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Background: Drug shortages represent a growing global problem, with potentially serious consequences to patients and the health care system. Our study investigates the impacts of a major recall and shortage of valsartan, an angiotensin receptor blocker (ARB), in July 2018 in Canada., Methods: We conducted a time-series analysis of antihypertensive drugs dispensed in Canada between 2015 and 2019 using commercially available retail prescription data. Using autoregressive integrated moving average (ARIMA) modelling, we evaluated the change in valsartan use after the recall. We also measured the overall use of ARBs, angiotensin-converting-enzyme (ACE) inhibitors and other antihypertensive drug classes for the same period., Results: After the recall in July 2018, valsartan use decreased 57.8%, from 362 231 prescriptions dispensed in June 2018 to 152 892 in September 2018 (difference = 209 339, p < 0.0001). Overall use of the ARB drug class decreased 2.0%, from 1 577 509 prescriptions dispensed in June 2018 to 1 545 591 in September 2018 (difference = 31 918, p = 0.0003), but use of non-valsartan ARBs increased 14.6%, from 1 215 278 to 1 392 699 prescriptions dispensed (difference = 177 421, p < 0.0001) in the same time frame. Although use of ACE inhibitors initially declined, this reduction was not sustained. The valsartan recall was not associated with a significant impact on use of other antihypertensive drug classes., Interpretation: Our findings illustrate the impact of a major drug shortage, with the immediate and substantial reduction of valsartan dispensed and cascading effects on other ARBs, though future research is warranted to understand the consequences of such extensive shortages on clinical outcomes and health system costs. Improved policy strategies are needed to address the underlying causes of drug shortages and to mitigate their effects., Competing Interests: Competing interests: None declared., (© 2021 CMA Joule Inc. or its licensors.)

The concept of going 'green' and 'cold' has led to utilizing renewable resources for the synthesis of microbial biosurfactants that are both patient and eco-friendly. In this review, we shed light on the potential and regulatory aspects of biosurfactants in pharmaceutical applications and how they can significantly contribute to novel concepts for the Coronavirus 2019 (COVID-19) vaccine and future treatment. We emphasize that more specific guidelines should be formulated to regulate the approval of biosurfactants for human use. It is also crucial to implement a risk-based approach from the early research and development (R&D) phase in addition to establishing more robust standardized techniques and assays to evaluate the characteristics of biosurfactants., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The purpose of this narrative review is to describe the current use environment of both natural and synthetic cannabinoids while providing context for cannabinoid chemistry and pharmacology. In addition to a long history of recreational and nonmedical use, natural cannabinoids are increasingly used as prescription products, through medical cannabis programs, and as consumer health products. Despite anecdotal safety evidence, cannabis and cannabinoids are pharmacologically complex and pose risks for adverse drug events and drug-drug interactions. Synthetic cannabinoids, particularly agonists of cannabinoid receptors, are more potent than natural cannabinoids and can lead to more severe reactions and medical emergencies. This review provides a summary of approved uses and an overview of mechanisms of action for adverse drug events with natural and synthetic cannabinoids. Clinical considerations for special populations that may be at heightened risk for drug-drug interactions and adverse drug events while using natural or synthetic cannabinoids are examined, and recommendations are provided., (© 2021, The American College of Clinical Pharmacology.)

Introduction : A survey was conducted among national regulatory authorities' members of the International Pharmaceutical Regulators Programme (IPRP) to collect and share experiences of reliance approaches. Reliance allows formally, or informally, one regulatory authority to use assessments made by other regulatory authorities while remaining responsible for the final decision. Reliance is an essential concept to increase the efficiency of the global regulatory oversight of medical products by national regulatory authorities. Areas covered : This article describes the findings and recommendations from the IPRP survey. It shows that reliance in the area of medical product oversight is broadly accepted. The first part presents the acceptance and reasons for accepting reliance including the need for trust, then gives examples of the most common areas for reliance, and explains the difference between unilateral or reciprocal reliance. Finally, the article analyzes the lessons learned including challenges and opportunities for reliance on regulatory authorities to facilitate patient access in their jurisdictions. Expert opinion : Regulatory reliance facilitates regulatory approvals and allows to use resources in a more efficient way and ultimately serves patients by facilitating earlier access to quality-assured, safe, and effective medicines.

