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Older people are often affected by impaired organ and bodily functions resulting in multimorbidity and polypharmacy, turning them into the main user group of many medicines. Very often, medicines have not specifically been developed for older people, causing practical medication problems for them like limited availability of easy to swallow formulations, easy to open packaging and dosing instructions for enteral administration. In 2020, the European Medicines Agency (EMA) published a reflection paper 'Pharmaceutical development of medicines for use in the older population', which discusses how the emerging needs of an ageing European population can be addressed by medicines regulation. The paper intends to help industry to better consider the needs of older people during pharmaceutical/clinical medicines development by summarising data on the most relevant topics, providing early suggestions on how to move forward and prompting expert discussions and studies into knowledge gaps. Topics include patient acceptability, (dis)advantages of an administration route, formulation, dosage form, packaging, dosing device and user instruction. While the paper is directed at older people and the pharmaceutical industry, the reflections are also relevant to younger patients with similar disease‐related needs and of value to other stakeholders parties, e.g., healthcare professionals, academics, patients and caregivers, as the paper makes clear what can be expected from industry and where collaborative work is needed. This commentary provides an overview of the different steps in the development of the reflection paper, discusses points considered most controversial and/or subject to (multidisciplinary) expert discussions and indicates their value for real world clinical practice. [ABSTRACT FROM AUTHOR]

Membrane transport proteins are involved in the absorption, disposition, efficacy, and/or toxicity of many drugs. Numerous mechanisms (e.g., nuclear receptors, epigenetic gene regulation, microRNAs, alternative splicing, post‐translational modifications, and trafficking) regulate transport protein levels, localization, and function. Various factors associated with disease, medications, and dietary constituents, for example, may alter the regulation and activity of transport proteins in the intestine, liver, kidneys, brain, lungs, placenta, and other important sites, such as tumor tissue. This white paper reviews key mechanisms and regulatory factors that alter the function of clinically relevant transport proteins involved in drug disposition. Current considerations with in vitro and in vivo models that are used to investigate transporter regulation are discussed, including strengths, limitations, and the inherent challenges in predicting the impact of changes due to regulation of one transporter on compensatory pathways and overall drug disposition. In addition, translation and scaling of in vitro observations to in vivo outcomes are considered. The importance of incorporating altered transporter regulation in modeling and simulation approaches to predict the clinical impact on drug disposition is also discussed. Regulation of transporters is highly complex and, therefore, identification of knowledge gaps will aid in directing future research to expand our understanding of clinically relevant molecular mechanisms of transporter regulation. This information is critical to the development of tools and approaches to improve therapeutic outcomes by predicting more accurately the impact of regulation‐mediated changes in transporter function on drug disposition and response. [ABSTRACT FROM AUTHOR]

The medicalisation of marijuana has occurred rapidly, albeit nonuniformly, across the US and around the world over the past 3 decades. This paper centres on the medicalisation of marijuana in Minnesota—which has one of the most restrictive programs in the country—as a case for evaluating the negotiation of institutional boundaries with the shift from criminalisation to medicalisation after nearly a century of criminal prohibition. Drawing upon Foucauldian discourse analyses of the medical and law enforcement associations' position statements and legislative hearings that shaped medical marijuana policy in Minnesota, this paper demonstrates a symbiotic convergence between medicine and law enforcement through the deployment of shared discursive strategies in their opposition to medical marijuana that reinforce marijuana's criminalised status by solidifying the boundaries between proper medicine and dangerous drugs. Criminal justice and medical institutions draw upon one another's definitions, logics, and practices in a mutually constitutive manner, while still maintaining distinct user subjects and institutional interventions for each based on the user's access to state‐approved forms of marijuana. The consequences for the governing of marijuana in Minnesota are explored, as well as the broader implications for the sociological study of medicalisation and criminalisation with respect to the governance of drugs and health. [ABSTRACT FROM AUTHOR]

Inflammation is a possible cause of variability in drug response and toxicity due to altered regulation in drug‐metabolizing enzymes and transporters (DMETs) in humans. Here, we evaluate the clinical and in vitro evidence on inflammation‐mediated modulation of DMETs, and the impact on drug metabolism in humans. Furthermore, we identify and discuss the gaps in our current knowledge. A systematic literature search on PubMed, Embase, and grey literature was performed in the period of February to September 2020. A total of 203 papers was included. In vitro studies in primary human hepatocytes revealed strong evidence that CYP3A4 is strongly downregulated by inflammatory cytokines IL‐6 and IL‐1β. CYP1A2, CYP2C9, CYP2C19, and CYP2D6 were downregulated to a lesser extent. In clinical studies, acute and chronic inflammatory diseases were observed to cause downregulation of CYP enzymes in a similar pattern. However, there is no clear correlation between in vitro studies and clinical studies, mainly because most in vitro studies use supraphysiological cytokine doses. Moreover, clinical studies demonstrate considerable variability in terms of methodology and inconsistencies in evaluation of the inflammatory state. In conclusion, we find inflammation and pro‐inflammatory cytokines to be important factors in regulation of drug‐metabolizing enzymes and transporters. The observed downregulation is clinically relevant, and we emphasize caution when treating patients in an inflammatory state with narrow therapeutic index drugs. Further research is needed to identify the full extent of inflammation‐mediated changes in DMETs and to further support personalized medicine. [ABSTRACT FROM AUTHOR]

The human absorption, distribution, metabolism and elimination study administering radiolabeled drugs to human volunteers is an important clinical study in the development program of new drug candidates. The manufacture of radiolabeled Active Pharmaceutical Ingredients is covered by national drug laws and may come within the scope of regulatory GMP requirements. Additionally, authorities may request an appropriate environmental zoning to minimize the risk of microbiological contaminations particularly during the synthesis of radiolabeled Active Pharmaceutical Ingredients intended for parenteral application. Thus, a radioactive clean room lab facility in line with both GMP and radiation safety regulations was installed and the environmental zoning validated by appropriate testing of technical parameters and microbial and particle monitoring. The considerations detailed in this paper cover only GMP aspects related to the synthesis of radioactive drug substance. The subsequent, final formulation step in the overall process for manufacturing of radioactive drug product for any kind of administration is not within the scope of this paper. Under these qualified and controlled environmental conditions, we are now in a position to provide radiolabeled drug substances for all kinds of drug administration including both po and iv. [ABSTRACT FROM AUTHOR]

