Is 2023 the Year for OTC Naloxone?

On February 15, 2023, the Nonprescription Drugs Advisory Committee (NDAC) and the Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) held a joint meeting to discuss an application pending before FDA that would switch Narcan (naloxone) Nasal Spray from prescription to over-the-counter (OTC) status.  All 19 members of the joint Advisory Committee agreed that the benefit-risk profile of Narcan Nasal Spray (NNS) is “supportive of its use as a nonprescription opioid overdose reversal agent.”  While this outcome is non-binding, an Advisory Committee’s recommendation—particularly a unanimous recommendation from a joint Advisory Committee meeting—does hold significant weight with FDA.

Background

FDA has faced mounting pressure in recent years to take meaningful action in response to the ongoing opioid crisis.  For the 12-month period ending September 2022, over 100,000 drug overdose deaths were reported.  In August 2022, FDA announced the creation of the Overdose Prevention Framework with the vision to “undertake impactful, creative actions to prevent drug overdoses and reduce deaths.”  We previously blogged on FDA’s September 2022 guidance exempting and excluding specific naloxone transactions (e.g., sales of naloxone from a wholesale distributor to a harm reduction program) from certain requirements under the Drug Supply Chain Security Act.  The Framework also includes an action to support the goal of encouraging harm reduction as expanding availability and access to overdose reversal products, including naloxone, by supporting accelerated product review and “exploring over-the-counter access.”

Many states already have standing orders that allow for the dispensing of naloxone without an individual prescription and other public health initiatives to increase naloxone access.  For example, here in the District of Columbia, residents can access naloxone (free of charge with no identification requirements) at designated pharmacies throughout the District or have naloxone shipped to their address.  While laypeople are already using NNS in a number of states, FDA has cautioned that the current community use differs from OTC use because many of these programs provide patient counseling and instructions for use that go beyond what is included in the current NNS labeling.

The scope of the standing orders varies significantly state-by-state and both harm reduction experts and FDA agree that the prescription status for naloxone continues to pose a barrier to wider access.  However, FDA cannot unilaterally switch a product from prescription to OTC status.  A sponsor must submit a new application or efficacy supplement to an existing application for an Rx-to-OTC switch that includes both efficacy and safety data demonstrating that the drug is safe to use in the nonprescription setting, as well as data that demonstrate consumers can use the drug safely and effectively without the supervision of a healthcare professional.

With the Rx-to-OTC switch objective in mind, FDA took the “unprecedented” step of developing and testing a model drug facts label (DFL) for OTC naloxone and published a label comprehension study and model DFLs for naloxone administered via nasal spray and auto-injector in 2019.  In November 2022, FDA published a preliminary assessment that certain types of naloxone products (nasal spray up to 4 mg, autoinjector up to 2 mg) “may be approvable as safe and effective for nonprescription use.”  Essentially, FDA already prepared a sample DFL and made the preliminary determination that there are sufficient safety and efficacy data to support an Rx-to-OTC switch, but still needed product-specific data on the nonprescription user interface design, including packaging and labeling, to make a conclusive determination.

February 2023 Advisory Committee for NNS Rx-to-OTC Switch

Narcan Nasal Spray was originally approved by FDA in November 2015 (NDA 208411).  In September 2022, the sponsor, Emergent BioSolutions, submitted an efficacy supplement for a full Rx-to-OTC switch of NNS which was the subject of this week’s joint Advisory Committee meeting.  To support their application, the sponsor conducted a human factors validation study (HFVS) designed to verify that participants from all representative user groups could use the proposed DFL to appropriately administer NNS in a simulated overdose setting.  Other than the product-specific administration directions in Step 2, the sponsor’s proposed DFL is adopted verbatim from the FDA model DFL.  The primary endpoints of the HFVS were to evaluate if participants could successfully perform the following product-specific dosing tasks using only the proposed DFL as guidance:

