Background

“We as an institution, as a profession, don’t actually sell research as being an important thing that we do in hospitals. And it should be.”

There is a growing body of literature documenting the methodological limitations of published randomized controlled trials (RCTs) in pediatrics [1–7]. Of particular concern is the evidence that RCTs in child health are susceptible to a high risk of bias, increasing the likelihood that reported treatment benefits and/or harms are being exaggerated [8–10]. In order to ensure clinical relevance and to prevent unnecessary and wasteful research, it is crucial that measures are taken to maximize the internal validity of studies that are conducted [11, 12]. The global investment in research is enormous, with funding of $100 billion annually [11], plus the time and effort committed by the researchers, clinicians, and children and families. When participants agree to take part in a trial, they expect that the study will be conducted and reported to the highest standard to accurately answer the research question. When this expectation is met, trial results are important in providing children with the best possible treatment; however, when biased research is conducted instead, research dollars and professionals’ time are wasted, and the children’s contributions are unavailing.

Evidence describing the negative impact of bias on RCTs and how to minimize it is available [13–22], as is research on a number of specific challenges inherent in conducting RCTs in pediatrics [23–27], such as recruitment and consent procedures. However, the research-practice gap regarding methodological rigor in this population has not yet been addressed.

As the first step in the development of a knowledge translation strategy to address the reduction of bias in pediatric RCTs, the objective of this study was to determine and describe the barriers and facilitators that pediatric trialists face in the design and conduct of unbiased trials, with an emphasis on the Canadian context. Quantitative survey and qualitative interview data were collected to gain a broad perspective of the problem and researchers’ experiences.

Methods

Design

We used an explanatory mixed methods design, with semi-structured interviews building upon the results of a quantitative survey. We connected data from the two phases to provide detailed descriptions of the barriers and facilitators pediatric trialists face in designing and conducting studies with high internal validity [28]. We obtained ethical approval from the Health Research Ethics Board at the University of Alberta.

Data collection

Quantitative: survey

We sent an Internet-based survey (SurveyMonkey) to a sample of Canadian and international pediatric trialists between September 2010 and February 2011. We searched the Cochrane Central Register of Controlled Trials for pediatric RCTs published in 2008 and 2009 and identified 7,535 articles. Corresponding authors of all relevant trials identified using a Canadian-specific search filter (n=90), and a geographically representative sample of 600 international trialists chosen from a randomly ordered list were invited to participate in the survey. We sent an invitation e-mail with a link to the survey and two reminder e-mails separated by two week intervals. The questionnaire was informed by the Cochrane Collaboration’s Risk of Bias tool [29], the BARRIERS Scale [30], and the framework proposed by Cabana et al. [31], described in Table 1.

Table 1 Tools used for survey development
Full size table

Twelve methodologists and clinicians evaluated the questionnaire for appropriateness and accuracy of content and 5 national and international pediatric trialists completed pilot testing for clarity and ease of use; we made revisions based on their feedback. The survey included 23 questions and pilot testing indicated that it would take approximately 15 minutes to complete. We developed items to determine: 1) researcher knowledge and awareness of bias; and 2) perceived barriers and facilitators in conducting clinical trials.

Due to a low response rate using the sample described above (154/644; 23.9%), we expanded the survey population to recruit participants from the membership of the Maternal Infant Child and Youth Research Network (MICYRN), a Canadian network linking investigators from 17 academic health centres involved in pediatric clinical research. We identified potential respondents through a publicly available network inventory maintained by MICYRN (http://www.micyrn.ca/Networks.html) and invited all individuals listed as network contacts via email to participate in both the survey and the interview portion of the study (n=163). The survey included an item asking whether respondents would be willing to be contacted for an interview, and if so, to provide their name and preferred means of initial contact. As a result of problems with access to SurveyMonkey, we administered this wave via REDCap, an alternate secure, online application for managing surveys.

Qualitative: interviews

Due to low participation rates from survey respondents, we augmented recruitment with members of MICYRN with trial experience and referrals from participants and established pediatric trialists. We used purposive sampling based upon pediatric subspecialty and geographic location, aiming to reach saturation, which typically occurs around 12 participants [33]. Interviews followed a semi-structured format built upon the results of the survey and were focused on participants’ experiences and attitudes towards conducting pediatric research and how these interacted with the appropriate design and conduct of methodologically sound trials. Each participant was sent an electronic consent form that they signed and returned via fax or email prior to the conduct of the interview. Interviews were 30 to 60 minutes and conducted by telephone by the lead author between April and July 2011. All interviews were recorded and transcribed verbatim.

Data analysis

We analyzed survey data descriptively, using means and standard deviations, medians and interquartile ranges (IQR), or proportions where appropriate. We used content analysis to code interviews, identifying categories in the data and patterns in beliefs and values that could help explain the potential for bias in pediatric RCTs [34]. Coding was conducted by the lead author in consultation with the rest of the study team. We conducted qualitative data collection and analysis concurrently, following an iterative process. We integrated the survey and interview data at the data interpretation phase [35], using the method of connecting data [28]. We used Stata and NVivo to manage quantitative and qualitative data, respectively.

