Naloxone Switch: Door Opener For Other NDAs That Swing On Consumer Education

Health care professionals provide naloxone in an outpatient setting in “highly successful programs,” but FDA approval of a switch rests on whether “just putting the drug on the store shelf for anyone to purchase with no training or guidance on use” will be safe, says nonprescription drug division head Theresa Michele.

A proposal that clears FDA’s high bar for an OTC switch of naloxone opioid overdose treatment could smooth the nonprescription pathway for other drug ingredients marked by consumer education concerns.

Theresa Michele, director of FDA’s Division of Nonprescription Drug Products, made clear the agency’s thinking about a potential switch on July 2 during a public meeting on expanding access to naloxone.

Michele, among the final speakers for the two-day event, said researchers, health care providers and emergency medical service professionals who preceded her reported on “highly successful programs that are providing use of naloxone in the outpatient setting.”

“The difference between these programs and what we’re talking about with over-the-counter approval is the amount of education that goes on before the product is dispensed compared to just putting the drug on the store shelf for anyone to purchase with no training or guidance on use,” she said at FDA’s White Oak campus headquarters in Silver Spring, Md.

Adapt Pharma Makes Naloxone Play

Despite the obstacles FDA makes clear, Adapt Pharma Ltd. is in the hunt for wider distribution of naloxone through a “rolling” new drug application for a nasal spray formulation.

A rolling NDA submission allows completed portions to be submitted and reviewed by FDA on an ongoing basis. Adapt Pharma is collaborating with the National Institute on Drug Abuse to develop a naloxone nasal spray that would be suitable for use in the community setting by non-medically trained personnel.

The Dublin-based firm on July 1 said after previously filing its NDA, it obtained a license to the Narcan trademark and acquired the naloxone HCl injection NDA linked to the brand, which in 1971 was the first naloxone product FDA approved for opioid overdose but has not been distributed since 2009.

According to FDA’s database, the NDA approval for injectable Narcan was owned by Endo Pharmaceuticals Inc.

Emphasizing that a naloxone switch would face unprecedented consumer education hurdles, Michele outlined the agency’s suggestions for consumer studies needed for a new drug application or supplemental NDA to make the drug available nonprescription (see table below).

Naloxone is an opioid receptor antagonist currently approved for use by injection only for the reversal of opioid overdose; it most commonly is administered by trained emergency medical personnel, in hospitals, other facilities and ambulances.

Estimating the potential market for a nonprescription naloxone or other opioid receptor antagonist is difficult without knowing potential limits on distribution, but sales would not likely rival demand for OTC treatments for high cholesterol, diabetes, hypertension or other chronic conditions, for which FDA is encouraging drug firms to make switch proposals.

Potential switches for chronic conditions also pose consumer education challenges for sponsors and for FDA. The agency has rejected three proposals for a statin switch after advisory panels questioned whether consumers could accurately self-diagnose their need for a cholesterol treatment and correctly manage their use of the drug.

Pfizer Inc., though, is considering its first NDA for a statin switch. The firm says by the end of 2015 it will decide whether to propose a Lipitor switch based on results of a 1,200-subject trial that looked at whether consumers taking 10 mg atorvastatin would get blood tests to see if the drug is improving their cholesterol and make the correct decisions based on those results (Also see "Pfizer Would Explore Where No Other Firm Has Gone Before With Lipitor Switch" - Pink Sheet, 5 May, 2015.).

‘Tiny’ Label, Large Message

Like most switches and perhaps more than any other, sponsors will be challenged by developing labeling for nonprescription naloxone.

“There really isn’t very much real estate on a label. It’s a pretty small space, so sometimes I think we’re asking this tiny little label to leap tall buildings with a single bound and that’s kind of a lot to expect,” Michele said.

“Under current regulations it’s difficult for FDA to consider other means such as the use of technology to improve the safe and effective use of OTC drugs.”

And that is why the agency continues work on its Nonprescription Safe Use Regulatory Expansion initiative (see story this issue, (Also see "NSURE In Play If Not Yet In FDA’s Regulatory Playbook" - Pink Sheet, 13 Jul, 2015.)).

