Source: https://www.fdli.org/2018/10/spotlight-on-tobacco-future-developments-in-the-regulation-of-electronic-nicotine-delivery-systems-potential-over-the-counter-pathway/
Timestamp: 2019-04-26 16:11:06+00:00

Document:
In 2009, Congress passed the landmark Family Smoking Prevention and Tobacco Control Act (TCA), amending the Food, Drug and Cosmetic Act (FDCA) to give the U.S. Food and Drug Administration (FDA) authority to regulate the manufacture, sale, distribution, and marketing of tobacco products. The enactment of the TCA coincided with the introduction of new, reduced-harm products—namely, e-cigarettes or Electronic Nicotine Delivery Systems (ENDS)—that have since transformed the tobacco industry.
FDA also maintains authority to regulate nicotine-containing products, including ENDS, as drugs or medical devices if they are marketed in a manner that triggers such classification. In this regard, FDA has recently indicated that it is exploring ways in which ENDs may be regulated as over-the-counter (OTC) nonprescription drugs.
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During the decade following the Supreme Court’s decision in FDA v. Brown & Williamson, industry, public health stakeholders, and lobbyists worked with Congress to amend the existing FDCA to include tobacco products—ultimately resulting in the TCA.
“Tobacco product” is broadly defined in Section 900 of the TCA to include “anything made or derived from tobacco intended for human consumption, including components, parts and accessories,” which captures a host of tobacco- and nicotine-containing products. However, when the TCA was enacted, it only gave FDA immediate authority over certain categories of tobacco products, i.e., cigarettes, cigarette tobacco, smokeless tobacco, and roll-your-own tobacco, but the TCA also permitted FDA to use its rulemaking authority to “deem” other tobacco products to be regulated pursuant to the TCA.
On August 8, 2016, FDA’s “Deeming Rule” became effective. As required by the rule, all new tobacco products must comply with a host of TCA regulatory requirements such as registration, ingredient listing, warnings, age-restrictions and, most critically, premarket authorization for any new products first marketed or modified after the February 15, 2007 “grandfather date.” With respect to premarket authorization, because there are no known grandfathered ENDS, all such products, including those that have been on the market for years, are required to obtain FDA marketing authorization through the Premarket Tobacco Product Application (PMTA) process. Under the agency’s current premarket review “compliance policy,” which it has recently indicated it may be reconsidering for certain types of e-cigarettes,5 manufacturers of deemed noncombustible tobacco products such as ENDS that were on the market when the Deeming Rule went into effect have until August 8, 2022 to submit PMTAs, and can remain on the market through that date and pending FDA review.6 New ENDS intended for introduction to the U.S. market after August 8, 2016 require up-front PMTA-authorization.
Manufacturer claims related to “smoking cessation in the context of curing or treating nicotine addiction and its symptoms” would bring a product within the disease prong of the drug or device definition under this new rule. This would include claims, for example, that an ENDS can help a smoker quit or treat their nicotine addiction. Indeed, FDA is clear that it considers smoking cessation claims to “create a strong suggestion of intended therapeutic benefit” that would be difficult to overcome. Beyond smoking cessation or quit claims, any claims that a product may be used to diagnosis, cure, mitigate, treat or prevent of disease (particularly tobacco-related disease) would cause a product made or derived from tobacco to be a medical product.
Claims that a tobacco product affects the “structure or function” of the body in any way related to the effects of nicotine may also trigger FDA’s drug authority. FDA’s new rule states that the only nicotine structure/function claims permissible are those that were customarily used by tobacco companies to market cigarettes and smokeless tobacco prior to March 21, 2000—the date of the U.S. Supreme Court decision in FDA v. Brown & Williamson. In other words, claims that were commonly and legally made in the marketing of cigarettes or smokeless tobacco prior to March 21, 2000 will not cause products made or derived from tobacco to be marketed as medical products.
