Assessing Heterogeneity of Treatment Effect in Real-World Data.

Increasing availability of real-world data (RWD) generated from patient care enables the generation of evidence to inform clinical decisions for subpopulations of patients and perhaps even individuals. There is growing opportunity to identify important heterogeneity of treatment effects (HTE) in these subgroups. Thus, HTE is relevant to all with interest in patients' responses to interventions, including regulators who must make decisions about products when signals of harms arise postapproval and payers who make coverage decisions based on expected net benefit to their beneficiaries. Prior work discussed HTE in randomized studies. Here, we address methodological considerations when investigating HTE in observational studies. We propose 4 primary goals of HTE analyses and the corresponding approaches in the context of RWD: to confirm subgroup effects, to describe the magnitude of HTE, to discover clinically important subgroups, and to predict individual effects. We discuss other possible goals including exploring prognostic score- and propensity score-based treatment effects, and testing the transportability of trial results to populations different from trial participants. Finally, we outline methodological needs for enhancing real-world HTE analysis.

Ambulatory noninsulin treatment of type 2 diabetes mellitus in the United States, 2015 to 2019.

OBJECTIVE: To examine trends in the noninsulin drug treatment of type 2 diabetes, including first- and second-line therapies on top of metformin, from 2015 to 2019. PARTICIPANTS AND METHODS: We conducted a descriptive analysis of cross-sectional data using the IQVIA National Disease and Therapeutic Index, a nationally representative audit of ambulatory physician practices in the United States. We focused on the use of noninsulin pharmacological treatments for type 2 diabetes among individuals aged 35 years and older between January 1, 2015 and December 31, 2019. The main outcome was type 2 diabetes visits where a prescription drug was used ("treatment visit"). RESULTS: Ambulatory diabetes visits decreased from 30.1 million treatment visits in 2015 to 29.5 million treatment visits in 2019. Among treatment visits where a single drug was prescribed, the use of metformin declined from 57.0% of monotherapy in 2015 to 46.0% of monotherapy in 2019, while during the same period the share of monotherapy accounted for by glucagon-like peptide-1 (GLP-1) receptor agonists increased from 4.3% to 8.5% and the share accounted for by sodium-glucose cotransporter-2 (SGLT2) inhibitors increased from 7.3% to 19.5%. Among treatment visits where metformin plus another drug was prescribed, the share of second-line therapy accounted for by dipeptidyl peptidase-4 (DPP-4) inhibitors decreased from 21.9% of treatment visits in 2015 to 20.8% of treatment visits in 2019; sulphonylurea use declined from 45.2% to 32.7%, use of SGLT2 inhibitors increased from 14.5% to 21.2% and use of GLP-1 receptor agonists increased from 9.8% to 18.2%. CONCLUSIONS: Significant changes in the landscape of ambulatory care for diabetes have taken place during the past 6 years, including moderate declines in metformin monotherapy, moderate declines in second-line sulphonylurea use, and large increases in SGLT2 use. These changes underscore the dynamic nature of drug utilization for diabetes in the United States, and reflect the effects of emerging evidence, evolving clinical guidelines and evolving regulatory and payment policies.

Key Evidence Supporting Prescription Opioids Approved by the U.S. Food and Drug Administration, 1997 to 2018.

BACKGROUND: Little is known about the evidence required by the U.S. Food and Drug Administration (FDA) for new approvals of opioid analgesics. OBJECTIVE: To characterize the quality of safety and efficacy data in new drug applications (NDAs) for opioid analgesics approved by the FDA between 1997 and 2018. DESIGN: Cross-sectional analysis. SETTING: Data from ClinicalTrials.gov, FDA reviews, and peer-reviewed publications. PARTICIPANTS: Patients with pain who participated in phase 3 pivotal trials. INTERVENTION: FDA-approved opioid analgesics. MEASUREMENTS: Key characteristics of each NDA, including the number, size, and duration of pivotal trials; trial control groups; the use of enriched trial populations; and systematically measured safety outcomes. RESULTS: Most of the 48 NDAs evaluated were for new dosage forms (n = 25 [52.1%]) or new formulations (n = 9 [18.8%]); only 1 (2.1%) was for a new molecular entity. Of 39 NDAs approved for treating chronic pain, only 21 products were supported by at least 1 pivotal trial; these trials (n = 28) had a median duration of 84 days (interquartile range [IQR], 25 to 84 days) and enrolled a median of 299 patients (IQR, 174 to 525 patients). Seventeen (81%) of these products were approved on the basis of designs that excluded patients who could not tolerate the drugs, had early adverse effects, or reported few immediate benefits. Among NDAs for chronic pain, 8 (20.5%) included pooled safety reviews that reported systematic assessment of diversion, 7 (17.9%) reported systematic measurement of nonmedical use, and 15 (38.5%) assessed development of tolerance. Eight of 9 products for acute pain were supported by at least 1 pivotal trial; the pivotal trials (n = 19) had a median duration of 1 day (IQR, 1 to 2 days) and enrolled a median of 329 patients (IQR, 199 to 456 patients). Although all but 1 of the 48 approved NDAs were for previously approved moieties, analysis of available NDAs for referent products yielded similar findings. LIMITATIONS: The analysis was limited to approved opioids. Animal studies and nonpivotal trials were excluded. Evidence for safety in NDAs was presented for chronic pain only. CONCLUSION: Between 1997 and 2018, the FDA approved opioids on the basis of pivotal trials of short or intermediate duration, often in narrowly defined pain populations of patients who could tolerate the drug. Systematic collation of certain important safety outcomes was rare. PRIMARY FUNDING SOURCE: None.

