Clinical Evidence Supporting US Food and Drug Administration Clearance of Novel Therapeutic Devices via the De Novo Pathway Between 2011 and 2019

PURPOSE The US Food and Drug Administration–expanded access program (EAP) uses a single patient use (SPU) mechanism to provide patient access to investigational agents in situations where no satisfactory or comparable therapy is available. Genomic profiling of de novo and relapsed or refractory childhood cancer has led to increased identification of new drug targets in the last decade. The aim of this study is to examine the SPU experience for genomically targeted therapies in patients with pediatric cancer. PATIENTS AND METHODS All genomically targeted therapeutic SPUs obtained over a 5-year period were evaluated at four large pediatric cancer programs. Data were collected on the type of neoplasm, agents requested, corresponding molecularly informed targets, and clinical outcomes. RESULTS A total of 45 SPUs in 44 patients were identified. Requests were predominantly made for CNS and solid tumors (84.4%) compared with hematologic malignancies (15.6%). Lack of an available clinical trial was the main reason for SPU initiation (64.4%). The median time from US Food and Drug Administration submission to approval was 3 days (range, 0-12 days) and from Institutional Review Board submission to approval was 5 days (range, 0-50 days). Objective tumor response was seen in 39.5% (15 of 38) of all evaluable SPUs. Disease progression was the primary reason for discontinuation of drug (66.7%) followed by toxicity (13.3%). CONCLUSION SPU requests remain an important mechanism for pediatric access to genomically targeted agents given the limited availability of targeted clinical trials for children with high-risk neoplasms. Furthermore, this subset of SPUs resulted in a substantial number of objective tumor responses. The development of a multi-institutional data registry of SPUs may enable systematic review of toxicity and clinical outcomes and provide evidence-based access to new drugs in rare pediatric cancers.

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Drug Repurposing in Neurological Disorders: Implications for Neurotherapy in Traumatic Brain Injury

The Neuroscientist ◽

10.1177/1073858420961078 ◽

2020 ◽

pp. 107385842096107

Author(s):

Zaynab Shakkour ◽

Karl John Habashy ◽

Moussa Berro ◽

Samira Takkoush ◽

Samar Abdelhady ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Drug Administration ◽

Neurological Disorders ◽

De Novo ◽

Food And Drug Administration ◽

Drug Repurposing ◽

Adverse Outcomes ◽

Minimal Risk ◽

Wide Range

Traumatic brain injury (TBI) remains a significant leading cause of death and disability among adults and children globally. To date, there are no Food and Drug Administration–approved drugs that can substantially attenuate the sequelae of TBI. The innumerable challenges faced by the conventional de novo discovery of new pharmacological agents led to the emergence of alternative paradigm, which is drug repurposing. Repurposing of existing drugs with well-characterized mechanisms of action and human safety profiles is believed to be a promising strategy for novel drug use. Compared to the conventional discovery pathways, drug repurposing is less costly, relatively rapid, and poses minimal risk of the adverse outcomes to study on participants. In recent years, drug repurposing has covered a wide range of neurodegenerative diseases and neurological disorders including brain injury. This review highlights the advances in drug repurposing and presents some of the promising candidate drugs for potential TBI treatment along with their possible mechanisms of neuroprotection. Edaravone, glyburide, ceftriaxone, levetiracetam, and progesterone have been selected due to their potential role as putative TBI neurotherapeutic agents. These drugs are Food and Drug Administration–approved for purposes other than brain injuries; however, preclinical and clinical studies have shown their efficacy in ameliorating the various detrimental outcomes of TBI.

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Disagreements Within the US Food and Drug Administration Regarding Approval of Novel Therapeutic Agents, 2011-2015

JAMA Network Open ◽

10.1001/jamanetworkopen.2020.9498 ◽

2020 ◽

Vol 3 (7) ◽

pp. e209498 ◽

Cited By ~ 1

Author(s):

Andrea MacGregor ◽

Audrey D. Zhang ◽

Joshua D. Wallach ◽

Joseph S. Ross ◽

Matthew Herder

Keyword(s):

Drug Administration ◽

Food And Drug Administration ◽

Therapeutic Agents ◽

The Us ◽

Novel Therapeutic

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

Otolaryngology ◽

10.1177/0194599817721689 ◽

2017 ◽

Vol 157 (4) ◽

pp. 608-617 ◽

Cited By ~ 2

Author(s):

Vinay K. Rathi ◽

Shekhar K. Gadkaree ◽

Joseph S. Ross ◽

Elliott D. Kozin ◽

Rosh K. Sethi ◽

...

Keyword(s):

Drug Administration ◽

Clinical Evidence ◽

Clinical Performance ◽

Food And Drug Administration ◽

Performance Data ◽

Supporting Evidence ◽

Moderate Risk ◽

Cross Sectional ◽

The Us ◽

Sectional Analysis

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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Postmarket Clinical Evidence for High-Risk Therapeutic Medical Devices Receiving Food and Drug Administration Premarket Approval in 2010 and 2011

JAMA Network Open ◽

10.1001/jamanetworkopen.2020.14496 ◽

2020 ◽

Vol 3 (8) ◽

pp. e2014496

Author(s):

Vinay K. Rathi ◽

Harlan M. Krumholz ◽

Frederick A. Masoudi ◽

Joseph S. Ross

Keyword(s):

High Risk ◽

Drug Administration ◽

Medical Devices ◽

Clinical Evidence ◽

Food And Drug Administration ◽

Premarket Approval

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Clinical Evidence Supporting Pharmacogenomic Biomarker Testing Provided In US Food And Drug Administration Drug Labels: An Update

Value in Health ◽

10.1016/j.jval.2016.03.756 ◽

2016 ◽

Vol 19 (3) ◽

pp. A289

Author(s):

S. Baradaran ◽

K.R. Keyloun ◽

L. Chin ◽

J. Pham ◽

W. Canestaro ◽

...

Keyword(s):

Drug Administration ◽

Clinical Evidence ◽

Food And Drug Administration ◽

Biomarker Testing

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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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Food and Drug Administration (FDA)'s impact on laboratory performance: FDA's perspective

Clinical Chemistry ◽

10.1093/clinchem/42.5.786 ◽

1996 ◽

Vol 42 (5) ◽

pp. 786-789

Author(s):

S Gutman

Keyword(s):

Drug Administration ◽

De Novo ◽

Clinical Laboratory ◽

Food And Drug Administration ◽

Scientific Review ◽

Regulatory Issue ◽

In Vitro Diagnostic ◽

Intended Use

Abstract The Division of Clinical Laboratory Devices is responsible for the premarket review of in vitro diagnostic devices (laboratory tests). We currently process >1000 diverse applications per year. New versions of old devices are handled as premarket notifications, so-called 510(k) submissions. The review objective is to establish that the new product is "substantially equivalent" to its predicate. Fundamentally new devices are handled as premarket applications. The review objective is to establish de novo that the product is ¿safe and effective.¿ A central regulatory issue over the past several years has been the development of a standardized model for scientific review. The Food and Drug Administration contributes to the quality of in vitro diagnostic devices by providing oversight and objective review, by setting thresholds for product safety and effectiveness, and by ensuring that organized data and appropriate labeling is present in support of a device's intended use.

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