Drug Development--Stuck in a State of Puberty?: Regulatory Reform of Human Clinical Research to Raise Responsiveness to the Reality of Human Variability

Scathing critiques of the Food and Drug Administration\u27s (“FDA”) performance by the Government Accountability Office and Institutes of Medicine, a plummet in innovative new drug approvals in spite of significant annual investment increases in biopharmaceutical research and development (“R&D”), and market controversies such as the painkiller Vioxx and the diabetes drug Avandia (both associated with significantly escalated risks of heart attacks and strokes) have raised doubts about the sufficiency of FDA *364 regulation. This Article questions how prescription medicines reach the market and proposes law-policy reforms to enhance the FDA\u27s science standard for human clinical trials and new drug approvals. The core message is that relying too heavily on clinical research data generated through the global “gold standard” of group experimental design--reliance on statistical analysis to compile and compare group averages--risks predicting little about the actual impact of prescription medicines on individuals, including members of the groups under study. This Article introduces a law-policy methodology based upon commercial incentives and intervention by Congress and the FDA to raise the science standard for human clinical research, and to make drug development more closely parallel the reality of drug delivery in the practice of medicine. The objectives of this proposal are to promote several pressing needs: maximize drug performance and minimize adverse events; end the pattern of putting new prescription medications on the market with too much dependence on the medical profession to introduce meaningful clinical understanding of drugs through patient use over time; improve biopharmaceutical R&D decision making; align the regulatory standard with the infusion of added precision associated with contemporary genetics-based R&D; and realize more sound scientific information directly through the regulatory process to support the integrity of science in an age of academia-industry integration, aggressive commercialization, secrecy in science, and constantly, rapidly evolving technology

The Drug Repurposing Ecosystem: Intellectual Property Incentives, Market Exclusivity, and the Future of New Medicines

The pharmaceutical industry is in a state of fundamental transition. New drug approvals have slowed, patents on blockbuster drugs are expiring, and costs associated with developing new drugs are escalating and yielding fewer viable drug candidates. As a result, pharmaceutical firms have turned to a number of alternative strategies for growth. One of these strategies is drug repurposing -finding new ways to deploy approved drugs or abandoned clinical candidates in new disease areas. Despite the efficiency advantages of repurposing drugs, there is broad agreement that there is insufficient repurposing activity because of numerous intellectual property protection and market failures. This Article examines the system that surrounds drug repurposing, including serendipitous discovery, the application of big data methods to prioritize promising repurposing candidates, the unorthodoxly regulated off-label prescription practices of providers, and related prohibitions on pharmaceutical firms\u27 off-label marketing. The Article argues that there is a complex ecosystem in place and that additional or disruptive IP or market exclusivity incentives may harm as much as help in promoting repurposing activity. To illustrate this threat, the Article traces the trajectory of metformin, a common diabetes drug that shows promise for conditions ranging from polycystic ovary syndrome to breast cancer. From the initial reasons for Bristol-Myers Squibb to refuse to invest in promising alternative uses, to the institutions, researchers, and regulators who identified possibilities for metformin treatment, this Article aims to map the role of intellectual property protection, market exclusivity, and search for capital that led to metformin\u27s ascent as a repurposed drug. The Article contributes a concrete understanding to an important problem in pharmaceutical law and policy, one for which scholars have quickly suggested more powerful patent and market exclusivity protection when doing so may undermine the very processes now leading to effective alternative uses for existing drugs

The Drug Repurposing Ecosystem: Intellectual Property Incentives, Market Exclusivity, and the Future of New Medicines

The pharmaceutical industry is in a state of fundamental transition. New drug approvals have slowed, patents on blockbuster drugs are expiring, and costs associated with developing new drugs are escalating and yielding fewer viable drug candidates. As a result, pharmaceutical firms have turned to a number of alternative strategies for growth. One of these strategies is drug repurposing -finding new ways to deploy approved drugs or abandoned clinical candidates in new disease areas

