Barriers & Facilitators in Pediatric Randomized Trials

1. A Mixed Methods Study of Barriers and Facilitators to Methodological Rigor in Pediatric Randomized Trials KT Canada Seminar Series March 8, 2012 Michele Hamm, MSc Alberta Research Centre for Health Evidence

2. Objectives • To review the empirical evidence describing risk of bias in pediatric randomized controlled trials.      • To describe barriers and facilitators in conducting methodologically rigorous trials, as identified by pediatric trialists. • To discuss how these findings can be applied in the development of a knowledge translation intervention.

3. Introduction • There is a growing body of literature documenting the limitations and methodological flaws of pediatric research, specifically risk of bias. • The introduction of bias into a trial can lead to the overestimation of treatment benefits or underestimation of treatment harms.

4. Risk of Bias • Risk of bias relates to internal validity • Design features associated with effect estimate magnitude: • Sequence generation • Allocation concealment • Blinding - participants/personnel, outcome assessors • Incomplete outcome data • Selective outcome reporting • “Other” sources of bias

5. Quality of Pediatric Trials • Thomson et al: trends in RCTs from 1948-2006 (PLoS One 2010;5:9) • Hartling et al: 163 trials presented as abstracts from 1992-1995 (BMJ 2009; 339:b4012) • Crocetti et al: 146 trials published in high impact journals in 2007-2008 (Pediatrics 2010; 126(2):298-305) • Hamm et al: 300 trials published in 2007 (BMC Pediatrics 2010;10:96)

6. Risk of Bias Assessments by Domain (n=300)

7. Effect Sizes and Risk of Bias

8. Mixed Methods Study of Pediatric Trialists • Objective: To determine the barriers and facilitators faced by pediatric trialists in the design and conduct of methodologically rigorous trials, using both quantitative and qualitative data.

9. Methods • Explanatory mixed methods design • Survey • Semi-structured interviews

10. Survey Methods • Internet-based survey (SurveyMonkey) • Surveyed corresponding authors of pediatric trials published in 2008 and 2009 • Entire sample of Canadian researchers (n=90) • Random sample of international researchers (n=600) • Questions to determine: 1) knowledge and awareness of bias 2) perceived barriers and facilitators in conducting trials 3) utility of potential KT strategies for future interventions

11. Survey Challenges • 19.9% response rate (128/644; 46 undeliverable) • SurveyMonkey to REDCap • Sampled from MICYRN membership (n=163)

12. Survey Results • 23.0% response rate (186/807) • 44.6% trained in medicine; 35.5% had formal research training • Median number of trials involved in: • As PI: 3 (IQR 1-5) • As part of study team: 5 (IQR 2-10) • Most common subspecialties represented: • Public health (8.6%) • Developmental, psychosocial, and learning problems (7.5%) • Mental health or psychiatry (7.0%)

13. Survey Results 1) Knowledge and awareness of bias • Identification of bias: responses ranged from Strongly Agree to Strongly Disagree • Self-rated confidence in understanding of bias: mean 5.4/7

14. Survey Results 2) Barriers and facilitators • Barriers: • Lack of sufficient funding (70.3%); • Overwhelming volume of literature (63.1%); • Logistics make it difficult to minimize bias (52.9%) • Open-ended responses: blinding, buy-in from clinicians and organizational leadership

15. Survey Results 2) Barriers and facilitators • Facilitators: • Interest in staying current with literature (93.0%); • Opportunities to discuss methods with knowledgeable colleagues (92.8%); • Rigorous methods encouraged by colleagues (80.4%) • Open-ended responses: culture supportive of research, strong collaborators

16. Survey Results 3) KT strategies • Checklists or reminders (90.7%) • Online resources (88.7%) • Lectures or seminars (76.7%) • Opinion leaders (73.2%) • Educational materials (62.0%)

17. Interview Methods • Semi-structured interviews building upon quantitative survey data • MICYRN survey respondents invited to participate in an interview • Target sample size of 12 pediatric trialists • Questions to determine: • Relationships between participants’ beliefs, behaviours, and attitudes about conducting research on children and appropriate design and conduct of methodologically sound trials

18. Interview Results • 13 interviews conducted • Necessary to augment original sample: • 3 respondents from survey, 3 from MICYRN, 7 referrals • 7 trained in medicine, 4 trained in both medicine and research, and 2 trained in research • Subspecialties represented: anesthesiology, clinical epidemiology, critical care, emergency medicine, infectious disease, neonatology, neurology, oncology, psychology, rheumatology

19. Interview Results Individual Factors - Barriers • Knowledge/training regarding research methods • Lack of formal training – on the job learning • Emphasize certain aspects, overlook others

20. Interview Results Individual Factors – Barriers “Probably we don’t look at, we don’t know all the bias that can be, that can happen in a trial because we don’t check, we don’t believe there’s bias. We may miss some, we may forget some, and then do not report the bias because we don’t know it exists.” “Because there’s almost zero research training in the clinical curriculum for most clinicians these days. Like there’s almost nothing in the med school program, there’s almost nothing in the rehab program – there really needs to be somebody on the protocol who’s got a little bit more training.”

