The National Center for Complementary and Integrative Health (NCCIH) provides support for research on a broad spectrum of complementary health approaches, with the goal of developing scientific evidence to inform clinical decisions by the public, health care providers, and health policymakers.
Evidence from the scientific literature may provide a plausible rationale for clinical investigation of many complementary interventions. However, investigators often lack critical information about biological effects of the intervention, outcome measures, logistical feasibility, or recruitment and retention strategies needed to design a rigorous and successful efficacy or effectiveness trial. In most cases exploratory or developmental research and pilot testing is needed to address these and related issues prior to the design and initiation of large-scale clinical studies.
Multi-phase paradigms for addressing these research needs have been very well described for pharmacologic interventions, and successfully applied to the study of many dietary supplements, botanical medicines, and probiotics. The figure above provides an analogous conceptual framework for thinking about some of the unique challenges inherent in developing and testing mind and body interventions.
The purpose for this framework as it applies to NCCIH’s interest in mind and body clinical research is to:
- Provide a conceptual framework for NCCIH’s clinical research in the mind and body program
- Clearly delineate the purpose of each stage of research development and testing
- Help investigators align their research interests, questions, and approach with the appropriate stage of development
- Provide some guidance on the available or appropriate funding mechanism(s) for each stage of research.
While this framework is presented in a linear fashion, investigation can be proposed at any stage along this continuum depending on extant data, the research environment and question, the clinical population, and the investigative team, among other factors. Below, each stage (circle) of the conceptual framework is further described.
Studies To Demonstrate Clinically Meaningful Signal
The initial stage in the conceptual framework is to determine whether the intervention of interest can demonstrate a biologically and/or clinically meaningful and measurable effect when employed. This initial detection of a signal and approximations of its variance can be demonstrated in a variety of methods including: a case series, a small uncontrolled trial looking at pre-post outcomes, or a retrospective chart review. This is an initial assessment to determine whether the potential impact of the intervention is strong enough to warrant investment in further research on the specific indication that was assessed.
Intervention Development, Refinement, and Standardization
Rigorous clinical research requires an intervention that can be reliably replicated in independent research. Hence, at this stage the intervention is more fully developed, refined, and/or standardized for research purposes. This may require determining the appropriate dose, frequency, or duration of the intervention; an optimal method of intervention delivery (e.g., in person, online, etc.); the appropriate participant population; and the outcomes and measurement tools that will be used in subsequent, more definitive studies to assess those outcomes. An intervention manual is developed and refined so that the intervention can be delivered consistently to all research participants. The intervention refinement is often done in an iterative process with the third stage of pilot testing the intervention.
Feasibility and Pilot Studies
This stage involves pilot testing in a patient population likely to be involved in subsequent studies. This is where the feasibility and acceptability of the intervention can be assessed to determine whether participants can/will adhere to the protocol (attend all visits, perform or tolerate the intervention, complete study measures, etc.). Recruitment and retention methods are tested to demonstrate that the enrollment criteria identify the appropriate patient population and exclude those that cannot safely (or appropriately) participate in the study. This sometimes identifies a need to go back to stage 2 to further refine the intervention protocol, recruitment/retention methods, enrollment criteria, or study measures. The culmination of this stage is a pilot study to determine whether a subsequent larger study of the fully refined intervention can be successfully implemented, and provide robust and clinically useful evidence regarding efficacy and safety. Although this pilot is usually not sufficiently powered to determine statistical significance of efficacy, it should provide reliable estimates of effect size that are needed to design efficacy studies.
Efficacy Studies With Appropriate Comparison
The fourth stage is the typical efficacy trial to test the clinical benefit of an intervention when delivered in a setting optimized to detect an effect (best-trained providers, specific enrollment criteria, extensive followup, precise study protocol, etc.). Trials are fully powered to detect significant differences in outcome compared to a clinically relevant control group, and therefore usually include a large number of participants. The selection of the appropriate comparison group requires careful thought by the investigators. Each option for the comparison group slightly changes the research hypothesis of the trial and may have a profound impact on the number of participants needed. For example, a time and attention comparison group in the same frequency and duration as the study intervention will provide a “control” intervention, thus the hypothesis will assess whether the specific intervention has benefit beyond the attention paid to the participants. In contrast, an active comparison group that is known to have benefit could be used to determine if the new study intervention is as good as or better than the active control. In this case, the trial is a non-inferiority design and will usually require many more participants than a time and attention control.
Effectiveness or Comparative Effectiveness Research
This stage aims to determine effects of the intervention as it would be administered in the health care setting (as opposed to an optimized research setting). Effectiveness trials typically involve a broader and more heterogeneous range of providers, generally have less restrictive enrollment criteria resulting in greater heterogeneity in the participants, and typically allow a greater degree of flexibility, which mimics more closely the setting of real-world health care. This enhanced heterogeneity of participants and intervention delivery often results in a smaller effect size than was seen in the more precisely controlled efficacy trial, so power calculations should take this into account. Specific forms of effectiveness trials include comparative effectiveness where two or more interventions are compared; and cost effectiveness research, which gathers additional data on the costs of the intervention and other relevant cost information. There are some scenarios in which the most relevant research question is an effectiveness study rather than an efficacy study; however, it is more common for an efficacy study to be conducted prior to effectiveness trials.
Dissemination and Implementation Studies
The final stage of the intervention development process is to take those interventions that have been found to be efficacious and/or effective and determine how to best disseminate and get the interventions implemented into clinical care. There are research methods to assess how best to improve uptake of interventions into health care systems or to enhance the public’s utilization of a particular intervention. For useful interventions to have the largest public impact, researchers should continue their work to learn how best to disseminate and implement interventions that have been found to be beneficial.