guidance document

February 22, 2024: Updated Template Provides Guidance for Reporting of Pragmatic Trial Results

Posted on by Damon Seils

An updated template from the NIH Pragmatic Trials Collaboratory provides guidance for the transparent reporting of the primary results of pragmatic clinical trials.

The template includes elements from the Consolidated Standards of Reporting Trials (CONSORT) statement and its extensions. It also addresses secondary use of electronic health record data, involvement of research partners and healthcare systems in the conduct of pragmatic trials, and special ethical and regulatory considerations.

Download the template.

The updated template is organized by the recommended reporting elements presented in the CONSORT checklist and draws on recent experiences and lessons learned from the NIH Collaboratory Trials. Appendices include links to CONSORT and its relevant extensions, the Pragmatic-Explanatory Continuum Indicator Summary (PRECIS-2) tools and resources, and examples of figures to include in pragmatic trial reports.

July 14, 2022: Grand Rounds Podcast Now Available, Featuring Dr. John Concato on FDA Draft Guidance on Real-World Evidence

Posted on by terren.green@duke.edu

Headshot of Dr. John ConcatoIn the latest episode of the NIH Collaboratory Grand Rounds podcast, Dr. John Concato and Dr. Richard Platt continue their discussion about the FDA draft guidance on real-world evidence.

The full June 24 Grand Rounds webinar with Dr. Concato is also available.

June 24, 2022: FDA Draft Guidance on Real-World Evidence (John Concato, MD, MS, MPH)

Posted on by terren.green@duke.edu

Speaker

John Concato, MD, MS, MPH
Associate Director for Real-World Evidence Analytics
Office of Medical Policy (OMP)
Center for Drug Evaluation and Research (CDER)
Food and Drug Administration (FDA)

 

 

Keywords

Big data; Real-word evidence; Real-world data; 21st Century Cures Act; FDA Draft Guidance

 

Key Points

  • Big Data, a term first used in the 1990s, leverages modern technology to increase the quantity, forms, speed, and capability to manipulate large-scale data. Real-world data (RWD) is a term with specific regulatory implications referring to health care data routinely collected from a variety of sources. Real-world evidence (RWE) is clinical evidence derived from analysis of RWD regardless of study design.
  • Terminology is important in research work, and we should strive to be as precise as possible with the terminology we use.
  • With the 21st Century Cures Act of 2016, the FDA established a program to evaluate the potential use of real-world evidence to support new indications for drugs and satisfy post-approval study requirements.
  • In 2021, the FDA issued 4 draft guidance documents for Real-world data and Real-world evidence intended to guide the selection and management of data sources to appropriately address the study question and support decision-making for drug and biological products.

Discussion Themes

– Could real-world data sources be certified and preclude the need for submission of source data on a study specific basis? From the FDA point-of-view, while reliability can be more readily evaluated and would tend to be more stable, the relevance to a particular study could not be determined as easily.

– While there can be a reflex that says we can never be sure about major confounding, it should not be the miasma of the 21st century. A thoughtful approach that considers the characteristics that matter is the best approach.

 

Read Dr. Concato’s publication Randomized, observational, interventional, and real-world—What’s in a name? and the FDA Draft Guidance for RWD/RWE.

Tags

#pctGR, @Collaboratory1

August 25, 2021: Good Clinical Trials Collaborative Seeks Input on Draft Guidance for Randomized Controlled Trials

Posted on by Damon Seils

Logo for Good Clinical Trials CollaborativeThe Good Clinical Trials Collaborative has opened a 6-week public consultation period on its draft guidance for randomized controlled trials. The consultation period will last until September 15.

Launched in June 2020 with the support of Wellcome, the Bill & Melinda Gates Foundation, and the African Academy of Sciences, the Collaborative is developing guidance “to enable and promote informative, ethical, and efficient randomized controlled clinical trials.” The purpose of the guidance is to identify the fundamental principles of randomized controlled trials and enable their application to a wide range of healthcare settings and interventions.

Through a web-based survey, the Collaborative is seeking feedback to help shape the guidance and ensure that it is applicable in all settings. Read more about the draft guidance and provide your feedback.