A clinical decision support system for the treatment of common toxin overdose

Poisonings account for 0.8% of emergency room visits each year. Our review of current toxicological resources revealed a gap in their ability to provide expedient calculations and recommendations, as they are broad in scope and time-consuming to read. Time is crucial in a toxicologic emergency. Delay in first dose can lead to life-threatening sequelae. To bridge the gap, we developed the Antidote Application (AA), a computational system that automatically provides patient-specific antidote treatment recommendation(s) and individualized dose calculation(s). We implemented 27 algorithms that describe FDA approved use and evidence-based practices found in primary literature for the treatment of common toxin exposure. The AA covers 29 antidotes recommended by Poison Control and toxicology experts, 31 toxins from 19 toxin classes, and over 200 toxic entities. We implemented the AA in two formats: a standalone downloadable application for offline use and an online web application. The AA represents a unique educational resource for the study of toxicology with the potential of being adopted for point of care decision support. The system also provides guidance for reporting toxic exposures regionally and nationally as required by accrediting bodies and some states. The AA system has the potential for reducing initial dose delays and medication errors. To the best of our knowledge, the AA is the first educational and decision support system in toxicology that provides patient-specific treatment recommendations and drug dose calculations. The downloadable and online Antidote Applications are publically available at http://www.met-hilab.org/files/antidote/antidote_application.jar and http://projects.met-hilab.org/antidote/ respectively

Off-Label Speech

This Article argues that the Food and Drug Administration (“FDA”) should regulate drug manufacturer speech about off-label uses based on the evidentiary support for the relevant use. The more evidence that an off-label use is safe and effective, the less restrictive the regulation should be. The less evidence that an off-label use is safe and effective, the more restrictive the regulation should be. Although intuitive, this is not exactly how current regulation of off-label information works. If the FDA approves a drug, the manufacturer can advertise to doctors and patients for the approved indication. Drug manufacturers cannot, however, promote or provide information about an approved drug for an unapproved use—so-called “off-label” use—unless they fall within two narrow safe harbors. Yet many off-label uses are just as safe and effective as on-label (approved) ones. Other off-label uses are supported by quality clinical trial data even though they are not approved. While the FDA recognizes that not all off-label uses are equally (un)supported by the same level of evidence, it has faced legal and practical challenges regulating information about them in a nuanced way. Courts have held unconstitutional the FDA’s regulations purporting to ban promotional off-label speech by drug manufacturers. And the safe harbors it has constructed are too shallow for much useful speech. To address these challenges, this Article proposes a new approach: working collaboratively with the Centers for Medicare and Medicaid Services, the FDA can use drug compendia—which identify, evaluate, and rate off-label uses—to create a graded system for regulating how drug manufacturers disseminate information about off-label uses that links informational restrictions to the level of evidence supporting the disseminated use. Not only does this system enable a flexible and evidence-based regulatory regime, it also can be easily designed to survive constitutional scrutiny

Should Human Milk Be Regulated?

Markets in human milk are booming. They take two main forms: informal markets—women giving or selling their milk peer-to-peer—, and formal markets—for-profit or non-profit organizations collecting, processing, and distributing donor milk to neonatal intensive care units and a few outpatients for a fee. The legal regime applicable to these human milk transactions is fragmented and unstable. The federal government does not define human milk as anything. The Food and Drug Administration has declined to regulate milk banks even though it oversees blood, cord, oocytes, semen, and stool banks. Only a handful of states have laws on the books pertaining to human milk. In light of the growing demand for human milk and public health professionals’ calls for government oversight due to fears of pathogen contamination, this Article asks whether human milk should be regulated more tightly and, if so, what types of legal reforms would be most desirable. It concludes that human milk should not be treated as a disembodied product under a food, drug, and tissue law paradigm, but rather as the product of a relationship between breastfeeders and breastfed babies. It is this relationship that is in urgent need of legal protections so that more parents can breastfeed their children and make extra milk available for others. Though the risks of contamination are real, they can be, and are, mitigated by milk banks, as well as by peer- to-peer donors and recipients. But many children who need donor milk do not obtain it either because it is unavailable or too expensive. Legal reforms should therefore focus on increasing the supply via robust breastfeeding and donor milk support, which in turn will make human milk accessible to all those who need it regardless of their socioeconomic status. This approach entails shifting from a single-minded focus on health and safety to considering the conditions of people who produce and donate milk and the health insurance market that often fails to cover it