UNITED STATES DISTRICT COURT DISTRICT OF … 8 - Joint Amicus...UNITED STATES DISTRICT COURT...

UNITED STATES DISTRICT COURT

DISTRICT OF MARYLAND

AMERICAN ACADEMY OF PEDIATRICS, et al.,

Plaintiffs,

v.

FOOD AND DRUG ADMINISTRATION, et al.,

Defendants.

Case No. 8:18-cv-883-PWG

AMICUS CURIAE BRIEF OF JOHN MIDDLETON, CO., ITG BRANDS LLC, JUUL

LABS, INC., THE CONSUMER ADVOCATES FOR SMOKE-FREE ALTERNATIVES

ASSOCIATION, NJOY LLC, THE AMERICAN E-LIQUID MANUFACTURING

STANDARDS ASSOCIATION, THE AMERICAN VAPING ASSOCIATION, THE

ARIZONA SMOKE FREE BUSINESS ALLIANCE, THE INDIANA SMOKE FREE

ASSOCIATION, IOWANS FOR ALTERNATIVE TO SMOKING AND TOBACCO, THE

KENTUCKY SMOKE FREE ASSOCIATION, THE MARYLAND VAPOR ALLIANCE,

THE NEW YORK STATE VAPOR ASSOCIATION, THE OHIO VAPOR TRADE

ASSOCIATION, THE RIGHT TO BE SMOKE-FREE COALTION, THE SMOKE FREE

ALTERNATIVES TRADE ASSOCIATION (SFATA), SFATA-CALIFORNIA, SFATA-

CONNECTICUT, SFATA-HAWAII, SFATA-LOUSIANA, SFATA-RHODE ISLAND,

SFATA-TEXAS, SFATA-WISCONSIN, THE TENNESSEE SMOKE FREE

ASSOCIATION, AND THE TEXAS VAPOR COALITION

Case 8:18-cv-00883-PWG Document 113 Filed 06/12/19 of 19

TABLE OF CONTENTS

INTERESTS OF AMICI CURIAE ...................................................................................................1

INTRODUCTION ...........................................................................................................................1

ARGUMENT ...................................................................................................................................3

I. This Court Must Remand for FDA to Complete Essential Regulatory Steps..........3

A. FDA Must Fill Significant Regulatory Gaps, and Allow the Time

Necessary for Manufacturer Testing and Applications, Before It

Can Review Applications ............................................................................3

B. A Remand Is Necessary for FDA to Complete the Requisite

Regulatory Steps ..........................................................................................8

II. Plaintiffs’ Proposed Remedy Is Unlawful .............................................................10

A. Plaintiffs’ Timeframe Would Invalidate the Deeming Rule ......................10

B. Plaintiffs’ Remedy Would Otherwise Violate the APA ............................12

III. Plaintiffs’ Proposal Would Devastate Industry and Jeopardize Public

Health .....................................................................................................................14


INTERESTS OF AMICI CURIAE

The interests of amici are set forth in the letters they filed expressing their intent to move

to intervene. Amici are manufacturers of cigars covered by the Deeming Rule, and manufacturers,

retailers, and users of electronic nicotine delivery system (ENDS) products also covered by that

Rule. For most cigar products, the pathway to FDA approval is through Substantial Equivalence

(SE) Reports, i.e., applications establishing substantial equivalence to products already on the

market. For ENDS products, the path involves Premarket Tobacco Applications (PMTAs), i.e.,

applications establishing that the product is appropriate for the protection of public health. Amici

have direct, substantial, and varying interests that will be affected by any remedy the Court

imposes. It is also “abundantly clear” that amici are knowledgeable about the practical realities of

the “filing and approval processes” that any remedy will affect. May 31, 2019 Letter Order.1

INTRODUCTION

For years, FDA has issued, then extended, deadlines for when ENDS and cigar

manufacturers must submit premarket review applications to keep existing products on the market.

That iterative process did not happen because FDA sat on its hands. Rather, one of the

cornerstones of the Deeming Rule—the rule that subjected ENDS and cigars to FDA’s powers

under the Tobacco Control Act (TCA)—was FDA’s flexibility to extend enforcement timetables

so it could lay out regulatory stepping stones that would instruct manufacturers what tests to

undertake, what studies to provide, and what other information FDA needs to assess their

applications. This process turned out to be staggeringly complicated, especially due to a host of

1 Amici submit this joint brief pursuant to the Court’s May 31, 2019 Letter Order, Dkt. No. 84,

without prejudice to their rights to appeal the denial of intervention or their ability to make

arguments in further proceedings based on their own interests. As the accompanying declarations

illustrate, amici are disparate entities in disparate industries with multiple disparate interests.


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novel and disparate technical issues affecting ENDS products and cigars. FDA has made progress:

in April 2019, it issued a notice of proposed rulemaking to clarify the contents of SE Reports, and

it recently announced that a proposed rule for PMTAs is under review at the Office of Management

and Budget (OMB). Just yesterday, FDA issued 52-page final guidance to ENDS manufacturers

regarding what their PMTA applications should include. See FDA Guidance, Premarket Tobacco

Product Applications for ENDS (June 11, 2019), available at https://tinyurl.com/yybbk93z (Final

Guidance). But all along the way, FDA has assured manufacturers that they would be given both

the guidance and the time necessary to successfully navigate its premarket approval process.

