FDA Asks For Road Map To Broader NRT Indications

While the agency appears to favor moving to a broad harm reduction framework for indications for NRTs, including lifting limits on recommended duration of use, there remains “a lot of devil in the details” of expanding indications.

The effectiveness of nicotine replacement therapy labels in helping consumers determine the most appropriate treatment could be a key factor in whether FDA allows expanded indications for the products.

At a Dec. 17 public hearing in Silver Spring, Md., FDA officials commented and asked questions indicating that the agency favors moving to a broad harm reduction framework for indications for NRTs, but asked stakeholders for details on how and why the changes should be made.

“There’s a lot of devil in the details,” said Celia Winchell, medical officer for the Center for Drug Evaluation and Research’s Division of Anesthesia, Analgesia and Rheumatology Products.

FDA conducted the Part 15 hearing to gather comments on accelerating its review and approval of smoking cessation products. With abrupt cessation the only approved indication in the U.S., industry and advocates request additional indications for NRTs including craving relief, relapse prevention and reduce to quit (Also see "FDA Delves Into Broader Smoking Cessation Approach" - Pink Sheet, 3 Dec, 2012.).

“Could there be a targeted way for people to self-select to help them know what could work for them? I think it’s an area where we could discuss it more.” – CDER OTC research chief Andrea Leonard-Segal

Agency officials asked smoking cessation experts, consumer advocates and representatives of the pharmaceutical and tobacco industries about how NRT manufacturers can provide data to support new indications, and to eliminate duration-of-use limits and label warnings on dual use of multiple products.

CDER Division of Nonprescription Clinical Evaluation Director Andrea Leonard-Segal asked whether manufacturers can format NRT labeling to help consumers identify the best product for them.

“I’m trying to envision a process whereby a label could help someone understand what products are most helpful to them,” said Leonard-Segal.

NRTs marketed OTC in the U.S. are available in gum, lozenge and transdermal patch forms, with duration of usage indicated for eight to 12 weeks. Spray and inhalant NRT products are available Rx in the U.S.

“It’s something we haven’t talked about much internally at all. Could there be a targeted way for people to self-select to help them know what could work for them? I think it’s an area where we could discuss it more,” Leonard-Segal added.

“As with all addictive disorders, you need a flexible approach, and that’s where we’ve struggled,” said Howard Marsh, chief medical officer for GlaxoSmithKline Consumer Healthcare LP, which makes Nicorette NRT products.

Jonathan Foulds, a professor of public health sciences at Penn State College of Medicine representing the Society for Research on Nicotine and Tobacco, maintained most smokers who decide to use NRTs are ready to quit without continuing to use combustible tobacco products. However, the contraindication against dual use implies that it would be dangerous to quit gradually and may discourage other smokers from trying.

“A new indication that could bring in behavior change – that could impact public health,” said Foulds.

Corrine Husten, senior medical advisor in FDA’s Center for Tobacco Products’ Office of Medical Products and Tobacco, said while dual use and extended use would be the first steps in expanding indications, higher dose products could have more impact.

Marsh said he is focusing on expanding indications for existing products but “a step to higher dose products would be a logical step.”

Gum and lozenge NRTs in the U.S. are available in 2- and 4-mg doses, and transdermal patches in 7-, 14- and 21-mg products.

FDA Leaning, But Needs Data

While Leonard-Segal and other FDA officials on the panel largely expressed agreement for a broad harm reduction framework for NRT indications and for eliminating limits on recommended duration of use, they also noted that those changes would draw opposition from some advocacy groups. Some questions indicated the agency is still determining what trials are needed to prove NRTs are safe and effective for additional indications.

For FDA to support reduce to quit as an NRT indication, “we need to understand the variances between experimental and placebo that would be clinically meaningful to take that regulatory action.” – Corrine Husten, CTP Office of Medical Products and Tobacco senior medical advisor

Husten pointed out manufacturers will need to define goals associated with indications other than cessation.

“We’re talking about reduce to quit, which is a wonderful goal, if we have data to support. For us to support reduce to quit, we need to understand the variances between experimental and placebo that would be clinically meaningful to take that regulatory action,” she said.

Marsh assured her that GSK and others have data supporting the indication. “There are data where it moves people. Some years ago we did a reduce-to-quit study, and there have been numerous other studies to demonstrate that,” he said.

A question from the lead FDA official for the hearing, Grail Sipes, senior regulatory counsel in CDER’s Office of Regulatory Policy, suggests the agency is undecided on whether new clinical trials are needed to support indications other than cessation.

Sipes asked whether Marsh expects all indications and dual-use directions will be supported by the same studies, or separate trials will be needed for different indications. “We’re trying to get at it conceptually,” she said. Harm reduction advocates recommend a flexible approach, "but there is a question about tying that to the support.”

“NRT is an aid to smoking cessation through the relief of cravings. Safety and efficacy have been proven again and again,” Marsh said, adding, “If you demonstrate improved craving control, it will be a safe and effective product and you wouldn’t need to keep repeating studies.”

In an interview, Marsh said the FDA officials’ questions could indicate the agency is leaning toward acting on requests from GSK and other industry stakeholders to expand NRT indications.

“It’s difficult to interpret their approach based on the questions, but I was impressed by the depth of the questioning and I think it was a good thing. Certainly, it seems that FDA is very much more open than they were a few years ago,” he said.

Ex-U.S. Examples

Marsh and other speakers reminded the FDA panel that U.S. policies on NRT indications, dual use of multiple products and duration of use conflict with prevailing expert recommendations and with the policies of other countries, including the U.K., GSK’s home.

