June 14, 2019: Good Clinical Practice Guidance and Pragmatic Trials: Balancing the Best of Both Worlds in the Learning Health System (Robert Mentz, MD)

Speaker

Robert J. Mentz, MD, FACC, FAHA, FHFSA
Associate Professor
Director, Duke Cooperative Cardiovascular Society
Associate Program Director, Duke Cardiovascular Disease Fellowship
Duke University Medical Center and Duke Clinical Research Institute

Topic

Good Clinical Practice Guidance and Pragmatic Trials: Balancing the Best of Both Worlds in the Learning Health System

Keywords

International Council for Harmonization (ICH); Good clinical practice (GCP); Learning health system; Pragmatic clinical trials; Institutional review board (IRB); Research oversight; Regulatory issues; Quality by design (QbD)

Key Points

  • Good clinical practice (GCP) guidance details the responsibilities, procedures, and recording that are necessary for appropriate trial conduct; for example, conducting the trial in accordance with an IRB-approved protocol with appropriate adverse event monitoring and reporting.
  • There is an urgent need to streamline randomized trials. Key obstacles are lack of transparency, lack of representativeness, and lack of evidence of competence.
  • In the United States, clinical investigators must abide by guidance from FDA, HHS, and ICH-GCP. Yet it is hard for investigators to keep track and to know how GCP applies to their study.
  • GCP as an overall construct is useful, but it does not deal well with issues particular to pragmatic trials or trials outside the FDA-regulated world.

Discussion Themes

With embedded pragmatic trials, informed consent is more nuanced. New considerations and approaches for consent have arisen since ICH GCP first came into effect.

Establishing quality by design will take time, effort, and educating IRBs to understand how QbD can be used to avoid errors in a trial and collect data that is fit-for-purpose.

It’s crucial that trials address an important question, answer that question reliably, and keep participants safe.

Read more about Dr. Mentz’s study of GCP and pragmatic trials.

Tags

#pctGR, @Collaboratory1, @RobMentz

April 22, 2019: TiME Trial Confirms Feasibility of Embedding Large Pragmatic Trials in Clinical Care

Laura Dember

The primary results of the Time to Reduce Mortality in End-Stage Renal Disease (TiME) trial, an NIH Collaboratory Demonstration Project, were published online this month in the Journal of the American Society of Nephrology. The study confirmed the feasibility of embedding a large pragmatic clinical trial in clinical care delivery.

Although maintenance hemodialysis has long been a staple of care for patients with end-stage renal disease, there are limited data from clinical trials to inform optimal approaches, including the optimal duration of hemodialysis sessions. The TiME trial investigators, in partnership with 2 large dialysis provider organizations, evaluated the effects of a longer hemodialysis session duration on mortality and hospitalization rate among more than 7000 patients receiving care in 266 dialysis facilities.

The TiME trial was discontinued early (median follow-up, 1.1 years) because there was an insufficient difference in mean hemodialysis session duration between the intervention group and the usual care group. The investigators observed no reduction in mortality or hospitalization rate in either group.

Despite ending early, the trial met important objectives for informing the implementation of large pragmatic clinical trials embedded in health care systems. In a large multicenter study with no onsite research personnel, the investigators quickly and efficiently enrolled a large number of participants using an opt-out consent approach. The study data were obtained entirely from the electronic health and administrative records of the partnering dialysis provider organizations and were generated from routine clinical care delivery.

“The TiME trial provides an important foundation for future pragmatic trials in dialysis as well as in other settings,” said Dr. Laura M. Dember of the University of Pennsylvania Perelman School of Medicine, the principal investigator of the TiME trial.

The TiME trial was supported within the NIH Collaboratory by a cooperative agreement from the National Institute of Diabetes and Digestive and Kidney Diseases and received logistical and technical support from the NIH Collaboratory Coordinating Center. Download a study snapshot about the TiME trial, and learn more about the NIH Collaboratory Demonstration Projects.

