Hospital Prices for Physician-Administered Drugs for Patients with Private Insurance.

BACKGROUND: Hospitals can leverage their position between the ultimate buyers and sellers of drugs to retain a substantial share of insurer pharmaceutical expenditures. METHODS: In this study, we used 2020-2021 national Blue Cross Blue Shield claims data regarding patients in the United States who had drug-infusion visits for oncologic conditions, inflammatory conditions, or blood-cell deficiency disorders. Markups of the reimbursement prices were measured in terms of amounts paid by Blue Cross Blue Shield plans to hospitals and physician practices relative to the amounts paid by these providers to drug manufacturers. Acquisition-price reductions in hospital payments to drug manufacturers were measured in terms of discounts under the federal 340B Drug Pricing Program. We estimated the percentage of Blue Cross Blue Shield drug spending that was received by drug manufacturers and the percentage retained by provider organizations. RESULTS: The study included 404,443 patients in the United States who had 4,727,189 drug-infusion visits. The median price markup (defined as the ratio of the reimbursement price to the acquisition price) for hospitals eligible for 340B discounts was 3.08 (interquartile range, 1.87 to 6.38). After adjustment for drug, patient, and geographic factors, price markups at hospitals eligible for 340B discounts were 6.59 times (95% confidence interval [CI], 6.02 to 7.16) as high as those in independent physician practices, and price markups at noneligible hospitals were 4.34 times (95% CI, 3.77 to 4.90) as high as those in physician practices. Hospitals eligible for 340B discounts retained 64.3% of insurer drug expenditures, whereas hospitals not eligible for 340B discounts retained 44.8% and independent physician practices retained 19.1%. CONCLUSIONS: This study showed that hospitals imposed large price markups and retained a substantial share of total insurer spending on physician-administered drugs for patients with private insurance. The effects were especially large for hospitals eligible for discounts under the federal 340B Drug Pricing Program on acquisition costs paid to manufacturers. (Funded by Arnold Ventures and the National Institute for Health Care Management.).

Class I Recalls of Cardiovascular Devices Between 2013 and 2022 : A Cross-Sectional Analysis.

BACKGROUND: Cardiovascular devices account for one third of all Class I recalls, the U.S. Food and Drug Administration's (FDA) most severe designation, indicating a reasonable probability of "serious adverse health consequences or death." Understanding recalls and their causes is important for patient safety. OBJECTIVE: To characterize Class I recalls of cardiovascular devices and the clinical evidence supporting authorization. DESIGN: In this cross-sectional study, cardiovascular device recalls from 1 January 2013 through 31 December 2022 were identified using the FDA's annual log. Information about devices was extracted from publicly available FDA decision summaries. SETTING: The FDA Medical Device Recalls database. PARTICIPANTS: Cardiovascular devices with Class I recalls. MEASUREMENTS: Recalls were characterized by their causes and scope. Devices were characterized by their regulatory history (product code, special designations) and clinical evidence (premarket testing, postmarket surveillance). Clinical studies were analyzed for quality, including end point selection (clinical vs. surrogate, use of composites). RESULTS: From 2013 to 2022, there were 137 Class I recall events affecting 157 unique cardiovascular devices, of which 112 (71.3%) were moderate-risk 510(k) devices and 45 (28.7%) were high-risk premarket approval (PMA) devices. Recalls affected a median of 7649 units (IQR, 953 to 28 446) and were most commonly attributed to device design (43 [31.4%]). Forty-two (26.8%) devices had multiple Class I recalls. Thirty (19.1%) devices underwent premarket clinical testing (7 [6.2%] 510(k) devices, 17 [85.0%] PMA devices, and 6 [24.0%] PMA supplement devices). Most studies used surrogate (27 [79.4%]) and composite (24 [70.6%]) measures as primary end points. Twenty-two (48.9%) PMA devices had required postapproval studies, with 14 reporting delays. No 510(k) devices were subject to postmarket surveillance. LIMITATION: Details about clinical testing may be missing from FDA summaries. CONCLUSION: Cardiovascular devices with Class I recalls were infrequently subjected to premarket or postmarket testing, with recalls affecting thousands of patients annually. PRIMARY FUNDING SOURCE: None.

Modernizing Medical Device Regulation: Challenges and Opportunities for the 510(k) Clearance Process.

