New FDA Regulation to Improve Safety Reporting in Clinical Trials

Sherman, Rachel Behrman; Woodcock, Janet; Norden, Janet M.; Grandinetti, Cheryl

doi:10.1056/nejmp1103464

Cited by 41 publications

(19 citation statements)

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“…Clinical trials should include explicit pre-specified monitoring of pharmacologically predictable adverse events and ensure adequate follow-up of withdrawn participants. Recent regulatory guidance from the FDA has limited the reporting of adverse events in clinical trials from sponsors to those that are unexpected and considered related to the drug [47]. It is unclear how isolated investigators will determine the causal relationship between a drug and its adverse events.…”

Section: Discussionmentioning

confidence: 99%

Drug safety assessment in clinical trials: methodological challenges and opportunities

Singh

Loke

2012

Trials

169

129

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Randomized controlled trials are the principal means of establishing the efficacy of drugs. However pre-marketing trials are limited in size and duration and exclude high-risk populations. They have limited statistical power to detect rare but potentially serious adverse events in real-world patients. We summarize the principal methodological challenges in the reporting, analysis and interpretation of safety data in clinical trials using recent examples from systematic reviews. These challenges include the lack of an evidentiary gold standard, the limited statistical power of randomized controlled trials and resulting type 2 error, the lack of adequate ascertainment of adverse events and limited generalizability of trials that exclude high risk patients. We discuss potential solutions to these challenges. Evaluation of drug safety requires careful examination of data from heterogeneous sources. Meta-analyses of drug safety should include appropriate statistical methods and assess the optimal information size to avoid type 2 errors. They should evaluate outcome reporting biases and missing data to ensure reliable and accurate interpretation of findings. Regulatory and academic partnerships should be fostered to provide an independent and transparent evaluation of drug safety.

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Section: Discussionmentioning

confidence: 99%

Drug safety assessment in clinical trials: methodological challenges and opportunities

Singh

Loke

2012

Trials

169

129

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“…Trial end points are established early during the trial design with specific definitions and form the basis for event‐driven trial completion and regulatory approval 1. AEs, commonly reported by study participants during trial follow‐up, follow a regulatory path if they meet criteria for seriousness and represent a key element of the product label 2, 3. Traditionally, these events are captured with unique data elements and criteria, but overlap exists.…”

Section: Introductionmentioning

confidence: 99%

Reporting Clinical End Points and Safety Events in an Acute Coronary Syndrome Trial: Results With Integrated Collection

Guimarães

Lópes

Stevens

et al. 2017

JAHA

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BackgroundEnd points and adverse events (AEs) are collected separately in clinical trials, yet regulatory requirements for serious AE reporting vary across regions, so classifying end points according to seriousness criteria can be useful in global trials.Methods and ResultsIn the Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE‐2) trial, patients with a recent acute coronary syndrome were randomized to apixaban or placebo for the prevention of recurrent ischemic events. Suspected end points (myocardial infarction, stroke, or bleeding) were adjudicated by an independent clinical events classification committee. Safety criteria were collected for suspected end points and AEs. Patient‐level event rates per 100 patient‐days of follow‐up, modeled using Poisson regression, explored the influence of region and patient characteristics on event reporting. Overall, 13 909 events were reported by 858 sites in 39 countries; 8.4% (n=1166) were suspected end points, and 91.6% (n=12 743) were AEs. Overall, 66.0% of suspected end points were confirmed by the clinical events classification committee. Most clinical events classification committee‐confirmed end points met criteria to be classified as serious (94.0%); many clinical events classification committee‐negated end points also did (63.2%), but fewer AEs met seriousness criteria (17.9%). The most common seriousness criterion was hospitalization (79.9%, n=2594). Region explained 28.7% of end point‐ and 26.4% of serious AE‐reporting variation, and patient characteristics explained an additional 25.4% of end point and 13.4% of serious AE variation. Nonserious AE‐reporting variation was not explained by adjustment.ConclusionsAn integrated collection of end points and serious AEs is feasible in a multinational trial and illustrates the shared characteristics of events. Tailoring event collection to fit the phase and purpose of the trial is achievable and informative.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00831441.

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“…Surgical resection of early (stage Ia-Ib) lung cancer has a 10-year survival of 88% [1] or more. The recent published data from the National Lung Screening Trial (NLST) confirmed that early diagnosis of lung cancer by CT scan screening improves survival by 20% when compared to chest radiography [2]. However, screening CT scan has a high false-positive rate (25% in NLST and up to 50% in our series [3]) which leads to the need for additional CT scans with their attendant radiation exposure, PET scans, and/or invasive procedures such as bronchoscopy with biopsy or transthoracic fine needle aspiration with even greater risks, costs (up to 20-40-fold more than watchful waiting) and anxiety.…”

Section: Introductionmentioning

confidence: 99%