Elsevier

Contemporary Clinical Trials

Volume 46, January 2016, Pages 100-105
Contemporary Clinical Trials

Embedding clinical interventions into observational studies

https://doi.org/10.1016/j.cct.2015.11.017Get rights and content

Abstract

Novel approaches to observational studies and clinical trials could improve the cost-effectiveness and speed of translation of research. Hybrid designs that combine elements of clinical trials with observational registries or cohort studies should be considered as part of a long-term strategy to transform clinical trials and epidemiology, adapting to the opportunities of big data and the challenges of constrained budgets. Important considerations include study aims, timing, breadth and depth of the existing infrastructure that can be leveraged, participant burden, likely participation rate and available sample size in the cohort, required sample size for the trial, and investigator expertise. Community engagement and stakeholder (including study participants) support are essential for these efforts to succeed.

Introduction

The field of epidemiology has well-developed standards for the definition and conduct of many types of studies. This has resulted in a somewhat artificial dichotomy between clinical trials and observational studies in research, training and practice. Observational studies can include cohort studies and patient registries. Clinical trials may include randomized or non-randomized efficacy or effectiveness trials of drugs, procedures or behavioral interventions. Trials could target individuals within a cohort with specific phenotypes or attributes. Trials to consider could include implementation or policy trials at individual (patient), clinic level, or community levels. Hybrid designs can include embedding clinical trials into existing observational studies or designing joint observational and trial components together in a single unified design.

In planning new studies, investigators should consider from the beginning a framework that includes the potential opportunities for concurrent or future intervention research or opportunities to extend clinical trials with an observational component. The factors that favor hybrid vs. separate study designs should be articulated and weighed. Optimal timing is important as it can become difficult to randomize once an intervention is introduced in the community. Ethical considerations including informed consent, medical referrals, and appropriateness of experimentation should be evaluated. It is also important to assess the appropriateness of specific cohorts for a particular clinical trial question as the inclusion and exclusion criteria, outcome assessments, and other logistic factors could differ. Investigators involved in existing cohorts and registries should thoroughly evaluate, on an ongoing basis, the potential types of interventions that could be incorporated. Registries should also be examined for opportunities to conduct trials as they are typically larger than population-based cohort studies, more inclusive of “real world” patients, less expensive to assemble, and may be better for detecting safety signals. This report expands on an NIH workshop conducted to review these issues [1]. Specific examples from ongoing trials and observational studies are provided with recommendations for moving the field forward.

Section snippets

Experience with combined cohort studies and clinical trials

Several studies have been conducted that have leveraged existing or concurrent cohorts in their design. The experience with these studies is provided with specific examples. Each illustrates a unique approach.

Pros and cons of hybrid observational and clinical trial design

There is a need for more rapid translation from observational studies to clinical trials. Intervention studies may be initiated in a more timely fashion if embedded in an existing study. This could foster more rapid testing and translation of new prevention and/or treatment strategies. The state of the science for individual study questions should set the timing for the introduction of interventions in observational studies vs. new studies. As observational studies demonstrate the importance of

Examples of hybrid designs based on registries and comparative effectiveness

Randomized clinical trials suffer from uncertainty about generalizability to broader populations, expense and limited power, especially in subgroups. Randomized trials may also not address questions of societal interest. Thus, non-randomized approaches using data from observational databases can be used to address questions of clinical interest. However, the problem with comparing therapeutic or diagnostic strategies with observational data is residual treatment selection bias due to unmeasured

Pros and cons of registries

Registries offer researchers large populations of well-characterized patients with a wide variety of diseases, conditions, and interactions with clinical care. Researchers should consider linking clinical registry databases with administrative databases, in particular for enabling efficient recruitment, screening, and follow-up. Limitations of registries may include lack of a biorepository, disease-specificity that may render them less valuable for primary prevention trials, potential need for

Need for partnerships

Observational studies have often gained broad community engagement to support the need for long term follow-up. If an intervention is considered for an observational study, researchers should strongly consider engaging pertinent stakeholders, including the study participants and their communities, in the formulation of the research questions, the oversight, and implementation of the intervention study. Diversity and inclusiveness are important principles. Many of the populations in need of new

Summary of recommendations

Based on the considerations discussed above, the authors agree that established observational registries and cohort studies offer an infrastructure essential for embedding clinical trials, and specific opportunities for the implementation of this hybrid model should be developed. Building on the existing infrastructure would foster more rapid translation of findings from observational studies or registries into clinical applications. At the same time, the significance, impact and timing of the

Conflict of interest

The authors report no conflict of interest.

Acknowledgments

We gratefully acknowledge the significant contributions of the following personnel: Bruce Psaty, MD, PhD, for his review and insightful comments; Michelle Utz-Kiley for her expert manuscript preparation.

This paper is a result of the workshop “Embedding Clinical Interventions into Observational Studies” held on April 8–9, 2013 and sponsored by the National Heart, Lung and Blood Institute [1].

The views expressed in this manuscript are those of the authors and do not necessarily represent the

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