US Food and Drug Administration Clearance of Moderate-Risk Otolaryngologic Devices via the 510(k) Process, 1997-2016

Objective The US Food and Drug Administration (FDA) clears moderate-risk devices via the 510(k) process based on substantial equivalence to previously cleared devices; evidence of safety and effectiveness is not required. We characterized the premarket evidence supporting FDA clearance of otolaryngologic devices. Study Design Retrospective cross-sectional analysis. Setting Publicly available FDA documents. Subjects and Methods Recently cleared (1997-2016) moderate-risk otolaryngologic devices were categorized by type (diagnostic/therapeutic), subspecialty, implantable designation (yes/no), and recall history (yes/no). Supporting evidence was categorized by type (clinical/nonclinical/none; nonclinical and clinical mutually inclusive) and public availability of nonclinical and clinical performance data (available/not provided/not applicable). Results Between 1997 and 2016, the FDA cleared 377 moderate-risk otolaryngologic devices. The majority were therapeutic (n = 240/377 [63.7%]) and otologic (n = 311/377 [82.5%]); roughly one-third (n = 121/377 [32.1%]) were implantable. Few (n = 10/377 [2.7%]) devices were subject to recall. FDA documents summarizing premarket evidence were accessible for two-thirds (n = 247/377 [65.5%]) of devices. Among these devices, one-quarter (n = 66/247 [26.7%]) were supported by clinical evidence. The majority (n = 177/247 [71.7%]) were supported by nonclinical evidence, although nearly one-quarter (n = 58/247 [23.5%]) were cleared without supporting evidence. Therapeutic devices were more often cleared without supporting evidence (therapeutic: n = 53/170 [31.2%]; diagnostic: n = 5/77 [6.5%]; P < .0001). Nonclinical and clinical performance data were rarely available (nonclinical: n = 49/247 [19.8%]; clinical: n = 32/247 [13.0%]) within public summaries. Conclusion The FDA cleared most moderate-risk otolaryngologic devices for marketing via the 510(k) process without clinical evidence of safety and effectiveness. Otolaryngologists should be aware of limitations in premarket evidence when considering the adoption of new devices into clinical practice.

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Postmarketing commitments for novel drugs and biologics approved by the US Food and Drug Administration: a cross-sectional analysis

BMC Medicine ◽

10.1186/s12916-019-1344-3 ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 2

Author(s):

Joshua D. Wallach ◽

Anita T. Luxkaranayagam ◽

Sanket S. Dhruva ◽

Jennifer E. Miller ◽

Joseph S. Ross

Keyword(s):

Drug Administration ◽

Food And Drug Administration ◽

Cross Sectional ◽

Cross Sectional Analysis ◽

Novel Drugs ◽

The Us ◽

Sectional Analysis

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

Clinical Trials ◽

10.1177/17407745211005044 ◽

2021 ◽

pp. 174077452110050

Author(s):

Joshua J Skydel ◽

Audrey D Zhang ◽

Sanket S Dhruva ◽

Joseph S Ross ◽

Joshua D Wallach

Keyword(s):

Drug Administration ◽

Clinical Studies ◽

Clinical Evidence ◽

Food And Drug Administration ◽

Median Number ◽

Cross Sectional Study ◽

Interquartile Range ◽

New Drugs ◽

Cross Sectional ◽

The Us

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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Clinical Evidence Supporting FDA Clearance of First-of-a-Kind Therapeutic Devices via the De Novo Pathway Between 2011 and 2019: A Retrospective Cross-Sectional Analysis

10.1101/2020.04.23.20077164 ◽

2020 ◽

Author(s):

James L. Johnston ◽

Sanket S. Dhruva ◽

Joseph S. Ross ◽

Vinay K. Rathi

Keyword(s):