21. Interview Results Individual Factors – Facilitators • Sense of ownership • Opportunity to generate enthusiasm, gain support, and educate colleagues

22. Interview Results Individual Factors – Facilitators “So you really have to take the time to engage people and be the one that’s proactive, engaging them. Because they’re busy, they might not even know what your study is unless you’re the change agent that really goes out there and talks to them about it and gets them motivated about why you think it’s important.” “Listen to what [your colleagues] need to execute the study so that when you develop your protocol, you’ve built that into the approach. Or, if you couldn’t, you’ve at least had that dialogue with them about how scientifically you can’t be as flexible as might be ideal… so that they at least understand the rationale.”

23. Interview Results Institutional Factors – Barriers • Negative research culture • Lack of recognition of distinction between clinical care and clinical research • Variable across institutions

24. Interview Results Institutional Factors – Barriers “I think that other people view [research] as kind of a thorn in their side. It’s something they play along with if they have to and the division head tells them they have to.” “I think a lot of investigators really have a hard time separating what decision they would make clinically from what decision they would make as part of a trial… because the feeling is I want to be convenient to the family, and I really know this stuff because I’m an expert in this clinical area, and I don’t think they realize that there’s a pretty clear demarcation between what you do in clinical care and what you do as research.”

25. Interview Results Institutional Factors – Facilitators • Cohesive study teams • Clinicians, methodologists, research staff • Networks within subspecialties • Reliable internal review processes

26. Interview Results Institutional Factors – Facilitators “We have the help of the research institute and you can have a person for any kind of question or any kind of design that can help, and we have access to those kinds of resources.” “I think the fact that [research network] is there enables you to think of multi-centre RCTs, whereas if it wasn’t there, you’d kind of have to go and find things from scratch. But by existing, it brings people together with shared interests and I think that that is a huge asset when it comes to even the thought of designing a multi-centre RCT. It’s like you want to design one for [research network].”

27. Interview Results Policy Factors – Barriers • Funding • Ethics review process

28. Interview Results Policy Factors – Barriers “We all tend to want to make the budget as small as we can to increase our chances to actually get it funded and the reality is that some trials really require the full-time effort of somebody who’s got a lot of experience, and therefore comes with a price tag. And it can be hard to make the argument to ensure that you’ve got funding, right? So I think that’s where you start cutting other corners, and you don’t have the data quality, and at the end of the day, you maybe don’t have the rigorous, homerun kind of trial that you had envisioned.” “Most of the problem is to ask for revisions and they are not consistent one between the others. So you can have a question in one and the other one… wants a different answer.”

29. Interview Results Policy Factors – Facilitators • None

30. Interview Results Specific Biases • Blinding • Cost of placebo, blinding non-pharmacological interventions, additional groups (i.e., parents) • Parental resistance to randomization • Group imbalances due to small sample size

31. Discussion • Internal validity is not a primary concern – overshadowed by pragmatics and generalizability • Internal validity is a prerequisite for external validity • Lack of formal training and negative research culture contribute to acceptance of sub-optimal trials • Importance of mentorship and clinician-scientists

32. Strengths and Limitations • Combines quantitative and qualitative findings • Response rates were low • Survey: international representation • Interviews: reached saturation, sampled from different subspecialties and institutions across Canada • Emphasis on Canadian context – specific insights into the national clinical and research frameworks

33. Future Directions • Objectives: To design and evaluate a tailored KT intervention to improve methodological rigor in child health trials. • Researcher involvement sought throughout • Potential interventions: online modules, checklists

34. Future Directions • Consideration of traditional KT interventions • Adaptation for changing researcher behaviour, rather than clinician behaviour • Social media component • Wiki platform • Incorporates successful elements of KT interventions: interactivity, presentation of materials in multiple formats, endorsement by opinion leaders • Informed by Diffusion of Innovations, Social Influences Theory, and Theory of Planned Behaviour

35. Future Directions • StaR Child Health • Risk of Bias Standard Development Group • Research agenda includes support for knowledge translation initiatives • Envision online support and resources for researchers

36. Acknowledgements Supervisory Committee: Dr. Lisa Hartling Dr. Terry Klassen Dr. Shannon Scott Dr. David Moher