A balanced approach using an integrated combination of strategies, namely, demand reduction, supply reduction and harm reduction, was suggested to be implemented in a balanced way to the policy vision of a South Africa 'free of substance abuse'. Responding on the call for a comprehensive review of the National Drug Master Plan 2013–2017 to ensure consistency in policy approach, this article explores the integrative propositional analysis (IPA)‐based analysis to evaluate 'how systemic' and integrated were the policy strategies applied. The analysis draws insights from the internal consistency of the policy and provides complementary evidence on the systemic breakdown of the policy, which correlates with previous studies. The findings are indicative of the usefulness of the IPA‐based tools to more pragmatically develop policy that better reflects the systemic/integrated relationship of the three strategies based on their conceptual systemic integrity. This research has implications for interdisciplinary scholars and practitioners, of policy and theory. [ABSTRACT FROM AUTHOR]

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

Context Until the last decade of the 20th century, France had no equivalent to the US Food and Drug Administration. In this paper we describe and interpret the complex series of events that led to the passage by the French Parliament in December 1992 of a law incorporating such an agency, the Agence du Médicament (literally, 'medicines agency'). The broad aim of this project was to learn how public health policy change comes about by detailed analysis of a specific instance. More specifically, we aimed to better understand the circumstances under which public health crisis leads to significant public health policy reform. Methods This paper is based on detailed analysis of primary documents (eg, archived French health ministry papers, recorded parliamentary debates, government reports, newspaper articles) and oral history interviews covering a period from 1988 to 1993. Thematic analysis of these materials was initially grounded in theories of organizational change, moving to constructs that emerged from the data themselves. Findings Policy entrepreneurs positioned to frame adverse events and seize opportunities are key to public health policy reform. However, whether these entrepreneurs will have the requisite institutional power is contingent both on political structure and on the power of competing institutional actors. Health crises may catalyze institutional reform, but our analysis suggests that whether reform occurs, or even whether adverse episodes are labeled as crises, is highly contingent on circumstances of history, political structure, and political ideology and is extremely difficult to predict or control. Conclusions Actors positioned to shape public health policy need to have a detailed understanding of the circumstances that facilitate or impede policy reform. Health crises are now more often global than not. Comparative, theoretically grounded, cross-national research that looks in detail at how different countries respond to similar health crises would be extremely valuable in informing both policymakers and researchers. [ABSTRACT FROM AUTHOR]

Background: This paper provides a critical review of the decision‐making process of the Ontario Ministry of Health and Long‐Term Care (MOHLTC) regarding which migraine treatment drugs will be covered under the Ontario Drug Benefit Formulary (ODB). Main Text: Under MOHLTC policy, triptans and OnabotulinumtoxinA are available to patients only through the Exceptional Access Program (EAP). This policy, and justifications for it, are examined with reference to clinical guidelines, patient experiences, and health policy literature. The contexts and consequences of compromised access are outlined. Improvements in access to these treatments are suggested by highlighting how a country with similar healthcare infrastructure – Australia – employs policies that more adequately meet the needs of migraine patients as they secure treatments. Conclusions: Despite clinically significant gains in the discovery of safe and effective migraine‐specific treatments the ODB thus far has failed to align its practice with current clinical recommendations. This forces patients to rely heavily on medication that, while still effective for some, is potentially suboptimal. This review concludes it is prudent, at minimum, to follow clinical recommendations that advocate for the removal of triptans from EAP and recategorize them as Limited Use drugs. Ideally, moving them to a general benefit would further remove the barriers experienced by patients attempting to access this treatment. [ABSTRACT FROM AUTHOR]

Model‐informed drug development (MIDD) refers to the application of a wide range of quantitative models in drug development to facilitate the decision‐making process. MIDD was formally recognized in Prescription Drug User Fee Act (PDUFA) VI. There have been many regulatory applications of MIDD to address a variety of drug development and regulatory questions. These applications can be broadly classified into four categories: dose optimization, supportive evidence for efficacy, clinical trial design, and informing policy. Case studies, literature papers, and published regulatory documents are reviewed in this article to highlight some common features of these applications in each category. In addition to the further development and investment in these established domains of application, new technology, and areas, such as more mechanistic models, neural network models, and real‐world data/evidence, are gaining attention, and more submissions and experiences are being accumulated to expand the application of model‐based analysis to a wider scope. [ABSTRACT FROM AUTHOR]

Background and aims: The short‐lived regulated legal market for new psychoactive substances (NPS) in New Zealand marked a radical departure from the traditional prohibition‐based approach to drugs. This paper aimed to enhance understanding of this policy change using Punctuated Equilibrium Theory (PET). Methods: The analysis draws on 3 years of evaluative research, including interviews with key stakeholders, analysis of legislation and policy documents and academic and grey literature. Results: The reframing of the NPS issue from one of drug control to the need for stricter market regulation was achieved by the efforts of strategic policy entrepreneurs, including the legal high industry, drug law reform advocates, influential politicians and an independent legal advisory institution. This reframing was aided by the perceived saliency of the NPS problem and ineffectiveness of previous prohibition‐based responses. In the absence of any political opposition to the regulatory approach, the Psychoactive Substances Act rapidly progressed through the Parliament. However, once the interim legal market was established, portrayal of the issues shifted away from experts and lobbyists to critique from local communities, local government, animal rights activists and the media, who viewed the new regime as a source of social and health problems. The mobilization of criticism ('Schattschneider mobilization') drew on ideas of animal welfare and community safety. With a looming national election, the government responded by ending the interim market with the urgent passage of amendment legislation. Conclusions: Punctuated Equilibrium Theory (PET) helps explain how New Zealand's Psychoactive Substances Act (PSA) policy first emerged on the political agenda and how the initial positive tone of expert support for reform shifted to a tide of popular criticism during the interim regime. However, with its emphasis on explaining agenda‐setting, PET does not account for the legislative design shortcomings of the PSA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and aims Prohibitions on producing, distributing and selling cannabis are loosening in various jurisdictions around the world. This paper describes the diversification of cannabis supply laws and discusses the challenges to and opportunities for learning from these changes. Methods We document changes in cannabis supply laws that de jure legalized cannabis production for medical and/or non-medical purposes (excluding industrial hemp) in Australasia, Europe, North America and South America. We also highlight challenges to evaluating these legal changes based on our experiences studying cannabis laws and policies in the United States. Findings As of August 2016, two countries have passed laws to legalize large-scale cannabis production for non-medical purposes at the national (Uruguay) or subnational level (four US states). At least nine other countries legally allow (or will soon allow) cannabis to be supplied for medicinal purposes. Most of the changes in cannabis supply laws have occurred since 2010. The data available in most countries are inadequate for rigorously evaluating the changes in cannabis supply laws. Conclusion The evidence base for assessing changes in cannabis supply laws remains weak. Efforts should focus upon collecting information about quantities consumed and market transactions as well as validating self-report surveys. [ABSTRACT FROM AUTHOR]