“The disconnect between current expert recommendations and OTC regulations is a missed opportunity for effective lifesaving treatment,” Marsh said.

“The goal should be to help those who smoke quit for good. Taking actions we’ve proposed is a public health imperative,” he added.

With abrupt cessation the only approved indication in the U.S., and labels required to include a warning against dual use of products, some stakeholders said most smokers are better suited to a slower transition period, decreasing their intake of nicotine gradually with multiple products.

James Walmsley, U.K. medical director for Johnson & Johnson, saidforeign regulatory agencies provide examples for “FDA to bring NRT labeling in line with accepted guidance.”

Foulds suggested FDA look to post-marketing surveillance data in other countries where NRTs are indicated for tobacco-use reduction without duration-of-use limits.

“Sometimes we don’t need to do another study in this country. If something else has been done in another country, that should influence whether we go that way,” Foulds said.

Often noted as a model for NRT regulation changes FDA should consider, the U.K. since 2005 has recognized NRTs for use "to cut down smoking as a 'stepping stone' to quitting completely for smokers unable to stop abruptly."

In 2009 the U.K. Medicines and Healthcare products Regulatory Agency approved a broader indication for Nicorette Inhalator, marketed there by J&J, to include helping a smoker "reduce smoking, with no limit on the treatment duration, with the aim of quitting when they are ready." The indications include helping smokers "quit (abruptly stop)," "temporarily avoid smoking in front of others, so minimizing the risks associated with passive smoking" and "reduce compensatory smoking (smoking more intensely and/or using higher nicotine content cigarettes) after forced abstinence (e.g. in smoke-free environments, during hospitalization)" (Also see "U.K. NRT Harm Reduction Indication Could Be Model For U.S." - Pink Sheet, 15 Feb, 2010.).

GlaxoSmithKline PLC submitted a letter that year asking FDA to allow similar claims for NRT products (Also see "GSK Asks FDA To Mull Expansion Of NRT Indications" - Pink Sheet, 7 Dec, 2009.).

The agency also has received two citizen petitions making the requests, in 2008 from New York state health officials and in 2010 from Foulds’ SNRT group, which receives support from firms including GSK and J&J (Also see "NRT Petition Calls On FDA To Greatly Expand Indications, Availability" - Pink Sheet, 1 Mar, 2010.).

A spokeswoman for GSK said FDA has not acted on the requests stated in the firm’s 2009 letter, nor on the two petitions.

Smoking Is the “Real” Comparator

The panel also discussed how NRTs should be evaluated as safe and effective, whether to calculate health outcomes by comparing a placebo group of nonsmokers to former smokers using NRTs, or compare NRT users to active smokers.

Danny McGoldrick, VP of research at the Campaign for Tobacco Free Kids advocacy group, said FDA must compare NRT use with continued use of tobacco. Rather than evaluate whether NRT users’ health improves to the level of non-smokers, the outcome that should be measured is whether a harm reduction framework for indications, including no limits on duration of use, would help consumers cut down while using NRTs and improve their health in comparison to those who do not curb their combustible tobacco use.

David Abrams, executive director of the Schroeder Institute for Tobacco Research and Policy Studies at tobacco-use prevention group Legacy, agreed. “It’s imperative that comparison for safety and risk be weighed against continuing smoking.”

The only “real comparator [to NRTs] is continued smoking,” which is why having more products on market with more flexibility in duration of time and dual use is imperative, Walmsley said.

Wider Access, Broader Package Sizes

Stakeholders also are asking FDA to allow firms to market NRTs in single-use packages and other sizes smaller than those available today, and to allow sales of the products in retail locations beyond where FDA currently allows – drugstores, mass merchandisers and supermarkets.

With smaller packages – comparable to a cigarette pack – and with wider retail access allowed, more retail locations would be able to stock the products and smokers trying to quit would have more help finding an NRT, especially when most needed.

The first of the three NRT indication petitions FDA received, in 2008 from the New York State Department of Health, suggests the agency allow NRT sales anywhere cigarettes are sold, including in vending machines as well as at retailers of all sizes (Also see "Make Smoking Cessation OTCs As Available As Cigarettes – Petition" - Pink Sheet, 25 Feb, 2008.).

Foulds made the same argument during the hearing, saying that smokers trying to quit are dissuaded when they see they can purchase cigarettes most anywhere but NRTs at far fewer locations. “That becomes a barrier to access,” he said.

Transdermal products are offered in seven- and 14-count packages as one- and two-week supplies. NRTs in other formats – which deliver nicotine faster and are better suited to relieve a smoker’s craving – have been available in the U.S. in packages starting at 40-count packages of gum, but with packages of most gums and lozenges starting at 70-count.

NRT package size is set when FDA evaluates each NDA for one of the products or when a firm asks for approval to market a previously approved product in packages containing a different quantity.

Glaxo, though, recently launched 20-count “Pocket Packs” of Nicorette gum in the U.S. The firm expects the smaller packs “will help make NRT more accessible for some smokers.”

A GSK spokeswoman said while “the original thinking” around OTC NRT approval was that larger pack sizes sent the message of using the products “over the time period of greatest risk of a return to smoking,” and health care regulators “postulated that the availability of very small package sizes and/or ‘samples’ would undermine the intended treatment regimen concept.”

However, that “thinking has moved on to recognize the cost and convenience benefits of smaller package sizes,” according to the Glaxo spokeswoman.