FDA Helps E-Cigarettes Navigate NDA Process With Nonclinical Tests Guidance
This article was originally published in The Pink Sheet & The Rose Sheet
Executive Summary
Commissioner Gottlieb highlights the first of two draft guidances US FDA will publish on developing "novel, inhaled nicotine replacement therapies that could be submitted to the FDA for approval as new drugs, similar to current" OTC nicotine replacement therapies. FDA has had a contentious history with manufacturers of electronic nicotine devices, but officials have said the products are eligible for review as NRTs through the NDA process.
FDA is emphasizing its interest in putting electronic cigarettes to work as OTC drugs by publishing a draft guidance on information needed from studies with animals for new drug applications for smoking cessation or similar indications.
In the draft guidance published Aug. 3, FDA states it provides "recommendations on the nonclinical information necessary to support development and approval of orally inhaled nicotine-containing drug products, including electronic nicotine delivery systems intended for smoking cessation and other chronic uses."
Commissioner Scott Gottlieb says the document is the first of two draft guidances the agency will publish on developing "novel, inhaled nicotine replacement therapies that could be submitted to the FDA for approval as new drugs, similar to current over-the-counter pharmaceutical" nicotine replacement therapy (NRT) products. While there has been frequent discussion of how e-cigarettes impact use of combustible tobacco, manufacturers currently are precluded from making smoking cessation claims. But while the guidances will open the door to such claims, many potential sponsors may find the path to approval challenging.
Nonclinical Testing of Orally Inhaled Nicotine-Containing Drug Products
Guidance for Industry- General Principles
- General Toxicology Studies
- Developmental and Reproductive Toxicology
- Carcinogenicity
- Genetic Toxicology
Docket FDA-2018-D-2583; 60-day comment period begins Aug. 6.
Most NRTs currently available in gum, patch and lozenge forms, in Rx and OTC formulations, have been approved for more than 20 years, but novel forms of nicotine delivery – e-cigarettes and other electronic nicotine devices (ENDs) – are much newer in the US marketplace. "It's possible that new kinds of NRTs – with different characteristics or routes of delivery – can offer additional opportunities for smokers to quit combustible tobacco," the commissioner said in a statement announcing the draft.
FDA has had a contentious history with ENDs manufacturers, beginning with attempting to block sales of all of the products in 2010, but agency officials consistently have said the products are eligible to be considered for approval as NRTs through the agency's NDA process.
"The FDA is intrigued about electronic nicotine delivery systems (ENDS) as a harm-reduction/smoking cessation/tobacco use cessation tool. That has been evident for some time," said Kathleen Hoke, director of the Center for Tobacco Regulation at the University of Maryland Carey School of Law, where she is a professor.
Hoke, also director of the Network for Public Health Law, Eastern Region, added that the draft "further exemplifies this fascination and takes it a step further to public exploration of the possibility of ENDS as cessation tools." FDA continues "signaling that they are going to treat ENDS differently from 'traditional' tobacco products, particularly cigarettes," she said.
FDA's most substantial statement about ENDs' potential role as medical devices was its November 2017 launch of a Nicotine Steering Committee, headed by Gottlieb, to re-evaluate and modernize it approach to the development and regulation of NRTs. (Also see "FDA's Nicotine Replacement Standards Review Could Open Door For E-Cigarettes" - Pink Sheet, 29 Nov, 2017.)
The committee's launch was followed in January with a public meeting on evidence needed to show safety and efficacy for novel products and with speakers also emphasizingd the psychological toll from deaths linked to combustible tobacco and smokers' emotional connection with tobacco and nicotine,. (Also see "Emotional Backdrop Smolders As FDA Reviews Smoking Cessation Category" - Pink Sheet, 31 Jan, 2018.)
More Than Nicotine Must Be Studied
While toxicity information for nicotine is plentiful, it may not be available for other compounds contained in liquid nicotine, such as flavorings and heat-generated chemicals, used in ENDS.
"Some chemicals may be novel, not found in relevant, previously approved drug products, or may not have adequate toxicity information available. Local and systemic exposure should be addressed in the toxicity assessment," the draft states.
FDA explains that nonclinical toxicity assessments appropriate for approval should include general and developmental and reproductive studies; an assessment of carcinogenic potential; and supporting toxicokinetic and nonclinical pharmacokinetic studies.
Additionally, guidance available from FDA on assessment of impurities in drug substance and products should be followed by sponsors of novel NRT NDAs, particularly when considering if nicotine derived from plant-based products may be associated with genotoxic impurities.
"Nicotine-specific impurities that are present at higher levels than in approved drug products, considering the route of administration, population, dose, and duration, are a concern if the drug products also exceed relevant [International Conference on Harmonization]-recommended limits. FDA will assess such impurities on a case-by-case basis," the draft states.
Gottlieb said that because some consumers use products FDA has approved as NRTs indefinitely, "it’s important to understand the risks to humans from these exposures, including developmental and reproductive toxicity and carcinogenicity."
Guidance Doesn't Lower Approval Bar
Specifying information necessary for an NDA and the processes sponsors should use to prepare those applications, though, doesn't lower the bar for approval nor sponsors' costs, which makers of ENDs say they cannot afford.
"It is costly and time-consuming and they are hoping for an easier path," Hoke told the Pink Sheet.
She pointed out that comments on the draft from public health researchers and advocates, ENDS industry stakeholders and other parties helps "the agency to take the next step in this exploration," but the guidance does not signal FDA is committed to adding novel products to the list of approved NRTs.
The NDA pathway for an NRT indication has always been open to ENDs firms, and FDA's guidance reinforces that option, she said. "To some extent I think that’s a fair reading of where the FDA is."
FDA has not moved from its position of smoking cessation as the lone indication for NRTs. But speakers at the January public meeting added to the chorus of requests that the agency allow additional product claims, such as harm reduction, which focuses stopping use of combustible tobacco such as cigarettes, even if users turn to another form of nicotine, possibly indefinitely.
The draft guidance, Hoke said, could be a sign FDA is listening. "As long as individual and public health are considered in the agency’s decision-making, I think that is a good place for the agency to be."
From the editors of the Tan Sheet.