Competitive Foods' Nutritional Quality and Compliance with Smart Snacks Standards: An Analysis of a National Sample of U.S. Middle and High Schools.

Snacks and beverages are often sold in addition to meals in U.S. schools ("competitive foods"), but their current nutritional quality and compliance with national Smart Snacks standards are unknown. This study assessed competitive foods in a national sample of 90 middle and high schools. Differences in compliance by school characteristics were measured using mixed methods analysis of variance. Overall, 80% of the schools in the sample sold competitive foods; but they were less commonly available in schools with universal free school meal (UFSM) policies. A total of 840 unique products were documented and, on average, 75% were compliant with Smart Snacks standards. A total of 56% aligned with recommended added sugar limits (<10% of calories); and 340 unique products (40%) aligned with both sugar and Smart Snacks standards. Approximately one-fifth of competitive foods contained synthetic dyes, and 31% of beverages contained artificial sweeteners. Smart Snacks standards compliance was greater when competitive foods were overseen by food service departments, in comparison with others (e.g., principals, student organizations, or outside vendors [77% vs. 59% compliance; p = 0.003]). Therefore, district wellness policies should consider requiring food service departments to oversee competitive foods. Federal and state policies should limit added sugars, artificial sweeteners, and synthetic dyes. This appears to be highly feasible, given the substantial number of products that meet these criteria. UFSM policies should also be considered to support healthier school meal environments more broadly.

Effects of in-store marketing on food and beverage purchases: a longitudinal study of households with children.

OBJECTIVE: Most food retailers display foods in prominent locations as a marketing strategy (i.e. 'placement promotions'). We examined the extent to which households with children change their food and beverage purchases in response to these promotions. DESIGN: We analysed a novel dataset of all products promoted in two supermarkets from 2016 to 2017, including promotion dates and locations (e.g. aisle endcaps and front registers). We linked promotions to all purchases from the supermarkets from 2016 to 2017 by a cohort of households with children. We calculated the number of weekly promotions in each of thirteen food and beverage groups (e.g. bread; candy) and used fixed effects regressions to estimate associations between number of weekly promotions and households' weekly food purchases, overall and by Supplemental Nutrition Assistance Program (SNAP) participation. SETTING: Two large supermarkets in Maine, USA. PARTICIPANTS: Eight hundred and twenty-one households with children. RESULTS: Most promotions (74 %) were for less healthy foods. The most promoted food groups were sweet and salty snacks (mean = 131·0 promotions/week), baked goods (mean = 68·2) and sugar-sweetened beverages (mean = 41·6). Households generally did not change their food group purchases during weeks when they were exposed to more promotions for those groups, except that a 1-sd increase in endcap candy promotions (about 1 promotion/week) was associated with $0·19/week (about 14·5 %) increase in candy purchases among SNAP nonparticipants (adjusted P < 0·001). CONCLUSIONS: In-store placement promotions for food groups were generally not associated with purchases of promoted food groups, perhaps because exposure to unhealthy food marketing was consistently high. Substantial changes to in-store food marketing may be needed to promote healthier purchases.

Evaluation of health and economic effects of United States school meal standards consistent with the 2020-2025 dietary guidelines for Americans.

BACKGROUND: The current school meal nutrition standards, established in 2010, are not fully aligned with the 2020-2025 Dietary Guideline for Americans (DGA). This study evaluates the potential short-term and long-term health and economic benefits of strengthening the school meal standards on added sugars, sodium, and whole grains to be aligned with current guidelines. METHODS: We used comparative risk assessment frameworks based on nationally representative data incorporating current demographics, dietary habits, and risk factors of United States children aged 5-18 y from 3 cycles of the National Health and Nutrition Examination Survey (2013-2018). To estimate short-term impact, the model incorporated estimated dietary changes owing to potential new DGA-aligned school meal nutrition standards and the effect of these changes on childhood body mass index (in kg/m2) and blood pressure. To estimate long-term impact, the model further incorporated data on the sustainability of childhood dietary changes into adulthood, and on demographics and risk factors of United States adults, diet-disease associations, and disease-specific national mortality. RESULTS: In a best-case scenario assuming full school compliance, implementing new DGA-aligned nutritional standards would lower elementary children's BMI by an average 0.14 (95% UI: 0.08-0.20) kg/m2 and systolic blood pressure by 0.13 (95% UI: 0.06-0.19) (95% mm Hg. Later in life, the new standards were estimated to prevent 10,600 [95% uncertainty interval (UI): 4820-16,800) annual deaths from cardiovascular disease (CVD), diabetes, and cancer in adulthood; and save 355,000 (95% UI: 175,000-538,000) disability-adjusted life years and $19.3 (95% UI: 9.35-30.3) B in direct and indirect medical costs each year. Accounting for plausible (incomplete) school compliance, implementation would save an estimated 9110 (95% UI: 2740-15,100) deaths, 302,000 (95% UI: 120,000-479,000) disability-adjusted life years, and $15.9 (95% UI: 4.54-27.2) B in healthcare-related costs per year in later adulthood. CONCLUSIONS: Stronger school meal nutrition standards on added sugars, sodium, and whole grains aligned with the 2020-2025 DGA recommendations may improve diet, childhood health, and future adult burdens of CVD, diabetes, cancer, and associated economic costs.

