1. 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

2. 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

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

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

5. 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?

6. 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)

8. 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

9. 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

10. 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.

11. 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

12. 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)?

13. 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.

14. Use of Timeline cluster tools recommended!

15. 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

16. 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

17. 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.”

18. 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.

19. Example 1: cluster-cluster

20. 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.

21. Example 2: professional-cluster

22. 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

23. Example 3: individual-cluster trial

24. 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.

25. Precis: Some useful tools for trialists

26. 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

27. 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.

28. Further work in progress