Clinical research organizations along with pharmaceutical and biotechnology companies called for certain clarifications and terminology harmonization in the US Food and Drug Administration’s (FDA) recently released draft guidance on adaptive clinical trial designs.
The Association of Clinical Research Organizations (ACRO), the Biotechnology Innovation Organization (BIO) and Janssen Research and Development, among others, submitted
comments to FDA just ahead of the Friday deadline to provide feedback on the draft guidance issued
in September. Their recommendations seek to ensure consistency in implementation of the new policies across sponsors.
A common theme across comments from ACRO, BIO and Janssen relates to a lack of harmonization in the draft guidance’s use of certain terms, including the term “interim analysis.” This type of analysis is conducted on data generated while the trial is ongoing and can be used for trial protocol modifications.
ACRO and BIO took issue with the decision to deviate from the “interim analysis” definition developed via the International Council for Harmonization (ICH) and adopted in FDA’s 2017 addendum
to ICH E9: Statistical Principals for Clinical Trials
. ACRO argued the different definitions “may result in confusion for sponsors” developing adaptive clinical trials of drugs and biologics and recommended adopting the term “intermediate analysis” to avoid confusion, while BIO argued for retaining the ICH E9 definition.
ACRO also raised concerns with the use of the terms “effectiveness” and “efficacy.” This is because the draft guidance proposed to use the former in the context of real-world evidence and the latter for study results, the group noted. Janssen echoed these concerns and urged the agency to promote consistency in use of these terms and add definitions for both in the draft guidance’s “important concepts” section.
Another shared concern among commenters involves early interactions with agency staff to ensure a sponsor’s development program is aligned with FDA policies on adaptive studies. “The guidance should encourage and indicate FDA’s willingness to discuss the adaptive design considerations early in the planning period,” Janssen said. BIO recommended further promoting early FDA interactions as well.
BIO and Janssen also called for clarifications on recommendations for adaptive designs in early-phase exploratory trials. Janssen suggested rephrasing the language in the draft guidance around early stopping to state that this process “should ensure that the potential reduced size of the study will allow an adequate sample size for safety as well as relevant information for important secondary endpoints.”
Other concerns among commenters include stating the role of “interpretability” in the context of what FDA deems to be a reliable estimation of treatment effects, clarifying expectations in demonstrating estimation of bias as well as identifying the benefits and disadvantages of using adaptive study designs.
All three commenters, however, also commended FDA’s move to issue the draft guidance and set the stage for planning and applying adaptive study designs in accordance with the agency’s expectations.
“Janssen believes that the guidance will facilitate wider use of these innovative and more efficient designs in drug development,” said Mike Krams, head of quantitative services at Janssen Research and Development.
The draft “offers greater opportunity for discussion and agreement between sponsors and FDA on different options of adaptive designs to support regulatory decision-making,” Krams added.