Questioning accuracy

The director of the FDA’s CTP, Mitch Zeller, says the accuracy of self-reporting in respiratory cases should be questioned.

By Timothy S. Donahue

Things are still quite unclear. However, vaping is less risky than smoking combustible cigarettes, according to Mitch Zeller, director of the U.S. Food and Drug Administration’s (FDA) Center for Tobacco Products (CTP). He told more than 300 attendees of the Global Tobacco & Nicotine Forum (GTNF) that “if you are an addicted cigarette smoker and you have been able to successfully transition to e-cigarettes, the last thing [the FDA] would want to see is someone going back to a combustible product.”

He reminded the packed audience of British psychologist and tobacco harm reduction expert Michael Russell’s adage that people smoke for the nicotine but die from the tar. “Nicotine does not cause the cancer, lung disease and heart disease; the nicotine gets you hooked to a product that … with each puff of smoke, you are inhaling the chemicals associated with those diseases,” he said. “There is a public health opportunity to move smokers down the continuum [of risk].”

Most of those in attendance wanted to hear Zeller’s understanding of the current pulmonary illnesses that have caused, as of this writing, 18 deaths in 15 states. The FDA and Drug Enforcement Administration (DEA) have opened a criminal probe into the vaping-related illnesses. “We are working very closely with our colleagues at the CDC and the [U.S. states where illnesses have occurred] as we try to get to the bottom of … how many cases are we talking about?” he explained. “The numbers that you see … are only going one direction and that is up. The CDC will be revising the numbers shortly.”

Hours after Zeller’s keynote address, the CDC released new figures stating that 1,080 lung injury cases associated with using e-cigarette or vaping products had been reported to the CDC from 48 states and one U.S. territory. “Most patients report a history of using THC-containing products,” the CDC release states. “The latest national and regional findings suggest products containing THC play a role in the outbreak.”

The role of the FDA in the pulmonary cases is to work in a complementary role with the CDC and other necessary federal organizations, such as the DEA, Zeller said. “When states have collected product samples and have made the decision to share them with [the FDA] then those samples go to our forensic chemistry center—these are expert analytical chemists—as we try to understand what is in these products,” he said. “The challenge we are all facing is [that] there is no common thread … there is no common thread in these self-reports from patients who have informed state officials in the first place.”

Attendees were told that it is “certainly looking like many of the cases involve” THC-based vapor products. However, there were also cases of CBD and nicotine, and some patients claimed to use more than one product, according to Zeller, who added that all of reports were done on a voluntary basis. This means results may not be accurate. For example, a self-reporter may live in a state where THC products are illegal and doesn’t want to disclose THC use for fear of prosecution.  

“We maybe might want to question the accuracy of the self-report, but some of the self-reports are [from] individuals claiming the only product they used was a nicotine-containing product,” he said. “This is a challenge for everyone involved in this … investigation, but the right level of coordination exists between federal agencies and with the state health departments that are more boots on the ground for this. We are always looking for any information for any adverse effect for any tobacco product, including e-cigarettes, to be reported to the FDA.”

When asked whether consumers using nicotine-based pod systems should be concerned about pulmonary illness, Zeller said the FDA is still “trying to get around this on a case-by-case basis,” and some of the self-reports do claim to have only used nicotine-containing products. “When we are doing the analytical chemistry, obviously we are not talking to the person and are not asking questions about what products they used,” he said. “In some of these cases, there are multiple products being said they are being used with each case … many of these cases appear to be THC related … it’s complicated; it’s challenging.”

An attendee also asked Zeller if the FDA was concerned that current users may be switching back to combustible cigarettes. Zeller said that the FDA is a science-based agency that follows the science when it comes to this set of products (e-cigarettes). “Our point is that [electronic nicotine-delivery systems (ENDS)] are illegal and remain on the market through enforcement. Removing all vaping products from the market would be like pressing a reset button …. I want smokers to quit smoking or switch to less harmful products. The door is open for pre-submission meetings. The door is open for the companies to come in. The burden should be on companies to show the FDA that the products meet the burden of being for the protection of public health.”

Confronting other issues

Zeller told attendees that the FDA’s vision for the future of tobacco remains unchanged since the introduction of the regulatory agency’s Comprehensive Plan for Tobacco and Nicotine in July of 2017. “We still envision a world where cigarettes as we know them would no longer create or sustain addiction, and adults that are still [seeking to use nicotine] can get it from alternative and less harmful sources,” he said. “Even at this acute moment in time—as we are dealing with the vaping illnesses, as we are dealing with the epidemic use of e-cigarettes by kids in the United States—it’s still an opportunity to pause and acknowledge that the continuum exists.”

