Determining the Suitability of Registries for Embedding Clinical Trials in the United States: A Project of the Clinical Trials Transformation Initiative.

BACKGROUND: Patient registries are organized systems that use observational methods to collect uniform data on specified outcomes in a population defined by a particular disease, condition, or exposure. Data collected in registries often coincide with data that could support clinical trials. Integrating clinical trials within registries to create registry-embedded clinical trials offers opportunities to reduce duplicative data collection, identify and recruit patients more efficiently, decrease time to database lock, accelerate time to regulatory decision-making, and reduce clinical trial costs. This article describes a project of the Clinical Trials Transformation Initiative (CTTI) intended to help clinical trials researchers determine when a registry could potentially serve as the platform for the conduct of a clinical trial. METHODS: Through a review of registry-embedded clinical trials and commentaries, semi-structured interviews with experts, and a multi-stakeholder expert meeting, the project team addressed how to identify and describe essential registry characteristics, practices, and processes required to for conducting embedded clinical trials intended for regulatory submissions in the United States. RESULTS: Recommendations, suggested practices, and decision trees that facilitate the assessment of whether a registry is suitable for embedding clinical trials were developed, as well as considerations for the design of new registries. Essential registry characteristics include relevancy, robustness, reliability, and assurance of patient protections. CONCLUSIONS: The project identifies a clear role for registries in creating a sustainable and reusable infrastructure to conduct clinical trials. Adoption of these recommendations will facilitate the ability to perform high-quality and efficient prospective registry-based clinical trials.

Gastrointestinal bleeding prophylaxis for critically ill patients: a clinical practice guideline.

CLINICAL QUESTION: What is the role of gastrointestinal bleeding prophylaxis (stress ulcer prophylaxis) in critically ill patients? This guideline was prompted by the publication of a new large randomised controlled trial. CURRENT PRACTICE: Gastric acid suppression with proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) is commonly done to prevent gastrointestinal bleeding in critically ill patients. Existing guidelines vary in their recommendations of which population to treat and which agent to use. RECOMMENDATIONS: This guideline panel makes a weak recommendation for using gastrointestinal bleeding prophylaxis in critically ill patients at high risk (>4%) of clinically important gastrointestinal bleeding, and a weak recommendation for not using prophylaxis in patients at lower risk of clinically important bleeding (≤4%). The panel identified risk categories based on evidence, with variable certainty regarding risk factors. The panel suggests using a PPI rather than a H2RA (weak recommendation) and recommends against using sucralfate (strong recommendation). HOW THIS GUIDELINE WAS CREATED: A guideline panel including patients, clinicians, and methodologists produced these recommendations using standards for trustworthy guidelines and the GRADE approach. The recommendations are based on a linked systematic review and network meta-analysis. A weak recommendation means that both options are reasonable. THE EVIDENCE: The linked systematic review and network meta-analysis estimated the benefit and harm of these medications in 12 660 critically ill patients in 72 trials. Both PPIs and H2RAs reduce the risk of clinically important bleeding. The effect is larger in patients at higher bleeding risk (those with a coagulopathy, chronic liver disease, or receiving mechanical ventilation but not enteral nutrition or two or more of mechanical ventilation with enteral nutrition, acute kidney injury, sepsis, and shock) (moderate certainty). PPIs and H2RAs might increase the risk of pneumonia (low certainty). They probably do not have an effect on mortality (moderate certainty), length of hospital stay, or any other important outcomes. PPIs probably reduce the risk of bleeding more than H2RAs (moderate certainty). UNDERSTANDING THE RECOMMENDATION: In most critically ill patients, the reduction in clinically important gastrointestinal bleeding from gastric acid suppressants is closely balanced with the possibility of pneumonia. Clinicians should consider individual patient values, risk of bleeding, and other factors such as medication availability when deciding whether to use gastrointestinal bleeding prophylaxis. Visual overviews provide the relative and absolute benefits and harms of the options in multilayered evidence summaries and decision aids available on MAGICapp.

Informed consent in clinical research: Consensus recommendations for reform identified by an expert interview panel.

BACKGROUND: Informed consent is the cornerstone for protection of human subjects in clinical trials. However, a growing body of evidence suggests that reform of the informed consent process in the United States is needed. METHODS: The Clinical Trials Transformation Initiative conducted interviews with 25 experienced observers of the informed consent process to identify limitations and actionable recommendations for change. RESULTS: There was broad consensus that current practices often fail to meet the ethical obligation to inform potential research participants during the informed consent process. The most frequent single recommendation, which would affect all participants in federally regulated clinical research, was reform of the informed consent document. The interviews also identified the need for reform of clinical research review by institutional review boards, including transitioning to a single institutional review board for multi-site trials. CONCLUSION: The consensus recommendations from the interviewees provide a framework for meaningful change in the informed consent process. Although some proposed changes are feasible for rapid implementation, others such as substantive reform of the informed consent document may require change in federal regulations.

A Proposed Framework to Address Needs of Clinical Data for Informed Medication Use in Pregnancy.

The objective of this paper is to communicate a proposed framework for addressing research limitations and communication barriers that contribute to a lack of data for making clinical treatment decisions about medication use in pregnancy. To address this global public health concern, a cross-stakeholder coalition composed of several workstreams is proposed. The intent is to foster collaborative discussion regarding potential solutions to address gaps in communication, engagement, and data generation and collection. Topic areas that require focus include development of awareness initiatives, cultural transformation efforts, collaboration initiatives, research standards, data compilation projects, and new data capture methods. Objectives to aid these efforts are outlined, and collaboration among researchers, regulators, health care providers, and patients is emphasized.

Clinical Data for Informed Medication Use in Pregnancy: Strengths, Limitations, Gaps, and a Need to Continue Moving Forward.

The objective of this paper is to explore the strengths, weaknesses, gaps, and needs in research on medication use in pregnancy, where opportunities have been bypassed to develop standards and collaborations for collecting data to better understand how medications can impact clinical outcomes in pregnant women and developing fetuses. The availability of existing data and the methods of its capture are reviewed, including registries, claims and health record databases, and meta-analyses. The paper focuses on why these efforts have not fundamentally provided benefit-risk information and clinical treatment algorithms for medication use in pregnant women. Methodological issues, such as lack of standardization and central data collection, are discussed. Common barriers are examined, including a lack of awareness and education, cultural hurdles, collaboration deficiency, and an insufficient development of new data collection methods.