Table 2.

Summary of opportunities recognised and challenges encountered during the rivaroxaban PASS programme, and recommendations to help effectively address these should they arise in future

Opportunities/challenges experienced	Recommendation
Alignment in identifying study outcomes and other covariates	Consider studies based on a CDM if analysis of multiple country-specific datasets is planned. Consider all data to inform the key safety concerns from the RMP. Consider potential impact on any section of the label.
Planning studies before product uptake is known	Maintain early, continuous, open communication with the regulator before programme initiation and during the interim reviews. Discuss with the regulator the potential benefit of studying drug use as a precursor to planning a safety study. Propose a stepwise approach with the potential of implementing changes to the study design (eg, adaptive designs) whenever uncertainty exists—such as the possibility of an evolving prescribing landscape, especially in the early period following product launch. Set milestones for the review of study objectives and design following an initial period of data collection; documenting any agreed changes (such as those made to respond to an evolving prescription environment from the introduction of competitor drugs and/or potential changes in clinical guidelines to ensure alignment and transparency). Including a statement in the study protocols that (a) premature study cessation will be considered whenever clinically justified, and (b) interim analyses will be conducted where the study objectives will be reviewed (ie, further objectives added where deemed necessary).
Plan for expectations relating to the RMP	Clear alignment of objectives in the protocols to address the key safety concerns in the RMP. Obtain scientific advice and ensure clear dialogue with the regulator before programme initiation to ensure alignment regarding the expectations of the study. Ensure this is discussed at the interim review periods (or other set milestone review periods).
Capturing long-term treatment, and accounting for changes in treatment guidelines and discontinuation	Consider use of nested case-control analyses to handle all varying episodes of drug use efficiently.9 10
New requests after study initiation addressing known study limitations (eg, available data) emerging interest in patient subgroups changes in the current standard of care relevant comparators	Ensure this is discussed during the interim reviews and/or at set milestone review periods so that: expectations remain aligned and are realistic dialogue can be undertaken in terms of protocol amendments (eg, incorporating new study objectives, such as addressing new patient populations or comparators; meaningful cut-off points for statistical analyses) investigators can undertake resource and operational planning. Anticipate potential changes to standard of care during planned programme duration, and allow for flexibility in the comparison groups in study designs, as stated in the study protocol.

CDM, common data model; EMA, European Medicines Agency; PASS, postauthorisation safety study; RMP, risk management plan.