Objective With growing access to the Internet, people who use drugs and traffickers started to obtain information about novel psychoactive substances (NPS) via online platforms. This paper aims to analyze whether a decreasing Web interest in formerly banned substances-cocaine, heroin , and MDMA-and the legislative status of mephedrone predict Web interest about this NPS. Methods Google Trends was used to measure changes of Web interest on cocaine, heroin, MDMA, and mephedrone. Google search results for mephedrone within the same time frame were analyzed and categorized. Results Web interest about classic drugs found to be more persistent. Regarding geographical distribution, location of Web searches for heroin and cocaine was less centralized. Illicit status of mephedrone was a negative predictor of its Web search query rates. The connection between mephedrone-related Web search rates and legislative status of this substance was significantly mediated by ecstasy-related Web search queries, the number of documentaries, and forum/blog entries about mephedrone. Conclusions The results might provide support for the hypothesis that mephedrone's popularity was highly correlated with its legal status as well as it functioned as a potential substitute for MDMA. Google Trends was found to be a useful tool for testing theoretical assumptions about NPS. [ABSTRACT FROM AUTHOR]

The medicines regulatory environment is evolving rapidly in response to the changing environment. Advances in science and technology have led to a vast field of increasingly complicated pharmaceutical and medical device products; increasing globalization of the pharmaceutical industry, advances in digital technology and the internet, changing patient populations, and shifts in society also affect the regulatory environment. In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) regulates medicines, medical devices and blood products to protect and improve public health, and supports innovation through scientific research and development. It works closely with other bodies in a single medicines network across Europe and takes forward UK health priorities. This paper discusses the range of initiatives in the UK and across Europe to support innovation in medicines regulation. The MHRA leads a number of initiatives, such as the Innovation Office, which helps innovators to navigate the regulatory processes to progress their products or technologies; and simplification of the Clinical Trials Regulations and the Early Access to Medicines Scheme, to bring innovative medicines to patients faster. The Accelerated Access Review will identify reforms to accelerate access for National Health Service patients to innovative medicines and medical technologies. PRIME and Adaptive Pathways initiatives are joint endeavours within the European regulatory community. The MHRA runs spontaneous reporting schemes and works with INTERPOL to tackle counterfeiting and substandard products sold via the internet. The role of the regulator is changing rapidly, with new risk-proportionate, flexible approaches being introduced. International collaboration is a key element of the work of regulators, and is set to expand. [ABSTRACT FROM AUTHOR]

All the while, Dick calmly explained the improvements underway at the FDA in more than 50 congressional hearings, many of which were made difficult by harsh but often unfair public criticism of the FDA. Dick will long be remembered by the drug development and drug regulatory communities for his highly influential role as Director of the US Food and Drug Administration (FDA) Bureau of Drugs from 1971-1982, a time during which much of what we now recognize as the essential features of a well-controlled study were identified and incorporated into drug development. Even these regulations had little impact on FDA review practices until the 1970s during Dick's tenure at the FDA. [Extracted from the article]

Background: The US Food and Drug Administration (FDA) has expanded the use of surrogate markers in drugs approved for oncology/hematology indications. This has likely resulted in a greater number of approvals and possibly drugs coming to market faster, but it is unknown whether these drugs also improve overall survival (OS) for patients taking them. Methods: We sought to estimate the percentage of oncology drugs that have shown to improve OS in a cross‐sectional analysis of US FDA oncology drug approvals (2006–2023). We searched for OS data in registration trials and the peer‐reviewed literature. Results: We found 392 oncology drug approvals. Eighty‐seven (22%) drug approvals were based on OS, 147 drug approvals were later tested for OS benefit (38% of all approvals and 48% of drugs approved on a surrogate), and 130 (33%) have yet to be tested for OS benefit. Of the 147 drug approvals later tested for OS, 109 (28% of all approvals and 74% of drugs later tested for OS) have yet to show OS benefit, whereas 38 (10% of all approvals and 26% of drugs later tested for OS benefit) were later shown to have OS benefit. In total, 125 out of 392 (32%) drugs approved for any indication have been shown to improve OS benefit at some point, and 267 (68%) have yet to show approval. Conclusion: About 32% of all oncology drug approvals have evidence for an improvement in OS. Higher standards are needed in drug regulation to ensure that approved drugs are delivering better patient outcomes, specifically in regards to survival. [ABSTRACT FROM AUTHOR]

In their paper, Istvan and colleagues hint at the similarities between the regulation policies of flunitrazepam and zolpidem to draw conclusions about zolpidem's use. Indeed, of the about 1400 cases of hospitalization for addiction to high doses of benzodiazepines and the like in our institution, none were due to flunitrazepam, while more than half of them were due to lormetazepam. Https://doi.org/10.1007/s11739-020-02538-2 5 Lugoboni F, Bertoldi A, Casari R, Mantovani E, Morbioli L, Tamburin S. Adult attention-deficit/hyperactivity disorder and quality of life in high-dose benzodiazepine and related Z-drug users. [Extracted from the article]

