The use of pharmaceuticals is their main pathway to the environment, making the public a major stakeholder in environmentally friendly pharmaceutical policies, including an environmental classification system for medicines. We studied the Finnish adult population\'s (n = 2030) preferences and willingness to pay (WTP) for an environmentally friendly pharmaceutical policy by means of an online survey employing a discrete choice experiment (DCE). We also studied the relative importance of the policy attributes, namely, the environmental impact, geographical scope, available information about the environmental impact of a pharmaceutical, and the effect of the respondents\' general environmental attitudes on the WTP. The total annual WTP of the Finnish adult population ranges from 37 million to 134 million euros, depending on the attribute levels. Moreover, the environmental attitude of a respondent had a significant impact on the WTP. Generally, the environmental impact of the policy was the most important attribute, the geographical scope of the policy the second, and information about the environmental impact of pharmaceuticals was the third most important attribute. However, the most environmentally friendly respondents preferred information as the second important attribute. This study provides insights into the environmental valuations of the public to be used in preparing new pharmaceutical policy measures.

Inappropriate use of narcotic drugs is a growing worldwide health challenge. The problem is even worse in Sub-Saharan Africa where organized supply chain regulations on dispensing and stock management are poor for controlling these global challenges.
A mixed method, descriptive cross-sectional and simulated client study design was used from September 10, 2020 to November 26, 2020 to assess the extent of utilization and compliance of narcotic drug dispensing in private pharmacy retail outlets of Gondar and Bahir Dar town of Amhara region, Ethiopia. A total of 107 private pharmacy outlets were on duty. But in simulated study, purposive sampling is a method that prioritizes study units having the data of interest.
A total of 107 private pharmacy retails outlets were included in the survey. The average compliance to the controlled prescription regulation of Ethiopia in all pharmacy outlets (107) of the five drugs were calculated and found to be poor, 23.9% (SD = 18.3%). Compliance to strong narcotics is extremely low, 3.3 % for pethidine and 8% for morphine. Religion of the professionals has significant association with compliance to the prescription of narcotic drugs (p < .001).
In the era of narcotic epidemics, as a result of growing global inappropriate use of controlled drugs, the finding of this study gives an insight for a serious and strict regulation in managing and controlling the overall distribution of the narcotic drugs.
The compliance of the private retail pharmacies of Ethiopia to the regulation of controlled drugs is low.

The COVID-19 pandemic has increased online purchases and heightened interest in existing treatments. Dexamethasone, hydroxychloroquine, and lopinavir-ritonavir have been touted as potential COVID-19 treatments.
This study assessed the availability of 3 potential COVID-19 treatments online and evaluated the safety and marketing characteristics of websites selling these products during the pandemic.
A cross-sectional study was conducted in the months of June 2020 to August 2020, by searching the first 100 results on Google, Bing, and Yahoo! mimicking a US consumer. Unique websites were included if they sold targeted medicines, were in English, offered US shipping, and were free to access. Identified online pharmacies were categorized as rogue, unclassified, or legitimate based on LegitScript classifications. Patient safety characteristics, marketing techniques, price, legitimacy, IP addresses, and COVID-19 mentions were recorded.
We found 117 websites: 30 selling dexamethasone (19/30, 63% rogue), 39 selling hydroxychloroquine (22/39, 56% rogue), and 48 selling lopinavir-ritonavir (33/48, 69% rogue). This included 89 unique online pharmacies: 70% were rogue (n=62), 22% were unapproved (n=20), and 8% were considered legitimate (n=7). Prescriptions were not required among 100% (19/19), 61% (20/33), and 50% (11/22) of rogue websites selling dexamethasone, lopinavir-ritonavir, and hydroxychloroquine, respectively. Overall, only 32% (24/74) of rogue websites required prescriptions to buy these medications compared with 94% (31/33) of unapproved and 100% (10/10) of legitimate websites (P<.001). Rogue sites rarely offered pharmacist counseling (1/33, 3% for lopinavir-ritonavir to 2/22, 9% for hydroxychloroquine). Drug warnings were unavailable in 86% (6/7) of unapproved dexamethasone sites. It was difficult to distinguish between rogue, unapproved, and legitimate online pharmacies solely based on website marketing characteristics. Illegitimate pharmacies were more likely to offer bulk discounts and claim price discounts, yet dexamethasone and hydroxychloroquine were more expensive online. An inexpensive generic version of lopinavir-ritonavir that is not authorized for use in the United States was available online offering US shipping. Some websites claimed hydroxychloroquine and lopinavir-ritonavir were effective COVID-19 treatments despite lack of scientific evidence. In comparing IP addresses to locations claimed on the websites, only 8.5% (7/82) matched their claimed locations.
The lack of safety measures by illegitimate online pharmacies endanger patients, facilitating access to medications without appropriate oversight by health care providers to monitor clinical response, drug interactions, and adverse effects. We demonstrated how easy it is to go online to buy medications that are touted to treat COVID-19 even when current clinical evidence does not support their use for self-treatment. We documented that illegitimate online pharmacies sidestep prescription requirements, skirt pharmacist counseling, and make false claims regarding efficacy for COVID-19 treatment. Health care professionals must urgently educate the public of the dangers of purchasing drugs from illegitimate websites and highlight the importance of seeking treatment through authentic avenues of care.

