PMID- 34187527 OWN - NLM STAT- MEDLINE DCOM- 20210701 LR - 20210703 IS - 1745-6215 (Electronic) IS - 1745-6215 (Linking) VI - 22 IP - 1 DP - 2021 Jun 29 TI - Survival analysis for AdVerse events with VarYing follow-up times (SAVVY)-estimation of adverse event risks. PG - 420 LID - 10.1186/s13063-021-05354-x [doi] LID - 420 AB - BACKGROUND: The SAVVY project aims to improve the analyses of adverse events (AEs), whether prespecified or emerging, in clinical trials through the use of survival techniques appropriately dealing with varying follow-up times and competing events (CEs). Although statistical methodologies have advanced, in AE analyses, often the incidence proportion, the incidence density, or a non-parametric Kaplan-Meier estimator are used, which ignore either censoring or CEs. In an empirical study including randomized clinical trials from several sponsor organizations, these potential sources of bias are investigated. The main purpose is to compare the estimators that are typically used to quantify AE risk within trial arms to the non-parametric Aalen-Johansen estimator as the gold-standard for estimating cumulative AE probabilities. A follow-up paper will consider consequences when comparing safety between treatment groups. METHODS: Estimators are compared with descriptive statistics, graphical displays, and a more formal assessment using a random effects meta-analysis. The influence of different factors on the size of deviations from the gold-standard is investigated in a meta-regression. Comparisons are conducted at the maximum follow-up time and at earlier evaluation times. CEs definition does not only include death before AE but also end of follow-up for AEs due to events related to the disease course or safety of the treatment. RESULTS: Ten sponsor organizations provided 17 clinical trials including 186 types of investigated AEs. The one minus Kaplan-Meier estimator was on average about 1.2-fold larger than the Aalen-Johansen estimator and the probability transform of the incidence density ignoring CEs was even 2-fold larger. The average bias using the incidence proportion was less than 5%. Assuming constant hazards using incidence densities was hardly an issue provided that CEs were accounted for. The meta-regression showed that the bias depended mainly on the amount of censoring and on the amount of CEs. CONCLUSIONS: The choice of the estimator of the cumulative AE probability and the definition of CEs are crucial. We recommend using the Aalen-Johansen estimator with an appropriate definition of CEs whenever the risk for AEs is to be quantified and to change the guidelines accordingly. FAU - Stegherr, Regina AU - Stegherr R AD - Institute of Statistics, Ulm University, Ulm, Germany. FAU - Schmoor, Claudia AU - Schmoor C AD - Clinical Trials Unit, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg im Breisgau, Germany. FAU - Beyersmann, Jan AU - Beyersmann J AD - Institute of Statistics, Ulm University, Ulm, Germany. FAU - Rufibach, Kaspar AU - Rufibach K AD - F. Hoffmann-La Roche, Basel, Switzerland. FAU - Jehl, Valentine AU - Jehl V AD - Novartis Pharma AG, Basel, Switzerland. FAU - Bruckner, Andreas AU - Bruckner A AD - Novartis Pharma AG, Basel, Switzerland. FAU - Eisele, Lewin AU - Eisele L AD - Janssen-Cilag GmbH, Neuss, Germany. FAU - Kunzel, Thomas AU - Kunzel T AD - F. Hoffmann-La Roche, Basel, Switzerland. FAU - Kupas, Katrin AU - Kupas K AD - Bristol-Myers-Squibb GmbH & Co. KGaA, Munchen, Germany. FAU - Langer, Frank AU - Langer F AD - Lilly Deutschland GmbH, Bad Homburg, Germany. FAU - Leverkus, Friedhelm AU - Leverkus F AD - Pfizer, Berlin, Germany. FAU - Loos, Anja AU - Loos A AD - Merck KGaA, Darmstadt, Germany. FAU - Norenberg, Christiane AU - Norenberg C AD - Bayer AG, Wuppertal, Germany. FAU - Voss, Florian AU - Voss F AD - Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany. FAU - Friede, Tim AU - Friede T AUID- ORCID: 0000-0001-5347-7441 AD - Department of Medical Statistics, University Medical Center Gottingen, Humboldtallee 32, Gottingen, 37073, Germany. tim.friede@med.uni-goettingen.de. LA - eng PT - Journal Article PT - Meta-Analysis DEP - 20210629 PL - England TA - Trials JT - Trials JID - 101263253 SB - IM MH - *Follow-Up Studies MH - Humans MH - Incidence MH - Probability MH - Survival Analysis PMC - PMC8244188 OTO - NOTNLM OT - Aalen-Johansen estimator OT - Adverse events OT - Competing events OT - Drug safety OT - Incidence density OT - Incidence proportion OT - Kaplan-Meier estimator COIS- KR and TK are employees of F. Hoffmann-La Roche (Basel, Switzerland). VJ and AB are employees of Novartis Pharma AG (Basel, Switzerland). LE, KK, FLa, FLe, AL, CN, and VF are employees of Janssen-Cilag GmbH (Neuss, Germany), Bristol-Myers-Squibb GmbH & Co. KGaA (Munchen, Germany), Lilly Deutschland GmbH (Bad Homburg, Germany), Pfizer Deutschland (Berlin, Germany), Merck KGaA (Darmstadt, Germany), Bayer AG (Wuppertal, Germany) and Boehringer Ingelheim Pharma GmbH & Co. KG (Ingelheim, Germany), respectively. TF has received personal fees for consultancies (including data monitoring committees) from Bayer, Boehringer Ingelheim, Janssen, Novartis, and Roche, all outside the submitted work. JB has received personal fees for consultancy from Pfizer, all outside the submitted work. CS has received personal fees for consultancies (including data monitoring committees) from Novartis and Roche, all outside the submitted work. The companies mentioned contributed data to the empirical study. RS has declared no conflict of interest. EDAT- 2021/07/01 06:00 MHDA- 2021/07/02 06:00 PMCR- 2021/06/29 CRDT- 2021/06/30 05:41 PHST- 2020/09/08 00:00 [received] PHST- 2021/06/04 00:00 [accepted] PHST- 2021/06/30 05:41 [entrez] PHST- 2021/07/01 06:00 [pubmed] PHST- 2021/07/02 06:00 [medline] PHST- 2021/06/29 00:00 [pmc-release] AID - 10.1186/s13063-021-05354-x [pii] AID - 5354 [pii] AID - 10.1186/s13063-021-05354-x [doi] PST - epublish SO - Trials. 2021 Jun 29;22(1):420. doi: 10.1186/s13063-021-05354-x.