Regulatory enforcement of the marketing of fixed-dose combinations in India: a case study of systemic antibiotics

\ua9 2023, The Author(s).Background: In India, states have licensed the manufacture of large numbers of fixed-dose combination (FDC) drugs without the required prior approval of the central regulator. This paper describes two major regulatory initiatives to address the problem, which began in 2007 and 2013, and examines whether they have been sufficient to remove centrally unapproved systemic antibiotic FDCs from the market. Methods: Information was extracted from documents published by the central regulator and the ministry of health, including the National List of Essential Medicines (NLEM), and court judgments, and analysed alongside sales volume data for 2008–2020 using PharmaTrac market dataset. Results: The regulatory initiatives permitted 68 formulations to be given de facto approvals (‘No Objection Certificates’) outside the statutory regime, banned 46 FDCs and restricted one FDC. Market data show that FDCs as a proportion of total antibiotic sales increased from 32.9 in 2008 to 37.3% in 2020. The total number of antibiotic FDC formulations on the market fell from 574 (2008) to 395 (2020). Formulations with a record of prior central approval increased from 86 (2008) to 94 (2020) and their share of the antibiotic FDC sales increased from 32.0 to 55.3%. In 2020, an additional 23 formulations had been permitted de facto approval, accounting for 10.6% of the antibiotic FDC sales. Even in 2020, most marketed formulations (70.4%, 278/395) were unapproved or banned, and comprised a 15.9% share of the antibiotic FDC sales. The share of NLEM-listed antibiotic FDC sales increased from 21.2 (2008) to 26.7% (2020). Conclusion: The initiatives had limited impact. Regulatory enforcement has been slow and weak, with many unapproved, and even banned, FDCs remaining on the market

Embedded dynamic programming networks for networks-on-chip

PhD ThesisRelentless technology downscaling and recent technological advancements in three dimensional integrated circuit (3D-IC) provide a promising prospect to realize heterogeneous system-on-chip (SoC) and homogeneous chip multiprocessor (CMP) based on the networks-onchip (NoCs) paradigm with augmented scalability, modularity and performance. In many cases in such systems, scheduling and managing communication resources are the major design and implementation challenges instead of the computing resources. Past research efforts were mainly focused on complex design-time or simple heuristic run-time approaches to deal with the on-chip network resource management with only local or partial information about the network. This could yield poor communication resource utilizations and amortize the benefits of the emerging technologies and design methods. Thus, the provision for efficient run-time resource management in large-scale on-chip systems becomes critical. This thesis proposes a design methodology for a novel run-time resource management infrastructure that can be realized efficiently using a distributed architecture, which closely couples with the distributed NoC infrastructure. The proposed infrastructure exploits the global information and status of the network to optimize and manage the on-chip communication resources at run-time. There are four major contributions in this thesis. First, it presents a novel deadlock detection method that utilizes run-time transitive closure (TC) computation to discover the existence of deadlock-equivalence sets, which imply loops of requests in NoCs. This detection scheme, TC-network, guarantees the discovery of all true-deadlocks without false alarms in contrast to state-of-the-art approximation and heuristic approaches. Second, it investigates the advantages of implementing future on-chip systems using three dimensional (3D) integration and presents the design, fabrication and testing results of a TC-network implemented in a fully stacked three-layer 3D architecture using a through-silicon via (TSV) complementary metal-oxide semiconductor (CMOS) technology. Testing results demonstrate the effectiveness of such a TC-network for deadlock detection with minimal computational delay in a large-scale network. Third, it introduces an adaptive strategy to effectively diffuse heat throughout the three dimensional network-on-chip (3D-NoC) geometry. This strategy employs a dynamic programming technique to select and optimize the direction of data manoeuvre in NoC. It leads to a tool, which is based on the accurate HotSpot thermal model and SystemC cycle accurate model, to simulate the thermal system and evaluate the proposed approach. Fourth, it presents a new dynamic programming-based run-time thermal management (DPRTM) system, including reactive and proactive schemes, to effectively diffuse heat throughout NoC-based CMPs by routing packets through the coolest paths, when the temperature does not exceed chip’s thermal limit. When the thermal limit is exceeded, throttling is employed to mitigate heat in the chip and DPRTM changes its course to avoid throttled paths and to minimize the impact of throttling on chip performance. This thesis enables a new avenue to explore a novel run-time resource management infrastructure for NoCs, in which new methodologies and concepts are proposed to enhance the on-chip networks for future large-scale 3D integration.Iraqi Ministry of Higher Education and Scientific Research (MOHESR)

