Moved from News from Cochrane
Tuesday, October 8, 2024
Cochrane helps launch new WHO guidance on best practices for clinical trials
Cochrane helps launch new WHO guidance on best practices for clinical trials | Cochrane
https://iris.who.int/bitstream/handle/10665/378782/9789240097711-eng.pdf?sequence=1
page 8
The Technical Advisory Group (TAG) for Development of Best Practices for Clinical Trials was constituted through a public call for nominations.
16 names including Karla Soares-Weisser, Cochrane
The document was drafted by 2 people, then there were multiple feedback rounds from different groups including the TAG.
page 12-13 (my bolding)
The remit includes:
• any design for a clinical trial: but with a focus on randomized clinical trials, including comparisons of two or more interventions, whether blinded or not, and whether parallel, cluster, crossover, factorial, adaptive platform, decentralized or other design;
• any health intervention: including (but not limited to) administration of pharmaceutical medicines, cells and other biological products, and vaccines; surgical or radiological procedures; diagnostics; use of medical devices, nutritional measures; cognitive, behavioural and psychological interventions; supportive or preventive care, including process-of-care changes; physical therapy interventions; digital and public health approaches; traditional or herbal measures; and screening processes. The interventions may be novel or pre-existing but being used in a different way (for example, repurposed or optimized) or to gain further knowledge about current practices;
• any purpose: including (but not limited to) evidence for guideline development; recommendations for clinical practice or public health strategies; and health technology assessments;
• any setting: any geographical, economic or societal context, and any context including clinical trials based in hospital, primary care or community settings; or where the intervention is delivered directly to a participant;
• any role: including researchers and clinicians, patient and public groups (including trial participants), regulators and other national health authorities, ethics committees and institutional review boards, research funders, and all trial sponsors (academic, government, nonprofit and commercial).
...
This document aims to complement other guidance in order to support implementation of universal ethical and scientific standards in the context of clinical trials, with a focus on under-represented populations; it does not represent a legal standard and does not supersede any existing guidance. I
page 26 onwards
2. Key scientific and ethical considerations for clinical trials
2.1 Good clinical trials are designed to produce scientifically sound answers to relevant questions
2.1.1 Robust intervention allocation
about the importance of randomisation
2.1.2 Blinding/masking of allocated trial intervention (where feasible)
Why this is important. In many clinical trials, knowledge of the allocated intervention can influence the nature and intensity of clinical management, the reporting of symptoms or the assessment of functional status or clinical outcomes, introducing bias. Where feasible, masking (or blinding) participants, investigators, health care providers, and those assessing outcomes to the assigned intervention through use of placebo medications or dummy interventions can help to prevent such issues, as can the use of information that is recorded separately from the clinical trial (for instance, in routine clinical databases and disease registries). These considerations are important for the assessment of both the efficacy and the safety of the intervention, including processes relating to adjudication of outcomes and considerations of whether an individual health event is believed to have been caused by the intervention.
. If blinding of an allocated trial intervention is not feasible (for example in trials of different types of patient management or surgical procedures), blinded or masked outcome assessment should be pursued for objectively determined outcomes, for example through use of a prospective randomized open-label blinded endpoint (PROBE) design (see also Section 2.1.9 ascertainment of outcomes).
2.1.3 Appropriate trial population
2.1.4 Adequate size
2.1.5 Adherence to allocated trial intervention
2.1.6 Completeness of follow-up
Discusses the importance of following up everyone to capture data on non compliance and harms.
2.1.7 Relevant measures of outcomes, as simple as possible
Discusses value of standardised core outcomes to enable comparison across trials.
Outcomes may include physiological measures, symptom scores, participant-reported outcomes (PROMs) (66) (that is, measurement tools that patients use to provide information on aspects of their health status that are relevant to their quality of life, including symptoms, functionality, and physical, mental and social health), functional status, clinical events or use of health care services. The way in which these are assessed should be sufficiently robust and interpretable (for example, clinically validated in a relevant context, particularly for surrogate outcomes given their potential limitations (67)).
2.1.8 Proportionate, efficient and reliable capture of data
2.1.9 Ascertainment of outcomes
Key message. Processes for ascertaining study outcomes should adopt an approach that is not influenced by the intervention trial participants or randomized groups receive. These measures include the frequency and intensity of assessments. For RCTs, particular care should be taken to ensure that the people assessing, clarifying and adjudicating study outcomes are not influenced by knowledge of the allocated intervention (that is, the outcome assessment is blinded or masked). Equally, the methods for acquiring, processing and combining sources of information (in order, for
example, to define participant characteristics or clinical outcomes) should be designed and operated without access to information about the intervention allocation for individual participants or knowledge of the unblinded trial results.
