The "Coming of Age" of Real-World Evidence in Drug Development and Regulation.

Real world evidence (RWE) has the potential to inform drug discovery, development, and regulatory decision making. The emergence and availability of large population-based datasets around the globe have stoked enthusiasm in the research community. However, much work remains to refine research methodologies, evolve the science, and define the place of RWE as a complementary source of evidence to randomized controlled trials.

The impact of proposed regulatory changes and rescheduling on low-dose codeine purchasing in Canada: a time-series analysis.

BACKGROUND: Low-dose codeine products can be purchased without a prescription in most of Canada. We explored trends in the purchasing of these products across the Canadian provinces from 2014 to 2019, evaluating the impact of Health Canada's 2016 announcement of a proposed regulatory change and the 2017 opening of a 60-day public comment period, as well as the impact of Manitoba's 2016 policy change requiring a prescription for the purchase of all codeine products in that province. METHODS: We evaluated population-adjusted monthly purchasing of codeine products from January 2014 to October 2019 using the IQVIA Canadian Drug Store and Hospital Purchases Audit database, stratified by province and over-the-counter (OTC) status. The primary outcomes were change in the monthly volume of low-dose codeine purchased after the 2016 federal regulatory proposal and the 2017 period of public comment across the provinces. Our secondary analysis was the impact of Manitoba's policy change in February 2016 requiring a prescription for low-dose codeine. We conducted a time-series analysis using interventional autoregressive integrated moving average models. RESULTS: Over the study period, 24 120 kg of codeine (3.025 billion units) and 937 867 kg of acetaminophen were sold as OTC, low-dose codeine products across the Canadian provinces. Health Canada's 2016 announcement did not significantly affect OTC codeine purchasing (p = 0.57). The initiation of a 60-day public comment period was associated with a roughly 44% decrease in OTC codeine purchasing (p = 0.03). In Manitoba, purchasing of the same codeine formulations decreased after rescheduling in February 2016 (p < 0.001). We observed no significant change in the rate of purchasing of higher dose codeine formulations in response to scheduling changes in Manitoba (p = 0.22). INTERPRETATION: Although Health Canada's 2016 announcement of a proposed regulatory change did not appear to have an effect on OTC codeine purchasing nationally, the 60-day comment period was associated with a decrease in purchasing. Further, Manitoba's 2016 policy change was associated with a significant and sustained decrease in the overall volume of codeine purchased. Given the potential risks of codeine dependence and acetaminophen toxicity with these products, a national rescheduling strategy should be considered.

Mechanisms underlying drug-mediated regulation of membrane protein function.

The hydrophobic coupling between membrane proteins and their host lipid bilayer provides a mechanism by which bilayer-modifying drugs may alter protein function. Drug regulation of membrane protein function thus may be mediated by both direct interactions with the protein and drug-induced alterations of bilayer properties, in which the latter will alter the energetics of protein conformational changes. To tease apart these mechanisms, we examine how the prototypical, proton-gated bacterial potassium channel KcsA is regulated by bilayer-modifying drugs using a fluorescence-based approach to quantify changes in both KcsA function and lipid bilayer properties (using gramicidin channels as probes). All tested drugs inhibited KcsA activity, and the changes in the different gating steps varied with bilayer thickness, suggesting a coupling to the bilayer. Examining the correlations between changes in KcsA gating steps and bilayer properties reveals that drug-induced regulation of membrane protein function indeed involves bilayer-mediated mechanisms. Both direct, either specific or nonspecific, binding and bilayer-mediated mechanisms therefore are likely to be important whenever there is overlap between the concentration ranges at which a drug alters membrane protein function and bilayer properties. Because changes in bilayer properties will impact many diverse membrane proteins, they may cause indiscriminate changes in protein function.

Tobacco Control Strategies Enrich the National Strategic Plan on Prevention and Control of Cancer in Sri Lanka.

