FDA’s preliminary discussion in 2012 considering broader access to naloxone, an opioid overdose treatment, opened a window onto the future of consumer behavior research under the agency’s evolving nonprescription safe use regulatory extension initiative, NSURE.

FDA’s approach to naloxone appears to presage an emergence of human factors research among the consumer studies that could be required for Rx-to-OTC switches proposed “under conditions of safe use.”

Human factors research largely has been considered a sub-category of self-selection studies, but could gain importance as FDA moves into considering a variety of novel switches.

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

While naloxone falls far outside traditional categories considered for nonprescription sale, it fits with the model of some emergency or rescue treatments mentioned in discussions of the agency’s evolving paradigm for switch.

In April, FDA conducted a workshop “to initiate a public discussion about the potential value of making naloxone more widely available outside of conventional medical settings to reduce the incidence of opioid overdose fatalities,” according to a Federal Register notice. 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 co-sponsored the workshop.

A human factors study “can help to improve complex dosing directions during the drug development process. … For naloxone, I think we probably would need one.”

– CDER OTC research director Andrea Leonard-Segal

The workshop covered “potential health concerns, social concerns, legal concerns, regulatory issues, and future research needs related to making naloxone more widely available,” the notice said.

Suggestions voiced at the workshop included making the drug available nonprescription and developing an intranasal version of the drug to increase the ease of use while maintaining the Rx status.

While the workshop was not a pre-investigational new drug meeting between FDA and a firm, nor an advisory committee meeting to consider whether to recommend making naloxone available nonprescription, the proceedings reflected components of both, the transcript reveals.

Despite the current apparent lack of a sponsor or an NDA, the interest of FDA and other health care research agencies in allowing broader access to naloxone could help make the drug an eventual candidate for switch.

Forging New Territory

“We get to hypothesize a lot about things” when considering an Rx-to-OTC switch, said Center for Drug Evaluation and Research OTC research director Andrea Leonard-Segal at the April 12 workshop. “We forge new territory. And certainly, considering naloxone as an over-the-counter drug is forging new territory.”

Her presentation addressed “considerations about what an over-the-counter development program for naloxone might look like – just hypothesis.”

Leonard-Segal, director of CDER’s Division of Nonprescription Clinical Evaluation, focused on evidence a new drug application sponsor would need to provide FDA for switching naloxone, and on how such a switch would differ from others the agency has considered.

She said FDA will want safety data on naloxone not only from clinical trials, but “from all over the place.” Since naloxone is OTC in Sweden – “not behind the counter, not prescription” – FDA would be interested in information on the drug’s safety history and OTC labeling there.

Leonard-Segal focused largely on consumer studies, which she said “certainly would be needed to support a naloxone switch.” She said FDA finds consumer studies “helpful” when a switch is first-in-class and when:

a product targets a population not previously targeted by an OTC
a “substantial labeling change” is made
“new directions for use not previously seen” on an OTC.

A nonprescription version of the drug most likely would not be an injectable treatment but in a different delivery form, perhaps an intranasal, and would be administered by people other than trained medical professionals.

The sponsor for a potential naloxone switch also would need to propose how distribution of the product would be controlled by conditions of safe use, such as qualifications for consumers who are allowed to purchase it.

Self-care expert Bill Soller notes a nonprescription naloxone product used for “preventing mortality in a critical care situation in the hands of a bystander,” would be new territory for switch. “That stretches the bounds,” he said. But he feels the agency laid out clearly how the drug could be switched.

“The core message was … this is what you need to do,” said Soller, professor and executive director of the Center for Consumer Self Care at the University of California, San Francisco, School of Pharmacy.

Bringing In Human Factors

Leonard-Segal’s discussion highlighted human factors research in particular. While self-selection studies evaluate whether consumers can determine accurately whether they should use a particular drug and then choose the product, human factors research gauges how well consumers can follow directions for administering a drug or other therapy.

Leonard-Segal said while a human factors study is not mandatory for a new drug application, the research likely will benefit a firm. “It can help to improve complex dosing directions during the drug development process,” she said, adding, “For naloxone, I think we probably would need one.”

“Human factors have to do with dexterity, coordination and those kinds of factors and linking that with intelligence,” notes Soller. Introducing any kind of intermediary or mechanism, human or not, could make human factor research more important in consumer studies for switches, he says.

For example, consumers using in-store kiosks to help select appropriately a drug is a condition of safe use frequently proposed in new switch paradigm discussions.

Soller said human factors research could help assess how well consumers are able to use the kiosk or other apparatus to access the appropriate information, in the context of a proposed switch. For OTC use of naloxone or other pharmaceutical therapy that requires administration by a second person, research can evaluate how well people can perform the treatment.

“That would require human factor research. You would need a study that would demonstrate [consumers] can self-select and you would evaluate the kiosks in relation to the number of errors as they went through this process,” he said.

“You get these quality assessments from the individual and it’s tied to the number of errors they might have going through the system. If you look at a device, you would look at how a person would administer a [spray] of placebo to another individual. You would watch how they manipulated the product, the ease with which they did it. You would put different measurement parameter around that.”

Leonard-Segal pointed out that naloxone would not be the first OTC drug approved with administration by a second person. “This OTC paradigm exists now. Parents self-select to treat symptomatic conditions in their minor children. So we do have a lot of precedent for this kind of drug administration.”

Label comprehension and actual-use studies also would be needed for a naloxone switch, Leonard-Segal said.

Big Problem, Small Market

While naloxone is not the first drug floated by prognosticators as a novel switch, an increase in the abuse of prescription opioids has made overdoses a public health problem and pushed naloxone into the realm of potential OTC switches.

“The problem … is an enormous one,” said Peter Lurie, a senior advisor in the Office of Policy and Planning in the Office of the FDA Commissioner, to open the workshop.

Lurie noted prescription drug overdose deaths have increased roughly threefold since 1999, and since 2003 the number of opioid analgesic overdose deaths have exceeded the number of deaths from cocaine and heroin combined.

“The question is, what can be done to further the use of this product, if appropriate, among illicit drug users and for those who are on long-term narcotics, for example, those with chronic cancer pain?” he said.

The potential market for a nonprescription naloxone or other opioid receptor antagonist is difficult to predict without knowing potential limits on distribution imposed as conditions of safe use, though the market for nonprescription naloxone would not likely rival demand for OTC statins, for instance.

Dan Wermeling, a pharmacy expert who spoke at the April workshop and who, with NIDA grant funding is developing an intranasal naloxone product, observed that weighing the costs of a naloxone switch NDA against the likely market size likely would dissuade firms from sponsoring an application.

Wermeling, a professor at the University of Kentucky College of Pharmacy and president and CEO of AntiOp Inc., estimated the U.S. market for injectable naloxone at $22 million. “That's not a market compared to other things that people invest in,” he said.

“If I look at the amount of money that has to go in versus trying to get money out to reimburse for the costs and the risks associated with investing in such a product that may cost $20 [million] or $30 million to do, will that money come back? Can you entice capital into this setting?” Wermeling said.

Naloxone Talk Sheds Light On Switch Research Future

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