January 18, 2019: Pragmatic Trials in End-stage Renal Disease (ESRD): HiLo (Myles Wolf, MD, MMSc)

Speaker

Myles Wolf, MD, MMSc
Charles Johnson, MD, Professor of Medicine
Chief, Duke Nephrology
Duke University School of Medicine

Topic

Pragmatic Trials in End-stage Renal Disease (ESRD): HiLo

Keywords

Pragmatic clinical trial; HiLo; End-stage renal disease; ESRD; Kidney disease; Hypophosphatemia; Serum phosphate; Hemodialysis; A vs B trials; Clinical equipoise; National Institute of Diabetes and Digestive and Kidney Diseases; NIDDK

Key Points

  • With high event rates and few proven therapies, patients with end-stage renal disease (ESRD) are in desperate need of clinical innovation.
  • The NIH Collaboratory’s HiLo Demonstration Project is a pragmatic, multicenter, cluster-randomized, open-label, noninferiority outcomes trial that will compare effects of two different phosphate management strategies in patients with ESRD.
  • The study hypothesizes that, compared with strict phosphate control, less stringent control will yield noninferior rates of all-cause hospitalization among patients with ESRD undergoing hemodialysis, as well as reduce the risk of all-cause mortality, enhance markers of diet and nutrition, and improve quality of life.

Discussion Themes

Dialysis clinic dieticians will have a pivotal role in implementing HiLo. They have established a rapport with patients and are among the most motivated caregivers on dialysis teams.

Individual patient-level informed consent for the HiLo trial will be via internet-linked tablets, paper forms, and educational materials including a video. Benefits of obtaining consent include promoting adherence, direct study updates and newsletters to participants, and ability to collect additional data without involving onsite study staff.

HiLo will be the first definitive clinical trial-grade evidence for opinion-based guidelines for phosphate management. Thus, results of HiLo have the potential to rapidly influence ESRD clinical practice.

Read more about the HiLo Demonstration Project in the Living Textbook.

Tags

#ESRD, #pctGR, @Collaboratory1, @DCRINews, @DukeKidney

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.

October 1, 2018: Meeting Minutes from NIH Collaboratory’s Ethics and Regulatory Core Discussions with the New Demonstration Projects

Meeting minutes and supplementary materials are available that summarize discussions related to the ethics and regulatory issues associated with each of the new UG3 Demonstration Projects. These discussions, which took place by teleconference, included representation from study principal investigators and study teams, members of the NIH Collaboratory Ethics and Regulatory Core, NIH staff, and NIH Collaboratory Coordinating Center personnel as well as some IRBs responsible for oversight of the projects.

February 5, 2018: Clinical Effectiveness Research Innovation Collaborative (CERIC) Aims to Streamline Oversight for Learning Activities

One of the Clinical Effectiveness Research Innovation Collaborative (CERIC) group’s priority actions is to create a supportive regulatory environment for learning activities that aim to provide evidence for healthcare improvement. In support of this goal, the National Academy of Medicine hosted a day-long meeting on January 25, 2018, to propose and communicate streamlined approaches for oversight of learning activities, informed consent, and privacy protection. The meeting attendees included key representatives from health systems, institutional review boards, patient groups, the Office for Human Research Protections (OHRP), and privacy experts. Dr. Richard Platt is a co-chair of the collaborative, and Dr. Jeremy Sugarman was part of a panel on the revisions to the Common Rule. Background materials for the meeting included articles from the Collaboratory Regulatory/Ethics Core’s special series in Clinical Trials.  Meeting attendees sought to clarify regulatory barriers to embedding continuous learning activities in health systems, practices, and health plans and also to suggest possible solutions that would help streamline approaches in support of an enduring learning health system.

Participants discussed the grey area between quality improvement and research, and the differences in regulations for each. One critical issue that was identified is that the foundations of the current regulatory environment are built on the Belmont Report, a forty-year old document originally intended to prevent incidents like the Tuskegee Syphilis Study from ever happening again. While the ethical principles in the Belmont Report—respect for persons, beneficence, and justice—are still relevant today, much has changed since the original writing of the document. Healthcare is increasingly complex and conducted in a digital world, and bold ideas may be needed to create an alternate system for the betterment of all. Next steps for the group include the creation of a document that describes a framework for learning activities and includes a series of case examples for OHRP to review in order to provide clarification and answers to frequently asked questions (FAQs).

