Delivery of a high-quality trial requires competent decision-making and coordinated execution. Good governance and good trial quality management can help achieve these features.
Competent advice and decision-making
Key Message: RCTs should be subject to sufficient scrutiny to support the delivery of an informative, ethical and efficient study, and to avoid, correct, or mitigate problems.
Why this is important:Effective and efficient governance (for example through a Trial Steering Committee) helps to maintain the scientific and ethical integrity of a trial and advise on appropriate courses of action. It should be structured to enable effective response to issues that may arise, particularly when multiple organizations are involved, and enable reasonably consistent implementation across the trial.
Membership of trial governance structures should reflect the expertise necessary to scrutinise key roles, responsibilities, and risks, and should build on the diverse strengths and capabilities of those involved. The need for a member orcomponent of the governance structure to have independence from trial sponsorship and management should be determined by assessing the risk that judgement and advice could be materially influenced (or perceived to be influenced) by the relationship.
Governance approaches should account for the opportunity cost of associated activities by considering the extent to which they might impede participants and communities from benefiting from an effective intervention or prolong the time an ineffective or hazardous intervention is used. Prolonged or excessive governance activities, which drive up unnecessary costs, deter trial designs of sufficient size or duration, or discourage clinicians and participants from being involved, should be avoided.
Protecting trial integrity
Key Message: The integrity of trial results should be protected by ensuring that decisions about trial design, delivery and analysis are not influenced by premature access to unblinded information about the emerging results.
Planning for success and focusing on issues that matter
Key message: Good quality should be prospectively built into the design and delivery of RCTs, rather than relying on retrospectively trying to detect issues after they have occurred (when often they cannot be rectified).RCTs should be described in a well-articulated, concise, and operationally viable protocol which is tailored to be practicable given the available infrastructure in relevant settings.
Why this is important:Rather than trying to avoid allpossible issues, the aim should be to identify the key issues that would have a meaningful impact on participant well-being and safety or on decision-making based on the trial results. Efforts can then be focused on minimizing, mitigating, and monitoring those issues. Such an assessment should consider the context of the RCT and what is additional or special about it by comparison with routine care. Broadly, these considerations come under four headings:
factors associated with the intervention (e.g. known and potential adverse effects; comorbidities or concomitant medications that might impact safety; special requirements for administering the intervention)
factors associated with evaluations required to answer the study objective that would not be expected in usual care (e.g. additional invasive investigations)
resource implications (e.g. need for specialist imaging or laboratory assays; unfamiliar or novel procedures requiring additional training)
ethical and privacy implications (e.g. access to medical records and sharing of health information with pharmaceutical companies, researchers, or regulators)
Such an assessment process can then be used to guide the development of error mitigation approaches such as standard operating procedures, training, and trial monitoring. Trial processes that add scientific or ethical value to RCTs should be prioritized, and those that do not, or where the additional complexity outweighs the benefit should be avoided.
Monitoring, auditing and inspection of study quality
Key message:The nature and frequency of any trial monitoring, auditing and inspection activities should be proportionate to any identified risks to study quality.
Why this is important: Good trial monitoring, auditing and inspection activities identify issues that matter (important deviations from the protocol or unanticipated issues that threaten to undermine the reliability of results or protection of participants’ rights and well–being) and provide an opportunity to further improve quality (e.g. through modifications to the protocol and procedures, training and mentoring staff, or information provided to participants). Excessive monitoring, auditing and inspection activities and failure to focus on details that have a material impact on trial quality wastes resources, creates distraction, and demotivates staff.
Rational monitoring focuses on the issues that will make a material difference to the participants in the trial and the reliability of the results (e.g. trial recruitment, adherence to allocated intervention, blinding, and completeness of follow-up). It informs corrective actions, supports staff, and enables improvements. It is important not to confuse more documentation for better quality. Example approaches that may be used include central review (including statistical analysis) of trial data and performance metrics to assess performance of staff and sites, in–person or virtual support and mentoring for trial staff (e.g. through observation of study visits, with participant consent), and visits to clinical trial sites and facilities.
Regulatory, auditing or inspection requirements should be proportionate and sensitive to the scientific and ethical qualities and objectives of a RCT. They should recognise the opportunity–cost of, and avoid, setting irrelevant or disproportionate requirements that might discourage the conduct or participation in good RCTs that are designed to address important questions.