Advancing structured decision-making in drug regulation at the FDA and EMA

The recent benefit–risk framework (BRF) developed by the Food and Drug Administration (FDA) is intended to improve the clarity and consistency in communicating the reasoning behind the FDA's decisions, acting as an important advancement in US drug regulation. In the PDUFA VI implementation plan, the FDA states that it will continue to explore more structured or quantitative decision analysis approaches; however, it restricts their use within the current BRF that is purely qualitative. By contrast, European regulators and researchers have been long exploring the use of quantitative decision analysis approaches for evaluating drug benefit–risk balance. In this paper, we show how quantitative modelling, backed by decision theory, could complement and extend the FDA's BRF to better support the appraisal of evidence and improve decision outcomes. After providing relevant scientific definitions for benefit–risk assessment and describing the FDA and European Medicines Agency (EMA) frameworks, we explain the components of and differences between qualitative and quantitative approaches. We present lessons learned from the EMA experience with the use of quantitative modelling and we provide evidence of its benefits, illustrated by a real case study that helped to resolve differences of judgements among EMA regulators

So near yet so far: why won't the UK prescribe medical cannabis?

Although cannabis-based products for medicinal use are now legal in the UK, it is still challenging for patients to gain access, and only very few National Health Service prescriptions have been written to date. This paper attempts to make sense of why the UK lags behind so many other countries which also have legalised medical cannabis. From consulting with parents and patients, prescribers, pharmacists and decision-makers it seems that there are a series of distinct barriers to prescribing that need to be overcome in order to improve patient access to medical cannabis in the UK. These include concerns about the perceived lack of scientific evidence. To alleviate these concerns, we highlight the importance of patient-centred approaches including patient-reported outcomes, pharmacoepidemiology and n=1 trials, which can contribute to the development of the evidence base for medical cannabis. We hope that this paper will help policymakers and prescribers understand the challenges to prescribing and so help them develop approaches to overcome the current situation which is detrimental to patients

Quantifying preference in drug benefit-risk decisions

Benefit-risk assessment is used in various phases along the drug lifecycle, such as marketing authorization and surveillance, health technology assessment (HTA), and clinical decisions, to understand whether, and for which patients, a drug has a favorable or more valuable profile with reference to one or more comparators. Such assessments are inherently preference-based as several clinical and nonclinical outcomes of varying importance might act as evaluation criteria, and decision makers must establish acceptable trade-offs between these outcomes. Different healthcare stakeholder perspectives, such as those from patients and healthcare professionals, are key for informing benefit-risk trade-offs. However, the degree to which such preferences inform the decision is often unclear as formal preference-based evaluation frameworks are generally not used for regulatory decisions, and, if used, rarely communicated in HTA decisions. We argue that for better decisions, as well as for reasons of transparency, preferences in benefit-risk decisions should more often be quantified and communicated explicitly

Gene Banks, Seed Libraries, and Vegetable Sanctuaries: The Cultivation and Conservation of Heritage Vegetables in Britain, 1970–1985

Individual seed saving and exchange are considered important components of contemporary efforts to conserve crop genetic diversity, which ramify at local, regional, and global scales. Yet the very fact that the contributions of these activities to conservation need to be made explicit by seed savers and those who study them indicates that the practices of seed saving and exchange may not immediately be recognized as conservation-oriented activities. This article investigates why and how individual seed saving came to be aligned with a broader conservation agenda in Britain through an historical examination of the promotion of seed saving by the Henry Doubleday Research Association (HDRA) in the 1970s and 1980s. It demonstrates how several HDRA initiatives that aimed to preserve vegetable diversity also re-inscribed British gardeners' ordinary labor as conservation work. This historical study complements sociological and ethnographic studies, highlighting the role of a prominent organization in creating pathways for individuals to engage in local, national, and international conservation through seed saving. It also serves as a reminder that the connections between these activities had to be made explicit—that is, that there was (and is) work involved in connecting individual acts of seed saving to conservation outcomes at different scales

The value of real world evidence: the case of medical cannabis

Randomised controlled trials (RCTs) have long been considered the gold standard of medical evidence. In relation to cannabis based medicinal products (CBMPs), this focus on RCTs has led to very restrictive guidelines in the UK, which are limiting patient access. There is general agreement that RCT evidence in relation to CBPMs is insufficient at present. As well as commercial reasons, a major problem is that RCTs do not lend themselves well to the study of whole plant medicines. One solution to this challenge is the use of real world evidence (RWE) with patient reported outcomes (PROs) to widen the evidence base. Such data increasingly highlights the positive impact medical cannabis can have on patients’ lives. This paper outlines the value of this approach which involves the study of interventions and patients longitudinally under medical care. In relation to CBMPs, RWE has a broad range of advantages. These include the study of larger groups of patients, the use of a broader range and ratio of components of CBMPs, and the inclusion of more and rarer medical conditions. Importantly, and in contrast to RCTs, patients with significant comorbidities–and from a wider demographic profile–can also be studied, so providing higher ecological validity and increasing patient numbers, whilst offering significant cost savings. We conclude by outlining 12 key recommendations of the value of RWE in relation to medical cannabis. We hope that this paper will help policymakers and prescribers understand the importance of RWE in relation to medical cannabis and help them develop approaches to overcome the current situation which is detrimental to patients

