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Hybrid study designs are research methodologies that seamlessly blend elements from multiple study designs to address specific research questions comprehensively. Such a hybrid approach allows researchers to capitalize on the strengths of each study design while mitigating their individual limitations. As a result, hybrid designs usually provide a more comprehensive and holistic view of the research question.(1, 2)

Hybrid study designs come in various forms, each tailored to specific research needs. One example for hybrid study designs are ambispective studies, which combine retrospective and prospective data, enabling the evaluation of research questions before and after specific episodes, making it particularly valuable for studying intervention impacts or rare events.(3, 4)

The hybrid study design strategy has been used to enhance the robustness of traditional clinical trials, resulting in the evolution of hybrid clinical trials. While traditional clinical trials have long been the gold standard for generating evidence to support the safety and efficacy of new interventions, they have faced limitations in capturing the complexities of everyday practice.  Hybrid trials aim to generate evidence that considers both the controlled rigor of an RCT and the real-world applicability of observational studies. They can provide insights that are relevant to both research and clinical practice and can embrace a more inclusive approach. Additionally, with access to retrospective data, hybrid trials can evaluate interventions over extended periods, providing valuable insights into the long-term impact of treatments and interventions on patient outcomes.(5)

Among hybrid clinical trials, one notable subtype is the Pragmatic Randomized Clinical Trial (RCT), which focuses on evaluating interventions under real-world conditions. By prioritizing applicability to routine clinical practice, pragmatic RCTs generate evidence that is directly relevant to everyday healthcare settings. This approach enables researchers to assess whether an intervention works in practical clinical scenarios, providing evidence that directly informs decision-making in clinical practice and healthcare policy. Embedded Pragmatic Randomized Trials take the concept of a pragmatic RCT even further. In an embedded trial, the intervention being studied is seamlessly integrated into routine patient care within the existing healthcare system. This integration ensures minimal disruptions to routine care for both healthcare providers and patients, making the trial highly feasible and practical.(6, 7)

There are other examples for hybrid clinical trials. The ‘Stepped-Wedge Cluster Randomized Trial’ design evaluates new interventions over time by sequentially randomizing different clusters to receive the intervention. The ‘Observational Study With Nested Randomized Trial’ design identifies participants from an observational study for an RCT exploring specific interventions within an existing cohort. The ‘Sequential Multiple Assignment Randomized Trial (SMART)’ randomizes participants to different treatments in multiple stages based on previous responses. These various designs offer flexibility and adaptability to address diverse research questions effectively.(8-10)

However, implementing hybrid study designs also presents some challenges. Integrating multiple data sources and research methods requires careful planning and coordination. Researchers must ensure the compatibility and coherence of the different data sets, establish rigorous data management procedures, and address potential biases or conflicts that may arise from the combination of data. Additionally, researchers need expertise in quantitative and qualitative methods to navigate the complexities of hybrid designs effectively.(2, 3)

In conclusion, hybrid designs represent remarkable steps forward in evidence generation. By merging existing data with newly collected information, these methodologies provide a holistic view of research questions, enabling researchers to uncover valuable insights and long-term trends. As healthcare continues to evolve, hybrid designs and hybrid clinical trials will play pivotal roles in bridging the gap between research and clinical practice, shaping a future where evidence is not only robust but also reflective of the diverse and ever-changing realities of patient care.

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References:

1. Soon GG, Nie L, Hammerstrom T, et al. Meeting the demand for more sophisticated study designs. A proposal for a new type of clinical trial: the hybrid design. BMJ Open. 2011 Jan 1;1(2):e000156.
2. Landes SJ, McBain SA, Curran GM. An introduction to effectiveness-implementation hybrid designs. Psychiatry Res. 2019 Oct;280:112513.
3. Curran GM, Bauer M, Mittman B, et al. Effectiveness-implementation hybrid designs: combining elements of clinical effectiveness and implementation research to enhance public health impact. Med Care. 2012 Mar;50(3):217-26.
4. Sessler DI, Imrey PB. Clinical research methodology 2: observational clinical research. Anesthesia & Analgesia. 2015 Oct 1;121(4):1043-51.
5. Zhu M, Sridhar S, Hollingsworth R, et al. Hybrid clinical trials to generate real-world evidence: design considerations from a sponsor’s perspective. Contemp Clin Trials. 2020 Jul;94:105856.
6. Koehler M, Donnelly ET, Kalanovic D, et al. Pragmatic randomized clinical trials: a proposal to enhance evaluation of new cancer therapies with early signs of exceptional activity. Annals of Oncology. 2016 Jul 1;27(7):1342-8.
7. Ramsberg J, Platt R. Opportunities and barriers for pragmatic embedded trials: triumphs and tribulations. Learning Health Systems. 2018 Jan;2(1):e10044.
8. Creswell JW, Clark VP. Mixed methods research. SAGE Publications. 2011.
9. Hemming K, Haines TP, Chilton PJ, et al. The stepped wedge cluster randomized trial: rationale, design, analysis, and reporting. BMJ. 2015 Feb 6;350.
10. Digitale JC, Stojanovski K, McCulloch CE, Handley MA. Study designs to assess real-world interventions to prevent COVID-19. Frontiers in public health. 2021 Jul 27;9:657976.