The impact of proposed price regulations on new patented medicine launches in Canada: a retrospective cohort study.

BACKGROUND: The Patented Medicine Prices Review Board (PMPRB), the agency that regulates the prices of patented medicines in Canada, published proposed amendments to the regulatory framework in December 2017. Because of a series of changes and delays, the revised policy has not yet been finalized. We sought to evaluate the potential early impact of the uncertainty about the PMPRB policy on patented-medicine launches. METHODS: We developed a retrospective cohort of patented medicines (molecules) sold in Canada and the 13 countries that the PMPRB currently uses or has proposed to use as price comparators, from sales data from the IQVIA MIDAS database for 2012-2021. The outcome was whether a molecule was launched (i.e., sold) in a specific country within 2 years of its global first launch (2-yr launch). We compared the change of 2-year launch before (2012-2017) and after the proposed amendments were published ("uncertain period," 2018-2021) in Canada with the change in the United States and the other 12 countries as a group ("other-countries group"), using interrupted time series and logistic regressions, respectively. We further conducted analyses for each individual country and subgroups by molecule characteristics, such as therapeutic benefit, separately. RESULTS: We included 242 and 107 new molecules launched before publication of the proposed amendments and during the uncertain period, respectively. The corresponding 2-year launch proportions were 45.0% and 30.8% in Canada, 81.4% and 82.2% in the US, and 83.9% and 70.1% in the other-countries group. All analyses showed changes in 2-year launch during the uncertain period in the US and in the other-countries group that were similar to the changes in Canada. Greater decreases were observed in Norway and Sweden than in Canada. The 2-year launch proportion for molecules with major therapeutic benefit decreased from 45.8% to 31.3% in Canada during the uncertain period and from 87.5% to 62.5% in the other-countries group, but increased from 91.7% to 100% in the US. INTERPRETATION: No negative impact of the PMPRB-policy uncertainty on molecule launches was observed when comparing Canada with price-comparator countries, except for molecules with major therapeutic benefit. The reduction in launches of medicines with major therapeutic benefit in Canada requires continuing investigation.

The appointment-based model in community pharmacies: Patient demographics and reimbursable clinical services uptake in Ontario.

Background: Community pharmacies typically require patients to request medication refills. The appointment-based model (ABM) is a proactive approach that synchronizes refills and schedules patient-pharmacist appointments. These appointments provide opportunities for medication reviews, medication optimization and health promotion services. The primary aim of this study was to describe the types of patients who received an ABM service in a community pharmacy in Ontario in 2017. The secondary aim was to describe reimbursable clinical service uptake. Methods: In September 2017, the ABM was implemented across 3 Ontario community pharmacies within a Canadian pharmacy banner. Patients who filled at least 1 chronic oral medication and consented to enrolment were eligible. In December 2018, data were extracted from pharmacies using pharmacy management software. Descriptive statistics and frequencies were generated. Results: Analysis of 131 patients (51.1% female; mean ± SD age 70.8 ± 10.5 years) revealed patients were dispensed a mean ± SD of 5.1 ± 2.7 medications, and 73 (55.7%) experienced polypharmacy. Hypertension (87.8%) and dyslipidemia (68.7%) were the most common medical conditions. There were 74 (56.5%) patients who received ≥1 medication review service (MedsCheck). Of 79 unique drug therapy problems (DTPs) identified, the most common categories related to patients needing additional drug therapy and adverse drug reactions. Discussion and conclusion: Patients enrolled in the ABM were generally older adults experiencing polypharmacy. The ABM presented opportunities for DTP identification and delivery of reimbursed services. Findings support continued exploration of the ABM to support integration of clinical services within community practice.

Modeling Tiered Pricing Frameworks: A Simulation Approach.

OBJECTIVE: Drug plans take different approaches to determining reimbursement prices for generic drugs. One common approach is to set the maximum reimbursement price as a percentage of the price of the interchangeable branded drug. In many countries this percentage depends on the number of generic entrants, a model we call "tiered pricing." This paper seeks to enhance understanding of how to set the tiers. METHODS: We construct a simple model of tiered pricing and set parameters to match evidence on generic drug costs and the distribution of revenues. Using simulation methods, we then assess different tier structures in terms of total surplus and average drug cost. RESULTS: We find when tiers are bunched tightly together welfare outcomes are poor. Moreover, there are large welfare gains from increasing the number of tiers from one to two, and only small welfare gains from increasing the number of tiers beyond four. CONCLUSIONS: The choice of tiers has substantial welfare and cost implications. While it is possible to refine the simulation analysis based on specific market characteristics, an optimal tier structure, such as the one we propose in the paper, should have at least two tiers.

