Workshop Executive Summary
April 8-9, 2013
The NHLBI convened a Working Group to engage in a dialogue on the development of opportunities to embed clinical trials into observational registries and cohort studies. These efforts would be 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. The Working Group identified a number of important considerations, including 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. The Working Group also noted that community engagement and stakeholder (including study participants) support are essential for these efforts to succeed.
A Working Group was convened to discuss the scientific potential and operational synergies achieved by incorporating clinical trials into observational registries and cohort studies. The Working Group considered a variety of trial types, including randomized efficacy clinical trials; effectiveness trials; trials that target cohort individuals with specific phenotypes or attributes; non-randomized comparative effectiveness of treatment studies; behavioral trials; and implementation or policy trials at individual (patient), clinic level, or community levels.
Experts in epidemiology, clinical care and clinical trials discussed: (1) the pros and cons of embedding trials into observational studies; (2) optimal timing; (3) ethical considerations, including informed consent, medical referrals, and appropriateness of experimentation; (4) logistics; (5) how to determine the appropriateness specific cohorts; and (6) different types of interventions that could be incorporated into existing cohorts and registries.
The Working Group reviewed prior experiences with interventions embedded into observational studies, including SANDS (Stop Atherosclerosis in Native Diabetics Study) in the Strong Heart Study; the Gingko Memory Study in the Cardiovascular Health Study; a pilot yoga intervention into the Jackson Heart Study; Centers for Medicare & Medicaid Services (CMS)-reimbursed obesity behavioral interventions in an existing clinic; and clinical trials and observational study performed in the Women?s Health Initiative. The Working Group also reviewed opportunities for the performance of low-cost intervention studies in registries, which 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 activity met Goal 3, and Strategies 3-8 of the NHLBI Strategic Plan.
Summary of Recommendations
- Develop opportunities for embedding clinical trials within established observational registries and cohort studies.
- The research community should note that the potential advantages of this approach accrue from pre-existing, well-characterized, and engaged populations that are already under active follow-up. Pre-existing procedures for case finding, retention, outcome ascertainment and event classification enable rapid trial initiation and obviate the need to separately establish (and fund) infrastructure for trial-related procedures.
- The research community should note that embedding an intervention study in a cohort study can enhance external generalizability and calibration of risk estimates.
- Researchers should consider the significance of the research question and the potential impact of the question on the health/disease status of the observational study population to determine whether the intervention study would be best conducted within that observational (cohort) study. In some cases, a new hybrid design (clinical trial with cohort component) may be needed.
- The state of the science for individual study questions should set the timing for the introduction of interventions in observational studies, according to the accumulation of the evidence for risk or benefit from observational designs.
- Researchers should consider how intervention studies may be initiated in a more timely fashion, including embedding in an existing study, in order to foster more rapid testing and translation of new prevention and/or treatment strategies.
- Researchers should make sure that the intervention study is a good fit with the design of the registry or observational study.
- Randomized drug/comparative effectiveness research/safety trials should be of sufficient impact and quality to contribute to evidence-base for public health and clinical practice guidelines.
- Researchers should recognize that some cohort studies may not offer sufficient sample size, particularly if effect sizes are small and/or there are multiple inclusion/exclusion criteria.
- Timing is critical.
- Testing interventions related to a new risk factor or involving a new technology should be done early enough before the treatment or new technology of interest are widely adopted. Once technologies are widely utilized in the community, especially when paid for by third party payers, insurance companies, etc., the ability to do trials are greatly limited because of the substantial "crossovers" within the trial, i.e., individuals obtaining diagnostic techniques or therapies from other sources than the trial. Timing considerations also are relevant to observational studies; once studies are established participants may be less willing to be part of a new study that requires more visits or procedures.
- There might be trade-offs between the needs of the intervention study and the observational study. In this situation, the intervention study needs to be important enough for embedding to be allowed to occur.
- Build on the cohort study infrastructure for the implementation of the intervention study.
- Researchers should include clinical trials expertise on their teams. Clinical trials experts can work with observational studies researchers to optimize trial design, infrastructure needs, statistical issues, screening and recruitment, informed consent, adverse-event reporting, event definitions and adjudication, and strategies on retention and adherence.
- Observational studies researchers can help clinical trialists achieve efficiencies by drawing on their own staff, infrastructure, follow-up, case finding, and event classifications procedures.
- Consider special opportunities offered by 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 additional data collection of data outside the administrative data or medical record (such as quality of life, adverse events, or adherence), and challenging requirements for statistical methodologies.
- Observational registry studies were not designed to test the efficacy or even effectiveness of specific therapies or technologies, but have their primary value in monitoring quality and quantity of outcomes and signals for unexpected adverse or even potentially beneficial effects, especially within specific disease subgroups defined on genetics, demographics, or health-related characteristics in non-randomized comparative effectiveness studies.
- While registry studies can be large, size does not overcome treatment selection bias.
- Establish partnerships with the stakeholders affiliated with observational studies.
- Researchers should strongly consider engaging pertinent stakeholders, from the observational study participants to their communities, in the formulation of the research questions, the oversight, and implementation of the intervention study.
- Develop partnerships and collaboration between funding agencies that sponsor medical research and support medical care.
Anne Newman, University of Pittsburgh (Chair)
Lewis Kuller, University of Pittsburgh
Gerardo Heiss, University of North Carolina at Chapel Hill
David Wendler, NIH Clinical Center Office of Bioethics
Cora E. (Beth) Lewis, University of Alabama at Birmingham
Herman Taylor, University of Mississippi Medical Center
Wm. James Howard, Medstar Health Research Institute and Medstar Washington Hospital Center, Washington DC
Garnet Anderson, Fred Hutchinson Cancer Research Center, Seattle, Washington
Jennifer Robinson, University of Iowa
Roberto P. Treviño, Social and Health Research Center San Antonio, Texas
William Weintraub, Christiana Care, Delaware
Mitchell Krucoff, Duke University
Ann Alston, Larissa Avilés-Santa, Denise Bonds, Dale Burwen, Susan Czajkowski, Patrice Desvigne-Nickens, Carmen Edghill,Richard Fabsitz, Larry Fine, David Gordon, Jane Harman, Lucy Hsu, Cashell Jaquish, Peter Kaufmann, Michael Lauer, Cay Loria, Alice Mascette, Cheryl Nelson, Hanyu Ni, Jean Olson, Gail Pearson, Jared Reis, Jacques Rossouw, Lorraine Silsbee, Paul Sorlie, Myron Waclawiw, Gina Wei, Jacqueline Wright
Barbara Linder (NIDDK) and Martha Daviglus (University of Illinois at Chicago)
Last Updated August 2013