Lessons learned from IDeAl — 33 recommendations from the IDeAl-net about design and analysis of small population clinical trials

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: Discussionmentioning

confidence: 99%

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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“…As awareness towards rare diseases is raising, specific programs and adaptions of guidelines for respective drug developments are established to address deficits and promote accessibility to innovative therapeutics for EB patients. These include new methodological strategies [94], fast track designations, or the possibility to receive an orphan drug status by agencies like FDA or EMA. The latter gives the holder certain advantages, like the creation of financial incentives to develop those drugs.…”

Section: Discussionmentioning

confidence: 99%

Small molecule drug development for rare genodermatoses – evaluation of the current status in epidermolysis bullosa

Wally

Reisenberger

Kitzmüller

et al. 2020

Orphanet J Rare Dis

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Background Hereditary epidermolysis bullosa (EB) comprises a heterogeneous group of rare genodermatoses, which are caused by mutations in genes involved in the maintenance of the structural and functional integrity of dermo-epidermal adhesion in various stratified epithelia. In severe variants, generalized skin disease, extracutaneous manifestations and multi-organ involvement cause considerable morbidity and mortality. Causal and early treatment by re-expression of a respective mutated gene is the major long-term goal in therapy development. However, characterization and targeted modulation of pathogenic molecular cascades in EB also holds great promise as a symptom-relieving approach to ameliorate phenotype, complications and quality of life. Small molecules are chemical structures of less than 900 Da that can diffuse across cell membranes and interfere with target biomolecules, thus influencing their function at different levels. They constitute the vast majority of active components of all approved drugs. Methods We performed PubMed and Google Scholar search for publications and screened FDA- and EMA-hosted clinical trial registries to identify studies using small molecule-based drugs for epidermolysis bullosa. Upon detailed analysis this resulted in the identification of a total of 84 studies. Results We identified 52 publications and 32 registered trials that investigate small molecules for their safety and efficacy as treatment for different aspects of epidermolysis bullosa. Further, a total of 38 different small molecules clinically used in EB were found. Most frequent outcome measures concerned wound healing, reduction in blister numbers, as well as reduction of itch and pain, predominantly for EBS and RDEB. Conclusion We provide a comprehensive summary of the current status of clinical small molecule development for EB and discuss prospects and limitations in orphan drug development for rare conditions like EB.

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“…For rare events, Bayesian approaches can be considered since they do not depend on asymptotic properties when handling rare events and can incorporate prior/external information (34). 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 Methodsmentioning

confidence: 99%

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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Lessons learned from IDeAl — 33 recommendations from the IDeAl-net about design and analysis of small population clinical trials

Cited by 27 publications

References 79 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

Small molecule drug development for rare genodermatoses – evaluation of the current status in epidermolysis bullosa

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

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