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US FDA Has Model Drug Facts Labels For OTC Naloxone, Needs Switch Proposals

Executive Summary

Development of the model DFLs was a first for agency. The project was "part of our broader commitment to addressing the opioid crisis" and should help sponsors with potential naloxone OTC switch NDAs, says Commissioner Scott Gottlieb.

FDA underscored its interest in proposals for allowing OTC access to naloxone for treating opioid overdose by taking the unprecedented step of developing model Drug Facts labels that potential sponsors can use for their own label comprehension studies.

The agency announced the release of the model DFLs on Jan. 17 along with publication of its review of independent research contractors' study of label comprehension for OTC use of nasal spray and auto-injector products, the two forms of naloxone currently available Rx-only "in consumer-friendly format." The contractors used a prespecified research design with more than 700 participants across a range of potential OTC naloxone users with separate DFLs for a nasal spray and an auto-injector.

In FDA's announcement, Commissioner Scott Gottlieb said agency staff concluded that the study showed the model DFLs, which include pictorials separate from the text, demonstrating how to administer either the nasal spray or injector, were well-understood by consumers and are acceptable for use by manufacturers in support of OTC naloxone proposals (see sidebar).

"Using this information, naloxone manufacturers can now focus their efforts on final label comprehension testing of how well consumers understand the product-specific information that hasn't been already tested in the model DFL," Gottlieb said.

The commissioner also noted that development of the model DFLs was a first for the agency, reflecting alarm about the growing public health crisis of overdoses from opioid abuse, with the number of deaths reaching nearly 48,000 in 2017.

"This is the first time the FDA has proactively developed and tested a DFL for a drug to support development of an OTC product," he said, adding it was "part of our broader commitment to addressing the opioid crisis."

Before submitting a new drug application or supplemental NDA for an OTC drug, firms must develop a DFL and conduct studies to show consumers understand how to use the product without supervision of a health care professional. FDA provided a template for that work by designing, testing and validating key labeling requirements to approve OTC sales of naloxone, which is an an opioid-receptor antagonist indicated for complete or partial reversal of overdose – including respiratory depression.

"Some stakeholders have identified the requirement to perform these studies as a barrier to development of OTC naloxone product," Gottlieb said.

FDA Center for Drug Evaluation and Research officials in May 2017 said the agency for one year had been developing and testing labeling that instructs consumers on administering naloxone through intramuscular injection or nasal delivery to a person experiencing an overdose. (Also see "FDA's OTC Naloxone Study Is A Starting Point For Other Switches, Not A Roadmap" - Pink Sheet, 16 May, 2017.)

Specifics Needed From Sponsors

Because the DFLs are models, a sponsor submitting an NDA for an OTC must still modify and test the label instructions for use that are specific to its product and demonstrate adequate comprehension through label-comprehension and human factor studies testing as requested by the agency.

Shutdown Slows FDA

In the announcement, Gottlieb also explained that evaluations of potential OTC naloxone applications might proceed slowly because FDA currently doesn't have a fiscal year 2019 appropriation. The federal government is in the fourth week of a partial shutdown due to an impasse on FY 2019 spending as Democrats in Congress oppose President Trump's insistence on including at least $5bn to pay for a security wall at the Mexican border.

Evaluations of NDAs and other applications for naloxone and other drugs requiring pre-market approval are supported by user fees, but FDA doesn't have access to fees that would be included in its FY 2019 budget.

Its reviews of existing medical product applications and associated policy development currently "are funded by limited carryover user fee balances," Gottlieb said. "We'll continue to update the public on how we're approaching our work during the lapse in appropriations."

Earlier in January, Gottlieb said in a Twitter social media post that the agency's first user-fee carryover balance likely to be exhausted is that for NDAs and it already had stopped accepting the majority of submissions. Nearly 60% of the agency's workforce is furloughed due to the shutdown. (Also see "Shutdown Week Three: Sponsors With Upcoming User Fee Dates Should Start Sweating " - Pink Sheet, 7 Jan, 2019.)

"Apart from this product-specific information, the model DFL otherwise contains all the key information needed for an untrained bystander to administer naloxone," Gottlieb said.

Harm Reduction Therapeutics Inc. already is working on an Rx-to-OTC switch for naloxone and intends to launch a product in the US around mid-2020. Michael Hufford, CEO of the Pittsburgh-based non-profit, says FDA is giving the industry a valuable assist with the model DFLs and the study results.

"Of course, the work is not yet done," Hufford said in an email.

He noted FDA explained in its announcement that DFLs must be specifically modified and tested for a sponsor's product. "Still, at some point you have to ask, what more can the agency do? It is up to industry to step forward and use these tools to enable OTC availability of naloxone," Hufford said.

HRT's work is supported partly by a $3.42m grant opioid drug maker Purdue Pharma LP made in September. Purdue is one of several drug companies and distributors facing litigation in multiple states linked to their opioid product marketing and commercial practices. (Also see "Naloxone OTC Switch Application On Horizon Thanks To $3.4M Funding From Purdue" - Pink Sheet, 6 Sep, 2018.)

The Pittsburgh-based organization is working with an undisclosed consumer health product company and has contacted more than 100,000 retail locations in the US to establish warehouse, supply chain and sales support for efficient distribution and available to consumers post-approval. HRT has licensed a naloxone formulation from another undisclosed firm.

FDA published the model DFLs and study results after conducting an advisory committee meeting in December on increasing naloxone access. An official in the agency's Division of Nonprescription Drug Products said during the two-day meeting that FDA is recruiting sponsors of potential OTC naloxone applications and interest is high. However, committee members and Rx naloxone manufacturers stated that pricing and the absence of physician-patient communication about using the product could be impediments to a switch. (Also see "OTC Switch For Naloxone Finding Interest Among Sponsors" - Pink Sheet, 19 Dec, 2018.)

Prescription naloxone products now available include the Evzio auto-injector marketed by kaleo Inc. and Adapt Pharma Ltd.’s Narcan Nasal Spray.

The drug most commonly is administered by emergency medical personnel and by medical staff in hospitals. However, national and community pharmacies have begun making Narcan or generic injectable naloxone available without prescriptions from pharmacists under policies set by states. Some states have made naloxone in formats appropriate for consumer use available nonprescription from pharmacies, or through pharmacists' prescriptions. Agreements for dispensing naloxone are similar to programs that allow pharmacists to provide flu shots to patients without each patient having a prescription. (Also see "Nonprofit Pharma Targets Making Naloxone Available OTC, Trimming Price" - Pink Sheet, 13 Dec, 2017.) 

From the editors of HBW Insight.

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