What is a Pragmatic Clinical Trial?
Section 2
The Embedded Pragmatic Clinical Trial Ecosystem
Definition of a Pragmatic Clinical Trial
According to Califf and Sugarman, there are “three key attributes of PCTs: (1) an intent to inform decision-makers (patients, clinicians, administrators, and policy-makers), as opposed to elucidating a biological or social mechanism; (2) an intent to enroll a population relevant to the decision in practice and representative of the patients or populations and clinical settings for whom the decision is relevant; and (3) either an intent to (a) streamline procedures and data collection so that the trial can focus on adequate power for informing the clinical and policy decisions targeted by the trial or (b) measure a broad range of outcomes. Given these attributes, a common-sense definition for a PCT would thus be as follows:
Designed for the primary purpose of informing decision-makers regarding the comparative balance of benefits, burdens and risks of a biomedical or behavioral health intervention at the individual or population level. (Califf and Sugarman 2015).
Watch the video module: What Are Pragmatic Clinical Trials?
Embedded PCTs Bridge Clinical Care and Research
To achieve generalizable results in an efficient manner, embedded PCTs (ePCTs) commonly take place in the setting where patients already receive their usual clinical care. In contrast with traditional RCTs, the intention is to avoid the need for a separately constructed infrastructure with specially trained research staff responsible for data collection. For a broader, more representative population, eligibility criteria are minimized and recruitment expanded to potentially all eligible individuals receiving care in the participating setting. Intervention delivery, participant follow-up, and adherence protocols are more flexible and closely align with usual care in order to understand the real-world implications of the intervention. Arguably, many of these pragmatic qualities occur along a spectrum, with some trials being more pragmatic than others (Thorpe et al. 2009).
NIH Collaboratory ePCT NIH Collaboratory Trials
To explore the potential of ePCTs and establish best practices, the NIH Collaboratory supports the design and execution of NIH Collaboratory Trials, which are ePCTs that address questions of major public health importance (Table).
Study Name ClinicalTrials.gov number |
Project Goal | Setting | Population | Unit of Randomization |
---|---|---|---|---|
ABATE
Active Bathing to Eliminate Infection NCT02063867 |
Determine if using antiseptic bathing for all patients and nasal ointments for patients harboring methicillin-resistant Staphylococcus aureus (MRSA) reduces multidrug-resistant organisms and bloodstream infections | 48 hospitals | 332,646 patients in adult medical, surgical, oncology, and step-down units | Cluster randomization by hospital |
ACP PEACE
Advance Care Planning: Promoting Effective and Aligned Communication in the Elderly NCT03609177 |
Test whether clinician communication skills training and patient video decision aids increase completion of advance care planning | 36 oncology clinics across 3 health systems | Patients >65 years of age with advanced cancer (~12,000 patients and clinicians) | Cluster randomization and stepped-wedge design |
BackInAction
Pragmatic Trial of Acupuncture for Chronic Low Back Pain in Older Adults |
Evaluate the safety and effectiveness of acupuncture in older adults with chronic low back pain | 4 performance sites | 789 adults ≥65 years of age with chronic low back pain | Individual randomization |
EMBED
Pragmatic Trial of User-Centered Clinical Decision Support to Implement Emergency Department-Initiated Buprenorphine for Opioid Use Disorder NCT03658642 |
Test the effectiveness of user-centered computerized clinical decision support on rates of ED–initiated buprenorphine/naloxone and referral for ongoing medication-assisted treatment in patients with opioid use disorder | 5 large health systems; 18 sites | ~2200 clinicians treating adult patients with opioid use disorder in the ED | Cluster randomization by ED site |
FM TIPS
Fibromyalgia TENS in Physical Therapy Study NCT04683042 |
Test the feasibility and effectiveness of adding transcutaneous electrical nerve stimulation (TENS) nonpharmacologic treatment for pain and fatigue in patients with fibromyalgia (FM) | 24 routine physical therapy clinics and 6 health systems in rural and urban settings | ~600 patients with FM | Cluster randomization by clinic |
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) NCT04040153
|
Test the feasibility and effectiveness of implementing a universal evidence-based anticipatory guidance curriculum (Guiding Good Choices) for parents of early adolescents | 3 large integrated health systems; 75 sites | Pediatric primary care practices serving families with adolescents 11-12 years of age (~3600 adolescents and families) | Cluster randomization by pediatrician within clinic |
HiLo
Pragmatic Trial of Higher vs. Lower Serum Phosphate Targets in Patients Undergoing Hemodialysis NCT04095039
|
Test the effects of liberalizing the serum phosphate target (“Hi”) versus maintaining aggressive phosphate control (“Lo”) | 2 large dialysis provider organizations; 100 sites | ~4400 patients with end-stage renal disease receiving maintenance hemodialysis | Cluster randomization |