Pharmacy location and medical need: regional evidence from Canada.

BACKGROUND: Pharmacists in Canada are assuming an increasingly important role in the provision of primary care services. This raises questions about access to pharmacy services among those with medical care needs. While there is evidence on proximity of residents of Ontario and Nova Scotia to community pharmacies, there is little evidence for the rest of Canada. I thus measured the availability of pharmacist services, both the number of community pharmacies and their hours of operation, at both the provincial and sub-provincial level in Canada. Next, I measured associations of indicators of medical need and the availability of pharmacist services across sub-provincial units. METHODS: I collected data, for each Forward Sortation Area (FSA), on medical need, measured using the fraction of residents aged 65 + and median household income, and pharmacist service availability (the number of community pharmacies and their hours of operation, divided by the FSA population). Linear regression methods were used to assess associations of FSA-level service availability and medical need. RESULTS: There are between 2.0 and 3.3 community pharmacies per 10,000 population, depending on the province. There are also provincial variations in the number of hours that pharmacies are open. Quebec pharmacies were open a median of 75 h a week. In Manitoba, pharmacies were open a median of 53 h a week. The per capita number of pharmacies and their total hours of operation at the FSA level tend to be higher in less affluent regions and in which the share of residents is aged 65 or older. Provincial differences in pharmacy availability were still evident after controlling for medical need. CONCLUSION: Community pharmacies in Canada tend to locate where indicators of health needs are greatest. The impact on patient health outcomes of these pharmacy locational patterns remains an area for future research.

Impact of age, hypercholesterolemia, and the vitamin D receptor on brain endogenous ß-amyloid peptide accumulation in mice.

Age, hypercholesterolemia, and vitamin D deficiency are risk factors that increase the brain accumulation of pathogenic ß-amyloid peptides (40 and 42), precursors leading to Alzheimer's disease (AD) in humans. The relative changes accompanying aging, high cholesterol, and/or treatment of calcitriol, active vitamin D receptor (VDR) ligand, under normal physiology are unknown. We examined these relative changes in C57BL/6 mice of ages 2, 4-8, and more than 10 months old, which were fed a normal or high fat / high cholesterol diet and treated with calcitriol, active ligand of the vitamin D receptor (0 or 2.5 µg/kg ×4, intraperitoneally, every other day to elicit cholesterol lowering in liver). Aß40 but not Aß42 accumulation in brain and lower P-glycoprotein (P-gp) and neprilysin protein expressions for Aß efflux and degradation, respectively, were found to be associated with aging. But there was no trend for BACE1 (ß-secretase 1, a cholesterol-sensitive enzyme) toward Aß synthesis with age. In response to calcitriol treatment, P-gp was elevated, mitigating partially the age-related changes. Although age-dependent decreasing trends in mRNA expression levels existed for Cyp46a1, the brain cholesterol processing enzyme, whose inhibition increases BACE1 and ApoE to facilitate microglia Aß degradation, mRNA changes for other cholesterol transporters: Acat1 and Abca1, and brain cholesterol levels remained unchanged. There was no observable change in the mRNA expression of amyloid precursor protein (APP) and the influx (RAGE) and efflux (LRP1) transporters with respect to age, diet, or calcitriol treatment. Overall, aging poses as a risk factor contributing to Aß accumulation in brain, and VDR-mediated P-gp activation partially alleviates the outcome.

Impact of a peer comparison intervention on seasonal influenza vaccine uptake in community pharmacy: A national cluster randomized study.

