Recommendations to improve adverse event reporting in clinical trial publications: a joint pharmaceutical industry/journal editor perspective

Lineberry, Neil; Berlin, Jesse A.; Mansi, Bernadette; Glasser, Susan; Berkwits, Michael; Klem, Christian; Bhattacharya, Ananya; Citrome, Leslie; Enck, Robert E.; Fletcher, John; Haller, Daniel G.; Chen, Tai-Tsang; Lainé, Christine

doi:10.1136/bmj.i5078

Cited by 89 publications

(90 citation statements)

References 43 publications

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“…This review agrees with other similar publications focusing on drug safety assessment in clinical trials that have noted the need for further improvement in the statistical analysis of the safety data [9,37]. This review concurs with a recent review that has noted that inappropriate handling of multiple test is prevalent, although their review focussed on four high impact journals, AE in general and a short time of review period [38].…”

Section: Discussionsupporting

confidence: 88%

Systematic review of statistical methods for safety data in malaria chemoprevention in pregnancy trials

Patson

Mukaka

Otwombe

et al. 2020

Malar J

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Background: Drug safety assessments in clinical trials present unique analytical challenges. Some of these include adjusting for individual follow-up time, repeated measurements of multiple outcomes and missing data among others. Furthermore, pre-specifying appropriate analysis becomes difficult as some safety endpoints are unexpected. Although existing guidelines such as CONSORT encourage thorough reporting of adverse events (AEs) in clinical trials, they provide limited details for safety data analysis. The limited guidelines may influence suboptimal analysis by failing to account for some analysis challenges above. A typical example where such challenges exist are trials of anti-malarial drugs for malaria prevention during pregnancy. Lack of proper standardized evaluation of the safety of antimalarial drugs has limited the ability to draw conclusions about safety. Therefore, a systematic review was conducted to establish the current practice in statistical analysis for preventive antimalarial drug safety in pregnancy.Results: Eighteen trials were included in this review that collected multiple longitudinal safety outcomes including AEs. Statistical analysis and reporting of the safety outcomes in all the trials used descriptive statistics; proportions/ counts (n = 18, 100%) and mean/median (n = 2, 11.1%). Results presentation included tabular (n = 16, 88.9%) and text description (n = 2, 11.1%). Univariate inferential methods were reported in most trials (n = 16, 88.9%); including Chi square/Fisher's exact test (n = 12, 66.7%), t test (n = 2, 11.1%) and Mann-Whitney/Wilcoxon test (n = 1, 5.6%). Multivariable methods, including Poisson and negative binomial were reported in few trials (n = 3, 16.7%). Assessment of a potential link between missing efficacy data and safety outcomes was not reported in any of the trials that reported efficacy missing data (n = 7, 38.9%). Conclusion:The review demonstrated that statistical analysis of safety data in anti-malarial drugs for malarial chemoprevention in pregnancy RCTs is inadequate. The analyses insufficiently account for multiple safety outcomes potential dependence, follow-up time and informative missing data which can compromise anti-malarial drug safety evidence development, based on the available data.

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Section: Discussionsupporting

confidence: 88%

Systematic review of statistical methods for safety data in malaria chemoprevention in pregnancy trials

Patson

Mukaka

Otwombe

et al. 2020

Malar J

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“…Future research work can further consider adapting/extending recently developed statistical methods for rare disease or small population clinical trials towards analysis of rare safety outcomes in IPTp trials (35)(36)(37). This review agrees with other similar publications focusing on drug safety assessment in clinical trials that have noted the need for further improvement in the statistical analysis of the safety data (8,38).…”

Section: Reported Statistical Methodssupporting

confidence: 84%

Systematic review of statistical methods for safety data in malaria chemoprevention in pregnancy trials

