Ethics in cluster randomized trials Current Developments in Cluster randomized and Stepped Wedge Designs Queen mary university of london, Nov 2018 Monica taljaard Senior scientist, Ottawa hospital research institute Associate Professor, School of Epidemiology and Public Health, University of Ottawa

outline Introduction (45 min) CRTs and ethical issues they raise Overview of the Ottawa Statement Ethical analysis of 3 examples Quiz and trying out the audience response system Interactive Discussion (45 min): Case 1: WHO Surgical Safety Checklist Trial BREAK – Coffee and posters Interactive Discussion (60 min): Case 2: B-Free trial

What makes a crt different? Unit of randomization Unit of intervention Unit of observation

… Compared to patient randomized trial Unit of randomization Unit of intervention Unit of observation SIMPLER!

Frequently asked questions This is a KT / QI intervention: do I still need ethics approval? How do I approach informed consent when it is a cluster-level intervention which cluster members can’t easily avoid? Can the head of the hospital consent on behalf of patients? The research ethics committee is requiring me to obtain consent from every cluster member, but because of size, this would make the trial infeasible The intervention is designed to improve the care delivered by doctors ─ do I need to tell patients about the trial? Is it acceptable to randomize clusters without the prior consent of patients targeted by the trial? What should they be told after their cluster has been randomized? Is it acceptable to not tell patients about the trial to avoid selection bias and/or contamination?

Specific Guidance for crts Lack of guidance for researchers and research ethics committees contributed to uncertainty and variation in practice The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials (2012) aimed to address this gap Recommendations to be “interpreted in light of the laws and regulations of the host country or countries, as well as other applicable international standards” Has influenced subsequent international guidance (e.g., CIOMS 2016) and national regulations (UK, USA)

Overview of the Ottawa statement 5-year collaboration funded by the Canadian Institutes of Health Research (2007, 2008) Team of investigators from Canada, USA, UK Study objectives: To identify ethical issues arising in the design, review, and conduct of CRTs: To analyze ethical issues in CRTs systematically To develop guidelines for the ethical conduct and review of CRTs through an international consensus process

Overview of Project ETHICAL ISSUES in CRTs Empirical work Key informant interviews Review of 300 published trials Survey of authors of published trials Survey of REC chairs Conceptual work Evolving framework of ethical issues Ethical analysis of identified issues Series of discussion papers in Trials E-consultation Independent Expert Panel Consensus meeting E-consultation Ottawa Statement

Key findings from Empirical work (1) Agree or strongly agree Trialists (N=182) REC Chairs (N=194) There is a need for ethics guidelines for CRTs 133 (74%) 148 (85%) Ethics committees could be better informed about distinct ethical issues surrounding CRTs 126 (70%) 162 (93%) Experienced significant variability in review of CRTs 47 (46%) - Experienced negative impact of research ethics review process on the CRT 65 (38%) We don’t have time to go into details The main results from the trialist and research ethics chair surveys were that the vast majority of CRT investigators and ethics chairs agree or strongly agree that there is a need for ethics guidelines and that ethics committees could be better informed about distinct ethical issues in CRTs. Also, substantial proportions of respondents indicated that they experienced problems in the ethics review process of their trials, including variability among different ethics committees and negative impact on the quality of the trial.

Key findings from Empirical work (2) A key paper from our review of the 300 published CRTs was published in the BMJ It found serious deficiencies in the ethical reporting of CRTs

Key findings from Empirical Studies (2) Low prevalence of reporting of ethical aspects of CRTs (N=300) No information about REC review: 26% No information about informed consent: 31% Even if consent reported, details often unclear (“we obtained consent from all participants”) From whom (e.g., providers? patients?) For which aspects of the trial (study interventions and / or data collection)? How (verbal, written, other)? When (before or after randomization)?