On the other hand, statements that a product can “relieve tension” or “promote weight loss” would be considered structure/function claims that are related to the pharmacological effects of nicotine but that were not commonly and lawfully used prior to March 21, 2000. Absent evidence to the contrary, FDA would likely consider products subject to those claims to be medical products.
A company seeking to market an ENDS as an actual smoking cessation tool (i.e., with smoking cessation claims) such as the nicotine gum or patch would need FDA premarket approval as a “drug,” because smoking cessation claims trigger the first prong of the drug or device definition, described above. Such FDA approval generally requires demonstrating, typically through significant nonclinical and clinical evaluations, that a product is “safe and effective” for its intended use. The process of getting a drug approved for a particular indication is complicated, takes many years, and can also cost millions of dollars. New medical products are also approved for a particular indication, virtually always requiring a prescription. With adequate data (both safety, effectiveness and consumer label comprehension), some drugs, including several NRTs, have been able to make the “Rx-to-OTC” switch.
The history of FDA’s establishment of the OTC drug pathway has its roots in 1962 when the FDCA was amended to require all drug manufacturers demonstrate the safety and effectiveness of their drugs before approval.16 The term “new drug” is defined in section 321(p) of the FDCA, in part, as any drug that is not generally recognized as safe and effective, or has become so recognized, but has not been used to a material extent or for a material time.17 All new drugs must be approved before marketed. As noted above, a product whose intended use falls within the definition of “drug,” and which is also a “new drug,” must obtain premarket approval from FDA through submission of a new drug application (NDA) or an abbreviated NDA (ANDA).
Today, through the OTC monograph system, FDA reviews products by therapeutic category rather than individually.20 A three-phase public rulemaking process results in the establishment of standards (drug monographs) for an OTC therapeutic drug class. If an OTC drug meets the standards set out in a monograph, it is considered generally recognized as safe and effective (GRASE) and therefore not subject to FDA premarket approval.
In an effort to reform the regulation of the OTC monograph system, the Over-the-Counter Monograph Safety, Innovation, and Reform Act of 2018 was introduced in the U.S. Senate on January 17, 2018.21 A version of the Senate bill passed the U.S. House of Representatives (H.R. 5333) on July 16, 2018. The Senate bill would replace the current OTC rulemaking procedures with an administrative order process, whereby through initiation by the agency or at the request of a requestor (i.e., any person or group of persons marketing, manufacturing, processing, or developing a drug), FDA could issue an administrative order determining whether there are conditions under which specific drugs, classes of such drugs, or combinations of such drugs are generally recognized as safe and effective. Notably, the Senate bill would create an incentive to bring innovative OTC products to consumers, granting two years of exclusivity to makers of innovative OTC products.
As it currently stands, the PMTA process presents a significant barrier to market entry for ENDS deemed as tobacco products. When FDA’s premarket review compliance policy for these products comes to a close, whether in August 2022 or sooner, thousands of e-cigarettes on the market not subject to PMTAs will be adulterated. While pharmaceutical companies may already be developing ENDS with claims that will need drug approval, Dr. Gottlieb’s comments may be an invitation to other companies in the recreational ENDS industry that they, too, consider the relative benefits of making NRT claims vs. overcoming the challenges of PMTA clearance.
Interestingly, the same landscape exists for the ENDS industry today: most products on the market contain liquids with similar ingredients and use common delivery device features. As such, FDA could create an OTC monograph for e-liquids, for example, which would create a standardized predicate e-liquid that all products would compare against, and require Harmful and Potentially Harmful Constituents (HPHCs) testing, toxicity analysis, and compliance with pharmaceutical GMPs, etc. Ultimately, such a system has the potential to create a uniform approach towards FDA regulation of ENDS products as drugs, which will be aided by Congress’ action in streamlining the OTC drug monograph system.