The Gattini cameras for optical sky brightness measurements at Dome C, Antarctica

The Gattini cameras are two site testing instruments for the measurement of optical sky brightness, large area cloud cover and auroral detection of the night sky above the high altitude Dome C site in Antarctica. The cameras have been operating since installation in January 2006 and are currently at the end of the first Antarctic winter season. The cameras are transit in nature and are virtually identical both adopting Apogee Alta CCD detectors. By taking frequent images of the night sky we obtain long term cloud cover statistics, measure the sky background intensity as a function of solar and lunar altitude and phase and directly measure the spatial extent of bright aurora if present and when they occur. The full data set will return in December 2006 however a limited amount of data has been transferred via the Iridium network enabling preliminary data reduction and system evaluation. An update of the project is presented together with preliminary results from data taken since commencement of the winter season

Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation.

Methamphetamine (MA) is a highly addictive psychomotor stimulant, with life-time prevalence rates of abuse ranging from 5-10% world-wide. Yet, a paucity of research exists regarding MA addiction vulnerability/resiliency and neurobiological mediators of the transition to addiction that might occur upon repeated low-dose MA exposure, more characteristic of early drug use. As stimulant-elicited neuroplasticity within dopamine neurons innervating the nucleus accumbens (NAC) and prefrontal cortex (PFC) is theorized as central for addiction-related behavioral anomalies, we used a multi-disciplinary research approach in mice to examine the interactions between sub-toxic MA dosing, motivation for MA and mesocorticolimbic monoamines. Biochemical studies of C57BL/6J (B6) mice revealed short- (1 day), as well as longer-term (21 days), changes in extracellular dopamine, DAT and/or D2 receptors during withdrawal from 10, once daily, 2 mg/kg MA injections. Follow-up biochemical studies conducted in mice selectively bred for high vs. low MA drinking (respectively, MAHDR vs. MALDR mice), provided novel support for anomalies in mesocorticolimbic dopamine as a correlate of genetic vulnerability to high MA intake. Finally, neuropharmacological targeting of NAC dopamine in MA-treated B6 mice demonstrated a bi-directional regulation of MA-induced place-conditioning. These results extend extant literature for MA neurotoxicity by demonstrating that even subchronic exposure to relatively low MA doses are sufficient to elicit relatively long-lasting changes in mesocorticolimbic dopamine and that drug-induced or idiopathic anomalies in mesocorticolimbic dopamine may underpin vulnerability/resiliency to MA addiction

CMBPol Mission Concept Study: Prospects for polarized foreground removal

In this report we discuss the impact of polarized foregrounds on a future CMBPol satellite mission. We review our current knowledge of Galactic polarized emission at microwave frequencies, including synchrotron and thermal dust emission. We use existing data and our understanding of the physical behavior of the sources of foreground emission to generate sky templates, and start to assess how well primordial gravitational wave signals can be separated from foreground contaminants for a CMBPol mission. At the estimated foreground minimum of ~100 GHz, the polarized foregrounds are expected to be lower than a primordial polarization signal with tensor-to-scalar ratio r=0.01, in a small patch (~1%) of the sky known to have low Galactic emission. Over 75% of the sky we expect the foreground amplitude to exceed the primordial signal by about a factor of eight at the foreground minimum and on scales of two degrees. Only on the largest scales does the polarized foreground amplitude exceed the primordial signal by a larger factor of about 20. The prospects for detecting an r=0.01 signal including degree-scale measurements appear promising, with 5 sigma_r ~0.003 forecast from multiple methods. A mission that observes a range of scales offers better prospects from the foregrounds perspective than one targeting only the lowest few multipoles. We begin to explore how optimizing the composition of frequency channels in the focal plane can maximize our ability to perform component separation, with a range of typically 40 < nu < 300 GHz preferred for ten channels. Foreground cleaning methods are already in place to tackle a CMBPol mission data set, and further investigation of the optimization and detectability of the primordial signal will be useful for mission design.Comment: 42 pages, 14 figures, Foreground Removal Working Group contribution to the CMBPol Mission Concept Study, v2, matches AIP versio