Clock Ticking for FDA’s “Nicotine Limit” Rule

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Following its recent ANPRM, the United States’ FDA is set to eventually enact a new rule requiring all cigarettes sold in the country to have “minimally or non-addictive” nicotine levels. While the news has unsettled a good many players, there is at least one company that awaits that moment well prepared.

By Thomas Schmid

It caused quite a stir among tobacco companies in the United States and elsewhere when US Food and Drug Administration (FDA) commissioner Dr. Scott Gottlieb in July 2017 dropped his bombshell announcing that the federal agency would introduce a new regulation that would limit nicotine in cigarettes to “minimally or non-addictive levels.” It had long been known, Gottlieb said at the time, that nicotine is the primary addictive component of cigarettes and if smokers lost their addiction, they’d be “free to choose when and how often to smoke.” By extension, limiting nicotine in cigarettes could save millions of lives, help current smokers kick their habit, as well as prevent countless future smokers from picking up a nicotine addiction.

Gottlieb’s bombshell didn’t just “evaporate into thin smoke,” so to speak, as some tobacco industry executives had perhaps hoped for. On March 16 of this year, FDA embarked on the first step in the rule-making process by issuing an Advance Notice of Proposed Rule Making (ANPRM) to obtain information “for consideration in developing a tobacco product standard to set the maximum nicotine level for cigarettes.” Stakeholders – tobacco growers, manufacturers, academic institutions, public health organizations, NGOs - were given until July 16 to submit detailed arguments why – or why not – the proposed new regulation should be introduced, particularly “scientific data and research relevant to the empirical basis for regulatory decisions related to a potential nicotine product standard.” Due to the obvious complexity of the subject matter paired with the ramifications that it carries for tobacco producers and manufacturers alike, the ANPRM posting now suddenly got stakeholders scrambling head over heels, with several of them filing requests for an extension of the comment period.

It is helpful to know at this point that FDA already was granted legal authority to formulate a rule to lower the amount of nicotine in cigarettes when the Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act) was signed into law on June 22, 2009. While that law does not allow FDA to use its new product standard authority to reduce nicotine yields of a tobacco product to zero, it grants the agency the power to determine whether nicotine can be reduced to levels that do not cause or sustain addiction, and, if so, to require the reduction of nicotine yields to those levels. Hence, the tobacco industry at large should have recognized the signs almost a decade ago that a nicotine-curtailing rule might emerge sooner rather than later. But, it appears that almost nobody devised any concrete measures to be prepared when and if that would happen. While it can still take years before the new rule is effective, the clock is definitely ticking, and the countdown already started with Gottlieb’s announcement.

Dawn of the 22nd Century

Enter 22nd Century Group Inc., a plant biotechnology company headquartered in the small town of Williamsville, New York. The New York Stock Exchange-listed enterprise (ticker symbol XXII) invested years of research and countless millions of dollars into its stated mission “to reduce the harm caused by smoking.” Among the company’s most important achievements to-date are the development of a proprietary genetic engineering technology that allows it to regulate the level of nicotine (and other nicotinic alkaloids) in the tobacco plant itself, as well as the development of Spectrum®, a very-low nicotine content (VLNC) research cigarette brand used in a long line of independent studies and clinical trials on smoking cessation and harm reduction.

A New Breed of Tobacco

22nd Century Group claims to be “the only company in the world growing virtually nicotine-free tobacco,” according to communications director James Vail. To make this clear: the company’s scientists have genetically modified the tobacco plant in such a way that during its natural growing phase it develops at least 95% less nicotine than conventional strains of the tobacco plant. That means that after harvesting and curing, no special extraction process needs to be utilized to artificially reduce the nicotine content to the desired level.  Cigarettes made from 22nd Century’s tobacco automatically yield the “minimally or non-addictive levels” of nicotine FDA is pushing for. “Our tobacco is grown with very low levels of nicotine and no [later] extraction process is needed,” confirmed Juan Sanchez Tamburrino, Ph.D., the company’s vice president of research and development.

Such post-harvest extraction processes do of course exist, whereas the naturally-high nicotine content of tobacco can be lowered by applying steam, a solvent, or a so-called supercritical fluid process. But, the downside of all these methods is that they also remove other substances from the tobacco that are crucially important to its sensory properties, negatively affecting a cigarette’s taste characteristics and aroma. In short, it tastes and smells flat, shallow, and unexciting. By contrast, “22nd Century Group’s technology offers a viable alternative to more costly and detrimental extraction-based processes which have a significant impact on taste profiles,” Tamburrino said.

