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.
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 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 Demonstration Projects:
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: Pragmatic Trial of Parent-Focused Prevention in Pediatric Primary Care: Implementation and Adolescent Health Outcomes in Three Health Systems (Guiding Good Choices for Health)
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 Demonstration Projects 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:
The Active Bathing to Eliminate (ABATE) Infection trial (ClinicalTrials.gov #NCT02063867) has completed its intervention phase—the first NIH Health Care Systems Research Collaboratory UH3 Demonstration Project to reach this major milestone. The large-scale, cluster-randomized pragmatic clinical trial (PCT) was designed to assess an approach for reducing multidrug-resistant organisms and hospital-associated infections (HAIs) in nearly 200 non-critical care hospital units affiliated with Hospital Corporation of America (HCA) across the United States.
The ABATE study is led by principal investigator Dr. Susan Huang of the University of California, Irvine, who stated “We are elated to reach the successful completion of the trial thanks to an incredible investigative team at HCA, Harvard Pilgrim Health Care, Rush University, the University of Massachusetts Amherst, and UC Irvine. We look forward to what the trial data will tell us and hope that we can continue to find effective ways to protect patients from infection.”
In the ABATE study, patients hospitalized in non-critical care units were bathed either according to the hospital unit’s usual care procedures (the control group) or bathed with the topical antibacterial agent chlorhexidine (plus nasal administration of the antibiotic mupirocin for those patients who were colonized or infected with, or had a history of methicillin-resistant Staphylococcus aureus [MRSA] [the intervention group]). The study investigators will compare the number of unit-attributable, multidrug-resistant organisms in clinical cultures between the study arms; these organisms include vancomycin-resistant enterococci (VRE), MRSA, and gram-negative bacteria. In addition, the investigators will compare the number of unit-attributable infections in the bloodstream and urinary tract (all pathogens) and Clostridium difficile infections. Cultures were collected at baseline and post intervention and will be assessed to determine whether resistance emerged to decolonization products.
“We are elated to reach the successful completion of the trial thanks to an incredible investigative team at HCA, Harvard Pilgrim Health Care, Rush University, the University of Massachusetts Amherst, and UC Irvine.We look forward to what the trial data will tell us and hope that we can continue to find effective ways to protect patients from infection.”
Healthcare-associated infections caused by common bacteria, including MRSA and VRE, are a leading cause of preventable illness and death in the United States and are associated with upward of $6.5 billion in annual healthcare costs. Although these bacteria normally live on the skin or in the nose, under certain circumstances they can cause serious or even life-threatening infections. Hospitalized patients who are ill or who have weakened immune systems are especially at risk for such infections. Because these pathogens are resistant to many antibiotics, they can be difficult to treat.
In intensive care units (ICUs), reducing the amount of such bacteria (a process referred to as decolonization) by treating patients’ skin with chlorhexidine and their noses with mupirocin ointment has been shown to reduce MRSA infections and all-cause bacteremias. However, relatively little is known about the effects of decolonization in hospital settings outside of critical care units, although this is where the majority of such infections occur. The ABATE trial, in contrast, is testing its bathing and decolonization strategy in adult medical, surgical, oncology, and step-down units (pediatric, psychology, peri-partum, and bone marrow transplantation units were excluded).
Over the course of the study, more than a million showers and baths were taken, and all sites have completed the intervention. The next steps for the ABATE investigators are to finish strain collection over the coming weeks, and then clean, validate, and analyze the data over the coming months.
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:
Dr. Greg Simon and the Suicide Prevention Team have enrolled the first participants in the Pragmatic Trial of Population-Based Programs to Prevent Suicide Attempt. This groundbreaking study was developed by researchers at Group Health Cooperative in Seattle, Washington, Health Partners Medical Group in Minnesota, and Kaiser Permanente of Colorado, in collaboration with patients who have experienced suicidal thoughts or survived suicide attempts themselves.
Over 9 million adults in the United States experience suicidal thoughts, and more than 1 million adults attempt suicide each year. However, patients at risk for suicidal behavior are not routinely identified, and successful interventions for depression and suicide are not routinely implemented. New evidence suggests that patients who report frequent thoughts of death or self-harm on a commonly-used depression questionnaire are at higher risk for suicide attempt and death over the following year.
This study aims to address the significant problem of suicide by identifying patients who are at risk for suicidal behavior and testing two suicide prevention strategies. Patients at participating institutions will complete a standard depression severity questionnaire during routine clinical care, and the results will be stored in their electronic health records (EHR). Investigators will use the responses in the EHR to identify at-risk individuals, and once identified, the patients will be randomly assigned to either usual care or to two treatment programs. The first is a collaborative care-management approach; the second is an online skills training program called “Now Matters Now,” which is designed to help people manage painful emotions and stressful situations.