Assessing and communicating heterogeneity of treatment effects for patient subpopulations: Keynote and panel discussion on communicating heterogeneous treatment effects across populations.

How do we communicate nuanced regulatory information to different audiences, recognizing that the consumer audience is very different from the physician audience? In particular, how do we communicate the heterogeneity of treatment effects - the potential differences in treatment effects based on sex, race, and age? That is a fundamental question at the heart of this panel discussion. Each panelist addressed a specific "challenge question" during their 5-minute presentation, and the list of questions is provided. The presentations were followed by a question and answer session with members of the audience and the panelists.

Assessment of the FDA Risk Evaluation and Mitigation Strategy for Transmucosal Immediate-Release Fentanyl Products.

IMPORTANCE: Transmucosal immediate-release fentanyls (TIRFs), indicated solely for breakthrough cancer pain in opioid-tolerant patients, are subject to a US Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) to prevent them from being prescribed inappropriately. OBJECTIVES: To evaluate knowledge assessments of pharmacists, prescribers, and patients regarding appropriate TIRF use; to describe sponsor assessments, based on claims data, of whether the REMS program was meeting its goals; and to characterize how the FDA responded to REMS assessments. DESIGN, SETTING, AND PARTICIPANTS: Qualitative analysis of 4877 pages of FDA documents obtained through a Freedom of Information Act request, including 6 annual REMS assessment reports (2012-2017), FDA evaluations of these reports, and FDA-sponsor correspondence about safety issues. EXPOSURE: A REMS program to reduce the risk of adverse outcomes, including misuse, abuse, addiction, and overdose, arising from use of TIRFs. MAIN OUTCOMES AND MEASURES: (1) Knowledge assessments of pharmacists, prescribers, and patients; (2) survey and claims-based prescribing assessments; (3) FDA and TIRF sponsor communications; (4) modifications to the REMS program; and (5) disenrollment of noncompliant prescribers. RESULTS: Twelve months after initiation of the program, 24 of 302 pharmacists (7.9%), 35 of 302 prescribers (11.6%), and 5 of 192 patients (2.6%) incorrectly reported that TIRFs can be prescribed to opioid-nontolerant patients, with similar levels of misunderstanding maintained in the subsequent reports. At 60 months, product-specific analyses of claims data indicated that between 34.6% and 55.4% of patients prescribed TIRFs were opioid-nontolerant. In the 48-month survey, 106 of 310 prescribers (34.2%) reported prescribing TIRFs for opioid-tolerant patients with chronic, noncancer pain; at 60 months, 54 of 302 prescribers (18.4%) and 148 of 310 patients (47.7%) erroneously reported that TIRFs were FDA-approved for such use. Over the 60-month period examined, there were few substantive changes made to the REMS to address evidence of high rates of off-label TIRF use, and, although the REMS program had a noncompliance plan, there was no report of prescribers being disenrolled for inappropriate prescribing. CONCLUSIONS AND RELEVANCE: In this review of FDA documents pertaining to the TIRF REMS, surveys of pharmacists, prescribers, and patients reflected generally high levels of knowledge regarding proper TIRF prescribing, yet some survey items as well as claims-based analyses indicated substantial rates of inappropriate TIRF use. Despite these findings, the FDA did not require substantive changes to the program.

Clinical trial registration and reporting: a survey of academic organizations in the United States.

