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The Consortium for Medical Marijuana Clinical Outcomes Research, a multi-university collaboration established by the state of Florida in the USA, hosted its second annual Cannabis Clinical Outcomes Research Conference (CCORC) in May 2022. CCORC was held as a hybrid conference, with a scientific program consisting of in-person and virtual sessions. CCORC fostered and disseminated current research on clinical outcomes of medical marijuana while stimulating collaboration and engagement between the scientific community, policymakers, industry representatives, clinicians, and other interested stakeholders. Three themes emerged from conference sessions and speakers: (1) disentangling research findings comparing use and outcomes of medical and nonmedical cannabis, (2) addressing barriers and promoting facilitators for clinical cannabis research, and (3) resolving uncertainties around cannabis dosing. The third annual CCORC is planned for the summer of 2023 in Florida, USA. Keywords: Cannabis clinical outcomes research conference, Conference proceedings, Medical marijuana, Cannabis, Cannabinoids, Cannabidiol, Marijuana efficacy, Marijuana clinical outcomes, Author(s): Nicole E. Smolinski (corresponding author) [a,b,c]; Ruba Sajdeya [c,d]; Robert Cook [c,d,e]; Yan Wang [c,d]; Almut G. Winterstein [a,b,c]; Amie Goodin [a,b,c] Introduction Currently, some form of cannabis is [...]

Objective: More patients are turning to medical marijuana as an alternative treatment, yet there are apparent knowledge gaps on the risk benefit of medical marijuana for a variety of indications. This study aimed to determine the priorities for medical marijuana research from the perspective of multiple stakeholders including patients, clinicians, and industry representatives. Methods: An anonymous survey was administered to attendees of the 2019 American Medical Marijuana Physicians Association annual meeting in Orlando, Florida. Respondents completed the survey on paper or smartphone via Qualtrics. The survey included questions on demographics and medical marijuana research priorities under the following broad categories: clinical conditions, safety issues, marijuana types, populations, and others. Results: Forty-six participants (56.5% female, mean age = 51.6 ± 14.1) responded to the survey. A majority were medical marijuana qualified physicians in Florida (56.5%), 30.5% other physicians or clinicians, and 21.7% medical marijuana patients (multiple choices allowed). The top conditions prioritized for research by this group were chronic pain, cancer, and anxiety, and the top priority safety issues were dosing/product choice, complications from smoking/vaping, and drug interactions. Regarding marijuana types, the group prioritized research on THC/CBD ratios, different modes of consumption, and terpenes. Conclusions: Findings from this survey indicate that medical marijuana stakeholders perceived a broad range of research topics as priorities. More research is needed to advance the evidence in these areas and provide guidance to patients, physicians, and the medical marijuana industry. Keywords: Medical marijuana, Research priorities, Survey, Cannabis, Education, Author(s): Jennifer Jean-Jacques [a]; Robert Cook [a]; Almut G. Winterstein [a,b,c]; Amie Goodin [b]; Joshua D. Brown [b,c]; Sebastian Jugl [b,c]; Yan Wang [a] Introduction Medical marijuana (MM) is increasingly [...]

The Cannabis Clinical Outcomes Research Conference (CCORC) 2021 was held virtually on April 8 and 9, 2021. The conference was hosted by the Consortium for Medical Marijuana Clinical Outcomes Research, a research organization instituted by the state legislature of Florida in the United States. The inaugural annual CCORC 2021 was organized as a scientific meeting to foster and disseminate research on medical marijuana (MM) clinical outcomes, while promoting engagement among MM researchers, patients, clinicians, policymakers, and industry partners. Key conference themes included: (a) the disconnect between policy, practice, and evidence and steps towards reconciliation, (b) approaches to overcome common barriers to MM research, and (c) the use of focused translational approaches utilizing both mechanistic and clinical research methodology to tackle the complexities of MM outcomes. CCORC 2022 is planned for spring 2022 in Orlando, Florida, United States. Keywords: Conference proceedings, Medical marijuana, Cannabis, Marijuana clinical outcomes, Author(s): Amie J. Goodin (corresponding author) [a,b,c]; Debbie L. Wilson [a]; Robert L. Cook [c,d,e]; Yan Wang [c,d]; Joshua Brown [a,b,c]; Almut G. Winterstein [a,b,c,d] Florida is one of 36 [...]