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 (E max and EC 50 ) 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 E max /EC 50 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., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutic.)

Background: Track and trace systems are increasingly being implemented as a technological solution to secure pharmaceutical supply chains. Turkey was the first country to implement a full pharmaceutical track and trace system throughout the entire regulated domestic supply chain. This article explores the emergence and functioning of this system and the consequences for substandard and falsified medicine with a focus on the underlying political and economic factors., Methods: This study uses an explanatory case study approach that combined interviews with purposefully selected key informants and document analyses., Results: The main drivers for implementing the pharmaceutical track and trace system in Turkey centered on the elimination of reimbursement fraud and the prevention of falsified medicine in the regulated supply chain. Although stakeholders experienced both physical and software-related problems in implementation, the alignment of incentives of all stakeholders with the power of the state, along with leeway for adaptations, ultimately resulted in a successful process. This track and trace system provides a clean regulated supply chain, minimizes reimbursement fraud, facilitates fast market recalls, and can flag likely medicine shortages. Staff previously engaged in pharmacy inspections now concentrate on ensuring production quality, which reduces the risk of substandard medicines., Conclusions: In Turkey, 4 factors drove the successful implementation of pharmaceutical track and trace: the political determination to eliminate reimbursement fraud, a large pharmaceutical market dominated by a single payer, medicine reimbursement being contingent on verified dispensing and prescription, and flexibility to adapt the system according to the needs of stakeholders during implementation., (© Parmaksiz et al.)

Objectives: In the United States, rising rates of overdose deaths and recent outbreaks of hepatitis C virus and HIV infection are associated with injection drug use. We updated a 2014 review of systems-level opioid policy interventions by focusing on evidence published during 2014-2018 and new and expanded opioid policies., Methods: We searched the MEDLINE database, consistent with the 2014 review. We included articles that provided original empirical evidence on the effects of systems-level interventions on opioid use, overdose, or death; were from the United States or Canada; had a clear comparison group; and were published from January 1, 2014, through July 19, 2018. Two raters screened articles and extracted full-text data for qualitative synthesis of consistent or contradictory findings across studies. Given the rapidly evolving field, the review was supplemented with a search of additional articles through November 17, 2019, to assess consistency of more recent findings., Results: The keyword search yielded 535 studies, 66 of which met inclusion criteria. The most studied interventions were prescription drug monitoring programs (PDMPs) (59.1%), and the least studied interventions were clinical guideline changes (7.6%). The most common outcome was opioid use (77.3%). Few articles evaluated combination interventions (18.2%). Study findings included the following: PDMP effectiveness depends on policy design, with robust PDMPs needed for impact; health insurer and pharmacy benefit management strategies, pill-mill laws, pain clinic regulations, and patient/health care provider educational interventions reduced inappropriate prescribing; and marijuana laws led to a decrease in adverse opioid-related outcomes. Naloxone distribution programs were understudied, and evidence of their effectiveness was mixed. In the evidence published after our search's 4-year window, findings on opioid guidelines and education were consistent and findings for other policies differed., Conclusions: Although robust PDMPs and marijuana laws are promising, they do not target all outcomes, and multipronged interventions are needed. Future research should address marijuana laws, harm-reduction interventions, health insurer policies, patient/health care provider education, and the effects of simultaneous interventions on opioid-related outcomes.

Purpose: This article aims to analyse the key regulatory guidelines across the globe concerning biosimilars., Materials and Methods: Review of the current literature., Results: Biosimilars are well regulated with the majority of regulators having enforced the guidelines for the development and approval, and new biosimilar drugs are appearing on the horizon to provide a therapeutic option to a wider population base because of its cost-effectiveness and proven safety. Due to their extensive analytical data, clinical data and pharmacovigilance studies, their development should not be considered similar to generic drugs., Conclusion: This review discusses the biosimilars, their regulation globally and their difference from generics from ophthalmic perspective., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The current status of policies on illicit drugs has implications for Collective Health that need to be discussed in depth. This essay aims to explore, in light of the best evidence, the public health impact of drug policies focused on the criminalization of growing, selling, and consuming psychoactive substances. Brazil provides the context for the main analysis. The principal points addressed in this work include drugs as a social issue and the definition of the prohibitionist paradigm, evidence of the unhealthy relationship between this paradigm and the population's health, the issue of a model of care for users of psychoactive substances focused on therapeutic communities, and future paths to be explored to overcome the prohibition of illicit drugs as the principal approach to the issue. Among the main problematic elements in the repressive approach in the Brazilian context, the study highlights violence and homicides, the health impacts of incarceration and blocked access to the health system, and potential new therapies derived from currently banned psychoactive substances. As proposals for future policy changes, the study highlights decriminalization of the use, possession, and small-scale sale of drugs; the reduction of the violence and discrimination associated with policing; focus on harm reduction policies; approach to gender-related specificities; and inclusion of social variables as metrics for successful treatment of problematic drug use. In conclusion, it is relevant that the social issue and drug policy have become the object of more studies in the field of Collective Health.