BACKGROUND: Seasonal influenza vaccine (SIV) uptake in the United States remains suboptimal, requiring new and innovative strategies. OBJECTIVE: To evaluate the impact of a behavioral peer comparison (PC) intervention on SIV uptake in community pharmacies across the United States. METHODS: A cluster randomized study was conducted across a national network of Walmart community pharmacies (> 4500 sites) during the 2019-2020 influenza season. The clusters consisted of 416 markets, each containing an average of 11 pharmacies. All pharmacies in a market were randomly assigned to either no intervention or the PC intervention, a software-delivered communication informing on-site staff, including pharmacists and pharmacy technicians, of their pharmacy's weekly performance, measured as SIV doses administered, compared with that of peer pharmacies within their market. The outcome was the pharmacy-level cumulative SIV doses administered during the intervention period (September 1, 2019,-February 29, 2020). Linear regression models were used to estimate the PC impact, with multiway cluster-robust SEs estimated by market and state. RESULTS: A total of 4589 pharmacies were enrolled in the study, with 2297 (50.1%) randomized to the control group and 2292 (49.9%) randomized to the PC intervention group. Overall, compared with the control pharmacies, the PC pharmacies administered 3.7% (95% CI -0.3% to 7.9%) additional SIV doses. Among large-format pharmacies, the PC pharmacies administered 4.1% (95% CI 0.1%-8.3%) additional SIV doses compared with the controls. Historically low-performing large-format PC pharmacies administered 6.1% (95% CI 0.5%-11.9%) additional SIV doses compared with the controls. No statistically significant treatment effects were observed among small-format pharmacies. CONCLUSION: Our findings demonstrate that PCs can improve SIV uptake among large-format community pharmacies, with historically low-performing pharmacies potentially exhibiting the greatest relative impact. Wide-scale implementation of PCs in community pharmacies may help to further improve SIV uptake in these settings.

The health impact of delaying direct-acting antiviral treatment for chronic hepatitis C: A decision-analytic approach.

BACKGROUND & AIMS: Direct-acting antivirals (DAAs) are highly effective, but expensive treatments for chronic hepatitis C (CHC). To manage costs, drug plans worldwide have rationed access to DAAs in a variety of ways. This study quantifies the health impact of formulary restrictions and presents a clinical decision tool for informing treatment timing decisions. METHODS: A decision-analytic model was developed to quantify the health impact of delaying DAAs for subpopulations stratified by age, fibrosis level, viral genotype, and injection drug use over their lifetime. The health impact was quantified in terms of quality-adjusted life expectancy (quality-adjusted life years, or QALYs) and life expectancy (years). RESULTS: Deferring DAAs for patients with no or mild fibrosis (F0/F1) for 1-5 years is unlikely to result in life expectancy losses and leads only to marginal losses of 0.02-0.06 QALYs per year of delay. However, for 30-50-year-olds with advanced fibrosis (≥F3) delays as short as a year results in a considerable health loss (0.25-1.04 QALYs and 0.19-1.53 years). Reimbursement limits for those with substance use are associated with large health losses. People who actively inject drugs with advanced fibrosis (≥F3) may lose 0.18-1.05 QALYs and 0.13-1.16 years per year of delay, despite the risk of reinfection and competing mortality. Results are robust to parameter uncertainty and key assumptions. CONCLUSIONS: We present a clinical decision tool for informing treatment timing for various CHC subpopulations. In general, findings suggest that patients with at least moderate fibrosis should be treated promptly regardless of active drug use.

Uptake and impact of regulated pharmacy technicians in Ontario community pharmacies.

BACKGROUND: Since 2010, most provincial Colleges of Pharmacists have licensed pharmacy technicians. The colleges hoped this would give pharmacists time to provide "expanded scope" activities such as medication reviews. Little is known, however, about the uptake and impact of pharmacy technicians on pharmacists' provision of such services. We address these questions using data for Ontario community pharmacies. METHODS: Data on pharmacists and pharmacy technicians were obtained from the Ontario College of Pharmacists website in September 2016. Their place of employment was used to calculate the number of full-time equivalent (FTE) pharmacists and technicians employed at each community pharmacy. Pharmacy claims data for the 12-month period ending March 31, 2016, were obtained from the Ontario Public Drug Programs (OPDP). These data included number of MedsChecks performed, type of MedsCheck and number of prescriptions dispensed to OPDP beneficiaries. RESULTS: Pharmacy technicians were employed in 24% of the pharmacies in our sample. Technician employment rates were highest in Central Fill pharmacies and pharmacies serving long-term care facilities. In general, pharmacies employing 1 or fewer technician full-time equivalents (FTEs) had a slightly higher probability of providing MedsChecks and, of those that did provide Meds Checks Annuals, provided more of them. Pharmacies that hired 3 or more technician FTEs were markedly less likely to provide MedsChecks. CONCLUSIONS: Pharmacies differ in their employment of technicians and in the apparent impact of technicians on the provision of MedsChecks. However, these represent associations. Additional research is needed to assess the causal effect of technician employment on the provision of MedsChecks.

