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

May 16, 2019: NIH Collaboratory Investigators Author Recommendations for Responding to Guideline or Policy Changes That Affect Ongoing Pragmatic Trials

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

February 22, 2019: Proposed Rule to Implement Provisions of the 21st Century Cures Act

The Office of the National Coordinator for Health Information Technology (ONC) and the Centers for Medicare and Medicaid (CMS) have announced a proposed rule intended to advance interoperability and support the access, exchange, and use of electronic health information. Notably, the rule would require that patients have the ability to electronically access their health information at no cost.

The rule also proposes a United States Core Data for Interoperability (USCDI) standard, which, if adopted, would add data beyond those included in the current common clinical data model to support nationwide interoperability of CMS data. Specifically, clinical notes, data provenance, pediatric vital signs, patient address and phone number (to support data matching) will be added if the measures are adopted.

“Today’s announcement builds on CMS’ efforts to create a more interoperable healthcare system, which improves patient access, seamless data exchange, and enhanced care coordination,” — CMS Administrator Seema Verma, from the NPRM Press Release

There are nine fact sheets on other important aspects of the rule, including sheets on interoperability, the Cures Act, and electronic health information export for patient and provider access.

January 11, 2019: FDA Releases Framework for Evaluating the Use of Real-World Evidence

To help fulfill the requirements of the 21st Century Cures Act by accelerating medical product development and fostering innovation and advances in medicine, FDA recently created a framework for evaluating the use of real-world evidence. The framework is intended to help evaluate trials that use real-world data for the creation of real-world evidence.

  • Real-world data: routinely collected information about a person’s health status in the electronic health record, claims, registries, and other sources, including patient-generated sources.
  • Real-world evidence: reliable, clinical information derived from real-world data about risks, benefits, and burdens of therapies.

This framework will apply to various pragmatic clinical trials embedded in health care systems and conducted as part of routine care (and will not apply to more traditional clinical trials conducted parallel to care).

Three main considerations are included in the framework:

  1. Will the real-world data be fit for use (do they reliably and adequately represent the concept)?
  2. Will the evidence generated by the trial provide adequate evidence to help answer regulatory questions?
  3. Will the conduct of the study meet FDA regulatory requirements?

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 13, 2018: Summary of Workshop on Pragmatic Trials of Therapeutic A vs B Interventions Now Available

The NIH Collaboratory recently convened a workshop to explore embedded pragmatic clinical trials comparing two or more therapeutic medical interventions. These “A vs B” trials are meant to test existing, viable treatment alternatives where there is uncertainty about which treatment is best in which populations. There are unique barriers that make these types of pragmatic trials especially challenging to implement. For the workshop, a panel of experts gathered to discuss challenges and solutions regarding partnering with healthcare systems to conduct the trials, unique legal and ethical issues, and design and operational considerations. The summary of the workshop is now available: Workshop Summary: Embedded Pragmatic Clinical Trials of Therapeutic A vs. B Interventions

 

Additional Resources:

Embedded pragmatic clinical trials of therapeutic A vs. B interventions workshop videocast.

 

October 12, 2018: MDEpiNet RAPID and SPEED Projects: Leveraging Real World Evidence to Get Better, Faster, Cheaper Medical Devices for Physicians and Patients (Renee Mitchell, MT, CLS, Terrie Reed, MSIE, Roseann White, MA)

Speakers

Renee Mitchell, MT(ASCP), CLS(NCA)
Regulatory Affairs
Boston Scientific Corporation, Inc.

