By Katherine Devlin and Tom Pruen
This is appearing rather belatedly, but is our analysis of the guidance provided for those who wish to seek an MA for electronic cigarette products. It was produced on the 1st of August, immediately following the publication of the guidance by the MHRA.
The MHRA’s guidance1 is aimed at assisting vendors of NCPs in successfully applying for a Marketing Authorisation for their product(s). Assessing the applicability of this advice to NCPs other than electronic cigarettes is outside our remit, and no comment is made on this.
The MHRA begins its guidance by declaring uncertainty as to the final form the EU regulation will take. Since there is still debate at the European level as to whether electronic cigarettes should be reclassified as medicinal products, there is the possibility that the MHRA’s attempt to pre-empt the regulation may yet have an embarrassing lack of support at EU level. Certainly, France has expressed reservations about this course of action, in part because, in France, this would limit the sale of electronic cigarettes to being through pharmacies only. The same is true of 20 of the 28 EU Member States.
Presumably to avoid this, the MHRA is suggesting that applicants should apply for Marketing Authorisations (MAs) on the basis of presentation (i.e. should make a medicinal claim which will require testing for efficacy). This evades the current debate in Europe, as well as the questionable legality of determining electronic cigarettes as medicines by function. Regulation as a medicine by presentation is universally accepted as a legally viable option; it is the regulation of the products in the absence of medical claims that is legally questionable (according to the Opinion of Sir Francis Jacobs QC2).
The potential future importance of the difference between classification as a medicine by function, or by presentation, is not mentioned in MHRA’s guidance. This is likely to mislead applicants who may not understand that they would be effectively ‘trapped’ by having made medicinal claims for otherwise non-medicinal products.
The vast majority of the advice consists of links to existing documents on the method of applying for an MA, and does not discuss how these relate to electronic cigarettes (or indeed other NCPs). The Q&A section does, however, attempt to clarify the position as regards electronic cigarettes.
- Emissions testing would require that nicotine liquids are only sold for use on specific devices – this is not the way the market currently operates;
- Flavours without available literature on inhalation would be impossible to license, even if there is also no evidence of harm;
- The cost of a single SME electronic cigarette company applying for MAs for its products (£315m, minimum) exceeds the total value of over-the-counter NRT market (£100m);
- Ability of users to combine different products (an important aspect of the current market) is extremely problematic within the medicines framework in many areas
- This user combination of products will make pharmacovigilance effectively impossible;
- Medicines regulation completely ignores electronic cigarettes that do not contain nicotine – even where the devices are the same;
- The creation of two completely different regulatory frameworks will increase the cost and difficulty of regulation;
- There is an absence of evidence that such expensive and complicated regulation is actually required.
The first question is “What is involved in the marketing authorisation application – what do I need to submit?”
This provides guidance on literature searches and pharmacokinetic studies that would be expected. However, it also states:
“The safety of the product can be supported by literature only, assuming that the vapour produced by the device does not contain any components that may raise concerns and that the literature data supports the safety of all components of the formulation via the inhaled route.”
This is directly contradicted by comments made in a face to face meeting between ECITA and the MHRA on the same day that the guidance was published. Amongst the MHRA representatives at this meeting was Dr Ryan Tomlinson, Unit Manager of the Product Lifecycle Assessment Team, who, we were told, would be assessing any applications from electronic cigarette companies. Dr Tomlinson said that not only does the MHRA have concerns about the potential for acrolein and formaldehyde in the vapour due to publications in the literature, but it has not had any data submitted to it on this point; in his words: “we don’t know” if the products of vapourisation are acceptably safe. (We would suggest the published literature, particularly a recent meta-study perform by Dr Igor Burstyn3 indicate that there is good evidence to suggest that the products of vapourisation are acceptably safe). When ECITA pointed out that the emissions from an electronic cigarette would depend on both the liquid used and the device used to vapourise it, Dr Tomlinson suggested that data would have to be generated for each liquid and every device it was intended for use in. Given that there are upwards of 20 atomising device designs currently in widespread use, this would require either that the applicant conduct 20 sets of testing for each nicotine solution that they placed on the market, or that the applicant restrict such liquids only for use in a single specified device. This is not the way the market currently functions, and would not fit with the expectations, needs, or use-patterns of consumers.