Clinical and microbiological epidemiology of early and late infectious complications among solid-organ transplant recipients requiring hospitalization.

There is limited literature describing the clinical and microbiological characteristics of solid-organ transplant recipients requiring hospitalization for infectious complications. This study reports on the rate and timing of these syndromes and describes the associated microbiological epidemiology. This prevalence cohort study evaluated solid-organ transplant recipients requiring hospitalization during 2007-2011. We reported infectious complications requiring hospitalization in 603 of 1414 readmissions at a rate of 0.43 episodes per 1000 transplant-days (95% CI, 0.40-0.47), with 85% occurring >6 months post-transplantation. The most frequent infectious complications were as follows: respiratory (27%), sepsis or bacteremia (13%), liver or biliary tract (12%), genitourinary (12%), and cytomegalovirus related (9%). Approximately 53% presented without fever, 45% had no pathogen isolated, and multidrug-resistant organisms were isolated in 27% of those with an identified microbiological etiology. Infectious-related complications continue to pose a high clinical burden on our acute care center, with the majority occurring in the late transplant period. Clinicians are faced with the difficult task of prescribing adequate antimicrobial therapy.

Cost Consequence Analysis of Implementing the Low Risk Ankle Rule in Emergency Departments.

STUDY OBJECTIVE: Implementation of the Low Risk Ankle Rule can safely reduce radiographs for children with acute ankle injuries. The main objective of this study is to examine the costs and consequences of implementing the rule. METHODS: For children aged 3 to 16 years and with an acute ankle injury, we collected data on health care provider visits, imaging, and treatment at the index emergency department (ED) visit and days 7 and 28 post-ED discharge. This was done during 3 consecutive 6-month phases at 6 EDs. After the baseline phase 1, the Low Risk Ankle Rule was introduced in phases 2 and 3 in 3 intervention EDs, but not in the 3 pair-matched control EDs. We compared the effect of the Low Risk Ankle Rule on health care and patient-paid costs, the proportion of radiographs ordered, the proportion of missed clinically important fractures, and the follow-up use of health care resources. RESULTS: We enrolled 2,151 children with ankle injuries, 1,055 at the intervention and 1,096 at the control EDs. Health care costs were $36.93 less per patient at intervention compared with control sites (P=.02). Out-of-pocket costs to the patients were $2.09 more per patient at intervention sites (P=.30). In intervention versus control sites, the main contributor to cost reduction was the 22.9% reduction in ankle radiography. Furthermore, there were no significant differences in the frequency of missed clinically important fractures (0.1% versus 0.9%) or follow-up use of health care resources. CONCLUSION: Widespread implementation of the Low Risk Ankle Rule may lead to reduction of unnecessary radiographs for children and result in cost savings.

Intended and unintended effects of restrictions on the sale of cigarillos to youth: evidence from Canada.

BACKGROUND: Youth consumption of cigarillos (ie, little cigars) has increased markedly in recent years. In July 2010, the Canadian government banned the sale of flavoured cigarillos and required unflavoured cigarillos to be sold in packs of at least 20 units. This paper assesses changes in young persons' use of cigarillos and regular cigars, which are potential substitutes, following the policy. METHODS: To investigate of the change in cigar smoking following the policy, we constructed a segmented regression model that allowed the policy to change the height and the slope of the trend in the outcome variables. The model was estimated using data from the 2007-2011 Canadian Tobacco Use Monitoring Surveys. RESULTS: We obtained visual and regression-based evidence that use of cigarillos among youth declined following the policy. We also found a small, gradual increase in their use of regular cigars, possibly due to their compensatory switching from cigarillos to regular cigars. Overall, there was a net reduction in cigar use among youth after the intervention. INTERPRETATION: The policy achieved its goal of reducing youth's consumption of cigarillos, but may have an unintended consequence of increasing their use of regular cigars. Policymakers should address the possibility that youth switch to regular cigars in response to restricted access to cigarillos. Possible ways of discouraging this substituting behaviour include extending the ban to cover all flavoured cigars and mandating a minimum pack size for all cigars, or raising taxes on flavoured cigars.

