ethics

Grand Rounds April 21, 2023: Personalised Cooler Dialysate for Patients Receiving Maintenance Haemodialysis (MyTEMP): A Pragmatic, Cluster-randomised Trial (Amit Garg, MD, MA, FRCPC, FACP, PhD; Stephanie N. Dixon, PhD MSc)

Posted on by Elizabeth Mccamic

Speakers

Amit Garg, MD, MA (Education) FRCPC, FACP, PhD
Associate Dean, Clinical Research, Schulich School of Medicine and Dentistry
Lead, Institute for Clinical Evaluative Sciences Kidney, Dialysis and Transplantation Provincial Program
Director, Institute for Clinical Evaluative Sciences (ICES) Western Facility
Nephrologist, London Health Sciences Centre
Professor, Medicine, Epidemiology & Biostatistics, Western University

Stephanie N. Dixon, PhD MSc
Staff Scientist, Institute for Clinical Evaluative Sciences Kidney, Dialysis and Transplantation Research Program
Biostatistician, London Health Sciences Centre

 

Keywords

MyTEMP, Pragmatic Clinical Trials, Ethics, Biostatistics

 

Key Points

  • For each hemodialysis treatment clinicians typically set the temperature of dialysate on the machine to 36.5 or 37.0 degrees Celsius. The reasoning for this temperature is unclear, though it likely represents what was considered the average body temperature of most patients.
  • In a recent international survey of more than 270 centers, nearly half now use a cooler temperature dialysate in patient care of less than or equal to 36.0 degrees C. This change in practice is based on data that suggests the at cooler (vs. standard) temperature dialysate is beneficial. However, in two recent systematic reviews the overall quality of evidence for dialysate cooling was deemed low with a high risk of bias.
  • The MyTEMP trial is a pragmatic, cluster randomized controlled trial in Ontario, Canada, to determine if adopting a default center-wide policy of personalized cooler dialysate is superior to a standard temperature dialysate of 36.5 degrees C.
  • MyTEMP was innovative and pragmatic, implemented as part of a learning healthcare system, with covariate constrained randomization, registry-based, and embedded in routine care delivered by more than 2,000 nurses at 84 centers.
  • During the 4-year study period, about 8,000 patients were randomized for the personalized cooler dialysate and about 7,400 were randomized for the standard temperature dialysate. The mean temperature for the standard group was 36.4 degrees C, and the mean temperature for cooler group was 35.8 degrees C.
  • The primary composite outcome was cardiovascular mortality or hospital admission with MI, stroke, or heart failure. There is a high risk of these events in the hemodialysis population with a cumulative instance at 30% at 4 years. There was no appreciable difference in the estimate for the cooler temperature group. Additionally, the cooler temperature group reported a higher likelihood of discomfort.
  • The lack of cardiovascular benefit and higher likelihood of patient discomfort provides no justification to adopt cooler dialysate as a center-wide policy vs. use of 36.5 degrees. After MyTEMP, centers in Ontario stopped adopting colder temperature dialysate as a center-wide policy, and patients felt less discomfort during hemodialysis care.
  • Cluster randomized trials of hemodialysis center-wide policies raise complex ethical issues. Many patients who receive hemodialysis are vulnerable. A patient or their nephrologist could decide to opt-out of the randomly allocated center-wide default policy but could not opt out of the symptom data but not de-identified health records. The REB approved the MyTEMP request to use an altered patient consent process because the research was deemed of minimal risk to patients.
  • MyTEMP worked with patients and caregivers to develop the trial, and Kidney Patient and Family Advisory Councils guided the choice of additional outcomes. Participants were debriefed on the trial results.

Learn more

Read about the MyTEMP trial in The Lancet.

Read about the MyTEMP statistical analysis plan.