Nearly all medical devices reviewed by the U.S. Food and Drug Administration (FDA) are authorized via the 510(k) clearance process. Established in 1976, this review pathway bases authorizations on the comparability of new devices to previously authorized devices ("predicates"). This evaluation usually does not require clinical evidence of safety and effectiveness. Advocates of the 510(k) clearance process tout its support for device innovation and rapid market access, and critics of the 510(k) clearance process express that it may inadequately protect patient safety. In September 2023, the FDA issued 3 guidance documents that, if finalized, would significantly change medical device regulation. This article provides clinical and regulatory context for the proposed guidance documents, which focus on predicate selection, clinical testing requirements, and implantable devices, and identifies opportunities for further reforms that promote transparency and patient safety.

Informational Postcards Increase Engagement with Remote Monitoring Among Veterans with Pacemakers and Implantable Cardioverter-Defibrillators: a Stepped-Wedge Randomized Controlled Trial.

BACKGROUND: Remote monitoring (RM) of pacemakers and implantable cardioverter-defibrillators (ICDs) reduces morbidity and mortality. However, many patients are not adherent to RM. OBJECTIVE: To test the effect of informational postcards on RM adherence. DESIGN/PATIENTS: Stepped-wedge randomized controlled trial among Veterans with pacemakers and ICDs. INTERVENTION: In wave 1, Veterans who had sent at least 1 transmission within the past 2 years but had become non-adherent were randomly assigned to receive a postcard or no postcard. Those receiving postcards were randomized to 1 of 2 messages: (1) a"warning" postcard describing risks of non-adherence or (2) an "encouraging" postcard describing benefits of adherence. In wave 2, Veterans who had either not received a postcard in wave 1 or had since become non-adherent were mailed a postcard (again, randomized to 1 of 2 messages). Patients who did not send an RM transmission within 1 month were mailed a second, identical postcard. MAIN MEASURES: Transmission within 70 days. KEY RESULTS: Overall, 6351 Veterans were included. In waves 1 and 2, postcards were mailed to 5657 Veterans (2821 "warning" messages and 2836 "encouraging" messages). Wave 1 included 2178 Veterans as controls (i.e., not mailed a postcard), some of whom received a postcard in wave 2 if they remained non-adherent. In wave 2, 3473 postcards were sent. Of the 5657 patients mailed a postcard, 2756 (48.7%) sent an RM transmission within 70 days, compared to 530 (24.3%) of 2178 controls (absolute difference 24.4%, 95% confidence interval [CI] 22.2%, 26.6%). Of those who sent a transmission, 71.8% did so after the first postcard. Transmission rates at 70 days did not significantly differ between "warning" and "encouraging" messages (odds ratio 1.04, 95% CI 0.92, 1.18). CONCLUSIONS: Informational postcards led to a 24.4% absolute increase in adherence at 70 days among Veterans with pacemakers and ICDs who were non-adherent to RM.

Use of electronic health records to characterize patients with uncontrolled hypertension in two large health system networks.

BACKGROUND: Improving hypertension control is a public health priority. However, consistent identification of uncontrolled hypertension using computable definitions in electronic health records (EHR) across health systems remains uncertain. METHODS: In this retrospective cohort study, we applied two computable definitions to the EHR data to identify patients with controlled and uncontrolled hypertension and to evaluate differences in characteristics, treatment, and clinical outcomes between these patient populations. We included adult patients (≥ 18 years) with hypertension (based on either ICD-10 codes of hypertension or two elevated blood pressure [BP] measurements) receiving ambulatory care within Yale-New Haven Health System (YNHHS; a large US health system) and OneFlorida Clinical Research Consortium (OneFlorida; a Clinical Research Network comprised of 16 health systems) between October 2015 and December 2018. We identified patients with controlled and uncontrolled hypertension based on either a single BP measurement from a randomly selected visit or all BP measurements recorded between hypertension identification and the randomly selected visit). RESULTS: Overall, 253,207 and 182,827 adults at YNHHS and OneFlorida were identified as having hypertension. Of these patients, 83.1% at YNHHS and 76.8% at OneFlorida were identified using ICD-10-CM codes, whereas 16.9% and 23.2%, respectively, were identified using elevated BP measurements (≥ 140/90 mmHg). A total of 24.1% of patients at YNHHS and 21.6% at OneFlorida had both diagnosis code for hypertension and elevated blood pressure measurements. Uncontrolled hypertension was observed among 32.5% and 43.7% of patients at YNHHS and OneFlorida, respectively. Uncontrolled hypertension was disproportionately higher among Black patients when compared with White patients (38.9% versus 31.5% in YNHHS; p < 0.001; 49.7% versus 41.2% in OneFlorida; p < 0.001). Medication prescription for hypertension management was more common in patients with uncontrolled hypertension when compared with those with controlled hypertension (overall treatment rate: 39.3% versus 37.3% in YNHHS; p = 0.04; 42.2% versus 34.8% in OneFlorida; p < 0.001). Patients with controlled and uncontrolled hypertension had similar incidence rates of deaths, CVD events, and healthcare visits at 3, 6, 12, and 24 months. The two computable definitions generated consistent results. CONCLUSIONS: While the current EHR systems are not fully optimized for disease surveillance and stratification, our findings illustrate the potential of leveraging EHR data to conduct digital population surveillance in the realm of hypertension management.