Results

The survey response rate was 23.0% (186/807) and 13 interviews were conducted. Characteristics of the survey and interview participants are described in Tables 2 and 3 and Additional file 1. Survey results were similar across geographic boundaries and were therefore combined and used as a whole to inform a detailed examination of how barriers and facilitators manifest in Canadian research. Results are presented according to their classification as individual, institutional, or policy level factors. Themes are outlined in Table 4.

Table 2 Demographics of survey population
Full size table
Table 3 Characteristics of interview participants
Full size table
Table 4 Interview themes and relevance to risk of bias
Full size table

Individual factors

Survey findings indicated that 68.1% of respondents agree that bias is a problem in pediatric RCTs and 72.0% reported that they felt there was sufficient evidence to support the need to change some aspects of how RCTs are conducted. However, knowledge of bias among respondents was variable. There was no consistency in responses to questions which asked the respondent to rate the degree to which they agreed that a study design factor would introduce bias into a study. Identification of specific biases was strongest for sequence generation, blinding, and selective outcome reporting, while there was more uncertainty surrounding identification of problems with allocation concealment, incomplete outcome data, and “other sources of bias” (see Additional file 2). Despite this range of awareness of issues relevant to bias, 94.2% of respondents felt confident in their ability to evaluate the quality of published trials.

The interviews highlighted two important themes regarding barriers and facilitators at the individual level: knowledge and training regarding research methods, and engagement or ownership in the research process (Table 5). While most survey respondents indicated that bias is a problem, the interview data suggested that trialists often do not have the knowledge to first, recognize, and second, address bias in their studies. They often mentioned a lack of formal training, instead relying on skills learned on the job.

Table 5 Perspectives on individual-level factors
Full size table

Conversely, a sense of ownership can contribute to a rigorous study design. Actively taking responsibility for the direction of the trial was seen as an opportunity for the investigators to generate enthusiasm, gain support, and educate colleagues about the rationale for rigorous methodology and how it impacts the ability to accurately answer the research question.

"“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.”"

Institutional factors

While 93.0% of survey respondents demonstrated an interest in learning about and staying current with literature describing and analyzing research methods, only 50.3% felt that they were able to do so due to other constraints. Logistical issues such as meeting institutional requirements (29.2%) and having sufficient staff (30.4%) were identified as challenges, while access to knowledgeable colleagues (92.8%) was identified as the most significant facilitator (see Additional file 2).

Consistently, interview respondents felt that environmental factors within their institutions were not conducive to research, often as the result of perceptions of research (Table 6). They reported the underlying culture to be overwhelmingly negative towards research at all levels, with resistance from trainees, nurses, physicians, administrators, and the pharmaceutical industry. While respondents felt that the products of research tend to be valued once they are demonstrated to improve practice, they stated that there is little appreciation of the methods necessary to achieve that goal. Logistically, respondents felt that having staff dedicated to research would improve this situation, as research procedures would then not consistently be placed at the lowest priority. Recognition of the division between the paradigms of clinical care (e.g., protecting the interests and comfort of patients) and clinical research (e.g., maintaining clinical equipoise) was also identified as a challenge. Clinical investigators often have difficulty with this distinction, which allows for the possibility of compromised trial protocols.

Table 6 Perspectives on institution-level factors
Full size table

"“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.”"

The degree to which institutional barriers were perceived as a threat to research varied according to the size of the site of the respondent. A clear distinction was noted between larger research-intensive institutions and other sites in which researchers struggled due to a lack of infrastructure. Trialists from the former viewed the conduct of research much more positively and generally felt that they had the necessary resources available to conduct rigorous trials, while those from the latter reported greater levels of difficulty positioning their research as an important part of the clinical landscape.

"“Space, resources, and training for research assistants, research managers, graduate students… there’s all sorts of hurdles and headaches around those things that I think most established clinical research programs… already know how to make the system work.”"

Similar to the survey results, cohesive study teams with positive working relationships were reported as the most significant facilitator to conducting rigorous trials. At the institutional level, this often included combining the expertise of experienced trialists, methodologists, and the staff that would be responsible for implementing the trial; however, this integration was more common at sites with more support for research. Positive relationships were also mentioned in the context of subspecialties, with productive research networks across sites enabling researchers to benefit from a collective expertise, as well as facilitating study-specific elements such as the conduct of multi-centre trials. A final facilitator, which was more prominent in certain institutions than others, was a reliable internal review process. Respondents viewed this as a major asset when it was available, but many felt that existing processes were fragmented and inconsistent.