Discussion Themes

–We run into situations where we are talking to stakeholders and thinking about criteria for waiver of consent and it’s just not right. Where the risks and benefits are equal, but I wouldn’t want to be randomly assigned. There is a natural assertion of autonomy. Did some of these questions of autonomy vs. risk come up? I think it is very complex, and it is not black and white. You need to identify the principles before the process. In terms of the dialysis component, in routine care we get consent when we start treatment but there are many things in the background. As a clinician when I am providing care, I’m not discussing these concerns; we are talking about other things. Am I delivering great medicine when I’m not sure what to do here when there is practice variability?

Tags

#pctGR, @Collaboratory1

April 6, 2023: New Chapter of Living Textbook Describes the Ethical Considerations of Sharing Data From Embedded Pragmatic Clinical Trials

Posted on by Karen Staman

The NIH Pragmatic Trials Collaboratory published a new chapter of its Living Textbook of Pragmatic Clinical Trials this week. The chapter, “Ethical Considerations of Data Sharing in Pragmatic Clinical Trials,” describes human subjects research regulations that may impact sharing data from embedded pragmatic clinical trials (ePCTs) and the ethical considerations for respecting the interests of patients who become ePCT participants.

When data are collected with a waiver or alteration of informed consent, as is often the case in ePCTs, a person may be unaware they are participating in research and therefore could not  have consented to have their data used in future research. This suggests need for investigators and health systems to consider additional ways to fulfill the ethical obligation of respecting patient-participants when sharing their data from PCTs.

For more on the ethical considerations of ePCTs, see the chapters on Privacy Considerations; Identifying Those Engaged in Research; Consent, Waiver of Consent, and Notification; Collateral Findings; and Data and Safety Monitoring.

For more on data sharing and ePCTs, see the chapter on Data Sharing and Embedded Research.

 

March 23, 2023: AJOB Calls for Peer Commentaries on Ethics in Pragmatic Trials

Posted on by Damon Seils

American Journal of Bioethics cover imageThe American Journal of Bioethics (AJOB) this week issued a call for peer commentaries for a forthcoming special issue on pragmatic clinical trials. Both of the target articles for the special issue are from the NIH Pragmatic Trials Collaboratory’s Ethics & Regulatory Core.

Unlike AJOB‘s typical Open Peer Commentaries, commentaries for the special issue may be written either in response to the 2 target articles or on the topic of pragmatic trials in general. Proposals of approximately 1 paragraph are due Friday, April 7, and should be submitted via the AJOB editorial website.

After evaluating the proposals, the journal’s editorial office will contact authors to inform them of whether their proposal has been selected to be submitted as a full Open Peer Commentary. Invited commentaries will be due Wednesday, April 26. Authors are limited to a single Open Peer Commentary.

Target articles:

  • “Think Pragmatically: Investigators’ Obligations to Patient-Subjects When Research is Embedded in Care” by Stephanie Morain and Emily Largent: Growing interest in embedded research approaches—where research is incorporated into clinical care—has spurred numerous studies to generate knowledge relevant to the real-world needs of patients and other stakeholders. However, it also has presented ethical challenges. An emerging challenge is how to understand the nature and extent of investigators’ obligations to patient-subjects. Prior scholarship on investigator duties has generally been grounded upon the premise that research and clinical care are distinct activities, bearing distinct duties. Yet this premise—and its corresponding implications—are challenged when research and clinical care are deliberately integrated. After presenting three case studies from recent pragmatic clinical trials, we identify six differences between explanatory trials and embedded research that limit the application of existing scholarship for ascertaining investigator duties. We suggest that these limitations indicate a need to account for the implications of usual care and to move beyond a narrow focus on the investigator-subject dyad, one that better reflects the team- and institution-based nature of contemporary health systems.
  • “Do Clinicians Have a Duty to Participate in Pragmatic Clinical Trials?” by Andrew Garland, Stephanie Morain, and Jeremy Sugarman: Clinicians have good moral and professional reasons to contribute to pragmatic clinical trials (PCTs). We argue that clinicians have a defeasible duty to participate in this research that takes place in usual care settings and does not involve substantive deviation from their ordinary care practices. However, a variety of countervailing reasons may excuse clinicians from this duty in particular cases. Yet because there is a moral default in favor of participating, clinicians who wish to opt out of this research must justify their refusal. Reasons to refuse include that the trial is badly designed in some way, that the trial activities will violate the clinician’s conscience, or that the trial will impose excessive burdens on the clinician.

