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London - From Apple Pie to Bubbly Bubble Gum, Irish Car Bomb or Martian bar - from Mars!, the flavours of electronic cigarettes offer something for every taste.
Researchers have counted 7 764 varieties of "vape". That adds up to one of many challenges - from practical constraints to conflicts of interest - in working out how safe e-cigarettes are, and whether they help smokers quit.
Most scientists agree e-cigarettes have potential as a stop-smoking aid. They can be used with or without nicotine and are free of the thousands of toxins in conventional cigarettes. But e-cigarettes also throw up some unusual obstacles.
Drug firms usually test one treatment against another. With e-cigarettes, the huge variety of constantly evolving products means it would be prohibitively expensive to test every flavour and vaporiser.
"E-cigs are really the first product I'm aware of that have challenged pharma in this way," said Chris Bullen, an associate professor at the University of Auckland and author of one of two randomised trials of e-cigarettes in a recent major review of the science. "I guess many alternative 'natural' products raise similar issues when they start to make health claims."
E-cigarettes can look like ordinary smokes but are metal and plastic battery-powered gadgets that heat flavoured liquids into a cloud which users suck in, then exhale as dense white plumes. Invented in their present form in China about a decade ago, e-cigarettes generated $4bn to $5bn in sales in 2014, according to Euromonitor, a market research firm.
The gadgets themselves come in hundreds of brands and are constantly morphing, at the hands of both users and the small-scale distributors who sell them online.
Because they are a strange hybrid between smoking - which kills nearly 6 million people a year - and stop-smoking medications, e-cigarettes rival both tobacco and pharma. Tobacco companies have responded to that threat by buying up e-cigarettes businesses, and are now funding research. Pharma firms have kept their distance.
The products have also opened a rift between researchers who see their goal as eliminating nicotine in all its forms, and others who believe it makes more sense to reduce the harm of smoking.
"You've got people who've taken a position and they're looking at the evidence only in relation to the position they've got," David Sweanor, an e-cigarette enthusiast and law professor at the University of Ottawa, told an e-cigarette symposium in London in November.
Pharma bows out
There are more than 2 000 papers on e-cigarettes in the scholarly journals covered by the Web of Science, a database. Of those in the highest impact journals, most have been funded by public bodies. Only a few contain original research; methodological problems or potential bias are common, scientists have found.
Last month, in an attempt to clear matters up, Bullen and other scientists in Britain and New Zealand published their assessment of the most impartial studies. Known as a Cochrane Review - a study of the best science on a subject - it aimed to see if e-cigarettes can help people stop smoking.
The review concluded that e-cigarettes may help smokers quit, and that there is little sign that they hurt users.
But it found the evidence thin and data poor. Of almost 600 studies analysed, only 13 published papers were up to the Cochrane standard. Just two were randomised controlled trials, the most rigorous test.
Big Pharma is not helping. The pharmaceutical industry has backed efforts to restrict e-cigarettes and is not sponsoring a single current e-cigarette trial in the US National Institutes of Health database.
For drugs firms, smoking cessation is a small business, generating $2.4bn in sales in 2013, according to Euromonitor. That's just a fraction of the $206bn the industry generated in global consumer health products.
"We've decided we're not going to play (in e-cigs)," GlaxoSmithKline Chief Executive Andrew Witty told Reuters. "We've consciously had a think about it but we're not going to play."
Vested interest
This leaves e-cigarette companies to fund their own research, giving rise to concerns over conflicts of interest.
In 2010 one European e-cigarette distributor, Italian firm Arbi Group Srl, sponsored a significant body of work by a team at Catania University in Sicily. Catania researchers are among the most prolific, records in the Web of Science show. They conducted the second of the two randomised trials included in the Cochrane Review and are working on nine of the 48 trials on e-cigarettes logged with the US National Institutes of Health (NIH).
The Catania randomised trial took 300 smokers who did not intend to quit and found that, with or without nicotine, e-cigarettes cut cigarette consumption and helped some people stop completely, without significant adverse effects. That supported claims e-cigarettes had a role reducing the harm of smoking.
"At the end of the day we were stuck accepting money from e-cigarette owners because there was no other way to carry out research," said Catania professor Riccardo Polosa, who designed the trial. He said he had also received funding from pharma.
That, says Charlotta Pisinger, a Danish doctor who runs stop-smoking clinics, is a problem. Last October she published a review which found one in three e-cigarette studies had a conflict of interest because they were funded by e-cig manufacturers, pharma or tobacco, or a combination. She saw evidence of bias: "We must exercise the utmost caution in trusting their conclusions," she wrote.
Experienced medical researchers say industry funding to test new products is the norm.
"The majority of clinical research is sponsored by the manufacturers," said David Tovey, editor in chief of the Cochrane Library, which vets Cochrane Reviews. Another Cochrane study has found that scientific studies sponsored by private industry generally reported greater benefits and fewer harmful side effects than studies industry did not sponsor.
"Moral stance"
E-cigarette opponents are also being scrutinised for bias.
A 2014 US review of the literature, carried out for the World Health Organization at the University of California, San Francisco (UCSF), said that the two randomised trials had shown e-cigarettes were no better than other nicotine replacement therapies at helping people quit.
In August, the World Health Organisation recommended that smokers should be encouraged to try already approved treatments, rather than e-cigs.
Stanton Glantz, a veteran campaigner in the war against Big Tobacco and professor at UCSF, was one author of the US review. But some researchers say activists like Glantz may have been prejudiced against e-cigarettes by their past battles with the tobacco industry.
Robert West, a professor at University College London, is an e-cigarette enthusiast who has been funded by pharma, but not by e-cigarettes makers. He says some opponents present themselves as unbiased, but "their professional and moral stance represents a substantial vested interest."
Glantz says he started his review "completely agnostic."
Image makeover
To add to the controversy, Big Tobacco is getting more deeply involved. E-cigarettes are a threat to the $722bn retail sales of conventional cigarettes globally in 2013, but they are also an opportunity. Fewer people are smoking in the rich world. Shane MacGuill, senior tobacco analyst at Euromonitor, calls tobacco a "terminally sick" industry. E-cigarettes may offset the decline.
Firms including Reynolds American and Imperial Tobacco Group PLC have sponsored seven of the e-cigarette trials in the NIH trials database.
Tobacco executives mingled with researchers and anti-smoking activists at the London symposium last November. The conference was held at the Royal Society, an association of scientists whose fellows include around 80 Nobel Laureates. Beneath portraits of such illustrious figures as Stephen Hawking, delegates puffed on vaporisers.
Some delegates said they found being in the same room as tobacco firms discomfiting. The industry's history of suppressing the truth about tobacco's risks still prompts some universities and academic journals to shun tobacco, and the World Health Organisation is forbidden from collaborating with it.
E-cigarettes are helping tobacco companies transform their image. Firms that for years denied tobacco's harms now emphasise that nicotine itself is not harmful, we just need safer ways to administer it. Some are stepping into smoking cessation: British American Tobacco already has a medical licence for a medicinal nicotine inhaler. A Reynolds subsidiary sells nicotine gum.
Big Tobacco has some support among those in public health who think it won't be necessary to eliminate nicotine, so we should reduce the harm of smoking. But as universities ban association with tobacco firms, it will become even harder for independent researchers to study vaping.
