Speakers at a workshop on nicotine-replacement therapy point abroad for guidance on expanding indications for smoking-cessation products as an FDA official says the agency likely will put the question before an advisory committee.

Center for Drug Evaluation and Research official Bob Rappaport spoke at the close of a scientific workshop Oct. 26-27 in Arlington, Va., conducted to hear evidence on the benefits and risks of more liberal indications on nicotine-replacement therapy labeling.

Quick Facts

FDA workshop included experts' presentations on long-term NRT use.
Industry reps stressed quitting without nicotine will not work for all smokers.
CDER's Rappaport says NRT indication "quite likely" will go to advisory committee.

"We may well take this to an advisory committee in the future. In fact, I think that's quite likely," he said.

Current labeling indicates the products should be used for up to 12 weeks and should not be used with other NRTs or cigarettes.

Rappaport, deputy director of the Division of Anesthesia, Analgesia and Rheumatology Products, said at the workshop FDA could receive information from experts who, due to conflicts of interest, would be prohibited from participating in an advisory committee (Also see "CDER-Tobacco Center Joint Meeting Could Signal Talks On NRT Indications" - Pink Sheet, 8 March, 2010.).

At the outset of the workshop, Celia Winchell, team leader in the Division of Anesthesia, Analgesia and Rheumatology Products, pointed out that interest in the topic came from within FDA.

"We have, for many years, expressed an interest in chronic use of NRTs," Winchell said.

Witnesses Encourage Global View

Industry representatives, who testified in the public hearing during the workshop's second day, in particular emphasized the safety and efficacy of NRT use in other countries under more liberal indications.

NRT label limits in many other countries are for longer than 12 weeks, said Kevin Bridgman, VP of Regulatory and Medical Affairs for Europe and the Middle East at McNeil Consumer Healthcare.

Bridgman noted the average limit in other countries is 12 months, varying from six months in Spain to no duration limit in the U.K. and Australia.

Citing independently verified data, he said McNeil has not found large numbers of adverse events in either short- or long-term NRT use in 30 years of global sales of the products.

McNeil markets Nicorette gum brand overseas and the Nicorette Inhalator in the U.S.

GlaxoSmithKline manufactures NicoDerm CQ patches and Commit NRT lozenges and has a license from McNeil to market Nicorette products in the U.S.

In a separate presentation, Tom Leigh, an official with the U.K. Medicines and Healthcare products Regulatory Agency, made points similar to Bridgman's.

The U.K. has dramatically higher rates of smoking-related deaths than other European countries, but since 2001 all NRT products – inhalers, gum, lozenges, patches and sprays – have been available in general sales, the equivalent of OTC in the U.S.

"We have seen no increased risk of harm from the OTC availability," he said.

A 2005 U.K. government working group noted labeling should indicate NRT use is preferable to smoking. The country in 2010 approved a harm reduction indication for NRTs, with labels stating the products can be used to cut down cigarette use without complete abstinence (Also see "U.K. NRT Harm Reduction Indication Could Be Model For U.S." - Pink Sheet, 15 February, 2010.).

In an interview, Howard Marsh, GSK's chief medical officer for consumer health care, said FDA was right to look overseas and bring in experts from around the world.

“We have seen no increased risk of harm from the OTC availability.”

– U.K. health official Leigh

The two-day process examining the variety of potentially conflicting evidence was the right approach, he said.

"If it was easy, they would have done it by now," he added.

During public presentations, Marsh, Bridgman and Consumer Healthcare Products Association executive David Spangler emphasized that quitting without nicotine always should be the first option, but will not work for all smokers.

"Every smoker is unique and many require a more flexible approach to help them quit for good," Marsh said.

The industry representatives also worked to keep FDA focused on comparing the safety of NRTs to the risks of smoking. Before the meeting, Spangler said he was concerned the meeting would focus on the safety of NRTs in a vacuum, rather than the more useful discussion of comparing use of the products with smoking.

"These medications are not only safe in their own right, but are orders of magnitude safer than continued smoking," Marsh said in his presentation.

Several other speakers noted FDA's advice on long-term NRT use currently conflicts with that of the U.S. Public Health Service. The service, headed by the surgeon general, recommends extended use of smoking-cessation products.

Swedish Snuff May Be Good Comparison

Several researchers presenting and speakers during the public hearing noted a Swedish study of users of a purified form of chewing tobacco known as snus. The product, which R.J. Reynolds Tobacco Co. markets in the U.S. under its Camel brand, has similar levels of nicotine to cigarettes, but with fewer carcinogens snus may be a good comparison for NRTs.

While consumers of snus and similar tobacco products will use the products for long periods, which is conducive to generating research data, limited research has been possible into long-term use of NRTs.

Many smokers "require a more flexible approach to help them quit for good."

– GSK medical officer Marsh

Snus users actually had a lower rate of lung cancer than those who never smoked and comparable levels of oral cancers, emphasized Saul Shiffman, a professor at University of Pittsburgh and consultant with Bethesda, Md.-based Pinney Associates.

Shiffman acknowledged snus users showed a higher level of pancreatic cancer than smokers and those who did not use any tobacco products.

Research Indicates Adverse Effects Unlikely

Highlights of research presented included:

Hildegard Schuller, University of Tennessee, discussed a study showing nicotine may exacerbate the growth of some lung cancers in rats. She cautioned, though, that the research is limited to one particular type of cancer and the differences in the way humans and rats metabolize nicotine limits potential comparisons to humans.
Bob Newhouse, University of Vermont, showed data indicating few withdrawal symptoms or other adverse events in older adults given intravenous nicotine as a treatment for cognitive impairment, a precursor to Alzheimer's disease.
FDA's Winchell concluded that, based on several presentations, current formulations of NRTs are unlikely to be abused, but innovations – including new formulas and flavors – may alter the risk.

The consensus of the event appeared to be that NRTs are generally safe for long-term use, though some safety concerns linger in very specific conditions.

More research is needed to examine their safety, but panelists noted such studies would be feasible if long-term indications were approved, and that few consumers use NRTs for more than about a year.

Stanford University researcher John Cooke said while he would "line up solidly behind those advocating extension," he cautioned "there are some things we don't know."

Additional Topics Unaddressed

Other regulations that would allow increased access to NRTs were not addressed during the workshop. When the workshop was announced, tobacco treatment experts suggested allowing sales of the products in smaller packets, at more retail locations and with more limited warning labels (Also see "FDA Will Mull OTC Smoking Cessation Long-Term Use As Support Builds" - Pink Sheet, 6 September, 2010.).

Bill Godshall, electronic cigarette advocate and executive director of Smokefree Pennsylvania, urged FDA to "stop protecting cigarettes from market competition" and allow higher-dose NRT products and sale of cheaper NRT packets in more places.

He also urged the agency to look at e-cigarettes as a viable smoking cessation treatment alternative, a practice that has drawn warning letters from FDA (Also see "Smoking Cessation Claims For E-Cigarettes Draw FDA Warnings" - Pink Sheet, 13 September, 2010.).

Godshall said Principal Deputy Commissioner Josh Sharfstein's "misleading and fear-mongering claims" about e-cigarettes at a 2009 media briefing should be "corrected and clarified" by the agency (Also see "FDA Warns Electronic Cigarettes Pose Public Health Risk" - Pink Sheet, 27 July, 2009.).

By Carolyn B. Phenicie

Advisory Committee On NRT Indications Appears Likely Following Workshop

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