Background New Zealand has recently attempted to address the underlying drivers of the escalating new psychoactive substances ( NPS) ('legal highs') problem by establishing the world's first pre-market approval regulatory regime for NPS. NPS products which can be shown with clinical trial data to pose a 'low risk' of harm will be approved for legal manufacture and sale. Aims and method This paper critically assesses the new regime, drawing on experience of the pharmaceutical sector and legal BZP market. Findings A number of characteristics of the recreational use of NPS may not be well addressed by standard medical clinical trials, including binge use, polydrug use, use by vulnerable groups and high-risk modes of administration. The overt advertising and covert promotion of approved NPS products on the internet may make them fairly visible to young people. The black market for unapproved NPS may be difficult to suppress given that unapproved NPS will be physically identical to approved NPS. If the legal market for NPS encourages the use of NPS, alcohol and other drugs there may be an increase in drug-related harm. Alternatively, if the legal NPS market reduces the use of more harmful drugs, there may be a considerable public health benefit. Conclusions The clinical trials required for NPS products should address the characteristics of recreational NPS use. Enforcement resources and technical solutions are required to clearly distinguish legal NPS products. The impact the new NPS regime has on other drug use is a key issue and demands further study. [ABSTRACT FROM AUTHOR]

I read with interest the excellent paper by Powell I et al i .1 entitled "Drug Dosing Recommendations for All Patients: A Roadmap for Change", wherein they discuss "adjusting drug development and regulation to enable effective dosing for all." If drug developers studied wide dose ranges throughout drug development, and regulators subsequently approved wide dose ranges, we would have a pragmatic framework for delivering personalized dosing based on dose titration for each patient. Personalized Dosing = Approved Wide Dose Ranges + Dose Titration. [Extracted from the article]

The article presents the interview summary with epidemiologist Ingeborg Rossow who discusses her experience helping patients and meeting all sorts of people, and conducting dental research. Also her participation in the alcohol and suicide prevention project aimed researchers to look at whether the association between alcohol consumption and suicide rates varied throughout different drinking cultures.

Breast cancer with bone metastasis accounts for serious cancer-associated pain which significantly reduces the quality of life of affected patients and promotes cancer progression. However, effective treatment using nanomedicine remains a formidable challenge owing to poor drug delivery efficiency to multiple cancer lesions and inappropriate management of cancer-associated pain. In this study, using engineered macrophage membrane (EMM) and drugs loaded nanoparticle, we constructed a biomimetic nanoplatform (EMM@DJHAD) for the concurrent therapy of bone metastatic breast cancer and associated pain. Tumor tropism inherited from EMM provided the targeting ability for both primary and metastatic lesions. Subsequently, the synergistic combination of decitabine and JTC801 boosted the lytic and inflammatory responses accompanied by a tumoricidal effect, which transformed the tumor into an ideal decoy for EMM, resulting in prolonged troop migration toward tumors. EMM@DJHAD exerted significant effects on tumor suppression and a pronounced analgesic effect by inhibiting μ-opioid receptors in bonemetastasismousemodels.Moreover, the nanoplatformsignificantly reduced the severe toxicity induced by chemotherapy agents. Overall, this biomimetic nanoplatform with good biocompatibility may be used for the effective treatment of breast cancer with bone metastasis. [ABSTRACT FROM AUTHOR]

Physiologically based pharmacokinetic modeling could be used to predict changes in exposure during pregnancy and possibly inform medicine use in pregnancy in situations in which there is currently limited or no available clinical PK data. The Medicines and Healthcare Product Regulatory Agency has been evaluating the available models for a number of medicines cleared by hepatic clearance mechanisms. Models were evaluated for metoprolol, tacrolimus, clindamycin, ondansetron, phenytoin, caffeine, fluoxetine, clozapine, carbamazepine, metronidazole, and paracetamol. The hepatic metabolism through cytochrome P450 (CYP) contributes significantly to the elimination of these drugs, and available knowledge of CYP changes during pregnancy has been implemented in the existing pregnancy physiology models. In general, models were able to capture trends in exposure changes in pregnancy to some extent, but the magnitude of pharmacokinetic change for these hepatically cleared drugs was not captured in each case, nor were models always able to capture overall exposure in the populations. A thorough evaluation was hampered by the lack of clinical data for drugs cleared by a specific clearance pathway. The limited clinical data, as well as complex elimination pathways involving CYPs, uridine 5′‐diphospho‐glucuronosyltransferase and active transporter for many drugs, currently limit the confidence in the prospective use of the models. Pregnancy‐related changes in uridine 5′‐diphospho‐glucuronosyltransferase and transport functions are emerging, and incorporation of such changes in current physiologically based pharmacokinetic modeling software is in progress. Filling this gap is expected to further enhance predictive performance of models and increase the confidence in predicting PK changes in pregnant women for hepatically cleared drugs. [ABSTRACT FROM AUTHOR]

Rapid detection and identification of opioids are of great significance and an urgent need in drug regulation and forensic science. Fentanyl is an extremely potent synthetic drug of abuse that unfortunately cannot be accurately detected. Therefore, techniques combining fast, highly sensitive and portable for fentanyl detection need to be developed. Surface‐enhanced Raman spectroscopy (SERS) has emerged as a promising detection technique owing to its high sensitivity and selectivity. Here, we reported a nonmetal SERS substrate used for trace fentanyl detection. The lowest detectable concentration was 10−7 M, and the MoO2 substrate exhibited excellent thermal and chemical stability, which could even ensure high‐temperature heating, laser irradiation, and corrosion of strong acid or alkali. [ABSTRACT FROM AUTHOR]

The article explores what addiction specialists in the United States might learn from Estonia regarding their response to problems relating to drug addiction and overdose. Particular focus is given to the use of fentanyl, which has been a major contributor to the overdose death epidemic in both Estonia and the United States. Other topics discussed include methodologies for harm reduction, the development of early warning systems (EWS) that can inform users of the dangers and harms of new fentanyl analogues, and the effectiveness of naloxone.

