FDA's OTC Naloxone Model Labels Confirmed In CONFER Study
Executive Summary
Participants in FDA-commissioned CONFER study were scored on following label instructions for checking whether a potential patient has overdosed and administering a naloxone dose before calling for emergency help as well as on a "composite of cognitive walkthrough" of all those steps. Participants were in four groups: adult users of heroin and prescription opioids; those persons' friends and family members 18 years old and up; and separate groups of volunteers, 15- to 17-year-olds and adults.
A study of making naloxone available OTC study supports model Drug Fact labels FDA designed even though agency officials noted concern that some participants didn't meet a "clinically critical endpoint" of contacting emergency services immediately after administering the opioid-overdose treatment.
On Jan. 17, FDA published a report on agency staff's review of independent research contractors' study of label comprehension for OTC use of nasal spray and auto-injector products, Comprehension for OTC Naloxone (CONFER) Pivotal Label Comprehension Study. The report showed the model DFLs were well-understood by consumers and are acceptable for use by manufacturers in support of new drug applications of making naloxone available OTC.
From May 21 through Aug. 2, 2018, the contractors – nonprofit RTI International of Research Triangle Park, M.C., and Concentrics Research LLC, Indianapolis – used a research design set by FDA with 710 participants across a range of potential OTC naloxone users. The model DFLs were a first for FDA (see sidebar).
In addition to the "call 911 immediately" endpoint, the 710 CONFER participants were scored on following label instructions for checking whether a person has overdosed and administering a naloxone dose before calling for emergency help as well as on a "composite of cognitive walkthrough" of all those steps (see tables below for results).
A second set of endpoints in the study were:
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stay until help arrives;
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repeat dose every 2 to 3 minutes until the person is fully awake or until emergency personnel arrive;
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use of naloxone for opioid overdose;
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if they think a person used an opioid and will not wake up or is breathing irregularly, those are signs of overdose.
Participants in CONFER were divided into four groups: adult users of heroin and prescription opioids; those persons' friends and family members 18 years old and up; and two groups of other volunteers, 15- to 17-year-olds and adults.
Primary Endpoints Comprehension: Cognitive Walkthrough
of the eight primary endpoints in the tables above and below, six met or exceeded the Lower bound threshold and seven exceeded the point estimate scores of 90%.
Comprehension for OTC Naloxone Pivotal Label Comprehension Study – FDA Report
FDA reported that 237 participants (33.4%) were of low literacy. The agency designed the study to include at least 30% low-literacy participants "to ensure that there would be an adequate number represented in the study to assess comprehension in the low-literacy population," according to the report.
Officials including the director of FDA's Division of Nonprescription Drug Products said in their review of the study that analysis of data from the research suggests that comprehension of the call 911 immediately "endpoint may be higher than was captured, particularly in the population most likely to use naloxone."
Additionally, FDA staff say in their review that 88% total score for the endpoint "was close to meeting" 90% lower-bound (LB) threshold for correct-acceptable, while the results "were very conservatively coded," meaning that responses likely were recorded as incorrect when researchers determined that some doubt remained whether it was correct.
"Because naloxone is a potentially life-saving treatment, it may be reasonable to consider a LB of 88% to be acceptable. If naloxone is given and most users call 911, many lives can be saved, and this is a much better alternative than not giving naloxone at all," FDA staff wrote.
Primary Endpoints Comprehension: Questionnaire and Cognitive Walkthrough
They added, though, that "it is important that efforts continue to ensure the best possible comprehension of this message."
At Harm Reduction Therapeutics Inc., a Pittsburgh-based non-profit working on an Rx-to-OTC switch for naloxone, CEO Michael Hufford agreed with FDA's conclusion about the study results and about the call 911 endpoint score.
"While the 'call 911 immediately’ endpoint was missed, the agency clearly understands that the risk-benefit calculus around naloxone is truly unique among OTC products, as its effects are acutely life-saving," Hufford said in an email.