The National Cancer Control Programme Sri Lanka is the main government organization and focal point for coordinating the national response to prevention and control of cancer activities. Present National strategic plan on Cancer Prevention and Control (2020-2024) was developed by multi-sectoral expert groups. The present strategy derives its mandate from the overarching National policy documents including the NATA Act. Strategic objectives one and two of the National Strategic Plan identified the tobacco control measures. Several databases were searched to find out the relevant literature relevant to tobacco control strategies in Sri Lanka and the rest was collected from the university libraries, experts, and key persons in the field from the legal, and health sectors. It was identified more than 200 documents relevant to tobacco control. Strong legal legislations are available for measures to reduce the demand for tobacco products. Those are Protection from exposure to tobacco smoke, regulation of the contents of tobacco products, regulation of tobacco product disclosures, packaging and labeling of tobacco products, tobacco advertising, promotion and sponsorship, licit trade in tobacco products, sales to under 21, Provision of support for economically viable alternative activities. These legislations are covering by the NATA act. New formula for tobacco taxation was submitted to the Ministry of Health. Conclusion: Strong tobacco controlling laws and legislations are available in Sri Lanka that supports achieving one and two of the strategic objectives of the National strategic plan on cancer prevention and control in Sri Lanka. Policies are needed to regularize the increased tax rates to adjust for inflation and Gross Domestic Product. WHO has categorized Sri Lanka as one of the countries which can likely achieve a decrease in tobacco smoking prevalence (30%) by 2025.

Implementation of MPOWER Package in the South-East Asia Region: Evidence from the WHO Report on the Global Tobacco Epidemic (2009-2021).

The WHO MPOWER package is a set of six evidence-based and cost-effective measures which was introduced on 7 February 2008 to facilitate the implementation of the provisions of the WHO Framework Convention on Tobacco Control at the ground level. These measures are: Monitoring tobacco use and prevention policies (M); Protecting people from tobacco smoke (P); Offering help to quit tobacco use (O); Warning about the dangers of tobacco (W); Enforcing bans on tobacco advertising, promotion and sponsorship (E); and Raising taxes on tobacco (R). Since its launch, the MPOWER package has become the guiding principle for all the countries of the South-East Asia Region in their crusade against the tobacco epidemic. This review article tracks the implementation of the MPOWER measures in the 11 member countries of the Region based on the last seven WHO Report on the Global Tobacco Epidemic (GTCR), i.e., GTCR2/2009-GTCR8/2021. This is with an aim to enable the countries to review their progress in implementing the MPOWER measures and to take steps to improve their advancement towards reducing the demand for tobacco products at the country level.

[NMR Study of the Discrimination of Enantiomers of Methamphetamine and Its Raw Materials Using Chiral Solvating Agents].

Some controlled substances, such as stimulants and narcotics, have asymmetric carbons in their molecules. Because the enantiomers do not always show the same pharmacological effects, and there are substances with different controls due to differences in their stereochemistry, a simple and unambiguous method for assessment of the composition of enantiomers is necessary. In this study, to develop a simple and rapid stereoscopic identification method for methamphetamine and its raw materials (ephedrine and pseudoephedrine), the 1H-NMR method was studied using three commercially available chiral solvating agents (CSAs); 1,1'-bi(2-naphthol)(BINOL), 2,2,2-trifluoro-1-(9-anthryl)ethanol (TFAE) and α-methoxy-α-(trifluoromethyl)phenylacetic acid (MTPA). In addition, the accuracy of the optical purity, which was measured using samples mixed with enantiomers in various ratios, was investigated. The NMR peaks of the enantiomers were separated by adding (R)- or (S)-form of BINOL, TFAE or MTPA to the chloroform-d solution of methamphetamine, ephedrine or pseudoephedrine. A sufficient discrimination of enantiomers was obtained by adding about 10 equal amounts of each CSA to the solutions. With regard to the optical purity, it was possible to determine accurately the mixing of small amounts of enantiomers of about 5% even if the NMR peaks did not reach the baseline separation, when impurity peaks do not overlap. This method will be one of the useful techniques for the rapid and simple discrimination of enantiomers of illegal methamphetamine and its raw materials.

Civil society involvement in harm reduction drug policy: reflections on the past, expectations for the future.

