Benefit/risk evaluation of NVPs

The TGA has asked the Australian medical community to enable current smokers to access NVPs regulated as Schedule 4 medicines.

Currently, no NVPs are licensed as therapeutic goods in Australia or anywhere else. Accordingly, the TGA requires GPs to use the unapproved medicines prescribing routes.

Health professionals are responsible for the benefit-risk consideration when prescribing unapproved medicines to patients. The benefits of NVPs are that:

• They may promote smoking cessation in patients who cannot stop smoking with other therapies.
• They reduce or eliminate the exposure to toxicants in cigarette smoke responsible for tobacco-related diseases.

However, risks may arise in association with the product formulation and delivery/device characteristics.

Consequently, products that GPs prescribe must deliver nicotine effectively while meeting high-quality standards and having a well-characterised safety profile.

Effectiveness for smoking cessation

The main limitation on nicotine replacement therapy efficacy is the low patient adherence due, in part, to low nicotine kinetics from NRT compared with cigarettes. Products capable of delivering nicotine effectively to patients are more likely to promote adherence.

Multiple clinical trials have shown that closed systems with nicotine salts generate moderate blood plasma levels in novice NVP users and cigarette-like levels have been observed in experienced users. Critically, participants in these studies report positive subjective evaluations similar to those from their usually smoked brand of cigarettes.

Population efficacy

‘Gold standard’ RCTs have been conducted in the UK and NZ using open systems with sub 20 mg/mL liquids (per EU regulations). One RCT found smoking cessation to be twice as effective as NRT in a population of people who smoke seeking treatment. In another study of smokers that previously struggled to quit, 20% of the e-cigarette arm were abstinent from cigarettes at year 1, compared with 3% of the NRT arm.

In the US, where nicotine concentration is not limited, a major longitudinal study conducted by JUUL Labs Inc. showed 58% of people who smoked at baseline reported cigarette abstinence one year after purchasing a JUUL starter kit.

This remarkable claimed efficacy is due to multiple factors, including the usability and effective dosing in nicotine-salt closed systems. Additional factors include the wide availability of JUUL in the US market and the compounding effects of behavioural modelling from peer adoption.

Potential blockers to Effectiveness

Some researchers have raised concerns about the poor and declining understanding of the relative risk between cigarettes and NVPs. In the UK, for example, most smokers hold inaccurate harm perceptions of NVPs, with individuals from disadvantaged groups significantly more likely to be misinformed.

Poor public understanding of the safety of nicotine, both in absolute terms and relative to cigarettes, is an additional factor in lack of adherence to NRT, continued smoking, and in some instances, a propensity to persist in dual-use, rather than move to solus use of NVPs or NRT.

Effectiveness for nicotine abstinence

Clinical experience under the Australian medicinal model for NVPs represents a significant opportunity to discover the best path to abstinence in NVP users who have successfully stopped smoking.

Patient motivation has always been the critical determinant of successful smoking cessation with the historic treatment approach.

NVPs can reduce reliance on patient motivation to stop smoking by replicating the nicotine kinetics and behavioural characteristics.

Nicotine abstinence, however, will always require patient motivation. It is currently unknown if NVPs increase patient motivation for abstinence or make it easier to achieve when attempted.

Insights from NVP literature

Daily users of NVPs appear to be less dependent on NVPs than their former cigarette use. A moderating factor could be NVP users’ tendency to shift to a ‘grazing’ usage pattern from the cigarette ‘peaks and troughs’ pattern.

Around half the successful quitters in the NVP treatment arm of the UK RCT were cigarette and nicotine abstinent at the end of one year. This proportion corresponds with the total number of successful abstainers in the NRT arm. This finding suggests that there may be no significant effect of treatment type on those patients genuinely motivated to become nicotine abstinent.

The safety of NVPs and Nicovape® Q

In state-of-the-science reviews, including that conducted by the US National Academy of Science, Engineering and Medicine, the reviews concluded that NVPs have the potential to deliver nicotine with significantly reduced levels of Harmful or Potentially Harmful Constituents (HPHCs) compared to combustible cigarettes:

• The number of chemicals in cigarette smoke, more than 7,000, exceeds that of NVP aerosol by approximately two orders of magnitude; and
• Among potentially toxic substances common to both, cigarette smoke generally contains substantially higher quantities than NVP aerosol.

With Nicovape® Q, Liber utilises technological developments and quality manufacturing processes to deliver nicotine with the potential to reduce the risk of tobacco-related disease compared to continuing smoking by implementing:

• Systematic processes for flavour ingredient selection, formulation, and toxicological risk assessment; and
• Product development and aerosol analytical evaluation to minimise the presence of HPHCs in the aerosol compared to tobacco smoke.

Ingredients in Nicovape® Q

Liber has characterised the safety of Nicovape® Q’s flavouring ingredients and mixtures of ingredients by evaluating their acute and long-term health risks from inhalation exposure. Liber has evaluated the ingredients across critical health endpoints, including chronic effects, and has formulated ingredients without classified:

• Carcinogens and Mutagens;
• Reproductive and developmental toxicants;
• Respiratory sensitisers;
• Repeated dose toxicants; and
• TGO 110 excluded chemicals, such as vitamin E acetate*.

These evaluations exceed the requirements of TGA’s Therapeutic Goods Order 110. Liber has not yet conducted the long-term health evaluations of Nicovape® in clinical populations.

Liber developed the Nicovape® Q system to minimise long-term risks from inhalation exposure. Like all new medicines, post-market surveillance of the clinical population will provide an additional assessment of NVP safety in the patient population.

*Vitamin E acetate is a cutting agent in illicit cannabis vaping products and is confirmed to be the causal factor of a widely publicised spate of lung injuries in 2019 that USCDC initially attributed to NVP usage.

Product design and characterisation

NVP manufacturers should complete a comprehensive evaluation of their products’ aerosol for harmful and potentially harmful compounds.

The Nicovape® Q device, cartridges, and liquid composition are designed to minimise exposures to potentially harmful constituents.

Nicovape® Q is a closed system designed to deliver nicotine with a similar nicotine pharmacokinetic profile to cigarettes. Nicovape® Q contains design features to:

• Ensure satisfying nicotine delivery while minimising exposure to other excipients in the aerosol; and
• Minimise aerosol yields of harmful constituents that are present in cigarette smoke.

In contrast, open systems with low levels of nicotine can lead to increased toxicants in the aerosol due to:

• Higher power settings, increased volumes of liquid, and many potential liquid/device combinations; and
• Compensatory (additional) puffing due to lower nicotine levels.

Understanding nicotine delivery

Nicotine delivery in the aerosol of any given NVP depends on the nicotine concentration, the device characteristics (such as the operating power), and user behaviour.

Liber has assessed the nicotine levels in the aerosol generated from Nicovape® Q to ensure it is delivered consistently and in the expected quantities.

Please see Module 5: About NVP technology for more information about nicotine delivery.