Regulation of Innovation Under Follow-On Biologics Legislation: FDA Exclusivity as an Efficient Incentive Mechanism

As part of its broader effort to reform the American health care system, Congress has recently enacted legislation that creates a statutory pathway for FDA approval of generic "follow-on" biologics products. A crucial debate leading up to the passage of this legislation was whether and to what extent it should provide originator biologics manufacturers with a period of FDA data exclusivity protection as an incentive for future innovation. This debate was particularly significant because of the ongoing reevaluation in the United States of the appropriate role of patent law in fostering technological advance, with recent Supreme Court decisions indicating a trend towards retrenchment of the scope of available patent protections. In the end, the bill adopted by Congress and signed into law by President Obama affords manufacturers of new biologics products with 12 years of data exclusivity. The central thesis of this Article is that optimal biologics innovation policy would situate FDA exclusivity as the industry's primary incentive mechanism, displacing patent law in that role. The inclusion of a lengthy 12-year data exclusivity period in the newly enacted legislation is a laudable step in the right direction. But reliance on patenting in the biologics innovation process would also likely have to be substantially curtailed in order to attain optimal levels of innovation. If this were achieved, FDA exclusivity would act as an adequate surrogate for the incentives offered by patents, while a number of pathologies currently associated with patenting in the biomedical research context would be eliminated. This Article also argues that Congress should adopt a regime of market exclusivity protection instead of the data exclusivity protection presently included in the new legislation. Market exclusivity would permit the FDA to adopt rules requiring public disclosure of both basic research results (which may cease to be published absent strong patent rights) and clinical trials data (which cannot be divulged under a data exclusivity regime) in exchange for FDA approval. Such disclosure rules would contribute to efficient, disaggregated research into new and improved therapeutic approaches

Tilted frames of reference have similar effects on perception of the gravitational vertical and the planning of vertical saccadic eye movements

We investigated the effects of a tilted reference frame (i.e., allocentric visual context) on perception of the gravitational vertical and saccadic eye movements along a planned egocentric vertical path. Participants (n=5) in a darkened room fixated a point in the center of a circle on an LCD display, and decided which of two sequentially presented dots was closer to the unmarked ‘6 o’clock’ position on that circle (i.e., straight down towards their feet). The slope of their perceptual psychometric functions showed that participants were able to locate which dot was nearer the vertical with a precision of 1-2°. For three of the participants, a square frame centered at fixation and tilted (in the roll direction) 5.6° from the vertical caused a strong perceptual bias, manifest as a shift in the psychometric function, in the direction of the traditional ‘rod and frame’ effect, without affecting precision. The other two participants showed negligible or no equivalent biases. The same subjects participated in the saccade version of the task, in which they were instructed to shift their gaze to the 6 o’clock position as soon as the central fixation point disappeared. The participants who showed perceptual biases showed biases of similar magnitude in their saccadic end points, with a strong correlation between perceptual and saccadic biases across all subjects. Tilting of the head 5.6° reduced both perceptual and saccadic biases in all but one observer, who developed a strong saccadic bias. Otherwise, the overall pattern and significant correlations between results remained the same. We conclude that our observers' saccades-to-the-vertical were dominated by perceptual input, which outweighed any gravitational or head-centered input

The impact of hypoxia on B cells in COVID-19

Background: Prominent early features of COVID-19 include severe, often clinically silent, hypoxia and a pronounced reduction in B cells, the latter important in defence against SARS-CoV-2. This presentation resembles the phenotype of mice with VHL-deficient B cells, in which Hypoxia-Inducible Factors are constitutively active, suggesting hypoxia might drive B cell abnormalities in COVID-19. Methods: Detailed B cell phenotyping was undertaken by flow-cytometry on longitudinal samples from patients with COVID-19 across a range of severities (NIHR Cambridge BioResource). The impact of hypoxia on the transcriptome was assessed by single-cell and whole blood RNA sequencing analysis. The direct effect of hypoxia on B cells was determined through immunisation studies in genetically modified and hypoxia-exposed mice. Findings: We demonstrate the breadth of early and persistent defects in B cell subsets in moderate/severe COVID-19, including reduced marginal zone-like, memory and transitional B cells, changes also observed in B cell VHL-deficient mice. These findings were associated with hypoxia-related transcriptional changes in COVID-19 patient B cells, and similar B cell abnormalities were seen in mice kept in hypoxic conditions. Interpretation: Hypoxia may contribute to the pronounced and persistent B cell pathology observed in acute COVID-19 pneumonia. Assessment of the impact of early oxygen therapy on these immune defects should be considered, as their correction could contribute to improved outcomes. Funding: Evelyn Trust, Addenbrooke's Charitable Trust, UKRI/NIHR, Wellcome Trus

