On March 29, 2023, the FDA approved the first OTC naloxone nasal spray in the US: https://www.fda.gov/news-events/press-announcements/fda-approves-first-over-counter-naloxone-nasal-spray. PEGUS was pleased to have one of our senior consultants, Sarah Farnsworth, PhD, participate in the 15 February 2023 FDA public advisory committee meeting for nasal naloxone. The committees voted unanimously (19 to 0) in favor of OTC availability.
We warmly congratulate the sponsor on this success, and enthusiastically endorse the approval of nasal naloxone as a new nonprescription product to address the ongoing opioid overdose crisis in the US.
Presentations and other materials from the meeting can be found here: https://www.fda.gov/advisory-committees/advisory-committee-calendar/february-15-2023-joint-meeting-nonprescription-drugs-advisory-committee-and-anesthetic-and-analgesic.
While the meeting was highly successful, the FDA review of the Human Factors Validation Study (HFVS) focused on several concerns or perceived limitations. Here are PEGUS perspectives on those limitations identified by the FDA:
- Age range of adolescent user groups: FDA noted that data collected in the HFVS cannot be generalized to the untested age range (users less than 15 years of age). This is true. However, the HFVS did not include young adolescent participants for the same reason the FDA explained that children less than 15 years of age were not included in their CONFER label comprehension study for the naloxone model DFL (ethical concerns about including younger children in a high-stress simulated research situation, which were echoed by the bioethics and pediatric specialists on the panels).
- Inadequate representation of limited literacy participants: FDA’s HF guidance is silent regarding representation for low-health-literacy (LHL) participants. The HFVS study collected 29.6% LHL overall, and only 2 study groups fell lower than 30% (Adult General Population = 22.2% and Associates of Opioid Users = 27.8%). With small group sizes, that means these groups were each only 1-2 LHL participants below 30%. These small differences are judged to result in zero meaningful bias, especially in a study where LHL participants performed better than normal literacy participants on all primary and secondary endpoints.
- Familiarization period, leading language, and think aloud method: It is true no time limit was imposed on familiarization, but participants were not informed of this or told to take all the time that they needed. Directions to participants were minimal to clearly explain the HF demonstration task while maintaining as much realism as possible for the simulated overdose emergency. Participants were informed that they were free to verbally tell the interviewer what they were doing or would do during task performance if they wanted but were not specifically encouraged or reminded to ‘think aloud.’ Our experience is that participants naturally wish to verbalize as they perform HF tasks, and to our knowledge no data exist to show this meaningfully alters performance (whereas telling participants to remain silent could, conversely, increase discomfort with the research process and impact performance). PEGUS believes these elements were appropriately balanced and did not introduce bias with tendency toward positive performance.
- Data collection methods: FDA opined that:
- Predetermined quantitative performance thresholds were used. A qualitative approach is highly valuable in HF studies, primarily during the iterative, formative process needed to develop a new device or new user interface. However, in the Rx-to-OTC switch context, studies are focused on developing and validating the OTC instructions for use to accompany an existing Rx device. This HFVS was unique because not only is the Rx device established and not expected to change, but most of the OTC labeling as well, per FDA’s directives for implementing the naloxone model DFL. Performance thresholds were used to increase the rigor of the validation, rather than a purely post hoc, qualitative assessment.
- Verbal descriptions of tasks may have been scored as acceptable. FDA’s HF Guidance presents information about including Knowledge Tasks in HF testing, described as tasks that involve users’ understanding of label information, and notes, “certain types of Knowledge Task studies are also used in the development of non-prescription products. Generally, these are quantitative studies that evaluate whether results are statistically significant.”1 Thus, given the combination of tasks to administer naloxone that are best assessed by behavior (Step 2), and knowledge or understanding (other steps on the labeling), the study design included both types of assessments.
- Root cause analysis was not collected in all instances. Qualitative data were gathered from participants and summarized in the body of the study report, and detailed patient listings were provided. However, we acknowledge FDA would have preferred the qualitative information in more detail and grouped by use error type rather than by subject, with additional detail on root cause analysis and potential mitigations.
[1] Draft Guidance for Industry and FDA Staff: Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and Development, p. 12, Downloaded from URL: https://www.fda.gov/media/96018/download