Open Peer Commentaries are typically between 500 and 1500 words and contain no more than 10 references. A guide to writing an Open Peer Commentary is available under the Resources section “Instructions and Forms” on the AJOB editorial website.

Grand Rounds Ethics and Regulatory Series February 10, 2023: Informing and Consenting: What Are the Goals? (P. Pearl O’Rourke, MD; David S. Wendler, PhD, MA; Miguel Vazquez, MD; P. Michael Ho, MD, PhD)

Posted on by Elizabeth Mccamic

Speakers

Pearl O’Rourke, MD (retired)
Harvard Medical School

David S. Wendler, PhD, MA
Senior Researcher
Head, Section on Research Ethics
Department of Bioethics
NIH Clinical Center

Miguel Vazquez, MD
Professor of Internal Medicine
UT Southwestern Medical Center

Michael Ho, MD, PhD
Professor of Medicine
University of Colorado School of Medicine

 

 

Keywords

Ethics and Regulatory, Consent, Waiver of Consent, Notification

 

Key Points

  • Using informed consent addresses two of the Belmont Principles, respect for persons by informing and autonomy by allowing choice. The regulations recognize that consent is not always possible and allow for alteration, where some of the required elements of informed consent can be altered or not included, and waiver of consent, where no consent is required.
  • It is not uncommon to see waivers of consent in pragmatic clinical trials because many trials meet minimal risk criteria and involve numerous institutions and thousands of subjects. There are also concerns that obtaining consent could alter the “real-world” medical care being studied, may introduce an alteration of routine care, may introduce bias or make research impossible to conduct.
  • Informed consent is not the only way to inform. Think about methods of notification, from detailed study-specific information to a general statement that research is being conducted. There are consequences of notification, such as logistics and cost. If you are notifying, when do you offer an opt-out option and what do you do when potential subjects have questions or do not want to be in the research?
  • ICD-Pieces studied patients with chronic kidney disease (CKD), diabetes and hypertension. The intervention was to facilitate delivery of guideline-based care. The study had a waiver of informed consent. The study used a patient-information sheet to inform patients about the research, how patient data would be handled, and an option to opt-out of including their data in the study.
  • The Nudge Study is a pragmatic clinical trial seeking to improve medication adherence to patients’ already-prescribed cardiovascular medications through a series of theory-based text or voice messages that served as “nudges.” The study mailed patients an opt-out packet that included an introductory letter from the site PI, a FAQ sheet and opt-out form. If they did not opt-out within a month, we would monitor their prescription refills and send a nudge if one went unfilled for more than 7 days.
  • Participants always know some things and agree to some extent. When not getting full regulatory consent, the relevant questions are: What should they know? What should they agree (not object) to?

 

Discussion Themes

– How did the various types of notifications in the ICD-Pieces study impact opt-outs? The patient population and geography across sites was very different. The opt-outs were also very different. It was up to individuals how to deliver or make information about the study available than other sites in the study. It would be difficult for us to say a poster or letter is better.

– Whichever type of notification was used, did you tell people they could opt-out and explain how they could opt-out and give them assurance that opting-out would not impact care? For ICD-Pieces, there was a bullet that stated clearly that patients could opt-out and a phone number to opt-out. There was also a statement that said they would receive the best care from their provider. For NUDGE, there was the initial letter where patients could opt-out by sending a postcard and they could also opt-out in response to the text messages. Opt-outs were different across health systems.

