FDA Policy and Cardiovascular Medicine

Ross, Joseph S.; Kesselheim, Aaron S.

doi:10.1161/circulationaha.114.010295

Cited by 7 publications

(5 citation statements)

References 57 publications

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“…To our knowledge, our study is the first to systematically review medical devices cleared via the FDA De Novo pathway. In contrast to the oft scrutinized 510(k) process, 2,15 the De Novo pathway typically requires manufacturers to submit clinical evidence of device safety and effectiveness. When pivotal studies are not required, the FDA often considers alternative clinical data sources, although these may be limited by biases due to selective publication or the challenges of detecting postmarket safety signals.…”

Section: Discussionmentioning

confidence: 99%

Clinical Evidence Supporting FDA Clearance of First-of-a-Kind Therapeutic Devices via the De Novo Pathway Between 2011 and 2019

Johnston

Dhruva

Ross

et al. 2020

Preprint

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Importance: In recent years, the US Food and Drug Administration (FDA) and manufacturers have increasingly sought to expedite patient access to first-of-a-kind devices via the De Novo premarket review pathway. Understanding the strength of clinical evidence supporting FDA clearance through this pathway can help guide clinical adoption of novel devices and ongoing regulatory development of the postmarket surveillance infrastructure. Objective: Our primary objective was to characterize the strength of clinical evidence supporting FDA clearance of therapeutic De Novo devices. Key secondary objectives were 1) characterization of FDA post-marketing requirements for De Novo devices and 2) study of the use of these devices as the basis for devices subsequently cleared via the 510(k) process. Design: Retrospective cross-sectional analysis Setting: Publicly available online FDA databases, including the De Novo database, the 510(k) clearance database, the 522 Post Market Surveillance database, and the Recalls of Medical Devices database Participants: All moderate-risk therapeutic devices cleared via the De Novo pathway between January 1, 2011, and December 31, 2019. Main Outcome Measures: (1) proportion of De Novo devices cleared based on evidence from a pivotal clinical study, (2) proportion of pivotal study primary effectiveness endpoints that were met, (3) proportion of De Novo devices subject to FDA-required postmarket studies, and (4) proportion of De Novo devices serving as the basis for at least one subsequently cleared 510(k) device (i.e., new models or competitor products). Results: There were 63 (of 65; 96.9%) moderate-risk therapeutic devices cleared by FDA via the De Novo pathway between 2011 and 2019 for which decision summary documentation was publicly available. Of the 63 devices, 51 (81.0%) were supported by pivotal clinical studies (n=54 studies); the remainder (n=12; 19.0%) were not supported by a pivotal clinical study. The majority of pivotal studies were randomized (57.4%), multi-armed (61.1%), and used an active (25.9%) or sham (35.2%) comparator arm; 17 (31.5%) failed to meet at least one primary effectiveness endpoint. Among the 63 devices cleared via the De Novo pathway, one (1.6%) was subject to an FDA-required posttmarket study and 32 (47.8%) served as a predicate device for new models or competitor devices subsequently cleared through the 510(k) process. Conclusions: Between 2011 and 2019, the FDA cleared the majority of first-of-a-kind moderate-risk therapeutic devices via the De Novo pathway based on premarket evidence from pivotal clinical studies. However, 43% of devices were cleared without clinical evidence from pivotal studies or based on pivotal studies that failed to meet at least one primary effectiveness endpoint. The FDA rarely required postmarket studies of these devices, which often served as the basis for new models and competitor products subsequently cleared via the 510(k) process.

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Section: Discussionmentioning

confidence: 99%

Clinical Evidence Supporting FDA Clearance of First-of-a-Kind Therapeutic Devices via the De Novo Pathway Between 2011 and 2019

Johnston

Dhruva

Ross

et al. 2020

Preprint

Self Cite

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“…To receive regulatory approval by the US Food and Drug Administration (FDA), new small-molecule drugs and biologics (“therapeutics”) are generally required to be supported by two or more well-controlled studies demonstrating safety and efficacy. 1,2 However, FDA has increasingly emphasized postmarket evidence generation in support of lifecycle evaluation of therapeutics. 3 Furthermore, the use of FDA’s expedited review programs, 4 intended to speed the entry of therapeutics to market, 5,6 has contributed to more therapeutics being approved on the basis of fewer pivotal trials, 7 and trials using surrogate markers as primary endpoints.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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“…To receive regulatory approval by the U.S. Food and Drug Administration (FDA), new small molecule drugs and biologics (“therapeutics”) are generally required to be supported by two or more well-controlled studies demonstrating safety and efficacy. 1,2 However, FDA has increasingly emphasized postmarket evidence generation in support of lifecycle evaluation of therapeutics. 3 Furthermore, use of FDA’s expedited review programs, 4 intended to speed the entry of therapeutics to market, 5,6 has contributed to more therapeutics being approved on the basis of fewer pivotal trials, 7 and trials using surrogate markers as primary endpoints.…”

Section: Introductionmentioning

confidence: 99%

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

Skydel

Zhang

Dhruva

et al. 2020

Preprint

Self Cite

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Background/Aims: The U.S. Food and Drug Administration (FDA) outlines clinical studies as postmarketing requirements and commitments to be fulfilled following FDA approval of new drugs and biologics ("therapeutics"). As regulators have increasingly emphasized lifecycle evaluation of approved therapeutics, postmarketing studies are intended to advance our understanding of therapeutic safety and efficacy, yet little is known about how often clinical studies are outlined or the indications they investigate. To assess FDA's use of postmarket clinical studies to generate evidence of therapeutic safety and efficacy, we characterized FDA postmarketing requirements and commitments for new therapeutics approved from 2009-2018. Methods: We conducted a cross-sectional study of all novel therapeutics, including small molecule drugs and biologics, receiving original FDA approval from 2009-2018, using approval letters accessed through the Drug@FDA database. Outcomes included the number and characteristics of FDA postmarketing requirements and commitments for new therapeutics at original approval, including types of studies outlined, indications to be investigated, and clinical evidence to be generated. Results: From 2009-2018, FDA 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 nor commitments for clinical studies were outlined, while at least 1 was outlined for 272 (79.3%; median = 2 (IQR, 1-4)). Among these 272 therapeutics, the number of postmarketing requirements and commitments for clinical studies per therapeutic did not significantly change from 2009 (median 2 (IQR, 1-4)) to 2018 (median 2 (IQR, 1-3); P = .54). 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: Most therapeutics are approved by FDA with at least 1 postmarketing requirement or commitment for a clinical study, which outline investigations of safety or efficacy for both approved and unapproved indications. However, the median number of 2 clinical studies outlined has remained relatively constant over the last decade, despite increasing emphasis on lifecycle evaluation of approved therapeutics.

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FDA Policy and Cardiovascular Medicine

Cited by 7 publications

References 57 publications

Clinical Evidence Supporting FDA Clearance of First-of-a-Kind Therapeutic Devices via the De Novo Pathway Between 2011 and 2019

Clinical Evidence Supporting FDA Clearance of First-of-a-Kind Therapeutic Devices via the De Novo Pathway Between 2011 and 2019

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

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

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