Updated reporting guidelines Explicit recommendations incorporated into CONSORT guidelines CONSORT extension to CRTs (Campbell et al., 2010) Item 10c: From whom consent was sought… and whether consent was sought before or after randomisation CONSORT extension for SW-CRTs (Hemming et al., 2018) Item 10c: Whether, from whom and when consent was sought and for what; whether this differed between treatment conditions Item 26: Whether the study was approved by a research ethics committee, with identification of the review committee(s). Justification for any waiver or modification of informed consent requirements.

Use of Timeline cluster tools recommended!

The Ottawa Statement 15 recommendations pertaining to: Monica Charles Justifying the cluster randomised design Research ethics committee review Identifying research participants Obtaining informed consent Gatekeepers Assessing benefits and harms Protecting vulnerable participants Monica Charles

Rationale for CRT CRTs are inefficient (have less statistical power) relative to individually randomised designs and are subject to increased risks of bias Reasons for adopting the CRT design are diverse, and can range from sheer necessity, to other scientific, practical or logistical considerations An inappropriate reason to adopt a CRT is the mistaken belief that the need to seek informed consent can be avoided by using cluster randomisation

Research Ethics Review Most CRTs in health research meet the definition of human participants research and, as such, must be reviewed by a research ethics committee Research ethics committees ought to undertake a proportional approach to the review of study protocols “When a CRT poses low risk to research subjects and does not involve vulnerable subjects, an expedited review process may be appropriate.”

Three examples Three main types of CRTs based on unit of intervention “Cluster-cluster” trial “Professional-cluster” trial “Individual-cluster” trial Eldridge SM, Ashby D, Feder GS. Informed patient consent to participation in cluster randomized trials: an empirical exploration of trials in primary care. Clin Trials. 2005;2(2):91-8.

Example 1: cluster-cluster

Example 1: cluster-cluster Objective: To evaluate a community-level physical activity intervention to increase activity levels in rural communities Interventions: Individually tailored physical activity opportunities for all age groups, provided for 12 weeks Design: SW-CRT design in 128 rural villages Primary outcome: Proportion of adults reporting sufficient physical activity to meet guidelines Data collection: Repeated cross-sectional postal surveys of a random sample of 50 households per village at 5 time points Results: 10,412 adults completed the survey (response rate 32.2%). No significant improvement in physical activity.

Example 2: professional-cluster

Example 2: professional-cluster Objective: To evaluate the use of a computerised system to support evidence based clinical decision-making for the management of asthma and angina in adults Interventions: Computerized decision support system integrated into practice software versus paper copies of guidelines only Design: Parallel arm CRT involving 60 general practices in England Data collection: Adherence to guidelines, based on reviews of clinical records from ~40-50 angina and asthma patients per practice; patient reported outcomes from postal questionnaires Results: No significant impact on either the process or outcomes of care

Example 3: individual-cluster trial

Example 3: individual-cluster trial Objective: To evaluate the effectiveness of topical application of chlorhexidine to the umbilical cord to prevent infection and death Interventions: Community health workers cleaning the umbilical stump with chlorhexidine versus soap and water versus dry cord care Design: Parallel arm CRT involving 413 communities in Nepal Data collection: Incidence of infection through clinical examination during household visits (~15,000 infants); Neonatal mortality; Household questionnaires about neonatal care Result: Chlorhexidine reduced infection by 75% and neonatal mortality by 24%. Trial stopped early for benefit.

Precis: Some useful tools for trialists

Who is the research subject? 1. Directly intervened upon by investigators? Research subjects Yes No 2. Deliberately intervened upon via manipulation of their environment? Research subjects Yes No 3. Interact with investigators for the purpose of collecting data? Research subjects Yes No 4. Identifiable information used to generate data? NOT research subjects No

Whose informed consent is required? Is the individual a research subject? No Consent is not required Is informed consent feasible? Yes Are conditions for a waiver met? Is informed consent feasible prior to randomization? Study cannot proceed ethically without consent Consent is not required Informed consent should be sought prior to randomisation* Informed consent should be sought as soon as possible after randomisation, but prior to any study intervention or data collection procedures. ** *Standard disclosure requirements apply **Subjects must be provided with a detailed description of the interventions in the trial arm to which their cluster has been randomised.

Further work in progress