How Real is Intention-To-Treat (ITT) Analysis in Non-Interventional Post Authorization Safety Studies? We Can Do Better

Kiri, Victor A.; MacKenzie, Gilbert

doi:10.2174/157488609788173008

Cited by 9 publications

(5 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the intention‐to‐treat approach (ITT), the initial drug exposure is assumed to be unchanged until the end of FU, irrespective of treatment's changes 46 . The as‐treated approach (AT) is considered more suitable for the exposure ascertainment in observational cohort studies; the AT approach computes the specific drug exposure's time from exposure's start until the drug's discontinuation.…”

Section: Resultsmentioning

confidence: 99%

Cardiovascular outcomes, heart failure and mortality in type 2 diabetic patients treated with glucagon‐like peptide 1 receptor agonists (GLP‐1 RAs): A systematic review and meta‐analysis of observational cohort studies

Comoglio

Vidal

2020

Int J Clin Pract

View full text Add to dashboard Cite

Background Cardiovascular outcomes trials (CVOTs) have assessed the effects of glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) on major adverse cardiovascular events (MACE) and mortality in high cardiovascular (CV) risk populations. Observational research can provide complementary evidence about these effects in unselected populations. Aim To systematically review retrospective observational cohort studies conducted in electronic healthcare databases (EHDs) assessing GLP‐1 RAs´ effects on MACE and/or hospitalisation for heart failure (HHF) and/or all‐cause mortality in Type 2 diabetes mellitus (T2DM) patients. Methods We systematically searched studies meeting inclusion criteria, compared design, methods and population characteristics, assessed risk for bias and did a meta‐analysis (MA) using a random‐effects model to calculate overall hazard ratios (HRs) and 95% CI (confidence intervals). Results Sixteen studies included 285,436 T2DM patients exposed to GLP‐1 RAs (exenatide bid, liraglutide, lixisenatide, long‐acting exenatide), n ranged from 219 to 160,803 patients. Comparators included: no exposure, other antidiabetic medications (OADs), combined OADs, canagliflozin or multiple comparators. Ten studies estimated all‐cause mortality, hazard ratios (HRs) ranged from 0.17 (95% CI 0.02‐1.22) to 1.29 (95% CI 0.54‐3.13). Thirteen studies assessed cardiovascular events and/or MACE; HRs ranged from 0.27 (95% CI 0.14‐0.53) to 1.11 (95% CI 0.99‐1.24). Eight studies assessed HHF, HRs ranged from 0.12 (95% CI 0.02‐0.66) to 1.64 (95% CI 1.28‐2.13). Excluding two studies because of temporal bias, we obtained pooled estimates for all‐cause mortality: HR 0.63 (0.44‐0.89), CV outcomes HR 0.84 (0.75‐0.94) and HHF; HR 0.94 (0.78‐1.14), (high between‐study variability: I2 = 83.35%; I2 = 70.3%; and I2 = 90.1%, respectively). Conclusion Pooled results of EHDs’ studies assessing GLP‐1 RAs effects favoured GLP‐1 RAs for all‐cause mortality and MACE while were neutral for HHF. Results should be interpreted cautiously because of studies’ substantial heterogeneity and limitations of observational research.

show abstract

Section: Resultsmentioning

confidence: 99%

Cardiovascular outcomes, heart failure and mortality in type 2 diabetic patients treated with glucagon‐like peptide 1 receptor agonists (GLP‐1 RAs): A systematic review and meta‐analysis of observational cohort studies

Comoglio

Vidal

2020

Int J Clin Pract

View full text Add to dashboard Cite

show abstract

“…[8][9][10][11] The problem of time-varying treatment arguably provides the main rationale for the popularity of the nested case-control design in safety studies and today, most published pharmacoepidemiological safety studies are based on the design despite the known problems of bias associated with the design. [11][12] To minimize the potential effects of confounding factors-the main source of bias-we match cases to controls on at least, the most important confounding covariates in preference over modeling their effects. This is a process that involves sampling of potential controls and although there are many sampling approaches, that of incidence density sampling is widely recognized as the best.…”

Section: Resultsmentioning

confidence: 99%

Programming challenges of sampling controls to cases from the dynamic risk sets in nested case–control studies