Changes in Medical Cannabis Use After Recreational Cannabis Legalization in Canada.

Background: As part of its recreational cannabis legalization in October 2018, Canada imposed an excise tax of 10% (or $1 a gram, whichever is higher) on both recreational and medical cannabis. There is little evidence to inform the ongoing debate on whether the legalization had adverse impacts on medical cannabis use. Methods: We used an interrupted time series design and data on medical cannabis shipments (i.e., mail-order deliveries of cannabis from a licensed producer to a patient authorized to obtain medical cannabis) in Canada between quarter 1 of 2014 and quarter 1 of 2020. We examined changes in medical cannabis shipments after Canada's recreational cannabis legalization both across Canada and for each province. As this study used publicly available, province-level aggregate data, ethics approval was not required. Results: Recreational cannabis legalization was associated with significant reductions in medical cannabis use in 7 out of 10 Canadian provinces. Compared with the counterfactual estimated from prelegalization trends, the reduction in quarter 1 of 2020 varied from 500 shipments per 100,000 population (95% CI=312-688 shipments per 100,000 population) or 32% (95% CI=22-43%) in Newfoundland and Labrador to 3,778 shipments per 100,000 population (95% CI=2,972-4,585 shipments per 100,000 population) or 74% (95% CI=68-79%) in Alberta. At the national level, the number of medical cannabis shipments decreased by 823 per 100,000 population (95% CI=725-921 shipments per 100,000 population) or 48% (95% CI=45-52%). Conclusions: Recreational cannabis legalization was associated with reductions in medical cannabis use. Our findings call for policy attention to address possible adverse impacts of recreational cannabis legalization on medical cannabis users.

A Systematic Review and Meta-Analysis of the Cancer.

OBJECTIVE: Prostate cancer is the second- leading cause of cancer death among men. We aimed to evaluate high-intensity focused ultrasound (HIFU), open radical prostatectomy (ORP), robot-assisted radical prostatectomy (RARP), and external beam radiation therapy (RT) in the treatment of localized low- and intermediate-risk prostate cancer. METHODS: We searched bibliographic databases for case-control, cohort, and randomized controlled studies. We used MeSH subject headings and free text terms for prostate cancer, HIFU, ORP, RARP, RT, failure-free survival (FFS), biochemical disease-free survival (BDFS), urinary incontinence (UI), and erectile dysfunction (ED). RESULTS: Fourteen studies were included in the review, for a total of 34 927 participants. Among the 8 studies of HIFU as the primary treatment of localized low- and intermediate- risk prostate cancer, 4 studies reported 5-year FFS rates ranging from 67.8% to 97.8%, 3 studies reported 5-year BDFS ranging from 58% to 85.4%, 5 studies reported 1-year UI rates ranging from 0% to 6%, and 4 studies reported 1-year ED rates ranging from 11.4% to 38.7%. Furthermore, our search revealed a 5-year FFS benefit favoring ORP compared to RT, a 1-year UI rate favoring ORP compared to RARP, and a 1-year ED rate favoring ORP compared to RARP. CONCLUSION: Our systematic review and meta-analysis revealed lack of studies with active comparators comparing HIFU to standard of care (ORP, RARP, or RT) in primary treatment of localized low- and intermediate-risk prostate cancer. Open radical prostatectomy has favorable efficacy outcomes compared to RT, while RARP has beneficial functional outcomes compared to ORP, respectively.

Association between non-medical cannabis legalization and alcohol sales: Quasi-experimental evidence from Canada.

BACKGROUND: There is increasing interest in understanding the impact of non-medical cannabis legalization on use of other substances, especially alcohol. Evidence on whether cannabis is a substitute or complement for alcohol is both mixed and limited. This study provides the first quasi-experimental evidence on the impact of Canada's legalization of non-medical cannabis on beer and spirits sales. METHODS: We used the interrupted time series design and monthly data on beer sales between January 2012 and February 2020 and spirits sales between January 2016 and February 2020 across Canada to investigate changes in beer and spirits sales following Canada's cannabis legalization in October 2018. We examined changes in total sales, nationally and in individual provinces, as well as changes in sales of bottled, canned and kegged beer. RESULTS: Canada-wide beer sales fell by 96 hectoliters per 100,000 population (p=0.011) immediately after non-medical cannabis legalization and by 4 hectoliters per 100,000 population (p>0.05) each month thereafter for an average monthly reduction of 136 hectoliters per 100,000 population (p<0.001) post-legalization. However, the legalization was associated with no change in spirits sales. Beer sales reduced in all provinces except the Atlantic provinces. By beer type, the legalization was associated with declines in sales of canned and kegged beer but there was no reduction in sales of bottled beer. CONCLUSIONS: Non-medical cannabis legalization was associated with a decline in beer sales in Canada, suggesting substitution of non-medical cannabis for beer. However, there was no change in spirits sales following the legalization.

