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.
Robert J. Mentz, MD
Associate Professor of Medicine
Duke University School of Medicine
Kevin J. Anstrom, PhD
Professor of Biostatistics and Bioinformatics
Director of Biostatistics, Duke Clinical Research Institute
Duke University School of Medicine
Eric Eisenstein, DBA
Associate Professor in Medicine
Duke University School of Medicine
Stephen J. Greene, MD
Fellow, Division of Cardiology and Duke Clinical Research Institute
Duke University School of Medicine
Eric J. Velazquez. MD, FACP, FACC, FASE, FAHA
Robert W. Berliner Professor of Medicine, Yale University
Chief, Cardiovascular Medicine, Yale New Haven Hospital
Physician-in-Chief, Heart and Vascular Center, Yale New Haven Health
Topic
TRANSFORMing Research for Patients With Heart Failure
Keywords
Pragmatic clinical trial; Heart failure; PRECIS-2; Hospitalization; TRANSFORM-HF; Clinical equipoise; Electronic health records; National Heart, Lung, and Blood Institute (NHLBI)
Key Points
The traditional approach to conducting clinical trials is unsustainable in many respects, including operational complexities, low enrollment rates, high costs, and failure to leverage existing resources. Incorporating pragmatic elements in the design of trials may improve efficiencies and conduct.
TRANSFORM-HF is a pragmatic trial evaluating torsemide versus furosemide treatment for long-term clinical outcomes among patients hospitalized for heart failure. Study randomization is 1:1, and the primary endpoint is all-cause mortality.
Advantages of trials with pragmatic designs include real-world effectiveness; broad patient/provider groups; reduced number and complexity of visits; streamlined data collection; potential for faster results; and results that will be more generalizable.
Discussion Themes
The clinical question involving starting a treatment (Should we start with furosemide or torsemide?) versus switching a treatment (Should we attempt to switch patients from furosemide to torsemide?) would seem to lead to different study designs.
While the peer review process for funding TRANSFORM-HF was challenging and required modifying the approach, it ultimately led to a better design.
Read more about PRECIS-2 domains along the explanatory-pragmatic continuum of a clinical trial in the Living Textbook.
The Food and Drug Administration (FDA) is proposing a rule to allow for a waiver or alteration of informed consent for clinical investigations posing no more than minimal risk to human participants. This rule would align FDA regulations with the Common Rule, reduce burden and costs for Institutional Review Boards, and be expected to lead to advances in healthcare.
“We expect benefits in the form of healthcare advances from minimal risk clinical investigations and from harmonization of FDA’s informed consent regulations with the Common Rule’s provision for waiver of informed consent for certain minimal risk research.” — Federal Register /Vol. 83, No. 221
Currently, FDA allows a waiver or alteration of consent only in life-threatening situations. If aligned with the Common Rule, a waiver or alteration would be allowed if the IRB finds and documents that 1) the research involves no more than minimal risk, 2) the rights and welfare of subjects will not be adversely affected, 3) the research could not practicably be carried out without a waiver, and 4) the participants will be provided with additional pertinent information after completion of the trial.
Penny Randall, MD, MBA
VP and Global Therapeutic Head, CNS
IQVIA
Topic
A New Path Forward for Using Decentralized Clinical Trials
Keywords
Decentralized clinical trials; Telemedicine; Mobile health; Clinical Trials Transformation Initiative; FDA
Key Points
Decentralized clinical trials (DCTs) are defined as those executed through telemedicine, mobile, or local healthcare providers (HCPs), using procedures that vary from the traditional clinical trial model; for example, shipping investigational medical product directly to the trial participant.
DCTs are not “all or nothing.” They exist in a broad continuum and can expand the reach of traditional clinical trial sites.
Potential benefits of DCTs apply to all trials in all disease areas but may offer particular advantages in rare diseases, where patients are generally limited in number or are highly geographically dispersed.
Mobile HCP training is similar to that required for standard investigative sites: Good clinical practice, protocol-specific training, human subject protections, data protection, and clinical trial billing.
Discussion Themes
Will a decentralized trial lead to less diverse patient populations as participants will need to be technology literate and have access to technology?
Decentralized clinical trial safety monitoring plans should not be held to a higher standard than with traditional trials unless merited by a particular circumstance. It is important to develop protocol-specific safety monitoring and communication escalation plans.
Kidney transplantation is the preferred treatment for patients with end-stage renal disease (ESRD), but an insufficient organ supply renders dialysis the only viable treatment option for most patients. Though clinical outcomes among patients receiving dialysis have improved modestly in recent years, annual rates of hospitalization and mortality remain unacceptably high, and quality of life is poor. Poor outcomes are driven primarily by increased risk of cardiovascular disease (CVD), but interventions that improve outcomes in the general population by targeting traditional CVD risk factors have mostly failed in patients with ESRD. Current clinical practice guidelines advocate aggressive treatment of high serum phosphate to near-normal levels using dietary phosphate binders and restrictive diets. The benefits of this approach, however, are unproven, the optimal serum phosphate target remains unknown, and potential harms of aggressive treatment have not been definitively identified.
The Pragmatic Trial of Higher vs. Lower Serum Phosphate Targets in Patients Undergoing Hemodialysis (HiLo) plans to address these clinically important questions in a large, pragmatic, cluster-randomized trial that will evaluate the effects of liberalizing the serum phosphate target (“Hi”) versus maintaining aggressive phosphate control (“Lo”) for patients receiving treatment with maintenance hemodialysis.