Unfortunately, a prerequisite to monograph status is that the products covered by the monograph are GRASE. The legislative changes being contemplated would not alter that requirement. General recognition of the safety of inhaled ENDS components in the foreseeable future is unlikely. FDA’s ability to manage products covered by OTC monographs is in need of enhancement, but the legislative changes being contemplated would not eliminate the biggest obstacle to issuing a monograph for ENDS.
If FDA does establish an OTC pathway for ENDS, pharmaceutical companies with prior experience navigating the complex and costly FDA drug approval process for NRTs, and whose products are competing with recreational ENDS on the nicotine market, would certainly be better positioned to navigate that regulatory scheme compared to the thousands of small businesses that make up the vaping industry today. Nevertheless, recreational ENDS manufacturers should eep a close watch on the potential for an OTC drug option either as an alternative to or in addition to a PMTA tobacco product clearance. Ultimately, it remains to be seen whether FDA can develop a clear OTC pathway for ENDS, and what types of companies would be able to take advantage of it.
81 Fed. Reg. 28974 (May 10, 2016).
See Favor Smokeless Cigarettes Regular – vintage American Cigarette Pack. CIGARETTE COLLECTOR,(Apr. 04, 2017), http://cigarettecollector.net/2017/04/04/favor-smokeless-cigarettes-regular-vintage-american-cigarette-pack/#content-container.
See FDA v. Brown & Williamson Tobacco Corp. et al., 529 U.S. 120 (2000).
Sottera, Inc. v. U.S. Food and Drug Admin., 627 F.3d 891 (D.C. Cir. 2010).
U.S. Food & Drug Admin., FDA News Release, FDA Takes New Steps to Address Epidemic of Youth E-Cigarette Use, Including a Historic Action Against More Than 1,300 Retailers and 5 Major Manufacturers for Their Roles Perpetuating Youth Access (Sept. 12, 2018), https://tinyurl.com/yaf4mw8g.
Guidance for Industry: Extension of Certain Tobacco Product Compliance Deadlines Related to the Final Deeming Rule (Revised) (August 2017), https://www.fda.gov/downloads/TobaccoProducts/Labeling/RulesRegulationsGuidance/UCM557716.pdf.
21 U.S.C. § 387j(c) (2018).
FDA’s Draft Guidance on PMTAs for Electronic Nicotine Delivery Systems, FDA.GOV (May 2016), https://www.fda.gov/downloads/tobaccoproducts/labeling/rulesregulationsguidance/ucm499352.pdf.
21 C.F.R. § 1100.5 (2017). This is slightly different from the drug definition in the FDCA, which defines “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease,” as well as “articles (other than food) intended to affect the structure or function of the body” to be drugs. See section 201(g)(1) of the FDCA.
82 Fed. Reg. 2200 (January 9, 2017).
Brad Rodu, CDC: E-cigarettes more popular than FDA-approved quitting aids. RSTREET (Apr. 19, 2017), https://www.rstreet.org/2017/04/19/cdc-e-cigarettes-more-popular-than-fda-approved-quitting-aids/.
Niall McCarthy, Poll: U.S. Smoking Rate Falls To Historic Low [Infographic], FORBES (Jul. 26, 2018, 07:45 AM), https://www.forbes.com/sites/niallmccarthy/2018/07/26/poll-u-s-smoking-rate-falls-to-historic-low-infographic/.
Teresa W. Wang, Andrea Gentzke, Saida Sharapova, Karen A. Cullen, Bridget K. Ambrose, Tobacco Product Use Among Middle and High School Students — United States, 2011–2017, CDC WEEKLY, (Jun. 8, 2018,), https://www.cdc.gov/mmwr/volumes/67/wr/mm6722a3.htm.
Gottlieb, S. et al., (2017). Advancing Medicinal Nicotine Replacement Therapies as New Drugs – A new step in FDA’s comprehensive approach to tobacco and nicotine. [Blog] FDA Voice, https://blogs.fda.gov/fdavoice/index.php/2017/11/advancing-medicinal-nicotine-replacement-therapies-as-new-drugs-a-new-step-in-fdas-comprehensive-approach-to-tobacco-and-nicotine/ [Accessed 13 Sep. 2018].