In-Store Marketing and Supermarket Purchases: Associations Overall and by Transaction SNAP Status.

INTRODUCTION: In-store placement promotions are used widely in supermarkets, but their effects on customer purchases remain largely unknown. This study examined associations of supermarket placement promotions with customer purchases overall and by Supplemental Nutrition Assistance Program (SNAP) benefit use. METHODS: Data on in-store promotions (e.g., endcaps, checkout displays) and transactions (n=274,118,338) were obtained from a New England supermarket chain with 179 stores from 2016 to 2017. Product-level analyses examined multivariable-adjusted changes in products' sales when they were promoted (versus not) across all transactions and stratified by whether the transaction was paid for with SNAP benefits. Food group-level analyses examined the extent to which a 20% increase from the mean number of weekly promotions for a food group (e.g., increasing the number of candy promotions from 17.0 to 20.4) was associated with total food group sales. Analyses were conducted in 2022. RESULTS: Across stores, the mean (SD) number of promotions per week was highest for sweet/salty snacks (126.3 [22.6]), baked goods (67.5 [18.4]), and sugar-sweetened beverages (48.6 [13.8]) and lowest for beans (5.0 [2.6]) and fruits (6.6 [3.3]). Product sales were between 16% (low-calorie drinks) and 136% (candy) higher when promoted versus not promoted. In 14 of 15 food groups, associations were stronger among transactions made with SNAP benefits than among those not made with SNAP benefits. The number of in-store promotions was generally not associated with total food group sales. CONCLUSIONS: In-store promotions, which were mostly for unhealthy foods, were associated with large product sales increases, particularly among SNAP purchasers. Policies limiting unhealthy in-store promotions and incentivizing healthy promotions should be explored.

Spurious early ecological association suggesting BCG vaccination effectiveness for COVID-19.

BACKGROUND: Several ecologic studies have suggested that the bacillus Calmette-Guérin (BCG) vaccine may be protective against SARS-CoV-2 infection including a highly-cited published pre-print by Miller et al., finding that middle/high- and high-income countries that never had a universal BCG policy experienced higher COVID-19 burden compared to countries that currently have universal BCG vaccination policies. We provide a case study of the limitations of ecologic analyses by evaluating whether these early ecologic findings persisted as the pandemic progressed. METHODS: Similar to Miller et al., we employed Wilcoxon Rank Sum Tests to compare population medians in COVID-19 mortality, incidence, and mortality-to-incidence ratio between countries with universal BCG policies compared to those that never had such policies. We then computed Pearson's r correlations to evaluate the association between year of BCG vaccination policy implementation and COVID-19 outcomes. We repeated these analyses for every month in 2020 subsequent to Miller et al.'s March 2020 analysis. RESULTS: We found that the differences in COVID-19 burden associated with BCG vaccination policies in March 2020 generally diminished in magnitude and usually lost statistical significance as the pandemic progressed. While six of nine analyses were statistically significant in March, only two were significant by the end of 2020. DISCUSSION: These results underscore the need for caution in interpreting ecologic studies, given their inherent methodological limitations, which can be magnified in the context of a rapidly evolving pandemic in which there is measurement error of both exposure and outcome status.

COVID-19 vaccine misinformation in English-language news media: retrospective cohort study.