Step 2: Give 1st dose of Narcan OTC Nasal Spray

1. HOLD the Narcan OTC Nasal Spray with your thumb on the bottom of the plunger
2. INSERT the tip of the nozzle into either NOSTRIL
3. PRESS the plunger firmly to give the 1st

The HFVS enrolled a total of 71 participants with an age range of 15-76.  The study results exceeded the pre-defined performance thresholds for Steps 2a and 2b.  Five participants did not adequately demonstrate Step 2c and the lower limit of the 95% confidence interval fell just short of the target, but with an observed proportion of 94.4% of participants with acceptable performance of this step.  As a result of the HFVS, the sponsor changed the layout of the carton panels, and increased the font size, color, and background of the text above the pictograms.

As discussed extensively in the briefing materials and presentation, the sponsor conducted the HFVS without requesting comment and guidance from FDA regarding the methodology or protocol.  FDA flagged five study limitations for the Advisory Committee’s consideration:

1. The HFVS did not include participants in the 10-14 age group.
2. Two user groups did not include at least 30% limited literacy participants.
3. Participants were allowed to review the DFL and packaging for an “unlimited” period which is not representative of a high-risk scenario.
4. Moderators encouraged participants to “think aloud” which is also not reflective of an actual use scenario and may have influenced participant behavior/performance.
5. The “mock” carton labeling tested in the HFVS differs from the intend-to-market carton labeling.

The inclusion of the first limitation was particularly interesting given that FDA’s own label comprehension study also did not include the 10-14 age group.  FDA explained that their Institutional Review Board objected to including children under 15 because participating in response to a simulated overdose situation would potentially be “traumatic” to younger children.  However, as noted by NDAC member Dr. Walker-Harding, seeing a loved one die from an overdose and not being able to do anything is not just potentially traumatic to younger children, but is an unfortunate reality in the current opioid crisis.  Younger children will, tragically, be in situations where they may be the only person available to administer naloxone.

The joint Advisory Committee didn’t disagree that there were certain limitations to the methodology of the HFVS and that the DFL and packaging could be better designed and some members offered suggestions for consideration in making improvements (e.g., including a QR code that links to additional training).  In fact, the DFL and packaging has been redesigned, but the redesign has not been studied in another HFVS.  However, in reaching their unanimous decision, committee members emphasized that (1) naloxone is effective in treating opioid overdoses, (2) there are extensive data that demonstrate naloxone is safe, even when administered in the absence of opioids (i.e., mistakenly administered to a patient who is not experiencing an overdose), and (3) an Rx-to-OTC switch for NNS will save lives.  Several committee members noted that the urgency in increasing access to naloxone—a drug with a well established safety and efficacy profile—is far more significant than perfecting the label.

What’s next?

As noted, the Advisory Committee’s recommendation is important, but is not determinative of FDA’s ultimate decision of whether or not to approve Emergent’s application for an Rx-to-OTC switch.  After completing its review of the application, FDA will approve the drug or may issue a complete response letter outlining the deficiencies that preclude approval.  As was briefly discussed during the Advisory Committee meeting, FDA has no statutory or regulatory mechanism to impose a postmarketing requirement on NNS in this particular context.  FDA could not, for example, approve the NNS Rx-to-OTC switch and also require that the sponsor conduct a new HFVS with the updated DFL and packaging.  The Prescription Drug User Fee Act (PDUFA) goal date by which a decision is expected is March 29, 2023.

FDA is also reviewing an application for OTC naloxone under the trade name RiVive submitted by Harm Reduction Therapeutics last year.  Harm Reduction Therapeutics’ application differs slightly in that it is a new application for a direct-to-OTC approval, rather than an Rx-to-OTC switch of an existing approved application.  The joint NDAC and AADPAC will meet again on March 20 to discuss RiVive and the PDUFA date for that application is April 28, 2023.  FDA could theoretically act on Emergent’s application at any time—before or after the Advisory Committee meets to discuss RiVive.