ICD-Pieces
Improving Chronic Disease management with Pieces NCT02587936
|
Improve care for patients with chronic kidney disease, diabetes, and hypertension by using a novel technology platform (Pieces) that uses the electronic health record to identify patients and by assigning practice facilitators within primary care practices or community medical homes | 4 health systems; 143 sites | ~11,000 patients with multiple comorbid conditions (chronic kidney disease, diabetes, and hypertension) | Stratified cluster randomization of clinical practices within health systems |
LIRE
Lumbar Image Reporting with Epidemiology NCT02015455
|
Determine if inserting epidemiological benchmarks (essentially representing the normal range) into lumbar spine imaging reports reduces subsequent tests and treatments | 4 health systems; 98 clinics | 250,401 patients with low back pain | Cluster randomization by clinic; stepped-wedge, one-way crossover design |
NOHARM
Nonpharmacologic Options in Postoperative Hospital-based and Rehabilitation Pain Management NCT04570371
|
Evaluate the feasibility of EHR-embedded patient- and clinician-facing decision support for nonpharmacologic pain care after surgery | 4 large integrated health systems; 22 practice clusters | ~54,000 postoperative patients | Randomized by practice clusters |
Nudge
Personalized Patient Data and Behavioral Nudges to Improve Adherence to Chronic Cardiovascular Medications NCT03973931 |
Use pharmacy refill data to test effectiveness of medication reminder nudges delivered to patients’ mobile phones, and test an interactive chat bot mechanism that optimizes content | 3 large integrated health systems | 14,700 patients with chronic cardiovascular conditions who take medications | Individual randomization |
OPTIMUM
Group-Based Mindfulness for Patients With Chronic Low Back Pain in the Primary Care Setting NCT04129450 |
Evaluate a group-based mindfulness program (mindfulness-based stress reduction) for patients with chronic low back pain within primary care | Primary care clinics in 3 large health systems | ~450 patients with chronic low back pain | Individual randomization |
PPACT
Pain Program for Active Coping and Training NCT02113592 |
Help patients adopt self-management skills for chronic pain, limit use of opioid medications, and identify factors amenable to treatment in the primary care setting | 3 staff model health plans; 106 primary care providers | 860 patients with chronic pain on long-term opioid therapy | Cluster-randomization by primary care provider |
PRIM-ER
Primary Palliative Care for Emergency Medicine NCT03424109 |
Test effectiveness of primary palliative care education, training, and technical support for emergency medicine | 33 emergency departments | Patients ≥66 years of age in the ED with serious, life-limiting illness (4,983 providers) | Cluster randomization; stepped-wedge design |
PROVEN
Pragmatic Trial of Video Education in Nursing Homes NCT02612688 |
Determine if showing advanced care planning videos in nursing homes affects the rates of hospitalization | 2 nursing home health systems; 359 nursing homes | Nursing home health systems serving long-stay (>12 months) patients with advanced comorbid conditions (166,196 patients) | Cluster randomization by nursing home |
SPOT
Suicide Prevention Outreach Trial NCT02326883 |
Compare outcomes in patients who receive care-management or online skills training for suicide prevention versus usual care | 4 large health systems | 18,889 individuals at elevated risk for suicide on a depression scale | Individual randomization |
STOP CRC
Strategies and Opportunities to Stop Colon Cancer in Priority Populations NCT01742065 |
Improve the rates of colorectal cancer screening by mailing fecal immunochemical testing tests to patients at federally qualified health centers | 26 federally qualified health center clinics | 62,155 individuals eligible for colorectal screening per the US Preventive Task Force guidelines | Cluster randomization by clinic |
TiME
Time to Reduce Mortality in End-Stage Renal Disease NCT02019225 |
To determine whether increasing hemodialysis session duration reduces mortality and hospitalization rates for patients receiving maintenance hemodialysis care | 266 dialysis facilities operated by 2 dialysis provider organizations | 7035 adults who have initiated treatment with maintenance hemodialysis within the past 120 days | Cluster randomization by dialysis facility |
TSOS
Trauma Survivors Outcomes and Support NCT02655354 |
To coordinate care and improve outcomes for trauma survivors with post-traumatic stress disorder (PTSD) and comorbidity and to provide the American College of Surgeons with multisite pragmatic trial evidence that could further inform regulatory policy | 25 US level 1 trauma centers | 635 trauma survivors with PTSD and comorbidity | Cluster randomization by trauma center; stepped-wedge design |
This table is based on a table previously published by the Collaboratory in a white paper titled Lessons Learned from the NIH Health Care Systems Research NIH Collaboratory Trials and is used with permission (NIH Collaboratory Healthcare Systems Interactions Core 2016).