A novel mixed-methods platform study protocol for investigating new surgical devices, with embedded shared learning: Ibra-net breast lesion localisation study

Introduction: New medical devices must have adequate research, such that outcomes are known, enabling patients to be consented with knowledge of the safety and efficacy of the device to be implanted. Device trials are challenging due to the learning curve and iterative assessment of best practice. This study is designed to pilot a national collaborative approach to medical device introduction by breast surgeons in the UK, using breast localisation devices as an exemplar. The aim is to develop an effective and transferable surgical device platform protocol design, with embedded shared learning. Methods and analysis: The iBRA-net localisation study is a UK based prospective, multi-centre platform study, comparing the safety and efficacy of novel localisation devices with wire-guided breast lesion localisation for wide local excision, using Magseed® as the pilot intervention group. Centres performing breast lesion localisation for wide local excision or excision biopsy will be eligible to participate if using one of the included devices. Further intervention arms will be added as new devices are CE marked. Outcomes will be collected via an online database. The primary outcome measure will be identification of the index lesion. Participating surgeons will be asked to record shared learning events via online questionnaires and focus group interviews to inform future study arms. Ethics and dissemination: The study will aim to collect data on 950 procedures for each intervention (Magseed® and wire localisation) from UK breast centres over an 18-month period. Shared learning will be prospectively evaluated via thematic analysis to refine breast localisation technique and to promote early identification of potential pitfalls and problems. Results will be presented at national and international conferences and published in peer reviewed journals. Registration: This is a UK national audit registered with Manchester University NHS Foundation Trust

C3 Glomerulopathy and Related Disorders in Children: Etiology-Phenotype Correlation and Outcomes

BACKGROUND AND OBJECTIVES: Membranoproliferative GN and C3 glomerulopathy are rare and overlapping disorders associated with dysregulation of the alternative complement pathway. Specific etiologic data for pediatric membranoproliferative GN/C3 glomerulopathy are lacking, and outcome data are based on retrospective studies without etiologic data. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 80 prevalent pediatric patients with membranoproliferative GN/C3 glomerulopathy underwent detailed phenotyping and long-term follow-up within the National Registry of Rare Kidney Diseases (RaDaR). Risk factors for kidney survival were determined using a Cox proportional hazards model. Kidney and transplant graft survival was determined using the Kaplan-Meier method. RESULTS: Central histology review determined 39 patients with C3 glomerulopathy, 31 with immune-complex membranoproliferative GN, and ten with immune-complex GN. Patients were aged 2-15 (median, 9; interquartile range, 7-11) years. Median complement C3 and C4 levels were 0.31 g/L and 0.14 g/L, respectively; acquired (anticomplement autoantibodies) or genetic alternative pathway abnormalities were detected in 46% and 9% of patients, respectively, across all groups, including those with immune-complex GN. Median follow-up was 5.18 (interquartile range, 2.13-8.08) years. Eleven patients (14%) progressed to kidney failure, with nine transplants performed in eight patients, two of which failed due to recurrent disease. Presence of >50% crescents on the initial biopsy specimen was the sole variable associated with kidney failure in multivariable analysis (hazard ratio, 6.2; 95% confidence interval, 1.05 to 36.6; P50% crescents on the initial biopsy specimen. CONCLUSIONS: Crescentic disease was a key risk factor associated with kidney failure in a national cohort of pediatric patients with membranoproliferative GN/C3 glomerulopathy and immune-complex GN. Presenting eGFR and crescentic disease help define prognostic groups in pediatric C3 glomerulopathy. Acquired abnormalities of the alternative pathway were commonly identified but not a risk factor for kidney failure

Exploring men's and women's experiences of depression and engagement with health professionals: more similarities than differences? A qualitative interview study

