Use of Bayesian Decision Analysis to Minimize Harm in Patient-Centered Randomized Clinical Trials in Oncology
with Vahid Montazerhodjat; Shomesh E. Chaudhuri; Daniel J. Sargent, JAMA Oncology (2017)
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.”
with Esther S. Kim, Forthcoming Journal of Investment Mangement
Duchenne muscular dystrophy (DMD) is a rare genetic disorder affecting thousands of individuals, mainly young males, worldwide. Currently, the disease has no cure, and is fatal in all cases. Advances in our understanding of the disease and innovations in basic science have recently allowed biotechnology companies to pursue promising treatment candidates for the disease, but so far, only one drug with limited application has achieved FDA approval. In this case study, we profile the work of an early-stage life sciences company, Solid Biosciences, founded by a father of a young boy with DMD. In particular, we discuss Solid’s one-disease focus and its strategy to treat the disease with a diversified portfolio of approaches. The company is currently building a product pipeline consisting of genetic interventions, small molecules and biologics, and assistive devices, each aimed at addressing a different aspect of DMD. We highlight the potential for Solid’s business model and portfolio to achieve breakthrough treatments for the DMD patient community.
with Tomas Philipson and Andrew von Eschenbach, JAMA Oncology 2(2016), 17–18.
Americans are increasingly apprehensive about our future, so it is inspiring when Congress produces legislation intended to both enhance our health and expand our economy. The 21st Century Cures Act, recently passed by the House with an impressive bipartisan majority vote of 344 to 77, intends to accelerate the many-step process of drug discovery and development, from basic scientific research to clinical development to delivery, distribution, and ongoing monitoring. Among other things, the legislation boosts National Institute of Health funding, dramatically speeds up the US Food and Drug Administration (FDA) approval process, and aims to make use of new information technology to better monitor the performance of medical products after they reach the market. This landmark bill now awaits a comparable piece of legislation being developed by the Senate Health Education, Labor, and Pensions Committee. Together, they will transform the biomedical ecosystem and provide the foundation for the next several decades of innovative life-saving and health-enhancing solutions for our nation and the world.
with Tito Fojo , Lancet Oncology 17(2016), 3–5.
The reports by Wim van Harten and colleagues and Sabine Vogler and colleagues in The Lancet Oncology on the costs of cancer drugs in European countries deserve special attention from all oncology and biopharmaceutical stakeholders. van Harten identified that, in 15 European countries, list prices can be up to 92% lower than the highest reported, with actual prices paid up to 58% lower. These findings are backed up by Vogler and colleagues' study 2 in 16 European countries, Australia, and New Zealand, which documented that highest-minus-lowest list price differences ranged from 28% to 388% for cancer drugs. Such variability argues strongly for greater transparency in drug pricing and the circumstances leading to such differences. But most importantly, it underscores the need to establish the true value of cancer therapies, and those who have championed this cause have been handed unequivocal evidence confirming what they have long suspected: drug prices are typically driven by what the market will bear.
with David Weinstock, The Boston Globe
"A new class of medications was recently approved that cures more than 95 percent of people with Hepatitis C in only six weeks at a cost of about $84,000 per person, and new therapies with price tags that are likely to exceed $1 million per person are now available or coming soon. How can patients possibly afford them? "In an article published in the journal Science Translation Medicine, we outline a feasible market-based solution that could immediately expand access to transformative medications, including cures for Hepatitis C and cancer. The basic concept is to convert a large upfront medical expense into a series of more affordable payments, akin to getting a mortgage when buying a house. The challenge of curative medications that only require a short course of therapy is that the whole price is paid upfront — how many homeowners could buy their houses using only cash? Instead, most home buyers get a mortgage and make monthly payments for as long as they benefit from owning the house or until the full amount is paid. We propose the same solution to overcome the liquidity problem that prevents access to curative medications, which we call “health care loans,” or HCLs..."
with Vahid Montazerhodjat and David M. Weinstock, Science Translational Medicine 8(2016), 327ps6.
A crisis is building over the prices of new transformative therapies for cancer, hepatitis C virus infection, and rare diseases. The clinical imperative is to offer these therapies as broadly and rapidly as possible. We propose a practical way to increase drug affordability through health care loans (HCLs)—the equivalent of mortgages for large health care expenses. HCLs allow patients in both multipayer and single-payer markets to access a broader set of therapeutics, including expensive short-duration treatments that are curative. HCLs also link payment to clinical benefit and should help lower per-patient cost while incentivizing the development of transformative therapies rather than those that offer small incremental advances. Moreover, we propose the use of securitization—a well-known financial engineering method—to finance a large diversified pool of HCLs through both debt and equity. Numerical simulations suggest that securitization is viable for a wide range of economic environments and cost parameters, allowing a much broader patient population to access transformative therapies while also aligning the interests of patients, payers, and the pharmaceutical industry.
Is the FDA Too Conservative or Too Aggressive?: A Bayesian Decision Analysis of Clinical Trial Design
with Leah Isakov and Vahid Montazerhodjat
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 Gary P. Pisano, Sloan Management Review 57(2015), 47–57.
with Edward Jung, Project Syndicate
"As price-gouging practices by a handful of drug companies attract headlines, one troubling aspect of the story remains underplayed. Exorbitant increases in the prices of existing drugs, including generics, are motivated not just by crass profiteering but by a deep skepticism about the economic feasibility of developing new drugs. That skepticism is justified. "Traditional models for funding drug development are faltering. In the US and many other developed countries, the average cost of bringing a new drug to market has skyrocketed, even as patents on some of the industry’s most profitable drugs have expired. Venture capital has pulled back from early-stage life-sciences companies, and big pharmaceutical companies have seen fewer drugs reach the market per dollar spent on research and development..."
with Jose Maria Fernandez and Roger M. Stein