• July 21, 2024

Certified Medicine

 Certified Medicine

Credit: Krakenimage

Credit: Krakenimage

More than a year after the U.K.’s MHRA updated guidance, there are still no medicinal vapes on the market.

By Pete Lomas

The U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA) updated its guidance for licensing electronic nicotine-delivery systems (ENDS) as medicinal products on Oct. 29, 2021. The new guidance marked a shift in approach from the MHRA as it began actively encouraging applications and sought to support companies through the process. Over a year on, however, we have to wonder why the industry doesn’t have any medicinal vapes on the market.

The change in direction by the MHRA was likely spurred by the U.K. government’s desire to meet its “Smoke-Free by 20301 target, which stipulates that less than 5 percent of the population should be smokers by the end of the decade. Using ENDS can be a good way to reduce the harmful effects of smoking, and the hope is that this new approach will change the perception of ENDS, bringing them more in line with other nicotine-replacement therapies, including gums, sprays and patches.

Pete Lomas

The pathway via which e-cigarette products can be certified as medicinal products is known as a marketing authorization application (MAA). Since nicotine is not a new chemical entity, the MAA can be abbreviated with respect to safety and efficacy information. Instead, the application will rely primarily on a pharmacokinetic study to compare the new product with an appropriate reference medicinal product. Given the intended route of administration, an already approved inhaled nicotine product such as the Nicorette 15 mg Inhalator has been suggested by the MHRA as a suitable comparator.

As well as conforming to the MAA requirements, any ENDS devices will also need to be proven to be electromechanically safe. In the U.K., this will require it to be U.K. Conformity Assessed marked, following assessment by an authorized approved body.

Encourage licensing

In a bid to elucidate the new application process, the MHRA initially ran a webinar titled “Licensing Electronic Cigarettes as Medicines,” which was retroactively made available on YouTube.2 In short, the MHRA is committed to providing as much assistance as is needed to ensure potential applicants understand the process and feel able to make applications in a timely manner.

But the MHRA has gone beyond simply putting on talks and answering questions—it has also widened the goalposts slightly, making applications more likely to succeed. One way this has been done is by adapting how delivered dose uniformity (DDU) is measured. As a medicinal product, vapes are classified in a similar way to conventional pressurized metered dose inhalers (pMDIs), meaning the criteria that must be met before approval is very similar.

E-cigarettes, however, are a fundamentally different technology to pMDIs. Whereas pMDIs use a pressurized canister calibrated to deliver an exact amount of aerosol per puff, an e-cigarette is traditionally based on coil and wick technology. This difference makes the DDU per-puff of an e-cigarette much less consistent, and that is before considering self-titration (the patient taking larger or smaller puffs based on preference and habit) is even considered.  

So, if ENDS are subjected to DDU regulations on a per-puff basis, then most will fall short—what to do then? To address this, the MHRA has instead set DDU requirements that are averaged over 10 puffs, rather than one, thus making it easier for vapes to comply.

Achieving DDU

Despite the leeway given by the MHRA, delivering dose uniformity is still very important. For products to reach medicinal standards, they must be designed to be as consistent, puff to puff, as possible. In that respect, any applicant seeking approval will need to focus on three key points: consistent power, consistent delivery of liquid and consistent airflow—achieve all three and a device stands a good chance of complying with the new guidance.

Modern developments in vape technology will help address the issue of DDU further. Non-heated vaping technologies based on ultrasonics, piezo-ceramic mesh and micro-nozzles are now being used to develop these products and offer greater inhalation consistency. Piezo-ceramic technology, in particular, is well suited for medicinal products as it offers the ability to fine-tune the mesh, vibration frequency or other parameters within the device, depending on the liquid formulation.

Another key difference between ENDS and their inhaler cousins is that the performance of electronic products tends to vary at the beginning and end of the product’s lifecycle. That means priming and end-of-life doses may not deliver the same uniformity as is expected for the bulk of the product’s use. Within the new guidance, applicants will now be able to define these different doses and exclude them from the uniformity criteria, so long as appropriate justification is provided and information on these differences is communicated to the end users.

Achieving MAA licensing

To date, only one e-cigarette product has successfully passed through the MAA process, around a decade ago. However, smokers did not find the product sufficiently satisfying to make a permanent switch. It was withdrawn from the market only a couple of years after launch due to low smoker compliance. Technology has evolved much since then, resulting in products that are much more satisfying for smokers, allowing them to transition away from combustible cigarettes altogether.