Drug losses and theft from the healthcare system are accelerating; hospitals are pressured to implement safeguards to prevent drug diversion. Thus far, no reviews summarize all known risks and potential safeguards for hospital diversion. Past incidents of hospital drug diversion have impacted patient and staff safety, increased hospital costs, and resulted in infectious disease outbreaks. We searched MEDLINE, Embase, PsycINFO, CINAHL, Scopus, and Web of Science databases and the gray literature for articles published between January 2005 and June 2018. Articles were included if they focused on hospital settings and discussed either: (1) drug security or accounting practices (any drug) or (2) medication errors, healthcare worker substance use disorder, or incident reports (only with reference to controlled drugs). We included 312 articles and extracted four categories of data: (1) article characteristics (eg, author location), (2) article focus (eg, clinical areas discussed), (3) contributors to diversion (eg, factors enabling drug theft), and (4) diversion safeguards. Literature reveals a large number of contributors to drug diversion in all stages of the medication-use process. All health professions and clinical units are at risk. This review provides insights into known methods of diversion and the safeguards hospitals must consider to prevent them. Careful configuration of healthcare technologies and processes in the hospital environment can reduce the opportunity for diversion. These system-based strategies broaden the response to diversion beyond that of individual accountability. Further evidence is urgently needed to address the vulnerabilities outlined in this review and prevent harm.

The US Food and Drug Administration's Center for Drug Evaluation and Research (CDER) developed an investigational Public Health Assessment via Structural Evaluation (PHASE) methodology to provide a structure-based evaluation of a newly identified opioid's risk to public safety. PHASE utilizes molecular structure to predict biological function. First, a similarity metric quantifies the structural similarity of a new drug relative to drugs currently controlled in the Controlled Substances Act (CSA). Next, software predictions provide the primary and secondary biological targets of the new drug. Finally, molecular docking estimates the binding affinity at the identified biological targets. The multicomponent computational approach coupled with expert review provides a rapid, systematic evaluation of a new drug in the absence of in vitro or in vivo data. The information provided by PHASE has the potential to inform law enforcement agencies with vital information regarding newly emerging illicit opioids., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

This workshop report summarizes the presentations, the breakout session outcomes, and the speaker panel discussions from the PDA Biosimilars Workshop held September 27-28, 2018, in Washington, DC. This format was deliberately selected for the workshop with the expectation of delivering a post-workshop paper on current best practices and existing challenges for sponsors. The event, co-chaired by Dr. Stephan Krause (AstraZeneca Biologics) and Dr. Emanuela Lacana (CDER/FDA), was attended by 140 agency and industry representatives. The workshop was separated into three major sessions P1: Regulatory Perspective, P2: Challenges in Biosimilar Development, and P3: Demonstrating Analytical Similarity. Each of the three sessions started with agency and industry presentations. Participants then split into two concurrent roundtable discussion groups to hear the answers to questions that had been provided to all participants one week prior to the event. The sessions were recorded. This paper provides consolidated answers to specific case studies for current challenges to sponsors and agencies. In addition, the panel discussion notes following each breakout roundtable session, as well as brief talk summaries of all speakers, are provided. The first session explored the challenges encountered with submission of biosimilar marketing applications from the perspectives of regulatory agencies. Expectations for a successful submission of the chemistry, manufacturing, and controls (CMC) information were described. The second session addressed high-level technical challenges and how to avoid pitfalls frequently encountered during biosimilar candidate development, including data quality expectations, creation of the final control strategy, and strategic choices necessary for candidate selection and development. Both regulatory perspectives and industry experience were shared. The last session explored the use of statistical tools to provide meaningful contributions to the demonstration of analytical similarity. The presentations highlighted common issues and practical challenges that arise during the application of statistical tools. LAY ABSTRACT: Significant challenges are still-remaining for sponsors and agencies to successfully develop and license Biosimilars. A Biosimilars Workshop was therefore held on 27-28 September 2018 in Washington, DC, to find practical solutions to the remaining challenges. The workshop planning committee with members from industry and agencies prepared specific case studies focused on some of most difficult situations. The workshop was separated into three major sessions (P1 - Regulatory Perspective; P2 - Challenges in Biosimilar Development; P3 - Demonstrating Analytical Similarity) and each session attempted to provide practical solutions to the relevant case studies. This first session explored the challenges encountered with submission of biosimilar marketing applications from the regulatory agencies' perspectives. Expectations for a successful submission of the CMC information were described. The second session addressed high-level technical challenges frequently encountered during biosimilar candidate development, including data quality expectations, the creation of the final control strategy, and strategic choices necessary for candidate selection and development. The last session explored the use of statistical tools to provide meaningful contributions to the demonstration of analytical similarity and practical challenges that arise during the application of statistical tools., (© PDA, Inc. 2019.)