BACKGROUND: Many clinical trials conducted by academic organizations are not published, or are not published completely. Following the US Food and Drug Administration Amendments Act of 2007, "The Final Rule" (compliance date April 18, 2017) and a National Institutes of Health policy clarified and expanded trial registration and results reporting requirements. We sought to identify policies, procedures, and resources to support trial registration and reporting at academic organizations. METHODS: We conducted an online survey from November 21, 2016 to March 1, 2017, before organizations were expected to comply with The Final Rule. We included active Protocol Registration and Results System (PRS) accounts classified by ClinicalTrials.gov as a "University/Organization" in the USA. PRS administrators manage information on ClinicalTrials.gov. We invited one PRS administrator to complete the survey for each organization account, which was the unit of analysis. RESULTS: Eligible organization accounts (N = 783) included 47,701 records (e.g., studies) in August 2016. Participating organizations (366/783; 47%) included 40,351/47,701 (85%) records. Compared with other organizations, Clinical and Translational Science Award (CTSA) holders, cancer centers, and large organizations were more likely to participate. A minority of accounts have a registration (156/366; 43%) or results reporting policy (129/366; 35%). Of those with policies, 15/156 (11%) and 49/156 (35%) reported that trials must be registered before institutional review board approval is granted or before beginning enrollment, respectively. Few organizations use computer software to monitor compliance (68/366; 19%). One organization had penalized an investigator for non-compliance. Among the 287/366 (78%) accounts reporting that they allocate staff to fulfill ClinicalTrials.gov registration and reporting requirements, the median number of full-time equivalent staff is 0.08 (interquartile range = 0.02-0.25). Because of non-response and social desirability, this could be a "best case" scenario. CONCLUSIONS: Before the compliance date for The Final Rule, some academic organizations had policies and resources that facilitate clinical trial registration and reporting. Most organizations appear to be unprepared to meet the new requirements. Organizations could enact the following: adopt policies that require trial registration and reporting, allocate resources (e.g., staff, software) to support registration and reporting, and ensure there are consequences for investigators who do not follow standards for clinical research.

National Trends in Use of Sodium-Glucose Cotransporter-2 Inhibitors and Glucagon-like Peptide-1 Receptor Agonists by Cardiologists and Other Specialties, 2015 to 2020.

Background Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) mitigate cardiovascular risk in individuals with type 2 diabetes, but most eligible patients do not receive them. We characterized temporal trends in SGLT2i and GLP-1RA use by cardiologists compared with other groups of clinicians. Methods and Results We conducted a descriptive analysis of serial, cross-sectional data derived from IQVIA's National Prescription Audit, a comprehensive audit capturing ≈90% of US retail prescription dispensing and projected to population-level data, to estimate monthly SGLT2is and GLP-1RAs dispensed from January 2015 to December 2020, stratified by prescriber specialty and molecule. We also used the American Medical Association's Physician Masterfile to calculate average annual SGLT2is and GLP-1RAs dispensed per physician. Between January 2015 and December 2020, a total of 63.2 million SGLT2i and 63.4 million GLP-1RA prescriptions were dispensed in the United States. Monthly prescriptions from cardiologists increased 12-fold for SGLT2is (from 2228 to 25 815) and 4-fold for GLP-1RAs (from 1927 to 6981). Nonetheless, cardiologists represented only 1.5% of SGLT2i prescriptions and 0.4% of GLP-1RA prescriptions in 2020, while total use was predominated by primary care physicians/internists (57% of 2020 SGLT2is and 52% of GLP-1RAs). Endocrinologists led in terms of prescriptions dispensed per physician in 2020 (272 SGLT2is and 405 GLP-1RAs). Cardiologists, but not noncardiologists, increasingly used SGLT2is over GLP-1RAs, with accelerated uptake of empagliflozin and dapagliflozin coinciding with their landmark cardiovascular outcomes trials and subsequent US Food and Drug Administration label expansions. Conclusions While use of SGLT2is and GLP-1RAs by cardiologists in the United States increased substantially over a 6-year period, cardiologists still account for a very small proportion of all use, contributing to marked undertreatment of individuals with type 2 diabetes at high cardiovascular risk.

Trends in Insulin Types and Devices Used by Adults With Type 2 Diabetes in the United States, 2016 to 2020.