Clinical Studies ◽

Clinical Evidence ◽

De Novo ◽

List Type ◽

Patient Access ◽

Moderate Risk ◽

Cross Sectional ◽

The Us ◽

New Models ◽

Sectional Analysis

ABSTRACTObjectiveThe US Food and Drug Administration established the De Novo premarket review pathway for first-of-a-kind moderate-risk devices in 1997 in order to reduce barriers to technological innovation and patient access. We sought to characterize three key features of this pathway: (1) the strength of clinical evidence supporting FDA clearance of therapeutic De Novo devices; (2) FDA post-marketing requirements for these devices; and (3) use of these devices as the basis for devices subsequently cleared via the 510(k) process.DesignRetrospective cross-sectional analysisSettingPublicly 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 databaseParticipantsAll 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).ResultsThere 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.ConclusionsBetween 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 primary effectiveness endpoints. 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.KEY POINTSWhat is already known on this topicThe US Food and Drug Administration (FDA) established the De Novo premarket review pathway for first-of-a-kind moderate-risk devices in 1997 in order to reduce barriers to technological innovation and patient access.In recent years, manufacturers have increasingly received FDA clearance to market devices through the De Novo pathway.The importance of the De Novo pathway will continue to grow as the FDA seeks to expedite patient access relative to international regulators.What this study addsAlthough the FDA clears the majority of therapeutic De Novo devices based on premarket evidence from pivotal clinical studies, 43% were cleared without such evidence or based on pivotal studies with failed primary effectiveness endpoints.The FDA rarely required postmarket studies of therapeutic De Novo devices, which often served as the basis for new models and competitor products subsequently cleared via the 510(k) process.

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Postmarket studies required by the US Food and Drug Administration for new drugs and biologics approved between 2009 and 2012: cross sectional analysis

BMJ ◽

10.1136/bmj.k2031 ◽

2018 ◽

pp. k2031 ◽

Cited By ~ 18

Author(s):

Joshua D Wallach ◽

Alexander C Egilman ◽

Sanket S Dhruva ◽

Margaret E McCarthy ◽

Jennifer E Miller ◽

...

Keyword(s):

Drug Administration ◽

Food And Drug Administration ◽

New Drugs ◽

Cross Sectional ◽

Cross Sectional Analysis ◽

The Us ◽

Sectional Analysis

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Characterization of Pharmacogenetic Information in Food and Drug Administration Drug Labeling and the Table of Pharmacogenetic Associations

Annals of Pharmacotherapy ◽

10.1177/1060028020983049 ◽

2020 ◽

pp. 106002802098304

Author(s):

Christine M. Cheng ◽

Thomas W. So ◽

Jeff L. Bubp

Keyword(s):

Clinical Outcome ◽

Drug Administration ◽

Gene Pair ◽

Drug Disposition ◽

Food And Drug Administration ◽

Cross Sectional ◽

Drug Labeling ◽

Gene Pairs ◽

Genetic Test Results ◽

Sectional Analysis

Background: The US Food and Drug Administration (FDA) recommends using only FDA-reviewed pharmacogenetic information to make prescribing decisions based on genetic test results. Such information is available in drug labeling and in the Table of Pharmacogenetic Associations (“Associations table”). Objective: To compile a list of drug-gene pairs from drug labeling and the Associations table and categorize the pharmacogenetic information and clinical outcome associated with each drug-gene pair. Methods: This was a cross-sectional analysis of pharmacogenetic information in the Associations table and individual drug labeling in March 2020. We used the Table of Pharmacogenomic Biomarkers in Drug Labeling to identify drug labels to review. We categorized the pharmacogenetic information for each drug-gene pair according to whether the purpose was to describe (1) polymorphisms affecting drug disposition (metabolism or transport), (2) polymorphisms affecting a direct drug target, (3) variants associated with adverse drug reaction (ADR) susceptibility, (4) variants associated with therapeutic failure, (5) a biomarker-defined indication, or (6) a biomarker-defined ADR. We also categorized the clinical outcome—efficacy, safety, or unknown—associated with each drug-gene pair. We reported counts and proportions of drug-gene pairs in each pharmacogenetic information and clinical outcome category. Results: We identified 308 drug-gene pairs, of which 36% were associated with a biomarker-defined drug indication, 33% with polymorphic drug metabolism, and 28% with ADR susceptibility. Most drug-gene pairs (n = 267, 87%) were associated with an efficacy or safety-related outcome. Conclusion and Relevance: FDA-reviewed pharmacogenetic information is available for more than 300 drug-gene pairs and can help guide prescribing decisions.

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