This article analyses how two key instruments of European Union pharmaceuticals legislation—good manufacturing practices and environmental risk assessment of pharmaceuticals—address known risks posed by the release of pharmaceuticals in the environment to human health and the environment and identifies the challenges that they face in regulating global manufacturing supply chains. The analysis reveals that these instruments fail to address the environmental challenges posed by pharmaceuticals within global manufacturing supply chains. Based on these findings, we propose to revise European pharmaceuticals legislation by expanding the scope and information requirements of both human and veterinary environmental risk assessment and increasing its weight in the risk–benefit analysis for human pharmaceuticals; by including direct environmental requirements for certain prioritized pharmaceuticals; and by integrating environmental considerations and related verification mechanisms into good manufacturing practices. [ABSTRACT FROM AUTHOR]

Policy PointsPeople are dying at record numbers from overdose in the United States.Concerted action has led to a number of successes, including reduced inappropriate opioid prescribing and increased availability of opioid use disorder treatment and harm‐reduction efforts, yet ongoing challenges include criminalization of drug use and regulatory and stigma barriers to expansion of treatment and harm‐reduction services.Priorities for action include investing in evidence‐based and compassionate policies and programs that address sources of opioid demand, decriminalizing drug use and drug paraphernalia, enacting policies to make medication for opioid use disorder more accessible, and promoting drug checking and safe drug supply. [ABSTRACT FROM AUTHOR]

Zelentsova et al. utilized NMR metabolomic profiling to quantify and compare biomarkers in human serum, aqueous humor (AH), and vitreous humor (VH). SP [ sp [10] SP ] sp They identified promising targets that correlated well with PMI and proposed a model based on several metabolites in AH and VH. Nuclear magnetic resonance (NMR) spectroscopy has a long history in structure elucidation of molecules both small and large. With the reemergence of lower field strength, permanent magnet, benchtop NMR systems operating at 40-100 MHz, there has been a renewed interest in NMR for routine drug analysis as evident in articles discussed in the previous section. In their article " I Benchtop nuclear magnetic resonance spectroscopy in forensic chemistry i ", Draper and McCarney provide an excellent literature review of the use of benchtop NMR systems in forensic chemistry applications largely spanning the last 5 years of developments. SP [ sp [2] SP ] sp This review covers a broad range of methods now being explored to push the application limits of benchtop NMR in forensic as well as other applications. [Extracted from the article]

Amphetamine and cathinone derivatives are abused recreationally due to the sense of euphoria they provide to the user. Methodologies for the rapid detection of the drug derivative present in a seized sample, or an indication of the drug class, are beneficial to law enforcement and healthcare providers. Identifying the drug class is prudent because derivatisation of these drugs, to produce regioisomers, for example, occurs frequently to circumvent global and local drug laws. Thus, newly encountered derivatives might not be present in a spectral library. Employment of benchtop nuclear magnetic resonance (NMR) could be used to provide rapid analysis of seized samples as well as identifying the class of drug present. Discrimination of individual amphetamine‐, methcathinone‐, N‐ethylcathinone and nor‐ephedrine‐derived fluorinated and methylated regioisomers is achieved herein using qualitative automated 1H NMR analysis and compared to gas chromatography–mass spectrometry (GC–MS) data. Two seized drug samples, SS1 and SS2, were identified to contain 4‐fluoroamphetamine by 1H NMR (match score median = 0.9933) and GC–MS (RRt = 5.42–5.43 min). The amount of 4‐fluoroamphetamine present was 42.8%–43.4% w/w and 48.7%–49.2% w/w for SS1 and SS2, respectively, from quantitative 19F NMR analysis, which is in agreement with the amount determined by GC–MS (39.9%–41.4% w/w and 49.0%–49.3% w/w). The total time for the qualitative 1H NMR and quantitative 19F NMR analysis is ~10 min. This contrasts to ~40 min for the GC–MS method. The NMR method also benefits from minimal sample preparation. Thus, benchtop NMR affords rapid, and discriminatory, analysis of the drug present in a seized sample. [ABSTRACT FROM AUTHOR]

Introduction and Aims: There have been many changes to cannabis laws across the globe, some dramatic but more often incremental. This study explored the experiences after an incremental cannabis law reform in the Australian Capital Territory, Australia.Method: Semi-structured interviews (n = 30) were conducted in March and April 2021, 14 months after the introduction of cannabis law reform, with people aged 18 and over who had grown and/or consumed cannabis in the previous 12 months. Participants were asked about recent and past cannabis use, growing cannabis and changes to their practices after the introduction of the legislation.Results: Incremental cannabis law change resulted in regulatory grey areas. How people interpreted and navigated such grey areas were connected to their relative privileges, circumstances and histories. Those who were highly policed were more likely to experience the grey areas negatively. Those who were not highly policed found the grey areas confusing or 'half-arse' (insufficiently executed), but mostly experienced the new laws positively through new cannabis cultivation or perceived reduction in stigma and fear of arrest. Those with self-identified privilege were unconcerned with grey areas of the legislation.Discussion and Conclusion: Incremental policy change can result in grey areas that require some navigation. Vulnerable populations appear less likely to experience the full benefits of such incremental drug law reform. It is vital to attend to the inequities that can arise from incremental law reform so that positive experiences are shared across the population regardless of relative privilege. [ABSTRACT FROM AUTHOR]

Half of all pregnancies in the USA are unintended, suggesting a high incidence of either improper or nonuse of contraceptives. Emergency birth control (EBC) provides individuals with additional insurance against unplanned pregnancy in the presence of contraception failure. This study is the first to estimate the impact of switching EBC from prescription to nonprescription status in the USA on abortions and risky sexual behavior as measured by STD rates. Utilizing state-level variation in access to EBC, we find that providing individuals with over-the-counter access to EBC leads to increase STD rates and has no effect on abortion rates. Moreover, individual-level analysis using the National Longitudinal Survey of Youth indicates that risky sexual behavior such as engaging in unprotected sex and number of sexual encounters increases as a result of over-the-counter access to EBC, which is consistent with the state-level STD findings. [ABSTRACT FROM AUTHOR]

The development of specific drug therapy for children was a paradigm‐changing event that transformed paediatric medical practice. However, a series of tragedies involving drug treatment for children resulted in a gap developing between drug regulation and practice, with the majority of drugs used in child healthcare being used off‐label, rendering children therapeutic orphans. Over the past two decades changes in drug regulation led by the US Food and Drug Administration and followed by the European Union's European Medicines Agency have led to substantial changes in how new drugs with potential use in children are studied and labelled. While these changes have substantially improved labelling for new drugs, there has been much less progress with older drugs. Although the unique challenges of conducting clinical research in children have been addressed by novel clinical trial designs, many of these innovations have not been translated into approaches accepted for the drug approval process. The regulations applying to the need for paediatric studies currently are only applicable in the United States and the European Union, and there is less impetus for paediatric labelling in other jurisdictions. This impacts on a number of issues beyond labelling, including the availability of child‐friendly formulations. Finally, the impact of Brexit on paediatric drug studies in the UK remains unclear and is subject to ongoing negotiations between the UK government and the European Union. [ABSTRACT FROM AUTHOR]