FDA's suggestions for consumer studies needed for a new drug application or supplemental NDA to make naloxone available nonprescription.

SOURCE: FDA Division of Nonprescription Drug Products

Like all OTC drugs, a nonprescription naloxone label would have to state a specific indication. FDA recognizes that while Rx naloxone’s use to treat for opioid overdoses is clear to emergency health care professionals, consumers might consider an OTC version of the drug an antidote to overdoses linked to other causes.

“Consumers must be able to correctly diagnose opioid overdose and recognize that naloxone would not be beneficial in other kinds of overdoses and also to differentiate overdose conditions from therapeutic use,” Michele said.

In addition to understanding of naloxone’s indication, studies for a switch would need to show consumers can follow directions on labels for use of a device such as an auto-injector or a nasal spray to administer a correct dose.

Studies Build On Label Comprehension ‘Foundation’

Label comprehension, first in a switch sponsor’s studies, would test consumers’ understanding of directions for monitoring for cardiovascular effects, aspiration and opioid withdrawal; that explain the drug may have limited efficacy on overdoses caused by partial or mixed antagonists; and state contraindications for consumers allergic to the ingredient.

Additionally, those studies will need to show consumers understand “probably the most important issue,” Michele said. “The duration of the naloxone effect is shorter than the duration of opioid effect and so they must seek additional medical care immediately and additional doses may be needed. In other words, consumers must understand that naloxone is not a substitute for medical care.”

Self-selection studies for a naloxone switch would look at an end point of consumers deciding whether the drug would be appropriate based on a particular medical situation; and actual use clinical trials – most often self-reported, open-label studies – that determine whether consumers would use the product correctly, and likely also need to look at why failures or misuses occurred.

FDA also would expect switch sponsors to conduct human factor studies to “evaluate the interaction between a consumer and a device or other technology,” Michele said.

The human factor is a consumer’s ability to use the device correctly based only on directions stated on a Drug Fact label. “The focus here is on the risks associated with observed errors,” she said.

“While label comprehension may give some idea of how a consumer would use a product, better proof comes from the actual use and human factor studies that show how a consumer uses the product and handles the device,” Michele added.

She expects that naloxone switch actual-use and human-factor studies might include participants administering the drug to a mannequin. “We’re most interested in whether consumers can correctly seek emergency medical care with use and administer the product correctly.”

While injection delivery “in theory” could be approved for an OTC drug, “some dosage forms are certainly more consumer-friendly than others,” Michele said.

“A drug requiring systemic delivery like naloxone is likely to require some sort of consumer-friendly device and packaging in order for consumers to be able to correctly administer the product themselves without specific training by a health care professional.”

A naloxone switch study would help FDA learn about consumer comprehension of delivery formats for OTC products other than oral, nasal or topical, even if the agency did not approve a potential application.

Michele said while Rx naloxone’s use provides a “fairly good understanding” of “intrinsic factors” such as an adverse event profile, information on “extrinsic factors related to self-administration” are not well known.

“Given this, a strong consumer development program could potentially aid with extrinsic factors for a specific dosage form,” she said.

The meeting was FDA’s second on naloxone since announcing NSURE in February 2012. The agency, the National Institute of Drug Abuse, the Centers for Disease Control and Prevention and the Department of Health and Human Services’ Office of the Assistant Secretary for Health in April that year co-sponsored a by-invitation workshop to discuss the value of making naloxone more widely available outside of conventional medical settings to reduce the incidence of opioid overdose fatalities (Also see "Naloxone Talk Sheds Light On Switch Research Future" - Pink Sheet, 7 Jan, 2013.).

FDA’s interest in expanding nonprescription access to naloxone and other rescue medicines under NSURE has spurred opposition from some health care advocates who argue the move would delay necessary long-term care for consumers (Also see "Rescue Medicine Switch Concept Draws Criticism" - Pink Sheet, 2 Apr, 2012.).