Regulatory enforcement of the marketing of fixed-dose combinations in India: a case study of systemic antibiotics

Background: In India, states have licensed the manufacture of large numbers of fixed-dose combination (FDC) drugs without the required prior approval of the central regulator. This paper describes two major regulatory initiatives to address the problem, which began in 2007 and 2013, and examines whether they have been sufficient to remove centrally unapproved systemic antibiotic FDCs from the market. Methods: Information was extracted from documents published by the central regulator and the ministry of health, including the National List of Essential Medicines (NLEM), and court judgments, and analysed alongside sales volume data for 2008–2020 using PharmaTrac market dataset. Results: The regulatory initiatives permitted 68 formulations to be given de facto approvals (‘No Objection Certificates’) outside the statutory regime, banned 46 FDCs and restricted one FDC. Market data show that FDCs as a proportion of total antibiotic sales increased from 32.9 in 2008 to 37.3% in 2020. The total number of antibiotic FDC formulations on the market fell from 574 (2008) to 395 (2020). Formulations with a record of prior central approval increased from 86 (2008) to 94 (2020) and their share of the antibiotic FDC sales increased from 32.0 to 55.3%. In 2020, an additional 23 formulations had been permitted de facto approval, accounting for 10.6% of the antibiotic FDC sales. Even in 2020, most marketed formulations (70.4%, 278/395) were unapproved or banned, and comprised a 15.9% share of the antibiotic FDC sales. The share of NLEM-listed antibiotic FDC sales increased from 21.2 (2008) to 26.7% (2020). Conclusion: The initiatives had limited impact. Regulatory enforcement has been slow and weak, with many unapproved, and even banned, FDCs remaining on the market

Towards a functional petroleum industry in Nigeria :a critical analysis of Nigeria's petroleum industry reform

PhD ThesisThis thesis seeks to enquire into the role of law in the reform programme for the Nigerian petroleum industry (NPI), in order to determine the extent to which it can be utilised to actualise a functional petroleum industry. The thesis will seek to test the hypothesis that an effectively managed petroleum industry will be efficiently regulated, have a significant local content, and will invariably be dependent on how sustainable and efficient petroleum revenues are distributed. My significant contribution to knowledge is that Nigeria should seek to develop local content and industry regulation, and aim to effectively distribute petroleum revenues, by pursuing industry reforms as an integrated whole. To that extent, it would require a coherent legal framework, and the development of policies that recognise the interconnectedness and interdependency of several factors in the petroleum industry. To that extent, a suitable and strategic legal architecture should be erected in Nigeria: one that will give room for co-operation without stifling independence and innovation. This thesis also notes that the development of a viable National oil company is imperative and should be anchored around which other industry reforms should revolve. Such a firm should however be privatised in a manner that guarantees its performance and promotes good corporate governance, whilst limiting avenues for external interference. It advocates that Nigeria should seek a national oil company model that is deliberately tailored to restrain ‘external interference’ in the daily workings of the NOC. Finally, this thesis argues that for an efficient regulation and management of the industry will require the active participation of all actors in the industry, and that the government should not have prerogative over the industry, especially in the light of past failures to effectively turn the industry around. There should thus be a deliberate effort to restrain government interference in the NOC, empower citizens in regulation and encourage the development of indigenous petroleum exploration and production companies (PEPCs), while in utilization of petroleum resources; there should be direct citizenship participation.ETF Scholarship, University of Ibadan, Nigeria

