CONTEXT: Cell and gene therapies (CGTs) offer treatment to rare and oftentimes deadly diseases. Because of their high price and uncertain clinical outcomes, US insurers commonly restrain patient access to CGTs, and these barriers may create or perpetuate existing disparities. A reconsideration of existing insurance policies to improve access and reduce disparities is currently underway. One method insurers use to support access and protect them from large, unexpected claims is the purchase of reinsurance. In exchange for an upfront per-member-per-month (PMPM) premium, the reinsurer pays the claim and rebates the insurer at the end of the contract period if there are funds leftover. However, existing reinsurance plans may not cover CGTs or charge exorbitant fees for coverage.

METHODS: We simulate the incremental annual per-person reinsurer costs to cover CGTs existing or expected between 2023 and 2035 for the US population and by payer type based on previously published estimates of expected US spending on CGTs, assumed US population of 330 persons, and current CGT reinsurance fees. We illustrate our methods by estimating the incremental annual per-person costs overall payers and to state Medicaid plans of sickle cell disease–targeted CGTs.

FINDINGS: We estimate annual incremental spending on CGTs 2023–2035 to amount to $20.4 billion, or $15.69 per person. Total annual estimated spending is expected to concentrate among commercial plans. Sickle cell–targeted CGTs add a maximum of $0.78 PMPM in costs to all payers and will concentrate within state Medicaid programs. Reinsurance fees add to expected costs.

CONCLUSIONS: Annual per-person costs to provide access to CGTs are expected to concentrate in commercial and state Medicaid plans. Policies that improve CGT coverage and affordability are needed.

Fusion energy faces many hurdles. The history of the biotech industry offers lessons for how to build public trust and create a robust investment ecosystem to help fusion achieve its potential.

Biomedicine is experiencing an inflection point in which the origins of many human diseases have been decoded, leading to new treatments and, in some cases, complete cures. Many domain experts acknowledge that the gating factor to innovation is not knowledge, but rather a lack of financial resources to translate theory into practice, the so-called “valley of death” between scientific discovery and the clinical testing that must be done with human subjects before regulators will approve a new drug or medical device. This process of translational medicine is largely an exercise in risk management—organized as a carefully planned sequence of experiments, each one involving a progressively larger number of subjects that may or may not be allowed to continue, depending on the results of the prior experiment. It is, therefore, a natural setting in which to apply modern portfolio theory. The authors describe one such application involving a biotechnology company focused on genetic diseases and the lessons learned from that experience.

Humans are not homo economicus (i.e., rational economic beings). As humans, we exhibit systematic behavioral biases such as loss aversion, anchoring, framing, etc., which lead us to make suboptimal economic decisions. Insofar as such biases may be embedded in text data on which large language models (LLMs) are trained, to what extent are LLMs prone to the same behavioral biases? Understanding these biases in LLMs is crucial for deploying LLMs to support human decision-making. We propose utility theory-a paradigm at the core of modern economic theory-as an approach to evaluate the economic biases of LLMs. Utility theory enables the quantification and comparison of economic behavior against benchmarks such as perfect rationality or human behavior. To demonstrate our approach, we quantify and compare the economic behavior of a variety of open- and closed-source LLMs. We find that the economic behavior of current LLMs is neither entirely human-like nor entirely economicus-like. We also find that most current LLMs struggle to maintain consistent economic behavior across settings. Finally, we illustrate how our approach can measure the effect of interventions such as prompting on economic biases.

We propose a new performance attribution framework that decomposes a constrained portfolio’s holdings, expected returns, variance, expected utility, and realized returns into components attributable to (1) the unconstrained mean-variance optimal portfolio; (2) individual static constraints; and (3) information, if any, arising from those constraints. A key contribution of our framework is the recognition that constraints may contain information that is correlated with returns, in which case imposing such constraints can affect performance. We extend our framework to accommodate estimation risk in portfolio construction using Bayesian portfolio analysis, which allows one to select constraints that improve—or are least detrimental to—future performance. We provide simulations and empirical examples involving constraints on environmental, social, and governance portfolios. Under certain scenarios, constraints may improve portfolio performance relative to a passive benchmark that does not account for the information contained in these constraints.

Within the contemporary context of environmental, social, and governance (ESG) investing principles, the authors explore the risk–reward characteristics of portfolios in the United States, Europe, and Japan constructed using the foundational tenets of Markowitz’s modern portfolio theory with data from six major ESG rating agencies. They document statistically significant excess returns in ESG portfolios from 2014 to 2020 in the United States and Japan. They propose several statistical and voting-based methods to aggregate individual ESG ratings, the latter based on the theory of social choice. They find that aggregating individual ESG ratings improves portfolio performance. In addition, the authors find that a portfolio based on Treynor–Black weights further improves the performance of ESG portfolios. Overall, these results suggest that significant signals in ESG rating scores can enhance portfolio construction despite their noisy nature.

We identify some of the most pressing issues facing the adoption of large language models (LLMs) in practical settings, and propose a research agenda to reach the next technological inflection point in generative AI. We focus on three challenges facing most LLM applications: domain-specific expertise and the ability to tailor that expertise to a user’s unique situation, trustworthiness and adherence to the user’s moral and ethical standards, and conformity to regulatory guidelines and oversight. These challenges apply to virtually all industries and endeavors in which LLMs can be applied, such as medicine, law, accounting, education, psychotherapy, marketing, and corporate strategy. For concreteness, we focus on the narrow context of financial advice, which serves as an ideal test bed both for determining the possible shortcomings of current LLMs and for exploring ways to overcome them. Our goal is not to provide solutions to these challenges—which will likely take years to develop—but to propose a framework and road map for solving them as part of a larger research agenda for improving generative AI in any application.

