Gold Nuggets

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Gaining insights from the FDA’s final PMTA rule

By Willie McKinney and Cheryl K. Olson

On Jan. 19, the U.S. Food and Drug Administration finalized a “foundational rule” about the “minimum requirements for the content, format and review of premarket tobacco product applications (PMTAs).” Within days, before many of us had a chance to download the 516-page document, let alone read it, the rule disappeared. The link says, “page not found.”

Don’t worry. This is part of a normal review by the incoming Biden administration of recent rules from the old regime. Given that little FDA staff turnover is expected, their thinking, and the rule, will probably stay the same. The document will be back, nicely formatted.

What to do while we wait for the final-final rule to appear on the FDA’s site? Well, the bulk of the document addresses “about 1,000 comments” (!) the FDA received on the proposed rule issued in 2019, including many questions from industry folks confused about PMTAs.

Understanding the subtleties and subtext of the FDA’s responses to comments can dramatically increase your chances of getting a marketing granted order. Ignoring them can lead to a significant waste of time and money.

Let’s wade into the FDA’s responses and see what gold nuggets of insight we can pan. What fuzzy areas affecting your strategy are now clear? What costly studies or paperwork might be trimmed or skipped?


A PMTA is not a box-ticking exercise

We can begin with how the FDA thinks and what that means for PMTA strategy. Remember, interacting with tobacco product makers and sellers is still relatively new for the FDA’s staff and consultants. As they read comments, held conversations and began reviewing the recent flood of PMTAs, they realized that companies couldn’t figure out what the FDA was asking for. We know this because the PMTA rule lays out, much more clearly than in previous documents, what the FDA needs from companies. There are details on required content and format. The rule contains dozens of “musts”—must list, must include, must state and so on.

The FDA also says what can happen if you don’t meet minimal requirements: Do this, and we won’t accept or file. Or: This will slow the review process. Think of it as a series of red lights (“FDA will refuse to accept a PMTA … where it lacks constituent testing information required by § 1114.7(i)(1)(v)”) and yellow lights (“FDA may refuse to accept or file an incomplete application for review”). All of this is welcome clarity.

That doesn’t mean, as we’ve heard it described, that having a PMTA accepted and filed is a check-the-box exercise. Parts of a PMTA are like that, but the substantive review of data definitely is not.

Many of the comments to the FDA hint at frustration. “Why can’t they just tell me what studies to do so I can market my product?” The short answer is that a PMTA is partly a checklist of required information, but it’s also a narrative. You’re telling a story about why your product is appropriate for the protection of public health (APPH), illustrated by data. An effective PMTA is driven by story—explaining why your product on balance is likely to benefit public health—and merely organized by the PMTA format

If you try to follow the rule document like a cookbook recipe—add a cup of pharmacokinetics (PK) studies and a tablespoon of label comprehension, and it’s baked—you will likely fail. That’s because the rule is descriptive but not prescriptive; it doesn’t tell you how to deliver. Why? First, because each product is different, with its own particular characteristics and target customers and therefore a distinctive set of potential public health benefits and risks that need to be demonstrated or mitigated. Second, a how-to list would tie the FDA’s hands as they make and rethink decisions about what is APPH. In Response 105, the agency notes that “Due to the nature of the Federal rulemaking process … FDA may not be able to update such standards in a timely manner.”


Expect APPH to evolve

APPH is about relative health risks; it’s about “net benefit to the health of the population as a whole.” A definition like that, based on comparing ever-evolving tobacco products, will create a moving target. See FDA’s Response 123: “Because market conditions will change over time, what might be APPH at one point in time may no longer be APPH in the future.”

A static approach for granting marketing orders means the FDA couldn’t keep riskier products off the market, “thus undermining its core statutory mandate to reduce the harm caused by tobacco product use.” Basically, if you can show that your novel tobacco product is less risky than today’s cigarettes, that’s great. But as more tobacco users move to reduced-risk products, both the comparators and the risk equation will change. And if your tobacco product has, say, slightly more of a potentially harmful chemical than others in its category, adding your product to (or keeping it among) consumers’ options is not reducing harm.