Importance: Despite rising costs and public scrutiny devoted to insulin, less is known regarding recent trends in its ambulatory use in the United States. Objective: To characterize trends in ambulatory insulin use, overall and based on insulin characteristics, among adults with type 2 diabetes in the United States from January 1, 2016, through December 31, 2020. Design, Setting, and Participants: This serial cross-sectional study included patients whose data were collected in IQVIA's National Disease and Therapeutic Index (NDTI), a 2-stage, all-payer, nationally representative audit of outpatient care. Approximately 4800 physicians each calendar quarter completed a form for 2 consecutive days regarding visits for each of their patients, including diagnoses, treatments, and demographic information. Data were collected from January 2016 through December 2020. Exposures: Ambulatory use of insulin. Main Outcomes and Measures: Nationally representative projections for ambulatory use of insulin (ie, treatment visits), overall and aggregated by insulin molecule (insulins regular, neutral protamine Hagedorn [NPH], lispro, glulisine, glargine, detemir, degludec, and aspart), delivery devices (vials/syringes or pens), therapeutic class (short-acting, rapid-acting, long-acting, intermediate-acting, and premixed insulin), insulin type (human, analog, and biosimilar), and date of approval (newer: before 2010; and older: after 2010). Results: There were 27 860 691 insulin treatment visits between 2016 and 2020. Among all patient encounters that indicated use of insulin in 2020, 1 989 154 (43.9%) were among those aged 60 to 74 years; 2 372 629 (52.4%) among men; 2 646 247 (58.4%) among White patients; 811 639 (17.9%) among Black patients; and 701 912 (15.5%) among Hispanic patients. Insulin glargine was the most frequently used insulin from 2016 to 2020, accounting for approximately half of treatment visits (eg, 2020: 2.6 of 4.9 million visits; 95% CI, 2.1-3.1 million). Among insulin classes, long-acting insulin accounted for approximately two-thirds of treatment visits during this period (eg, 2020: 3.7 million visits; 95% CI, 3.0-4.4 million). Treatment visits for insulin pens increased from 36.1% in 2016 (2.2 of 6.0 million visits; 95% CI, 1.7-2.7 million) to 58.7% in 2020 (2.9 million visits; 95% CI, 2.3-3.5 million), while use of insulin vials/syringes declined in parallel. Analog insulin use predominated and accounted for more than 80% of total treatment visits across all years (eg, 2020: 4.3 million visits; 95% CI, 3.4-5.1 million). Newer insulins were increasingly used, from 18.1% of total treatment visits in 2016 (1.1 million visits; 95% CI, 0.8-1.4 million) to 40.9% in 2020 (2.0 million visits; 95% CI, 1.5-2.5 million). The use of biosimilar insulin, which was first approved in 2015, increased from 2.6% in 2017 (0.1 of 5.3 million visits; 95% CI, 0.04-0.2 million) to 8.2% in 2020 (0.4 million visits; 95% CI, 0.2-0.6 million) of total insulin treatment visits. The total number of insulin treatment visits declined from a peak of 6.0 million visits in 2016 to a nadir of 4.9 million visits in 2020 (approximately 18% decline). Conclusions and Relevance: In this study, ambulatory insulin use in the United States during the past 5 years remained dominated by the use of insulin analogs and insulin pen delivery devices, with increasing uptake of newer products as they have been brought to market.

Lower Use of Biologics for the Treatment of Asthma in Publicly Insured Individuals.

BACKGROUND: Despite bearing a disproportionate burden of poorly controlled asthma, publicly insured individuals are less likely to receive biologics. OBJECTIVE: To assess biologic use by payer among individuals with asthma. METHODS: We used IQVIA's National Disease and Therapeutic Index, a nationally representative, all-payer audit of ambulatory care in the United States, to describe the patterns of use by payer. RESULTS: Asthma treatment visits in which a biologic product was reported increased from approximately 0.1% of asthma-related visits in 2003 to 1% in 2015 and doubled to 2% by 2019. Omalizumab use initially increased from 2003 to 2006 and plateaued till 2015 when its use declined modestly, coinciding with the release of additional biologic products. In 2019, omalizumab accounted for 37% of biologic treatment visits, mepolizumab 21%, benralizumab 27%, dupilumab 15%, and reslizumab <1%. Biologic treatment visits were higher for privately insured individuals (28.3 per 1000 visits) compared with publicly insured individuals (16.3 per 1000 visits). This difference persisted after accounting for age, sex, and race using nationally representative estimates. White patients accounted for a disproportionate amount of biologic treatment visits among the publicly insured (80%) despite accounting for only 60% of publicly insured asthma treatment visits. No biologic treatment visits were observed for individuals who were uninsured. Half of dupilumab visits were for publicly insured patients, compared with 22% of mepolizumab/benralizumab and 27% of omalizumab visits. CONCLUSION: Biologics were uncommonly used among patients with asthma, and the basis for disproportionately lower use of biologics among the publicly insured, where the burden of uncontrolled asthma is greatest, merits further investigation.

