A new section in the Living Textbook describes the considerations for using “real-world” data for inpatient-based event ascertainment. There are many sources for acquiring this information, and they have different time lags in their availability and varying degrees of error and bias. In order to use inpatient endpoints in pragmatic clinical trials, these factors must be understood during the design, conduct, and analysis phases of an embedded pragmatic clinical trial.
“The pragmatic trial community needs to collectively determine which endpoints are relevant for pragmatic trials, how they can be measured and validated, and how the accuracy of these measurement methods may impact hypothesis testing sample size estimates.” —Eisenstein et al 2019
Topics in the chapter include:
Pragmatic trial inpatient endpoints
Inpatient event data sources
Secondary data sources: EHR
Secondary data sources: claims
Case studies: ICD-Pieces, TRANSFORM-HF, ADAPTABLE, and TRANSLATE ACS
JoAnn E. Manson, MD, DrPH
Chief, Division of Preventive Medicine, Brigham and Women’s Hospital
Professor of Medicine and the Michael and Lee Bell Professor of Women’s Health
Harvard Medical School
Professor, Department of Epidemiology
Harvard T.H. Chan School of Public Health
The VITamin D and OmegA-3 TriaL (VITAL): Design and Results of a Large Pragmatic Trial
The VITAL pragmatic trial evaluated the effects of dietary supplements (vitamin D and omega-3) on reducing risk for developing cancer, heart disease, and stroke in the general population.
Study recruitment involved nationwide and targeted mailings, media reports, advertising, and brochures. Retention included participant newsletters, incentive gifts, and honoraria.
Findings included that neither omega-3s nor vitamin D significantly reduced the primary endpoints of major cardiovascular disease events or total invasive cancer. Omega-3s did reduce total myocardial infarction by 28%, with greatest reductions in those with low dietary fish intake and in African Americans.
VITAL’s hybrid design—remote or mail-based intervention plus serial in-clinic visits in a sample—has advantages in promoting quality and cost-efficiency.
Next steps for VITAL include continued follow-up for 5 years; genetic studies; and fostering new ancillary studies through nationwide collaborations.
A new perspective article by NIH Collaboratory investigators describes the unique, unexpected challenges researchers face when clinical practice guidelines and policies change during the conduct of a pragmatic clinical trial (PCT). The article was published online this week in Clinical Trials.
The NIH Collaboratory Demonstration Projects are PCTs that test interventions to address urgent public health problems. They involve hundreds to thousands of participants and generally include usual care as a control arm. During the course of these years-long trials, clinical practice guidelines and policies changed due to new evidence from observational studies, small trials, and shifting expert opinion. Such changes can have profound effects on usual care and, therefore, threaten the ability of the PCTs to address the questions they were designed to answer. Investigators must strike a balance between the primary ethical obligation to protect patients by adhering to new best-practice guidelines and policy and the secondary, yet crucial, obligation to develop high-quality evidence to improve care.
“PCTs are an important means of producing high-quality evidence needed to better inform clinical practice. However, when guidelines or reimbursement policies change during the conduct of a PCT, the ethical obligation to gather information to develop evidence-based practices may conflict with the primary ethical obligation to participants.” — Curtis et al, Clinical Trials, 2019
Based on their aggregate experience with the NIH Collaboratory, the authors provide broad recommendations and strategies for overcoming these challenges, including protecting the well-being of patients; involving stakeholders, health system leaders, and the entity charged with data and safety monitoring; and actively monitoring changes and site-level responses to them. If changes to the standard of care are merited, investigators should provide equal opportunity and support for the recommended changes. Finally, during the design phase, investigators should communicate with the entities charged with creating guidelines to see what is needed and to anticipate possible future changes.
“The ability to appropriately address the tension between modifications to clinical guidelines and the need to generate quality evidence to support those guidelines is a crucial consideration for the fulfilment of a learning health system.” — Curtis et al, Clinical Trials, 2019
Janet Prvu Bettger, ScD, FAHA
Duke Department of Orthopaedic Surgery
Duke Clinical Research Institute
The VERITAS Trial: Virtual Exercise Rehabilitation at the Intersection of Evidence, Implementation, and Policy
Rehabilitation; Virtual physical therapy; Patient outcomes; Physical therapy; Orthopaedic surgery; Total knee replacement; Digital technology; Telehealth
The VERITAS trial evaluated the effects of physical therapy–supported virtual exercise compared with traditional home- or clinic-based physical therapy after total knee replacement. Outcome measures included 90-day health service use costs; patient-centered outcomes; and differential improvement from 6 weeks to 3 months.
The Center for Connected Health Policy found that while most states currently have established telehealth policies for primary care providers, these often do not include physical or occupational therapists.
Tele-rehabilitation facilitates communication between the patient and physical therapist in real time. The VERA™ technology provides a virtual physical therapist assistant for patients and clinicians, offering a digital interface that includes patient education, longitudinal functional assessments, telehealth video conferencing, personalized exercises, and remote monitoring of patient progress.