Extending the Reach of the ePCT Ecosystem
PCORnet
The National Patient-Centered Clinical Research Network (PCORnet) links multiple integrated health systems and ‘‘patient-powered’’ networks to conduct comparative effectiveness research and explore questions about conditions, care, and outcomes that matter most to patients and their families. PCORnet consists of clinical data research networks and patient-powered research networks that are linked through a distributed research network (DRN) to facilitate multi-site, observational, and interventional research (Fleurence et al. 2014). The DRN harnesses data from the electronic health record for research, allows each participating organization to maintain physical and operational control over their data, and minimizes the transfer of individual-level clinical data (Fleurence et al. 2014). PCORnet’s first PCT is ADAPTABLE: the Aspirin Study (Johnston et al. 2016).
Pain Management Collaboratory
The Pain Management Collaboratory (PMC) is jointly supported by the National Institutes of Health (NIH), Department of Defense (DoD), and Veterans Affairs (VA). The program aims to develop the capacity to implement cost-effective large-scale pragmatic clinical research in military and veteran health care delivery organizations focusing on nonpharmacologic approaches to pain management and other comorbid conditions. The PMC supports 11 NIH Collaboratory Trials addressing such clinical areas as chronic low back pain, postoperative pain, and behavioral treatments for pain, among others.
National Institute on Aging (NIA) IMPACT Collaboratory
The NIA IMPACT Collaboratory aims to increase the nation’s capacity to conduct pragmatic clinical trials embedded within healthcare systems for people living with dementia and their caregivers. The NIA IMPACT Collaboratory is funding 1-year pilot studies that are meant to generate the preliminary data necessary to design and conduct full-scale ePCTs that will be funded through other grant mechanisms such as the NIH or other sources.
Real-World Data and Real-World Evidence
We believe that when the term "real-world evidence" is used, the primary attribute that distinguishes it from other kinds of evidence is related to the context in which the evidence is gathered—in other words, in clinical care and home or community settings as opposed to research-intensive or academic environments. (Sherman et al. 2016)
ePCTs can also be viewed within the context of recent discussions about real-world data (RWD) and real-world evidence (RWE). RWD is data relating to patient health status or the delivery of healthcare routinely collected from a variety of sources, such as electronic health records (EHRs), claims and billing activities, product and disease registries, patient-generated data, and data gathered from sources that can inform on health status (FDA). RWE is the clinical evidence regarding the usage and potential benefits or risks of a medical product derived from analysis of real-world data. RWE can be generated by different study designs or analyses, including but not limited to, randomized trials, including large simple trials, pragmatic trials, and observational studies (prospective and/or retrospective).
- For more on the role of RWD and RWE in ePCTs, read Real World Evidence: Mobile Health in the Living Textbook.
- In Advances at the Intersection of Digital Health, Electronic Health Records, and Pragmatic Clinical Trials: Real World Evidence: Contemporary Experience and Future Directions, a PCT Grand Rounds webinar, a panel discusses how quality real-world evidence cannot be built without quality real-world data.
- In late 2021, the FDA issued 4 draft guidances for real-world data and real-world evidence intended to guide the selection and management of data sources to appropriately address study questions and support decision-making for drug and biological products. These draft guidances include:
- Real-World Data: Assessing Electronic Health Records and Medical Claims Data To Support Regulatory Decision-Making for Drug and Biological Products
- Data Standards for Drug and Biological Product Submissions Containing Real-World Data
- Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products Guidance for Industry
- Considerations for the Use of Real-World Data and Real-World Evidence To Support Regulatory Decision-Making for Drug and Biological Products
Dr. John Concato, Associate Director for Real-World Evidence Analytics with the Food and Drug Administration (FDA), discusses this FDA guidance in the June 24, 2022 PCT Grand Rounds Webinar titled “ FDA Draft Guidance on Real-World Evidence,” and the July 14, 2022 Grand Rounds Podcast.
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REFERENCES
Califf RM, Sugarman J. 2015. Exploring the ethical and regulatory issues in pragmatic clinical trials. Clin Trials. 12:436–441. doi:10.1177/1740774515598334.
Fleurence RL, Curtis LH, Califf RM, Platt R, Selby JV, Brown JS. 2014. Launching PCORnet, a national patient-centered clinical research network. J Am Med Inform Assoc. 21:578–582. doi:10.1136/amiajnl-2014-002747.
Johnston A, Jones WS, Hernandez AF. 2016. The ADAPTABLE Trial and Aspirin Dosing in Secondary Prevention for Patients with Coronary Artery Disease. Curr Cardiol Rep. 18:81. doi:10.1007/s11886-016-0749-2.
Sherman RE, Anderson SA, Dal Pan GJ, et al. 2016. Real-World Evidence - What Is It and What Can It Tell Us? N Engl J Med. 375:2293-2297. doi:10.1056/NEJMsb1609216. PMID: 27959688.
Thorpe KE, Zwarenstein M, Oxman AD, et al. 2009. A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers. J Clin Epidemiol. 62:464–475. doi:10.1016/j.jclinepi.2008.12.011. PMID: 19348971.