The general objective of this study was to identify and prioritize the critical success factors required for the adoption of a system to create value for pharmaceutical supply chain stakeholders, and the pharmaceutical supply network as a whole, by using a multi-perspective framework that combines elements of the technology-organization-environment (TOE) contexts for enterprises. The methodology is based on a literature review and expert interviews following the analytic hierarchy process (AHP). This paper identifies and prioritizes 18 critical success factors from three categories: technological, organizational, and environmental. From a practical point of view, this research contributes to the literature by providing expert insight on the topic of drug traceability, especially in terms of how possible values can be captured by companies.

Medical facilities in the United States are faced with the challenge of meeting the December 2019 requirements of U.S. Pharmacopeial Convention General Chapter <800> (USP <800>) Hazardous Drugs-Handling in Healthcare Settings. A 300-bed hospital in western Washington formed a practice improvement group to address the requirements of USP <800>. The development of a hazardous drug control program at the hospital not only met the requirements of USP <800> but also helped staff members understand what hazardous drugs are and the safety measures that are necessary when handling them.

Background: In Australia and elsewhere, the impacts of drug prohibition have sparked a critical dialogue about the state of current drug laws. While a range of 'experts' have offered their opinion and participation in these deliberations, the voices of the affected community have largely been excluded. This study aimed to gather the opinions and preferences of people who use drugs about the current or alternative models of drug laws, in addition to how they think drug laws could be changed Author Conflict of Interest Declaration., Methods: In March 2018, four focus groups (n = 37) were conducted with people who were in receipt of social welfare services in Sydney, Australia, where participants were encouraged to share their views about the current drug laws, drug law reform options, and important messages to politicians. Several themes were identified through a thematic analysis., Results: Models of drug law reform were often understood and expressed in language and constructs different to those commonly used by researchers. Opinions were diverse and there was no consensus on a preferred model, although discussions flowed around decriminalisation, legalisation, and a medical/prescription model; the latter being the preferred approach. Participants shared pessimistic views of the drug laws ever changing, and argued that public opinion would need to adjust for reform to succeed. Furthermore, they argued that the views of the affected community are vital to any drug law reform campaign., Conclusions: Participants affinity towards a medical/prescription approach to drug regulation was an unexpected finding. This study serves as an important example of the opinions and experiential knowledge of the affected community and this knowledge could be solicited alongside other forms of 'expertise' in drug law reform campaigns., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: "Lock-in" programs (LIPs) are used by health insurers to address potential substance (eg, opioid) misuse among beneficiaries. We sought to (1) examine heterogeneity in trajectories of dispensed opioids (in average daily morphine milligram equivalents (MMEs)) over time: prior to, during, and following release from a LIP, and (2) assess associations between trajectory patterns and beneficiary characteristics., Methods: Medicaid claims were linked to Prescription Drug Monitoring Program records for a cohort of beneficiaries enrolled in the North Carolina Medicaid LIP (n = 2701). Using latent class growth analyses, we estimated trajectories of average daily MMEs of opioids dispensed to beneficiaries across specific time periods of interest., Results: Five trajectory patterns appeared to sufficiently describe underlying heterogeneity. Starting values and slopes varied across the 5 trajectory groups, which followed these overall patterns: (1) start at a high level of MMEs, end at a high level of MMEs (13.1% of cohort); (2) start medium, end medium (13.2%); (3) start medium, end low (21.5%); (4) start low, end medium (22.6%); and (5) start low, end low (29.6%). We observed strong associations between patterns and beneficiaries' demographics, substance use-related characteristics, comorbid conditions, and healthcare utilization., Conclusions: In its current form, the Medicaid LIP appeared to have limited impact on beneficiaries' opioid trajectories. However, strong associations between trajectory patterns and beneficiary characteristics provide insight into potential LIP design modifications that might improve program impact (eg, LIP integration of substance use disorder assessment and referral to treatment, assessment and support for alternate pain therapies)., (© 2018 John Wiley & Sons, Ltd.)