BACKGROUND: A range of civil society organisations (CSOs) such as drug user groups, non-governmental/third sector organisations and networks of existing organisations, seek to shape the development of drugs policy at national and international levels. However, their capacity to do so is shaped by the contexts in which they operate nationally and internationally. The aim of this paper is to explore the lived experience of civil society participation in these contexts, both from the perspective of CSOs engaged in harm reduction advocacy, and the institutions they engage with, in order to inform future policy development. METHODS: This paper is based on the presentations and discussions from a workshop on 'Civil Society Involvement in Drug Policy hosted by the Correlation - European Harm Reduction Network at the International Society for the Study of Drugs Policy (ISSDP) annual conference in Paris, 2019. In the aftermath of the workshop, the authors analysed the papers and discussions and identified the key themes arising to inform CSI in developing future harm reduction policy and practice. RESULTS: Civil society involvement (CSI) in policy decision-making and implementation is acknowledged as an important benefit to representative democracy. Yet, the accounts of CSOs demonstrate the challenges they experience in seeking to shape the contested field of drug policy. Negotiating the complex workings of political institutions, often in adversarial and heavily bureaucratic environments, proved difficult. Nonetheless, an increase in structures which formalised and resourced CSI enabled more meaningful participation at different levels and at different stages of policy making. CONCLUSIONS: Civil society spaces are colonised by a broad range of civil society actors lobbying from different ideological standpoints including those advocating for a 'drug free world' and those advocating for harm reduction. In these competitive arena, it may be difficult for harm reduction orientated CSOs to influence the policy process. However, the current COVID-19 public health crisis clearly demonstrates the benefits of partnership between CSOs and political institutions to address the harm reduction needs of people who use drugs. The lessons drawn from our workshop serve to inform all partners on this pathway.

Initial development of a brief assessment of cocaine demand.

Cocaine demand is a behavioral economic measure assessing drug reward value and motivation to use drug. The purpose of the current study was to develop a brief assessment of cocaine demand (BACD). Results from the BACD were compared with self-report measures of cocaine use. Participants consisted of treatment-seeking individuals with cocaine use disorder (N = 22). Results revealed that indices of brief demand were significantly associated with various self-report measures of cocaine use. Overall, these results support the utility of a BACD for assessing cocaine demand.

From Pharmacology Research, to Pharmacology Regulation, and Back-as Inspired by the Teachings of Dr. Gavril Pasternak.

Dr. Gavril Pasternak, M.D., Ph.D. was an inspiration to many of his students, including myself. It was with great sadness that I learned about the passing of Dr. Gavril Pasternak in February 2019 after his brief battle with pancreatic cancer. I worked with Dr. Pasternak while I was an undergraduate chemistry student and as one of his technicians, collaborating with Dr. Charles Inturrisi and Dr. Eliot F. Hahn on opiate agonists and antagonists for opioid receptor subtypes. Dr. Pasternak inspired me and set me on the road to a career in pharmacology and encouraged me to pursue the fruitful paradigm of moving therapeutics from bench to bedside.

Public Workshop Summary Report on Fiscal Year 2021 Generic Drug Regulatory Science Initiatives: Data Analysis and Model-Based Bioequivalence.

On May 4, 2020, the US Food and Drug Administration (FDA) hosted an online public workshop titled "FY 2020 Generic Drug Regulatory Science Initiatives Public Workshop" to provide an overview of the status of the science and research priorities and to solicit input on the development of Generic Drug User Fee Amendments fiscal year 2021 priorities. This report summarizes the podium presentations and the outcome of discussions along with innovative ways to overcome challenges and significant opportunities related to model-based approaches in bioequivalence assessment for breakout session 4 titled, "Data analysis and model-based bioequivalence (BE)." This session focused on the application of model-based approaches in the generic drug development, with a vision of accelerating regulatory decision making for abbreviated new drug application assessments. The session included both podium presentations and panel discussions with three topics of interest: (i) in vitro study evaluation methods and their clinical relevance, (ii) challenges in model-based BE, (iii) emerging expertise and tools in implementing new BE approaches.