 

Tags

#pctGR, @Collaboratory1

February 8, 2023: Goals of Informing and Consenting, This Friday in the Ethics and Regulatory Grand Rounds Series

Posted on by Damon Seils

Headshots of Pearl O'Rourke, Dave Wendler, Miguel Vazquez, and Michael HoThis Friday’s PCT Grand Rounds will feature the next installment of our special series, Ethical & Regulatory Dimensions of Pragmatic Clinical Trials. Pearl O’Rourke, Dave Wendler, Miguel Vazquez, and Michael Ho will present “Informing and Consenting: What Are the Goals?”

The Grand Rounds session will be held on Friday, February 10, 2023, at 1:00 pm eastern.

O’Rourke is the director of human research affairs at Partners HealthCare Systems in Boston and an associate professor of pediatrics at Harvard. She serves as cochair of the NIH Collaboratory’s Ethics and Regulatory Core. Wendler is the head of the Section on Research Ethics in the NIH Clinical Center and a member of the Ethics and Regulatory Core. Vazquez is a professor of internal medicine at UT Southwestern Medical Center and the principal investigator of the ICD-Pieces NIH Collaboratory Trial. Ho is a professor medicine at the University of Colorado and the principal investigator of the Nudge NIH Collaboratory Trial.

Join the online meeting.

This special Grand Rounds series features moderated webinar discussions with panels of experts. The sessions focus on a range of topics, including the ethics of data sharing; ethical and regulatory considerations in the design and conduct of pragmatic trials; pragmatic research involving patients with dementia; and the use of waivers and alterations of consent.

Read the full program.

Podcast January 25, 2023: Ethical Considerations When Vulnerable Populations are Subjects in Pragmatic Clinical Trials (Emily A. Largent, JD, PhD, RN)

Posted on by Lauren Stewart

This podcast continues the discussion with Dr. Emily Largent as she discusses ethical considerations for vulnerable populations participating in pragmatic clinical trials. Click on the recording below to listen to the podcast.

Want to hear more? View the full Grand Rounds presentation. For alerts about new episodes, subscribe free on Apple Podcasts or SoundCloud. Read the transcript.

February 6, 2023: Postdoctoral Fellowship Available in Ethics and Regulatory Aspects of Pragmatic Trials

Posted on by Damon Seils

Johns Hopkins Berman Institute of Bioethics logoThe Johns Hopkins Berman Institute of Bioethics is accepting applications for its 2023-2024 Postdoctoral Fellowship in the Ethics and Regulatory Aspects of Pragmatic Clinical Trials.

From the announcement:

The Johns Hopkins Berman Institute of Bioethics invites applications for a Postdoctoral Fellowship in the Ethics and Regulatory Aspects of Pragmatic Clinical Trials. This position includes pursuing independent research, working alongside faculty members involved with the ethics and regulatory aspects of large-scale pragmatic clinical trials and participating in the Hecht-Levi Postdoctoral Fellowship in Bioethics.

The postdoctoral fellow is expected to pursue one or more projects addressing the ethics and regulatory aspects of pragmatic clinical trials in collaboration with Berman Institute faculty members. The Fellow will actively engage with the Ethics and Regulatory Cores of the [NIH Pragmatic Trials Collaboratory] and the Pragmatic and Implementation Studies for the Management of Pain to Reduce Opioid Prescribing (PRISM) Resource Coordinating Center.

As a member of the Hecht-Levi cohort of Bioethics Postdoctoral Fellows at the Berman Institute, the Fellow will have access to Berman Institute faculty and resources, including weekly seminars, presentations, discussions with leading academics and policy makers, professional development training, outreach efforts, and teaching opportunities commensurate with experience and background.

Read the full information about the fellowship. Applications will be considered on a rolling basis through April 30, 2023.