In recent years, marketing of highly innovative and costly biologics improved the management of high-burden diseases such as autoimmune diseases, cancers, and chronic renal failure. Several widely prescribed biologics have recently lost or will shortly lose their patents, thus opening avenues to the marketing of a growing number of biosimilars worldwide, which are products similar in terms of quality, safety, and efficacy to already licensed reference products, thus allowing for potential savings in pharmaceutical expenditure. Numerous debates about the interchangeability between biosimilars and reference products are still ongoing, owing to concerns about potential immunogenicity raised by switching, which may cause a lack of effect and toxicity. Patients successfully treated with biologic therapy may theoretically receive biosimilars to contain costs, if reference product and related biosimilar are judged as interchangeable. However, the positions of regulatory agencies on the interchangeability and automatic substitution of biologics with biosimilars are very different. The benefit-risk profile of biosimilars has been often questioned by clinicians owing to the limited amount of pre-marketing information on clinical efficacy and safety, despite biosimilarity being based on a comparability exercise with the reference product to gain the biosimilar approval. Nevertheless, after more than 10 years of marketing from the first biosimilar approval in Europe, no proof of differences in terms of the safety profile of biosimilars and originators has been reported. In this context, post-marketing evaluation of both biologics and biosimilars safety profiles through analyses from spontaneous reporting databases and claims databases is crucial. An important issue for the pharmacovigilance of biologics concerns the traceability, indicating the brand name and batch number in spontaneous adverse drug reaction reports, but this requirement is not frequently addressed. This review aims to provide an overview of the characteristics and potential challenges in the safety profile assessment of biologics with a focus on the post-marketing setting.

The outcome of the first series of health claim applications for probiotics in Europe as evaluated by the European Food Safety Authority (EFSA) has, up to 2013 almost completely yielded negative results. All recent applications also have been rejected, including the latest on prevention of mastitis in breastfeeding mothers. In other developed countries, such as Switzerland, Japan and Canada, the health effects of probiotics, for which scientific evidence has been provided, can be communicated to potential consumers. The number of clinical trials with probiotics over recent years shows a trend to level off or even decline. At the same time, clinical research into the role of (gut) microbiota in a wide variety of diseases and conditions is booming. Ultimately, this may offer new indications for gut microbiota management by probiotics, prebiotics or other food supplements.

Background Rational drug use and drug safety are becoming increasingly important concerns in China with the increasing public access to drugs and the health-care system, and this has led to the development of pharmacovigilance in China. Aim of the review To provide a brief introduction about pharmacovigilance in China in terms of system development, utilization and challenges. Method Relevant studies on pharmacovigilance related to the study aim was undertaken through literature search to synthesize the extracted data. Results The creation and evolvement of China's pharmacovigilance system spans across 30 years since 1989. The system consists of four progressing administrative layers: county, municipal, provincial and national levels. China has passed over 20 laws and regulations related to pharmacovigilance covering the processes of drug development, manufacture, distribution and use with the aim to guard drug safety. An online spontaneous self-reporting Adverse Drug Reaction (ADR) Monitoring System was established in 2003. ADRs are mainly reported by medical institutions, pharmaceutical manufacturers, and drug distributors. Currently there is no mandatory ADR reporting requirement for pharmaceutical manufacturers, and a proposed regulation under public comment will likely change this. China has started to build active pharmacovigilance surveillance programs in addition to the passive ADR reporting system. The China Food and Drug Administration has established the intensive Safety Monitoring Program and the National Adverse Drug Reaction Monitoring Sentinel Alliance Program based on electronic health records to further the efforts of ADR reporting, monitoring and analysis. Conclusion The practice of ADR monitoring and pharmacovigilance in China have made great progress. More efforts are needed both in system building, and creation of laws and regulations to strengthen the safe use of medicines.