Study results support effectiveness and safety hypotheses: that tele-rehabilitation is noninferior to traditional physical therapy with respect to range of motion, walking speed, pain, or rehospitalization. However, it was not shown that the intervention is noninferior with respect to falls after hospital discharge.
Because virtual physical therapy interventions can save total costs, prevent readmissions, and improve mobility, it will be important to expand access to tele-rehabilitation and to advance policies that include physical therapists.
Michael S. Avidan, MBBCh
Dr. Seymour and Rose T. Brown Professor of Anesthesiology
Chief, Division of Clinical and Translational Research
School of Medicine, Department of Anesthesiology
Washington University in St. Louis
The ENGAGES Pragmatic Trial and the Power of Negative Thinking
The ENGAGES pragmatic trial evaluated whether electroencephalogram-guided anesthetic administration decreases postoperative delirium incidence in older patients undergoing major surgery.
Delirium is a disturbance in consciousness or change in cognition for a short period of time as a consequence of a medical illness. 25% to 50% of older adults experience delirium after major surgery, and the number is even higher for ICU patients.
The ENGAGES trial found that, among older adults undergoing major surgery, EEG-guided anesthetic administration, compared with usual care, did not decrease the incidence of postoperative delirium.
Aside from the intensity of patient follow-up and the expertise needed to deliver the EEG-guided protocol, the ENGAGES study fulfilled the criteria for a pragmatic clinical trial as shown in PRECIS-2 ratings.
Clinicians participating in ENGAGES were not researchers but carried out the intervention on the ground. They understood the appeal of it and found it easy to implement.
With respect to study findings, instead of referring to “negative” or “null” findings, why not say, “this is what we found and these are interesting findings.”
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
TRANSFORMing Research for Patients With Heart Failure
Pragmatic clinical trial; Heart failure; PRECIS-2; Hospitalization; TRANSFORM-HF; Clinical equipoise; Electronic health records; National Heart, Lung, and Blood Institute (NHLBI)
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.
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
A New Path Forward for Using Decentralized Clinical Trials
Decentralized clinical trials; Telemedicine; Mobile health; Clinical Trials Transformation Initiative; FDA
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.
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.
Khaled El Emam, PhD
Department of Pediatrics, University of Ottawa
Children’s Hospital of Eastern Ontario Research Institute
Assessing and Reducing Risk of Re-identification When Sharing Sensitive Research Datasets
Clinical trials; Research ethics; Data security; Data sharing; Sensitive research data; De-identified data
The cycle of risk de-identification involves setting a risk threshold, measuring the risk, evaluating the risk, and applying transformations to reduce the risk.
The Safe Harbor method of de-identification (removal of 18 categories of data) is a legal minimum standard that does not take context into account, and may not be sufficient when sharing sensitive data publicly.
A higher standard for de-identification is the “Expert Determination” method, whereby an expert with contextual knowledge of the broader data ecosystem can determine whether the risk is “not greater than very small.”
With increasing concern about the risks of sensitive data sharing, it is important to be transparent with data participants and continue to build trust for data uses.
When is a dataset safe for sharing? What is the risk of re-identification, and how can we reduce the risk? Consider who you are releasing the data to and what other kinds of data might they have access to that could potentially lead to re-identification.
For more information on the de-identification of protected health information, visit the U.S. Department of Health and Human Services’s Guidance Regarding Methods for De-identification of Protected Health Information in Accordance with the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule.
John Hubbard, PhD
Healthcare Strategic Advisory Board
Barry Peterson, PhD
Cheryl Grandinetti, PharmD
Office of Compliance, Office of Scientific Investigations, Division of Clinical Compliance Evaluation
Center for Drug Evaluation and Research
Food and Drug Administration
Advancing the Use of Mobile Technologies for Data Capture & Improved Clinical Trials
Clinical trials; Mobile health technologies; Clinical Trials Transformation Initiative; CTTI; FDA; Data integrity
The goal of CTTI’s Mobile Clinical Trials program is to develop evidence-based recommendations that affect the widespread adoption and use of mobile technology in clinical trials for regulatory submission.
Potential benefits of using mobile technology include higher quality, patient-centric endpoints and fewer barriers to participation in clinical trials.
Data access issues to consider before selecting a mobile technology include:
How will the data generated by the mobile technology be accessed and used by the manufacturer?
What data will be provided by the manufacturer to the sponsor?
The mobile era creates new data security demands.
CTTI’s recommendations aim to help sponsors determine the right device to use, how to write the protocol for remote data capture, and how to protect and analyze the data.
Know what you want to measure before selecting the mobile technology. The appropriateness of the selection should be justified through verification and validation processes.
Ensure the authenticity, integrity, and confidentiality of data over its entire lifecycle.
To reduce risk in large trials, conduct feasibility studies before full implementation.