Manufacturers can hardly be faulted for having taken FDA at its word.

All agree that this Court’s holding invalidating FDA’s August 2017 Guidance cannot

suddenly subject ENDS and cigar products to TCA enforcement actions for failure to file the very

applications that FDA authorized manufacturers to file later. Remanding that Guidance to FDA

without vacatur would avoid upending FDA’s massive existing regulatory efforts and causing

unwarranted harm to consumers and manufacturers. Such a remand would allow FDA to continue

fleshing out parameters for premarket applications and would give manufacturers sufficient time

to prepare the technical data necessary for quality applications that include the kind of information

that Plaintiffs themselves claim to want and need. Such a remand would also provide FDA

sufficient time to resolve each completed application without products being forced off the market

in the interim. A remand is the customary remedy in these circumstances.

By contrast, any court-fixed timetable would defy black-letter law prohibiting judicial

intervention in the substance of agency rulemaking. Dictating a timetable to FDA would risk

invalidating the Deeming Rule itself, which presupposed that FDA retains the flexibility to ensure

that newly deemed products have the time and means to successfully navigate premarket review.


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Plaintiffs’ unrealistic proposed timetable would also cause this Court to preside over a regulatory

train wreck that would unlawfully deprive manufacturers of a meaningful ability to submit

thousands of anticipated PMTA applications and SE Reports and would short-circuit FDA review.

To satisfy Plaintiffs’ timelines, FDA would be forced to act precipitately, without regard for the

law, public health, FDA’s pending rulemakings, or devastating economic consequences.

Make no mistake: amici share the Court’s concerns about youth usage, which they are

strongly combatting and consider unacceptable at any level. Youth cigar usage continues to

decline. And ENDS manufacturers have taken a number of steps, and spent tens of millions of

dollars on programs, to prevent youth usage. But the answer is not to force from the market

products on which millions of American adults rely in their efforts to quit smoking cigarettes.

ARGUMENT

I. This Court Must Remand for FDA to Complete Essential Regulatory Steps

A. FDA Must Fill Significant Regulatory Gaps, and Allow the Time Necessary for

Manufacturer Testing and Applications, Before It Can Review Applications

1. As FDA has frequently acknowledged, it must undertake a host of preliminary

regulatory actions to ensure that manufacturers know what to file and have time to prepare their

applications. Starting in 2011, FDA acknowledged (with respect to cigarettes, cigarette tobacco,

roll-your-own tobacco, and smokeless tobacco) that “interested parties need clarity as to FDA’s

expectations regarding [SE] reports,” pledging to “initiate a rulemaking that would establish

requirements and standards for SE.” Guidance for Industry and FDA Staff (Jan. 2011) at 1–2.

FDA’s initial efforts focused on the four tobacco product types identified in the TCA; FDA only

began devoting comparable efforts to the SE requirements for newly-deemed products after FDA

issued the 2016 Deeming Rule. Time and again, FDA has insisted that further regulatory action


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is imperative before ENDS and cigar manufacturers face compliance deadlines.2 And rightly so.

FDA could not conceivably satisfy the APA by requiring applicants to submit applications without

first telling them what rules applications must follow. Yet despite FDA’s decision to deem cigars

and ENDS products subject to the TCA, manufacturers remain in dire need of clarity to this day.

2. For ENDS products, significant pieces of the application puzzle are still missing. ENDS

products generally require PMTAs. But manufacturers have had little to go on in preparing them.

FDA has approved two PMTAs ever, and has never approved a PMTA for an ENDS product.

Bauersachs Decl. ¶ 20; FDA, Premarket Tobacco Product Marketing Orders (June 11, 2019),

https://tinyurl.com/yyxfqzdw (approval of two PMTA applications comprising 12 products). The

estimated timeframe to prepare a PMTA for any type of tobacco product is at least two years.

Bauersachs Decl. ¶ 23; Engelke Decl. ¶ 20; Benson Decl. ¶ 25.

Fleshing out the rules for ENDS products has proven particularly challenging given the

newness of those products and the dearth of existing studies. For starters, until only yesterday,

2 See Guidance for Industry and FDA Staff: Demonstrating Substantial Equivalence for Tobacco

Products (Jan. 2011) at 1–2, https://tinyurl.com/y4x3dd62 (pledging to initiate a “[new]

rulemaking that would establish requirements and standards for [SE]”); FDA Comm’r S. Gottlieb,

Protecting American Families: Comprehensive Plan for Nicotine and Tobacco (Jul. 28, 2017),

https://tinyurl.com/y5lsxn4o (“One area of emphasis will be to make sure we have the foundational

regulatory architecture to ensure proper oversight of ENDS . . . . Part of this will be developing

regulations that we have not yet pursued because the Agency’s tobacco program itself is so new.”);

FDA Comm’r S. Gottlieb, Address at National Press Club (Nov. 3, 2017),

https://tinyurl.com/y5hdqbu3 (33:15) (“The foundational regulations for the tobacco program were

never put in place and so we’re going to take the time to put those in place so we have a firm

foundation from which to regulate.”); FDA, Advancing Tobacco Regulation to Protect Children

and Families (Aug. 2, 2018) (stating that “foundational proposed rules” are needed “regarding the

basic rules of the road, especially when it comes to what’s expected in premarket applications.”),

https://tinyurl.com/yysms73g; FDA Comm’r S. Gottlieb, Testimony to House Approp. Subcomm.

for Agriculture, Rural Development, Food and Drug Administration, and Related Agencies (Feb.