Considerations from the Innovation and Quality Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Guidelines on Model Fitting and Recommendations on Time Course for In Vitro Cytochrome P450 Induction Studies Including Impact on Drug Interaction Risk Assessment.

Translational and ADME Sciences Leadership Group Induction Working Group (IWG) presents an analysis on the time course for cytochrome P450 induction in primary human hepatocytes. Induction of CYP1A2, CYP2B6, and CYP3A4 was evaluated by seven IWG laboratories after incubation with prototypical inducers (omeprazole, phenobarbital, rifampicin, or efavirenz) for 6-72 hours. The effect of incubation duration and model-fitting approaches on induction parameters (Emax and EC50) and drug-drug interaction (DDI) risk assessment was determined. Despite variability in induction response across hepatocyte donors, the following recommendations are proposed: 1) 48 hours should be the primary time point for in vitro assessment of induction based on mRNA level or activity, with no further benefit from 72 hours; 2) when using mRNA, 24-hour incubations provide reliable assessment of induction and DDI risk; 3) if validated using prototypical inducers (>10-fold induction), 12-hour incubations may provide an estimate of induction potential, including characterization as negative if <2-fold induction of mRNA and no concentration dependence; 4) atypical dose-response ("bell-shaped") curves can be addressed by removing points outside an established confidence interval and %CV; 5) when maximum fold induction is well defined, the choice of nonlinear regression model has limited impact on estimated induction parameters; 6) when the maximum fold induction is not well defined, conservative DDI risk assessment can be obtained using sigmoidal three-parameter fit or constraining logistic three- or four-parameter fits to the maximum observed fold induction; 7) preliminary data suggest initial slope of the fold induction curve can be used to estimate Emax/EC50 and for induction risk assessment. SIGNIFICANCE STATEMENT: Regulatory agencies provide inconsistent guidance on the optimum length of time to evaluate cytochrome P450 induction in human hepatocytes, with EMA recommending 72 hours and FDA suggesting 48-72 hours. The Induction Working Group analyzed a large data set generated by seven member companies and determined that induction response and drug-drug risk assessment determined after 48-hour incubations were representative of 72-hour incubations. Additional recommendations are provided on model-fitting techniques for induction parameter estimation and addressing atypical concentration-response curves.

Análisis del cumplimiento del plan de consumo de los medicamentos de alto costo. Matanzas. 2012-2017 / Analysis of the fulfillment of the consumption plan of high cost medications. Matanzas. 2012 - 2017

RESUMEN Introducción: los medicamentos de alto costo son medicamentos nuevos, altamente específicos y utilizados en condiciones clínicas complejas, como el tratamiento de algunos tipos de cáncer; enfermedades que comprometen el sistema inmunológico, enfermedades inflamatorias o infecciosas. Objetivo: determinar cumplimiento del plan de consumo de los medicamentos de alto costo en la provincia de Matanzas, en el quinquenio 2012-2017. Materiales y métodos: estudio descriptivo, observacional de seguimiento sobre el cumplimiento del plan de consumo de los medicamentos de alto costo, en la población matancera del año 2012 al 2017. Se analizó el universo de medicamentos incluidos en esta categoría, a partir de la base de datos de suministro de medicamentos que emplea la Empresa Comercializadora de Medicamentos. Se identificaron las variables estudiadas. Resultados: en todo el período de estudio se observó un incremento creciente de los medicamentos de alto costo, en el 88,9 % de ellos el consumo ha estado por encima de la planificación realizada por la provincia. Los costos se incrementaron en un 233 % y además en las prescripciones realizadas de estos productos, se encontraron problemas como escaques vacíos, antibióticos sin impresión diagnóstica y omisión de la forma de presentación del medicamento y/o dosis indicada. Conclusiones: el consumo de muchos medicamentos de alto costo fue mayor que la planificación realizada en la provincia de Matanzas, durante el período analizado. Implicó un incremento significativo del presupuesto destinado a estos fines y se detectaron dificultades en el cumplimiento de lo establecido en las prescripciones de dichos medicamentos (AU).

