Patient-centered clinical trials2018
We apply Bayesian decision analysis (BDA) to incorporate patient preferences in the regulatory approval process for new therapies. By assigning weights to type I and type II errors based on patient preferences, the significance level (a) and power (1 b) of a randomized clinical trial (RCT) for a new therapy can be
optimized to maximize the value to current and future patients and, consequently, to public health. We find that for weight-loss devices, potentially effective low-risk treatments have optimal as larger than the traditional one-sided significance level of 5%, whereas potentially less effective and riskier
treatments have optimalas below 5%. Moreover,the optimal RCT design, including trial size, varies with the risk aversion and time-to-access preferences and the medical need of the target population.
Estimation of clinical trial success rates and related parameters2018
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 success rates and durations. We also compute disaggregated estimates across several trial features including disease type, clinical phase, industry or academic sponsor, biomarker presence, lead indication status, and time. In several cases, our results differ significantly in
detail from widely cited statistics. For example, oncology has a 3.4% success rate in our sample vs. 5.1% in prior studies. However, after declining to 1.7% in 2012, this rate has improved to 2.5% and 8.3% in 2014 and 2015, respectively. In addition, trials that use biomarkers in patient-selection have higher overall
success probabilities than trials without biomarkers.
On Black’s Leverage Effect in Firms with No Leverage2018
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 (1976), who attributed it to the effects of financial or operating leverage. This paper documents that firms which had no debt (and thus no financial leverage) from January 1973 to December 2017 exhibit Black’s leverage effect. Moreover, it finds that
the leverage effect of firms in this sample is not driven by operating leverage. On the contrary, in this sample the leverage effect is stronger for firms with low operating leverage as compared to those with high operating leverage. Interestingly, the firms with no debt from the lowest quintile of operating leverage exhibit the leverage effect that is on par with or stronger than that of debt-financed firms.
Pricing for Survival in the Biopharma Industry: A Case Study of Acthar Gel and Questcor Pharmaceuticals2017
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.
Just how good an investment is the biopharmaceutical sector?2017
Uncertainty surrounding the risk and reward of investments in biopharmaceutical companies poses a challenge to those interested in funding such enterprises. Using data on publicly traded stocks, we track the performance of 1,066 biopharmaceutical companies from 1930 to 2015—the most comprehensive financial analysis of this sector to date. Our systematic exploration of methods for distinguishing biotech and pharmaceutical companies yields a dynamic, more accurate classification method. We find that the performance of the biotech sector is highly sensitive to the presence of a few outlier companies, and confirm that nearly all biotech companies are loss-making enterprises, exhibiting high stock volatility. In contrast, since 2000, pharmaceutical companies have become increasingly profitable, with risk-adjusted returns consistently outperforming the market. The performance of all biopharmaceutical companies is subject not only to factors arising from their drug pipelines (idiosyncratic risk), but also from general economic conditions (systematic risk). The risk associated with returns has profound implications both for patterns of investment and for funding innovation in biomedical R&D.
Re-inventing drug development: A case study of the I-SPY 2 breast cancer clinical trials program2017
In this case study, we profile the I-SPY 2 TRIAL (Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And molecular anaLysis 2), a unique breast cancer clinical trial led by researchers at 20 leading cancer centers across the US, and examine its potential to serve as a model of drug
development for other disease areas. This multicenter collaboration launched in 2010 to reengineer the drug development process to be more efficient and patient-centered.
The Growth of Relative Wealth and the Kelly Criterion2017
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 relative wealth, the Kelly criterion is optimal only under certain conditions, which are identified. The initial relative wealth plays a critical role in determining the deviation of optimal behavior from the Kelly criterion regardless of whether the investor is myopic across a single time period or maximizing wealth over an infinite horizon. We relate these results to population genetics, and discuss testable consequences of these findings using experimental evolution.
Accelerating Biomedical Innovation: A Case Study of the SPARK Program at Stanford University, School of Medicine2017
Translating academic medical research into new therapies is an important challenge for the biopharmaceutical industry and investment communities, which have historically favored later-stage assets with lower risk and clearer commercial value. The Stanford SPARK program is an innovative model for addressing this challenge. The program was created in 2006 to educate students and faculty about bringing academic research from bench to bedside. Every year, the program provides mentorship and funding for approximately a dozen SPARK ‘scholars,’ with a focus on impacting patient lives, regardless of economic factors.
By reviewing the detailed structure, function and operation of SPARK we hope to provide a template for other universities and institutions interested in de-risking and facilitating the translation of biomedical research.
Stop-loss Strategies with Serial Correlation, Regime Switching, and Transaction Costs2017
Stop-loss strategies are commonly used by investors to reduce their holdings in risky assets if prices or total wealth breach certain pre- specified thresholds. We derive closed-form expressions for the impact of stop-loss strategies on asset returns that are serially correlated, regime switching, and subject to transaction costs. When applied to a large sample of individual U.S. stocks, we show that tight stop-loss strategies tend to under-perform the buy-and-hold policy in a mean-variance frame work due to excessive trading costs. Outperformance is possible for stocks with sufficiently high serial correlation in returns. Certain strategies succeed at reducing downside risk, but not substantially.
Use of Bayesian Decision Analysis to Minimize Harm in Patient-Centered Randomized Clinical Trials in Oncology2017
There is general agreement in the biomedical community that the development of therapies for certain diseases should take priority. This ethic has motivated
legislative initiatives, such as the Orphan Drug Act of 1983, and underpins several important innovations in regulatory approval processes, such as the US Food and Drug Administration’s (FDA) fast-track, breakthrough-therapy,
accelerated-approval, and priority-review designations. However, none of these innovations directly address the critical issue of how to incorporate the patient’s perspective in deciding whether a drug candidate should be approved or not.
The current approach in clinical trial design is to minimize the chance of ineffective treatment caused by a type 1 error, that is, a false-positive result. However, the arbitrary nature of the threshold for the probability of type 1 error, alpha, raises an ethical question about its justification.A 2.5% threshold may
not be appropriate for terminal illnesses that have no effective therapies; such patients may prefer to take a bigger chance on a false-positive result, even if the likelihood of an effective therapy is small. To quote the noted biostatistician
Donald Berry, “We should also focus on patient values, not just P values.”