On August 26, 2021, FDA denied marketing orders for around 55,000 flavored e-cigarettes because the manufacturers had not made the case that authorizing the sale of these products was “appropriate for the protection of public health,” the standard in the 2009 Family Smoking Prevention and Tobacco Control Act that gave the FDA jurisdiction over tobacco products. While there is no question that was a step in the right direction, three statements in the FDA press release raise concerns about the Center for Tobacco Products’ (CTP) future e-cigarette decisions.
In particular, they raise concerns about whether FDA CTP would authorize sale of a menthol Juul before the September 9 deadline for action. By virtue of a federal court order, any products, including Juul, that remain on the market after September 9 without an FDA marketing order must be removed from the market or risk FDA enforcement action.
FDA CTP IS USING THE WRONG STANDARD WHEN USING RANDOMIZED CONTROLLED TRIALS TO JUDGE WHETHER E-CIGARETTES HELP SMOKERS QUIT
The press release stated that “Based on existing scientific evidence and the agency’s experience conducting premarket reviews, the evidence of benefits to adult smokers for such products would likely be in the form of a randomized controlled trial or longitudinal cohort study, …”
Using randomized controlled trials (RCT) is the wrong standard.
Randomized controlled trials are the gold standard for evaluating medicines that are given to specified patients to treat specific conditions, often by prescription. In a high quality RCT everything is prespecified and controlled: the people (patients) receiving the drugs, their specific medical conditions, and, most important, the specific drug and dosing schedule. Patients are then randomly assigned to receive the drug or not (i.e., be in the control group, receiving a placebo [sugar pill] or conventional therapy), then followed for a specified time to see if people receiving the drug to better than the control group. This is the process used to demonstrate that the COVID-19 vaccines work.
Thus, when the FDA Center for Drug Evaluation and Research (CDER) approves a medicine based on the results of a RCT, it approves it for use with the patients studied in the trial with the specific illnesses they have for the specific dosing regime studied. (While doctors are free to prescribe drugs “off label,” i.e., outside the FDA approved uses, companies cannot advertise off-label uses and doing so is discouraged.)
You can see how RCTs guide policy with the emergency use authorization and subsequent approval for COVID-19 vaccines. Once the randomized controlled trials demonstrated efficacy (and safety) the FDA proceeded to provide emergency use authorization for the three COVID-19 vaccines and, more recently, full approval for the Pfizer vaccine. Most important, the FDA did not give a general approval for anyone to take the vaccines, but rather approved specific doses delivered at specific times. Moreover, as the CDC noted, the fact that the vaccines have been administered in accordance with the same protocols that were used in the RCTs is why the vaccines have performed as well in the real world as they did in the RCTs.
But e-cigarettes, as regulated by the FDA Center for Tobacco Products, are consumer products not medicines.
Unlike the FDA Center for Drug Evaluation and Research, that approves medicines, the FDA Center for Tobacco Products cannot specify who should use e-cigarettes or how they are or should be used. They cannot require medical supervision or require a prescription for an e-cigarette or put restrictions on how e-cigarettes are used.
As a result, the RCT is not the appropriate standard to judge what effect e-cigarettes have on cigarette smoking. In the case of a consumer product like e-cigarettes that has been on the market for years and that essentially any adult can buy and use however they want, population observational studies are the appropriate way to assess the effect of e-cigarette use on smoking cessation.
Because unlike the highly controlled situation of an RCT, the population observational studies assess what is actually happening in the real world as a broad mix of people use e-cigarettes however they use them.
This is an important point because the RCTs show that when e-cigarettes are provided to adult smokers under medical supervision, often combined with smoking cessation counseling, they do increase quitting cigarettes. In contrast, when used by the general population as unsupervised consumer products, e-cigarettes are not associated with smoking cessation.
Thus, by prioritizing RCTs in their analysis, CTP is biasing their assessment of the effects of e-cigarettes toward finding a quitting benefit, which is not supported by real world experience as documented in the population studies.
On course, if the e-cigarette companies want FDA to make decisions about e-cigarettes based on the RCTs, there would be no problem with the company submitting an application to CDER (the medicines part of FDA) to try and get e-cigarettes approved as a smoking cessation therapy. (As discussed in our meta-analysis of e-cigarettes and smoking cessation – reproduced at the end of this blog post — they might run into safety problems, but they should be free to try and make the case to CDER).