Primary care physicians' preparedness to treat opioid use disorder in the United States: A cross-sectional survey.

BACKGROUND: Efforts to increase opioid use disorder (OUD) treatment have focused on primary care. We assessed primary care physicians' preparedness to identify and treat individuals with OUD and barriers to increasing buprenorphine prescribing. METHODS: We conducted a cross-sectional survey from January-August 2020 which assessed perceptions of the opioid epidemic; comfort screening, diagnosing, and treating individuals with OUD with medications; and barriers to obtaining a buprenorphine waiver and prescribing buprenorphine in their practice. Primary care physicians were sampled from the American Medical Association Physician Master File (n = 1000) and contacted up to 3 times, twice by mail and once by e-mail. RESULTS: Overall, 173 physicians (adjusted response rate 27.3 %) responded. While most were somewhat or very comfortable screening (80.7 %) and diagnosing (79.3 %) OUD, fewer (36.9 %) were somewhat or very comfortable treating OUD with medications. One third of respondents were in a practice where they or a colleague were waivered and 10.7 % of respondents had a buprenorphine waiver. The most commonly cited barriers to both obtaining a waiver and prescribing buprenorphine included lack of access to addiction, behavioral health, or psychiatric co-management, lack of experience treating OUD, preference not to be inundated with requests for buprenorphine, and the buprenorphine training requirement. CONCLUSIONS: While most primary care physicians reported comfort screening and diagnosing OUD, fewer were comfortable treating OUD with medications such as buprenorphine and even fewer were waivered to do so. Addressing provider self-efficacy and willingness, and identifying effective, coordinated, and comprehensive models of care may increase OUD treatment with buprenorphine.

Variation in the estimated costs of pivotal clinical benefit trials supporting the US approval of new therapeutic agents, 2015-2017: a cross-sectional study.

OBJECTIVES: Little is routinely disclosed about the costs of the pivotal clinical trials that provide the key scientific evidence of the treatment benefits of new therapeutic agents. We expand our earlier research to examine why the estimated costs may vary 100-fold. DESIGN: A cross-sectional study of the estimated costs of the pivotal clinical trials supporting the approval of 101 new therapeutic agents approved by the US Food and Drug Administration from 2015 to 2017. METHODS: We licensed a software tool used by the pharmaceutical industry to estimate the likely costs of clinical trials to be conducted by contract research organisations. For each trial we collected 52 study characteristics. Linear regression was used to assess the most important factors affecting costs. PRIMARY AND SECONDARY OUTCOME MEASURES: The mean and 95% CI of 225 pivotal clinical trials using varying assumptions. We also assessed median estimated costs per patient, per clinic visit and per drug. RESULTS: Measured as pivotal trials cost per approved drug, the 101 new molecular entities had an estimated median cost of US$48 million (IQR US$20 million-US$102 million). The 225 individual clinical trials had a median estimate of US$19 million (IQR US$12 million-US$33 million) per trial and US$41 413 (IQR, US$29 894-US$75 047) per patient. The largest single factor driving cost was the number of patients required to establish the treatment effects and varied from 4 patients to 8442. Next was the number of trial clinic visits, which ranged from 2 to 166. Our statistical model showed trial costs rose exponentially with these two variables (R2=0.696, F=257.9, p<0.01). CONCLUSIONS: The estimated costs are modest for measuring the benefits of new therapeutic agents but rise exponentially as more patients and clinic visits are required to establish a drug effect.

Association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and lower extremity amputation: A systematic review and meta-analysis.