27, 2019), https://tinyurl.com/y62ps5pe (1:51:05) (August 2017 Guidance is needed “to give

[FDA] the time to put in place the implementing regulations and guidance that would . . . provide

the rules of the road for how to effectively traverse the PMTA process[.]”).


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FDA had not issued final guidance on what PMTAs for ENDS products should include, and it had

expressly warned that its draft guidance did not necessarily reflect FDA’s current thinking. See

Draft Guidance, Premarket Tobacco Product Applications for ENDS, 81 Fed. Reg. 28,781 (May

10, 2016). Manufacturers have barely had time to digest that 52-page “nonbinding” document,

but it plainly does not resolve many open questions. The guidance contemplates the need for

further rulemaking, see, e.g., Final Guidance at 1, 11, and that PMTAs will not be a one-size-fits-

all process. FDA still has not specified the kind of testing (if any) ENDS manufacturers should

conduct to produce reliable data regarding product characteristics or public health consequences.

The Final Guidance identifies a wide variety of studies or materials that “should” or “could” be

conducted or included, but acknowledges limits on what is actually feasible, and encourages

manufacturers to meet with FDA before submitting an application to discuss what to include. Id.

at 3, 50–52. That reflects the reality that there is substantial variation among ENDS products,

which come in different configurations and flavors and are sold or distributed in different ways.

Woessner Decl. ¶¶ 4–8. What FDA requires for one product may prove different than for another.

FDA also appears poised to clarify what PMTAs for all tobacco products must include, but

much work remains on that front as well. The government just announced that OMB is reviewing

FDA’s draft Notice of Proposed Rulemaking on PMTAs—but that notice is not expected to issue

until at least September 2019. See OMB RIN 0910-AH44, HHS-FDA Proposed Rule, Premarket

Tobacco Product Applications and Recordkeeping Requirements (May 31, 2019). Then would

come the comment period, which would likely produce tens of thousands of comments—all of

which FDA must carefully consider in its final rule to avoid invalidation. Int’l Union, United Mine

Workers of Am. v. Mine Safety & Health Admin., 626 F.3d 84, 94 (D.C. Cir. 2010).

Even when manufacturers know what tests or studies FDA wants, that is just the first step


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in a long process. FDA must allow manufacturers time to conduct and analyze those studies before

they can be submitted. Human clinical studies are time-consuming. Determining whether and

how the chemical composition of liquid in an ENDS pod changes during a year of shelf-life

requires study preparation, then the required year of observation. Surveys tracking consumers’

consumption patterns take time to set up. Engelke Decl. ¶¶ 37, 42–50; Graham Decl. ¶¶ 10, 14.

Finally, in determining what applications should include and when manufacturers should

submit them, FDA must continue considering substantial reliance interests—not just of

manufacturers who have been promised a path to demonstrate that their products should remain

on the market, but of the millions of American adults who use ENDS products to help them quit

smoking cigarettes. Manufacturers cannot be faulted for not prematurely committing resources to

costly studies they may have to redo if they guessed wrongly as to what FDA would want. And

forcing manufacturers into a process where they would lack a meaningful opportunity to submit

applications would be quintessential arbitrary and capricious agency action given the reliance

interests FDA has created. See Encino Motorcars, LLC v. Navarro, 136 S. Ct. 2117, 2126 (2016).

That said, ENDS manufacturers have not just sat around. They have done what they can

to prepare for the PMTA process. Engelke Decl. ¶¶ 21–56; Graham Decl. ¶¶ 10–11, 16–17. But

as the signatories to this brief reflect, ENDS manufacturers come in different shapes and sizes,

with vastly different levels of resources to devote to trying to anticipate what FDA would require.

For example, there are not enough accredited third-party laboratories qualified to conduct various

types of testing, and small manufacturers lack the resources to do those tests themselves. Engelke

Decl. ¶ 35; Woessner Decl. ¶¶ 9, 12; Anton Decl. ¶ 12; Benton Decl. ¶¶ 6, 24.

ENDS manufacturers have not been dilatory in addressing youth usage, either. Amici reject

any youth use of nicotine-containing products, and ENDS manufacturers have been tackling youth


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usage head-on. They have spent tens of millions of dollars on programs to prevent youth usage,

have proposed limits on how their products can be sold, and have spearheaded youth education

initiatives, among other efforts. Many have supported a nationwide increase in the minimum age

for buying tobacco products. E.g., Engelke Decl. ¶ 9. But as FDA has stated, ENDS products

present fewer health risks than cigarettes and help many adult smokers move down the “continuum

of risk” for nicotine use,3 and the premarket review process must fully account for this.