Background: Clinical researches of stem cell‐based therapies are highly active in China, while it was arduous to determine the most effective way of clinical translation of those advanced therapies. Methods: This article briefly introduced the regulatory framework development, the progress in stem cell clinical researches and clinical trials of commercially developed stem cell‐based products, as well as the clinical review concerns of stem cell‐based products in China. Main findings: The current regulatory framework of stem cell clinical researches in China was launched in 2015, when regulatory authorities issued "Administrative Measures on Stem Cell Clinical Research" (AMSCCR) detailing the rules of stem cell clinical research. Thereafter, the rapidly growing stem cell clinical researches were rigorously managed and clinical use of stem cell therapy was halted. Meanwhile, commercially developed stem cell‐based products are supervised by Drug Administration Law (DAL). Conclusion: The regulatory framework of stem cell‐based therapy in China has progressed in the last few decades, which is currently regulated according to AMSCCR and DAL. Well‐designed and patient‐focused clinical trial is required for commercially developed stem cell‐based products, and definite clinical benefit evidence is crucial to obtain marketing authorization. [ABSTRACT FROM AUTHOR]

Aim: To evaluate and document the impacts of re-scheduling codeine to a prescriptiononly medication in Australia in February 2018. Design: Prospective cohort study. Participants completed an on-line survey with a range of outcome measures at four time-points, once before codeine was re-scheduled (November 2017) and three times after the event: 1 month after (February 2018), 4 months after (June 2018) and 12 months after (February 2019). Setting: Australia. Participants: Participants were 260 Australians aged 18 years and above who reported regular over-the-counter (OTC) codeine use and, at the time of the study, were not engaged in treatment for codeine dependence. Measurements: Survey measures included estimates of daily average codeine use (mg) and overall daily average opioid use [calculated using an oral morphine equivalent daily dose (OMEDD, mg)], opioid use disorder with regard to codeine use (using a modified Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV), pain and pain self-efficacy, anxiety and depression and health service use. Findings: A reduction in total daily codeine use (mg) from 64.3 mg [95% confidence interval (CI) = 46.7-81.9] in November 2017 (baseline) to 27.6 mg (95% CI = 19.2-36.0) in February 2019 (final time-point) was observed. A decline in the proportion of participants who met criteria for an opioid use disorder was also evident, with 51.2% (n = 133) at baseline relative to 33.3% (n = 58) at the 12-month follow-up. This study had an overall participant retention rate of 67% at the final time-point. Conclusion: Re-scheduling codeine in Australia has been accompanied by significant reductions in codeine use and prevalence rates of opioid use disorder in a cohort of individuals who regularly use the medication, without apparent adverse impacts on pain or measures of anxiety and depression. [ABSTRACT FROM AUTHOR]

BACKGROUND: Photopharmacology is a fast‐growing photonics‐based technology, which realizes the high‐resolution regulation of drugs in time and space through light. The purpose of this research was to introduce photochromic groups into the isoxazoline structure to realize the regulation of γ‐Aminobutyric acid receptors (GABARs) targeting insect behavior. RESULTS: Azobenzene‐Fluralaner analogs ABF02, ABF03 and ABF04 have been proven to have larvicidal activity against mosquito larvae. Cis‐ABF03 had excellent larvicidal activity against mosquito larvae with a median lethal concentration (LC50) value of 1.63, which was better than that of trans‐ABF03 (LC50 = 3.90). In particular, ABF03 also showed insecticidal activity against Mythimna separata. Further experiments showed that ABF03 (1 μm) induced depolarization of dorsal unpaired median neurons after ultraviolet light irradiation, enhanced affinity to the receptor, and blocked ligand‐gated chloride channels of GABARs. ABF03 (1 μm) realized the real‐time photoregulation of the behavior of mosquito larvae, which indicated that the synthesized ligand can complete the binding and off‐target action of drugs and targets in vivo under the regulation of light. CONCLUSION: Azobenzene‐Isoxazoline as photopharmacological ligand was synthesized and evaluated for optical control of insect GABARs and behavior for the first time. ABF03 completed the differential regulation of cockroach neurons and the real‐time reversible regulation of insect behavior. The establishment of photochromic ligands provides a new strategy for basic and convenience‐oriented research on GABARs in invertebrates. © 2021 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

An introduction to the article "Supervised consumption sites: a nuanced assessment of the causal evidence," by J. P. Caulkins, B. Pardo and B. Kilmer is presented, which also includes insights on public drug policy in the U.S. as of 2019, notably the provision of safe injection sites for intravenous drug use.

Policy PointsIn the absence of federal action on rising prescription drug costs, we reviewed the details of five states that have enacted prescription drug–pricing boards seeking to lower drug prices based on products' value. Within these states, six such boards are currently authorized; they have similarities but vary in terms of structure, authority, scope, and leverage.As of June 2021, only one of the boards in our sample has conducted pricing reviews; legislators in other states can learn from the successes and challenges of existing boards.Prescription drug–pricing boards represent a novel and promising way to curb state spending and pay for value in prescription drugs but face legal and political barriers in implementation. Context: Rising prescription drug costs are consuming a growing proportion of state and private budgets. In response, lawmakers have experimented with a variety of policies to contain spending and achieve value in prescription drugs. As part of this series of reforms, some state legislatures have recently authorized prescription drug–pricing boards to address the high prices of brand‐name prescription drugs and assess the value of those drugs. Methods: We identified state prescription drug–pricing boards in the United States, defined as any agency authorized by a state legislature to review specific drugs and pursue value‐based drug prices. To describe the characteristics of the boards, we obtained public records of authorizing legislation, guidance documents, and board meeting minutes. We compared the boards' powers and responsibilities and analyzed completed pricing reviews. Findings: Six state drug‐pricing boards in five states met our definition; their design varied substantially. Two of the boards (New York Medicaid and Massachusetts) have authority over drug rebates paid by state Medicaid programs, one (New York Drug Accountability Board) has jurisdiction over state‐regulated commercial insurance, and another three (Maine, Maryland, and New Hampshire) oversee non‐Medicaid, state‐funded insurance. Three boards are authorized to require manufacturers to confidentially submit information related to the pricing and clinical effectiveness of reviewed drugs to inform value determinations. Only one board (New York Medicaid) had completed pricing reviews as of June 3, 2021. Conclusions: Boards' structure, scope, and statutory leverages to compel manufacturers to negotiate lower net costs are key factors that influence whether and to what extent boards can achieve cost savings for states. Though legal constraints may limit the effective reach of prescription drug–pricing boards, these agencies can enable states to address rising prescription drug costs, in part by virtue of their very existence. To overcome practical limitations, states seeking to implement similar policies can build on the experiences and designs of current boards. [ABSTRACT FROM AUTHOR]

