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IRB Review of Adaptive Design Studies

February 24th, 2017 by Michele Russell-Einhorn, JD, VP of Human Research Protection Services and Institutional Official

The popularity of adaptive design in clinical research continues to grow. Adaptive design can be more efficient than traditional study design, and it can help speed decision making. Considering these benefits, plus the ever-increasing cost of conducting clinical research, it’s no wonder adaptive design is so appealing to researchers.

Adaptive design may involve changes to study eligibility, treatment arms and regimens (like dosage and duration), randomization procedures, schedule of events, primary and/or secondary endpoints, and other elements of a study all on an on-going basis. Consider the following characteristics of good adaptive design:

  • It is proactive—changes are made based on pre-planned decision points in the study, not unplanned reactions to things that happen as the study moves along.
  • It does not reduce the study’s integrity.
  • It provides benefits or enhancements to the overall study design strategy.
  • Adaptations are typically based on study data.
  • It can be carefully and safely implemented.
  • Depending on the situation, it can involve clinical, statistical and/or regulatory aspects of a clinical trial.

IRBs that continuously review changes in research can certainly understand the need for innovative approaches like adaptive design. When reviewing a study that incorporates adaptive design, an IRB will need to pay particular attention to the study’s scientific validity, subject safety, informed consents, and the research site’s qualifications. One problematic area is that the risks for subjects may well change when the design of the study changes. For each of these elements, I’ve assembled typical questions an IRB may ask during review. These may also be useful for researchers to consider as they develop adaptive design studies.

Scientific Validity
  • Are basic good design principles (like those listed above) in place?
  • Is there a benefit to the adaptive design?
  • Is there sound design that will answer the research question(s)?
  • Has bias been introduced by the adaptive design?
  • Does blinding, where appropriate, remain intact?
  • Will the results reflect the target population?
Subject Safety
  • Is there adequate preclinical data to support the design?
  • Are the right safety measures and monitoring plan in place?
  • Is there appropriate data and safety monitoring?
  • Are adaptive options clearly and definitely described?
  • Are things like safety criteria, stopping rules, maximum doses, and other protections well defined?
  • How are dosing schedules described in the protocol?
  • Is there sufficient time to assess safety data prior to decision points?
  • Who will be making the decisions at the decision points?
  • How are decisions documented and reported?
  • What are the contingency plans if safety issues should arise?
Informed Consent

In addition to standard requirements, IRBs will also consider how the informed consent form (ICF) addresses the following:

  • The design’s level of complexity
    • Break it up where possible to help ensure comprehension
  • Differences between treatment arms
    • Include risk language that relates to the individual participant’s participation
  • Design elements that address safety
    • Communicate boundaries and safeguards
  • How treatments are assigned
    • Do participants have a choice?

Bear in mind that describing the expected changing nature of the research in the ICF can be challenging.

Research Site Qualifications
  • Expertise of the principal investigator and his/her staff
  • Experience levels are appropriate for the complexity of the design
  • Staffing levels at the site and experience
  • Facilities and equipment are appropriate for the particular study
  • Emergency readiness
  • Contingency plans

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Adaptive study design can be a smart and effective strategy that offers many benefits. When developing a study with adaptive design, be sure to pay close attention to these added complexities to help ensure participants are appropriately informed and protected.

Want to learn more about adaptive design? View our webinar on adaptive design in Phase I studies.