3. Seeking approval for cigars poses its own challenges. FDA has substantially more

experience with SE Reports, having received over 5,000 of these types of applications for other

tobacco products. Folmar Decl. ¶ 6. But that experience does not bode well for efforts to prescribe

a fixed timetable. FDA as of April 2018 has issued final orders for only about 191 provisional

products, in no small part because FDA’s current SE process involves a litany of time-consuming

back-and-forth steps (including multi-disciplinary scientific review).4

Here, too, regulatory gaps abound. Cigars are different than cigarettes and present unique

additional challenges. There are currently no standardized testing methodologies for cigar smoke;

cigars do not fit standardized cigarette testing machines, and may have other unique attributes (like

plastic tips that affect inhalation). As with ENDS products, FDA has not yet provided guidance

as to which Harmful and Potentially Harmful Constituents (“HPHC”) manufacturers should test

for in cigars or how such testing should be conducted, see 21 U.S.C. § 387d(a)(3), and there is a

lack of accepted HPHC testing standards, methods, and equipment for these products. Bauersachs

Decl. ¶ 15; see Final Guidance at 28 & n.35. Nor has FDA grappled with how to standardize

3 See Protecting American Families: Comprehensive Plan for Nicotine and Tobacco, supra n.2;

Engelke Decl. ¶¶ 6–7.

4 See FDA, Substantial Equivalence: The Review Process, https://tinyurl.com/y3sm3lvt; Update

on Provisional Substantial Equivalence Review (Apr. 5, 2018), https://tinyurl.com/yyrhcwjt.


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testing results for cigar tobacco leaf, which displays much higher variability with respect to HPHC

yields than cigarette tobacco. FDA thus instructed manufacturers to stop submitting applications

on a trial-and-error basis pending further FDA action. Bauersachs Decl. ¶ 26.5

FDA is now amidst a rulemaking that may substantially affect all SE Reports. In April

2019, FDA issued a notice of proposed rulemaking to clarify what SE Reports should generally

include. Content and Format of Substantial Equivalence Reports, 84 Fed. Reg. 12,740 (April 2,

2019). The comment period (which FDA is extending) will close on July 17, 2019. FDA then

must decide how to finalize the rule in response to comments, as well as undergo OMB review.

Those processes will take time. And the proposed rule does not elucidate what cigar manufacturers

should submit for this unique product category, instead inviting “comments and information

[regarding] the parameters that may be needed to support an SE Report.” 84 Fed. Reg. 12,762.

Meanwhile, FDA is still weighing comments submitted in response to advance notices of proposed

rulemakings on “Regulation of Flavors in Tobacco Products,” 83 Fed. Reg. 12,294 (Mar. 21,

2018), and “Regulation of Premium Cigars,” 83 Fed. Reg. 12,901 (Mar. 26, 2018).

B. A Remand Is Necessary for FDA to Complete the Requisite Regulatory Steps

Given these considerations, the only proper remedy is a remand of the Guidance. FDA

cannot lawfully enforce any application deadline before it takes needed steps to flesh out the

premarket review process for ENDS and cigar products, and determines how much time is needed

for acceptable applications to obtain approval. But that process defies any predetermined

5 Trade associations have challenged the Deeming Rule’s premarket authorization provisions for

cigars and pipe tobacco. Cigar Ass’n of Am. v. FDA, No. 1:16-cv-1460, ECF No. 1 (D.D.C.).

After FDA announced the August 2017 Guidance, the parties, with court approval, agreed to defer

those challenges to give FDA time to act. Id., ECF No. 51 at 2–3. That suit has proceeded on the

understanding that FDA would undertake regulatory actions, including issuing a substantial

equivalence rule, to clarify the premarket review process for newly deemed products. Id., ECF

Nos. 53, 110, 112, 115, 119. The Court should not interfere with that process.


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timetable, not least because hard technical problems cannot be resolved at will. A remand is

needed so that FDA is not straitjacketed into a timetable that precludes reasoned deliberations.

1. No one argues that invalidating the August 2017 Guidance means that ENDS and cigar

products that were on the market as of August 8, 2016 (which are the only products to which that

guidance applies) should suddenly be forced off the market. As the Court recognized, that

Guidance replaced earlier guidance documents setting application deadlines that have already

passed. Op. at 9–10, 53. And, as the Court noted, “[i]t is undisputed that the FDA has some

discretion to adapt [TCA] provisions to the special circumstances of products that become subject

to the TCA . . . by virtue of deeming and, to that end, to permit a compliance period for newly

deemed products.” Id. at 8. Even Plaintiffs’ remedy presupposes that manufacturers and FDA

must have some period to submit and review applications, respectively.

But FDA, not the courts, must set that timetable in the first instance. “If courts were

empowered to enter general orders compelling compliance with broad statutory mandates, they

would necessarily be empowered, as well, to determine whether compliance was achieved.”

Norton v. S. Utah Wilderness All., 542 U.S. 55, 66 (2004). If so, “it would ultimately become the

task of the supervising court, rather than the agency, to work out compliance with the broad

statutory mandate, injecting the judge into day-to-day agency management.” Id. at 66–67. But

“[t]he prospect of pervasive oversight by federal courts over the manner and pace of agency

compliance with such congressional directives is not contemplated by the APA.” Id. at 67; see

City of New York v. DOD, 913 F.3d 423, 429–31 (4th Cir. 2019) (similar).