The purpose of this study was to identify key deficiencies in pediatric oncology early phase clinical trial protocols in Germany and to provide guidance for efficient trial protocol development. A systematic review of the response letters of German competent authorities (CAs) and Ethics Committees to phase I/II pediatric oncology trial submissions in the period from 2014 to 2019 was performed. Documents were requested from all five Society for Paediatric Oncology and Haematology in Germany (GPOH) phase I/II trial networks plus all nine German Innovative Therapies for Children with Consortium Cancer (ITCC) centers. A blinded dataset containing aggregated data from 33 studies was analyzed for validation. All deficiencies were reviewed, listed, and weighted using a structured matrix according to frequency, category, significance, and feasibility. In total, documents of 17 trials from 6 different sites were collected. Two hundred fifty deficiencies identified by the CAs were identified and categorized into eight categories. \"Toxicity and safety\" was the most prominent category (27.6%), followed by \"Manufacturing and Import\" (18%). The majority of deficiencies were categorized as minor and potential measures as easy to address, but an important group of major and difficult to implement deficiencies was also identified. The blinded validation dataset confirmed these findings. The majority of the EC deficiencies could be resolved by changing the wording in the patient-facing documents. In conclusion, this study was able to detect a pattern of key deficiencies. Most of the shortcomings can be anticipated by minor changes in the protocol and increased awareness can prevent time-consuming revisions, withdrawals, or even rejections. A corresponding guideline describing key regulatory aspects is provided.

The US Congress created the Breakthrough Therapy designation in 2012 to expedite drug development and review through efficient clinical trial design and intensive interaction with US Food and Drug Administration (FDA) reviewers. Yet, of the 116 pivotal trials supporting Breakthrough-designated drugs approved 2013-2018, 96 (83%) were already underway or completed when the designation was granted, limiting the potential of the designation to influence trial design. We found no difference between these trials and the 20 (17%) that had not yet begun when the designation was granted (which had greater potential to be impacted by the designation) with respect to phase, size, intervention model (single-arm vs. multi-arm), or use of surrogate end points under the Accelerated Approval (AA) pathway. This finding suggests that, in contrast to previous studies, observed trial characteristics were not likely attributable to the designation, and instead other factors such as disease category (e.g., oncology) may be driving both trial design and Breakthrough designation. The 20 trials in our sample that began after designation was granted were, however, over 8 months shorter than trials of nondesignated drugs. This suggests that designations granted early in clinical development may reduce trial time by influencing aspects of clinical programs other than design characteristics, such as timelines for FDA responses. Alternately, certain drugs may be more likely to both receive an early designation and have a shorter trial duration, for example, because of therapeutic category or large effect size.

This \"methods paper\" focusses on one specific and limited aspect of drug safety evaluations required for all new drug entities that affect the central nervous system - the drug discrimination (DD) assay. We focus on three critical factors involved in experimental design and protocol development for the conduct of DD studies for abuse liability risk assessment that comply with the Good Laboratory Practice Guidelines (GLPs). The selection of 1) the reference drug(s) choice, 2) training dose selection, and 3) the selected route-of-administration will determine the applicability of the data to meet the regulatory expectations of the 8-factors determinative of schedule control recommendations. The study conduct and resulting data submission to the FDA are intended for drug scheduling review by the Controlled Substances Staff in the Center for Drug Evaluation and Research (CDER) at the US Food & Drug Administration (FDA). These animal studies are required to meet the statutory requirements of the Controlled Substances Act of 1970. The abuse liability study is conducted during Phase II and III of human clinical trials. Procedural or method-based errors this late in drug development can result in a significant economic and business threat to the program.

