Hamilton’s rule [W. D. Hamilton, Am. Nat. 97, 354–356 (1963); W. D. Hamilton, J. Theor. Biol. 7, 17–52 (1964)] quantifies the central evolutionary ideas of inclusive fitness and kin selection into a simple algebraic relationship. Evidence consistent with Hamilton’s rule is found in many animal species. A drawback of investigating Hamilton’s rule in these species is that one can estimate whether a given behavior is consistent with the rule, but a direct examination of the exact cutoff for altruistic behavior predicted by Hamilton is almost impossible. However, to the degree that economic resources confer survival benefits in modern society, Hamilton’s rule may be applicable to economic decision-making, in which case techniques from experimental economics offer a way to determine this cutoff. We employ these techniques to examine whether Hamilton’s rule holds in human decision-making, by measuring the dependence between an experimental subject’s maximal willingness to pay for a gift of $50 to be given to someone else and the genetic relatedness of the subject to the gift’s recipient. We find good agreement with the predictions of Hamilton’s rule. Moreover, regression analysis of the willingness to pay versus genetic relatedness, the number of years living in the same residence, age, and sex shows that almost all the variation is explained by genetic relatedness. Similar but weaker results are obtained from hypothetical questions regarding the maximal risk to her own life that the subject is willing to take in order to save the recipient’s life.

The long-run impact and implications of an endowment’s spending policy and asset allocation decisions are examined. Using a dynamic model, the authors explore how different endowment spending rules influence the dynamics of an endowment’s size and future spending. They find that different parameters within each spending rule have significant long-term impact on wealth accumulation and spending capacity. Using Merton's (1993) endowment model and compiled asset allocation data, they estimate the intertemporal preferences and risk aversion of several major endowments and find significant variation across endowments in their propensity to increase portfolio risk in response to increased spending needs.

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 households make panic sales when there are sharp market downturns, a phenomenon we call ‘freaking out.’ We show that panic selling and freak-outs are predictable and fundamentally different from other well-known behavioral patterns such as overtrading or the disposition effect.

In this article, 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; they use this measure to group companies into clusters and construct hedged portfolios. In the peer groupings, companies grouped in the same clusters had strong homogeneous risk and return profiles, whereas different clusters of companies had diverse, varying risk exposures. The authors extensively evaluated the clusters and found that companies grouped by their method had higher out-of-sample return correlation but lower stability and interpretability than companies grouped by a standard industry classification system. The authors also develop an interactive visualization system for identifying AI-based clusters and similar companies.

IMPORTANCE: Randomized clinical trials (RCTs) currently apply the same statistical threshold of alpha = 2.5% for controlling for false-positive results or type 1 error, regardless of the burden of disease or patient preferences. Is there an objective and systematic framework for designing RCTs that incorporates these considerations on a case-by-case basis?

OBJECTIVE: To apply Bayesian decision analysis (BDA) to cancer therapeutics to choose an alpha and sample size that minimize the potential harm to current and future patients under both null and alternative hypotheses.

DATA SOURCES: We used the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database and data from the 10 clinical trials of the Alliance for Clinical Trials in Oncology.

STUDY SELECTION: The NCI SEER database was used because it is the most comprehensive cancer database in the United States. The Alliance trial data was used owing to the quality and breadth of data, and because of the expertise in these trials of one of us (D.J.S.).

DATA EXTRACTION AND SYNTHESIS: The NCI SEER and Alliance data have already been thoroughly vetted. Computations were replicated independently by 2 coauthors and reviewed by all coauthors.

MAIN OUTCOMES AND MEASURES: Our prior hypothesis was that an alpha of 2.5% would not minimize the overall expected harm to current and future patients for the most deadly cancers, and that a less conservative alpha may be necessary. Our primary study outcomes involve measuring the potential harm to patients under both null and alternative hypotheses using NCI and Alliance data, and then computing BDA-optimal type 1 error rates and sample sizes for oncology RCTs.

RESULTS: We computed BDA-optimal parameters for the 23 most common cancer sites using NCI data, and for the 10 Alliance clinical trials. For RCTs involving therapies for cancers with short survival times, no existing treatments, and low prevalence, the BDA-optimal type 1 error rates were much higher than the traditional 2.5%. For cancers with longer survival times, existing treatments, and high prevalence, the corresponding BDA-optimal error rates were much lower, in some cases even lower than 2.5%.

CONCLUSION AND RELEVANCE: Bayesian decision analysis is a systematic, objective, transparent, and repeatable process for deciding the outcomes of RCTs that explicitly incorporates burden of disease and patient preferences.