BACKGROUND: The association between sodium-glucose cotransporter 2 inhibitors (SGLT2i's) and lower extremity amputation is unclear. PURPOSE: To systematically review randomized control trials (RCTs) and observational studies quantifying risk of lower extremity amputations associated with SGLT2i use. DATA SOURCES AND STUDY SELECTION: We searched PubMed, EMBASE, Scopus, and the Cochrane Central Register of Controlled Trials from January 2011 to February 2020 for RCTs and observational studies including lower extremity amputation outcomes for individuals with type 2 diabetes mellitus treated with SGLT2i's vs. alternative treatments or placebo. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data. MAIN OUTCOMES AND MEASURES: Our primary outcome was risk of lower limb amputation. Secondary outcomes included peripheral arterial disease, peripheral vascular disease, venous ulcerations, and diabetic foot infections. We also evaluated the risk of bias. We conducted random and fixed effects relative risk meta-analysis of RCTs. RESULTS: After screening 2,006 studies, 12 RCTs and 18 observational studies were included, of which 7 RCTs and 18 observational studies had at least one event. The random effects meta-analysis of 7 RCTs suggested the absence of a statistically significant association between SGLT2i exposure with evidence of substantial statistical heterogeneity (n = 424/23,716 vs n = 267/18,737 in controls; RR 1.28, CI's 0.93-1.76; I2 = 62.0%; p = 0.12) whereas fixed effects analysis showed an increased risk with statistical heterogeneity (RR 1.27, 1.09-1.48; I2 = 62%; p = 0.003). Subgroup analysis of canagliflozin vs placebo showed a statistically significantly increased risk in a fixed effects meta-analysis (n = 2 RCTs, RR 1.59, 1.26-2.01; I2 = 88%; p = 0.0001) whereas the meta-analysis of dapagliflozin or empagliflozin (n = 2 RCTs each) and a single RCT for ertugliflozin did not show a significantly increased risk. The findings from observational studies were too heterogeneous to be pooled in a meta-analysis and draw meaningful conclusions. Both randomized and observational studies were of generally good methodological quality. CONCLUSIONS: Overall, there was no consistent evidence of SGLT2i exposure and increased risk of amputation. The increased risk of amputation seen in the large, long-term Canagliflozin Cardiovascular Assessment Study (CANVAS) trial for canagliflozin, and select observational studies, merits continued exploration.

Use and Content of Primary Care Office-Based vs Telemedicine Care Visits During the COVID-19 Pandemic in the US.

Importance: Little is known about the association between the coronavirus disease 2019 (COVID-19) pandemic and the level and content of primary care delivery in the US. Objective: To quantify national changes in the volume, type, and content of primary care delivered during the COVID-19 pandemic, especially with regard to office-based vs telemedicine encounters. Design, Setting, and Participants: Analysis of serial cross-sectional data from the IQVIA National Disease and Therapeutic Index, a 2-stage, stratified nationally representative audit of outpatient care in the US from the first calendar quarter (Q1) of 2018 to the second calendar quarter (Q2) of 2020. Main Outcomes and Measures: Visit type (office-based or telemedicine), overall and stratified by patient population and geographic region; assessment of blood pressure or cholesterol measurement; and initiation or continuation of prescription medications. Results: In the 8 calendar quarters between January 1, 2018, and December 31, 2019, between 122.4 million (95% CI, 117.3-127.5 million) and 130.3 million (95% CI, 124.7-135.9 million) quarterly primary care visits occurred in the US (mean, 125.8 million; 95% CI, 121.7-129.9 million), most of which were office-based (92.9%). In 2020, the total number of encounters decreased to 117.9 million (95% CI, 112.6-123.2 million) in Q1 and 99.3 million (95% CI, 94.9-103.8 million) in Q2, a decrease of 21.4% (27.0 million visits) from the average of Q2 levels during 2018 and 2019. Office-based visits decreased 50.2% (59.1 million visits) in Q2 of 2020 compared with Q2 2018-2019, while telemedicine visits increased from 1.1% of total Q2 2018-2019 visits (1.4 million quarterly visits) to 4.1% in Q1 of 2020 (4.8 million visits) and 35.3% in Q2 of 2020 (35.0 million visits). Decreases occurred in blood pressure level assessment (50.1% decrease, 44.4 million visits) and cholesterol level assessment (36.9% decrease, 10.2 million visits) in Q2 of 2020 compared with Q2 2018-2019 levels, and assessment was less common during telemedicine than during office-based visits (9.6% vs 69.7% for blood pressure; P < .001; 13.5% vs 21.6% for cholesterol; P < .001). New medication visits in Q2 of 2020 decreased by 26.0% (14.1 million visits) from Q2 2018-2019 levels. Telemedicine adoption occurred at similar rates among White individuals and Black individuals (19.3% vs 20.5% of patient visits, respectively, in Q1/Q2 of 2020), varied by region (low of 15.1% of visits [East North Central region], high of 26.8% of visits [Pacific region]), and was not correlated with regional COVID-19 burden. Conclusions and Relevance: The COVID-19 pandemic has been associated with changes in the structure of primary care delivery, with the content of telemedicine visits differing from that of office-based encounters.

Evaluation of the Extended-Release/Long-Acting Opioid Prescribing Risk Evaluation and Mitigation Strategy Program by the US Food and Drug Administration: A Review.

