Living Textbook Offers New Content on Design and Analysis of Pragmatic Clinical Trials

Members of the NIH Collaboratory’s Biostatistics and Study Design Core contributed 3 new sections to the Living Textbook exploring issues in the design and analysis of pragmatic clinical trials. The new sections offer insights into emerging issues in embedded pragmatic clinical trials and lessons learned from the NIH Collaboratory’s first round of Demonstration Projects.

  • The Designing to Avoid Identification Bias section addresses a type of selection bias that can occur in pragmatic clinical trials that use information from electronic health records to determine study population eligibility and in which the study intervention influences who undergoes screening or receives a diagnosis in clinical care.
  • The Alternative Cluster Randomized Designs section describes alternative design choices for cluster randomized trials and their implications for statistical power and sample size calculations. Modified cluster randomized designs, such as cluster randomization with crossover, may reduce the sample size required for a pragmatic clinical trial and may be particularly feasible in trials embedded in healthcare systems with electronic health records.
  • Case Study: STOP CRC Trial explores challenges in design and analysis that were faced in the Strategies and Opportunities to Stop Colorectal Cancer in Priority Populations (STOP CRC) trial, one of the NIH Collaboratory Demonstration Projects. The case study illustrates how the study team dealt with pragmatic issues during the planning and conduct of the trial.

In addition to contributing content to the Living Textbook, the Biostatistics and Study Design Core works with the NIH Collaboratory Demonstration Projects to address challenges in their statistical plans and study designs during the planning phase and to develop guidance and technical documents related to study design and biostatistical issues relevant to pragmatic clinical trials.

Podcast February 19, 2019: Paramedic Airway Management in Out-of-Hospital Cardiac Arrest – The Pragmatic Airway Resuscitation Trial (PART)

February 13, 2019: Proposals Due for Pragmatic Trials of Acupuncture Treatment in Older Adults With Chronic Low Back Pain

Proposals are due March 15 in response to an NIH funding opportunity announcement for embedded pragmatic clinical trials that address pain management and the opioid crisis. The NIH will support 1 to 2 pragmatic trials that evaluate acupuncture treatment in older adults with chronic low back pain. The projects will join the NIH Health Care Systems Research Collaboratory as phased UG3/UH3 cooperative research.

Read the full announcement: Pragmatic Randomized Controlled Trial of Acupuncture for Management of Chronic Low Back Pain in Older Adults

The request for applications is part of the NIH Heal (Helping to End Addiction Long-term) Initiative, which was created in April 2018 in an effort to speed scientific solutions for addressing the national opioid public health crisis.

Podcast January 29, 2019: A Learning Health System Story: Perinatal Outcomes Associated with a Major Change in Gestational Diabetes Screening

Listen to the episode here:

At least once a month, we will release interviews with Grand Rounds speakers that delve into their topic of interest and give listeners bonus time with these featured experts.

Please let us know what you think by providing your feedback through the podcast page. We also encourage you to listen and share the recordings with your colleagues!

January 22, 2019: New Self-Paced ePCT Training Course Available

The NIH Collaboratory is pleased to announce the availability of a new self-paced, 10-module introductory course on how to design, conduct, and disseminate embedded PCTs (ePCTs). This course presents condensed material from the inaugural ePCT Training Workshop held in 2018 and provides users with important things to know and do when designing an ePCT, along with helpful links to additional learning resources within the Living Textbook.

Also available in the Living Textbook are links to videocast workshops hosted by the NIH on a range of ePCT topics including:

  • Embedded PCTs of therapeutic A versus B interventions
  • Unique opportunities for disseminating, implementing, and sustaining evidence-based practices into clinical care
  • Ethical and regulatory issues of PCTs

For these and other ePCT resources, visit the Training Resources webpage.

January 18, 2019: NIH Collaboratory Investigators Respond to FDA’s Proposed Rule on Informed Consent

NIH Collaboratory leadership and Demonstration Project Principal Investigators have responded to the U.S. Food and Drug Administration’s (FDA’s) proposed rule to allow for a waiver or alteration of informed consent.

“We applaud the proposed rule to allow for a waiver or alteration of informed consent for clinical investigations posing no more than minimal risk to a human participant and including appropriate safeguards.

We agree about the broad benefits described in the proposed rule—healthcare advances, reduction in burden from harmonizing FDA’s regulations with the Common Rule, and reduced burden and costs for the IRB…”

The full letter is available for download and includes the list of signatories.

January 11, 2019: FDA Releases Framework for Evaluating the Use of Real-World Evidence

To help fulfill the requirements of the 21st Century Cures Act by accelerating medical product development and fostering innovation and advances in medicine, FDA recently created a framework for evaluating the use of real-world evidence. The framework is intended to help evaluate trials that use real-world data for the creation of real-world evidence.

  • Real-world data: routinely collected information about a person’s health status in the electronic health record, claims, registries, and other sources, including patient-generated sources.
  • Real-world evidence: reliable, clinical information derived from real-world data about risks, benefits, and burdens of therapies.