 

January 18, 2018: Implementation of Revised Common Rule Delayed

On January 17, 2018, the Department of Health and Human Services and 15 other federal departments and agencies announced a delay to both the effective and compliance dates for the revisions to the “Federal Policy for the Protection of Human Subjects” (also known as the Common Rule). Most provisions in the revised Common Rule were scheduled to go into effect on January 19, 2018. The Interim Final Rule announced a delay until July 19, 2018, with the option for further delay, to give institutions additional time to prepare to implement the revisions. Before July 19, 2018, institutions may only begin implementing provisions of the revised Common Rule that do not conflict with the pre-2018 Common Rule.

A notice of proposed rulemaking (NPRM) is also in development to seek public comment on a proposal for further delay in the required implementation of the revised Common Rule (for example, until January 21, 2019). A decision will be made after considering public comments.

November 20, 2017: NIH Collaboratory Core Working Group Interviews: Reflections from the Ethics and Regulatory Core

We recently asked Drs. Jeremy Sugarman and Kevin Weinfurt, Co-chairs of the Ethics and Regulatory Core, to reflect on the first 5 years of the Core as well as on the challenges ahead. The regulatory and ethical landscape for pragmatic clinical trials was not well defined when the Core began 5 years ago, and the Core helped to map and navigate the emerging landscape to enable the implementation of Demonstration Projects in ways that satisfied ethical and regulatory criteria.

“The Core’s work has led to the creation of a substantial body of scholarship contributing to the ongoing policy and ethics debates about pragmatic clinical trials.” – Drs. Sugarman and Weinfurt

Download the interview (PDF).

CTTI Releases 2015 Annual Report


The Clinical Trials Transformation Initiative (CTTI) has released its Annual Report for 2015. The report describes major achievements from the previous year, including new recommendations and related tools and checklists for improving the safety, efficiency, and overall quality of clinical research.

Cover page of CTTI Annual Report with embedded link to CTTI webpage containing report.
2015 CTTI Annual Report

Highlights of the 2015 Annual Report include recommendations on topics including:

  • Ethics review processes
  • Good Clinical Practice training for trial investigators
  • Research protocol design
  • Engagement of patient groups as equal partners in clinical research
  • Informed consent processes
  • Safety reporting systems for research participants

A public-private partnership whose many stakeholders include government agencies, advocacy groups, professional societies, academic research organizations, and representatives from the medical products industry, CTTI’s mission is to “identify and promote practices that will increase the quality and efficiency of clinical trials.”

Previous Annual Reports are also available on the CTTI website.


 

Recent Collaboratory Publications on Research Ethics


The American Journal of Bioethics has recently published three articles authored by members of the Regulatory/Ethics core group describing various questions related to research on medical practices:

  • Is shared decision making an appropriate analytic frame for research on medical practices (Sugarman 2015) discusses the role of shared decision making (SDM) in research on medical practices. The author cautions that “while SDM is in many ways similar to informed consent, there are some important differences, especially in the research setting.” This publication is freely accessible through PubMed Central.
  • Patients’ views concerning research on medical practices: implications for consent (Weinfurt et al. 2015) describes the results of focus group sessions that elicited a range of patients’ views and opinions about different types of research on usual medical practices. The authors state that “our data suggest that effective policy and guidance will involve balancing different patients’ interests and potentially different sets of interests for different types of research studies on usual medical practices.”
  • Ethics of research in usual care settings: data on point (Sugarman 2016) introduces a special five-article supplement in the American Journal of Bioethics, stating that the “growing empirical ethics literature regarding research in usual care settings provides data to inform conceptual and policy debates regarding this research and suggests areas that require further study.”

These publications were supported by a bioethics supplement awarded to the Regulatory/Ethics Core group by the NIH’s Office of the Director.