March 13, 2020: Impact of Regulatory Guidance on Evaluating Cardiovascular Risk of New Glucose-Lowering Therapies to Treat Type 2 Diabetes Mellitus–Lessons Learned and Future Directions (Abhinav Sharma, MD, PhD; Christopher Granger, MD)

Posted on by Gina Uhlenbrauck

Speakers

Abhinav Sharma, MD, PhD
Assistant Professor of Medicine
McGill University

Christopher B. Granger, MD, FAHA, FACC
Professor of Medicine
Director, Cardiac Intensive Care Unit
Duke University Medical Center

Topic

Impact of Regulatory Guidance on Evaluating Cardiovascular Risk of New Glucose-Lowering Therapies to Treat Type 2 Diabetes Mellitus–Lessons Learned and Future Directions

Keywords

Type 2 diabetes; Regulatory; Cardiovascular risk; Food and Drug Administration; FDA; Patient outcomes; Anti-hyperglycemic medications

Key Points

  • The hallmark of type 2 diabetes mellitus is insulin resistance and relative insulin deficiency. Ninety percent of all cases of diabetes are type 2 diabetes, and the diagnosis can occur at any age.
  • While people with type 2 diabetes can often initially manage their condition through exercise and diet, over time most people will require oral drugs or insulin.
  • Strategies are needed reduce the burden of cardiovascular outcomes in patients with diabetes.
  • In 2008, the U.S. Food and Drug Administration (FDA) issued guidelines for sponsors to demonstrate that their anti-hyperglycemic medications do not increase the risk of cardiovascular disease. In March 2020, the FDA updated the guidance in a draft for comment: Type 2 Diabetes Mellitus: Evaluating the Safety of New Drugs for Improving Glycemic Control Guidance for Industry.

Discussion Themes

Is the cardiovascular protection of some anti-hyperglycemic drugs independent of the effect on blood glucose?

How can regulators, industry, academia, payers, and patient advocacy groups assure that evidence generation to improve care is incentivized without undue regulatory burdens?

Should post-marketing studies include comparative effectiveness pragmatic trials in order to improve translation into clinical practice?

Read more on this topic from Sharma and colleagues in a recent publication in Circulation.

Tags
#pctGR, @Collaboratory1

February 11, 2020: ADAPTABLE Roundtable Produces Consensus Statement on Analysis and Integration of Patient-Reported Data in Clinical Trials

Posted on by Damon Seils

A roundtable discussion organized by the NIH Collaboratory in 2017 has produced consensus findings on the analysis and integration of patient-reported health (PRH) data in clinical trials. The report is part of an effort by the ADAPTABLE Supplement project team “to address best practices for capturing PRH data in pragmatic studies and optimal analytic approaches for integrating PRH with other data sources.”

The consensus statement was published online ahead of print this month in the Journal of the American Medical Informatics Association.

The report discusses strengths and limitations of PRH data, approaches for ascertaining and classifying study end points, and methods for addressing incompleteness, data alignment, and data concordance. Roundtable participants used experiences from the ADAPTABLE trial as a case study to inform their discussions.

ADAPTABLE, the first major randomized comparative effectiveness trial conducted by the National Patient-Centered Clinical Research Network (PCORnet), seeks to determine the optimal dose of aspirin therapy for secondary prevention of atherosclerotic cardiovascular disease. The trial relies on both existing EHR data sources and PRH data.

This work was supported by a supplemental grant award to the NIH Collaboratory Coordinating Center from the National Center for Complementary and Integrative Health.

August 5, 2019: New Section of Living Textbook Addresses Missing Data in Intention-to-Treat Analyses

Posted on by Damon Seils

A new section of the NIH Collaboratory’s Living Textbook of Pragmatic Clinical Trials discusses challenges associated with missing data that result from noncompliance, crossover, and dropout.

Many randomized controlled trials use an intention-to-treat (ITT) analysis to measure the real-world effects of the intervention. The newly published section, Missing Data and Intention-to-Treat Analyses, considers the population-level causal effects in these trials when there is noncompliance or missing outcome data.

“One rationale for the ITT approach is that it evaluates the real-world effects of the intervention. However, a common misconception is that the ITT analysis will be unbiased regardless of crossover or missing data.”

The new section also introduces a white paper from the NIH Collaboratory’s Biostatistics and Study Design Core, “Analyses of Randomized Controlled Trials in the Presence of Noncompliance and Study Dropout.” This working document offers analysts a more detailed discussion of treatment effects in ITT analyses, including a case example and recommended strategies for estimating and reporting both ITT effects and average causal effects.

The Biostatistics and Study Design Core works with the NIH Collaboratory Trial teams to create guidance and technical documents regarding study design and biostatistical issues relevant to pragmatic clinical trials.