There is also very limited information in the literature about the safety profile of inhaled flavourings, making such a search much more problematic than the MHRA implies.
Since food flavourings (in order to be considered safe for use in food at the levels found) must have a plausible method of metabolism or excretion in order to be safe in food, there is limited prospect of them being dangerous if inhaled. It is also important to note that the quantities of flavoured nicotine solution consumed in a day are quite small, with almost every user consuming between 2 and 5 millilitres per day (approximately 2 to 5 grams) of ‘eliquid’, containing at most 20% flavourings. This would result in users consuming no more than 0.4 to 1 millilitre (approximately 0.4 to 1 gram) of the flavourings over the course of 24 hours. (The amount of flavouring added is usually closer to 10%, so this represents the most extreme example.) The MHRA position, therefore, is a prohibition on flavours that cannot be proven to be safe based on existing data, rather than a more sensible prohibition on flavours that have been proven dangerous, or those that are proven so in the future.
This point is also addressed in questions 3 and 12 “What do I need for the non-clinical (safety) part of the marketing authorisation application?” which also discusses the potential problem of leaching from the atomising device into the liquid/vapour, and “Do I need a marketing authorisation if my product is an e-liquid or nicotine liquid only?”
The MHRA guidance states:
“A comprehensive evaluation of the potential extractables and leachables originating from all components of the electronic cigarette should also be provided, with associated toxicological review.”
“It would thus be possible to apply for a MA for the nicotine liquid only. However, it would be necessary to demonstrate that the liquid is safe and effective in specified electronic cigarettes. Furthermore, such electronic cigarettes would need to be licensed.”
How this might be achieved, when – in the current market – a large proportion of users buy the liquid and hardware separately (and not infrequently from different vendors), is not addressed. We can only assume that this would again require the liquid to be sold for use only in one or more specified licensed devices. As Dr Tomlinson said during the meeting between MHRA and ECITA, “It would become very complicated.”
Question 4 addresses efficacy: “What do I need for the clinical (efficacy and safety) part of the marketing authorisation application?” Oddly, this does not appear to make any reference back to the claim made when presenting the product (while the MHRA is taking voluntary applications on the basis of presentation), but assumes that nicotine delivery is the key measure, which is to treat the product as a medicine by function. The guidance does, however, then state that the product must “demonstrate safe and efficacious levels of nicotine for each claimed indication”, which seems to contradict this. Furthermore, it does not provide any useful information on the MHRA’s stated intent to regulate the products by function (i.e with no claims made). The bulk of the evidence required for this, according to the guidance, is comparison of bioequivalence of the product with an existing medicinal NRT product, in a small scale clinical trial. The form of these trials was discussed at the meeting between MHRA and ECITA, specifically concerning the effect this might have on the pace of innovation within the market, particularly with regard to the introduction of new electronic cigarettes. During this discussion, Dr Tomlinson informed us that these studies (as well as lab testing) would need to be done to determine if a design change to a product would make it sufficiently different to ‘trigger’ a new Marketing Authorisation. This would have to be done prior to placing a new product on the market, and the clinical trial alone, according to the MHRA estimates, would cost between 50 and 100 thousand pounds.
This would clearly have a negative effect on innovation within the market.
Question 5 addresses the regulation of the electronic cigarette hardware as medical devices:
“The MHRA considers the part of the electronic cigarette containing the battery together with any associated charging accessories to be a Class IIa medical device as an active therapeutic medical device.”
However, a significant proportion of electronic cigarette products are sold with nicotine supplied separately from hardware (i.e. the liquid is sold separately from the hardware it is to be used with). Where this is the case, the MHRA has stated (in question 10 of their guidance) that if an electronic cigarette contains no nicotine, and makes no medical claims, then they do not intend to regulate it.
This would create a situation where the same hardware would be on the market, but regulated in completely different ways, solely on the basis of the inclusion of nicotine. This places a disproportionate burden on those companies who supply prefilled products, and since in most cases the same hardware would be available with much lighter regulatory costs, prevent such companies remaining competitive.