Why this is important. If the methods used to assess, clarify or classify outcomes differ between the assigned interventions, the results may be biased in one direction or other leading to inappropriate conclusions about the true effect of the intervention. Therefore, the approach used to assess what happens to participants should be the same regardless of the assigned intervention, and those making judgements about the occurrence or nature of these outcomes should be unaware of the assigned intervention (or features, such as symptoms or laboratory assays, that would make it easier to guess the assignment) for each participant.
2.1.10 Statistical analysis
Key messages. The trial should be designed to robustly answer a clearly articulated key question on which the primary analysis should focus. It is not good practice to seek to answer multiple questions through secondary analyses, which can often be misleading. Trial results should be analysed in accordance with the protocol and statistical analysis plan, with the latter being developed and clearly specified when the protocol is written, and finalized at the latest before the study results become known (that is, before conduct of any unblinded analyses on study outcomes). Any analyses conducted after the initial results are known should be clearly identified as such
For RCTs, the main analyses should follow the intention-to-treat principle, ...
Why this is important. A statistical analysis plan should be specified before any knowledge of the trial results (for example, unblinding of the treatment allocation in a RCT) in order to avoid the possibility that choices about the analysis approach may be biased (8). ...
Discussion of use of secondary outcomes and subgroup analyses.
Although a sound statistical approach is critical in clinical research, it is equally important to focus on the clinical magnitude and relevance of any effect size rather than solely its statistical significance (75–78), as well as any new findings in the context of previous findings (for example, using the Grading of Recommendations Assessment, Development and Evaluation [GRADE] approach(79))
2.1.11 Assessing beneficial and harmful effects of the intervention
Key messages. Data generated during the course of conducting a clinical trial may reveal new information about the effects of the intervention which is sufficiently clear that it necessitates alteration of the ways in which the trial is conducted and participants are cared for or which is sufficiently compelling as to warrant a change in the use of the intervention both within and outside the trial. Potential harms of the intervention should be considered alongside potential benefits and in the wider clinical and health contexts.
page 33
2.1.12 Monitoring emerging information on benefits and harms
Key messages. An independent data monitoring committee provides a robust means to evaluate safety and efficacy data from an ongoing trial, including for RCTs unblinded comparisons of the frequency of particular events, without prematurely unblinding any others involved in the design, conduct or governance of the trial...
A data management committee (DMC) should include members with relevant skills to understand and interpret the emerging safety and efficacy data, and where appropriate take into consideration patient and public perspectives. A DMC should review analyses of the emerging data, unblinded to any randomized intervention group so as to be able to make informed decisions given knowledge about the potential adverse effects of a specific treatment (which would not be possible if they were not unblinded). The DMC should advise the trial organizers when there is clear evidence to suggest a change in the protocol or procedures, including cessation of one or more aspects of the trial. Such changes may be due to evidence of benefit or harm or futility (where continuing the trial is unlikely to provide any meaningful new information). In making such recommendations, a DMC should take account of both the unblinded analyses of the trial results and information available from other sources (including publications from other trials).
Why this is important. All those involved in the design, conduct and oversight of an ongoing trial should remain unaware of the interim results until after the conclusion of the study so as not to introduce bias into the results (as in the case, for example, of stopping the trial early when the results happen by chance to look favourable or adverse). The requirement for, and timing and nature of, any interim analyses should be carefully considered so as not to risk premature decision-making based on limited data.
page 34
2.2 Good clinical trials respect the rights and well-being of participants
2.2.1 Appropriate communication with participants
About timely and accessible information.
2.2.2 Relevant consent
Key messages. The trial consent process should clearly explain to potential trial participants (or, where applicable, their legal representatives) 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 ...
Why this is important. Consent is valid if it is informed, voluntary and competently given before entry into a trial....
mainly about capacity to give consent and safety.
2.2.3 Changing consent
Key message. Participants should be free to stop or change the nature of their participation without affecting the usual care received. Where possible and acceptable to the participant, efforts should be made to determine the intended meaning of such individual decisions and to explain the potential impact of any such decisions.
Importance of clarifying with participant what they are withdrawing from, eg treatment, or consent for data to be used...
page 36
2.2.4 Implications of changing consent
Key message. The rights of an individual participant to change or withdraw consent for use of trial data should be balanced against 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. (For example, important safety signals may be missed.)...
2.2.5 Managing the safety of individual participants in the clinical trial
Key messages. Detection and management of safety of trial participants should be tailored to the trial population and to what is already known about the intervention. Such approaches may be modified as new information emerges (for example, 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.
2.2.6 Communication of new information relevant to the intervention
Key message. During an ongoing trial, new information may become available (from within the trial or external sources) that materially changes what is known about the effects of the intervention for some or all participants. This information should be communicated to those involved in overseeing, conducting or participating in the clinical trial for whom it is relevant (for example, 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 (for example, participants, clinicians and regulators).
up to page 36
you're definitely not pacing. I downloaded it from the Cochrane thread, saw it was yet another single line space 70 odd page document to plough through and thought - hell no! Safety, safety, safety. The WHO have been highlighting this since 2004.