2. A remand without vacatur is the only appropriate remedy under the APA. Black-letter

administrative law dictates that “set[ting] aside” unlawful agency action under 5 U.S.C. § 706(2)

is limited to either remanding the action to the agency (i.e., allowing the action to remain in effect


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while the agency considers next steps) or vacating it (i.e., preventing the action from having further

force or effect). See Sierra Club v. Army Corps of Eng’s, 909 F.3d 635, 655 (4th Cir. 2018). And

courts have chosen remands when eliminating the agency action would leave a destabilizing void

or uncertainty while the agency determines what further action to take. E.g., N. Carolina v. EPA,

550 F.3d 1176, 1177–78 (D.C. Cir. 2008) (remanding without vacating an EPA rule despite having

concluded that EPA could not lawfully re-enact virtually any of it); see also Cal. Communities

Against Toxics v. EPA, 688 F.3d 989, 993–94 (9th Cir. 2012) (remanding without vacating rule

with concededly flawed rationale where vacatur “could well delay a much needed power plant”).

This case fits the same mold. The pre-Guidance deadlines cannot spring back into effect;

they have since expired (and also were not issued by rulemaking). See Op. at 53. But the Court

has concluded that any future timetable to replace the August 2017 Guidance likely must go

through notice-and-comment rulemaking. Id. at 53–54. To avoid confusion over the vacuum

created by vacating the existing Guidance in the interim, the Court should remand without vacatur.

At a minimum, the Court should avoid “impairing the interim administration” of the Deeming Rule

by staying any order to vacate the Guidance until FDA takes necessary next steps. See Northern

Pipeline Constr. Co. v. Marathon Pipe Line Co., 458 U.S. 50, 88–89 (1982).6

II. Plaintiffs’ Proposed Remedy Is Unlawful

A. Plaintiffs’ Timeframe Would Invalidate the Deeming Rule

Plaintiffs would give manufacturers a mere 120 days from the Court’s order to submit

applications, and would give FDA twelve more months to process those applications. Any

proposed remedy that could force amici’s products off the market without a full and fair

6 While the Court has indicated that it is vacating the Guidance, Op. at 53, courts have shifted from

vacatur to remand in similar circumstances. E.g., N. Carolina, 550 F.3d at 1177–78.


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opportunity to obtain marketing orders would expose the Deeming Rule to legal challenge under

the APA. The TCA does not empower FDA to summarily declare entire classes of tobacco (or

“deemed tobacco”) products illegal. See, e.g., 21 U.S.C. § 387g(d)(3); H.R. Rep. No. 111–58, pt.

1, at 2 (2009) (Act does not grant authority to “ban[] a class of nicotine products, such as all

cigarettes”). To the contrary, the TCA only gives FDA the power to deem products subject to the

statute. And the TCA plainly anticipates a process by which manufacturers may submit

applications seeking approval of those products—approval that FDA may deny only upon specific

consideration and findings. See, e.g., 21 U.S.C. § 387j(c)(2).

Cognizant of that reality, FDA did not contemplate in the Deeming Rule that it could force

existing products from the market before PMTAs or SE Reports could be submitted, reviewed,

and acted upon. Nor did that Rule address the impact of such a drastic outcome. Rather, one of

FDA’s core assumptions in that Rule was that FDA could consider and address these potential

impacts during the application review process, and after FDA clarified what the application

process should entail. See 81 Fed. Reg. 28,974, 29,010/1-2 (May 10, 2016). Indeed, when

commenters emphasized the public health benefits of ENDS and “argued that restrictions on access

to the newly deemed products would be detrimental to public health,” FDA responded that its

“consideration of [the] public health benefits” of the products “will be included in FDA’s review

of PMTAs based on the evidence.” Id. at 28,995/1 (emphasis added).

If, as plaintiffs maintain, the Deeming Rule may be administered in a way that pulls

thousands of products off the market without a real opportunity to seek FDA review, then the Rule

violates the TCA and the APA’s requirement that agencies consider an “important aspect of the

problem,” Motor Vehicle Mfrs. Ass’n v. State Farm Mut. Auto. Ins. Co., 463 U.S. 29, 43 (1983)—

namely, the economic consequences of devastating multi-billion dollar industries, and the


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attendant adverse effects on public health that FDA said it would assess before barring products.

Further, the Deeming Rule would fail for having “misconceived the law.” SEC v. Chenery

Corp., 318 U.S. 80, 94 (1943). The Rule rests on FDA’s legal view that “[a]gency compliance/

enforcement policies”—including “the relevant time periods” by which amici would be required

to submit a PMTA—are “not subject to the requirements that govern notice-and-comment

rulemaking,” and that FDA could extend those periods as needed. 81 Fed. Reg. at 28,977. If FDA

lacks the flexibility to allow products to remain on the market during the period needed to finalize

the application process and for applications to be received and reviewed, an essential legal premise

of the Rule is invalid, as is the Rule itself.