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 stigma surrounding opioids have discouraged investments and research in the pain industry. Using estimates from the literature, our simulations show that a portfolio of pharmaceuticals and medical devices for pain treatment and opioid use disorder, diversified and optimized across different development pathways, yields single digit annualized returns. This suggests that active collaboration between the public and private sectors is needed to incentivize investments in pain research.

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 quantify the impacts of debiasing in terms of financial value and drug safety.

METHODS: We instantiated the Debiasing Variational Autoencoder, the state-of-the-art model for automated debiasing. We trained and evaluated the model on the Citeline dataset provided by Informa Pharma Intelligence to predict the final drug development outcome from phase II trial results.

RESULTS: The debiased Debiasing Variational Autoencoder model achieved better performance (measured by the F₁ score 0.48) in predicting the drug development outcomes than its un-debiased baseline (measured by the F₁ score 0.25). It had a much higher true-positive rate than baseline (60% vs 15%), while its true-negative rate was slightly lower (88% vs 99%). The Debiasing Variational Autoencoder distinguished between drugs developed by large pharmaceutical firms and those by small biotech companies. The model prediction is strongly influenced by multiple factors such as prior approval of the drug for another indication, whether the trial meets the positive/negative endpoints, and the year when the trial is completed. We estimate that the debiased model generates financial value for the drug developer in six major therapeutic areas, with a range of US$763–1,365 million.

CONCLUSIONS: Our analysis shows that debiasing improves the financial efficiency of late-stage drug development. From the pharmacovigilance perspective, the debiased model is more likely to identify drugs that are both safe and effective. Meanwhile, it may predict a higher probability of success for drugs with potential adverse effects (because of its lower true-negative rate), thus it must be used with caution to predict the development outcomes of drug candidates currently in the pipeline.

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 life-saving treatments has declined over time while costs have increased. We make the argument that these structural features require drug development (i.e., biopharmaceutical) firms to rely on external financing and at the same time amplify market frictions that may hinder the ability of these firms to obtain financing, especially for treatments that may have large societal value relative to the benefits going to the firms and their investors. We then provide an overview of the evidence for various types of market frictions to which these drug development firms are exposed and discuss how these frictions affect their incentive to invest in the development of new drugs, leading to underinvestment in valuable treatments. In light of this evidence, numerous studies have proposed ways to overcome this funding gap, including the use of financial innovation. We discuss the potential of these approaches to improve outcomes.

BACKGROUND: The authors estimate the probability of successful development and duration of clinical trials for medications to treat neuropathic and nociceptive pain. The authors 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, duration, and survivorship of pain medication development programs between January 1, 2000, and June 30, 2020, conditioned on the phase, type of pain (nociceptive vs. neuropathic), and the abuse potential of the medication.

RESULTS: The overall probability of successful development of all pain medications from phase 1 to approval is 10.4% (standard error, 1.5%).Medications to treat nociceptive and neuropathic pain have a probability of successful development of 13.3% (standard error, 2.3%) and 7.1% (standard error, 1.9%), respectively. The probability of successful development of medications with high abuse potential and low abuse potential are 27.8% (standard error, 4.6%) and 4.7% (standard error, 1.2%), respectively. The most common period for attrition is between phase 3 and approval.

CONCLUSIONS: The authors’ data suggest that the unique attributes of pain medications, such as their abuse potential and intended pathology, can influence the probability of successful development and duration of development.

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 size of 137 patients. 

METHODS: We apply Bayesian decision analysis (BDA) to determine the optimal type I error rate (p-value) under which the clinical evidence of AMX0035 supports FDA approval. Using rigorous estimates of ALS disease burden, our BDA framework strikes the optimal balance between FDA’s need to limit adverse effects (type I error) and patients’ need for expedited access to a potentially effective therapy (type II error). We apply BDA to evaluate long-term patient survival based on clinical evidence from AMX0035 and Riluzole. 

RESULTS: The BDA-optimal type I error for approving AMX0035 is higher than the 3% p-value reported in the phase 2 trial if the probability of the therapy being effective is at least 30%. Assuming a 50% probability of efficacy and a signal-to-noise ratio of treatment effect between 25% and 50% (benchmark: 33%), the optimal type I error rate ranges from 2.6% to 26.3% (benchmark: 15.4%). The BDA-optimal type I error rate is robust to perturbations in most assumptions except for a probability of efficacy below 5%. 

CONCLUSION: BDA provides a useful framework to incorporate subjective perspectives of ALS patients and objective burden-of-disease metrics to evaluate the therapeutic effects of AMX0035 in its phase 2 trial.