Save with bridging, bundling and master files

Another reason the FDA “declines to require that an applicant conduct a list of new studies as part of every application” (Response 59) is that shortcuts are allowed. Applicants can also “provide scientific data to inform FDA’s review” through bridging. Rather than generating all new data on your product, you can sometimes leverage the research literature to show your product is APPH. Just a little new data connects you to more.

Suppose you show from chemistry that your product releases nicotine in the same way and has the same nicotine concentration as another product already tested in published literature. That may let you bridge to their PK and abuse liability studies, saving you hundreds of thousands or even millions of dollars. In Response 62, the FDA “declines to define” bridging but instead gives useful examples of how to do it.

Another cost-saving and time-saving shortcut is bundling or combining applications. Let’s say that you have four flavors or two nicotine strengths. The FDA sees them as separate products. But the FDA allows you to submit one PMTA for all of them. A bundled PMTA includes “a single, combined cover letter and table of contents across all products” (Response 19).

You still need to provide unique information about each product, but you can collect and present it more efficiently. For example, you might conduct and present one bundled perception and intention survey that asks noncustomers about perceptions of the labeling of each of your four flavors in turn. But be aware that the FDA will break up your bundle for review, so list in tables which parts of the PMTA apply to which products. 

Bundling isn’t always best. Are your harm reduction story and target audiences the same across products? A high nicotine vape may appeal to a heavily addicted smoker, but it has different health implications than a lower nicotine sister product. Combining the two into one PMTA might muddy your case for APPH status.

A third PMTA shortcut to know about is called a tobacco product master file (TPMF). A master file contains information you can reference again and again for multiple applications. In Response 17, the FDA defines a TPMF as “contain[ing] trade secret and/or confidential commercial information about a tobacco product or component that the owner [e.g., manufacturer, ingredient supplier] does not want to share with other persons” but is willing to share with the FDA. That’s useful if your new tobacco product uses an e-liquid made by a manufacturer who doesn’t want to share their formulation but who will give you a letter of authorization to cite their master file in your PMTA. 

There are other TPMF options. “When companies want to rely on the same pool of data, FDA encourages the use of shared resources, such as tobacco product master files, where appropriate” (Response 18). This might be the fruits of a thorough literature review on a particular topic. Rather than cite and submit 150 articles over and over, you can reference the master file.

More information is not always better

PMTA applicants now need to provide “only high-level marketing plan information” (Response 30) rather than detailed consumer research. The FDA’s main concern is youth exposure. It emphasizes descriptions of intended audiences and how they’ll be targeted. Note, however, that if you have already done consumer research, “the results of such research will be required” to go to the FDA. 

As Comment 14 notes, “the tobacco industry has a history of marketing its products to … vulnerable populations,” which may include low-income communities, racial/ethnic minority group members, rural residents and youth, among others. Your PMTA story should include how your product might improve (or not worsen) the well-being of some of these vulnerable populations. Harm and benefit to subgroups that are more likely to start, less likely to stop and/or more likely to get sick from using tobacco products “are an important part” of the FDA’s APPH calculations. Groups of interest “will vary depending on type of tobacco product and may change over time.”

However, the FDA does not clearly state that conducting research with some of these subgroups is unethical or unsafe. This includes people under the age of 21 and women “who are pregnant or trying to become pregnant.” (The document mentions the need for special attention to vulnerable populations, including children and incarcerated persons, when discussing FDA plans to issue future regulations concerning use of Institutional Review Boards for tobacco product clinical studies.)

In Response 79, the FDA allows for “studies using individuals under the minimum age of sale” with extra protections and parental consent but “does not require it [or] anticipate that it will be necessary.” Don’t go there. Instead, over-sample young adults in your studies as a proxy for youth. Report, for example, whether intentions to use your product were different for people under age 25 compared to the rest.