Project description:ImportanceThe US Food and Drug Administration (FDA) awards the breakthrough therapy designation to expedite development and review of therapeutics intended to treat serious conditions when preliminary clinical evidence demonstrates potential substantial improvement over existing therapies on clinically significant end points. Under the 21st Century Cures Act of 2016, the FDA is required to publish and routinely update a list of surrogate markers to provide industry sponsors with indication-specific information about end points that were or may be considered for approval. Therapeutics that are granted breakthrough therapy designation can receive accelerated or traditional approval; however, little is known about those approved through the latter pathway, where postmarketing confirmatory studies are typically not required, regardless of the end point used.ObjectiveTo evaluate the primary end points used in premarket pivotal trials supporting FDA breakthrough therapy-designated approvals and to determine whether postmarketing studies confirming efficacy were required for approvals based on pivotal trials using surrogate markers as primary end points.Design, setting, and participantsThis cross-sectional study used data from the Drugs@FDA database for all original breakthrough therapy-designated approvals from inception to December 31, 2023, in the US. The first designation was approved on November 1, 2013. Data analysis was performed in January 2024.Main outcomes and measuresDescriptive analyses were used to characterize the breakthrough therapy-designated indication approval pathways, the primary end points of pivotal efficacy trials, and their postmarketing requirements or commitments.ResultsFrom 2013 to 2023, the FDA approved 157 original indications with breakthrough therapy designation. Of these, 52 (33%) were granted accelerated approval and 105 (67%) were granted traditional approval. All accelerated approvals were based on pivotal trials using surrogate markers as primary end points and had FDA-required postmarketing studies to confirm efficacy. Of these 52 indications, 51 (98%) were approved based on surrogate end points listed in the FDA table of surrogate end points for the same indication. Among traditional approvals, 61 (58%) were based on pivotal trials using surrogate markers as primary end points, of which 4 (7%) had FDA-required postmarketing studies to confirm efficacy and 39 (64%) were approved based on surrogate end points listed in the FDA table for the same indication.Conclusions and relevanceIn this cross-sectional study of original FDA breakthrough therapy-designated approvals from 2013 to 2023, trials supporting these approvals often used surrogate markers as primary end points (even when not approved via accelerated approval) and lacked FDA-required postmarketing studies to verify clinical benefit. These findings suggest that requiring postmarketing studies for breakthrough therapy-designated indications approved based on surrogate markers, regardless of approval pathway, may increase patient and clinician certainty of the expected clinical benefit.

Project description:BackgroundThe FDA approves novel, high-risk medical devices through the premarket approval (PMA) process based on clinical evidence supporting device safety and effectiveness. Devices subsequently may undergo postmarket modifications that are approved via one of several PMA supplement review tracks, usually without additional supporting clinical data. While orthopaedic devices cleared via the less rigorous 510(k) pathway have been studied previously, devices cleared through the PMA pathway and those receiving postmarket PMA supplements warrant further investigation.Questions/purposesWe asked: What are (1) the types of original orthopaedic devices receiving FDA PMA approval, (2) the number and rate of postmarket device changes approved per device, (3) the types of PMA supplement review tracks used, (4) the types of device changes approved via the various review tracks, and (5) the number of device recalls and market withdrawals that have occurred for these devices?MethodsAll original PMA-approved orthopaedic devices between January 1982 and December 2014 were identified in the publically available FDA PMA database. The number of postmarket device changes approved, the PMA supplement review track used, the types of postmarket changes, and any FDA recalls for each device were assessed.ResultsSeventy original orthopaedic devices were approved via the FDA PMA pathway between 1982 and 2014. These devices included 34 peripheral joint implants or prostheses, 18 spinal implants or prostheses, and 18 other devices or materials. These devices underwent a median 6.5 postmarket changes during their lifespan or 1.0 changes per device-year (interquartile range, 0.4-1.9). The rate of new postmarket device changes approved per active device, increased from less than 0.5 device changes per year in 1983 to just fewer than three device changes per year in 2014, or an increase of 0.05 device changes per device per year in linear regression analysis (95% CI, 0.04-0.07). Among the 765 total postmarket changes, 172 (22%) altered device design or components. The majority of the design changes were reviewed via either the real-time review track (n = 98; 57%), intended for minor design changes, or the 180-day review track (n = 71; 41%), intended for major design changes. Finally, a total of 12 devices had FDA recalls at some point during their lifespan, two being for hip prostheses with high revision rates.ConclusionsRelatively few orthopaedic devices undergo the FDA PMA process before reaching the market. Orthopaedic surgeons should be aware that high-risk medical devices cleared via the FDA's PMA pathway do undergo considerable postmarket device modification after reaching the market, with potential for design "drift," ie, shifting away from the initially tested and approved device designs.Clinical relevanceAs the ultimate end-users of these devices, orthopaedic surgeons should be aware that even among high-risk medical devices approved via the FDA's PMA pathway, considerable postmarket device modification occurs. Continued postmarket device monitoring will be essential to limit patient safety risks.