With its modified tobacco plants already being grown in quasi-commercial quantities on a number of independently-owned farms in the US, 22nd Century uses the tobacco in a number of intuitive products, including its SPECTRUM® research cigarettes (see below). To assert and protect its intellectual property rights, the company currently holds a significant number of issued and pending patent applications around the world, including for the above mentioned tobacco-modifying biotechnology.

The SPECTRUM® of Things       

In partnership with independent researchers and officials from the National Institute on Drug Abuse (NIDA), the FDA, the National Cancer Institute (NCI), and the Center for Disease Control and Prevention (CDC), 22nd Century Group developed the ground-breaking SPECTRUM® research cigarettes. Not commercially available and solely deployed in independent research projects and studies, the main SPECTRUM® product line consists of a series of cigarette styles that vary nicotine yields over a 50-fold range – from very low nicotine yield (98% less nicotine than conventional brands - 0.4mg/g vs. 20mg/g) to relatively high yields.

As a subcontractor under federal government contracts, the company so far has supplied over 24 million SPECTRUM® cigarettes for NIDA, which is part of the National Institutes of Health (NIH). The cigarettes have been used in numerous high-profile studies by independent university researchers on smoking cessation and smoking behavior. The gist of these and other clinical trials that have been published in peer-reviewed articles and altogether have used a budget exceeding $100 million paid for by agencies of the US federal government has been that VLNC cigarettes (i.e. cigarettes containing only about 0.30mg nicotine per stick as opposed to the 12-17mg typical in commercial brands) are much more effective in helping people to quit smoking or reducing their consumption than other aids, such as nicotine patches, vaping, or nicotine chewing gums. “22nd Century’s SPECTRUM® cigarettes have facilitated numerous of independent studies that have demonstrated, conclusively, the public health benefits of minimally or non-addictive cigarettes,” explained Henry Sicignano III, the company’s president and chief executive officer. “What’s more,” he said, “is that 22nd Century’s proprietary very low nicotine content cigarettes show that FDA’s plan to mandate dramatically reduced nicotine levels in cigarettes is immediately feasible. We are proud to be a part of this exceptionally important public health initiative.”

The “Brand A” MRTP Application

SPECTRUM® cigarettes are exclusively used in research and not sold to end consumers in retail stores. But, this may change in the not too distant future. 22nd Century is soon going to refile a revised modified risk tobacco product (MRTP) application with FDA for an in-house developed commercial cigarette brand, currently identified with the placeholder brand name “Brand A”. If “Brand A” is approved and recognized as a genuine MRTP, it will break a long-standing spell, as to-date not one single tobacco company has succeeded with any MRTP application. “We are moving forward with a significantly expanded MRTP application with the FDA’s Center for Tobacco Products for the company’s Brand A cigarettes containing our proprietary VLN™ tobacco that has at least 95% less nicotine content than tobacco used in conventional cigarettes,” asserted James Vail.

He elaborated that Brand A cigarettes contain approximately 0.30mg nicotine per stick, or less than 0.05mg nicotine yield per cigarette. In each case, he said, this represented a “reduction of at least 95% less nicotine relative to ‘Big Tobacco’ cigarette brands.” “The company’s MRTP application to the CTP/FDA will request that Brand A packaging and marketing be allowed to disclose to consumers that the cigarettes reduce smokers’ exposure to nicotine,” Vail added. Like SPECTRUM®, Brand A will be made from the company’s proprietary, biotechnologically-engineered VLN™ tobacco. And since that tobacco has not been subjected to physical or chemical manipulation to remove its nicotine, the cigarettes will have the taste and sensory characteristics of conventional cigarettes. “We believe Brand A containing our proprietary VLN™ tobacco will prove invaluable in drastically reducing smokers’ exposure to nicotine,” explained Sicignano. “To this end, 22nd Century looks forward to continuing to work closely with FDA on this very important public health matter.”

So, there we have it. It is only going to be a matter of time before the new FDA rule will be upon us. That even could happen in less than two years, if some of the stakeholders have their way. In an open letter to FDA’s Commissioner dated May 21, 2018, a total of 41 undersigned top-of-the-tier public health and medical organizations in the U.S. called for the new rule to be finalized by March 2019 and take effect by March of 2020. The question on many tobacco firm executives’ minds around the world also is whether the FDA rule is going to have a domino effect. Historically, many countries – particularly in Europe – have regularly felt compelled to follow suit with their own corresponding rules whenever FDA had enacted an important new regulation.