotherapeutics (Agilis), a small private biotechnology company that has developed the most clinically advanced adeno-associated virus (AAV) gene therapy for the brain. In an international collaboration led by Agilis with National Ta...

The value added by an active investor is traditionally measured using alpha, tracking error, and the information ratio. However, these measures do not characterize the dynamic component of investor activity, nor do they consider the time horizons over which weights are changed. In this paper, we propose a technique to measure the value of active in...

Importance Few patient populations are as helpless and in need of advocacy as children with cancer. Pharmaceutical companies have historically faced significant financial disincentives to pursue pediatric oncology therapeutics, including low incidence, high costs of conducting pediatric trials, and a lack of funding for early-stage research. Obser...

We provide a survey of 31 quantitative measures of systemic risk in the economics and finance literature, chosen to span key themes and issues in systemic risk measurement and management. We motivate these measures from the supervisory, research, and data perspectives in the main text, and present concise definitions of each risk measure—including...

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 ar...

We propose an evolutionary framework for optimal portfolio growth theory in which investors subject to environmental pressures allocate their wealth between two assets. By considering both absolute wealth and relative wealth between investors, we show that different investor behaviors survive in different environments. When investors maximize their...

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 tha...

Previous estimates of drug development success rates rely on relatively small samples from databases curated by the pharmaceutical industry and are subject to potential selection biases. Using a sample of 406 038 entries of clinical trial data for over 21 143 compounds from January 1, 2000 to October 31, 2015, we estimate aggregate clinical trial s...