Pragmatic Clinical Trials: Testing Treatments in the Real-World

What is a Pragmatic Clinical Trial?

Clinical trials can be designed to be either pragmatic or explanatory. Explanatory trials are designed to find out whether a treatment has any efficacy (usually compared with placebo) under ideal, experimental conditions. In contrast to explanatory clinical trials, pragmatic clinical trials (PCTs) are designed to evaluate the comparative effectiveness of interventions within routine clinical settings (1,2). These trials are “pragmatic” because they focus on understanding how interventions work in real life as opposed to “explanatory” where the goal is to determine if and how an intervention works (2).

Why Pragmatic Clinical Trials are gaining popularity?

Explanatory clinical trials, especially randomized controlled trials (RCTs), are designed as experiments with high internal validity—the ability to determine cause-effect relationships. These experiments employ comprehensive designs to control for most, if not all, sources of bias (systematic errors) by means of randomization, blinding, allocation concealment, etc. Usually, extended inclusion and exclusion criteria are used to identify a clearly defined population group of participants who would benefit from the intervention under investigation. Although the above experimental design, if correctly applied, leads to well-controlled trials with statistically credible results; the applicability of these results to real-life practice may be questionable. Indeed, the same characteristics that contribute to the high internal validity of a trial (well-defined inclusion and exclusion criteria, blinding, controlled environment) can hamper its external validity, the ability to generalize the results in an extended population and clinical setting. Although hundreds of trials and RCTs have been performed so far in most clinical conditions, comparing dozens of interventions, there is growing concern that the results obtained from clinical research may not apply to “real-world” situations, because the research is often done under artificial conditions with volunteers who may not reflect the patients who actually live with a given disease or condition (3,4). Analyses of trials contained in the ClinicalTrials.gov database have shown that the vast majority of clinical trials are too small to provide sufficient statistical power to definitively answer clinical questions, they fail to address critical treatment priorities, or they suffer from shortcomings in design and execution that limit their usefulness (4).

The need for high-quality, widely applicable evidence is gaining momentum, especially amidst health care policy makers. The increased costs of interventions and health care in a resource-limited environment have fuelled the demand for clinically effective and applicable evidence (3).

A move to a learning health system is being recommended in which tools such as computing power, connectivity, team-based care, and systems engineering techniques will produce a culture of continuous learning at lower cost. Ideally, clinical trials would be embedded within a system of healthcare delivery where evidence is rapidly and continually fed back into clinical care, and clinical care itself would inform the further development of medical evidence (4, 5). More recently, the growing widespread availability of electronic health record (EHR) data in community practice and advances in information technology, has led to the potential to use such complex sets of data to streamline trials and conduct PCTs (4,6). Pragmatic trials are taking advantage of these settings and conducting research that is specific to the practitioners and patients involved in these complex systems. They use data collected in the EHR as part of routine care, or are “embedded” in routine care, and are a foundational component of such a system (7).

Key attribute differences between traditional RCTs and PCTs (4; NIH Pragmatic Trials Collaboratory)

Pragmatic–explanatory continuum indicator summary – 2 (PRECIS) Framework

Design decisions in domains that determine the extent to which a trial is pragmatic or explanatory need to be made. The proposal for the pragmatic–explanatory continuum indicator summary (PRECIS) was developed by an international group of interested people involved in conducting clinical trials at 2 meetings in Toronto between 2005 and 2008 (8). The PRECIS – 2 tool focuses on trial design choices which determine the applicability of a trial. The nine domains of PRECIS – 2 tool include eligibility, recruitment, setting, organization, flexibility (delivery), flexibility (adherence), follow-up, primary outcome and primary analysis (9).

