Putting It Into Practice: Why We Need Embedded Clinical Trials
By Lindsay Kehoe, M.S., C.G.C., Clinical Trials Transformation Initiative (CTTI)
Embedding elements of trials — such as randomization, informed consent, administration of a study drug, and/or data acquisition — into clinical practice is necessary to narrow the gap between clinical research and practice. Doing so would increase knowledge generation, reduce duplication of trial and care activities, and promote the translation of that knowledge into improved patient care. Throughout 2022, the Clinical Trials Transformation Initiative (CTTI) conducted in-depth interviews with trial designers and implementers of selected trials to identify the barriers and potential solutions to incorporating trials into clinical practice. Through those interviews, along with discussions with a multi-stakeholder project team and other experts, CTTI created a set of recommendations to facilitate embedding elements of randomized interventional trials into clinical practice.
In this article, we provide a rationale for integrating trials into clinical practice, offer design and operational approaches for embedding trials, and discuss the cultural shift needed to facilitate system-wide integration.
Why Should We Embed Trials Into Clinical Practice?
Currently, the clinical trials enterprise functions largely independently from clinical practice settings. Data are often collected and laboratory visits often requested separately for clinical care and for research purposes. Integration of research and clinical care has the potential to expand representative and generalizable evidence by enabling accessibility to patients at the point of care. It also provides the opportunity to use both randomization and real-world data (RWD) in the context of regulatory decision-making and may improve the ability to generate meaningful evidence during the next public health crisis. In addition, by reducing the duplication of trial and care activities, there is a potential to increase trial efficiency and cost savings and reduce the burden on patients participating in research.
What Are Some Trial Design And Operational Approaches For Embedding Trials?
The CTTI recommendations emphasize that elements of a trial can be embedded into clinical practice — and benefits can be gained — regardless of the number of elements integrated (i.e., not an “all or nothing” situation). But it’s important to assess whether clinical trial elements should be embedded into clinical practice by taking a Quality by Design approach. In other words, one should assess feasibility versus benefit in a way that optimizes embedding trial elements that matter to the credibility of conclusions, while avoiding processes that are inefficient or detract from the scientific question and could jeopardize the protection of participants during the trial.
To embed the use of existing healthcare data sources, the recommendations suggest that trial designers verify that data sources are fit for purpose — relevant and reliable. To do so, it’s important to review resources such as EMA guidelines and FDA guidance documents on RWD use and consult early and often with regulatory authorities.
The recommendations also stress streamlining trial design to align with clinical workflows, such as coordinating assessments with care delivery schedules or including endpoints that reflect events seen in routine care so that the operational conduct is minimally disruptive to healthcare providers.
Operationally, healthcare settings and sponsors should ensure site readiness to embed trial elements, including assessing resources and training requirements. It is also important to ensure that good clinical practice (GCP) requirements for participating clinical staff are not compromised, to support efforts to engage community clinicians, and to minimize the participation burden for patients, providers, and research staff. This can be accomplished by leveraging technology and automating, where possible, and by providing appropriate research support staff so that healthcare providers feel assisted and not overwhelmed. The recommendations also encourage the validation of the clinical data for research purposes to ensure that the trial data is complete, plausible, accurate, and traceable. This can be done by assessing for missing data as part of a feasibility assessment, performing periodic manual and automatic checks during the trial, and consulting with clinical and IT staff about potential quality issues related to data fields needed for trial purposes. Using data standards that have health care provider input and comply with healthcare data interoperability laws, such as US CORE data elements and Health Level 7 (HL7) international standards can also streamline the process by enabling interoperable, two-way transferring of data between clinical care and an embedded clinical trial.
How Can We Enable The Cultural Shift Needed To Facilitate The Integration Of Trials?
CTTI’s final two recommendations acknowledge that even the slightest adjustment to workflow requires a change in mindset and culture. There are financial, cultural, and data and technology barriers to overcome. Healthcare system leadership needs to recognize and invest in research activities. Healthcare system leadership should encourage incorporating trials into clinical treatment pathways and clinical decision support systems when appropriate, so that trials are considered an option. Leadership can also credit the time healthcare staff spends on research activities towards their overall productivity assessment and identify improvements in data infrastructure that can serve both care improvement and clinical research.
Government and policy organizations need to promote the basis for and ways to embed trial elements into clinical practice by advancing the message that embedding trials can improve evidence generation, and by supporting reusable networks, learning from trials and consortiums that are paving the way.
Ultimately, the entire clinical trials and health system enterprise has accountability to facilitate a cultural shift, by encouraging and enacting regulatory, reimbursement, and policy changes, developing standards and acknowledging international opportunities to align those standards, and supporting the sharing of learnings.
Facilitating Progress In Clinical Trial Integration
Five case examples accompany the recommendations demonstrating that embedding trial elements into care is possible. The case examples highlight experiences with embedding different components of a trial within and outside the U.S. They review challenges encountered when embedding trial elements, including challenges around site-readiness, data, and culture, and provide words of wisdom to those who might be thinking about integrating a trial into clinical practice.
For instance, the REMAP-CAP study embedded acquisition of data by aligning research outcomes and endpoints to data captured within routine care, appreciating the level of structured data existing and needed. This occurred at sites worldwide. The I-SPY breast cancer trial also embedded data acquisition by aligning research outcomes and endpoints to data captured within routine care for sites across the U.S. I-SPY also aims to integrate trial evidence, to make results of a representative population available in near-real time to clinicians and rapidly translate them into clinical practice.
CTTI acknowledges opportunities for further work that fell outside the scope of their Trials in Clinical Practice project, such as clarifying the ethical considerations when embedding trials into practice. Human participant protection, informed consent, and IRB oversight are as important when embedding trials as for any other clinical research. In addition, there are opportunities to answer questions about delegation of authority and accountability and to develop metrics to determine whether integration of research and clinical practice is improving the quality and efficiency of clinical trials.
In summary, embedding elements of a trial will depend on the ability to: access relevant and reliable data, align trial design with clinical workflow to minimize provider and patient burden, ensure site readiness with appropriately trained staff and technology resources, define clear channels of accountability, and raise awareness of the value of research and its subsequent impact on care.
By enabling healthcare systems to participate in embedded trials and assisting sponsors with their design and conduct, the CTTI recommendations aim to draw attention to areas where efficiency can be gained, identify future needs to encourage the further development of a learning health system, and improve clinical evidence generation.
About The Author:
Lindsay Kehoe, M.S., C.G.C., is a senior project manager at the Clinical Trials Transformation Initiative (CTTI), where she manages the development and implementation of CTTI projects. She has convened teams around disease progression modeling, embedding trials into clinical practice, and using digital health technologies to advance novel endpoint acceptance. Along with her CTTI colleagues, Ms. Kehoe is accelerating progress toward the Transforming Trials 2030 Vision.
Prior to joining CTTI, she was a rare disease specialist in collaboration with the NIH and served as a clinical trial lead and on the hospital’s IRB at Children’s National Medical Center in Washington, D.C. She is a certified genetic counselor with experience in pediatric and adult genetic counseling. She has worked in early phase drug development at Millennium Pharmaceuticals (now Takeda Oncology) and in post-marketing laboratory surveillance at Sanofi Genzyme. Ms. Kehoe has a bachelor’s degree from the University of Virginia and a master’s degree in genetic counseling from Boston University School of Medicine.