With the recent legalization of recreational cannabis in Canada, cannabis-impaired driving is an important public safety concern. Our aim was to examine the association between recreational cannabis legalization and fatal motor vehicle collisions using data from the United States, which present a timely natural experiment of cannabis legalization.
We conducted an ecologic study using the number of fatal motor vehicle collisions and the associated number of deaths for US jurisdictions with legalized recreational cannabis (2007-2018) retrieved from the US Fatality Analysis Reporting System. We examined jurisdiction-specific rates of fatal motor vehicle collisions and associated deaths before and after recreational cannabis legalization using Poisson regression and meta-analyzed estimates across jurisdictions using DerSimonian and Laird random-effects models.
After adjustment for calendar year, legalization was associated with increases in rates of fatal motor vehicle collisions (incidence rate ratio [IRR] 1.15, 95% confidence interval [CI] 1.06-1.26) and associated deaths (IRR 1.16, 95% CI 1.06-1.27). Differences between the first 12 months after legalization relative to subsequent months were inconclusive for rates of fatal motor vehicle collisions (IRR 0.92, 95% CI 0.84-1.02) and associated deaths (IRR 0.92, 95% CI 0.84-1.01).
Recreational cannabis legalization in the US was associated with a relative increased risk of fatal motor vehicle collisions of 15% and a relative increase in associated deaths of 16%, with no conclusive difference between the first and subsequent years after legalization. These findings raise concern that there could be a similar increase in fatal motor vehicle collisions and associated deaths in Canada following recreational cannabis legalization.

The General European Official Medicines Control Laboratory (OMCL) Network (GEON), co-ordinated by the European Directorate for the Quality of Medicines & HealthCare (EDQM), regularly organises market surveillance studies on specific categories of suspected illegal or illegally traded products. These studies are generally based on a combination of retrospective and prospective data collection over a defined period of time. This paper reports the results of the most recent study in this context with the focus on health products containing non-Anatomical Therapeutic Chemical-International Nonproprietary Name (ATC-INN) molecules. In total 1104 cases were reported by 16 countries for the period between January 2017 and the end of September 2019. The vast majority of these samples (83%) were collected from the illegal market, while only 3% originated from a legal source. For the rest of the samples, categorisation was not possible. Moreover, 69% of all the reported samples were presented as medicines, including sexual performance enhancers, sports performance enhancers, physical performance enhancers and cognitive enhancers or nootropic molecules that act on the central nervous system (CNS). Although the popularity of anabolics, PDE-5 inhibitors and CNS drugs in illegal products has already been reported, the study showed some new trends and challenges. Indeed, 11% of the samples contained molecules of biological origin, that is, research peptides, representing the second most reported category in this study. Furthermore, the study also clearly shows the increasing popularity of Selective Androgen Receptor Modulators and nootropics, two categories that need attention and should be further monitored.

Arsenosugars are a group of arsenic-containing ribosides that are found predominantly in marine algae but also in terrestrial organisms. It has been proposed that arsenosugar biosynthesis involves a key intermediate 5\'-deoxy-5\'-dimethylarsinoyl-adenosine (DDMAA), but how DDMAA is produced remains elusive. Now, we report characterization of ArsS as a DDMAA synthase, which catalyzes a radical S-adenosylmethionine (SAM)-mediated alkylation (adenosylation) of dimethylarsenite (DMAsIII ) to produce DDMAA. This radical-mediated reaction is redox neutral, and multiple turnover can be achieved without external reductant. Phylogenomic and biochemical analyses revealed that DDMAA synthases are widespread in distinct bacterial phyla with similar catalytic efficiencies; these enzymes likely originated from cyanobacteria. This study reveals a key step in arsenosugar biosynthesis and also a new paradigm in radical SAM chemistry, highlighting the catalytic diversity of this superfamily of enzymes.

OBJECTIVE: To examine the impact of new controlled drugs legislation introduced in May 2017 on benzodiazepine receptor agonist (BZRA) prescribing in Ireland.
METHODS: A repeated cross-sectional analysis was conducted using publically available monthly pharmacy claims data from the General Medical Services (GMS) database. The study population comprised all GMS-eligible individuals aged ≥ 16 years from January 2016 to September 2019. Monthly prevalence rates of individuals receiving BZRA prescriptions per 10,000 eligible population were calculated and trends examined over time. Segmented linear regression of prevalence rates was used to examine changes before and after introduction of the legislation stratified by gender and age groups. Regression coefficients (β) and 95% confidence intervals (CIs) for monthly change were calculated.
RESULTS: Pre-legislation (January 2016 to April 2017), there was a significant monthly decline in benzodiazepine prevalence rate (β = - 1.18; 95% CI - 1.84, - 0.51; p < 0.001) but no significant change in Z-drug prescribing. Post-legislation (May 2017 to September 2019), increases in prevalence rates were observed for benzodiazepines (β = 1.04; 95% CI 0.17, 1.92; p = 0.021) and Z-drugs (β = 1.04; 95% CI 0.26, 1.83; p = 0.010). Post-legislation trends showed increases in BZRA prevalence rates among the youngest subgroup (16-44 years), with variable changes in the middle-aged subgroup (45-64 years) and no changes in the oldest subgroup (≥ 65 years).
CONCLUSIONS: This study indicates that introduction of new legislation had limited impact on BZRA prescribing on the main public health scheme in Ireland. Interventions targeting specific population subgroups may be required to achieve sustained reductions in prescribing.