This study evaluated a newly developed paper analytical device (PAD) for screening amoxicillin samples in Blantyre urban townships. Covert shoppers attempted to buy amoxicillin from a geographically stratified selection of private pharmacies ( N = 22 out of 26) and drug stores ( N = 23 out of 103) in the township area. According to the PAD results, all 42 samples obtained by the shoppers contained amoxicillin and none contained suspicious filler materials. Next, the products were assayed using high-performance liquid chromatography. Consistent with the PAD results, all samples contained the correct amount of amoxicillin with no unexpected ingredients. However, one sample was purchased as amoxicillin and contained that ingredient, but was packaged in capsules that are normally used to package ampicillin. Almost every sample failed a simple packaging analysis. Nine in 10 samples were missing their original packaging and/or inserts (52.4% repackaged capsules and 35.7% repackaged blister packs). Only 33.3% of the packages had expiry dates, 16.7% had batch numbers, and 47.6% had the manufacturer's name. Dispensing practices were likewise unsatisfactory. Ninety-five percentage of the sellers sold the amoxicillin without a prescription, even though this medicine is regulated as prescription-only in Malawi. Although the chemical analysis showed that amoxicillin quality was good, our market survey revealed poor adherence to prescription-only medicine dispensing of antibiotics, which threatens antimicrobial stewardship efforts. Furthermore, the wide prevalence of repackaging deprives medicines of important information needed during patient's use, regulatory investigations, and pharmacovigilance reporting.

In the US, deaths from prescription opioids have quadrupled since 1999, prompting authorities to declare an "opioid abuse" crisis. Rising overdose deaths were attributed to trends in the overprescription of opioids, specifically the strength and duration of the initial prescription. We describe educational interventions designed to control healthcare professionals' (HCPs) opioid prescribing in the wake of this crisis. A review of relevant programs for practicing providers, medical residents, and medical students reveals a focus on educational interventions that we describe, borrowing from sociologist John McKinlay's metaphor for public health interventions, as "downstream." These downstream interventions concentrate on regulating and educating practicing HCPs rather than transforming the training environment for medical students and residents. We draw on theories of behavior change to call for the development of complementary "upstream" educational programs for future practitioners that focus on structural and psychosocial factors and may contribute to more sustainable behavior change outcomes., (© 2018 American Society for Clinical Pharmacology and Therapeutics.)

The United States has the ignominious distinction of leading the world in opioid prescribing, 1 and in opioid-related overdose deaths. The Centers for Disease Control (CDC) estimates that over 40,000 people died of an opioid-related overdose, with fentanyl-related deaths exceeding those of heroin or prescription opioids. 2 Opioid overdoses are now the leading cause of unintentional deaths in the US and of declining lifespan expectancies. 3 With a worsening crisis, agencies of the US government and others produced an array of reports on the opioid crisis. Yet the death rate escalated further from 2010 to the present., (© 2018 American Society for Clinical Pharmacology and Therapeutics.)

Our nation's ongoing prescription opioid abuse crisis, amounting to over 78 billion dollars in health and social costs annually, 1 is a critical priority for the US Food and Drug Administration (FDA). As a part of our mission to support the safe and effective use of prescription medicines, the FDA is taking a fresh look at potential scientific and regulatory actions we can take to address this crisis., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

The analgesic, sedative, antidepressant, euphoriant, intoxicating, and addictive properties of opium and its synthetic derivatives are well known and have been known for centuries. Hence, the current major public health problems due to excessive availability should be no surprise. What is unprecedented in the United States, and emerging elsewhere, is the extent of the profound consequences and complexity of addressing this public health crisis., (© 2018 American Society for Clinical Pharmacology and Therapeutics.)

