Determining whether a Behavioral or Social Science Focused Clinical Trial is Phase II or Phase III

I want to share some new resources for behavioral and social scientists to use when considering whether the trial they are planning is a Phase II or Phase III clinical trial. Distinguishing earlier phases of clinical trials (Phase 0 or I) is not usually difficult; however, distinguishing between a Phase II and III trial can be more challenging, particularly for non-drug clinical trials. It is important to delineate this distinction for a variety of reasons, not least of which is that a Phase III designation for an NIH-funded clinical trial generally requires following additional policies and practices beyond those that already apply to Phase II clinical trials, such as the requirement for a valid analysis and for a Data and Safety Monitoring Board (DSMB).

Across research or regulatory agencies, there are varying definitions for clinical trial phases. Prior to describing the resources, I want to start with the NIH definitions for Phase II and III trials.

  • Phase II trial definition included in the NIH glossary of terms is:
    • An NIH-defined Phase II Clinical Trial that studies the biomedical or behavioral intervention in a larger group of people (several hundred) to determine efficacy and further evaluate safety.
  • As indicated in the NOTOD-18-014, the NIH defines a Phase III trial as follows:
    • An NIH-defined Phase III clinical trial is a broadly based prospective Phase III clinical investigation, usually involving several hundred or more human subjects, for the purpose of evaluating an experimental intervention in comparison with a standard or controlled intervention or comparing two or more existing treatments. Often the aim of such investigation is to provide evidence leading to a scientific basis for consideration of a change in health policy or standard-of-care. The definition includes pharmacologic, non-pharmacologic, and behavioral interventions given for disease prevention, prophylaxis, diagnosis, or therapy. Community trials and other population-based intervention trials are also included.

The following are two new resources that can support behavioral and social scientists determine the appropriate phase designation for their planned trial—

  • Decision Support Tool: Features to Consider in Determining if a Clinical Trial is Phase II or Phase III. This document is the result of a working group led by OBSSR, with participants from other NIH Institutes, Centers, and Offices. It is designed to be a resource to help investigators, program officers, and reviewers determine if a behavioral or social science study is better characterized as a Phase II or a Phase III clinical trial. It can assist researchers by outlining features to consider, including the selection of a comparison condition, number of participants and sites, and the duration of the trial, and how those decisions might differ depending on the phase.
  • In October 2022, I was a guest, alongside Ms. Dawn Corbett, NIH’s Inclusion Policy Officer, on an episode of NIH’s All About Grants podcast, where we talked about Phase III trials, comparing them to earlier phases of clinical trials. In addition to delving into some distinctions about Phase III trials, a key takeaway for listeners of the podcast is —the best approach for researchers is to engage their program officer at NIH early on about phase determination and the accompanying requirements, addressing any discrepancies in perspective in advance, and then coming to an agreement on the best path forward.

Clarity on phase designation has implications for the application itself, the peer review process, as well as monitoring if the trial is funded. My hope is that these two resources are of assistance to behavioral and social science investigators as they make distinctions between Phase II or III within their team and in discussions with their NIH program officer.