Congressional 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."
with Richard Thakor, The Journal of Portfolio Management
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.
with Shomesh Chaudhuri, Katherine Cheng, Shirley Pepke, Sergio Rinaudo, Lynda Roman, and Ryan Spencer, The Journal of Investment Management
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.
with Yacine Aït-Sahalia and Whitney K. Newey, Journal of Econometrics
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.
with Kien Wei Siah and Chi Heem Wong, Harvard Data Science Review
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.
with Sonya Das, Samuel Huang, Drug Discovery Today
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.
Is the FDA Too Conservative or Too Aggressive?: A Bayesian Decision Analysis of Clinical Trial Design
with Leah Isakov and Vahid Montazerhodjat, Journal of Econometrics
Implicit in the drug-approval process is a trade-off between Type I and Type II error. We propose using Bayesian decision analysis (BDA) to minimize the expected cost of drug approval, where relative costs are calibrated using U.S. Burden of Disease Study 2010 data. The results for conventional fixed-sample randomized clinical-trial designs suggest that for terminal illnesses with no existing therapies such as pancreatic cancer, the standard thresh-old of 2.5% is too conservative; the BDA-optimal threshold is 27.9%. However, for relatively less deadly conditions such as prostate cancer, 2.5% may be too risk-tolerant or aggressive; the BDA-optimal threshold is 1.2%. We compute BDA-optimal sizes for 25 of the most lethal diseases and show how a BDA-informed approval process can incorporate all stakeholders’ views in a systematic, transparent, internally consistent, and repeatable manner.
with Shreyash Agrawal, Pablo D. Azar, and Taranjit Singh, The Journal of Portfolio Management
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.
with Shomesh E. Chaudhuri, Management Science
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.
with Sonya Das, Raphael Rousseau, Peter C. Adamson, JAMA Oncology
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.
Observations Review of published studies of pediatric oncology research and the cost of drug development, as well as clinical trials of pediatric oncology therapeutics at ClinicalTrials.gov, identified 77 potential drug development projects to be included in a hypothetical portfolio. The returns of this portfolio were simulated so as to compute the financial returns and risk. Simulated business strategies include combining projects at different clinical phases of development, obtaining partial funding from philanthropic grants, and obtaining government guarantees to reduce risk. The purely private-sector portfolio exhibited expected returns ranging from −24.2% to 10.2%, depending on the model variables assumed. This finding suggests significant financial disincentives for pursuing pediatric oncology therapeutics and implies that financial support from the public and philanthropic sectors is essential. Phase diversification increases the likelihood of a successful drug and yielded expected returns of −5.3% to 50.1%. Standard philanthropic grants had a marginal association with expected returns, and government guarantees had a greater association by reducing downside exposure. An assessment of a proposed venture philanthropy fund demonstrated stronger performance than the purely private-sector–funded portfolio or those with traditional amounts of philanthropic support.
Clinical Relevance A combination of financial and business strategies has the potential to maximize expected return while eliminating some downside risk—in certain cases enabling expected returns as high as 50.1%—that can overcome current financial disincentives and accelerate the development of pediatric oncology therapeutics.