Research
Estimating Probabilities of Success of Vaccine and Other Anti-Infective Therapeutic Development Programs
Lo, Andrew W., Kien Wei Siah, and Chi Heem Wong (2020), Estimating Probabilities of Success of Clinical Trials for Vaccines and Other Anti‐Infective Therapeutics, Harvard Data Science Review.
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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, 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.
Fair and Responsible Drug Pricing: A Case Study of Radius Health and Abaloparatide
Xu, Qingyang, and Andrew W. Lo (2020), Fair and Responsible Drug Pricing: A Case Study of Radius Health and abaloparatide, Journal of Investment Management 18 (1), 90-98.
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The 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.
Lo, Andrew W., and Richard T. Thakor (2019), Risk and Reward in the Orphan Drug Industry, Journal of Portfolio Management 45 (5), 30–45.
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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 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.
A Portfolio Approach to Accelerate Therapeutic Innovation in Ovarian Cancer
Chaudhuri, Shomesh E., Katherine Cheng, Andrew W. Lo, Shirley Pepke, Sergio Rinaudo, Lynda Roman, and Ryan Spencer (2019), A Portfolio Approach to Accelerate Therapeutic Innovation in Ovarian Cancer, Journal of Investment Management 17 (2), 5–16.
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We consider a portfolio-based approach to financing ovarian cancer therapeutics in which multiple candidates are funded within a single structure. Twenty-five potential early-stage drug development projects were identified for inclusion in a hypothetical portfolio through interviews with gynecological oncologists and leading experts, a review of ovarian cancer-related trials registered in the ClinicalTrials.gov database, and an extensive literature review. The annualized returns of this portfolio were simulated under a purely private sector structure both with and without partial funding from philanthropic grants, and a public–private partnership that included government guarantees. We find that public–private structures of this type can increase expected returns and reduce tail risk, allowing greater amounts of private sector capital to fund early-stage research and development.
Annals Issue in Honor of Jerry A. Hausman
Aït-Sahalia, Yacine, Andrew W. Lo, and Whitney K. Newey (2019), Annals Issue in Honor of Jerry Hausman: Editors’ Introduction, Journal of Econometrics 211 (1), 1–3.
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It is a rare privilege for students and friends to celebrate a scholar’s accomplishments even as he remains as active as ever. This volume marks just such an occasion, a permanent tribute to Jerry A. Hausman’s positive life-changing impact on so many over the years. The wide range of contributions of ‘‘Jerry’s kids’’ is a direct consequence of the extraordinary breadth and depth of Jerry’s interests, expertise, and generosity. No part of econometrics and economics more broadly was uninteresting to him, and every subfield Jerry touched was materially better for it. It is the hope and aspiration of every author in this volume that our scholarship measures up to the high standards that Jerry set with his remarkable example.
Machine Learning with Statistical Imputation for Predicting Drug Approvals
Lo, Andrew W., Kien Wei Siah, and Chi Heem Wong (2019), Machine Learning with Statistical Imputation for Predicting Drug Approval, Harvard Data Science Review 1 (1).
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We 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.
Momentum, Mean-Reversion, and Social Media: Evidence from StockTwits and Twitter
Agrawal, Shreyash, Pablo D. Azar, Andrew W. Lo, and Taranjit Singh (2018), Momentum, Mean-Reversion, and Social Media: Evidence from StockTwits and Twitter, Journal of Portfolio Management 44 (7), 85–95.
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In this article, the authors analyze the relation between stock market liquidity and real-time measures of sentiment obtained from the social-media platforms StockTwits and Twitter. The authors find that extreme sentiment corresponds to higher demand for and lower supply of liquidity, with negative sentiment having a much larger effect on demand and supply than positive sentiment. Their intraday event study shows that booms and panics end when bullish and bearish sentiment reach extreme levels, respectively. After extreme sentiment, prices become more mean-reverting and spreads narrow. To quantify the magnitudes of these effects, the authors conduct a historical simulation of a market-neutral mean-reversion strategy that uses social-media information to determine its portfolio allocations. These results suggest that the demand for and supply of liquidity are influenced by investor sentiment and that market makers who can keep their transaction costs to a minimum are able to profit by using extreme bullish and bearish emotions in social media as a real-time barometer for the end of momentum and a return to mean reversion.
Pricing for Survival in the Biopharma Industry: A Case Study of Acthar Gel and Questcor Pharmaceuticals
Burnham, Terence C., Samuel Huang, and Andrew W. Lo (2017), Pricing for Survival in the Biopharma Industry: A Case Study of Acthar Gel and Questcor Pharmaceuticals, Journal of Investment Management 15 (4), 69–91.
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Recent cases of aggressive pricing behavior in the biopharmaceutical industry have raised serious concerns among payers and policymakers about industry ethics. However, these cases should not be confused with price increases motivated by challenging business conditions that ultimately lead to greater investment in R&D and improved patient access to therapeutics. We study the example of Questcor Pharmaceuticals, which was forced to choose between increasing the price of an effective drug in 2007 and ceasing production and shutting down. We consider Questcor’s journey from inception to its acquisition in 2014, analyze the factors leading up to the price hike of its main revenue generator, Acthar Gel, and discuss its resulting impact on patients after 2007. A counterfactual financial simulation of the company’s prospects in the case where prices were not increased shows that Questcor would have become insolvent between 2008 and 2010.
Acceleration of Rare Disease Therapeutic Development: A Case Study of AGIL-AADC
Das, Sonya, Samuel Huang, and Andrew W. Lo (2019), Acceleration of Rare Disease Therapeutic Development: A Case Study of AGIL-AADC, Drug Discovery Today 24 (3), 678–684.
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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 Taiwan University (NTU) Hospital and the Therapeutics for Rare and Neglected Diseases (TRND) program of the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health, Agilis’ gene therapy for aromatic L-amino acid decarboxylase deficiency (AADC), AGIL-AADC, was granted biologics license application (BLA)-ready status by the FDA in 2018 only 18 months after being licensed from NTU by Agilis. Here, we highlight the factors that have enabled this remarkable pace of successful drug development for an ultra-rare disease.
Dynamic Alpha: A Spectral Decomposition of Investment Performance Across Time Horizons
Chaudhuri, Shomesh E., and Andrew W. Lo (2019), Dynamic Alpha: A Spectral Decomposition of Investment Performance Across Time Horizons, Management Science 65 (9), 4440–4450.
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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 investment that captures both the static and dynamic contributions of an investment process. This dynamic alpha is based on the decomposition of a portfolio’s expected return into its frequency components using spectral analysis. The result is a static component that measures the portion of a portfolio’s expected return resulting from passive investments and security selection and a dynamic component that captures the manager’s timing ability across a range of time horizons. Our framework can be universally applied to any portfolio and is a useful method for comparing the forecast power of different investment processes. Several analytical and empirical examples are provided to illustrate the practical relevance of this decomposition.