OBJECTIVES: To describe COVID-19 vaccine misinformation and track trends over time in traditional news media. DESIGN: Retrospective cohort study of a large database of online articles, July 2020-June 2021. SETTING: English-language articles from 100 news outlets with the greatest reach. MAIN OUTCOME MEASURES: Numbers and percentages of articles containing COVID-19 vaccine misinformation over the study period. Further analysis by misinformation themes and whether articles included primary misinformation, fact-checking or simply referred to misinformation. RESULTS: 41 718 (3.2% of all COVID-19 vaccine articles) contained at least one of the vaccine misinformation themes based on the Boolean string developed for this study. The volume of such articles increased beginning in November 2020, but their percentage of all articles remained essentially stable after October 2020. 56.2% contained at least one mention of a safety theme, followed by development, production, and distribution (26.6%), and conspiracies (15.1%). Of 500 articles through January 2021 randomly selected from those identified by the Boolean string, 223 were not relevant, and 277 included either fact-checking (175 articles), refers to misinformation (87 articles) or primary misinformation (15 articles). In eight study weeks, the reach of these 277 articles (defined as visitors to the sites containing the articles) exceeded 250 million people. Fact-checking accounted for 69.6% of all reach for these articles and the number of such articles increased after November 2020. Overall, approximately 0.1% (95% CI 0.05% to 0.16%) of all articles on COVID-19 vaccines in our sample contained primary misinformation. CONCLUSIONS: COVID-19 vaccine misinformation in traditional news media is uncommon but has the capacity to reach large numbers of readers and affect the vaccine conversation. Recent increases in fact-checking may counteract some of the misinformation currently circulating.

Agreement of treatment effects from observational studies and randomized controlled trials evaluating hydroxychloroquine, lopinavir-ritonavir, or dexamethasone for covid-19: meta-epidemiological study.

OBJECTIVE: To systematically identify, match, and compare treatment effects and study demographics from individual or meta-analysed observational studies and randomized controlled trials (RCTs) evaluating the same covid-19 treatments, comparators, and outcomes. DESIGN: Meta-epidemiological study. DATA SOURCES: National Institutes of Health Covid-19 Treatment Guidelines, a living review and network meta-analysis published in The BMJ, a living systematic review with meta-analysis and trial sequential analysis in PLOS Medicine (The LIVING Project), and the Epistemonikos "Living OVerview of Evidence" (L·OVE) evidence database. ELIGIBILITY CRITERIA FOR SELECTION OF STUDIES: RCTs in The BMJ's living review that directly compared any of the three most frequently studied therapeutic interventions for covid-19 across all data sources (that is, hydroxychloroquine, lopinavir-ritonavir, or dexamethasone) for any safety and efficacy outcomes. Observational studies that evaluated the same interventions, comparisons, and outcomes that were reported in The BMJ's living review. DATA EXTRACTION AND SYNTHESIS: Safety and efficacy outcomes from observational studies were identified and treatment effects for dichotomous (odds ratios) or continuous (mean differences or ratios of means) outcomes were calculated and, when possible, meta-analyzed to match the treatment effects from individual RCTs or meta-analyses of RCTs reported in The BMJ's living review with the same interventions, comparisons, and outcomes (that is, matched pairs). The analysis compared the distribution of study demographics and the agreement between treatment effects from matched pairs. Matched pairs were in agreement if both observational and RCT treatment effects were significantly increasing or decreasing (P<0.05) or if both treatment effects were not significant (P≥0.05). RESULTS: 17 new, independent meta-analyses of observational studies were conducted that compared hydroxychloroquine, lopinavir-ritonavir, or dexamethasone with an active or placebo comparator for any safety or efficacy outcomes in covid-19 treatment. These studies were matched and compared with 17 meta-analyses of RCTs reported in The BMJ's living review. 10 additional matched pairs with only one observational study and/or one RCT were identified. Across all 27 matched pairs, 22 had adequate reporting of demographical and clinical data for all individual studies. All 22 matched pairs had studies with overlapping distributions of sex, age, and disease severity. Overall, 21 (78%) of the 27 matched pairs had treatment effects that were in agreement. Among the 17 matched pairs consisting of meta-analyses of observational studies and meta-analyses of RCTs, 14 (82%) were in agreement; seven (70%) of the 10 matched pairs consisting of at least one observational study or one RCT were in agreement. The 18 matched pairs with treatment effects for dichotomous outcomes had a higher proportion of agreement (n=16, 89%) than did the nine matched pairs with treatment effects for continuous outcomes (n=5, 56%). CONCLUSIONS: Meta-analyses of observational studies and RCTs evaluating treatments for covid-19 have summary treatment effects that are generally in agreement. Although our evaluation is limited to three covid-19 treatments, these findings suggest that meta-analyzed evidence from observational studies might complement, but should not replace, evidence collected from RCTs.

Adverse events and labeling issues related to suspected sesame allergy reported in an online survey.