The impact of changing the reference countries on the list prices for patented medicines in Canada: A policy analysis.

BACKGROUND: Canada's Patented Medicine Prices Review Board (PMPRB) uses external and internal reference pricing (IRP) to regulate patented drug list prices. PMPRB has changed external reference countries from 7 to 11 to include countries with prices closer to the OECD median. We examined the impact on the list prices for patented medicines had the amendment been implemented from 2013. METHODS: Using IQVIA MIDAS® quarterly sales data, we selected branded products that were launched in Canada in 2013-2018. The list price for each product in each country was calculated as its average annual price during the 3rd year post Canadian launch. The median international price (MIP) was the median of the list prices of PMPRB7 (MIP7) and PMPRB11 (MIP11). We assumed the same IRP would be (scenario 1) or would not be used (scenario 2). RESULTS: Among the selected 400 products, 80.3 % (321) had MIP7 and MIP11 (launched in at least one reference country); 18.3 % did not have MIP11. The total current expenditures were $7,134.4 M. In scenario 1, MIP11 would not be binding for most products and expenditures would decline only by 0.7 %. If IRP were abolished, expenditures might decline by 14.1 % if the launching sequence would not change. CONCLUSIONS: MIP11 might not be binding for most medicines. The impact depends on whether to retain the IRP and approaches taken for medicines without MIP11.

Effect of the Low Risk Ankle Rule on the frequency of radiography in children with ankle injuries.

BACKGROUND: The Low Risk Ankle Rule is a validated clinical decision rule that has the potential to safely reduce radiography in children with acute ankle injuries. We performed a phased implementation of the Low Risk Ankle Rule and evaluated its effectiveness in reducing the frequency of radiography in children with ankle injuries. METHODS: Six Canadian emergency departments participated in the study from Jan. 1, 2009, to Aug. 31, 2011. At the 3 intervention sites, there were 3 consecutive 26-week phases. In phase 1, no interventions were implemented. In phase 2, we activated strategies to implement the ankle rule, including physician education, reminders and a computerized decision support system. In phase 3, we included only the decision support system. No interventions were introduced at the 3 pair-matched control sites. We examined the management of ankle injuries among children aged 3-16 years. The primary outcome was the proportion of children undergoing radiography. RESULTS: We enrolled 2151 children with ankle injuries, 1055 at intervention and 1096 at control hospitals. During phase 1, the baseline frequency of pediatric ankle radiography at intervention and control sites was 96.5% and 90.2%, respectively. During phase 2, the frequency of ankle radiography decreased significantly at intervention sites relative to control sites (between-group difference -21.9% [95% confidence interval [CI] -28.6% to -15.2%]), without significant differences in patient or physician satisfaction. All effects were sustained in phase 3. The sensitivity of the Low Risk Ankle Rule during implementation was 100% (95% CI 85.4% to 100%), and the specificity was 53.1% (95% CI 48.1% to 58.1%). INTERPRETATION: Implementation of the Low Risk Ankle Rule in several different emergency department settings reduced the rate of pediatric ankle radiography significantly and safely, without an accompanying change in physician or patient satisfaction. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT00785876.

Lessons from 20 years of medical cannabis use in Canada.