Informational letters or postcards to initiate remote monitoring among veterans with pacemakers and implantable cardioverter-defibrillators: A randomized, controlled trial.

BACKGROUND: Remote monitoring (RM) of pacemakers and implantable cardioverter-defibrillators (ICDs) is a Class 1, Level of Evidence A recommendation because of its multitude of clinical benefits. However, RM adherence rates are suboptimal, precluding patients from achieving these benefits. There is a need for direct-to-patient efforts to improve adherence. METHODS: In this national randomized, controlled trial conducted in the Veterans Health Administration (VHA), 2120 patients with a pacemaker or ICD who had not sent an RM transmission for ≥1 year (and usually ≥3 years) while under VHA care for their device were randomly assigned to be mailed a postcard (n = 1076) or a detailed letter (n = 1044). The postcard described what RM does and its key benefits (reduced mortality and fewer in-person visits). The letter provided a similar message but included more details about RM benefits and the process. The primary outcome was an RM transmission sent within 90 days of mailing, and a secondary outcome was an RM transmission sent within 365 days. RESULTS: The primary outcome was achieved in 121 (11.3%) in the postcard and 96 patients (9.2%) in the letter group (p = .12). The secondary outcome was achieved in 266 (24.7%) and 239 (22.9%), respectively (p = .32). CONCLUSIONS: This randomized trial showed no significant difference in the proportion of chronically non-adherent patients who sent an RM transmission after receiving a low-cost postcard or a detailed, higher-cost letter encouraging their participation in RM. However, as only a minority of patients responded to either, further work is needed to engage patients in the life-saving benefits of RM.

Physician responses to apple watch-detected irregular rhythm alerts.

BACKGROUND: While the US Food and Drug Administration (FDA) has cleared smartwatch software for detecting atrial fibrillation (AF), there is lack of guidance on management by physicians. We sought to evaluate the approach to management of Apple Watch alerts for AF by physicians and assess whether respondent and case characteristics were associated with their approach. METHODS: We conducted a case-based survey of physicians practicing primary care, emergency medicine, and cardiology at 2 large academic centers (Yale and University of California San Francisco) between September and December 2021. Cases described asymptomatic patients receiving Apple Watch AF alerts; cases varied in sex, race, medical history, and notification frequency. We evaluated physician responses among prespecified diagnostic testing, referral, and treatment options. RESULTS: We emailed 636 physicians, of whom 95 (14.9%) completed the survey, including 39 primary care, 25 emergency medicine, and 31 cardiology physicians. Among a total of 192 cases (16 unique scenarios), physicians selected at least one diagnostic test in 191 (99.5%) cases and medications in 48 (25.0%). Physicians in primary care, emergency medicine, and cardiology reported varying preference for patient referral (14%, 30%, and 16%, respectively; P=.048), rhythm monitoring (84%, 46%, and 94%, respectively; P<.001), measurement of BNP (8%, 20%, and 2%; P=.003), and use of antiarrhythmics (16%, 4%, and 23%; P=.023). There were few physician differences in reported practices across patient demographics (sex and race), clinical complexity, and alert frequency of the clinical case. CONCLUSIONS: In hypothetical cases of patients presenting without clinical symptoms, physicians opted for further diagnostic testing and often to medical intervention based on Apple Watch irregular rhythm notifications. There was also considerable variation across physician specialties, suggesting a need for uniform clinical practice guidelines. Additional study is required before irregular rhythm notifications should be used in clinical settings.