ABSTRACT Introduction: high cost medications (HCM) are new highly specific medications and used in complex clinical conditions as in treatment of some types of cancer, diseases that compromise the immunological system, inflammatory or infections disorders. Objective: to determine the fulfillment of the consumption plan of high-cost medications in the province of Matanzas in the period 2012-2017. Materials and methods: a descriptive, observational, follow up study on the fulfillment of the consumption plan of high-cost medication by the population of Matanzas2012 year to 2017. The universe of drugs included in this category was analyzed on the bases of the drug-supplying database used by the Drug Commercializing Enterprise (ENCOMED in Spanish). The studied variables were identified. Results: it was observed a growing increase of high-cost drugs use during all the period; in 88.9 % of them the consumption has been above the planning made in the province. The costs increased in 233 %, and besides that in the prescriptions made of these drugs there were found problems like empty boxes, antibiotics without diagnostic impression and omissions of the drug presentation forms and/or the prescribed doses. Conclusions: the consumption of many high-cost drugs was higher than the planning made in the province of Matanzas for the analyzed period. It implied a significant increase of the budget destined for these aims and difficulties were found in the fulfillment of the terms for prescribing these drugs (AU).

Regulatory post-market drug safety advisories on cardiac harm: A comparison of four national regulatory agencies.

Information on rare adverse effects is often limited when a medication is initially approved for marketing. Medicines regulators use safety advisories to warn health professionals and consumers about emerging harms. This study aimed to identify characteristics and advice provided in cardiac safety advisories released by regulators in Australia, Canada, the United Kingdom, and the United States. This was a retrospective study of safety advisories about cardiac-related adverse events issued by these four international medicines regulators between 2010 and 2016. A descriptive overview was followed by a more detailed content analysis, focusing on recommended actions for health professionals, including monitoring advice. For the latter, we applied the systematic information for monitoring (SIM) scale to assess adequacy. Over this period, 164 safety advisories about cardiac harms were issued by the four regulators. There were 61 drugs with advisories of cardiac risk, only 9 (14.7%) of which had advisories from all regulators in countries where the drug was approved. The most common adverse events were cardiac arrhythmias (n = 97, 59.1%) and coronary artery disorders (n = 39, 23.8%). The most frequent advice to prescribers was to monitor patients (n = 74, 45.1%), although only 41.2% of these advisories provided detailed advice on how monitoring should occur. We found many differences in the decision to warn and the advice provided. Patient monitoring was most often recommended, but key information such as frequency or thresholds for action was often lacking. Healthcare professionals and consumers need consistent information about rare serious harms so that they can make informed decisions.

Rapid qualitative evidence syntheses (rQES) in health technology assessment: experiences, challenges, and lessons.

Healthcare decision makers are increasingly demanding that health technology assessment (HTA) is patient focused, and considers data about patients' perspectives on and experiences with health technologies in their everyday lives. Related data are typically generated through qualitative research, and in HTA the typical approach is to synthesize primary qualitative research through the conduct of qualitative evidence synthesis (QES). Abbreviated HTA timelines often do not allow for the full 6-12 months it may take to complete a QES, which has prompted the Canadian Agency for Drugs and Technologies in Health (CADTH) to explore the concept of "rapid qualitative evidence synthesis" (rQES). In this paper, we describe our experiences conducting three rQES at CADTH, and reflect on challenges faced, successes, and lessons learned. Given limited methodological guidance to guide this work, our aim is to provide insight for researchers who may contemplate rQES. We suggest several lessons, including strategies to iteratively develop research questions and search for eligible studies, use search of filters and limits, and use of a single reviewer experienced in qualitative research throughout the review process. We acknowledge that there is room for debate, though believe rQES is a laudable goal and that it is possible to produce a quality, relevant, and useful product, even under restricted timelines. That said, it is vital to recognize what is lost in the name of rapidity. We intend our paper to advance the necessary debate about when rQES may be appropriate, and not, and enable productive discussions around methodological development.