The nature of pharmacokinetic interactions between cytochrome P450 (CYP) 2D6 (CYP2D6)-metabolized opioids and antidepressants among older nursing home residents is unclear. In this study of nursing home residents, concomitant use of CYP2D6-metabolized opioids with CYP2D6-inhibiting antidepressants was associated with higher adjusted rate ratios of worsening pain, pain-related hospitalization, pain-related emergency department visits, and opiate use disorder. These findings suggest the need for caution in prescribing these agents in older patients. Visual Abstract. Clinical and Adverse Outcomes Associated With Concomitant Use of CYP2D6-Metabolized Opioids With Antidepressants in Older Nursing Home Residents: The nature of pharmacokinetic interactions between cytochrome P450 (CYP) 2D6 (CYP2D6)-metabolized opioids and antidepressants among older nursing home residents is unclear. In this study of nursing home residents, concomitant use of CYP2D6-metabolized opioids with CYP2D6-inhibiting antidepressants was associated with higher adjusted rate ratios of worsening pain, pain-related hospitalization, pain-related emergency department visits, and opiate use disorder. These findings suggest the need for caution in prescribing these agents in older patients. Background: Limited evidence exists on the safety of pharmacokinetic interactions of cytochrome P450 (CYP) 2D6 (CYP2D6)-metabolized opioids with antidepressants among older nursing home (NH) residents. Objective: To investigate the associations of concomitant use of CYP2D6-metabolized opioids and antidepressants with clinical outcomes and opioid-related adverse events (ORAEs). Design: Retrospective cohort study using a target trial emulation framework. Setting: 100% Medicare NH sample linked to Minimum Data Set (MDS) from 2010 to 2021. Participants: Long-term residents aged 65 years and older receiving CYP2D6-metabolized opioids with a disease indication for antidepressant use. Intervention: Initiating CYP2D6-inhibiting versus CYP2D6-neutral antidepressants that overlapped with use of CYP2D6-metabolized opioids for 1 day or more. Measurements: Clinical outcomes were worsening pain, physical function, and depression from baseline to quarterly MDS assessments and were analyzed using modified Poisson regression models. The ORAE outcomes included counts of pain-related hospitalizations and emergency department (ED) visits, opioid use disorder (OUD), and opioid overdose and were analyzed with negative binomial or Poisson regression models. All models were adjusted for baseline covariates via inverse probability of treatment weighting. Results: Among 29 435 identified residents, use of CYP2D6-metabolized opioids concomitantly with CYP2D6-inhibiting (vs. CYP2D6-neutral) antidepressants was associated with a higher adjusted rate ratio of worsening pain (1.13 [95% CI, 1.09 to 1.17]) and higher adjusted incidence rate ratios of pain-related hospitalization (1.37 [CI, 1.19 to 1.59]), pain-related ED visit (1.49 [CI, 1.24 to 1.80]), and OUD (1.93 [CI, 1.37 to 2.73]), with no difference in physical function, depression, and opioid overdose. Limitation: Findings are generalizable to NH populations only. Conclusion: Use of CYP2D6-metabolized opioids concomitantly with CYP2D6-inhibiting (vs. CYP2D6-neutral) antidepressants was associated with worsening pain and increased risk for most assessed ORAEs among older NH residents. Primary Funding Source: National Institute on Aging. [ABSTRACT FROM AUTHOR]

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) is indicated after percutaneous coronary intervention (PCI) to reduce the risk of atherothrombotic events. Approximately 30% of the US population has a CYP2C19 no‐function allele that reduces the effectiveness of clopidogrel, but not prasugrel or ticagrelor, after PCI. We have shown improved outcomes with the integration of CYP2C19 genotyping into clinical care to guide the selection of prasugrel or ticagrelor in CYP2C19 no‐function allele carriers. However, the influence of patient‐specific demographic, clinical, and other genetic factors on outcomes with genotype‐guided DAPT has not been defined. In addition, the impact of genotype‐guided de‐escalation from prasugrel or ticagrelor to clopidogrel in patients without a CYP2C19 no‐function allele has not been investigated in a diverse, real‐world clinical setting. The Precision Antiplatelet Therapy after Percutaneous Coronary Intervention (Precision PCI) Registry is a multicenter US registry of patients who underwent PCI and clinical CYP2C19 testing. The registry is enrolling a diverse population, assessing atherothrombotic and bleeding events over 12 months, collecting DNA samples, and conducting platelet function testing in a subset of patients. The registry aims to define the influence of African ancestry and other patient‐specific factors on clinical outcomes with CYP2C19‐guided DAPT, evaluate the safety and effectiveness of CYP2C19‐guided DAPT de‐escalation following PCI in a real‐world setting, and identify additional genetic influences of clopidogrel response after PCI, with the ultimate goal of establishing optimal strategies for individualized antiplatelet therapy that improves outcomes in a diverse, real‐world population. [ABSTRACT FROM AUTHOR]