Grand Rounds Ethics and Regulatory Series January 13, 2023: Ethical Considerations When Vulnerable Populations are Subjects in Pragmatic Trials (Emily A. Largent, JD, PhD, RN)

Posted on by Elizabeth Mccamic

Speakers

Emily A. Largent, JD, PhD, RN
Emanuel & Robert Hart Assistant Professor of Medical Ethics and Health Policy
Department of Medical Ethics and Health Policy
University of Pennsylvania Perelman School of Medicine

 

 

Keywords

Ethics, Vulnerable Populations

 

Key Points

  • Vulnerability guidelines and regulations often refer to groups such as pregnant people, children, and prisoners. But this might obscure heterogeneity within groups, intersecting sources of vulnerability, and other vulnerable participants, such as people with dementia.
  • One definition of vulnerability is “an identifiably increased likelihood of incurring additional or greater wrongs,” as a result of research participation. We need to ask how might researchers wrong participants, and one way to think about this is how might researchers fail to discharge duties to them?
  • The Belmont Report lays out three principals of duties researchers have: respect for persons, beneficence, and justice. What is entailed by each of these duties? Respect for persons involves seeking voluntary informed consent or, if participants lack capacity, seek permission from a surrogate, and respect privacy. Beneficence involves minimizing risks, and ensuring they stand in reasonable relation to potential benefits. Justice involves ensuring the burdens and benefits of research are fairly distributed.
  • In a review of studies, researchers identified the ways participants in a particular study might be wronged and identified corresponding protections, such as conducting a capacity assessment if we are worried about participants having an inadequate understanding in informed consent. Going through this process helps researchers see where vulnerabilities might arise and how to address them.
  • The issue of informed consent comes up often with vulnerable populations that have dementia. Researchers seeking to enroll people living with dementia need a plan for assessing participants’ capacity to consent to research participation. When prospective participants lack capacity, researchers should identify a surrogate to give permission for enrollment and still find ways of involving the person with diminished capacity in research-related decision-making. Caregivers may also need to be enrolled and give their own consent as they may be more involved as the participant’s cognitive impairment worsens.
  • Many pragmatic clinical trials are conducted with waivers of informed consent, but when vulnerable populations are subjects in research, there may still be additional important considerations, such as outreach, identifying caregivers through the medical record, and being certain a diagnosis of dimension has already been disclosed to the patient.
  • It is ethically acceptable and imperative to enroll vulnerable subjects in research, but when they are enrolled it is important that we think about their vulnerability in systematic ways so that we know not only what they are vulnerable to but how we can protect them. Issues of consent and considerations for waivers of consent are particularly important for this population.

Learn more

Ethical Challenges in Conducting Research Using a Waiver of Informed Consent with People Living with Dementia.

Discussion Themes

- You noted that the criteria of waivers and alterations gets left out. How do you think about the fact that people are uncomfortable with waivers and that notification may turn people off? Any time we are not notifying because we might upset people is a sign we need to think more carefully how we are going to approach it. When you use a waiver, you need to go in and explain why a waiver is being used and why there was no meaningful way to opt out. Hopefully you can share what has been learned.

- Sometimes consenting in a “good moment” feels stressful because they may forget that they consented. You need to have a plan in place for assessing capacity and ability to consent. Take time to check in with the participant and caregiver to make sure they are on board and assess their continued willingness to participate.

-What if a patient has capacity to consent but their surrogate disagrees? That’s difficult. Take the individual’s consent as word; however, if they are dependent on the surrogate for transportation, etc., it can be a barrier.

Tags

#pctGR, @Collaboratory1

January 11, 2023: Ethics and Regulatory Grand Rounds Series Addresses Vulnerable Populations in Pragmatic Trials This Friday

Posted on by Damon Seils

Headshot of Dr. Emily LargentThis Friday’s PCT Grand Rounds will feature the next installment of our special series, Ethical & Regulatory Dimensions of Pragmatic Clinical Trials. Emily Largent will present “Ethical Considerations When Vulnerable Populations are Subjects in Pragmatic Trials.”

The Grand Rounds session will be held on Friday, January 13, 2023, at 1:00 pm eastern.