B. Plaintiffs’ Remedy Would Otherwise Violate the APA

1. Plaintiffs’ proposed court-imposed timetable would flout the APA by impermissibly

dictating the outcome of notice-and-comment rulemaking. Under the Court’s opinion, FDA

cannot impose such a “compliance period” without “adher[ing] to the notice and comment

requirements of the APA.” Op. 53; see id. at 54 (contemplating “notice and comment period” for

the adoption of “new Guidance”); Dkt. No. 84, at 2 (similar). Agencies cannot render the

rulemaking process a sham by pre-judging the outcome before commenters can convey concerns.

Citizens to Preserve Overton Park v. Volpe, 401 U.S. 402, 416 (1971). Forcing FDA to adopt a

fixed timetable would ensure that such a final rule is invalidated, which would only delay FDA.

2. Plaintiffs’ proposed remedy would also be arbitrary and capricious, for several reasons.

First, forcing manufacturers into a process where they would lack a meaningful opportunity to

submit applications or were abruptly forced to pull their products from the shelves would be

quintessential arbitrary and capricious agency action, particularly given the reliance interests FDA

has created. See Encino, 136 S. Ct. at 2126. FDA, after all, deemed products before establishing


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a process to review them, and assured manufacturers that they will have meaningful guidance and

meaningful time to submit applications. Forcing FDA to abandon those assurances and adopt a

timetable that makes a mockery of deliberation during the premarket review process would subject

FDA’s ensuing actions to invalidation.

Second, a key part of premarket review is what applications must contain for FDA to

meaningfully review them. But, despite the new PMTA Guidance, FDA still has not made clear

what it wants PMTAs to include, let alone filled gaps for SE Reports. In the next 120 days, FDA

cannot conceivably fill all of those holes. But it would be arbitrary and capricious to order FDA

to conduct premarket review in a manner that precludes it from considering centrally “important

aspect[s] of” what it seeks to regulate. State Farm, 463 U.S. at 43.

Third, Plaintiffs’ artificial 120-day deadline to file applications would ensure arbitrary and

capricious determinations by depriving manufacturers of a meaningful opportunity to submit

quality applications. ENDS products are novel and generally require time-consuming and

exhaustive PMTA applications, which require population-level data beyond individual safety. The

first PMTA for a smokeless tobacco product relied heavily on long-term (30+ year) epidemiology

data from Sweden, and the most recent PMTA, for the IQOS Tobacco Heating System, involved

about two million pages of submissions, over 35 studies, and over two years of FDA review (when

no other application had been accepted for filing). Engelke Decl. ¶ 20; Benson Decl. ¶¶ 15–17;

IQOS Briefing Document for Tobacco Prod. Sci. Advisory Comm. at 8 (Dec. 2017),

https://tinyurl.com/yy63pdl4. Ordering ENDS manufacturers to submit PMTA applications with

120 days thus may force FDA to forgo requests for studies and tests that it otherwise would

consider. Likewise, SE Reports involve amassing studies and technical data—but until FDA says

what it wants, cigar manufacturers would have to either forgo the information or take a kitchen-


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sink approach to their applications. Either way, this rushed process would unfairly hamper their

chances of navigating the premarket review process for products that have been on the market in

largely the same form for decades. Folmar Decl. ¶ 14; Bauersachs Decl. ¶¶ 2, 29, 31–33.

Fourth, Plaintiffs’ compressed timetable would deprive FDA of any meaningful time to

review applications. Plaintiffs would give FDA twelve months from receipt of an application to

review FDA’s existing backlog and all new applications, and would force any unapproved

products off the market thereafter. But, to date, FDA has resolved only 5% of some 5,000 PMTA

and SE Report submissions; any pending ENDS or cigar applications would apparently be swept

into Plaintiffs’ one-year timetable for an FDA decision. Folmar Decl. ¶ 6. There is reason to doubt

even one ENDS PMTA could be resolved under Plaintiffs’ schedule, let alone the thousands that

would be expected were the Court to enter Plaintiffs’ proposed remedial order. FDA has never

resolved a PMTA for an ENDS product, and the most recent PMTA for a non-ENDS product took

over two years to process (at a time when hardly any other PMTAs were pending). Engelke Decl.

¶ 20. Yet estimates of expected ENDS PMTAs range from 750 to tens of thousands. See Preamble,

Deeming Rule, 81 Fed. Reg. 29,078 (May 16, 2016); Deeming Rule, 81 Fed. Reg. 29,091 (May

10, 2016). As for cigars, Plaintiffs’ timetable similarly fails to allow for meaningful review given

FDA’s backlog of thousands of SE Reports and the agency’s track record of processing such

applications to date. Bauersachs Decl. ¶¶ 16–17; Folmar Decl. ¶¶ 6–8. But Plaintiffs’ proposal

would flood FDA with an unpreceded deluge of applications, all on a one-year clock.

III. Plaintiffs’ Proposal Would Devastate Industry and Jeopardize Public Health

Plaintiffs’ abrupt timetable would risk forcing ENDS products off the market and

destroying the multibillion-dollar ENDS industry. Manufacturers have planned the onset and

duration of long-term studies to correspond with FDA’s deadlines in the August 2017 Guidance.


