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

Wallach, John R.; Egilman, Alexander C; Dhruva, Sanket S.; McCarthy, M.; Miller, Jennifer E.; Woloshin, Steven; Schwartz, Lisa M.; Ross, Joseph S.

doi:10.1136/bmj.k2031

Cited by 56 publications

(114 citation statements)

References 22 publications

(39 reference statements)

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“…As previously described, 4 we identified all PMRs from the approval letters in the Drugs@FDA database for new drugs and biologics approved between 2009 and 2012. Approval letters include descriptions of PMRs and identify the regulatory authorities under which they are required (Accelerated Approval (AA), Pediatric Research Equity Act (PREA), or FDA Amendments Act (FDAAA)) ( Table 1).…”

Section: Methodsmentioning

confidence: 99%

“…We limited our sample to clinical PMR studies examining drug safety or efficacy, including new prospective cohort studies, clinical trials, and registries. 4 We collected FDA approval dates for each drug and milestone dates established by FDA for each PMR study, including final protocol submission, trial completion, and final report submission. We searched ClinicalTrials.gov for registration records to identify primary outcomes and the timing of their measurement (e.g., primary outcome ascertainment: change from baseline to day 56 in syndrome scale), as a proxy for expected study duration.…”

Section: Methodsmentioning

confidence: 99%

“…2 Furthermore, nearly one quarter of PMR results are either not reported on ClinicalTrials.gov or published in the peer-reviewed literature. 3,4 Therefore, our objective was to characterize the timeliness of PMR studies, comparing FDAestablished timeliness milestones with expected completion times outlined on ClinicalTrials.gov.…”

Section: Introductionmentioning

confidence: 99%

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Timeliness of Postmarket Studies for New Pharmaceuticals Approved Between 2009 and 2012: a Cross-Sectional Analysis

et al. 2018

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Timeliness of Postmarket Studies for New Pharmaceuticals Approved Between 2009 and 2012: a Cross-Sectional Analysis

et al. 2018

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“…Postmarketing studies may be observational or randomized trials. The FDA may require such studies when there are long‐term safety or effectiveness concerns at or after approval of a product . Observational studies may involve development of prospective cohorts or take advantage of existing real‐world data sources.…”

mentioning

confidence: 99%

“…The FDA may require such studies when there are long-term safety or effectiveness concerns at or after approval of a product. 14,15 Observational studies may involve development of prospective cohorts or take advantage of existing real-world data sources. Such data sources, for example, administrative health care claims, are rapidly collected and generated and are a more affordable option compared to prospective data collection.…”

mentioning

confidence: 99%

Real‐World Data Approaches for Early Detection of Potential Safety and Effectiveness Signals for Generic Substitution: A Metoprolol Extended‐Release Case Study

Brown

Henriksen

Vozmediano

et al. 2019

The Journal of Clinical Pharma

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Real‐world spontaneous adverse event reports and administrative health care data were utilized as one part of a multipronged approach to verify surveillance signals related to generic drug formulations. This study used metoprolol succinate extended release as a historic case example from which to develop an analytic framework. The US Food and Drug Administration Adverse Event Reporting System was utilized for disproportionality analyses and to identify outcomes of interest. Claims data were analyzed for generic uptake, proportion of prescriptions with “dispense as written” orders, time to discontinuation or switching, and relative rates of clinical events. Adverse Event Reporting System data showed that the Medical Dictionary for Regulatory Activities terms for product quality were higher for generic metoprolol cases and that a number of clinical events were increased that could be side effects of high or low variability in drug levels. Compared to amlodipine‐benazepril, which also had a first‐approved generic at the same time, market share data showed that metoprolol succinate had lower utilization and more prescriptions written as dispense as written. Switching and discontinuation were generally higher for metoprolol users compared to amlodipine‐benazepril users. Finally, clinical event rates were generally higher for generic versus brand metoprolol but lower for the same comparison for amlodipine‐benazepril users. In the claims‐based analyses, the 90‐day period immediately after generic entry provided stronger signal capture than using the entire study period. This analytic framework can be implemented to actively monitor new generic formulations for potential bioequivalence failures. Signals from these analyses require confirmation (eg, via pharmacometric analyses) to be informative for regulatory action.

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Clinical Trial Evidence Supporting FDA Approval of Drugs Granted Breakthrough Therapy Designation

Puthumana

Wallach

Ross

2018

JAMA

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The US Food and Drug Administration (FDA) Safety and Innovation Act of 2012 created the Breakthrough Therapy designation to expedite development and review of drugs and biologics intended to treat serious or life-threatening conditions for which preliminary clinical evidence may demonstrate substantial improvement over existing therapies, allowing the FDA to provide "intensive guidance on efficient drug development" and "rolling review." 1 Although physicians and patients often perceive that breakthrough approvals are based on rigorous clinical evidence, 2,3 no systematic evaluation of the evidence supporting breakthrough approvals has occurred. We reviewed all new FDA approvals granted Breakthrough Therapy designation, characterizing the pivotal clinical trials that serve as the basis of FDA approval, 4 and premarket development and review times. Methods |We identified all new drugs and biologics first approved by the FDA from January 2012 through December 2017 using the Drugs@FDA database. For each therapeutic indication granted Breakthrough Therapy designation, we abstracted FDA-determined regulatory and therapeutic characteristics, as well as postmarketing requirements. 5 Drugs granted Breakthrough Therapy designation may also qualify for other expedited review programs, including Accelerated Approval, Priority Review, and Fast Track. We then identified all pivotal trials supporting approval and determined use of randomization, blinding, comparator group, primary end point, and number of patients using methods described previously. 4 Next, we identified 3 regulatory dates using public FDA documents and patent extension notices: investigational new drug (IND) activation (when human testing can begin), new drug application (NDA) submission, and FDA approval.We used Stata (StataCorp), version 13.0, to conduct Wilcoxon, Kruskal-Wallis, and Fisher exact tests as appropriate. Statistical tests were 2-sided and used a Bonferroni-corrected P value of .01 to account for multiple comparisons for differences by 5 prespecified regulatory and therapeutic characteristics.

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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

Cited by 56 publications

References 22 publications

Timeliness of Postmarket Studies for New Pharmaceuticals Approved Between 2009 and 2012: a Cross-Sectional Analysis

Timeliness of Postmarket Studies for New Pharmaceuticals Approved Between 2009 and 2012: a Cross-Sectional Analysis

Real‐World Data Approaches for Early Detection of Potential Safety and Effectiveness Signals for Generic Substitution: A Metoprolol Extended‐Release Case Study

Clinical Trial Evidence Supporting FDA Approval of Drugs Granted Breakthrough Therapy Designation

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