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Clinical Trials Utilizing Innovative Study Designs To Assess Complementary Health Approaches and Their Integration Into Health Care

Introduction and Explanation of Need

To achieve the NCCIH mission of defining the usefulness and safety of complementary and integrative health care interventions (i.e., both mind and body modalities and use of natural products) and their roles in disease prevention, improving health, and managing symptoms, NCCIH supports clinical trials to assess the safety, efficacy, and effectiveness of these approaches. Efficacy studies supported by the NCCIH clinical research portfolio use standard randomized controlled trial designs. In general, however, a pilot or feasibility study is conducted prior to an efficacy study, and it typically focuses on establishing the frequency and duration of the intervention; selection of the appropriate patient population and outcome measures; ability of the participants to adhere to the study intervention requirements; and demonstration that the team can recruit and retain participants. For natural product clinical investigations, additional pharmacokinetics studies, identification of biological signatures, and determination of appropriate dosing may be needed before launching a larger efficacy study.

For larger scale studies, NCCIH can take advantage of recent innovations in designs and methodologies. Examples include establishing optimal doses using Bayesian dosing studies and assessing effectiveness in a more generalizable population and in real world settings using pragmatic cluster randomized trials or stepped wedge designs. Electronic record data within health care systems can also be used to leverage extant patient-centered data for generating hypotheses and examining the use and possible effectiveness of complementary and integrative health approaches. If these interventions are found to be beneficial, there are also innovative methods for investigators to study how they can be integrated into health care systems effectively and efficiently with dissemination and implementation studies. A targeted approach for which innovative study designs can be utilized and when they are appropriate will assist in shaping a strong NCCIH clinical portfolio.

What Does Success Look Like?

The clinical portfolio will comprise standard randomized controlled trial designs to assess the safety and efficacy of complementary health approaches, and when appropriate, trials with innovative designs to address unique hypotheses about what complementary health approaches are most effective, for whom, and under what conditions. Pragmatic clinical trials conducted within health care systems will be able to address hypotheses that inform the delivery of health care to patients and inform health policy decisions that have the potential to improve health care outcomes.

The incorporation of innovative designs in early-phase clinical studies will result in more optimized interventions and a better understanding of the dosages of natural products needed to be able to detect benefit (if it exists). The utilization of innovative effectiveness studies will result in leveraging existing infrastructures for data collection and reducing costs for trials, thus allowing NCCIH to fund more large-scale trials.


Early-Stage Clinical Studies

  • Utilize innovative early-phase methods such as Bayesian estimation dose-finding approaches, that are flexible, involve fewer participants, and can be used to identify safe and tolerable doses for natural products.
  • Encourage Multiphase Optimization Strategy (MOST) designs when mind and body interventions need to be refined, to determine which components are necessary to achieve the benefit, or when interventions are being combined, to determine which components need to be maintained.

Efficacy of Effectiveness Studies

  • Conduct pragmatic clinical trials to address questions about the integration of complementary health approaches into health care systems, or to study the effectiveness of complementary or integrative approaches in comparison to standard care.
  • Apply lessons learned from the NIH Health Care Systems Research Collaboratory pragmatic clinical trials initiative such as biostatistical guidelines for cluster randomization and recommended methods for data extraction from electronic medical records, to study the impact of complementary health approaches such as interventions for pain management and comorbid conditions, in health care systems such as the Veterans Health Administration and the Department of Defense’s TRICARE.
  • Utilize innovative designs such as Sequential Multiple Assignment Randomized Trials (SMART) for developing treatment algorithms or stepped-care strategies to determine the sequence of interventions, or at what times an intervention should be reassessed and modified.

Areas of Low Programmatic Priority

  • Large-scale clinical trials of mind and body interventions when there are no preliminary data to determine appropriate dose, duration, and frequency or whether the patient population can adhere to the proposed intervention.
  • Large-scale clinical trials of natural products when there are no preliminary data demonstrating the availability, bioavailability, and pharmacokinetics of the product; a replicable effect on a biologic signature; and dosing studies to determine the appropriate dose to impact the biologic signature.
  • Pragmatic trials of interventions that do not have preliminary data demonstrating clinical efficacy or effectiveness in large controlled trials.

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