Patson

Mukaka²,

Otwombe

et al. 2020

Preprint

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Background Drug safety assessments in clinical trials present unique analytical challenges. Some of these include adjusting for individual follow-up time, repeated measurements of multiple outcomes and missing data among others. Furthermore, pre-specifying appropriate analysis becomes difficult as some safety endpoints are unexpected. Although existing guidelines such as CONSORT encourage thorough reporting of adverse events (AEs) in clinical trials, they provide limited details for safety data analysis. The limited guidelines may influence suboptimal analysis by failing to account for some analysis challenges above. A typical example where such challenges exist are trials of antimalarial drugs for malaria prevention during pregnancy. Lack of proper standardized evaluation of the safety of antimalarial drugs has limited the ability to draw conclusions about safety. We have therefore conducted a systematic review to establish the current practice in statistical analysis for antimalarial drug safety in pregnancy. Methods We searched PubMed, Embase, Scopus, Malaria in Pregnancy Library and Cochrane Central Register of Controlled Trials for original English articles reporting Phase III (randomized controlled trials) RCTs on antimalarial drugs for malaria prevention in pregnancy published from January 2010 to July 2019. Results Eighteen trials were included in this review that collected multiple longitudinal safety outcomes including AEs. Statistical analysis and reporting of the safety outcomes in all the trials used descriptive statistics; proportions/counts (n=18, 100%) and mean/median (n=2, 11.1%). Results presentation included tabular (n=16, 88.9%) and text description (n=2, 11.1%). Univariate inferential methods were reported in most trials (n=16, 88.9%); including Chi-square/Fisher`s exact test (n=12, 66.7%), t-test (n=2, 11.1%) and Mann-Whitney/Wilcoxon test (n=1, 5.6%). Multivariable methods, including Poisson and negative binomial were reported in few trials (n=4, 22.2%). Assessment of a potential link between missing efficacy data and safety outcomes was not reported in any of the trials that reported efficacy missing data (n=7, 38.9%). Conclusion The review demonstrated that statistical analysis of safety data in antimalarial drugs for malarial chemoprevention in pregnancy RCTs are inadequate. The analysis insufficiently account for multiple safety outcomes potential dependence, follow-up time and informative missing data which can compromise antimalarial drug safety evidence development, based on the available data.

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“…One major common method is the so‐called crude rate, which despite its name is in fact a proportion and is defined as

\overset{P}{true} false(AE false) = a false/ n

, where a is the number of patients observed to experience at least one AE of a specific type, and n is the total number of study patients, see other studies and references therein. The crude rate is a correct estimator of the probability to experience at least one AE of the interesting type in case of complete data and identical follow‐up times for all patients.…”

Section: Statistical Methodologiesmentioning

confidence: 99%

“…Secondly, it is closely linked to the Mean Cumulative Function, which is based on the Nelson‐Aalen estimator and is also used in safety analyses . Thirdly, the Nelson‐Aalen estimator is the cumulative nonparametric counterpart of the commonly used incidence rate (or incidence density) of AEs:

I R_{AE} = \frac{a}{\sum t_{i}},

where t i is the time at risk for patient i , and

\sum t_{i}

denotes the population time (person‐years) at risk. The incidence rate is an estimator of the AE hazard α AE ( t ) under a constant hazard assumption, α AE ( t ) = α AE for all times t .…”

Section: Statistical Methodologiesmentioning

confidence: 99%

On estimands and the analysis of adverse events in the presence of varying follow‐up times within the benefit assessment of therapies

Unkel¹,

Amiri

Benda

et al. 2018

Pharmaceutical Statistics

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The analysis of adverse events (AEs) is a key component in the assessment of a drug's safety profile. Inappropriate analysis methods may result in misleading conclusions about a therapy's safety and consequently its benefit‐risk ratio. The statistical analysis of AEs is complicated by the fact that the follow‐up times can vary between the patients included in a clinical trial. This paper takes as its focus the analysis of AE data in the presence of varying follow‐up times within the benefit assessment of therapeutic interventions. Instead of approaching this issue directly and solely from an analysis point of view, we first discuss what should be estimated in the context of safety data, leading to the concept of estimands. Although the current discussion on estimands is mainly related to efficacy evaluation, the concept is applicable to safety endpoints as well. Within the framework of estimands, we present statistical methods for analysing AEs with the focus being on the time to the occurrence of the first AE of a specific type. We give recommendations which estimators should be used for the estimands described. Furthermore, we state practical implications of the analysis of AEs in clinical trials and give an overview of examples across different indications. We also provide a review of current practices of health technology assessment (HTA) agencies with respect to the evaluation of safety data. Finally, we describe problems with meta‐analyses of AE data and sketch possible solutions.

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Recommendations to improve adverse event reporting in clinical trial publications: a joint pharmaceutical industry/journal editor perspective

Cited by 89 publications

References 43 publications

Systematic review of statistical methods for safety data in malaria chemoprevention in pregnancy trials

Systematic review of statistical methods for safety data in malaria chemoprevention in pregnancy trials

Systematic review of statistical methods for safety data in malaria chemoprevention in pregnancy trials

On estimands and the analysis of adverse events in the presence of varying follow‐up times within the benefit assessment of therapies

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