For precision genetic medicines to fulfill their potential as treatments for ultra-rare diseases, fresh approaches to academic– industry partnerships and data sharing are needed, together with regulatory change and adaptation of reimbursement models. Advances in gene therapy and gene editing technologies could revolutionize the ability to treat individuals with genetic disease, allowing treatments to be devised that target specific genetic mutations in people with even the rarest of disease indications. In 2018, a seven-year-old child with Batten disease received attention for becoming the first recipient of a customized antisense oligonucleotide (ASO) therapy specifically designed for her unique mutation1. Since then, multiple patients with ultra-rare genetic conditions have been treated with precision ASOs through academic-investigator-initiated programs. Development of these ASOs has been rapid, justified by the severity of the conditions being treated (for example, rapidly progressive neurologic degeneration), following streamlined regulatory processes. Here we discuss possible models for drug development, regulation and reimbursement that could allow these tailored genetic interventions to be scaled.

We identify some of the most pressing issues facing the adoption of large language models (LLMs) in practical settings and propose a research agenda to reach the next technological inflection point in generative AI. We focus on three challenges facing most LLM applications: domain-specific expertise and the ability to tailor that expertise to a user’s unique situation, trustworthiness and adherence to the user’s moral and ethical standards, and conformity to regulatory guidelines and oversight. These challenges apply to virtually all industries and endeavors in which LLMs can be applied, such as medicine, law, accounting, education, psychotherapy, marketing, and corporate strategy. For concreteness, we focus on the narrow context of financial advice, which serves as an ideal test bed both for determining the possible shortcomings of current LLMs and for exploring ways to overcome them. Our goal is not to provide solutions to these challenges—which will likely take years to develop—but rather to propose a framework and road map for solving them as part of a larger research agenda for improving generative AI in any application.

This paper explores the relationship between a firm's legal contracting environment and its innovation incentives. Using granular data from the pharmaceutical industry, we examine a contracting mechanism through which incumbents maintain market power: "pay-for-delay'' agreements to delay the market entry of competitors. Exploiting a shock where such contracts become legally tenuous, we find that affected incumbents subsequently increase their innovation activity across a variety of project-level measures. Exploring the nature of this innovation, we also find that it is more "impactful’’ from a scientific and commercial standpoint. The results provide novel evidence that restricting the contracting space can boost innovation at the firm level. However, at the extensive margin we find a reduction in innovation by new entrants in response to increased competition, suggesting a nuanced effect on aggregate innovation.

We investigate the impact of information on biopharmaceutical stock prices via an event study encompassing 503,107 news releases from 1,012 companies. We distinguish between pharmaceutical and biotechnology companies, and apply three asset pricing models to estimate their abnormal returns. Acquisition-related news yields the highest positive return, while drug-development setbacks trigger significant negative returns. We also find that biotechnology companies have larger means and standard deviations of abnormal returns, while the abnormal returns of pharmaceutical companies are influenced by more general financial news. To better understand the empirical properties of price movement dynamics, we regress abnormal returns on market capitalization and a sub-industry indicator variable to distinguish biotechnology and pharmaceutical companies, and find that biopharma companies with larger capitalization generally experience lower magnitude of abnormal returns in response to events. Using longer event windows, we show that news related to acquisitions and clinical trials are the sources of potential news leakage. We expect this study to provide valuable insights into how diverse news types affect market perceptions and stock valuations, particularly in the volatile and information-sensitive biopharmaceutical sector, thus aiding stakeholders in making informed investment and strategic decisions.

Harry Markowitz, co-recipient with Merton Miller and William Sharpe of the 1990 Nobel Prize for Economic Sciences ‘for their pioneering work in the theory of financial economics’, passed away in June 2023. As this column explains, his monumental contributions to modern finance have deeply influenced both academia and practice. His analysis of portfolio selection and risk management paved the way for a more sophisticated understanding of financial markets. And his theories continue to be integral to financial modelling and decision-making processes.

We develop a mathematical framework for constructing optimal impact portfolios and quantifying their financial performance by characterizing the returns of impact-ranked assets using induced order statistics and copulas. The distribution of induced order statistics can be represented by a mixture of order statistics and uniformly distributed random variables, where the mixture function is determined by the dependence structure between residual returns and impact factors—characterized by copulas—and the marginal distribution of residual returns. This representation theorem allows us to explicitly and efficiently compute optimal portfolio weights under any copula. This framework provides a systematic approach for constructing and quantifying the performance of optimal impact portfolios with arbitrary dependence structures and return distributions.

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 trials that can be modified as new data are observed, i.e., adaptive trials, are more valuable than trials without this flexibility. To quantify this value, we propose modeling the accrual of information in a clinical trial as a sequence of real options, allowing us to systematically design early-stopping decision boundaries that maximize the economic value to the sponsor. In an empirical analysis of selected disease areas, we find that when a therapy is ineffective, our adaptive financing method can decrease the expected cost incurred by the sponsor in terms of total expenditures, number of patients, and trial length by up to 46%. Moreover, by amortizing the large fixed costs associated with a clinical trial over time, financing these projects becomes less risky, resulting in lower costs of capital and larger valuations when the therapy is effective.

We examine the leading role of the United States in the global equity markets by building daily snapshots of lead-lag price discovery networks using high-frequency country ETF returns. We find that the centrality of the U.S. equity market has been waning over time. Consistent with an explanation of gradual information diffusion, we empirically show that the shift to a multipolar system in the global equity markets can be explained by changes in information supply and demand. Using the COVID-19 pandemic as an exogenous shock, we document a causal relationship between news and country-specific price discovery network centralities.