BACKGROUND: Canada was one of the first countries to regulate the medical use of cannabis. However, literature on Canada's medical cannabis program is limited. METHODS: We use administrative data from the medical cannabis program, and licensed cannabis vendor catalog data to describe a) the participation of patients, physicians, and cannabis vendors in the program from its inception in 1999 to 2021, and b) trends in medical cannabis consumption, prices and potency. We also use national surveys conducted over the last several decades to estimate trends in regular cannabis use (medical or otherwise) and how it changed during the medical cannabis access regimes. RESULTS: In 2001, the Canadian government granted access to those with physician-documented evidence of a severe health problem that could not be managed using conventional therapies. Most patients accessed cannabis grown under a personal production license. By 2013, authorized daily cannabis dosages were very high. In 2014, the government, concerned over illegal diversion, required that cannabis be purchased from a licensed commercial grower; personal production was banned. Physicians were given responsibility for authorizing patient access. To fill the regulatory void, the physician regulatory bodies in Canada imposed their own prescribing restrictions. After these changes, the number of physicians who were willing to support patient cannabis use markedly decline but the number of patients participating in the program sharply increased. Medical cannabis use varied by province-rates were generally lower in provinces with stricter regulations on physician cannabis prescribing. Most varieties of cannabis oil available for sale are now high in CBD and low in THC. Dry cannabis varieties, conversely, tend to be high in THC and low in CBD. Inflation adjusted prices of most varieties of medical cannabis have declined over time. We find that rates of daily cannabis use (medical or otherwise) increased markedly after the 2014 policy regime. The fraction of Canadians using cannabis daily increased again after the 2018 legalization of recreational cannabis; at the same time, participation in the medical access program declined. CONCLUSION: The implications for patient health outcomes of changes in the medical cannabis program and legalization of recreational use remains an important area for future research.

Overview of the global vaccine ecosystem.

INTRODUCTION: Vaccination is an effective, relatively inexpensive, and easy to deliver approach to combating infectious diseases. Widespread vaccination of children has led to the eradication of smallpox and allowed for regional elimination or control of diseases like polio, measles, mumps, tetanus, diphtheria, and whooping cough. But, as we learned from efforts to combat the COVID-19 pandemic, a successful global vaccination program must overcome several hurdles. Failure at any stage can limit vaccine uptake and disease control. AREAS COVERED: In this review, we break down the vaccine journey from research and development to delivery into several steps. We also list all the important international organizations trying to support this ecosystem. Then we identify the role of each of these organizations in supporting each of the necessary steps for a successful vaccination program. EXPERT OPINION: The bottlenecks in vaccination can be different for different countries, based on their income and geography. Policy makers need to identify the weaknesses of this ecosystem in different regions of the world and make sure there is adequate global and local support to fill the gaps in the system.

The impact of national income and vaccine hesitancy on country-level COVID-19 vaccine uptake.

BACKGROUND: The rapid development and rollout of COVID-19 vaccines helped reduce the pandemic's mortality burden. The vaccine rollout, however, has been uneven; it is well known that vaccination rates tend to be lower in lower income countries. Vaccine uptake, however, ultimately depends on the willingness of individuals to get vaccinated. If vaccine confidence is low, then uptake will be low, regardless of country income level. We investigated the impact on country-level COVID-19 vaccination rates of both national income and vaccine hesitancy. METHODS: We estimated a linear regression model of COVID-19 vaccine uptake across 145 countries; this cross-sectional model was estimated at each of four time points: 6, 12, 18, and 24 months after the onset of global vaccine distribution. Vaccine uptake reflects the percentage of the population that had completed their primary vaccination series at the time point. Covariates include per capita GDP, an estimate of the percentage of country residents who strongly disagreed that vaccines are safe, and a variety of control variables. Next, we estimated these models of vaccine uptake by country income (countries below, and above the international median per capita GDP) to examine whether the impact of vaccine hesitancy varies by country income. RESULTS: We find that GDP per capita has a pronounced impact on vaccine uptake at 6 months after global rollout. After controlling for other factors, there was a 22 percentage point difference in vaccination rates between the top 20% and the bottom 20% of countries ranked by per capita GDP; this difference grew to 38% by 12 months. The deleterious impact of distrust of vaccine safety on vaccine uptake became apparent by 12 months and then increased over time. At 24 months, there was a 17% difference in vaccination rates between the top 20% and the bottom 20% of countries ranked by distrust. The income stratified models reveal that the deleterious impact of vaccine distrust on vaccine uptake at 12 and 24 months is particularly evident in lower income countries. CONCLUSIONS: Our study highlights the important role of both national income and vaccine hesitancy in determining COVID-19 vaccine uptake globally. There is a need to increase the supply and distribution of pandemic vaccines to lower-income countries, and to take measures to improve vaccine confidence in these countries.