 Examples of ePCTs

Pragmatic Clinical Trials have been benefitting health care for decades (examples include polio vaccines in 1950s and early studies of acute treatment of heart attack in 1980s and 90s (10).  Some examples of ePCTs, supported by National Institute of Health (NIH) Collaboratory, that address questions of major public health importance include (4):

• ABATE (Active Bathing to Eliminate Infection)
• ACP PEACE (Advance Care Planning: Promoting Effective and Aligned Communication in the Elderly)
• BackInAction (Pragmatic Trial of Acupuncture for Chronic Low Back Pain in Older Adults)
• EMBED (Pragmatic Trial of User-Centered Clinical Decision Support to Implement Emergency Department-Initiated Buprenorphine for Opioid Use Disorder)
• FM TIPS (Fibromyalgia transcutaneous electrical nerve stimulation in Physical Therapy Study)
• GGC4H (Pragmatic Trial of Parent-Focused Prevention in Pediatric Primary Care: Implementation and Adolescent Health Outcomes in Three Health Systems [GGC4H: Guiding Good Choices for Health])
• HiLo (Pragmatic Trial of Higher vs. Lower Serum Phosphate Targets in Patients Undergoing Hemodialysis)
• ICD-Pieces (Improving Chronic Disease management with Pieces)
• NOHARM (Nonpharmacologic Options in Postoperative Hospital-based and Rehabilitation Pain Management)
• Nudge (Personalized Patient Data and Behavioral Nudges to Improve Adherence to Chronic Cardiovascular Medications)
• PPACT (Pain Program for Active Coping and Training)
• PROVEN (Pragmatic trial Of Video Education in Nursing homes)
• PRIM-ER (Primary Palliative Care for Emergency Medicine)
• SPOT (Suicide Prevention Outreach Trial)
• TiME (Time to Reduce Mortality in End-Stage Renal Disease)
• TSOS (Trauma Survivors Outcomes and Support)

Pragmatic Clinical Trials in Canada

A program called REthinking Clinical Trials (REaCT), based in Ottawa hospital, is a unique research program aimed at improving the lives of people with cancer through patient-centred, pragmatic clinical trials. This program engages patients and their loved ones in research every step of the way, from generating ideas to setting priorities to designing studies and sharing results. Unlike most cancer clinical trials, which are focused on evaluating experimental treatments in a very narrow patient population, REaCT trials compare standard approved treatments in a real-world setting with a broad range of patients. In this way, REaCT trials can efficiently answer some of the most important questions for cancer patients and the health care system. REaCT is the largest pragmatic cancer clinical trials program in Canada, with more than 3,500 patients participating in 21 clinical trials at 16 centres in Canada (11).

Another group called the Pragmatic Trials Collaborative is a group of practicing primary care providers (including family physicians, nurse practitioners, registered nurses and pharmacists) who have come together to improve the care of their patients and answer pivotal healthcare questions along the way. Some of the trials being conducted by this group include:

• BedMed
• BedMed Frail
• OptimizeBP
• MinMed
• INRange

Approximately, 250 pragmatic clinical trials have been completed or are going on in Canada include (12). A few of them include:

• Electronic Patient Reported Outcome (ePRO) Mobile Application Pragmatic Trial – NCT02917954
• Coagulopathy of COVID-19: A Pragmatic Randomized Controlled Trial of Therapeutic Anticoagulation Versus Standard Care – NCT04362085
• Pilot Evaluation of "KeepWell" Using a Hybrid Effectiveness-Implementation Pragmatic Randomized Controlled Trial – NCT04437238
• Pragmatic Clinical Trials in Scleroderma (PCTS) – NCT03610217
• Personalized and Pragmatic Three-level Model of DBT-informed Care for Youth With Bipolar Disorder (DB3) – NCT05153369
• CENtral Blood Pressure Targeting: A Pragmatic RAndomized Pilot triaL in Advanced Chronic Kidney Disease (CENTRAL-CKD) – NCT05163158
• Patient-oriented Randomized Pragmatic Feasibility Trial With rTMS in Depression and Anxiety (PORT) – NCT05028738
• A Pragmatic Pilot Study of Cognitive Behavioural Therapy for Insomnia Among People Living With HIV – NCT02887209

Addressing ethical issues in Pragmatic Clinical Trials

In contrast to traditional clinical trials that study new therapies in highly controlled settings, pragmatic clinical trials rely on streamlined processes to measure outcomes in heterogeneous populations in real-world clinical settings. Some pragmatic trials use cluster randomization, in which groups (e.g., clinics, hospitals, cities) are randomized rather than individuals. Because of these differences, the application of ethical principles and regulations to pragmatic clinical trials is complex. Questions include, what constitutes research versus a quality improvement initiative under current regulatory guidelines; how should the criteria for determining what is minimal risk research be appropriately applied; and when is a waiver or alteration of informed consent ethical and justified (13).