Public health policy responses to the opioid epidemic require addressing both opioid supply and opioid demand. The growth in prescriptions of opioid analgesics, for example, is associated with escalating opioid overdose fatalities. 1 Enhanced access to opioid agonist treatment, conversely, is required to curb demands driven by opioid use disorders. Oregon's multidimensional approaches toward opioid misuse and abuse achieved 20% reductions in opioid prescribing and a 30% reduction in the opioid overdose fatality rate., (© 2018 American Society for Clinical Pharmacology and Therapeutics.)

Background: There is growing experience with the not-for-profit, consumer-driven cannabis social club (CSC) model that builds on self-supply, self-organization and harm-reduction; these are principles upon which people who use drugs (PWUD) have been engaging for decades. Recent legalization of cannabis in a number of jurisdictions and the related challenges in regulating production, sale, taxation and health-related matters have raised interest in non-commercial models of cannabis supply. The "codes of conduct" (CsoC) of CSC federations in Spain might reveal whether a consumer-based model could overcome these challenges., Methods: To examine the content of the CSC auto-regulatory documents, an online search using key terms to identify the CsoC was conducted. Six documents were found; analysis of the main thematic categories and overarching themes was conducted. It was discussed how these corresponded to the areas of cannabis policy regulation and what the main limitations of the CSC model were., Results: The CsoC detailed the rules for CSC administration, not-for-profit aims, "invitation only" and other conditions of membership, collective cultivation and security as well as for operation of the consumption venue and health-related initiatives. The themes in the CsoC overlapped with cannabis regulatory areas as outlined internationally. Concern over cannabis prices and potency was missing in the CsoC. The potential strengths of the CSC model might include safe environment for peer-delivered harm reduction practice, preventing illicit transactions, quality control, shifting economic surplus to the consumers and increased consumer responsibility. The limitations of the CSC model include high threshold, disguised motives, tax revenue and the risk of both under- and over-regulation., Conclusion: CSCs represent an opportunity to enhance consumer agency and responsibility. The right "to be self-supplied" with psychoactive substances can be granted to consumer associations - but authorities need to provide a framework to facilitate this voluntary self-organization, including minimum standards around public health and safety, and to involve consumers in the development of these regulations., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The European Medicines Agency (EMA) revises its guideline on minimizing risk in first-in-human trials to reflect changing practice and in light of a recent tragic incident., (© 2017 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The concept of Pharmacovigilance Planning and Risk Minimization Planning (PVP/RMP), initiated by the International Conference on Harmonization (ICH), addressed an important conceptual change from monitoring the safety of individual medicine to proactively conducting risk prevention for the minimization of medication error. However, the implementation of PVP/RMP is a challenge in societies like Taiwan where irrational medication and co-medication is prevalent. It is even more difficult in Taiwan where two regulatory bodies are governing pharmaceutical affairs, namely Taiwan Food and Drug Administration (TFDA) in charge of Western Medicine (WM) and the Department of Chinese Medicine and Pharmacy (DCMP) in charge of Traditional Chinese Medicine (TCM). There are thus dual-tract drug approval panels, two GMP controls and two independent adverse drug event reporting systems. This rendered irrational co-medication of WM and TCM undetectable and the standard tools for monitoring pharmacovigilance inapplicable. The bilateral regulatory system is conceptually unscientific in accordance with PVP/RMP and unethical from humanity point of view. The first part of this review delivers (1) social aspects of polypharmacy in Taiwan; (2) regulatory aspects of pharmaceutical administration; (3) risks undermined in the bilateral regulatory system and (4) pharmacoepidemiology in relation to the risk of polypharmacy. As evidence-based medicine (EBM) forms the fundamental risk-benefit assessment on medication, the second part of this review delivers (1) the scientific aspects of the beauty and the odds of biological system that governs host-xenobiotics interaction; (2) conceptual evolution from product management (pharmacovigilance) to risk management (PVP/RMP); (3) non-biased due process is essential for risk-benefit assessment on medicinal products and (4) the opinion of the authors on system building for safe medication., (Copyright © 2018. Published by Elsevier B.V.)