New Biostatistical Guidance Document Available: Small-Sample Robust Variance Correction for GEE

Posted on by Gina Uhlenbrauck

Tools for ResearchThe NIH Collaboratory’s Biostatistics and Study Design Core has just published a new guidance document by Andrea Cook, PhD, of the Group Health Research Institute, on using small-sample robust variance correction for generalized estimating equations (GEE) for use in cluster-randomized trials. The document, which includes guidance on methods available in the SAS and Stata statistical analysis packages, is available directly from the NIH Collaboratory Knowledge Repository here (opens as PDF), or via the Biostatistical Guidance Documents page in the Living Textbook.

This guidance document is one in a series of research tools focused on detailed aspects of statistical design for conducting pragmatic clinical trials. Each document in this series provides a synthesis of current developments, discusses possible future directions, and, where appropriate, makes recommendations for application to pragmatic clinical research.

FDA Issues Draft Guidance on Use of Electronic Informed Consent (eIC)

Posted on by Gina Uhlenbrauck

On March 9, 2015, the U.S. Food and Drug Administration (FDA) issued draft guidance on the Use of Electronic Informed Consent in Clinical Investigations (document opens as a PDF). In a question-and-answer format, the guidance provides recommendations for investigators, sponsors, and institutional review boards (IRBs) on the use of electronic media and processes to obtain informed consent for FDA-regulated clinical investigations of medical products, including human drug and biological products, and medical devices, and combinations thereof.

Electronic informed consent, or eIC, refers to the use of electronic systems and processes to convey information related to the study and to obtain and document informed consent. Electronic media formats may include text, graphics, audio, video, podcasts, and interactive websites, biological recognition devices, and card readers. Use of electronic systems may allow for rapid notification to study participants of any amendments pertaining to the informed consent, promote timely entry of eIC data into the study database, and allow for timely collection of the informed consent data from remote locations.

The guidance provides answers to these questions:

  • How should the information in the eIC be presented to the subject?
  • How and where may the eIC process be conducted?
  • How and when should questions from subjects be answered?
  • What steps may be taken to facilitate the subject’s understanding of the information being presented?
  • What steps may be taken to ensure that new or additional information is conveyed to the subject during the course of the clinical investigation?
  • Does FDA allow the use of electronic signatures to document eIC?
  • What special considerations should be given to the use of eIC for pediatric studies?
  • Should subjects receive a copy of their eIC and have easy access to the material and information presented to them in their eIC?
  • What steps can be taken to help ensure confidentiality of the information once eIC is obtained?
  • Can HIPAA authorizations for research, which are frequently combined with informed consent documents, be obtained electronically?
  • What are the IRB’s responsibilities in the eIC process?
  • What eIC documentation does FDA require for submission with applications?
  • What steps can be taken to ensure the system archives the documents appropriately?
  • What materials or documents will FDA require during an inspection?

The comment period ends May 7, 2015. Users can submit electronic comments using the docket number HHS-OPHS-2015-0002 at the Federal eRulemaking Portal: http://www.regulations.gov.

NIH Issues Draft Policy Proposing Use of Single IRB for Multisite Clinical Research Studies

Posted on by Gina Uhlenbrauck

On December 3, 2014, the National Institutes of Health (NIH) issued a draft policy promoting the use of a single institutional review board (IRB) for multisite studies. IRBs play a critical role in assuring the ethical conduct of research, and studies must be reviewed and approved by an IRB before they can begin. Yet over time, the clinical research landscape has become increasingly complex, expanding from studies formerly conducted at single institutions to large, diverse studies across networks and multiple sites. This situation challenges the practicality of using local IRBs to conduct initial and ongoing reviews for such studies.

The goal of permitting use of a single IRB—also called a central IRB or IRB of record—is to enhance and streamline the process of IRB review for multisite studies so that research can proceed efficiently without compromising ethical principles and protections. While both the FDA and Office for Human Research Protections support the use of a single IRB, too few institutions involved in multisite studies are taking advantage of the option.

 Read the NIH draft policy here.

“By using single IRBs in multi-site studies, we reduce duplication of effort, speed the initiation of important research, and save time and taxpayer funds.”
Francis S. Collins, MD, PhD, NIH Director

Among the current NIH programs incorporating the use of a single IRB are:

  • National Cancer Institute’s Central Institutional Review Board (CIRB)
  • National Institute of Neurological Disorders and Stroke’s Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT)
  • Network for Stroke Research (NIH StrokeNet)

Dr. Sally Rockney, NIH deputy director for extramural research, explains the NIH perspective in her blog. Public comment on the draft policy extends for 60 days, through January 29, 2015. When finalized, the policy will apply to all NIH-funded multisite studies carried out in the United States, whether supported through grants, contracts, or the NIH intramural program.