Living Textbook Offers New Content on Design and Analysis of Pragmatic Clinical Trials

Members of the NIH Collaboratory’s Biostatistics and Study Design Core contributed 3 new sections to the Living Textbook exploring issues in the design and analysis of pragmatic clinical trials. The new sections offer insights into emerging issues in embedded pragmatic clinical trials and lessons learned from the NIH Collaboratory’s first round of Demonstration Projects.

  • The Designing to Avoid Identification Bias section addresses a type of selection bias that can occur in pragmatic clinical trials that use information from electronic health records to determine study population eligibility and in which the study intervention influences who undergoes screening or receives a diagnosis in clinical care.
  • The Alternative Cluster Randomized Designs section describes alternative design choices for cluster randomized trials and their implications for statistical power and sample size calculations. Modified cluster randomized designs, such as cluster randomization with crossover, may reduce the sample size required for a pragmatic clinical trial and may be particularly feasible in trials embedded in healthcare systems with electronic health records.
  • Case Study: STOP CRC Trial explores challenges in design and analysis that were faced in the Strategies and Opportunities to Stop Colorectal Cancer in Priority Populations (STOP CRC) trial, one of the NIH Collaboratory Demonstration Projects. The case study illustrates how the study team dealt with pragmatic issues during the planning and conduct of the trial.

In addition to contributing content to the Living Textbook, the Biostatistics and Study Design Core works with the NIH Collaboratory Demonstration Projects to address challenges in their statistical plans and study designs during the planning phase and to develop guidance and technical documents related to study design and biostatistical issues relevant to pragmatic clinical trials.

February 15, 2019: Improving Qualification of Investigators: Recommendations from the Clinical Trials Transformation Initiative (Christine M. Hildebrand, PA-C, Janette Panhuis)

Speakers

Christine M. Hildebrand, PA-C
Physician Assistant
Sub-Investigator
Clinical Operations Lead
Amici Clinical Research

Janette Panhuis
Chief Operating Officer
Population Health Research Institute
David Braley Research Institute

Topic

Improving Qualification of Investigators: Recommendations from the Clinical Trials Transformation Initiative

Keywords

CTTI; Investigator qualifications; Investigator training; Site team training; Good clinical practice; Clinical trials

Key Points

  • There is little evidence that good clinical practice (GCP) training alone sufficiently qualifies investigators in the conduct of clinical trials. What is needed is a targeted and risk-based approach to educating clinical trial investigators and their delegates in GCP principles.
  • A culture shift is needed that eliminates the distinction between “qualification” and “preparation” and moves toward investigators and their delegates assuming greater ownership of training and documenting evidence of their qualification.
  • CTTI recommendations outline how to confirm that site teams are qualified while also reducing inefficiencies in training and increasing preparation for successful study execution.

Discussion Themes

Investigators and site teams come to the table with different levels of research experience, training, and credentials. How can we effectively address gaps in skills and knowledge of GCP principles?

With respect to pragmatic trials conducted within healthcare systems, are there approaches to site monitoring that address issues related to turnover of PIs and clinical and research staff?

Greater ownership of GCP training and qualification by investigators and delegates can lead to active remediation of deficiencies at the clinical site.

CTTI recommendations are meant to be adaptable to the protocol, even when conducted in a real-world clinical setting using electronic health records.

For recommendations and tools for improving investigator qualification, visit CTTI’s Investigator Qualification website.

Tags

#ClinicalTrials, #GCPtraining, #pctGR, @Collaboratory1 @CTTI_Trials

February 1, 2019: Promoting Effective Advance Care Planning Communication in the Elderly: The ACP-PEACE Trial (James Tulsky, MD, Angelo Volandes, MD, MPH)

Speakers

James Tulsky, MD
Chair, Department of Psychosocial Oncology and Palliative Care
Dana-Farber Cancer Institute
Professor of Medicine, Harvard Medical School
Chief, Division of Palliative Medicine
Brigham and Women’s Hospital

Angelo Volandes, MD, MPH
Associate Professor of Medicine
Massachusetts General Hospital
Harvard Medical School

Topic

Promoting Effective Advance Care Planning Communication in the Elderly: The ACP-PEACE Trial

Keywords

Pragmatic clinical trial; Advance care planning; ACP PEACE; Dana-Farber Cancer Institute; National Institute on Aging; Palliative care; Video declarations; Goal-concordant care; Patient preferences

Key Points

  • Many people with serious illness die without receiving goal-concordant care, and patients over the age of 65 with cancer experience this disproportionately. Helping patients engage in advance care planning (ACP) can empower them to express and record their goals so that their care can be aligned with their preferences.
  • The ACP PEACE Demonstration Project is a pragmatic, stepped-wedge, randomized trial of a comprehensive ACP program in oncology clinics at 3 health systems. It will involve a combination of 2 evidence-based programs:
    • VitalTalk teaches clinicians important communication skills in having empathic conversations with seriously ill patients.
    • ACP Decisions uses videos to promote planning and decision-making by patients and families.
  • The ACP PEACE study will monitor long-term outcomes to evaluate whether patients received the care they planned for and wanted.

Discussion Themes

The last element of the ACP PEACE trial is a video declaration (ViDec), recorded by a subset of patients. In recording the ViDec, patients are prompted by questions assessing their confidence with their decision, satisfaction, decisional regret, and patient-provider experience.

The ACP PEACE study team has a scaling strategy in place if the intervention proves effective. Implementing the intervention as standard of care will involve a culture shift from what is currently expected in health systems.

Read more about the ACP PEACE Demonstration Project in the Living Textbook.

