FDA Finalizes Guidance On Adaptive Clinical Study Designs
By Jof Enriquez,
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Final guidance from the U.S. Food and Drug Administration (FDA) for staff and sponsors lays out how to plan and implement adaptive designs for clinical studies when used in medical device development programs and submissions for Premarket Approval Applications (PMA), premarket notification (510(k)) submissions, de novo submissions (Evaluation of Automatic Class III Designation), Humanitarian Device Exemption (HDE) applications and Investigational Device Exemption (IDE).
In May 2015, FDA issued draft guidance for adaptive design, defined as "a clinical trial design that allows for prospectively planned modifications based on accumulating study data without undermining the trial’s integrity and validity." If implemented properly, FDA says, adaptive design can result in faster, more efficient, and more successful clinical studies.
The agency received 151 comments from seven entities, including the Advanced Medical Technology Association (AdvaMed), on the draft guidance and “incorporated most of them in this final guidance,” according to RAPS.
The final guidance can be applied throughout the clinical development program of a medical device, from feasibility studies to pivotal clinical trials, but does not apply to clinical studies of combination products or codevelopment of a pharmaceutical product with an unapproved diagnostic test, FDA states in a notice in the Federal Register.
Entitled, Adaptive Designs for Medical Device Clinical Studies, the final guidance document identifies both advantages and limitations of adaptive designs. Advantages include "more timely development decision-making" and the protection of patients from "ineffective or unsafe treatments and interventions at the earliest possible stage." Possible limitations include more complex planning and the potential for operational or statistical bias in evaluating the effect of an investigational device, though FDA outlined ways to minimize bias, as well as how to control the chance of erroneous conclusions.
For sponsors of a pivotal study deciding between an adaptive or a non-adaptive design, FDA recommends that they gauge the likelihood of multiple scenarios and calculate – through analytical techniques or computer simulation – for the adaptive design the chance of success, the average size of the study, and the operating characteristics, and then compare it with the characteristics of a non-adaptive design.
FDA provides several examples of adaptations using unblinded data, and recommends that details of proposed adaptations be clearly identified in submissions, which should contain information about “what, when, how, and why the adaptation will be performed.”
“The adaptation should be prospectively described at least generally in the protocol and in detail in the Statistical Analysis Plan, which should include the operating characteristics of the design,” states FDA.
The final guidance also itemizes special considerations, including those for diagnostics devices. It also describes the role of Data Monitoring Committees (DMCs) and Institutional Review Boards (IRBs) in the conduct of adaptive studies.
FDA emphasized the importance of holding pre-submission meetings between the agency and sponsors of pivotal studies utilizing adaptive designs.
“Procedures to ensure the proper conduct of adaptively-designed studies should be put into place so the study will provide valid scientific evidence that can be relied upon by the FDA to assess the benefits and risks of the investigational medical device.” states FDA. “Sponsors are strongly encouraged to discuss the planning of adaptive clinical study designs with the appropriate FDA review division in advance; the Agency has established mechanisms to enable such interactions in a timely and efficient manner.”