This framework will apply to various pragmatic clinical trials embedded in health care systems and conducted as part of routine care (and will not apply to more traditional clinical trials conducted parallel to care).

Three main considerations are included in the framework:

  1. Will the real-world data be fit for use (do they reliably and adequately represent the concept)?
  2. Will the evidence generated by the trial provide adequate evidence to help answer regulatory questions?
  3. Will the conduct of the study meet FDA regulatory requirements?

December 17, 2018: NIH Collaboratory Advances Knowledge in Peer-Reviewed Literature in 2018

The NIH Collaboratory program contributed knowledge from pragmatic clinical research with 12 peer-reviewed publications in 2018, including several reports of findings from Demonstration Projects and more:

NIH Collaboratory Coordinating Center

Identifying and supporting nonpharmacological dementia interventions ready for pragmatic trials: results from an expert workshop. J Am Med Dir Assoc. 2018;19(7):560-562.

NIH Collaboratory Distributed Research Network

Cancer screening results and follow-up using routinely collected electronic health data: estimates for breast, colon, and cervical cancer screenings. J Gen Intern Med. 2018 Oct 22. doi: 10.1007/s11606-018-4697-y. [Epub ahead of print]

STOP CRC Demonstration Project

Effect of reminding patients to complete fecal immunochemical testing: a comparative effectiveness study of automated and live approaches. J Gen Intern Med. 2018;33(1):72-78.

Predictors of colorectal cancer screening prior to implementation of a large pragmatic trial in Federally Qualified Health Centers. J Community Health. 2018;43(1):128-136.

Effectiveness of a mailed colorectal cancer screening outreach program in community health clinics: the STOP CRC cluster randomized clinical trial. JAMA Intern Med. 2018;178(9):1174-1181.

Positive predictive values of fecal immunochemical tests used in the STOP CRC pragmatic trial. Cancer Med. 2018;7(9):4781-4790.

Effectiveness of automated and live phone reminders after mailed-FIT outreach in a pilot randomized trialPrev Med Rep. 2018;12:210-213.

LIRE Demonstration Project

Comparison of natural language processing rules-based and machine-learning systems to identify lumbar spine imaging findings related to low back pain. Acad Radiol. 2018;25(11):1422-1432.

PROVEN Demonstration Project

Representation in the care planning process for nursing home residents with dementia. J Am Med Dir Assoc. 2018;19(5):415-421.

A dynamic application of PRECIS-2 to evaluate implementation in a pragmatic, cluster randomized clinical trial in two nursing home systems. Trials. 2018;19(1):453.

PPACT Demonstration Project

Interdisciplinary team-based care for patients with chronic pain on long-term opioid treatment in primary care (PPACT) – protocol for a pragmatic cluster randomized trial. Contemp Clin Trials. 2018;67:91-99.

Automating collection of pain-related patient-reported outcomes to enhance clinical care and research. J Gen Intern Med. 2018;33(Suppl 1):31-37.

December 14, 2018: New Alzheimer Trial to Be Planned Using the NIH Collaboratory Distributed Research Network

A new pragmatic trial planning grant supported by the National Institute on Aging will use the NIH Collaboratory’s Distributed Research Network (DRN) to characterize eligible patients and develop an intervention that tests the value of engaging health plan members and their caregivers, in addition to prescribers, to reduce potentially harmful medication use in patients with Alzheimer disease and related dementias (ADRD).

Patients with Alzheimer disease are at high risk for “prescribing cascades,” in which patients receive multiple, potentially unnecessary drug prescriptions to address side effects of their other medications. The Controlling and Stopping Cascades Leading to Adverse Drug Effects Study in Alzheimer’s Disease (CASCADES-AD) will be an embedded pragmatic clinical trial in 2 large healthcare systems. It would be the first evaluation of a large-scale, health plan–based educational intervention to improve medication safety and reduce the occurrence of preventable medication-related complications among patients with ADRD.

The study will characterize more than 22,500 patients with ADRD who will be identified through the DRN’s distributed data resources. The NIH Collaboratory DRN enables researchers to send queries to data partners and receive aggregate data without confidential information. Through its multiple data partners, the DRN has access to data for more than 90 million lives.

View an NIH Collaboratory Grand Rounds presentation about the status of the DRN, and learn more about the DRN in the Living Textbook.

December 13, 2018: New Living Textbook Chapter: Developing a Compelling Grant Application

A new chapter in the Living Textbook provides expert advice for investigators submitting an application for a pragmatic clinical trial to the NIH. The chapter covers finding the right Program Official and opportunity announcement, writing a strong proposal, addressing review criteria, and award status.

“First and foremost, develop and clearly define a clinical research question with a testable hypothesis and then select an experimental design best suited to answering the research question. The study question drives the research design.” —From Developing a Compelling Grant Application

Dr. Wendy Weber, the Program Officer for the NIH Collaboratory Coordinating Center, and Dr. Marcel Salive, a Program Officer from the National Institute on Aging, contributed to this chapter.