Background and aims: Over‐the‐counter codeine products were up‐scheduled to prescription only in Australia from February 2018. This trend study aimed to identify changes in codeine supply before and after the February 2018 implementation. Design, setting and cases: Time–series regression analysis of monthly medicine supplies in Australia from 2014 to 2018. The February 2018 up‐scheduling was pre‐specified as the intervention; outlier analysis was used to detect automatically sudden unexpected changes before February 2018. Measurements Per‐capita supplies based on national data for pharmaceutical wholesales and population exposure. Weight of supplies in milligrams for low‐dose codeine (≤ 15 mg per tablet or ≤ 1.92 mg per ml, originally sold over the counter but up‐scheduled after February 2018), high‐dose combination codeine (30 mg per tablet, prescription only throughout the study period) and all codeine. Findings Several level shifts in supply occurred during the 5 years, led by one of −4.4% [95% confidence interval (CI) = −6.6 to −2.1%] in high‐dose codeine in 2015, followed by shifts in low‐dose codeine of −40.0% (CI = −46.9 to −32.3%) and −82.2% (CI = −84.3 to −79.9%), respectively, before and after February 2018. High‐dose codeine supply increased by 4.4% (CI = 1.8–7.1%) immediately after up‐scheduling. Also detected were transient increases and decreases in 2016 and 2017. Compared with pre‐2015 levels, the February 2018 up‐scheduling was associated with reductions of 45.7% (CI = 43.2–48.0%) and 89.3% (CI = 87.9–90.6%), respectively, in all and low‐dose codeine supply but no change in high‐dose codeine supply. The level shifts and transient changes were located around various regulatory activities, including public announcements and expert advisory meetings on up‐scheduling. Conclusion: Up‐scheduling of over‐the‐counter codeine products in Australia in 2018 appears to have been associated with a near halving of Australia's national codeine supply. The transition occurred in multiple forms and phases. [ABSTRACT FROM AUTHOR]

We study tax and regulatory policy in the legal marijuana market using unique administrative data from Washington state. Washington's retail entry restrictions have resulted in firms with substantial market power who behave like local monopolists. We show how the presence of market power causes tax and regulatory policy recommendations to differ from standard models that assume perfect competition. Combining structural demand models with measured pass‐through, we show that marijuana is not overtaxed at 37% but is still on the upward sloping region of the Laffer curve and that these taxes have high social costs and are mainly borne by consumers. [ABSTRACT FROM AUTHOR]

Background and aims: Opening up access to scheduled drugs such as cannabis in the United Kingdom rarely happens, yet on 1 November 2018 the United Kingdom changed the law to allow cannabis‐derived products to be prescribed for medicinal purposes, albeit in tightly controlled circumstances. This followed substantial media interest in the cases of two children with epilepsy. This article focuses upon the role of scandal in bringing about legislative change. Methods: We used political science and social policy theories (punctuated equilibrium theory and scandal theory) to guide a qualitative content analysis of media articles published in 2018 in UK national newspapers. We focused in particular on the 6‐month period prior to the policy change. Results: The concentrated attention by the media given to the suffering of children with epilepsy appears to have prompted the rapid change in policy by the UK government. A variety of strategies were used to develop a highly emotive response to garner support for reform. Media stories emphasized the injustice of two extremely sick children being unable to access the medicine they apparently needed to enable them to have a 'normal' childhood. Three groups of 'claim‐makers' were identified as important in influencing public opinion: families, high‐profile individuals and campaigning groups. Conclusions: The case of medicinal cannabis in the United Kingdom suggests that policy reform can occur when a scandal is successfully manufactured. We must be cautious, however, about over‐emphasizing the role of scandal as a driver of policy change in this context: only a limited set of circumstances will permit a prescription for cannabis‐based medicine to be issued in the United Kingdom. [ABSTRACT FROM AUTHOR]

Scientific advice (SA) is an important tool offered by regulators to help developers generate robust evidence on a medicine's benefits and risks. Drawing on accumulated experience and looking at the SA provided by the European Medicines Agency in 2018 to advanced therapy medicinal products originally developed by public bodies, we discuss most commonly raised issues and the complexity and timings of the questions posed. Earlier and more frequent SA could help advanced therapy medicinal product developers to pre‐empt delays at the marketing authorisation stage. Carefully addressing quality and nonclinical issues before entering the pivotal phase of development will clear the path for a smooth clinical development and successful marketing authorisation. [ABSTRACT FROM AUTHOR]

Issues: Non-medical cannabis policies are changing, including towards legalisation-with-regulation frameworks. New Zealand will hold a public referendum on cannabis legalisation in 2020. We reviewed data on cannabis use and health/social harms; policy reform options; experiences with and outcomes of reforms elsewhere; and other relevant considerations towards informing policy choices in the upcoming referendum.Approach: Relevant epidemiological, health, social, criminal justice and policy studies and data were identified and comprehensively reviewed.Key Findings: Cannabis use is common (including in New Zealand) and associated with risks for health and social harms, mainly concentrated in young users; key harms are attributable to criminalisation. 'Decriminalisation' reforms have produced ambivalent results. Existing cannabis legalisation frameworks vary considerably in main parameters. Legalisation offers some distinct advantages, for example regulated use, products and user education, yet outcomes depend on essential regulation parameters, including commercialisation, and policy ecologies. While major changes in use are not observed, legalisation experiences are inconclusive to date, including mixed health and social outcomes, with select harms increasing and resilient illegal markets. It is unclear whether legalisation reduces cannabis exposure or social harms (e.g. from enforcement) for youth.Implications/conclusions: No conclusive overall evidence on the outcomes of legalisation elsewhere exists, nor is evidence easily transferable to other settings. Legalisation offers direct social justice benefits for adults, yet overall public health impacts are uncertain. Legalisation may not categorically improve health or social outcomes for youth. Legalisation remains a well-intended, while experimental policy option towards more measured and sensible cannabis control and overall greater policy coherence, requiring close monitoring and possible adjustments depending on setting-specific outcomes. [ABSTRACT FROM AUTHOR]