CONSIDERING LONGITUDINAL COHORT POPULATION-BASED STUDIES IS APPROPRIATE
In its press release the FDA said that it would consider longitudinal observational population studies in which smokers who do and do not use e-cigarettes are followed over time to see how e-cigarette use affects their smoking behavior. This is appropriate as long as they are monitoring real world behavior. The evidence available, however, does not support promoting e-cigarettes for smoking cessation. Our meta-analysis of 31 longitudinal studies did not show that e-cigarettes were statistically significantly associated with stopping cigarettes (OR 1.110; 95% CI 0.944 – 1.276; p=0.228).
This finding is not significantly (p=0.09) different from the results of 13 cross-sectional (a snapshot in time) population studies (OR 0.719; 95% CI 0.437 – 1.183; p=0.194). Pooling all 44 of the population studies also shows no significant association between e-cigarette use and adult smoking cessation (OR 0.947; 95% CI 0.772 – 1.160).
The whole purported benefit of e-cigarettes as consumer products hangs on the assumption that they help adults quit cigarettes. While some adult smokers (daily e-cig users) may quit more, for others (non-daily e-cigarette users) e-cigarettes make it harder to quit so the overall population effect is a wash. E-cigarettes also double the risk of relapse among former smokers. Because the CTP (unlike CDER) cannot mandate who should use or how e-cigarettes should be used they need to focus on this overall population effect, which does not support the conclusion that there are cessation benefits for adult smokers.
Absent that benefit, there is no way that permitting e-cigarettes to be sold as consumer products would be “appropriate for the protection of public health.”
THE FDA SEEMS TO BE WILLING TO TRADE OFF ACTUAL DAMAGE TO YOUTH FOR POTENTIAL BENEFITS TO ADULTS
According to the FDA press release, CTP Director Mitch Zeller said, “Flavored ENDS products are extremely popular among youth, with over 80 percent of e-cigarette users between ages 12 through 17 using one of these products. Companies who want to continue to market their flavored ENDS products must have robust and reliable evidence showing that their products’ potential benefit for adult smokers outweighs the significant known risk to youth.”
This is a remarkable statement because it sets a lower standard of proof for the purported adult benefits compared to demonstrated risks to kids. This view is particularly troubling because most of the rapidly accumulating evidence shows e-cigarettes have substantial adverse effects that increase risk of heart and lung disease. And evidence for cancer is even starting to appear. The fact is that e-cigarettes have been on the market for around 15 years (since 2006) and if e-cigarettes were having substantial actual health benefits for adults it would have been obvious by now and it is not.
Moreover, a well-done analysis of the tradeoff between adult quitting and youth starting that uses the RCT effect for e-cigarettes on cessation (and so is over-optimistic) shows that for every adult that quits 80 kids start. And even using the discredited assumption that e-cigarettes are 95% safer than cigarettes, there is still a net loss of 1.5 million life years.
This analysis was based on behavior before Juul introduced nicotine salts and youth use really took off, so the ratio today would be even higher — and infinite if there is no cessation benefit for adults for e-cigarettes as consumer products.
Finally, it is ethically questionable to be willing to trade off making an unrelated kid sick (nicotine addiction and subsequent illnesses) to treat someone else’s disease (smoking).
MENTHOL DOES NOT RAISE “UNIQUE CONSIDERATIONS”
In its press release, FDA said, “The scientific review of menthol ENDS, as compared to other non-tobacco-flavored ENDS products, raises unique considerations. … the FDA notes that its reviews will similarly examine whether the evidence in the application demonstrates a benefit to existing adult users that outweighs the known youth use of such products.”
While the FDA did not spell out what the “unique considerations” are, the FDA has exempted menthol flavor from its enforcement decision about pod-based flavored e-cigarettes on the grounds that many adult smokers smoke menthol cigarettes, something the FDA has yet to eliminate. This decision is implicitly based on the assumption that e-cigarettes as consumer products would help adults quit cigarettes and FDA wanted to keep that door open.
As noted above, that is an incorrect assumption for e-cigarettes as consumer products.
As 31 state attorneys general wrote the FDA on June 28, 2021, there is no question that menthol e-cigarettes contributes to youth use. Menthol needs to be banned together with all the other flavors.