Importance: Extended-release/long-acting (ER/LA) opioids have caused substantial morbidity and mortality in the United States, yet little is known about the efforts of the US Food and Drug Administration (FDA) and drug manufacturers to reduce adverse outcomes associated with inappropriate prescribing or use. This review of 9739 pages of FDA documents obtained through a Freedom of Information Act request aimed to investigate whether the FDA and ER/LA manufacturers were able to assess the effectiveness of the ER/LA Risk Evaluation and Mitigation Strategy (REMS) program by evaluating manufacturer REMS assessments and FDA oversight of these assessments. Observations: The REMS program was implemented largely as planned. The FDA's goal was for 60% of ER/LA prescribers to take REMS-adherent continuing education (CE) between 2012 and 2016; 27.6% (88 316 of 320 000) of prescribers had done so by 2016. Audits of REMS programs indicated close adherence to FDA content guidelines except for financial disclosures. Nonrepresentative cross-sectional surveys of self-selected prescribers suggested modestly greater ER/LA knowledge among CE completers than noncompleters, and claims-based surveillance indicated slowly declining ER/LA prescribing, although the contribution of the REMS to these trends could not be assessed. The effectiveness of the REMS program for reducing adverse outcomes also could not be assessed because the analyses used nonrepresentative samples, lacked adequate controls for confounding, and did not link prescribing or clinical outcomes to prescribers' receipt of CE training. Although the FDA had requested studies tracking adverse outcomes as a function of CE training, the FDA concluded that these studies had not been performed as of the 60-month report in 2017. Conclusions and Relevance: Five years after initiation, the FDA and ER/LA manufacturers could not conclude whether the ER/LA REMS had reduced inappropriate prescribing or improved patient outcomes. Alternative observational study designs would have allowed for more rigorous estimates of the program's effectiveness.

The Value of U.S. Pharmacopeial Standards: A Review of the Literature.

While there are many standard-setting health care organizations, the United States Pharmacopeial Convention's (USP) role includes the creation of documentary and physical standards for therapeutics, including chemical drugs, excipients, and biologics. Despite the ubiquity of these standards, little work has been carried out to characterize and quantify their value. We reviewed the peer-reviewed and gray literature relevant to such evaluations. The review yielded 36 articles, focused variously on accreditation and other standards in health care, the broad impact of pharmacopeial standards and evaluations of specific USP standards. We did not find any study quantifying the impact of USP or other pharmacopeial standards, but many reports have been published that suggest the utility of USP standards to drug development, quality assurance, and public health. Frequently cited areas of impact include equitably advancing the analytical capabilities of manufacturers; enabling the creation of legally enforceable naming conventions; detecting mislabeled and substandard drugs in the marketplace, especially in the context of increased globalization of drug markets; and facilitating the harmonization of diverse international drug quality standards. Our insights provide opportunities for empiric assessments of the effects of USP standards on important outcomes including their promotion of efficient drug development, market competition, drug quality, and patient safety.

Coverage of Nonpharmacologic Treatments for Low Back Pain Among US Public and Private Insurers.

Importance: Despite epidemic rates of addiction and death from prescription opioids in the United States, suggesting the importance of providing alternatives to opioids in the treatment of pain, little is known regarding how payers' coverage policies may facilitate or impede access to such treatments. Objective: To examine coverage policies for 5 nonpharmacologic approaches commonly used to treat acute or chronic low back pain among commercial and Medicare Advantage insurance plans, plus an additional 6 treatments among Medicaid plans. Design, Setting, and Participants: Cross-sectional study of 15 commercial, 15 Medicaid, and 15 Medicare Advantage health plans for the 2017 calendar year in 16 states representing more than half of the US population. Interviews were conducted with 43 senior medical and pharmacy health plan executives from representative plans. Main Outcomes and Measures: Medical necessity and coverage status for the treatments examined, as well as the use of utilization management tools and cost-sharing magnitude and structure. Results: Commercial and Medicare insurers consistently regarded physical and occupational therapy as medically necessary, but policies varied for other therapies examined. Payers most commonly covered physical therapy (98% [44 of 45 plans]), occupational therapy (96% [43 of 45 plans]), and chiropractic care (89% [40 of 45 plans]), while transcutaneous electrical nerve stimulation (67% [10 of 15 plans]) and steroid injections (60% [9 of 15 plans]) were the most commonly covered among the therapies examined for Medicaid plans only. Despite evidence in the literature to support use of acupuncture and psychological interventions, these therapies were either not covered by plans examined (67% of all plans [30 of 45] did not cover acupuncture) or lacked information about coverage (80% of Medicaid plans [12 of 15] lacked information about coverage of psychological interventions). Utilization management tools, such as prior authorization, were common, but criteria varied greatly with respect to which conditions and what quantity and duration of services were covered. Interviewees represented 6 Medicaid managed care organizations, 2 Medicare Advantage or Part D plans, 9 commercial plans, and 3 trade organizations (eg, Blue Cross Blue Shield Association). Interviews with plan executives indicated a low level of integration between the coverage decision-making processes for pharmacologic and nonpharmacologic therapies for chronic pain. Conclusions and Relevance: Wide variation in coverage of nonpharmacologic treatments for low back pain may be driven by the absence of best practices, the administrative complexities of developing and revising coverage policies, and payers' economic incentives. Such variation suggests an important opportunity to improve the accessibility of services, reduce opioid use, and ultimately improve the quality of care for individuals with chronic, noncancer pain while alleviating the burden of opioid addiction and overdose.

