Principle 2 outlines key considerations and expectations that support a trial to fulfil its ethical responsibilities regarding participants, future and current patients, and the public.
Ethical clinical trials combine seeking answers to important questions with scientific validity and appropriate protection and respect for all involved, particularly participants. Independent review of proposals for new research, through an Institutional Review Board (IRB), Research Ethics Committee (REC) or equivalent, is an important governance tool and can help ensure appropriate steps are taken to protect the rights and welfare of participants.
Key Message: At all stages of a RCT (before, during and after), relevant and easily understandable information should be shared with trial participants, carefully balancing the duty to inform against the risk of information saturation and taking account of the clinical context. Information should be provided in a clear manner and in suitable languages and formats for the intended audiences.
Why this is important: Providing timely and relevant information to participants during a trial facilitates ethical research with benefits to both the participants and the quality of the trial results. It is essential that potential or recruited trial participants are appropriately informed but presenting excessive or exhaustive detail can work against this objective by overwhelming, confusing or disconcerting potential participants. Care should be taken to communicate effectively and enable relevant discussion. The exact approach may be influenced by the context of the research, including clinical, cultural or other issues.
Key Message: The trial consent process should clearly explain to potential trial participants the reasons why the trial is being done, the questions it is seeking to answer, what is involved for them, and the potential benefits and risks of participation. The extent, nature and timing of information provided before and during the informed consent process should be guided by the level of additional risks and commitment that participation in the RCT would involve in the context of the usual clinical care or circumstances that the same individuals would normally receive. The information provided should prioritize the needs and expectations of the prospective participant rather than of the organization or individuals conducting the RCT. Consent information should be widely accessible and readily understandable (e.g. with respect to readability), avoid legalistic or other technical language, and be as succinct as possible. Approaches to obtaining and maintaining ongoing consent and communication should be relevant to the RCT it relates to.
Why this is important: Consent is valid if it is informed, voluntary, and competently given prior to entering the trial. There are some situations in which it is not possible for an individual to give informed consent (e.g. infants or individuals lacking mental capacity) or it is not practical to do so because of the urgency of the medical situation (e.g. trauma or medical emergencies). Such situations should not automatically preclude the conduct of RCTs (which may be the only way to provide reliable information on how best to manage such health issues), but appropriate safeguards should be put in place to maintain the rights of the individuals who participate. For some trials and in some individual situations, explicit consent may be unnecessary. In such cases, there should be minimal additional risks and burdens to participation in comparison to the usual care a prospective participant might receive outside the trial.
Key Message: Participants should be free to stop or change the nature of their participation without affecting the usual care received, and effort should be made to determine the intended meaning of such individual decisions.
Why this is important: The term ‘withdrawal’ can mean different things to different people, ranging from participants wishing to stop receiving the study intervention, to stopping attending study visits in person (but perhaps be happy to be contacted or for information about their health outcomes to be collected from their regular doctors or from routine health data systems), to their biological samples no longer being assayed or stored, or their data no longer being processed or shared. Therefore, it is clearer to avoid the term and instead clarify with the participant(s) what level of participation they wish to have and what they want to cease. If this is not properly explored, and the ‘withdrawal’ is interpreted with prejudice to mean complete removal from the study, trial participants may be unnecessarily and inadvertently lost to full or partial follow-up, with possible implications for the reliability of trial findings, and may miss out on aspects of the RCT that matter to them (e.g. attendance at study visits or being informed about the progress and results of the study).
Key Message: The rights of an individual participant to withdraw consent for use of trial data that has already been collected should be balanced with scientific and ethical requirements.
Why this is important: Removing data can result in unreliable or inconclusive findings, with ethical and clinical safety consequences for both participants continuing in the trial, and the care of future patients. (e.g. important safety signals may be missed). It can be appropriate to make data which has already been collected available for analysis in order to demonstrate or preserve research integrity. Those involved in a trial and those whose care is influenced by its results should be able to be assured that the data are valid, and that they have not been modified through inadvertent, deliberate, or malicious means.
Key Message: Detection and management of the safety of trial participants should be tailored to the trial population and to what is already known about the effects of the interventions. Such approaches may be modified as new information emerges (e.g. from other trials or clinical studies in the relevant population). In some circumstances it may be appropriate to exclude some groups of individuals from a trial if the likely risk to their health is excessive (compared with potential gain) and cannot be mitigated by reasonable clinical strategies. For some blinded trials, there may be occasions when knowledge of the allocated intervention for an individual participant could materially influence the immediate medical management of the participant. In such circumstances, it should be possible for the treatment allocation to be unblinded and disclosed to the relevant medical team without delay.
Why this is important: The procedures used to detect, investigate, and respond to unwanted health events for individual participants should be shaped by what is already known about the effects of the intervention from previous research or usage, as well as the background epidemiological and clinical features of the intended trial population (e.g. their demographics, comorbidities, and concomitant intervention). If new information emerges during the course of the trial (e.g. from other studies or as a consequence of advice provided by the trial Data Monitoring Committee), then processes and procedures for managing the safety of individual participants should be reviewed and may need to be modified (e.g. changes in the nature and timing of assessments, training provided to trial staff, information provided to participants, or in the eligibility criteria for the trial).
Key Message: During an ongoing trial, new information may become available (from within the trial or from external sources) which materially changes what is known about the effects of the intervention for some or all participants. This should be communicated to those involved in overseeing, conducting or participating in the clinical trial for whom it is relevant (e.g. because it might affect their understanding of the intervention or because they are required to take some action). Such communications and reports should be informative, timely and actionable.
Why this is important: Excessive, irrelevant or uninformative reports (particularly of individual cases) distract attention from those that require action. It is often preferable to produce and circulate contextualized periodic updates that are focused on safety issues that matter. Such reports may also be provided to the Data Monitoring Committee (for consideration in the context of the unblinded emerging trial data) and to regulatory bodies (for consideration of the implications for participants in other trials and for the wider group of patients and public). The distribution of reports should be in a format and timing that is commensurate with the action that is likely to be needed and the audience for which it is intended (e.g. participants, clinicians, regulators).