Physical parameter-aware Networks-on-Chip design

PhD ThesisNetworks-on-Chip (NoCs) have been proposed as a scalable, reliable and power-efficient communication fabric for chip multiprocessors (CMPs) and multiprocessor systems-on-chip (MPSoCs). NoCs determine both the performance and the reliability of such systems, with a significant power demand that is expected to increase due to developments in both technology and architecture. In terms of architecture, an important trend in many-core systems architecture is to increase the number of cores on a chip while reducing their individual complexity. This trend increases communication power relative to computation power. Moreover, technology-wise, power-hungry wires are dominating logic as power consumers as technology scales down. For these reasons, the design of future very large scale integration (VLSI) systems is moving from being computation-centric to communication-centric. On the other hand, chip’s physical parameters integrity, especially power and thermal integrity, is crucial for reliable VLSI systems. However, guaranteeing this integrity is becoming increasingly difficult with the higher scale of integration due to increased power density and operating frequencies that result in continuously increasing temperature and voltage drops in the chip. This is a challenge that may prevent further shrinking of devices. Thus, tackling the challenge of power and thermal integrity of future many-core systems at only one level of abstraction, the chip and package design for example, is no longer sufficient to ensure the integrity of physical parameters. New designtime and run-time strategies may need to work together at different levels of abstraction, such as package, application, network, to provide the required physical parameter integrity for these large systems. This necessitates strategies that work at the level of the on-chip network with its rising power budget. This thesis proposes models, techniques and architectures to improve power and thermal integrity of Network-on-Chip (NoC)-based many-core systems. The thesis is composed of two major parts: i) minimization and modelling of power supply variations to improve power integrity; and ii) dynamic thermal adaptation to improve thermal integrity. This thesis makes four major contributions. The first is a computational model of on-chip power supply variations in NoCs. The proposed model embeds a power delivery model, an NoC activity simulator and a power model. The model is verified with SPICE simulation and employed to analyse power supply variations in synthetic and real NoC workloads. Novel observations regarding power supply noise correlation with different traffic patterns and routing algorithms are found. The second is a new application mapping strategy aiming vii to minimize power supply noise in NoCs. This is achieved by defining a new metric, switching activity density, and employing a force-based objective function that results in minimizing switching density. Significant reductions in power supply noise (PSN) are achieved with a low energy penalty. This reduction in PSN also results in a better link timing accuracy. The third contribution is a new dynamic thermal-adaptive routing strategy to effectively diffuse heat from the NoC-based threedimensional (3D) CMPs, using a dynamic programming (DP)-based distributed control architecture. Moreover, a new approach for efficient extension of two-dimensional (2D) partially-adaptive routing algorithms to 3D is presented. This approach improves three-dimensional networkon- chip (3D NoC) routing adaptivity while ensuring deadlock-freeness. Finally, the proposed thermal-adaptive routing is implemented in field-programmable gate array (FPGA), and implementation challenges, for both thermal sensing and the dynamic control architecture are addressed. The proposed routing implementation is evaluated in terms of both functionality and performance. The methodologies and architectures proposed in this thesis open a new direction for improving the power and thermal integrity of future NoC-based 2D and 3D many-core architectures

Issues in public information systems development: The impact of regionalised organisational structure

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel UniversityThis thesis highlights the critical impact the effects of regionalised organisational structure and external political pressures have on the development of public sector information systems. Through the extension of a socio-technical systems (STS) model which encompasses these effects, a tool is provided for their investigation and evaluation in past and present information system (IS) developments. The foundations for this model were derived through an in-depth study of a large scale, national public IS development. Despite a large volume of research into the development and implementation of information systems, a high incidence of failure of such projects is still observed. With information systems now commonly integrated into many facets of an organisation’s business processes the costs and consequences of such failures can be far reaching. Given the additional scope and scale of many national public sector projects such consequences can be profound. While public sector IS failure has been studied in the literature, its focus is observed to be primarily that of an examination of e-government systems, neglecting the back-end (non-public facing) support systems. The focus of such studies is predominantly on the public’s interface and interaction with these systems together with their adoption and acceptance by the public. This view is a valid contribution but it does not inform the literature on the full range of unique problems that can be encountered across a complete IS development lifecycle within the public sector. Seeking to investigate these matters further, a collaboration was formed with a UK public body to facilitate the examination of the issues affecting the development and implementation of a national IS project. Onsite observations, interviews and document sampling were used across the development cycle to gather information from the perspectives of the stakeholders involved. The analysis of the data collected from this exercise highlighted a number of factors that were observed to have a significant effect on the project’s ultimate failure. Examination of this analysis from an STS perspective allowed for the extension of an existing STS model. It was extended to encompass the significant adverse effects that an organisational regionalised structure and external political pressure placed on the development of public information systems

Study on corrosion protection of organic coatings using electrochemical techniques: developing electrochemical noise method, effective of surface preparation and inhomogeneity of organic coatings