Identifying treatment heterogeneity in atrial fibrillation using a novel causal machine learning method.

BACKGROUND: Lifelong oral anticoagulation is recommended in patients with atrial fibrillation (AF) to prevent stroke. Over the last decade, multiple new oral anticoagulants (OACs) have expanded the number of treatment options for these patients. While population-level effectiveness of OACs has been compared, it is unclear if there is variability in benefit and risk across patient subgroups. METHODS: We analyzed claims and medical data for 34,569 patients who initiated a nonvitamin K antagonist oral anticoagulant (non-vitamin K antagonist oral anticoagulant (NOAC); apixaban, dabigatran, and rivaroxaban) or warfarin for nonvalvular AF between 08/01/2010 and 11/29/2017 from the OptumLabs Data Warehouse. A machine learning (ML) method was applied to match different OAC groups on several baseline variables including, age, sex, race, renal function, and CHA2DS2 -VASC score. A causal ML method was then used to discover patient subgroups characterizing the head-to-head treatment effects of the OACs on a primary composite outcome of ischemic stroke, intracranial hemorrhage, and all-cause mortality. RESULTS: The mean age, number of females and white race in the entire cohort of 34,569 patients were 71.2 (SD, 10.7) years, 14,916 (43.1%), and 25,051 (72.5%) respectively. During a mean follow-up of 8.3 (SD, 9.0) months, 2,110 (6.1%) of patients experienced the composite outcome, of whom 1,675 (4.8%) died. The causal ML method identified 5 subgroups with variables favoring apixaban over dabigatran; 2 subgroups favoring apixaban over rivaroxaban; 1 subgroup favoring dabigatran over rivaroxaban; and 1 subgroup favoring rivaroxaban over dabigatran in terms of risk reduction of the primary endpoint. No subgroup favored warfarin and most dabigatran vs warfarin users favored neither drug. The variables that most influenced favoring one subgroup over another included Age, history of ischemic stroke, thromboembolism, estimated glomerular filtration rate, Race, and myocardial infarction. CONCLUSIONS: Among patients with AF treated with a NOAC or warfarin, a causal ML method identified patient subgroups with differences in outcomes associated with OAC use. The findings suggest that the effects of OACs are heterogeneous across subgroups of AF patients, which could help personalize the choice of OAC. Future prospective studies are needed to better understand the clinical impact of the subgroups with respect to OAC selection.

A Critical Examination of Independent Medical Review Decision-making for Cardiovascular Procedures Shows Low Rate of Evidence Citation in Reviews.

BACKGROUND: The California Independent Medical Review (IMR) program was created in 2001 to provide an independent, external evaluation of insurers' denials of coverage of health services. OBJECTIVE: We sought to evaluate the quality and comprehensiveness of data used to support IMR decision-making between 2015 and 2020. RESULTS: Of the 159 cases submitted to IMR regarding denials of cardiovascular procedures, 52% of these denials were overturned by IMR, thus restoring coverage. Despite a state-wide requirement that specific references to medical and scientific evidence should be provided in IMR reviews, fewer than a quarter of reviews cited any evidence to support decision-making. Slightly more than one third of IMR review decisions were inconsistent with recommendations from professional societies and peer-reviewed evidence; the primary reason for these inconsistencies was that invasive interventions were often recommended by reviewers before utilizing guideline-directed medical or less invasive therapies. CONCLUSION: Our findings highlight an opportunity for improvement in the quality of IMR decision-making through a more consistent use of available scientific evidence to guide clinical reasoning.

Assessing the use of observational methods and real-world data to emulate ongoing randomized controlled trials.