15

Hobbling manufacturers’ ability to file adequate PMTAs, and forcing FDA to deny applications it

fails to complete on an unrealistic timetable, could drive ENDS products off the market. Wiping

out that industry would endanger public health, risking a significant reversal in the historic

downward trend of cancer-causing cigarette consumption. Many of the roughly 14 million ENDS

users have switched, or are transitioning, from very harmful cigarettes to ENDS products.

Woessner Decl. ¶ 15; Engelke Decl. ¶¶ 6-7.

Plaintiffs similarly overlook the serious hardships their proposal would inflict on the cigar

industry. Needless to say, forcing cigar products off the market if FDA could not complete its

premarket review process within a year would significantly harm manufacturers, and that could

translate into job losses, loss of tax revenue, and other unpredictable consequences. Bauersachs

Decl. ¶¶ 32—33; Anton Decl. ¶ 19. Meanwhile, Plaintiffs have not even tried to assert that their

proposal would somehow promote access to reliable public-health data, creating doubts about

whether their proposal redresses the injuries they claim. See Lewis v. Casey, 518 U.S. 343 (1996).

CONCLUSION

This Court should remand the Guidance to give FDA the flexibility it needs—and which

the APA demands—to clarify critical aspects of the TCA as applied to ENDS and cigar products

and to complete pending rulemakings. If instead the Court orders vacatur, it should stay that ruling

until FDA imposes another timetable, or otherwise make clear that deemed products may remain

on the market as an orderly process is established for their application and review.


Respectfully submitted,

/s/ Eugene Scalia (with permission)

Eugene Scalia (12182)

GIBSON, DUNN, & CRUTCHER LLP

1050 Connecticut Ave NW

Washington, DC 20036

(202) 955-8500 (Telephone)

(202) 530-9606 (Facsimile)

[email protected]

Counsel for JUUL Labs, Inc.

/s/ Philip Perry (with permission)

Philip J. Perry (Pro hac vice)

Andrew D. Prins (10597)

LATHAM & WATKINS LLP

555 Eleventh Street, N.W.

Suite 1000

Washington, D.C. 20004

(202) 637-2200 (Telephone)

(202) 637-2201 (Facsimile)

[email protected]

[email protected]

Counsel for ITG Brands LLC

/s/ Eric Gotting (with permission)

Eric Gotting (20278)

KELLER & HECKMAN LLP

1001 G Street, N.W.

Suite 500 West


(202) 434-4230 (Telephone)

(202) 434-4646 (Facsimile)

[email protected]

Counsel for Right to Be Smoke-Free

Coalition, et al.

/s/ Lisa S. Blatt

Lisa S. Blatt (Pro hac vice)

Liam J. Montgomery (28978)

David J. Ryan (20484)

WILLIAMS & CONNOLLY LLP

725 Twelfth Street, N.W.


(202) 434-5000 (Telephone)

(202) 434-5029 (Facsimile)

[email protected]

[email protected]

[email protected]

Counsel for John Middleton Co. and Consumer

Advocates for Smoke-Free Alternatives

Association

/s/ Paul D. Clement (with permission)

Paul D. Clement (Pro hac vice pending)

KIRKLAND & ELLIS LLP

1301 Pennsylvania Avenue, N.W.


(202) 389-5000 (Telephone)

(202) 389-5200 (Facsimile)

[email protected]

Jennifer A. Davidson (23012)

KLEINFELD, KAPLAN & BECKER LLP

1850 M Street, N.W.

Suite 800


(202) 223-5120 (Telephone)

(202) 223-5619 (Facsimile)

[email protected]

Counsel for NJOY LLC

Dated: June 12, 2019


mailto:[email protected]

mailto:[email protected]

CERTIFICATE OF SERVICE

I hereby certify that on June 12, 2019, I electronically filed the foregoing document with

the Clerk of the Court of the District of Maryland by using the CM/ECF system, which filing will

provide service to all parties and amici.

/s/ David J. Ryan

David J. Ryan (20484)


IN THE UNITED STATES DISTRICT COURT

DISTRICT OF MARYLAND

AMERICAN ACADEMY OF

PEDIATRICS, et al.,

Plaintiffs,

v.

FOOD AND DRUG ADMINISTRATION,

et al.,

Defendants.


INDEX OF EXHIBITS TO BRIEF OF AMICI CURIAE

Exhibit A Declaration of Ryan Bauersachs

Exhibit B Declaration of Julie Woessner

Exhibit C Declaration of Joanna Engelke

Exhibit D Declaration of Carole Folmar

Exhibit E Declaration of David Graham

Exhibit F Declaration of Mark Anton

Exhibit G Declaration of Stacey Benson

Case 8:18-cv-00883-PWG Document 113-1 Filed 06/12/19 Page 1 of 1

EXHIBIT A


EXHIBIT B


4

IN THE UNITED STATES DISTRICT COURT DISTRICT OF MARYLAND


Plaintiffs,

v. FOOD AND DRUG ADMINISTRATION, et al.,

Defendants.


I, Julia T. Woessner, declare as follows:

1. I am over 18 years of age. I am National Policy Director for the Consumer

Advocates for Smoke-Free Alternatives Association (“CASAA”). I have personal knowledge of the facts stated in this declaration.