Dr. Largent is the Emanuel and Robert Hart Assistant Professor of Medical Ethics and Health Policy at the University of Pennsylvania. Her work explores ethical and regulatory aspects of human subjects research as well the social, legal, and ethical considerations that arise when research findings are translated into care.

Join the online meeting.

This special Grand Rounds series features moderated webinar discussions with panels of experts. The sessions focus on a range of topics, including the ethics of data sharing; ethical and regulatory considerations in the design and conduct of pragmatic trials; pragmatic research involving patients with dementia; and the use of waivers and alterations of consent.

Read the full program.

Grand Rounds Ethics and Regulatory Series December 9, 2022: The Stepped Wedge Cluster Randomized Trial: Friend or Foe? (Monica Taljaard, PhD; David Magnus, PhD)

Posted on by Elizabeth Mccamic

Speakers

Monica Taljaard, PhD
Senior Scientist, Clinical Epidemiology Program
Ottawa Hospital Research Institute
Full Professor, Epidemiology and Community Medicine
University of Ottawa

David Magnus, PhD
Thomas A. Raffin Professor of Medicine and Biomedical Ethics and Professor of Pediatrics, Medicine, and by courtesy of Bioengineering
Director, Stanford Center for Biomedical Ethics
Associate Dean for Research

 

 

Keywords

Ethics, Stepped Wedge Cluster Randomized Trial, Study Design

 

Key Points

  • There are two main types of clinical trials: patient randomized trial and cluster randomized trial (CRT). The patient randomized trial is always preferable; cluster randomized trials should only be used when there is no other choice because CRTs will always require a larger sample size, have higher risks of bias, be more vulnerable to chance imbalance between arms, and are more complicated to design and analyze.
  • There are several good reasons to adopt a cluster randomization trial, including that the intervention is a cluster-level intervention or the research question of interest pertains to cluster-level effects.
  • If a cluster randomized trial is justified there are different types of CRT designs, the parallel arm CRT, parallel arm before and after CRT, cluster cross-over, and stepped wedge. Investigators should provide a justification for choice of stepped wedge CRT.
  • Five methodological arguments for stepped wedge CRTs are to improve rigor, to facilitate recruitment, to reduce the required sample size, to simplify logistics, and to reduce bias; however, most methodological arguments in favor of stepped wedge trials have a counter argument. Trialists should work with a biostatistician to come up with the most scientifically robust design given the practical constraints of the study. In most cases, a parallel arm or cluster cross would be a better choice.
  • In a study of more than 100 stepped wedge cluster randomized trials, the most common reason for the design was to be able to make the intervention available to all clusters by the end of the trial based on ethical or equity grounds rather than anything methodological.
  • During the Ebola crisis, the ethical argument for stepped wedge CRTs was that anything involving a placebo in the control arm was automatically considered unethical if the intervention arm holds a chance of benefit. This led to a shift to stepped wedge design trials, but in Ebola there was no evidence that benefits outweighed the harms of proposed therapeutics and vaccines and there was confusion that all participants get the intervention in a stepped wedge CRT, where each cluster may get the intervention but all participants may not get the intervention, depending on the design.
  • Arguments in favor often confuse individual belief in the benefit of intervention with equipoise (which requires consensus in the field that the intervention is of benefit). If truly not in equipoise, delay in providing the intervention is no more justified than the placebo. True protection is clinical equipoise and it is neutral between stepped wedge CRT and parallel research designs.

 

Discussion Themes

– Should we be allowing stepped wedge trials in the Collaboratory? As a statistician, I agree but it’s important to do the extra work and look at alternative designs. If stepped wedge design is the best option, you have to ensure that the analysis is robust and sound and that there is not recruitment bias. The policy level point is well taken; saying that they are prohibited might be too strong, but you do need a justification or rationale for stepped wedge design, especially over parallel.

– Could stepped wedge be a good design for implementation trials? It’s still important to look at how effective it is and is the juice worth the squeeze in this context? You should use the best statistical methods to answer the question you are trying to answer.

Tags

#pctGR, @Collaboratory1