The US Food and Drug Administration (FDA) has adopted a practical Q&A from the International Conference on Harmonisation (ICH) to help sponsors and CROs craft clinical study reports (CSRs), an expert says.
The Q&A focuses on the fact that the ICH E3 guidance from 1995 should not be misinterpreted as a set of requirements and that “rigid application” of the original guidance “can result in a cumbersome study report that can be redundant and unclear,” Donald Costello, executive director and global head, medical writing and publishing at Covance told In-Pharmatechnologist.com.
“In any CSR the ultimate goal is to present the study results to the regulatory reviewer clearly, accurately, and concisely,” Costello said.
The ICH Q&A also responds to problems related to the display of adverse event data in CSRs. “The presentation in the text of the report should be a reasonable length subset of the most frequent AEs, not the whole list,” Costello noted.
But when adverse event data are presented by subgroup, a display of overall adverse events should be included, the Q&A adds. “For example, for a drug for subjects with chronic kidney disease, adverse events could be tabulated separately for subjects receiving or not receiving dialysis, but a table that includes adverse events in all subjects should also be included,” it says.
The ICH also “answers a question that people have been arguing about for 15 years: what are the definitions of protocol deviations, important protocol deviations, and protocol violations. For that alone, it is worth reading the update,” Costello said.
The guidance defines a protocol deviation as “any change, divergence, or departure from the study design or procedures defined in the protocol,” whereas important protocol deviations are a subset of those “that might significantly affect the completeness, accuracy, and/or reliability of the study data or that might significantly affect a subject's rights, safety, or well-being.”
Important protocol deviations might include enrolling subjects in violation of key eligibility criteria designed to ensure a specific subject population or failing to collect data necessary to interpret primary endpoints. In addition, a protocol violation and important protocol deviation are “sometimes used interchangeably to refer to a significant departure from protocol requirements,” the ICH notes.
Documentation needed to review CSRs should also not only be included in the trial master file (TMF) but in the CSR appendices as well, because the TMF is not submitted in the marketing application, the ICH says.
But supportive documents -- such as investigator curricula vitae, ethics committee approvals, informed consent forms, and batch numbers per subject – should be included in the TMF or clinical supply database and should generally not be included in the CSR appendices, according to the Q&A.
The FDA was the last regulator to adopt the Q&A as the EU adopted it in July 2012, when it first came out, while Japan’s Ministry of Health, Labour and Welfare adopted it in October 2012.