Real‐world evidence (RWE) has an increasing role in preapproval settings to support the approval of new medicines and indications. The main objectives of this study were to identify and characterize regulatory use cases that utilized RWE and other related observational approaches through targeted review of publications and regulatory review documents. After screening and inclusion/exclusion, the review characterized 85 regulatory applications with RWE. A total of 31 were in oncology and 54 were in non‐oncology therapeutic areas. Most were for indications in adults only (N = 42, 49.4%), while 13 were in pediatrics only (15.3%), and 30 were in both (35.3%). In terms of regulatory context, 59 cases (69.4%) were for an original marketing application, 24 (28.2%) were for label expansion, and 2 (2.4%) were for label modification. Most also received special regulatory designations (e.g., orphan indication, breakthrough therapy, fast track, conditional, and accelerated approvals). There were 42 cases that utilized RWE to support single‐arm trials. External data to support single‐arm trials were utilized in various ways across use cases, including direct matching, benchmarking, natural history studies as well as literature or previous trials. A variety of data sources were utilized, including electronic health records, claims, registries, site‐based charts. Endpoints in oncology use cases commonly included overall survival, progression‐free survival. In 13 use cases, RWE was not considered supportive/definitive in regulatory decision‐making due to design issues (e.g., small sample size, selection bias, missing data). Overall, RWE is utilized in regulatory approval processes for new indications/label expansion across various therapeutic areas with wide range of approaches. Multifaceted cross‐sector efforts are needed to further improve the quality and utility of RWE in regulatory decision‐making. [ABSTRACT FROM AUTHOR]

Background: Hypertension among persons with childbearing potential is on the rise. Maintaining proper blood pressure during pregnancy is vital to prevent maternal and neonatal complications. Yet, limited evidence on the risk-benefit of various antihypertensives presents challenges for informed decision-making during this critical period. This study aimed to examine the utilization patterns of different classes of antihypertensives among persons with pre-existing hypertension before, during, and after pregnancy. Methods: We used MarketScan® Commercial Database 2011−2020 to analyze antihypertensive utilization among pregnant persons aged 12 to 55 identified via a validated algorithm. Pre-existing hypertension was defined as ≥1 inpatient or ≥2 outpatient encounters for hypertension within the 180 days preceding the LMP. Antihypertensive utilization was described during target periods: 0–3 months (0-3M) before pregnancy, 1st/2nd/3rd trimester (T1/2/3), 0-3M, and 4-6M after pregnancy. Results: We identified 1,950,292 pregnancies, of which 20,576 (12,978 live and 7,598 non-live) had pre-existing hypertension. Both groups had similar antihypertensive use (80.1% and 81.0%, respectively) during the 6 months before pregnancy (baseline). For live-birth pregnancies, 13.9% of baseline users discontinued treatment during pregnancy, while 28.9% of non-users initiated antihypertensives during pregnancy, and 17.2% started postpartum. Before pregnancy, the predominant antihypertensives included thiazide diuretics (21.9%), combined α- and β-blockers (18.4%), and dihydropyridines (16.2%). During pregnancy, thiazide diuretics, cardioselective β-blockers, and ACE inhibitors declined (T3: 3.0%, 4.2%, and 0.8%). Dihydropyridine use was steady during pregnancy, but preference shifted from amlodipine to nifedipine in T3 (2.2.% vs.10.8%). Central α2‐agonists increased during pregnancy (up to 15.2% in T3) compared to both pre- (9.8%) and post-pregnancy (5.7%). ARBs mirrored ACE inhibitors, with less than 1% utilization in later trimesters. Combination agents dropped from 10.8% pre-pregnancy to 0.8% in T3, then rebounded to 7.3% post-pregnancy. Conclusion: Research is warranted to evaluate the choice of antihypertensives and optimal timing to switch to safer alternatives, considering maternal and fetal outcomes. [ABSTRACT FROM AUTHOR]