Medicare costs for phosphate binders for US dialysis patients and patients with chronic kidney disease enrolled in Medicare Part D exceeded $1.5 billion in 2015. Previous data have shown that Part D costs for mineral and bone disorder medications increased faster than costs for all Part D medications for dialysis patients. Despite extensive use of phosphate binders and escalating costs, conclusive evidence is lacking that they improve important clinical end points in dialysis patients or non-dialysis-dependent patients with chronic kidney disease. Using dialysis patient data from the US Renal Data System and laboratory information from the Centers for Medicare & Medicaid Services (CMS) CROWNWeb data, we update information on trends in phosphate-binder use, calcium and phosphorus values, and costs for Medicare-covered dialysis patients. We discuss these results in the context of evidence from clinical trials, meta-analyses, and observational studies evaluating phosphate-binder efficacy, safety, comparative effectiveness, and cost-effectiveness. Based on our analysis, we note a need for US Food and Drug Administration guidance regarding clinical evaluation of new phosphate binders, and we suggest that it would be in CMS' best interest to fund a clinical trial to assess whether lower versus higher phosphate concentrations improve hard clinical outcomes, and if so, whether particular phosphate binders are superior to placebo or other binders in improving these outcomes., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The United Nations Convention against Illicit Traffic in Narcotic Drugs 1988 ("1988 Convention") expresses a strong normative preference for criminalising drug possession. Historically, the United Nations offices responsible for overseeing the treaties have held that decriminalisation of drug possession is contrary to the treaties. Leading up to and during UNGASS 2016, however, rather than emphasise criminalisation, the high-ranking officials from the drug control offices emphasised the treaties' allowance of alternatives to punishment for drug possession offences., Methods: This paper applies transnational social movement theory to analyse the political opportunity structure for drug law reform at the UN. Data was collected from documents created by important United Nations agencies in the lead up to UNGASS 2016. By analysing the statements of prominent UN officials within a social movement theory framework, we can assess whether those responsible for administering global drug policy are offering concession to drug law reform social movement and whether a political opportunity structure is opening up for drug law reformers to pursue further reforms., Results: from the United Nations documents demonstrated significant reference to local drug law reforms and the benefits of non-punitive treatment of drug users. However, given the strong normative preference and mandatory language ("shall") in the 1988 Convention, policy leaders at the UN can only offer very moderate concessions to drug law reformers - primarily the advocacy of alternatives to incarceration. Such policies still suffer many problems caused by using the criminal justice system to funnel people into treatment. Indeed, many other offices at the UN explicitly drew attention to the problem of pre-trial punishment in their contributions to UNGASS 2016., Conclusion: A schism is developing at the UN as other UN offices are pointing out that advocating for alternatives to punishment is inadequate due to the many problems of "pre-trial punishment". Social movement theory suggests that this schism represents an opening of the political opportunity structure as advocates for drug law reform can now more forcefully criticise, and even breach, the treaties and will have high-level support at the UN., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The prevention of drug use is one of the primary goals of the War on Drugs. However, despite investment in high-profile interventions such as social marketing campaigns and enforcement-based deterrence, these efforts have generally failed. With the emergence of novel policy frameworks to control and regulate drug use, a window of opportunity exists to test approaches to drug prevention that take into account existing evidence and the rights of individuals who use drugs. Specifically, there is a growing consensus that entry into drug use is a socially-defined event that individuals experience within particular socio-structural contexts. This understanding, coupled with a distinction between the value of preventing problematic drug use rather than all drug use, provides a useful framework within which to develop effective and rights-based approaches to drug prevention., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The war on drugs is usually associated with criminal policies aimed at stemming consumption of drugs such as heroin, cocaine, and cannabis, less so with enhancement drugs like those used in sport. As drug use in sport, or doping, has become more visibly widespread, policies aimed at combating the issue have become more restrictive, intrusive, and harsh. In this article we draw new comparisons between the wider war on drugs and recent developments in sports anti-doping. We identify a growing trend towards criminalisation of traffickers and users, and associate that with another growing trend: the testing of amateur athletes. This article reviews the current anti-doping system, including the recent amateur policies, then considers of the results of one such program in amateur cycling. We then shift to consider the possible implications for amateurs of criminal doping laws and the recent debates about allowing medical exemptions for therapeutic use of banned substances. We show that drug use in sport can be understood as a new front in the war on drugs, with some extreme measures and many negative unintended consequences. To remedy this, we argue that amateur athletes require a separate anti-doping policy focused on minimising harms of use., (Copyright © 2017 Elsevier B.V. All rights reserved.)