Terrie Reed, MSIE
Senior Advisor for UDI Adoption
U.S. Food and Drug Administration (FDA)

Roseann White, MA
Director of Innovative Clinical Trial Statistics
Duke Clinical Research Institute

Topic

MDEpiNet RAPID and SPEED Projects: Leveraging Real World Evidence to Get Better, Faster, Cheaper Medical Devices for Physicians and Patients

Keywords

Medical devices; Real-world evidence; Medical Device Epidemiology Network; MDEpiNet; Unique device identifier; UDI

Key Points

  • In partnership, clinicians, device developers, and FDA can benefit from the use of real-world evidence on medical devices:
    •  Clinicians can contribute to the generation of real-world evidence.
    •  Device manufacturers can use real-world evidence to evaluate and release new devices and expand indications.
    •  Regulatory bodies can increase the use of patient-level data for device approval.
  • Unique device identifiers (UDIs) make it possible to follow medical devices longitudinally, advancing the quality of real-world evidence and allowing more sophisticated analyses.

Discussion Themes

The vision for the future is that registries will transform into big data solutions using multiple sources and will be more robustly integrated with electronic health records (EHRs). Both EHRs and registries will play a role.

More organizations as partners brings greater diversity, advancing better data and results. When stakeholders work together, learning curves can be accelerated toward a transformational approach to real-world evidence.

Tags

#MedicalDevices, #pctGR, @PCTGrandRounds, @Collaboratory1, @MDEpiNet_ppp

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.

May 1, 2018: Proposal for 6-month Delay for Implementation of Revised Common Rule

On April 20, 2018, the Department of Health and Human Services and 15 other federal departments and agencies proposed a rule to delay 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). The Interim Final Rule initially announced a delay until July 19, 2018, and the new, proposed rule would delay by a further 6 months to January 21, 2019. This is intended to give institutions additional time to prepare to implement the revisions. Before January 21, 2019, institutions must comply with the pre-2018 Common Rule, except for these three proposed allowances, which are intended to reduce burden on regulated entities:

  1. Entities may use the 2018 definition of “research,” which deems certain activities not to be research,
  2. No annual continuing review is needed for certain categories of research, and
  3. Institutional review boards (IRBs) are not required to review grant applications related to research.

Comments on the proposal will be accepted until midnight EST on May 21, 2018, on the Federal eRulemaking Portal or through regular mail. To use the portal, search for “83 FR 17595” and click the box “Comment Now!”

March 15, 2018: New Resource for Understanding Ethical and Regulatory Architecture of Patient-Centered Outcomes Research Data

Using patient-centered outcomes research (PCOR) data requires balancing the need for sufficient private health information to support meaningful research with the need to protect patient privacy and autonomy. In support of this dual goal, The Office of the National Coordinator for Health Information Technology (ONC) has just released a document that provides a collection of tools and resources aimed at helping a broad audience of stakeholders understand the ethical and regulatory requirements related to collecting, using, sharing, and disclosing PCOR data.

“An architecture is necessary to ensure patient privacy is protected and health information is appropriately secured during collection, access, use, and disclosure as required by law, regulation, and/or policy.” —Legal and Ethical Architecture for PCOR Data

PCOR data will help expand the evidence base for therapies and improve health outcomes for individual patients.

Read the full document: Legal and Ethical Architecture for Patient-Centered Outcomes Research (PCOR) Data (“Architecture”)

The document is divided into 5 chapters:

Chapter 1: Overview of Legal and Ethical Architecture for PCOR Data provides background for the project and an overview of key ethical and regulatory requirements.

Chapter 2: Legal and Ethical Significance of Data for PCOR describes fundamental concepts for organizing data into categories such that legal and ethical frameworks can be applied. The chapter includes key considerations and types of data relevant to PCOR, such as clinical, administrative, patient-generated, etc.

Chapter 3: Linking Legal and Ethical Requirements to PCOR Data organizes the relevant legal provisions according to the key data considerations outlined in Chapter 2: identifiability, subject, source, access and use/purpose, consent/authorization, security, and legal status.

Chapter 4: Framework for Navigating Legal and Ethical Requirements for PCOR is designed as a decision tool that builds on the key data considerations described in Chapters 2 and 3. The goal of this chapter is to help researchers determine whether laws apply to particular data and if so, what requirements to attach to their collection and use.

Chapter 5: Mapping Research Flows to Legal Requirements identifies 6 hypothetical use cases, identifies decision trigger points, and maps representative data flows to the relevant legal requirements.