FDA labeling study helps clear path for OTC naloxone

Regulatory NewsRegulatory News
| 28 May 2020 | By Kari Oakes 

Consumers reading a model drug facts label for naloxone could understand labeling sufficiently to use the opioid antagonist safely and effectively without the support of a healthcare provider, according to a label-comprehension study conducted by the US Food and Drug Administration (FDA).
The unusual move by the FDA could help clear a hurdle to approval of over-the-counter injectable and intranasal naloxone; many public health experts concerned about the impact of the opioid crisis have called for wide access to the potentially life-saving drug. Naloxone rapidly reverses many of the signs and symptoms of opioid overdose, especially life-threatening respiratory depression, and may safely be given repeatedly during overdose treatment.

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In the FDA’s study of 710 adults and adolescents that included opioid users, their families, and individuals with low health literacy, participants met six of eight pre-specified thresholds of 80-90% in understanding all steps to administer naloxone to reverse opioid overdose, as well as additional concepts outlined in the model label.
The study, published Wednesday in the New England Journal of Medicine, found that point estimate scores for all but one of the endpoints exceeded 90%. The endpoint that did not meet the 90% threshold was the step that directed 911 to be called; here, the point estimate was 90.3%, but the confidence interval fell just below the prespecified cutoff.
“The regulatory challenge for any industry sponsor seeking approval of an over-the-counter drug product in the United States is to provide evidence through consumer studies that consumers can safely and effectively use the product without guidance from medical professionals,” wrote Barbara Cohen of the FDA Division of Nonprescription Drug Products, Office of New Drugs, Center for Drug Evaluation and Research, the study’s first author. “Potential industry sponsors have previously stated that the requirements for developing a label for over-the-counter naloxone and for assessing the effectiveness of the label through comprehension studies present barriers to bringing naloxone to the over-the-counter market.”
In developing the proposed label, Cohen and coauthors drew from prescribing information for Evzio and Narcan, two prescription opioid antagonists approved for community use.
Techniques that the FDA used to increase usability of the proposed model naloxone label included the use of ample white space and boldface type as well as breaking information into more easily understood “chunks.” The five steps involved in naloxone administration are also accompanied by pictographs.
Refinement of the label came during an initial qualitative phase of research, during which both the pictograms and the label language underwent multiple revisions based on feedback from in-depth one-on-one interviews with 36 participants. Then, a pilot label study involving another 36 participants allowed refinement of the study questions and protocol.
“FDA social scientists, statisticians, and clinicians designed a label-comprehension study that incorporated best practices from the FDA’s Guidance for Industry: Label Comprehension Studies for Nonprescription Drug Products,” noted Cohen and coauthors.
The study included “cognitive walkthroughs” completed by investigators in a one-to-one interview with participants. The walkthrough technique has not previously been used in nonprescription label comprehension studies. Cohen and her collaborators explained that  participants were asked to imagine that they were in a situation in which they had to use a product on a friend and to state how they would do this, on the basis of the instructions on the label. This allowed interviewers to assess how well participants understood both the steps to administer naloxone and the order in which they should be performed.
Primary endpoints of the study included the percent of participants who understood each of the five steps in the directions. Thresholds for understanding of these five steps were set at 85%, except for step 3, “Call 911 immediately,” which was deemed so important that the threshold was set at 90%.
For these primary endpoints, the threshold was met if the lower boundary of the 95% confidence interval for results for that endpoint was at or above the threshold.

Two additional primary endpoints were understanding of product use and signs of overdose as described on the label. These were each assigned target understanding thresholds of 80%.
Secondary endpoints, which did not have target thresholds assigned, included understanding of the following items on the label: That individuals might have symptoms after naloxone administration, that it is safe to repeat naloxone dosing, that the “call 911” step is completed in the correct order and performance of the five steps of the instructions.
Of the 710 participants, 430 either used opioids or were friends or family members of opioid users. An additional 280 participants from the general public also completed the interview; across both subgroups, one third (33.4%) had limited health literacy as assessed by the Rapid Estimate of Adult Literacy in Medicine or the adolescent version of this test. Participants were balanced by sex and slightly fewer than one third (31.1%) identified themselves as black.
Though the study did not quite meet the prespecified comprehension threshold for the “call 911” step, Cohen and her coauthors noted that responses to comprehension of this step were coded conservatively; many responses that were coded “incorrect” for not meeting strict criteria still mentioned calling 911 at some point in the naloxone administration process. “We think that industry sponsors should continue to consider additional ways to highlight ‘call 911’ on the label,” observed Cohen and her colleagues. They added, “It should be noted that performance on this endpoint was similar to that observed in many other successful label-comprehension studies in which the labels were ultimately approved on the basis of the overall assessment of benefit as compared with risk.”
The study’s overall success overcomes a big hurdle in securing over-the-counter naloxone availability, said Cohen and her colleagues: “We encourage industry sponsors to use this model label to accelerate development initiatives that will ultimately allow for wider access to naloxone.”
Cohen and colleagues reported no relevant conflicts of interest regarding their research.


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