BACKGROUND: Allergen avoidance is critical for those with immunoglobulin E-mediated food allergy, but can only be successful with accurate product information. Although the Food and Drug Administration maintains the Center for Food Safety and Nutrition Adverse Event Reporting System to collect adverse event (AE) reports related to foods, there is substantial underreporting, and information regarding product labeling issues is limited. OBJECTIVE: The purpose of this study was to describe allergic reactions associated with accidental oral exposure to sesame and the role of product labeling. METHODS: A questionnaire was developed and disseminated to online communities focused on sesame allergy. The questionnaire included questions on clinical characteristics, treatments, outcomes, and labeling issues. RESULTS: A total of 360 clinical reactions related to sesame were reviewed in 327 individuals. Anaphylaxis occurred in 68.9% of reactions. Hospitalization occurred in 47.8% of events and epinephrine was administered in 36.4% of cases. Events involving a packaged food product occurred in 67.5% of AEs with only 43.8% of these using the term "sesame." An alternative name was noted in 46.0% of products that did not include "sesame" on labeling, most of which was "tahini." CONCLUSION: We determined considerable sesame food allergy morbidity, in part owing to inconsistent allergen labeling. Our findings support the development of a more rapid process for the Food and Drug Administration to update the major allergen list and formulation of an improved system for reporting AEs related to foods.

Trials for second generation Covid-19 vaccines: Revisiting the debate over placebo use in developing country clinical trials.

This article compares the current debate over the use of placebos in developing country clinical trials of second generation Covid-19 vaccines with the debates over previous paradigmatic cases raising similar issues. Compared to the earlier zidovudine and Surfaxin trials, Covid-19 vaccine trials are likely to confer lower risk to placebo groups and to offer a greater number and variety of alternative study designs. However, turning to the developing world to conduct studies that would be unacceptable in developed countries, simply on the ground that Covid-19 vaccines are generally unavailable in developing countries, is not ethically justifiable. This is so whether the justification is rooted in total absence of vaccine in a given country or in developing country vaccine prioritisation practices, because at root both derive from economic, not scientific conditions. However, the advent of variants that may create genuine uncertainty as to comparator vaccine effectiveness could justify a placebo control, depending on vaccine characteristics, variant prevalence, the degree of variant resistance, and the acceptability of immune-bridging studies. These factors must be considered together in the necessary case-by-case assessment of the ethical justification for any proposed trial.

Opioid exposure associated with poppy consumption reported to poison control centers and the U.S. Food and Drug Administration.

OBJECTIVE: To assess characteristics of exposures to contaminated poppy and identify trends in exposure and poppy-related deaths. METHODS: Cross-sectional analysis of adverse events associated with exposure to poppy products (primarily poppy seeds) from the American Association of Poison Control Centers' National Poison Data System (NPDS), 2000-2018, supplemented with analysis of overdoses and deaths related to poppy from the U.S. Food and Drug Administration (FDA) Center for Food Safety and Applied Nutrition's Adverse Event Reporting System (CAERS) (2004-2018), and the FDA Adverse Event Reporting System (FAERS) (1968-2018). RESULTS: There were 591 NPDS exposure cases involving poppy between 2000 and 2018 including 392 in persons aged 13+. Rates of intentional exposures in NPDS increased among the age 13+ group over the study period. Most intentional exposures occurred in males in their teens and twenties. NPDS included 18 overdoses and three deaths likely attributable to poppy, most involving poppy seed tea. CAERS and FAERS included five additional deaths likely attributable to opioids in poppy. CONCLUSIONS: Including previously reported cases, there are now at least 19 U.S. deaths associated with poppy seeds in the literature. We recommend that practitioners working in opioid treatment and recovery be alert to use of poppy to treat pain and symptoms of withdrawal.

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.

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.

Systematic overview of Freedom of Information Act requests to the Department of Health and Human Services from 2008 to 2017.