Kiri¹

2012

Pharmaceutical Programming

View full text Add to dashboard Cite

Pharmacoepidemiological studies based on the cohort design are simpler to analyse and their results easier to interpret. However, these may not reflect real-life drug use which is a major strength of such studies. The nested case-control design is often used instead to avoid the computational burden associated with time-dependent explanatory variables. Unlike the classical case-control design which is generally easy to programme, that of the nested case-control can pose a number of challenges. Subjects can be chosen as controls more than once and a subject who is chosen as a control can later become a case. Indeed controls are chosen from among those in the cohort who are at risk of the event at that time (i.e. we sample from the risk set defined by the case). We highlight the main programming challenges of the design as well as describe and demonstrate approaches for resolution and appropriate implementation.

show abstract

“…To address this potential misclassification and to account for switching, patients were classified to a cohort based on the actual treatment administered rather than the initial treatment prescribed. Such “as-treated” analysis would be more applicable for this real-world study ( 34 ). Although misclassification of OHSS is also a possibility, this would be less likely given that the study outcome was prospectively reported by physicians.…”

Section: Discussionmentioning

confidence: 99%

Safety of Ovaleap® (Follitropin Alfa) in Infertile Women Undergoing Superovulation for Assisted Reproductive Technologies: A Multinational Comparative, Prospective Cohort Study

Kaplan

Levy‐Toledano²,

Davies

et al. 2021

Front. Endocrinol.

View full text Add to dashboard Cite

BackgroundOvaleap® (follitropin alfa), a recombinant human follicle stimulating hormone, is a biosimilar medicinal product to Gonal-f® and is used for ovarian stimulation. The main objective of this study was to assess the safety and effectiveness of Ovaleap® compared to Gonal-f® in one treatment cycle in routine clinical practice.MethodsSafety of Ovaleap® Follitropin alfa in Infertile women undergoing superovulation for Assisted reproductive technologies (SOFIA) was a prospective cohort study conducted in six European countries. Eligible patients were infertile women undergoing superovulation for assisted reproductive technology, who were administered Ovaleap® or Gonal-f® for ovarian stimulation and were naïve to follicle stimulating hormone treatment. The recruitment ratio was 1:1. The primary endpoint was incidence proportion of ovarian hyperstimulation syndrome (OHSS) and the secondary endpoint was OHSS severity (Grades I, II, III). The effect of risk factors or potential confounders on the odds ratio for OHSS incidence as well as treatment effect on OHSS incidence was explored using univariate logistic regression. Pregnancy and live birth rates were also assessed.ResultsA total of 408 women who were administered Ovaleap® and 409 women who were administered Gonal-f® were eligible for analysis. The incidence proportion of OHSS was 5.1% (95% CI: 3.4, 7.7) in the Ovaleap® cohort and 3.2% (95% CI: 1.9, 5.4) in the Gonal-f® cohort. This difference in OHSS incidence proportion between the two cohorts was not statistically significant neither before (p = 0.159) nor after univariate adjustment for each potential confounder (p > 0.05). The incidence proportion of OHSS severity grades was similar in the two treatment groups (3.4% versus 2.0% for Grade I, 1.2% versus 1.0% for Grade II, and 0.5% versus 0.2% for Grade III, in the Ovaleap® and Gonal-f® cohorts, respectively), without a significant statistical difference (p = 0.865, for each grade). Among patients who had embryo transfer, clinical pregnancy rates were 33% and 31% and live birth rates were 27% and 26%, in the two cohorts, respectively.ConclusionsFindings from the SOFIA study indicate that the incidence proportions of OHSS and OHSS severity, as well as pregnancy and live birth rates, are similar between Ovaleap® and Gonal-f® treatments and corroborate the safety and effectiveness of Ovaleap® as a biosimilar to Gonal-f®.

show abstract

How Real is Intention-To-Treat (ITT) Analysis in Non-Interventional Post Authorization Safety Studies? We Can Do Better

Cited by 9 publications

References 44 publications

Cardiovascular outcomes, heart failure and mortality in type 2 diabetic patients treated with glucagon‐like peptide 1 receptor agonists (GLP‐1 RAs): A systematic review and meta‐analysis of observational cohort studies

Cardiovascular outcomes, heart failure and mortality in type 2 diabetic patients treated with glucagon‐like peptide 1 receptor agonists (GLP‐1 RAs): A systematic review and meta‐analysis of observational cohort studies

Programming challenges of sampling controls to cases from the dynamic risk sets in nested case–control studies

Safety of Ovaleap® (Follitropin Alfa) in Infertile Women Undergoing Superovulation for Assisted Reproductive Technologies: A Multinational Comparative, Prospective Cohort Study

Contact Info

Product

Resources

About