BACKGROUND/AIMS: There has been growing interest in better understanding the potential of observational research methods in medical product evaluation and regulatory decision-making. Previously, we used linked claims and electronic health record data to emulate two ongoing randomized controlled trials, characterizing the populations and results of each randomized controlled trial prior to publication of its results. Here, our objective was to compare the populations and results from the emulated trials with those of the now-published randomized controlled trials. METHODS: This study compared participants' demographic and clinical characteristics and study results between the emulated trials, which used structured data from OptumLabs Data Warehouse, and the published PRONOUNCE and GRADE trials. First, we examined the feasibility of implementing the baseline participant characteristics included in the published PRONOUNCE and GRADE trials' using real-world data and classified each variable as ascertainable, partially ascertainable, or not ascertainable. Second, we compared the emulated trials and published randomized controlled trials for baseline patient characteristics (concordance determined using standardized mean differences <0.20) and results of the primary and secondary endpoints (concordance determined by direction of effect estimates and statistical significance). RESULTS: The PRONOUNCE trial enrolled 544 participants, and the emulated trial included 2226 propensity score-matched participants. In the PRONOUNCE trial publication, one of the 32 baseline participant characteristics was listed as an exclusion criterion on ClinicalTrials.gov but was ultimately not used. Among the remaining 31 characteristics, 9 (29.0%) were ascertainable, 11 (35.5%) were partially ascertainable, and 10 (32.2%) were not ascertainable using structured data from OptumLabs. For one additional variable, the PRONOUNCE trial did not provide sufficient detail to allow its ascertainment. Of the nine variables that were ascertainable, values in the emulated trial and published randomized controlled trial were discordant for 6 (66.7%). The primary endpoint of time from randomization to the first major adverse cardiovascular event and secondary endpoints of nonfatal myocardial infarction and stroke were concordant between the emulated trial and published randomized controlled trial. The GRADE trial enrolled 5047 participants, and the emulated trial included 7540 participants. In the GRADE trial publication, 8 of 34 (23.5%) baseline participant characteristics were ascertainable, 14 (41.2%) were partially ascertainable, and 11 (32.4%) were not ascertainable using structured data from OptumLabs. For one variable, the GRADE trial did not provide sufficient detail to allow for ascertainment. Of the eight variables that were ascertainable, values in the emulated trial and published randomized controlled trial were discordant for 4 (50.0%). The primary endpoint of time to hemoglobin A1c ≥7.0% was mostly concordant between the emulated trial and the published randomized controlled trial. CONCLUSION: Despite challenges, observational methods and real-world data can be leveraged in certain important situations for a more timely evaluation of drug effectiveness and safety in more diverse and representative patient populations.

Use of Recalled Devices in New Device Authorizations Under the US Food and Drug Administration's 510(k) Pathway and Risk of Subsequent Recalls.

Importance: In the US, nearly all medical devices progress to market under the 510(k) pathway, which uses previously authorized devices (predicates) to support new authorizations. Current regulations permit manufacturers to use devices subject to a Class I recall-the FDA's most serious designation indicating a high probability of adverse health consequences or death-as predicates for new devices. The consequences for patient safety are not known. Objective: To determine the risk of a future Class I recall associated with using a recalled device as a predicate device in the 510(k) pathway. Design and Setting: In this cross-sectional study, all 510(k) devices subject to Class I recalls from January 2017 through December 2021 (index devices) were identified from the FDA's annual recall listings. Information about predicate devices was extracted from the Devices@FDA database. Devices authorized using index devices as predicates (descendants) were identified using a regulatory intelligence platform. A matched cohort of predicates was constructed to assess the future recall risk from using a predicate device with a Class I recall. Main Outcomes and Measures: Devices were characterized by their regulatory history and recall history. Risk ratios (RRs) were calculated to compare the risk of future Class I recalls between devices descended from predicates with matched controls. Results: Of 156 index devices subject to Class I recall from 2017 through 2021, 44 (28.2%) had prior Class I recalls. Predicates were identified for 127 index devices, with 56 (44.1%) using predicates with a Class I recall. One hundred four index devices were also used as predicates to support the authorization of 265 descendant devices, with 50 index devices (48.1%) authorizing a descendant with a Class I recall. Compared with matched controls, devices authorized using predicates with Class I recalls had a higher risk of subsequent Class I recall (6.40 [95% CI, 3.59-11.40]; P<.001). Conclusions and Relevance: Many 510(k) devices subjected to Class I recalls in the US use predicates with a known history of Class I recalls. These devices have substantially higher risk of a subsequent Class I recall. Safeguards for the 510(k) pathway are needed to prevent problematic predicate selection and ensure patient safety.

Experts' Views on FDA Regulatory Standards for Drug and High-Risk Medical Devices: Implications for Patient Care.

