The Biotechnology Industry Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments on the “Draft Guidance on Classifying Significant Postmarket Drug Safety Issues.”
BIO represents more than 1,100 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products, thereby expanding the boundaries of science to benefit humanity by providing better healthcare, enhanced agriculture, and a cleaner and safer environment.
FDA should be applauded for providing this guidance to help FDA and industry align the way we assess our safety signals. BIO believes that the overall framework makes good sense. The process for the classification of standard vs. priority is clear. As discussed in our general comments, more examples or specific thresholds may be helpful for readers to understand the standards that FDA is going to follow in the classification of priority for significant postmarket drug safety issues.
A. Algorithm To Identify Safety Issues:
We request a description of the algorithm used to identify safety issues. It would be helpful to know what algorithm or method of detection FDA is using, as the nature of this method will affect the number and type of issues identified. This knowledge would also allow sponsors to take into account FDA’s methods when establishing their own methods.
B. Threshold for a TSI Classification:
We suggest that the guidance specify the overall thresholds that would lead a tracked safety issue (TSI) to be classified as priority, emergency, or standard. This knowledge would be useful in helping sponsors ensure that their internal criteria for escalation of safety issues are in line with FDA criteria. In the spirit of harmonization, and in recognition of the global nature of drug development, we further suggest that FDA consider aligning its criteria with those used by other countries’ regulatory agencies (e.g. EudraVigilance Statistical Signal Detection Methods1).
C. “High Priority” TSI
We also note that the guidance introduces the concept of an “emergency” TSI (lines 131-133). The classifications for standard and priority TSIs are discussed at length, but the Draft Guidance does not speak to the process for classifying a TSI as an “emergency.” Since most safety signals have not yet been verified at the time of TSI designation, declaring an emergency situation may be pre-mature and potentially contribute to unnecessary alarm or panic. We suggest that the term be removed or the more balanced term “high priority” be used in lieu of “emergency.” If the “high priority” classification is adopted, we still encourage the Agency to articulate under what circumstances this classification will be employed.
D. Timelines for Acting on TSIs:
We recommend including overall timelines for FDA action on priority, emergency, and standard TSIs, as well as a plan for communicating these timelines to affected sponsors. Currently the guidance only alludes to further delineation of an operational framework, in the Next Steps section. The earlier sponsors are notified, the better able they will be to contribute to the assessment in a timely fashion—for example, by performing their own data analysis and informing the FDA of the results.
E. Potential Outcomes from a TSI:
We would like the guidance to specify potential outcomes from a TSI, such as asking the manufacturer to revise product labeling. We also request a better description of how FDA works with the sponsor and how that might change based on whether a TSI is classified as standard, priority, or emergency.
F. TSI Triggered by Similar Products:
Please specify whether safety issues of a similar product can be the basis for a TSI, and, if so, provide an example, such as hepatotoxicity of a follow-on drug where identified for a first-in-class drug.
G. Communication with Sponsors
With some TSIs, there is little to no communication from the FDA to the sponsor about the ongoing assessment (methods used, scope of the TSI, etc.) until a regulatory action is requested. In order to improve the transparency of the Agency’s decisions, we suggest that the Agency discuss with the sponsor the scientific methods and regulatory action being sought. We recommend that the process be revised to include at a minimum a teleconference with the sponsor to share the Agency’s findings at the conclusion of the TSI review. Even if this is not deemed feasible, sponsors must be informed, at a minimum at the time of TSI initiation, of the nature and classification of the TSI (priority, emergency, or standard).
BIO appreciates this opportunity to comment on the “Draft Guidance on Classifying Significant Postmarket Drug Safety Issues.” Specific, detailed comments are included in the following chart. We would be pleased to provide further input or clarification of our comments, as needed.