BACKGROUND: The Freedom of Information Act (FOIA) provides access to unreleased government records that can be used to enhance the transparency and integrity of biomedical research. We characterized FOIA requests to Department of Health and Human Services (HHS) agencies, including request outcomes, processing times, backlogs, and costs. METHODS: Using HHS FOIA annual reports, we extracted data on the number of FOIA requests received and processed by HHS agencies between 2008 and 2017, as well as request outcomes. Processing times were reported in three time increments, < 1-20, 21-60, or 61+ days, and trends in backlog status were also described. Information about costs and fees collected were aggregated. RESULTS: Between 2008 and 2017, 69.6% of 530,094 HHS FOIA requests were received by the Centers for Medicare and Medicaid Services (CMS), 18.9% by the Food and Drug Administration (FDA), and 11.6% by all other HHS agencies. During this period, CMS processed 374,728 requests, FDA 114,938, and other HHS agencies 61,890. CMS and FDA reduced backlogged requests by 9396 (89.7%) and 4289 (65.3%), respectively, leaving backlogs of 1081 and 2279 requests at the end of 2017. CMS fully or partially granted 60.3% of requests whereas FDA fully or partially granted 72.4%. Of all requests to CMS, 82.0% were considered simple and 18.0% complex; 82.2% of simple requests and 54.9% of complex requests were processed in 20 days, and 5.6% and 29.9% were processed in 61+ days. In contrast, 60.2% of requests to FDA were considered simple and 39.8% complex; 28.8% of simple requests and 9.0% of complex requests were processed in 20 days, and 58.3% and 81.5% were processed in 61+ days. The costs to HHS associated with FOIA requests totaled $446.4 million ($809 per processed request), increasing from $28.1 million ($423 per request) in 2008 to $53.3 million ($1544 per request) in 2017. In total, HHS collected $8.5 million in fees (1.9% of total costs). CONCLUSIONS: FOIA is frequently used to obtain information about HHS and its agencies. With growing costs, minimal fees collected, and lengthy processing times, HHS agencies' FOIA programs might be made more efficient through greater proactive record disclosure.

Caffeinated energy drinks: adverse event reports to the US Food and Drug Administration and the National Poison Data System, 2008 to 2015.

OBJECTIVE: To describe and compare caffeinated energy drink adverse event (AE) report/exposure call data from the US Food and Drug Administration Center for Food Safety and Applied Nutrition's Adverse Event Reporting System (CAERS) and the American Association of Poison Control Centers' National Poison Data System (NPDS). DESIGN: Cross-sectional. SETTING: Data were evaluated from US-based CAERS reports and NPDS exposure calls, including report/exposure call year, age, sex, location, single v. multiple product consumption, outcome, symptom, intentionality (NPDS only), report type, product name (CAERS only). PARTICIPANTS: The analysis defined participants (cases) by the number of caffeinated energy drink products indicated in each AE report or exposure call. Single product cases included 357 from CAERS and 12 822 from NPDS; multiple product cases included 153 from CAERS and 931 from NPDS. RESULTS: CAERS v. NPDS single product cases were older and more frequently indicated serious symptoms. Multiple v. single product consumers were older in both. In CAERS, unlike NPDS, most multiple product consumers were female. CAERS single v. multiple product reports cited higher proportions of life-threatening events, but less often indicated hospitalization and serious events. NPDS multiple v. single product cases involved fewer ≤5-year-olds and were more often intentional. CONCLUSIONS: Despite limitations, both data sources contribute to post-market surveillance and improve understanding of public health concerns.

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.

Impact of the US Food and Drug Administration registration of antiretroviral drugs on global access to HIV treatment.

BACKGROUND: Since 2004, the US Food and Drug Administration's (USFDA) dedicated drug review process in support of President's Emergency Plan for AIDS Relief (PEPFAR) has made safe, effective and quality antiretrovirals (ARVs) available for millions of patients. Furthermore, the WHO and Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund) can add the USFDA-reviewed products to their respective formularies, through a novel process of 'one-way reliance'. We assessed the number of ARVs made available through WHO and Global Fund based on the USFDA review. METHODS: We conducted a cross-sectional study of all the USFDA-reviewed PEPFAR drugs between 1 December 2014 and 20 March 2017 to determine 1) the percentage that are included on the WHO and Global Fund formularies; 2) the number of the USFDA ARVs supporting the WHO HIV treatment guidelines, and their uptake by WHO and Global Fund and 3) time between the USFDA review and WHO review of the same ARVs. FINDINGS: Overall, 91% (204/224) of the USFDA products appeared on either the WHO/Prequalification of Medicines Programme (PQP) or the Global Fund ARV lists. Forty-five per cent (100/224) and 83% (184/224) appear on WHO/PQP and Global Fund formularies through one-way reliance, respectively. Forty-one per cent (91/224) of the USFDA products support the WHO-preferred first-line HIV treatment options. Of these 91 products, 38% and 85% of products were adopted by WHO/PQP and Global Fund through one-way reliance, respectively. Sixty-six products that were fully reviewed and registered by WHO (vs one-way reliance) had also undergone the USFDA review; 46 of these were registered by WHO after the USFDA review was complete (median delay of 559 days (IQR 233-798 days)). CONCLUSIONS: The USFDA's PEPFAR process is making safe and effective ARVs available worldwide, in part because the major global ARV procurement organisations rely on the USFDA registration as proof of quality. There is room for improved information sharing and collaboration to reduce duplication of effort, save resources and further expedite access to ARVs.