Project description:ImportanceThe US Food and Drug Administration (FDA) evaluates high-risk medical devices such as cardiac implantable electronic devices (CIEDs), including pacemakers, implantable cardioverter-defibrillators, and cardiac resynchronization therapy devices, via the premarket approval (PMA) process, during which manufacturers submit clinical data demonstrating safety and effectiveness. Subsequent changes to approved high-risk devices are implemented via "supplements," which may not require additional clinical testing.ObjectiveTo characterize the prevalence and characteristics of changes to CIEDs made through the PMA supplement process.DesignUsing the FDA's PMA database, we reviewed all CIEDs approved as original PMAs or supplements from 1979 through 2012. For each supplement, we collected the date approved, type of supplement (panel-track, 180-day, real-time, special, and 30-day notice), and the nature of the changes. We calculated the number of supplements approved per PMA and analyzed trends relating to different supplement regulatory categories over time. For supplements approved via the 180-day regulatory pathway, which often involve significant design changes, from 2010-2012, we identified how often additional clinical data were collected.ResultsFrom 1979-2012, the FDA approved 77 original and 5829 supplement PMA applications for CIEDs, with a median of 50 supplements per original PMA (interquartile range [IQR], 23-87). Excluding manufacturing changes that do not alter device design, the number of supplements approved each year was stable around a mean (SD) of 2.6 (0.9) supplements per PMA per year. Premarket approvals remained active via successive supplements over a median period of 15 years (IQR, 8-20), and 79% of the 77 original PMAs approved during our study period were the subject of at least 1 supplement in 2012. Thirty-seven percent of approved supplements involved a change to the device's design. Among 180-day supplements approved from 2010-2012, 23% (15/64) included new clinical data to support safety and effectiveness.Conclusions and relevanceMany CIED models currently used by clinicians were approved via the PMA supplement process, not as original PMAs. Most new device models are deemed safe and effective without requiring new clinical data, reinforcing the importance of rigorous postapproval surveillance of these devices.

Project description:ImportanceMany patients and physicians assume that the safety and effectiveness of newly approved therapeutic agents is well understood; however, the strength of the clinical trial evidence supporting approval decisions by the US Food and Drug Administration (FDA) has not been evaluated.ObjectivesTo characterize pivotal efficacy trials (clinical trials that serve as the basis of FDA approval) for newly approved novel therapeutic agents.Design and settingCross-sectional analysis using publicly available FDA documents for all novel therapeutic agents approved between 2005 and 2012.Main outcomes and measuresPivotal efficacy trials were classified according to the following design features: randomization, blinding, comparator, and trial end point. Surrogate outcomes were defined as any end point using a biomarker expected to predict clinical benefit. The number of patients, trial duration, and trial completion rates were also determined.ResultsBetween 2005 and 2012, the FDA approved 188 novel therapeutic agents for 206 indications on the basis of 448 pivotal efficacy trials. The median number of pivotal trials per indication was 2 (interquartile range, 1-2.5), although 74 indications (36.8%) were approved on the basis of a single pivotal trial. Nearly all trials were randomized (89.3% [95% CI, 86.4%-92.2%]), double-blinded (79.5% [95% CI, 75.7%-83.2%]), and used either an active or placebo comparator (87.1% [95% CI, 83.9%-90.2%]). The median number of patients enrolled per indication among all pivotal trials was 760 (interquartile range, 270-1550). At least 1 pivotal trial with a duration of 6 months or greater supported the approval of 68 indications (33.8% [95% CI, 27.2%-40.4%]). Pivotal trials using surrogate end points as their primary outcome formed the exclusive basis of approval for 91 indications (45.3% [95% CI, 38.3%-52.2%]), clinical outcomes for 67 (33.3% [95% CI, 26.8%-39.9%]), and clinical scales for 36 (17.9% [95% CI, 12.6%-23.3%]). Trial features differed by therapeutic and indication characteristics, such as therapeutic area, expected length of treatment, orphan status, and accelerated approval.Conclusions and relevanceThe quality of clinical trial evidence used by the FDA as the basis for recent approvals of novel therapeutic agents varied widely across indications. This variation has important implications for patients and physicians as they make decisions about the use of newly approved therapeutic agents.

Dataset Information

Assessment of FDA Approval for New High-risk Therapeutic Devices Not Meeting Pivotal Study Primary End Points, 2016-2020.

Publications

Assessment of FDA Approval for New High-risk Therapeutic Devices Not Meeting Pivotal Study Primary End Points, 2016-2020.

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