BACKGROUND: Drugs and high-risk medical devices are increasingly likely to receive Food and Drug Administration (FDA) approval through expedited pathways, which has implications for informed treatment consent (i.e., consent in clinical practice). OBJECTIVE: To obtain expert opinion about the clinical and ethical implications of the increasing availability of new drugs and devices approved through expedited development and regulatory review pathways. DESIGN: Qualitative study using individual semi-structured videoconference interviews. PARTICIPANTS: National leaders in medicine, ethics, and law (n=12) with expertise in medical product regulation, payor policymaking, bioethics, physician practice, patient advocacy, public health expertise/advocacy, clinical trials, the pharmaceutical and device industry, institutional review board oversight, and real-world evidence. MAIN MEASURES: Principal themes in 3 domains: expedited regulatory pathways, physician and patient understanding of and reliance on FDA approval, and informed treatment consent. KEY RESULTS: Respondents pointed out that more common use of expedited pathways translates to increased reliance on surrogate measures, some with uncertain clinical significance. While expedited development and review can have advantages, participants expressed worry that physicians were unaware when medical products were expedited and did not communicate about uncertainties in knowledge about new drug or device approvals effectively with patients. Many participants felt that informed treatment consent discussions about new drugs or devices should include some explanations of expedited pathways and use of surrogate measures. CONCLUSIONS: Experts identified advantages of expediting development and of FDA flexibility in applying its standards to new drugs and medical devices, but highlighted concerns that patients may not be adequately informed about the risks of shorter review times or about uncertainties in the evidence that result. There is a need to identify approaches to ensure effective clinical use of drugs and devices when approved through expedited pathways.

Gender Differences in Guideline-Directed Medical Therapy for Cardiovascular Disease Among Young Veterans.

BACKGROUND: There is an increasing burden of cardiovascular disease, including coronary artery disease (CAD) and heart failure (HF), among women Veterans. Clinical practice guidelines recommend multiple pharmacotherapies that can reduce risk of mortality and adverse cardiovascular outcomes. OBJECTIVE: To determine if there are disparities in the use of guideline-directed medical therapy by gender among Veterans with incident CAD and HF. DESIGN: Retrospective. PARTICIPANTS: Veterans (934,504; 87.8% men and 129,469; 12.2% women) returning from Operations Enduring Freedom, Iraqi Freedom, and New Dawn. MAIN MEASURES: Differences by gender in the prescription of Class 1, Level of Evidence A guideline-directed medical therapy among patients who developed incident CAD and HF at 30 days, 90 days, and 12 months after diagnosis. For CAD, medications included statins and antiplatelet therapy. For HF, medications included beta-blockers and renin-angiotensin-aldosterone system inhibitors. KEY RESULTS: Overall, women developed CAD and HF at a younger average age than men (mean 45.8 vs. 47.7 years, p<0.001; and 43.7 vs. 45.4 years, p<0.02, respectively). In the 12 months following a diagnosis of incident CAD, the odds of a woman receiving a prescription for at least one CAD drug was 0.85 (95% confidence interval [CI], 0.68-1.08) compared to men. In the 12 months following a diagnosis of incident HF, the odds of a woman receiving at least one HF medication was 0.54 (95% CI, 0.37-0.79) compared to men. CONCLUSIONS: Despite guideline recommendations, young women Veterans have approximately half the odds of being prescribed guideline-directed medical therapy within 1-year after a diagnosis of HF. These results highlight the need to develop targeted strategies to minimize gender disparities in CVD care to prevent adverse outcomes in this young and growing population.

A Policy Approach to Reducing Low-Value Device-Based Procedure Use.

Policy Points Low-value care is common in clinical practice, leading to patient harm and wasted spending. Much of this low-value care stems from the use of medical device-based procedures. We describe here a novel academic-policymaker collaboration in which evidence-based clinical coverage for device-based procedures is implemented through prior authorization-based policies for Louisiana's Medicaid beneficiary population. This process involves eight steps: 1) identifying low-value medical device-based procedures based on clinical evidence review, 2) quantifying utilization and reimbursement, 3) reviewing clinical coverage policies to identify opportunities to align coverage with evidence, 4) using a low-value device selection index, 5) developing an evidence synthesis and policy proposal, 6) stakeholder engagement and input, 7) policy implementation, and 8) policy evaluation. This strategy holds significant potential to reduce low-value device-based care.

Endoscopic transmission of carbapenem-resistant Enterobacteriaceae: implications for U.S. Food and Drug Administration approval and postmarket surveillance of endoscopic devices.