Typically, performing the necessary studies and data gathering for the application would be expected to take 12 months to 18 months. Once collected, the MHRA offers a 150-day accelerated assessment for “high-quality” MAAs, with an intervening “clock-off period” where further clarification and information can be provided, as required. The clock-off period should last no longer than 60 days.

For applicants with products undergoing a U.S. FDA premarket tobacco product application (PMTA) process, or for the 23 ENDS that have already been approved3 via this route, there is opportunity to reduce the number of new studies that are required for an MAA. The MHRA has said it is happy to discuss what data may be relevant for a U.K. MAA, therefore reducing the need for additional studies in some cases.

Even if the majority of the data from a PMTA cannot be used directly as part of the MAA, data generated for the PMTA can be used to help strengthen the Pharmaceutical Development section within Module 3 of the application. In addition, a successful product on the U.S. market will provide confidence to regulators of consumer acceptance, which can be an important consideration.

All told, any applicant beginning data collection for an MAA should anticipate the entire process, from product finalization to market approval, taking in the region of two years. This explains why we are yet to see a product reach approval since the guidance was only updated in October 2021. As we approach the two-year mark at the back end of 2023, it seems plausible that the first medicinally licensed ENDS could come on sale in the U.K.

Credit: Minerva Studio

Where to find medicinal vapes

If the license granted permits the product to be sold and supplied as a General Sales List (GSL) medicine, then the retailer does not need to be a pharmacy. Examples of common GSL medicines include ibuprofen and paracetamol, which can be purchased from retail outlets such as convenience stores and supermarkets, where they are available for self-selection, albeit with appropriate sale restrictions on purchaser age and quantity of the product.

Most existing nicotine-replacement therapies—products like patches, gum and sprays—are listed as GSL items, and so the assumption is that ENDS would be made available in the same way. That said, approval onto the GSL doesn’t automatically exclude a product from being prescribed to patients by a healthcare professional. Applicants may still wish to secure contracts with healthcare providers to distribute their product through alternative channels, which can include being exclusively sold as a prescription treatment.

Making a difference

It is fair to say that the perception of vaping, both in the eyes of the public and healthcare professionals, has declined in recent years. A 2021 survey by Action on Smoking and Health4 (ASH), for example, found that nearly a third (32 percent) of smokers incorrectly believe that vaping is more or equally as harmful as smoking. Whatever the reasons are behind this—I suspect there are several—it needs to change if we are to reach the smoke-free target by 2030.

The hope is that by licensing ENDS as medicinal products, it will provide credibility that these products are not just safe but have genuine harm reduction potential. MHRA approval will provide customers with confidence that they are making a healthy choice when switching from smoking to vaping.

A barrier to the success of this reclassification of vapes as medicinal products may be smokers’ perceptions of themselves. Many don’t want to be seen as “patients” per se, and so they might resist being bundled into such a group. Medicines, however, are as much about the prevention of disease as for its treatment, and given that these products will hopefully be available as GSL medicines, resistance to their purchase should be minimal. Most people don’t feel like a “patient” when purchasing ibuprofen after all.

The impacts of the change in guidance will only become apparent once we start seeing products approved via this route. For now, there are still over 6 million people5 in the U.K. who smoke cigarettes; e-cigarettes, which have been through the rigorous medicinal licensing process, could be a safe, effective and trusted part of the solution moving forward.

Pete Lomas is a managing consultant at Broughton Group (www.broughton-group.com), a consulting and lab services company.

1 www.gov.uk/government/publications/the-khan-review-making-smoking-obsolete/making-smoking-obsolete-summary

 2 www.youtube.com/watch?v=OnK4u_pO2RM

3 www.fda.gov/tobacco-products/premarket-tobacco-product-applications/premarket-tobacco-product-marketing-granted-orders

4 https://ash.org.uk/uploads/Use-of-e-cigarettes-vapes-among-adults-in-Great-Britain-2021.pdf                                   

5 www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/healthandlifeexpectancies/bulletins/adultsmokinghabitsingreatbritain/2021#:~:text=In%202021%2C%20the%20proportion%20of,14.0%25%20of%20the%20population