Prescription Drug Coverage for Treatment of Low Back Pain Among US Medicaid, Medicare Advantage, and Commercial Insurers.

Importance: Despite unprecedented injuries and deaths from prescription opioids, little is known regarding medication coverage policies for the treatment of chronic noncancer pain among US insurers. Objective: To assess medication coverage policies for 62 products used to treat low back pain. Design, Setting, and Participants: A cross-sectional study of health plan documents from 15 Medicaid, 15 Medicare Advantage, and 20 commercial health plans in 2017 from 16 US states representing more than half the US population and 20 interviews with more than 43 senior medical and pharmacy health plan executives from representative plans. Data analysis was conducted from April 2017 to January 2018. Main Outcomes and Measures: Formulary coverage, utilization management, and patient out-of-pocket costs. Results: Of the 62 products examined, 30 were prescription opioids and 32 were nonopioid analgesics, including 10 nonsteroidal anti-inflammatory drugs, 10 antidepressants, 6 muscle relaxants, 4 anticonvulsants, and 2 topical analgesics. Medicaid plans covered a median of 19 opioids examined (interquartile range [IQR], 12-27; median, 63%; IQR, 40%-90%) and a median of 22 nonopioids examined (IQR, 21-27; median, 69%; IQR, 66%-83%). Medicare Advantage plans covered similar proportions (median [IQR], opioids: 17 [15-22]; 57% [50%-73%]; nonopioids: 22 [22-26]; 69% [69%-81%]), while commercial plans covered more opioids (median [IQR], 23 [21-25]; 77% [70%-84%]) and nonopioids (median [IQR], 26 [24-27]; 81% [74%-85%]). Utilization management strategies were common for opioids in Medicaid plans (median [IQR], 15 [11-20] opioids; 91% [74%-97%]), Medicare Advantage plans (median [IQR], 15 [9-18] opioids; 100% [100%-100%]), and commercial plans (median [IQR], 16 [11-20] opioids; 74% [53%-94%]), generally relying on 30-day quantity limits rather than prior authorization. Step therapy was especially uncommon. Many of the nonopioids examined also were subject to utilization management, especially quantity limits (24%-32% of products across payers) and prior authorization (median [IQR], commercial plans: 2 [0-3] nonopioids; 9% [0%-11%]; Medicare Advantage plans: 4 [3-5] nonopioids; 19% [10%-23%]; Medicaid plans: 6 [1-13] nonopioids; 38% [2%-52%]). Among commercial plans, the median plan placed 18 opioids (74%) and 20 nonopioids (81%) in tier 1, which was associated with a median out-of-pocket cost of $10 (IQR, $9-$10) per 30-day supply. Key informant interviews revealed an emphasis on increasing opioid utilization management and identifying high-risk prescribers and patients, rather than promoting comprehensive strategies to improve treatment of chronic pain or better integrating pharmacologic and nonpharmacologic alternatives to opioids. Conclusions and Relevance: Given the effect of coverage policies on drug utilization and health outcomes, these findings provide an important opportunity to evaluate how formulary placement, utilization management, copayments, and integration of nonpharmacologic treatments can be optimized to improve pain care while reducing opioid-related injuries and deaths.

Correction to: Integrating multiple data sources (MUDS) for meta-analysis to improve patient-centered outcomes research: a protocol.

The correct title of the article [1] should be "Integrating multiple data sources (MUDS) for meta-analysis to improve patient-centered outcomes research: a protocol".

Correction to: Integrating multiple data sources (MUDS) for meta-analysis to improve patient-centered outcomes research: a protocol for a systematic review.

CORRECTION: The correct title of the article [1] should be "Integrating multiple data sources (MUDS) for meta-analysis to improve patient-centered outcomes research: a protocol". The article is a protocol for a methodological study, not a systematic review.