Products containing nicotine pose different levels of health risks to adult users with combustible products—like cigarettes with their toxic mix of more than 7,000 chemicals and efficient delivery of nicotine to maximize addiction potential—being the most harmful, nicotine replacement therapies (NRTs) being the least harmful and noncombustible products, such as ENDS products, falling somewhere in between, according to Zeller. “The public health return on this policy is generational,” he said.

The FDA is committed to protecting the public health of all Americans while regulating an addictive product that carries with it health risks, according to Zeller. To this end, the agency is conducting ongoing research on potentially less harmful forms of nicotine delivery for adults, such as ENDS products or e-cigarettes. “Though more research on both individual and population health effects is needed, many studies suggest e-cigarettes may be less harmful than combustible cigarettes,” Zeller said.

While ENDS products may be less risky than combustible products, Zeller said that recent proposals by the FDA to ban or restrict flavored tobacco products have been driven by an increase in use of ENDS products by youth. Zeller noted previously reported statistics from the 2018 National Youth Tobacco Survey (NYTS), which found that e-cigarette use among high schoolers had increased by 78 percent from 2017–2018.

“Think of it as a public health balancing act that has been made more challenging with the very disturbing 2019 NYTS results—more of which we will be sharing at a later date—where we saw the preliminary 2019 data showing more than 25 percent of high school students are current e-cigarette users. There will be more to come in [the] form of a paper [that] will be published,” Zeller said. “The reality is that not one of these products is lawfully on the market … not one of them—they have remained on the market since we gained regulatory authority in 2016 through regulatory enforcement. This balancing act by law requires us [to figure out] what’s going and what are the impacts on users and what are the impacts on nonusers … or what are the positive and negative impacts on initiation and the positive and negative impacts on cessation.”

There has been a lot of press lately surrounding teen use of Juul products because the device uses nicotine salts (in high concentrations), its small nature and how the product has been marketed. Zeller said that it is not just the Juul brand as there are numerous similar products on the market. “One of the real problems of concern are products that resemble USB flash drives,” said Zeller. “The product Juul has gotten most of the attention, but there are other products like Juul.”

In September of 2018, the FDA issued more than 1,300 warning letters and fines to numerous retailers for selling tobacco products to minors. Zeller said that what is more concerning is retailers who continue to sell products to youth despite warnings and fines from the FDA. In March, the FDA sent letters to 15 retailers for allegedly selling tobacco products to minors. These retailers include Walgreens, Walmart, Kroger, 7-Eleven, Family Dollar, BP and Citgo. The agency also requested information from more than 40 e-cigarette companies the agency thinks may have illegally introduced new products onto the market.

Concerning the premarket tobacco product application (PMTA) process, Zeller explained that the agency would soon release quality control requirements and considerations for tobacco-related good manufacturing practices (GMPs) or tobacco product manufacturing practices (TPMPs). Zeller could not comment on when the industry can expect this Foundational Rule and Guidance for TPMPs to be issued by the FDA; however, he did stress that the rule, along with the other foundational rules and guidances, is a priority for the CTP. “We take very seriously the commitment to making the process as efficient and transparent as possible,” he explained.

The FDA has already issued three advance notices of proposed rulemaking (ANPRMs) that have the potential to reframe the tobacco landscape. Zeller explained that the ANPRMs focus on “the role that flavors—including menthol—play in initiation, use and cessation of tobacco products.”

Input on these issues will assist in the consideration of the most impactful regulatory options the FDA could pursue to achieve the greatest public health benefit, according to Zeller. “We’re proceeding in a science-based fashion, building a strong administrative record by securing more information about the potential positives and negatives of flavors in both youth initiation and in getting adult smokers to quit or transition to potentially less harmful products,” Zeller stated in a press release about the ANPRMs.

Zeller also briefly discussed the PMTA authorization for the marketing of IQOS, a heat-not-burn device manufactured by Philip Morris. Following a rigorous science-based review through the PMTA pathway, the agency determined that authorizing these products for the U.S. market is appropriate for the protection of the public health because, among several key considerations, the products produce fewer or lower levels of some toxins than combustible cigarettes. “The FDA has placed stringent marketing restrictions on the products in an effort to prevent youth access and exposure,” said Zeller. “This was an application that got through the PMTA pathway because, at the end of the day, we were able to conclude that the marketing of this product would be appropriate for the protection of public health.”

Also speaking at the GTNF, Matthew Holman, the director of the CTP’s Office of Science, reiterated many of Zeller’s points. Holman said the FDA needs as much scientific data as it can possibly gather from numerous sources, and that is still a work in progress. Holman added that there was a “critical” need to share as much information as possible to work on regulations on new products of the tobacco industry that are less harmful for consumption. “Our goal is to be world leaders in understanding these products and regulations,” said Holman. “It is important to work in all disciplines, observing behavior, addiction, toxicity and many others, and not focus on a single point.”