Indeed, for the reasons discussed above, it is hard to see how any e-cigarette can be judged “appropriate for the protection of public health.”
CTP denying marketing orders for e-cigarettes would, of course, leave the door open for companies to apply to CDER for approval a smoking cessation medicines.
Here is the detailed discussion of these issues from our meta-analysis of e-cigarettes and smoking cessation:
Implications for FDA Regulation of E-Cigarettes
The observational studies have substantial implications for FDA regulation of e-cigarettes as tobacco (consumer) products. When determining whether a new tobacco product is appropriate for the protection of the public health, TCA §910(c)(4) requires FDA to consider the risks and benefits to the population as a whole including users and nonusers of the tobacco product, and taking into account (A) the increased or decreased likelihood that existing users of tobacco products will stop using such products; and (B) the increased or decreased likelihood that those who do not use tobacco products will start using such products.
Moreover, TCA §911(g)(1) provides that a Modified Risk Tobacco Product order (which would allow a company to sell their e-cigarette with claims that the product is less harmful than other tobacco products on the market or exposes the consumer to reduced exposure to substances found in other tobacco products) can be issued only if FDA determines that the applicant has
demonstrated that the product as it is actually used by consumers, will (A) significantly reduce harm and the risk of tobacco-related disease to individual tobacco users; and (B) benefit the health of the population as a whole taking into account both users of tobacco products and persons who do not currently use tobacco products.
If e-cigarette consumer product use is not associated with more smoking cessation, there is no population-level health benefit for allowing them to be marketed to adults who smoke, regardless of the relative harm of e-cigarettes compared with conventional cigarettes. Moreover, to the extent that people who smoke simply add e-cigarettes to their cigarette smoking (becoming so-called dual users), their risk of heart disease, lung disease, and cancer could increase compared with smoking alone.
The other 2 questions CTP is mandated to consider—the direct toxicity of e-cigarettes and the potential that e-cigarette availability increases smoking rates among the youths—are also important and not included in our metaanalysis. The fact that e-cigarettes have attracted millions of youths to nicotine, many of whom would have been unlikely to initiate nicotine use with conventional cigarettes, further undermines the idea that allowing the marketing of e-cigarettes would be “appropriate for the protection of public health.” Evidence of toxicity of e-cigarettes is also growing, including myocardial infarction and other heart disease, lung disease, and cancer.
By contrast, the RCTs suggest that specific e-cigarettes may meet the CDER standard as therapeutic interventions to be delivered to specific classes of patients at specified doses under
medical supervision. Among the 9 RCTs in this meta-analysis, provision of free e-cigarettes significantly increased smoking cessation compared with conventional therapies, including nicotine replacement therapy. The overall quality of evidence was judged “moderate” (Table 2), however, because whether the results from these clinical trials can be extrapolated to the thousands of products available on the global market is unknown. It is possible that differences in e-cigarette product, nicotine concentration of e-liquid, nicotine formulation (salt vs free-base), flavoring agents, distribution strategy (free e-liquid refills vs limited e-liquid refills; e-liquids with a consistent nicotine concentration vs e-liquids with a declining nicotine concentration),
and cointerventions would reduce the external validity of these findings when extrapolated to
different e-cigarette products or when extrapolated outside of the clinical trial setting.
Even with these problems, the RCTs suggest that a specific e-cigarette might be able to pass the “efficacy” test for approval as a smoking cessation therapy administered under medical supervision as part of a cessation program. Approval of e-cigarettes as a cessation therapy, however, also requires that they be “safe,” meaning that the benefit-to-risk ratio must be favorable. As noted previously, recent evidence links e-cigarette use to heart disease, lung disease, and cancer; this evidence raises questions about whether the benefit-to-risk ratio would
be favorable enough for approval as a medication. The fact that 80% of people who smoked in the e-cigarette arm of 1 of the RCTs were still using e-cigarettes a year later compared with 9% of nicotine replacement therapy users reinforces this concern.73 In addition, while outperforming
nicotine replacement therapy, the efficacy of e-cigarettes was similar to or below that of FDA-approved therapies including bupropion and varenicline. If approved as a medication, e-cigarettes should be only available under prescription because of their high abuse potential, similar to prescription only nicotine inhalers that have been approved as cessation medications. [references deleted]