Part of the changing research environment involves a shift toward patient-centeredness. Patient-centered outcomes research engages patients throughout the research process in determining what research questions are important, providing input during study design and conduct, and planning the dissemination and implementation of results. In keeping with patient-centered research principles, engaging patients in shaping ethical and regulatory guidelines for clinical research would promote autonomy and show respect for persons. National Institute of Health Collaboratory, in its recognition of the unresolved ethical and regulatory issues critical to the conduct of PCTs, initiated workgroups comprising of ethicists, clinical trialists, institutional review board professionals, and patient representatives and the culmination of this effort has resulted in special issue in Clinical Trials, addressing 11 ethical and regulatory priority issues in PCTs (13).

Author: Pratibha Duggal, ICON Plc.

References:

1. MacPherson H. Pragmatic clinical trials. Complementary therapies in medicine. 2004 Jun 1;12(2-3):136-40.
2. Anderson ML, Griffin J, Goldkind SF, Zeitler EP, Wing L, Al-Khatib SM, Sherman RE. The Food and Drug Administration and pragmatic clinical trials of marketed medical products. Clinical Trials. 2015 Oct;12(5):511-9.
3. Patsopoulos NA. A pragmatic view on pragmatic trials. Dialogues in clinical neuroscience. 2022 Apr 1.
4. Kevin Weinfurt. WHAT IS A PRAGMATIC CLINICAL TRIAL. Accessed on 06 October, 2022.  Available at: https://rethinkingclinicaltrials.org/chapters/pragmatic-clinical-trial/what-is-a-pragmatic-clinical-trial/.
5. Committee on the Learning Health Care System in America; Institute of Medicine. Best Care at Lower Cost: The Path to Continuously Learning Health Care in America. Smith M, Saunders R, Stuckhardt L, McGinnis JM, editors. Washington (DC): National Academies Press (US); 2013 May 10. PMID: 24901184.
6. Mentz RJ, Hernandez AF, Berdan LG, Rorick T, O’Brien EC, Ibarra JC, Curtis LH, Peterson ED. Good clinical practice guidance and pragmatic clinical trials: balancing the best of both worlds. Circulation. 2016 Mar 1;133(9):872-80.
7. Weinfurt KP, Hernandez AF, Coronado GD, DeBar LL, Dember LM, Green BB, Heagerty PJ, Huang SS, James KT, Jarvik JG, Larson EB. Pragmatic clinical trials embedded in healthcare systems: generalizable lessons from the NIH Collaboratory. BMC medical research methodology. 2017 Dec;17(1):1-0.
8. Thorpe KE, Zwarenstein M, Oxman AD, Treweek S, Furberg CD, Altman DG, Tunis S, Bergel E, Harvey I, Magid DJ, Chalkidou K. A pragmatic–explanatory continuum indicator summary (PRECIS): a tool to help trial designers. Journal of clinical epidemiology. 2009 May 1;62(5):464-75. 
9. Loudon K, Treweek S, Sullivan F, Donnan P, Thorpe KE, Zwarenstein M. The PRECIS-2 tool: designing trials that are fit for purpose. bmj. 2015 May 8;350.
10. Introduction to pragmatic clinical trials. NIH Collaboratory. Accessed on 06 October 2022. Available at: https://dcricollab.dcri.duke.edu/sites/NIHKR/KR/Introduction%20to%20pragmatic%20clinical%20trials.pdf.
11. REaCT REthinking Clinical Trials. The Ottawa Hospital Research Institute. Accessed on 06 October 2022. Available at: https://react.ohri.ca/.
12. Clinical Trials.gov. Accessed on 06 October 2022. Available at: https://clinicaltrials.gov/ct2/home.
13. Gina Uhlenbrauck. NIH PRAGMATIC TRIALS COLLABORATORY: Rethinking Clinical Trials. Ethical and Regulatory Issues in Pragmatic Clinical Trials: Special Issue of Clinical Trials. Accessed on 06 October 2022. Available at: https://rethinkingclinicaltrials.org/resources/ethical-and-regulatory-issues-in-pragmatic-clinical-trials/#9.