Background: The cost of medically attended RSV LRI (lower respiratory infection) is critical in determining the economic value of new RSV immunoprophylaxes. However, most studies have focused on intermittent RSV encounters, not the episode of care that captures the entirety of RSV illness. Methods: We created age‐ and condition‐specific cohorts of children under 5 years of age using MarketScan® data (2015–2019). We contrasted aggregating healthcare costs over RSV‐LRTI episodes to ascertaining costs based on RSV‐specific encounters only. Economic burden was estimated by multiplying costs per encounter or per episode by their respective incidence rates. Results: Average cost was higher per episode than per encounter regardless of settings (inpatient: $28,586 vs. $18,056 and outpatient/ED: $2099 vs. $407 for infants). Across ages, the economic burden was highest for infants and RSV‐LRTI requiring inpatient care, but the burden in outpatient/ED settings was disproportionately higher than costs due to higher incidence rates (for inpatient vs. outpatient episodes: $226,403 vs. $101,269; for inpatient vs. outpatient encounters: $151,878 vs. $38,819 per 1000 infant‐years). For high‐risk children, cost and burden were up to 3–10 times higher, respectively. Conclusions: With a comprehensive stratification by settings and risk condition, the encounter‐ versus episode‐based estimates provide a robust range for policymakers' economic appraisal of new RSV immunoprophylaxes. [ABSTRACT FROM AUTHOR]

Background: Most US children with acute otitis media [AOM] receive prompt antibiotic treatment, though guidelines encourage watchful waiting. Previous systematic reviews of antibiotics versus watchful waiting have focused on symptom resolution and RCTs, limiting the assessment of serious, rare complications. We sought to evaluate these complications by including observational studies. Methods: RCTs and observational studies that compared antibiotics to placebo or watchful waiting for pediatric clinician diagnosed AOM were identified [PubMed/MEDLINE, Embase, Cochrane Database of Systematic Reviews, Central Register of Controlled Trials, and Web of Science] and reviewed for meta-analysis. Two reviewers independently extracted study characteristics, patient characteristics, and outcomes. We assessed publication bias, study bias with ROBINS-1 and RoB-2 and used random-effects models to assess treatment effects. Results: 24 studies were included. Antibiotics decreased the risk of acute mastoiditis [incidence 0.02%, RR 0.48, 95% CI 0.40–0.59; NNT 5,368]. This protective effect may be underestimated because of misclassification of non-suppurative conditions as AOM. Intracranial complications remained too rare to assess. Antibiotics markedly increased the risk of adverse effects [incidence 10.5%, RR 1.49, 1.27–1.73; NNH 23]. Studies used non-specific criteria for acute mastoiditis, potentially underestimating treatment effects. Conclusions: Prompt antibiotic therapy reduces the risk for some AOM complications. The NNT to prevent serious, rare complications is high, while the NNH is relatively low. Large-scale population-based observational studies using real-world datasets with validated measures of severe complications are needed to improve understanding of risk factors for serious AOM complications, facilitate more selective antibiotic therapy, and optimize individual outcomes and public health. [ABSTRACT FROM AUTHOR]