Since the first widely reported case cluster of duodenoscope-associated transmission of carbapenem-resistant Enterobacteriaceae (CRE) in 2013 that affected 38 patients, similar outbreaks have occurred throughout the world. The U.S. Food and Drug Administration (FDA), Centers for Disease Control and Prevention, professional gastroenterology societies, and endoscope manufacturers have taken multiple steps to address this issue. Unlike prior outbreaks attributed to lapses in cleaning and reprocessing, transmission and outbreaks have continued to occur despite compliance with current reprocessing guidelines. A definitive method of duodenoscope reprocessing remains elusive, and the FDA recently recommended transition to new designs with disposable components that do not require reprocessing. The first fully disposable duodenoscope received FDA clearance as a "breakthrough" device in December 2019. Although the human, microbiologic, and endoscopic design factors responsible for infectious transmissions and disinfecting techniques to avoid them have been examined, discussion has not included the critical role of FDA regulation of duodenoscopes through the 510(k) clearance pathway and the mechanisms of postmarket surveillance, including adverse event reporting. We present an overview of the FDA approval of duodenoscopes by analyzing the FDA's 510(k) premarket notification database for data supporting clearance of duodenoscope models implicated in CRE-related outbreaks as well as subsequently required postmarket studies. We address the policy implications of CRE outbreaks on postmarketing surveillance and the need for increased gastroenterologist involvement in the life cycle of duodenoscopes and other medical devices. This includes reporting thorough adverse event data to the FDA and device manufacturers, supporting active surveillance studies to ensure safety and effectiveness, and evaluating implementation of recommendations to reduce adverse events.

US Food and Drug Administration utilization of postmarketing requirements and postmarketing commitments, 2009-2018.

BACKGROUND/AIMS: The US Food and Drug Administration outlines clinical studies as postmarketing requirements and commitments to be fulfilled following approval of new drugs and biologics ("therapeutics"). Regulators have increasingly emphasized lifecycle evaluation of approved therapeutics, and postmarketing studies are intended to advance our understanding of therapeutic safety and efficacy. However, little is known about the indications that clinical studies outlined in postmarketing requirements and commitments investigate, including whether they are intended to generate evidence for approved or other clinical indications. Therefore, we characterized US Food and Drug Administration postmarketing requirements and commitments for new therapeutics approved from 2009 to 2018. METHODS: We conducted a cross-sectional study of all novel therapeutics, including small-molecule drugs and biologics, receiving original US Food and Drug Administration approval from 2009 to 2018, using approval letters accessed through the Drug@FDA database. Outcomes included the number and characteristics of US Food and Drug Administration postmarketing requirements and commitments for new therapeutics at original approval, including the types of studies outlined, the indications to be investigated, and the clinical evidence to be generated. RESULTS: From 2009 to 2018, the US Food and Drug Administration approved 343 new therapeutics with 1978 postmarketing requirements and commitments. Overall, 750 (37.9%) postmarketing requirements and commitments outlined clinical studies. For 71 of 343 (20.7%) therapeutics, no postmarketing requirements or commitments for clinical studies were outlined, while at least 1 was outlined for 272 (79.3%; median 2 (interquartile range: 1-4)). Among these 272 therapeutics, the number of postmarketing requirements and commitments for clinical studies per therapeutic did not change from 2009 (median: 2 (interquartile range: 1-4)) to 2018 (median: 2 (interquartile range: 1-3)). Among the 750 postmarketing requirements and commitments for clinical studies, 448 (59.7%) outlined new prospective cohort studies, registries, or clinical trials, while the remainder outlined retrospective studies, secondary analyses, or completion of ongoing studies. Although 455 (60.7%) clinical studies investigated only original approved therapeutic indications, 123 (16.4%) enrolled from an expansion of the approved disease population and 61 (8.1%) investigated diseases unrelated to approved indications. CONCLUSIONS: The US Food and Drug Administration approves most new therapeutics with at least 1 postmarketing requirement or commitment for a clinical study, and outlines investigations of safety or efficacy for both approved and unapproved indications. The median number of 2 clinical studies outlined has remained relatively constant over the last decade. Given increasing emphasis by the US Food and Drug Administration on faster approval and lifecycle evaluation of therapeutics, these findings suggest that more postmarketing requirements and commitments may be necessary to address gaps in the clinical evidence available for therapeutics at approval.