This combination of heavy-handed and expensive regulation, while simultaneously allowing the current state of regulation to continue will also increase the problems of enforcement, since in order to determine how a product should be regulated, it will first require a determination as to whether or not it contains nicotine. This will make the role of the enforcement agents (Trading Standards Officers) much harder, and increase the costs of enforcement, since samples will have to be analysed for the presence of nicotine prior to even being sure which regulatory framework applies.
Question 6 addresses the costs of an MA, with a link to the MHRA table of periodic fees. This however provides rather less information than the costs estimated in the MHRA’s “Impact assessment to support the UK’s position in EU negotiations on the regulation of Nicotine Containing Products, which are currently being considered along with changes to the Tobacco Products Directive”4, which estimates the combined cost of an MA application at between £215,000 and £350,000 per application. Since the MHRA states that “An electronic cigarette would be expected to be a so-called complex application”, it is not unreasonable to assume that the costs would be at the upper end of this estimate.
This led to a situation where an ECITA member company contacted the MHRA directly, and was told that they would require 900 MAs to cover their product range. Based on the MHRA cost estimates, this would cost £315,000,000 purely for MAs. This does not include the associated costs of GMP compliance, nor importing, wholesale, or pharmacovigilance fees, which would also add significant costs. It also takes no account of future costs, such as R&D into new products, which would also require significant expenditure.
This is the cost for a mid-sized company with a turnover of around £5 million. Clearly, it is not possible for this type of company – which is very typical of the SMEs which make up the electronic cigarette industry – to invest such an excessive amount of money.
In its document “Proportionate regulation”5 the MHRA states that the value of the over-the-counter market in licensed NRT products is £100 million – less than the cost of a single electronic cigarette company applying for MAs for its product range, and with no guarantee that it will receive them.
It is also not clear why electronic cigarette companies should engage in pharmacovigilance for their products, when tobacco cigarettes – the most direct competition as a nicotine delivery method – do not, despite the very clearly demonstrated harms caused by smoking. It is also not clear how the MHRA intends to apply pharmacovigilance in an industry where a consumer can buy the three components of an electronic cigarette (battery, atomiser and nicotine solution) from three completely unrelated suppliers (except that, as noted, the current market would be destroyed by the MHRA’s regulatory proposal). It is difficult to reconcile this with the MHRA statement that “The cost of regulation need not affect price or competition…”.
This is precisely why the vast majority in the industry, and also the consumers of these products, view medicines regulation of these products as a de facto ban.
This does not appear to be proportionate regulation by any measure, particularly since the MHRA has not made a compelling argument that electronic cigarettes need to be shoe-horned into medicines regulation – despite the demonstrable lack of ‘fit’. The fact that the electronic cigarette industry covers such a vast range of products, supplied with and without nicotine, makes it particularly inappropriate to apply the medicinal regulatory framework, since this would leave all non-nicotine containing electronic cigarettes under an entirely different regulatory regime. If the MHRA considers the current regulations so unfit for purpose as to require the sledgehammer of medical regulations, why are they so willing to leave products on the market under the current regulatory framework?
Perhaps this is because, despite the concern they express over the current regulations, they have stated in their published documents:
“However, as yet there is an absence of scientific evidence that shows long term harm to health is occurring in reality because of product safety”6
“While contaminants in ENDS have been identified, and the long term health effects of inhaling ENDS vapour are unknown, so far there is an absence of evidence that shows that these problems create significant harm to health.”7
“Safety concerns have been reported. Given the extent of use, however, and despite the lack of a formal reporting mechanism (such as the yellow card scheme), these do not of themselves suggest a major public health concern.”8
“Given the low toxicity of nicotine at the doses observed and the fact that long before any dangerous levels of nicotine concentration could be reached, an over-enthusiastic user would be warned by nausea, there is little concern that e-cigarettes can harm their users by delivering toxic nicotine levels.”9
5 http://www.mhra.gov.uk/home/groups/comms-ic/documents/websiteresources/con286850.pdf (Note also, on this document, that ‘Light Touch Regulation’ has been recast as ‘Right Touch Regulation’.)