Background Injury, prevalent and potentially associated with prescription opioid use among older adults, has been implicated as a warning sign of serious opioid-related adverse events (ORAEs) including opioid misuse, dependence, and poisoning, but this association has not been empirically tested. The study aims to examine the association between incident injury after prescription opioid initiation and subsequent risk of ORAEs and to assess whether the association differs by recency of injury among older patients. Methods and findings This nested case-control study was conducted within a cohort of 126,752 individuals aged 65 years or older selected from a 5% sample of Medicare beneficiaries in the United States between 2011 and 2018. Cohort participants were newly prescribed opioid users with chronic noncancer pain who had no injury or ORAEs in the year before opioid initiation, had 30 days or more of observation, and had at least 1 additional opioid prescription dispensed during follow-up. We identified ORAE cases as patients who had an inpatient or outpatient encounter with diagnosis codes for opioid misuse, dependence, or poisoning. During a mean follow-up of 1.8 years, we identified 2,734 patients who were newly diagnosed with ORAEs and 10,936 controls matched on the year of cohort entry date and a disease risk score (DRS), a summary score derived from the probability of an ORAE outcome based on covariates measured prior to cohort entry and in the absence of injury. Multivariate conditional logistic regression was used to estimate ORAE risk associated with any and recency of injury, defined based on the primary diagnosis code of inpatient and outpatient encounters. Among the cases and controls, 68.0% (n = 1,859 for cases and n = 7,436 for controls) were women and the mean (SD) age was 74.5 (6.9) years. Overall, 54.0% (n = 1,475) of cases and 46.0% (n = 1,259) of controls experienced incident injury after opioid initiation. Patients with (versus without) injury after opioid therapy had higher risk of ORAEs after adjustment for time-varying confounders, including diagnosis of tobacco or alcohol use disorder, drug use disorder, chronic pain diagnosis, mental health disorder, pain-related comorbidities, frailty index, emergency department visit, skilled nursing facility stay, anticonvulsant use, and patterns of prescription opioid use (adjusted odds ratio [aOR] = 1.4; 95% confidence interval (CI) 1.2 to 1.5; P < 0.001). Increased risk of ORAEs was associated with current ([less than or equal to]30 days) injury (aOR = 2.8; 95% CI 2.3 to 3.4; P < 0.001), whereas risk of ORAEs was not significantly associated with recent (31 to 90 days; aOR = 0.93; 95% CI 0.73 to 1.17; P = 0.48), past (91 to 180 days; aOR = 1.08; 95% CI 0.88 to 1.33; P = 0.51), and remote (181 to 365 days; aOR = 0.88; 95% CI 0.73 to 1.1; P = 0.18) injury preceding the incident diagnosis of ORAE or matched date. Patients with injury and prescription opioid use versus those with neither in the month before the ORAE or matched date were at greater risk of ORAEs (aOR = 5.0; 95% CI 4.1 to 6.1; P < 0.001). Major limitations are that the study findings can only be generalized to older Medicare fee-for-service beneficiaries and that unknown or unmeasured confounders have the potential to bias the observed association toward or away from the null. Conclusions In this study, we observed that incident diagnosis of injury following opioid initiation was associated with subsequent increased risk of ORAEs, and the risk was only significant among patients with injury in the month before the index date. Regular monitoring for injury may help identify older opioid users at high risk for ORAEs., Author(s): Yu-Jung Jenny Wei 1,2,3,*, Cheng Chen 4, Ting-Yuan David Cheng 5, Siegfried O. Schmidt 6, Roger B. Fillingim 7, Almut G. Winterstein 1,2,8 Introduction Older adults in the United [...]

Background: Observational designs can complement evidence from randomized controlled trials not only in situations when randomization is not feasible, but also by evaluating drug effects in real‐world, considering a broader spectrum of users and clinical scenarios. However, use of such real‐world scenarios captured in routinely collected clinical or administrative data also comes with specific challenges. Unlike in trials, medication use is not protocol based. Instead, exposure is determined by a multitude of factors involving patients, providers, healthcare access, and other policies. Accurate measurement of medication exposure relies on a similar broad set of factors which, if not understood and appropriately addressed, can lead to exposure misclassification and bias. Aim: To describe core considerations for measurement of medication exposure in routinely collected healthcare data. Methods: We describe the strengths and weaknesses of the two main types of routinely collected healthcare data (electronic health records and administrative claims) used in pharmacoepidemiologic research. We introduce key elements in those data sources and issues in the curation process that should be considered when developing exposure definitions. We present challenges in exposure measurement such as the appropriate determination of exposure time windows or the delineation of concomitant medication use versus switching of therapy, and related implications for bias. Results: We note that true exposure patterns are typically unknown when using routinely collected healthcare data and that an in‐depth understanding of healthcare delivery, patient and provider decision‐making, data documentation and governance, as well as pharmacology are needed to ensure unbiased approaches to measuring exposure. Conclusions: Various assumptions are made with the goal that the chosen exposure definition can approximate true exposure. However, the possibility of exposure misclassification remains, and sensitivity analyses that can test the impact of such assumptions on the robustness of estimated medication effects are necessary to support causal inferences. [ABSTRACT FROM AUTHOR]