Policy factors

All interview respondents felt a lack of incentive to conduct pediatric trials. Difficulty in securing funding was frequently mentioned, but beyond that, participants reported that it is challenging to justify including financial support for a methodologist in grant application budgets in an environment where the funds awarded are anticipated to be less than requested. In this context, there is less assurance that study teams can include the necessary expertise. Meeting the requirements of several research ethics boards also presents a challenge, particularly with the preponderance of multi-centre trials in pediatrics. With separate ethics approval processes at each institution, the process can be lengthy and protocols are oftentimes changed to meet the inconsistent requests of the individual review panels (Table 7).

Table 7 Perspectives on policy-level factors
Full size table

Specific biases and pediatric-specific challenges

Addressing specific biases, survey and interview respondents reported challenges with blinding most frequently, which included the cost of providing a placebo, difficulties in blinding non-pharmacological interventions, and blinding all relevant parties, including parents. Other issues that were mentioned included difficulty getting adequate follow up in settings without an established clinician-patient relationship, parental resistance to randomization, and group imbalances due to small sample size.

Discussion

Bias is a recognized concern among pediatric trialists; however they may be lacking the knowledge, willingness, or resources to properly address it. Internal validity did not emerge as a primary concern in the analyses, being overshadowed by issues related to the pragmatics of running a trial and the generalizability of the results. While these issues warrant a great deal of consideration, it is crucial that studies start out being methodologically rigorous as this is a prerequisite for generalizability.

The major barriers to minimizing risk of bias in trials were related to awareness and environment. With little emphasis on research methodology in clinical curricula, many investigators are not adequately prepared to design trials with high levels of internal validity or to recognize and attend to issues as they arise. The existing ad hoc training system very likely contributes to an emphasis on certain areas and a deficit in others, as demonstrated by the disproportionate focus by respondents on issues related to external validity (i.e., generalizability of study results), despite being questioned on issues relevant to internal validity (i.e., avoiding bias through methodologically rigorous design). Additionally, the predominantly negative attitudes surrounding the research process reinforce the acceptance of sub-optimal RCTs. While research findings may be valued, more effort is required to ensure that the importance of high quality research is recognized at all stages, and by all stakeholders. Pediatric oncology is often cited as a model in developing an environment that fosters research. Available infrastructure and consistency in study protocols has resulted in the successful integration of research and clinical care leading to marked improvements in survival and other outcomes [24, 36, 37]. By embracing research as a critical component of providing best care, rather than viewing it as an imposition, investigators and clinicians in oncology have shown that setting a standard for conducting rigorous trials is an achievable goal with tangible benefits and impressive health outcomes.

Positive relationships that support the development of an interest in research are particularly relevant in an environment in which most training is dependent on mentorship and reinforcement from experienced trialists. Within this context, clinician-scientists have a key role in bridging the gap between the worlds of research and clinical practice. Combining knowledge of proper methodology with an appreciation for the demands of the clinical setting will increase the likelihood of producing both valid and realistic trials. Research networks such as the Canadian Critical Care Trials Group (CCCTG) and Pediatric Emergency Research Canada (PERC) have been quite successful in using this strategy, facilitating high quality trials by promoting a positive culture of research, providing access to individuals with expertise, and offering support and collegiality [38, 39].

With a solid evidence base demonstrating the gaps in methodological quality in pediatric RCTs [1–10], the research agenda must now focus on knowledge translation. Using barriers and facilitators identified by the target end-users, it will be important to develop tailored strategies to overcome the gap between what is known about methodological processes and how trials are designed and conducted in practice. This is one of the stated aims of StaR Child Health, an international initiative dedicated to improving the quality of pediatric clinical research [40].

Strengths and limitations

An advantage of this study is that it combines the breadth of survey responses with the depth of interview responses, allowing for a detailed picture of the barriers and facilitators pediatric trialists face in the conduct of methodologically rigorous trials. While the response rate to the survey was low, bringing into question the representativeness of the sample, it was in line with evidence that both electronic surveys [41] and physician surveys [42] are associated with low responses. However, respondents represented a wide range of pediatric specialties, training backgrounds, and geographies, helping to give shape to the subsequent interviews. While they may have represented researchers with a higher level of interest in methodology, the survey responses were used to form the interviews, in which researchers with trial experience were of interest so as to be able to account for the barriers and facilitators in pediatric research with first-hand knowledge. The recruitment of additional survey participants from the membership of MICYRN slightly changed the balance of geographical representation; however the Canadian context was weighted heavily throughout the study, therefore our emphasis was unchanged. The response rate to requests for interview participation was also low, but with our expanded recruitment strategy we were able to achieve saturation. The interviews emphasized the Canadian context and therefore can be used to inform future developments within the national health care and research framework, as well as provide considerations relevant to other settings.

Conclusions

Clinical research is inherently challenging, but these results can be used to focus efforts on improving the validity of trials that are conducted. The evidence is clear that improvement is necessary in pediatric RCTs and a substantial body of knowledge has accumulated around how to minimize bias. Before trials can improve, though, awareness of bias and attitudes towards research must be addressed. Research must be reframed as a valuable component of health care education, practice, and decision-making.