Angelica LaVito, FDA May Consider Over-the-counter Regulation for e-Cigarettes, CNBC (March 28, 2018, 4:06 PM) https://www.cnbc.com/2018/03/28/fda-may-consider-over-the-counter-regulation-for-e-cigarettes.html.
The Drug Efficacy Amendment of 1962, 76 Stat. 780 (codified as amended at 21 U.S.C. § 301).
The United States Federal Food, Drug, and Cosmetic Act § 321(p).
37 Fed. Reg. 85 (Jan. 5, 1972).
Drug Applications for Over-the-Counter (OTC) Drugs, FDA.GOV (Jan. 7, 2015), https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/over-the-counterdrugs/default.htm.
Over-the Counter Drug Safety, Innovation, and Reform Act, S. 2315, 115th Cong, (2018).
82 Fed. Reg. 56759 (November 30, 2017).
U.S. Food and Drug Administration (FDA) Statement from FDA Commissioner Scott Gottlieb, M.D., on New Steps the Agency is Taking to Support the Development of Novel Nicotine Replacement Drug Therapies to Help Smokers Quit Cigarettes, FDA. GOV, (Aug. 3, 2018), https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm615740.htm?utm_campaign=08032018_Statement_FDA%20statement%20on%20developing%20new.
U.S. Food and Drug Administration (FDA) Website, Nicotine Steering Committee, FDA.GOV (Sept. 13, 2018), https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/ucm587918.htm.
U.S. Food and Drug Administration (FDA) Website, Public Meeting on FDA Approach to Evaluating Nicotine Replacement Therapies, FDA.GOV (Sept. 13, 2018), https://www.fda.gov/NewsEvents/MeetingsConferencesWorkshops/ucm580561.htm.
U.S. Food and Drug Administration (FDA) Draft Guidance, Nonclinical Testing of Orally Inhaled Nicotine-Containing Drug Products Guidance for Industry, FDA.GOV (Sept. 13, 2018), https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm615575.pdf.
U.S. Food and Drug Administration (FDA) Statement from FDA Commissioner Scott Gottlieb, M.D., on New Steps the Agency is Taking to Support the Development of Novel Nicotine Replacement Drug Therapies to Help Smokers Quit Cigarettes, FDA.GOV (Aug. 3, 2018), https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm615740.htm?utm_campaign=08032018_Statement_FDA%20statement%20on%20developing%20new.
Dept. of Health and Human Services Food and Drug Admin., 113th Cong., Report to Congress: Innovative Products and Treatments to Achieve Abstinence from Tobacco Use, Reductions in Consumption of Tobacco, and Reductions in the Harm Associated with Continued Use, at 7 (Apr. 22, 2013), http://wayback.archive-it.org/7993/20161022200459/http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM348930.pdf.
37 Fed. Reg. 86 (Jan. 5, 1972).
While the data requirements needed for approval of a New Drug are substantial, applications can be filed under the procedure at Section 505 (b)(2) of the FDCA and rely on the vast data already in FDA’s possession with regard to the existing NRT approvals.
In 2013, FDA announced a revision to the “Drug Facts” labeling of OTC NRT products, which removed the recommendation that use of the NRT be stopped after a specific duration of use. 78 Fed. Reg. 19718 (April 2, 2013). In its announcement, FDA acknowledged that the agency did not identify any safety risks associated with longer-term use of NRTs (longer than 12 weeks) in the published literature. Id. FDA noted that as an approved NRT, nicotine inhalers are available by prescription only and are therefore outside the scope of the notice. Id. For the prescription nicotine inhaler (NICOTROL® Inhaler), the recommended duration of treatment is 3 months, after which patients may be weaned from the inhaler by gradual reduction of the daily dose over the following 6 to 12 weeks. 82 Fed. Reg. 56759 (Nov. 30, 2017).

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