1. Study Population and Setting
Borsika A. Rabin, Ph.D., M.P.H.
Department of Family Medicine and Colorado Health Outcome Program, School of Medicine
and
Department of Community and Behavior Health,
School of Public Health
University of Colorado
Pragmatic TRIALS

2. “Pragmatic trials are conducted in real-life settings encompassing the full spectrum of the population to which an intervention will be applied.”
Patsopoluos NA. Dialogues Clin Neurosci. 2011; 13(2): 217–224.

3. PRECIS-2 domains STUDY POPULATION ELIGIBILITY RECRUITMENT SETTING
ORGANIZATION
STUDY SETTING
The Study population domains are concerned with the questions of “Who is selected to participate in the study?” (Eligibility) and “How participants are recruited into the study?” (Recruitment). In the context of PRECIS-2, “participants" include patients or other individual recipients of an intervention, and/or providers of the intervention.
The Setting domains are concerned with the questions of “Where is the study being done?” (Setting) and “What expertise and resources are needed to deliver the intervention? (Organization).

4. STUDY POPULATION:
The Study populations domains are concerned with the questions of “Who is selected to participate in the study?” (Eligibility) and “How participants are recruited into the study?” (Recruitment). In the context of PRECIS-2, “participants" include patients or other individual recipients of an intervention, and/or providers of the intervention. This may include individual participants and/or one or more levels of clusters. For example, in a trial of a continuing education intervention, participants may be health professionals and trained instructors and the trial may be randomized into clusters at the level of the instructor. To assess the Eligibility domain, we want to evaluate to what extent are the participants in the trial similar to those who would receive this intervention if it was part of usual care. Explanatory studies tend to have more exclusion criteria than pragmatic ones. Typical reasons for exclusion include: (1) excluding participants not known/shown to be highly compliant to the interventions under study; (2) excluding participants not known/shown to be at high risk for the primary trial outcome (3) excluding participants not expected to be highly responsive to the experimental intervention. The goal of these exclusions is typically to exclude participants who are less likely to respond to the intervention (Thorpe, 2009).The Recruitment domain refers to the amount of extra effort that is made to recruit participants over and above what that would be used in the usual care setting to engage with patients?

5. Nallamothu BK et al. Circulation. 2008; 118: 1294-1303
“≈60% of patients with heart failure have concomitant renal insufficiency—with 15% having glomerular filtration rates <30 mL/min—and this is associated with a worse prognosis.
However, RCTs testing angiotensin-converting enzyme inhibitors, β-blockers, and spironolactone in patients with advanced heart failure have frequently excluded patients with renal insufficiency.”
Nallamothu BK et al. Circulation. 2008; 118:
Patient Selection Limitations
It is well recognized that differences between the efficacy and effectiveness of a therapy may result from the selective recruitment of patients in traditional RCTs. Substantial differences in age, gender, and comorbidities have been reported between patients in traditional RCTs and real-world registries because of explicit exclusion criteria and subtle recruitment biases.24,25 By necessity, traditional RCTs usually target a subgroup of individuals from the larger universe of potentially eligible patients on the basis of who is most likely to participate or respond to the therapy. This targeting is done in order to isolate the biological effect of a therapy and to minimize sample size requirements and cost. However, in routine clinical practice, the luxury of not including sicker or more complicated patients is not available. Paradoxically, such targeting can result in a paucity of empirical data on those patients most likely to require the therapy.
For example, ≈60% of patients with heart failure have concomitant renal insufficiency—with 15% having glomerular filtration rates <30 mL/min—and this is associated with a worse prognosis.26 However, RCTs testing angiotensin-converting enzyme inhibitors, β-blockers, and spironolactone in patients with advanced heart failure have frequently excluded patients with renal insufficiency.27 Others have reported similar issues for this same group of patients in RCTs of coronary artery disease.28 The potential danger of generalizing findings from RCTs to real-world settings was recently demonstrated in a large population-based study that found higher rates of hyperkalemia and mortality in hospitalized patients with heart failure who were treated with spirinolactone after publication of the Randomized Aldactone Evaluation Study (RALES) trial.29 These findings were primarily explained by the use of this drug in patients at greater risk for hyperkalemia than those in the RALES trial. Conversely, the lack of data in high-risk patients may also contribute to the well-described “risk-treatment paradox” found for other therapies. Under this scenario, those at greatest risk of death are the least likely to be treated, even when they are likely to receive the greatest absolute benefit.30,31

6. STUDY SETTING:
The Settings domains are concerned with the questions of “Where is the study being done?” (Setting) and “What expertise and resources are needed to deliver the intervention? (Organization).
The Setting domain in PRECIS-2 assesses how different is the setting of the study from the usual care setting. Pragmatic trials encourage the selection of multiple, diverse settings in which the intervention would be delivered. More explanatory trials would be characterized by fewer or a single source for the participants (Thorpe, 2009).
The Organization domain explores the difference between the resources, provider expertise and the organization of care delivery in the intervention arm of the study and those available in usual care. Increased resource needs, specialized provider expertise and deviance from usual care delivery processes pushes the study to the more explanatory end of the continuum. For example providers delivering the intervention can be restricted to ones with (1) some defined experience in working with the subjects like the ones to be enrolled in the study; (2) specialty certification relevant to the given intervention; (3) experience with the actual intervention (Thorpe, 2009).

7. Krist and colleagues in their pragmatic study of the implementation of the My Own Health Report (MOHR) intervention identified 18 sites to participate. Each collaborating research team identified one or two pairs of primary care practices within their network that were similar with respect to practice type (e.g., FQHC or PBRN, family practice or internal medicine), practice ownership, geographic region, EHR infrastructure, and patient population served. Practice pairs were purposefully selected to represent the diversity of primary care settings and populations to ensure greater generalizability of results.
Krist AH et al. Implementation Science. 2013, 8:73.

8. PRAGMATIC TRIALS…
Have fewer exclusion criteria than explanatory ones and include population that is characterized to be similar to individuals with the given condition;
Use recruitment approaches that build on exiting care procedures;
Are conducted in multiple settings similar to the ones in usual care;
Deliver the intervention via providers who interact with participants with the condition in usual care, require little or no additional resources, and line up the delivery of the intervention with existing care delivery processes as closely as possible.

9. Panel presentation 1:
Allison Kempe, MD, MPH: Effectiveness of Public-Private Collaboration in the Delivery of Influenza Vaccine

10. Panel presentation 2:
Elaine S. Belansky, PhD: The Working Together Project

11. Themes to listen for…

12. Eligibility: Who is selected to participate?
What criteria was used to select participants?
How did this criteria influence the research design and generalizability of the findings?
Did the participant selection process differ from one that is used in a traditional (non-pragmatic) trial? If so, how?

13. How are participants recruited?
Recruitment:
How are participants recruited?
What type of recruitment approach is used?
Did this approach differ from an approach used in a traditional (non pragmatic) trial? If so, how?

14. Setting: Where is the trial done?
What criteria was used to select sites?
How did the setting selection influence the research design and generalizability of the findings?
Did the site selection process differ from one that would be used in a traditional (non- pragmatic) trial? If so, how?

15. What expertise and resources are needed?
Organization:
What expertise and resources are needed?
What level of expertise was required for the delivery of the intervention?
Who delivered the intervention?
What type of resources were required for the delivery and implementation of the intervention?
How did these requirements influence the generalizability of the findings?

16. One more:
What were some barriers for making more pragmatic choices in these domains?