Background and Aims: Eleven US states and the District of Columbia have legalized the non‐medical use of marijuana. Public marijuana smoking is generally prohibited, although some states have considered exemptions. This study assessed attitudes about public marijuana smoking, perceptions of harm from marijuana second‐hand smoke (SHS) and self‐reported marijuana SHS exposure. Design Internet panel survey fielded in June–July 2018. Setting: United States. Participants: US adults aged ≥ 18 years (n = 4088). Measurements Current (past‐30 day) tobacco product use, current marijuana use, opinions about public indoor marijuana smoking, perceptions of harm from marijuana SHS and self‐reported past‐7 day exposure to marijuana SHS in public indoor or outdoor areas were assessed. Weighted prevalence estimates were computed and correlates were assessed using logistic and multinomial regression. Findings Overall, 27.4% [95% confidence interval (CI) = 25.7, 29.1] of adults reported past‐week marijuana SHS exposure in indoor and/or outdoor public areas; younger adults, blacks, Hispanics, those in the Northeast or West, and current marijuana and/or tobacco users were more commonly exposed (Ps < 0.0001). More than half of adults (52.4%; 95% CI = 50.7, 54.2) regarded marijuana SHS as harmful, and most (81.0%; 95% CI = 79.5, 82.4) opposed public marijuana smoking. Correlates of favoring public marijuana smoking included being male, younger (Ps < 0.01), black or Hispanic, past‐month tobacco and/or marijuana users and perceiving no/low harm from marijuana SHS (Ps < 0.0001). Conclusion: While one in four US adults report recent marijuana second‐hand smoke exposure, a majority believe marijuana second‐hand smoke is harmful and most oppose public marijuana smoking. [ABSTRACT FROM AUTHOR]

Over the last few years, marijuana has become legally available for recreational use to roughly a quarter of Americans. Policy makers have long expressed concerns about the substantial external costs of alcohol, and similar costs could come with the liberalization of marijuana policy. Indeed, the fraction of fatal accidents in which at least one driver tested positive for tetrahydrocannabinol has increased nationwide by an average of 10% from 2013 to 2016. For Colorado and Washington, both of which legalized marijuana in 2014, these increases were 92% and 28%, respectively. However, identifying a causal effect is difficult due to the presence of significant confounding factors. We test for a causal effect of marijuana legalization on traffic fatalities in Colorado and Washington with a synthetic control approach using records on fatal traffic accidents from 2000 to 2016. We find the synthetic control groups saw similar changes in marijuana‐related, alcohol‐related, and overall traffic fatality rates despite not legalizing recreational marijuana. [ABSTRACT FROM AUTHOR]

The second edition of Drug Policy and the Public Good presents up‐to‐date evidence relating to the development of drug policy at local, national and international levels. The book explores both illicit drug use and non‐medical use of prescription medications from a public health perspective. The core of the book is a critical review of the scientific evidence in five areas of drug policy: (1) primary prevention programs in schools and other settings; (2) treatment interventions and harm reduction approaches; (3) attempts to control the supply of illicit drugs, including drug interdiction and law enforcement; (4) penal approaches, decriminalization and other alternatives; and (5) control of the legal market through prescription drug regimens. It also discusses the trend towards legalization of some psychoactive substances in some countries and the need for a new approach to drug policy that is evidence‐based, realistic and coordinated. The accumulated evidence provides important information about effective and ineffective policies. Shifting the emphasis towards a public health approach should reduce the extent of illicit drug use, prevent the escalation of new epidemics and avoid the unintended consequences arising from the marginalization of drug users through severe criminal penalties. [ABSTRACT FROM AUTHOR]

Commentary to: Can new psychoactive substances be regulated effectively? An assessment of the British Psychoactive Substances Bill [ABSTRACT FROM AUTHOR]

The unique challenges in pediatric drug development require efficient and innovative tools. Model‐informed drug development (MIDD) offers many powerful tools that have been frequently applied in pediatric drug development. MIDD refers to the application of quantitative models to integrate and leverage existing knowledge to bridge knowledge gaps and facilitate development and decision‐making processes. This article discusses the current practices and visions of applying MIDD in pediatric drug development, regulatory evaluation, and labeling, with detailed examples. The application of MIDD in pediatric drug development can be broadly classified into 3 categories: leveraging knowledge for bridging the gap, dose selection and optimization, and informing clinical trial design. In particular, MIDD can provide evidence for the assumption of exposure‐response similarity in bridging existing knowledge from reference to target population, support the dose selection and optimization based on the "exposure‐matching" principle in the pediatric population, and increase the efficiency and success rate of pediatric trials. In addition, the role of physiologically based pharmacokinetics in drug‐drug interaction in children and adolescents and in utilizing ontogeny data to predict pharmacokinetics in neonates and infants has also been illustrated. Moving forward, MIDD should be incorporated into all pediatric drug development programs at every stage to inform clinical trial design and dose selection, with both its strengths and limitations clearly laid out. The accumulated experience and knowledge of MIDD has and will continue to drive regulatory policy development and refinement, which will ultimately improve the consistency and efficiency of pediatric drug development. [ABSTRACT FROM AUTHOR]

In 2018, the High Court ruled that CCGs can prescribe bevacizumab (Avastin) off‐label for wet age‐related macular degeneration (wet AMD). This article discusses the background to the case and its wider implications for drug licensing and clinical practice. [ABSTRACT FROM AUTHOR]

This article explores agency as an ability to act and exert power creatively when failure implies literal death. It draws on interviews with an ex‐narco and rappers who willingly accept narco‐commissions in 2010s Tamaulipas, Mexico, a context where precarity and necropolitical logics prevail. It asserts that many rappers exert power creatively, despite the risks. Rappers shape narco‐aesthetics by determining the lyrical and sonic elements of songs; draw on experiences of narco‐life to contribute to narco‐ethics; and mould narco‐masculinities by encouraging listeners to stay firm. It proposes that prevalent discursive Us–Them dichotomies facilitate Othering and stigmatisation of actors in the narco‐world, and serve to accentuate narco‐power. [ABSTRACT FROM AUTHOR]