“The question at hand is something we grapple with on a daily basis in every dialysis facility across the country. Either answer will be important new information that will help us do a better job taking care of patients and hopefully improve their quality of life.”
HiLo is led by Myles Wolf, MD, of Duke University with support from the National Institute of Diabetes and Digestive and Kidney Diseases. Read more about HiLo.
Check out the new program materials from the Collaboratory:
Study information for the 6 new UG3 NIH Collaboratory Trials:
ACP PEACE: Improving Advance Care Planning in Oncology: A Pragmatic, Cluster-Randomized Trial Integrating Patient Videos and Clinician Communication Training
EMBED: Pragmatic Trial of User-Centered Clinical Decision Support to Implement Emergency Department-Initiated Buprenorphine for Opioid Use Disorder
GGC4H: Guiding Good Choices for Health (GGC4H): Testing Feasibility and Effectiveness of Universal Parent-Focused Prevention in Three Healthcare Systems
Nudge: Personalized Patient Data and Behavioral Nudges to Improve Adherence to Chronic Cardiovascular Medications
PRIM-ER: Primary Palliative Care for Emergency Medicine
HiLo: Pragmatic Trial of Higher vs. Lower Serum Phosphate Targets in Patients Undergoing Hemodialysis
In addition, the May 2018 Steering Committee Meeting materials are now available, including presentations from the UG3 and UH3 NIH Collaboratory Trials and the full-day intensive workshop “Embedded Pragmatic Clinical Trials of Therapeutic A vs. B Interventions.”
A recent study published in BMC Medicine found that many randomized controlled trials (RCTs) self-labeled as “pragmatic” were actually explanatory in nature, in that they assessed investigational medicines compared with placebo to test efficacy before licensing. Of the RCTs studied, one-third were pre-licensing, single-center, or placebo-controlled trials and thus not appropriately described as pragmatic.
Appropriately describing the design and characteristics of a pragmatic trial helps readers understand the trial’s relevance for real-world practice. The authors explain that RCTs suitably termed pragmatic compare the effectiveness of 2 available medicines or interventions prescribed in routine clinical care. The purpose of such pragmatic RCTs is to provide real-world evidence for which interventions should be recommended or prioritized.
The authors recommend that investigators use a standard tool, such as the CONSORT Pragmatic Trials extension or the PRECIS-2 tool, to prospectively evaluate the pragmatic characteristics of their RCTs. Use of these tools can also assist funders, ethics committees, and journal editors in determining whether an RCT has been accurately labeled as pragmatic.
The BMC Medicine article cites NIH Collaboratory publications by Ali et al. and Johnson et al., as well as the Living Textbook, in its discussion of pragmatic RCTs and the tools available to assess their relevance for real-world practice.
“Submissions of RCTs to funders, research ethics committees, and peer-reviewed journals should include a PRECIS-2 tool assessment done by the trial investigators. Clarity and accuracy on the extent to which an RCT is pragmatic will help [to] understand how much it is relevant to real-world practice.” (Dal-Ré et al. 2018)
In a new video in the Living Textbook, Dr. Greg Simon describes the differences between individual, cluster, and stepped-wedge randomization using props, including marbles, Play-Doh, and glassware.
“In the end, it’s all about randomly assigning who gets which treatment, or who gets which treatment when, so that we’re able to make some un-biased judgement about which treatment is really better.” —Greg Simon, MD
As part of their ongoing effort to improve the speed and efficiency of conducting clinical trials, the NIH-FDA Joint Leadership Council has created a draft clinical trial protocol template. The template contains instructional and sample text intended to assist NIH-funded investigators in writing protocols for phase 2 or 3 clinical trials that require Investigational New Drug (IND) or Investigational Device Exemption (IDE) applications. Feedback is sought from investigators, investigator-sponsors, institutional review board members, and other stakeholders involved in protocol development and review.
Our goal is to provide an organized way for creative investigators to describe their plans so that others can understand them. – Dr. Pamela McInnes, NIH
Details on the rationale and development of the protocol template are on these blog posts:
Notice Number: NOT-OD-16-043. Responses accepted through April 17, 2016.
You can access the template document as well as a template shell, comment form, and other resources at NIH’s Clinical Research Policy website.
The National Patient-Centered Clinical Research Network (PCORnet) has recently made a draft protocol for its first randomized clinical trial available for stakeholder review. Researchers, clinicians, patients and the public are all invited to read the current draft of the study protocol and provide comments and feedback.
The ADAPTABLE Study (PDF), which will investigate whether lower- or higher-dose aspirin is better for preventing heart attack and stroke in patients at risk for heart disease, is PCORnet’s first randomized pragmatic clinical trial. Designed to leverage PCORnet’s Clinical Data Research Networks (CDRNs) and Patient-Powered Research Networks (PPRNs), the trial will serve as twofold purpose: answering a clinical question of direct importance for patients, families, and healthcare providers, and serving as a demonstration of PCORnet’s capabilities in conducting clinical research on a national scale.
Links to the proposed study protocol, a survey tool for capturing feedback, and other information about ADAPTABLE Study, including press releases, fact sheets, and infographics, are available at the link below:
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.