This study looks into two important aspects of corrosion protection of steel by organic coatings, steel surface preparation and ionic conduction through the coating, as well as development of the electrochemical noise method as an effective assessment method. Surprising and somehow controversial previous findings at the University of Northampton showed an inverse relationship between the roughness of metal substrate and performance of paint coating. So this study was initially launched to further study the effect of metal surface preparation. Four conventional surface preparation methods including ultra high pressure (UHP) hydroblasting, wet abrasive blasting, acid pickling and emery abrasion were studied and compared to an as received control surface. A particular interest of this work was the high demand for an environmentally friendly surface preparation method, e.g. as afforded by UHP hydroblasting, to replace the traditional wet abrasive blasting method. Results of this study revealed the important role of the innate native oxide film and the deleterious effect of contaminants on the protective performance of organic coating. Also it was shown that a highly active surface and large surface profile can be deleterious if an appropriate interaction between paint and metal is not achieved. Results of this study confirmed the earlier findings and suggested the UHP hydroblasting is a successful, cost effective and environmentally friendly surface preparation method and a modern replacement for wet abrasive blasting method. In addition to the effectiveness of metal surface preparation, the ability of organic coating in preventing ions access to metal plays an equally important role in defining the anti-corrosion performance of a coated metal. Hence the mechanism of ionic conduction through organic coatings and their inhomogeneity which are normally formed in crosslinking systems was extensively studied with the aim of finding the cause of formation of the more permeable areas and the ways by which they can be prevented. Several structural and environmental parameters were examined including the coating thickness, multi-layer paint application, curing temperature, partially non-functional resin, pigmentation and solvent. Experimental results showed that the solvent degree to which can escape, the non-functional polymer parts and inherently hydrophilic functional groups of organic coatings are the main parameters causing inhomogeneity and highly ion permeable areas. A statistical model was also developed that can be used to estimate number of permeable areas or corrosion initiation sites in a large area of coating. A particular concern of this work throughout the entire study was development of the electrochemical noise measurement (ENM) in the sense of a good assessing technique for protection efficiency of a coating system. Previous studies have shown great potential of ENM as a practical technique in the field. However, the technique always involved measuring the electrochemical noise between two or three isolated electrodes which cannot be easily provided in certain applications such as submerged structures or inside storage tanks. Also involvement of two or three electrodes in the measurement induces an ambiguity in regards to which electrode dominates the result. Here an attempt was made to perform the noise measurement on a single working electrode so that it can be used in more practical situations. Preliminary results indicate this approach holds promise

Communication Reliability in Network on Chip Designs

The performance of low latency Network on Chip (NoC) architectures, which incorporate fast bypass paths to reduce communication latency, is limited by crosstalk induced skewing of signal transitions on link wires. As a result of crosstalk interactions between wires, signal transitions belonging to the same flit or bit vector arrive at the destination at different times and are likely to violate setup and hold time constraints for the design. This thesis proposes a two-step technique: TransSync- RecSync, to dynamically eliminate packet errors resulting from inter-bit-line transition skew. The proposed approach adds minimally to router complexity and involves no wire overhead. The actual throughput of NoC designs with asynchronous bypass designs is evaluated and the benefits of augmenting such schemes with the proposed design are studied. The TransSync, TransSync-2-lines and RecSync schemes described here are found to improve the average communication latency by 26%, 20% and 38% respectively in a 7X7 mesh NoC with asynchronous bypass channel. This work also evaluates the bit-error ratio (BER) performance of several existing crosstalk avoidance and error correcting schemes and compares them to that of the proposed schemes. Both TransSync and RecSync scheme are dynamic in nature and can be switched on and off on-the-fly. The proposed schemes can therefore be employed to impart unequal error protection (UEP) against intra-flit skewing on NoC links. In the UEP, a larger fraction of the energy budget is spent in providing protection to those parts of the data being transmitted on the link which have a higher priority, while expending smaller effort in protecting relatively less important parts of the data. This allows us to achieve the prescribed level of performance with lower levels of power. The benefits of the presented technique are illustrated using an H.264 video decoder system-on-chip (SoC) employing NoC architecture. We show that for Akyio test streams transmitted over 3mm long link wires, the power consumption can be reduced by as much as 20% at the cost of an acceptable degradation in average peak signal to noise ratio (PSNR) with UEP

Design and application of reconfigurable circuits and systems

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