Tags

#AdvanceCarePlanning, #pctGR, @Collaboratory1 @VitalTalk, @ACPDecisions

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 22, 2019: New Self-Paced ePCT Training Course Available

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.

Also available in the Living Textbook are links to videocast workshops hosted by the NIH on a range of ePCT topics including:

  • Embedded PCTs of therapeutic A versus B interventions
  • Unique opportunities for disseminating, implementing, and sustaining evidence-based practices into clinical care
  • Ethical and regulatory issues of PCTs

For these and other ePCT resources, visit the Training Resources webpage.

December 7, 2018: Cluster Randomized Trials in Health Care Delivery Systems: Lessons from STIC2IT (Niteesh K. Choudhry, MD, PhD)

Speaker

Niteesh K. Choudhry, MD, PhD
Professor, Harvard Medical School
Executive Director, Center for Healthcare Delivery Sciences, Brigham and Women’s Hospital

Topic

Cluster Randomized Trials in Health Care Delivery Systems: Lessons from STIC2IT

Keywords

STIC2IT; Pragmatic clinical trial; Learning health system; Cluster randomization; Medication adherence; Telepharmacy; Electronic health record; Stakeholder engagement

Key Points

  • STIC2IT, a pragmatic, cluster-randomized trial, evaluated a telepharmacy intervention to improve medication adherence for people with chronic diseases.
  • Pragmatic aspects of STIC2IT included outcomes assessed using routinely collected data, cluster randomization by physician practice, intention-to-treat analysis, and use of the EHR to collect research data.
  •  While medication adherence did improve in the STIC2IT intervention group, secondary clinical outcomes did not improve. Future trials within health systems should incorporate multilevel engagement across the health system, physicians and staff, and patients.

Discussion Themes

It is important to do ongoing outreach at the health system leadership level to ensure understanding and commitment to the study and keep providers aware of the trial. Study teams should be mindful of the priorities of their partner health system.

Using the EHR for research data required some upfront work building special modules and generating custom reports.

For more information on conducting PCTs in health delivery systems, visit the Living Textbook chapter on engaging stakeholders and building partnerships.

Tags

@Collaboratory1, #pctGR, #HarvardMed, #telepharmacy

December 3, 2018: FDA Calls for Comments on Proposed Rule to Allow Exceptions to the Requirement for Informed Consent in Minimal-Risk Research

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.

Comments on the proposed rule are due by January 14, 2019.

November 16, 2018: Primary Palliative Care for Emergency Medicine (PRIM-ER) (Corita Grudzen, MD, MSHS)

Speaker

Corita R. Grudzen, MD, MSHS, FACEP
Vice Chair for Research
Associate Professor of Emergency Medicine and Population Health
Ronald O. Perelman Department of Emergency Medicine
NYU School of Medicine

Topic

Primary Palliative Care for Emergency Medicine (PRIM-ER)

Keywords

PRIM-ER; Emergency department; Palliative care; Demonstration project; Pragmatic trial; Stepped-wedge study design; Clinical decision support; Best practice alerts; Advance care planning

Key Point

  • The PRIM-ER trial is a pragmatic, cluster-randomized, stepped wedge Demonstration Project that will implement primary palliative care in emergency medicine across a diverse group of 35 emergency departments (EDs).
  • PRIM-ER’s clinical decision support intervention is tailored to each ED site. The study aims to enable system, organizational, and provider change in the emergency department workflow.
  • The study team is identifying and preparing site champions by conducting communication skills training in serious illness for emergency physicians and staff using the EM Talk program.

Discussion Themes

It is important to consider sustainability of the intervention during the planning phase of the trial. Plan for staff turnover and how new staff will be educated and oriented to the intervention.

The volume and sophistication of best practice alerts (BPAs) received by physicians varies across U.S. emergency departments. Alert “fatigue” can be a concern.

For more information on the PRIM-ER Demonstration Project, visit the PRIM-ER website on the Living Textbook.

Tags

@Collaboratory1, #pctGR, #EmergencyMedicine

October 19, 2018: A New Path Forward for Using Decentralized Clinical Trials (Jeffry Florian, PhD, Annemarie Forrest, Penny Randall, MD, MBA)

Speakers

Jeffry Florian, PhD
Clinical Analyst, Office of New Drugs
FDA Center for Drug Evaluation and Research (CDER)

Annemarie Forrest
Clinical Trials Transformation Initiative (CTTI)

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.

Download CTTI’s recommendations for decentralized clinical trials.

Tags

#telemedicine #pctGR, @PCTGrandRounds, @Collaboratory1, @CTTI_Trials @IQVIA_global @US_FDA

September 28, 2018: Assessing and Reducing Risk of Re-identification When Sharing Sensitive Research Datasets (Greg Simon, MD, MPH, Deven McGraw, JD, MPH, Khaled El Emam, PhD)

Speakers

Gregory Simon MD, MPH
Investigator, Kaiser Permanente Washington Health Research Institute

Deven McGraw, JD, MPH, LLM
General Counsel & Chief Regulatory Officer, Ciitizen

Khaled El Emam, PhD
Department of Pediatrics, University of Ottawa
Children’s Hospital of Eastern Ontario Research Institute

Topic

Assessing and Reducing Risk of Re-identification When Sharing Sensitive Research Datasets

Keywords

Clinical trials; Research ethics; Data security; Data sharing; Sensitive research data; De-identified data

Key Points

  • 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.

Discussion Themes

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.

The Health Information Trust Alliance de-identification framework identifies 12 criteria for a successful de-identification program and methodology.

Tags

#pctGR, #PragmaticTrials, #HealthData, @HealthPrivacy @Collaboratory1, @PCTGrandRounds