<p>Abstract</p> <p>Background</p> <p>It is argued that the ways in which women express emotional distress mean that they are more likely to be diagnosed with depression, while men's relative lack of articulacy means their depression is hidden. This may have consequences for communicating with health professionals. The purpose of this analysis was to explore how men and women with depression articulate their emotional distress, and examine whether there are gender differences or similarities in the strategies that respondents found useful when engaging with health professionals.</p> <p>Methods</p> <p>In-depth qualitative interviews with 22 women and 16 men in the UK who identified themselves as having had depression, recruited through general practitioners, psychiatrists and support groups.</p> <p>Results</p> <p>We found gender similarities and gender differences in our sample. Both men and women found it difficult to recognise and articulate mental health problems and this had consequences for their ability to communicate with health professionals. Key gender differences noted were that men tended to value skills which helped them to talk while women valued listening skills in health professionals, and that men emphasised the importance of getting practical results from talking therapies in their narratives, as opposed to other forms of therapy which they conceptualised as 'just talking'. We also found diversity among women and among men; some respondents valued a close personal relationship with health professionals, while others felt that this personal relationship was a barrier to communication and preferred 'talking to a stranger'.</p> <p>Conclusion</p> <p>Our findings suggest that there is not a straightforward relationship between gender and engagement with health professionals for people with depression. Health professionals need to be sensitive to patients who have difficulties in expressing emotional distress and critical of gender stereotypes which suggest that women invariably find it easy to express emotional distress and men invariably find it difficult. In addition it is important to recognise that, for a minority of patients, a personal relationship with health professionals can act as a barrier to the disclosure of emotional distress.</p

Exploring the contribution of alternative food networks to food security. A comparative analysis

[EN] Food (in)security has become a challenge not only for developing economies but also for High Income Countries. In parallel, food scholars have actively investigated the contribution of alternative food networks (AFNs) to the development of more sustainable and just food systems, paying attention to drivers, initiatives and policies supporting the development of alternatives to the dominant industrialised food system and its detrimental environmental and socio-economic impacts. However, few studies have directly addressed the contribution of AFNs to food security in the Global North. This paper aims to establish new linkages between food security debates and critical AFNs literature. For that purpose, we conduct a place-based approach to food security in a comparative analysis of initiatives of three different European contexts: Cardiff city-region (UK), the Flemish Region (Belgium) and the peri-urban area of the city of Valencia (Spain). The results unfold: i) how AFNs weave a more localised socio-economic fabric that creates new relationships between food security outcomes and specific territories, ii) hybridization processes within alternative but also conventional systems and iii) the role of advocacy and collective action at different levels. The analysis allows identification of key elements on which food security debates hinge and provides new insights to ground conceptual discussions on territorial and place-based food security approaches.This research is part of the project "Assessment of the impact of global drivers of change on Europe's food security" (TRANSMANGO), granted by the EU under 7th Framework Programme; theme KBBE.2013.2.5-01; Grant agreement no: 613532. Dr. Ana Moragues-Faus also acknowledges the funding of the European Commission and the Welsh Government that currently supports her Ser Cymru fellowship. 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Gene Expression Changes in GABAA Receptors and Cognition Following Chronic Ketamine Administration in Mice

Ketamine is a well-known anesthetic agent and a drug of abuse. Despite its widespread use and abuse, little is known about its long-term effects on the central nervous system. The present study was designed to evaluate the effect of long-term (1- and 3-month) ketamine administration on learning and memory and associated gene expression levels in the brain. The Morris water maze was used to assess spatial memory and gene expression changes were assayed using Affymetrix Genechips; a focus on the expression of GABAA receptors that mediate a tonic inhibition in the brain, was confirmed by quantitative real-time PCR and western blot. Compared with saline controls, there was a decline in learning and memory performance in the ketamine-treated mice. Genechip results showed that 110 genes were up-regulated and 136 genes were down-regulated. An ontology analysis revealed the most significant effects of ketamine were on GABAA receptors. In particular, there was a significant up-regulation of both mRNA and protein levels of the alpha 5 subunit (Gabra5) of the GABAA receptors in the prefrontal cortex. In conclusion, chronic exposure to ketamine impairs working memory in mice, which may be explained at least partly by up-regulation of Gabra5 subunits in the prefrontal cortex