Administrative information
Open Science
Introduction
Methods: Patient and public involvement, trial design
Methods: Participants, interventions, and outcomes
Methods: Assignment of interventions
Methods: Data collection, management, and analysis
Methods: Monitoring
Ethics
Objectives
Item 10: Specific objectives related to benefits and harms
Examples
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“The primary objective of this trial is to assess the effect of primary antibiotic prophylaxis with co-trimoxazole on overall survival compared to placebo in adults with cirrhosis and ascites, utilising a treatment policy estimand. Key secondary objectives include assessing the incidence of SBP, hospital admissions, Clostridium difficile (C. difficile)-associated diarrhoea and antimicrobial resistance, cost-effectiveness, and incidence of cirrhosis-related events, liver transplantation and treatment-related serious adverse events" [163].
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“5 Objectives
5.1 Efficacy
The objective is to assess the ability of day-and-night hybrid closed loop glucose control to maintain CGM [continuous glucose monitoring] glucose levels within the target range of 3.9 to 10 mmol/l (70 to 180 mg/dl) in comparison to sensor augmented pump therapy in young children with type 1 diabetes.
5.2 Safety
The objective is to evaluate the safety of day-and-night hybrid closed loop glucose control, in terms of frequency and severity of hypoglycaemia, as defined by International Society for Pediatric and Adolescent Diabetes, frequency of diabetic ketoacidosis (DKA), and nature and severity of other adverse events.
5.3 Utility
The objective is to determine the acceptability, duration and frequency of use of the closed loop system in this population. A series of questionnaires will be given to parents/guardians at the end of each intervention arm.
5.4 Human Factors
The objective is to assess emotional and behavioural characteristics of participating subjects and family members and their response to the closed loop system and clinical trial using quantitative (validated surveys) and qualitative data (interviews).
5.5 Health Economics
The objective is to perform a cost utility analysis on the benefits of closed loop insulin delivery to inform reimbursement decision-making" [164].
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Explanation
The study objective reflects the scientific question to be answered by the trial and defines its purpose and scope, with profound implications for many other aspects of the trial, e.g., the design (Item 12) and analysis (Item 27).
The "PICO" format to formulate the trial objective is often used. This entails defining the participant population (P); intervention (I); comparator (C); and outcomes (O) of main interest [165]. PICO is sometimes styled as PICOTS to include the timeframe and setting.
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Protocol authors should further report whether the intention of the trial is to evaluate potential benefits and harms. [166] and whether the aim is to assess superiority of the intervention, or non-inferiority/equivalence [167], versus the comparator. For example, the sample size calculation and statistical analyses for superiority trials will differ from those investigating non-inferiority.
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Authors should also indicate which treatment effect they are planning to investigate (e.g., the effect of assignment to the intervention irrespective of adherence, or the effect of adhering to the intervention (Box 1). They should also report whether the trial is intended to provide preliminary data (a pilot or feasibility trial) or confirmatory results.
If authors are planning a trial that involves re-adjusting the objective during the trial, for example in some platform trials or basket trials [168, 169], this should be reported. Trials can be designed to study the effect of the intervention under different conditions, often described on a spectrum from ideal conditions (explanatory trial) to routine clinical care conditions (pragmatic trial) [170].
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The objectives should generally be phrased using neutral wording (e.g., “to compare the effect of treatment A versus treatment B on outcome X for persons with condition Y …”) rather than in terms of a particular direction of effect [171]. For multi-arm trials, the objectives should clarify which treatment group comparisons are of interest (e.g., A versus B; A versus C).
Reviews of two samples of 108 and 292 trial protocols from 2016 found that 91% and 94% described the specific objectives of the trial, respectively [9, 10].
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Recently, some trials are being designed using the estimands framework to define the research question and trial objectives [172] Key concepts of this framework are presented in Box 1.​​
Box 1 Estimands
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Concerns have been raised that the precise research questions that randomised trials are intended to answer are often unclear [173]. In particular, there is often ambiguity around how events occurring after randomisation (termed intercurrent events) are handled. Research objectives can be specified using an estimands framework to improve clarity. We provide a brief overview of estimands and introduce terminology, so this framework can be applied and reported if used. A more detailed primer on the estimand framework, which provides practical guidance on estimands in studies of healthcare interventions, can be found elsewhere [174].
The European Medicines Agency [175] defines an estimand as “a precise description of the treatment effect reflecting the clinical question posed by a given clinical trial objective”. The estimands framework provides a structured description of the treatment effect in an attempt to bring clarity in specifying the research question, which can be used to guide the study design, data collection and statistical analysis methods. In brief, an estimand comprises five key attributes: 1) population, 2) treatment conditions, 3) endpoint, 4) summary measure and 5) handling of intercurrent events (Table i). A separate estimand should be defined for each study outcome and for some outcomes, more than one estimand may be defined.​​
The European Medicines Agency outlines five strategies for handling intercurrent events, which are at the core of the estimands framework [174, 175] (see Table ii).
While the terminology surrounding estimands may be new to some investigators, the concepts defined by the attributes and strategies of the framework are not new. A number of existing reporting guidelines have recently included estimands in their recommendations [176-178]. If the estimands framework has been used to design the trial and data collection or inform the statistical analysis (by choosing appropriate methods), then this should be clearly reported within the manuscript.
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Summary of key elements to address
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Trial objectives related to the benefits and harms, including the:
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Participants
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Intervention
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Comparator
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Primary outcome(s)
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Time point of main interest
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Description of trial estimand(s), as appropriate