I. CASAA’s Work and its Members.

2. CASAA is a 501(c)(4) non-profit with an all-volunteer board and a grassroots membership of more than 250,000 users of smoke-free alternatives from all walks of life.

3. As part of my work with CASAA, I am in continuous contact with our membership to determine what issues are most important to them. I am an administrator of a Facebook group of approximately 22,000 members, and I review and participate in discussions, which include, among other things, what factors our members believe are most important to them in terms of helping smokers replace their smoking habit with smoke-free alternatives. Moreover, I attend conventions open to consumers and regularly communicate with our members regarding advocacy-related issues.

4. In addition, from 2013 to 2018, I administered the CASAA Testimonials Project where our members share their success stories, often discussing in great detail the types of devices and specific brands and flavors of smoke-free alternatives that they find most satisfying. To date, we have collected over 11,000 testimonials. Our members consistently tell us that they value access to a diverse range of effective and enjoyable products at a reasonable cost, and they reject what they feel is overly restrictive or burdensome government regulation of these products.

5. In 2015, CASAA conducted an extensive member survey of various issues, including the role that flavors play in transitioning from cigarettes to vapor products (“CASAA’s


4

Survey”). CASAA’s Survey can be found at https://antithrlies.com/2016/01/04/casaa-ecig-survey-results/. In CASAA’s Survey, approximately 87% of the survey population (17,186 out of 19,823 individuals) indicated that they completely replaced their smoking habit after starting to use such products.

6. CASAA supports regulations that prevent youth exposure to vapor products. But the availability of flavors for adults is not a mere frivolity. There is no question from our data that flavors (including the availability of a variety of flavors) play an important role in permitting adults to successfully make and maintain a complete transition away from cigarette smoking. For example, many of our members report that the availability of a non-tobacco flavor was instrumental in allowing them to distance themselves from their smoking habit. Reducing adult users’ enjoyment by arbitrarily restricting the availability of flavors hinders their ability to switch, which in turn endangers public health overall.

7. CASAA’s members are concerned that, without a compliance period that allows manufacturers enough time to file pre-market applications with FDA, they will not have access to the wide variety of products on which they rely to significantly reduce their smoking or to completely switch away from their smoking habits and to remain smoke-free.

8. In the final analysis, if consumers do not have access to these products, there is a substantial risk that they will return to their old smoking habits or feel forced to rely on do-it-yourself (“DIY”) activities or an unregulated black market for liquids and devices. This is not merely a theoretical concern. In CASAA’s Survey, respondents were asked how they would respond if the only e-liquids that could be sold were tobacco and menthol flavored. The vast majority of the survey population—89%—indicated that they would continue to use their preferred flavors by purchasing from overseas, purchasing on the domestic black market, and/or by making or flavoring e-liquid themselves. When asked what they would do in response to a total ban on all vapor products, 93% of the survey population indicated they would continue to use the products they enjoy by either purchasing from overseas or a domestic black market, or by engaging in DIY activities.

II. Regulatory Process

9. Many manufacturers of vapor products are smaller companies that may lack the knowledge and resources to engage in a complex and uncertain regulatory process on the timelines Plaintiffs have proposed (indeed, it is my understanding that even sophisticated companies and the FDA itself would likely be unable to meet these timelines).

10. The process for vapor product manufacturers to submit premarket applications is still very uncertain. FDA only issued its Final Guidance for Industry on ENDS PMTAs on June 11, 2019. See FDA, Premarket Tobacco Product Applications for Electronic Nicotine Delivery Systems (June 11, 2019), available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/premarket-tobacco-product-applications-electronic-nicotine-delivery-systems-ends. Moreover, the Guidance leaves important issues unresolved and indicates that what FDA expects for ENDS PMTAs will continue to be a moving target. See, e.g., id. at 28


4

industry would be out of work or out of business, and adult consumers would be deprived of a product that helps to dramatically reduce their health risks by substantially reducing or completely eliminating their smoking habits.

15. This would leave as many as 14 million people who use vapor products with fewer or no options. Although some may quit entirely, our data indicate that most would likely turn back to other sources of nicotine, including smoking, which is indisputably the most harmful source of nicotine. Still others may turn to black-market products that carry their own potential health and safety risks, to say nothing of the increase in crime and loss of tax revenue caused by such illicit trade.


I declare under penalty of perjury that the foregoing is true and correct to the best of my knowledge, information, and belief.

Executed on June 11, 2019.

Julia T. Woessner


EXHIBIT C


IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF MARYLAND

Southern Division

* AMERICAN ACADEMY OF

PEDIATRICS, et al., * Plaintiffs, * * Case No.: PWG-18-883 v. * FOOD AND DRUG *

ADMINISTRATION, et al., * Defendants, *

JUUL LABS, INC., * * Amicus * * * * * * * * * * * * *

DECLARATION OF JOANNA ENGELKE ON BEHALF OF JUUL LABS, INC.

I, Joanna Engelke, pursuant to 28 U.S.C. § 2746, declare:

1. I am employed by JUUL Labs, Inc. (“JLI”) as its Chief Quality and Regulatory Officer.

I have worked at JLI since February, 2018. During that time I have provided quality and compliance

oversight to JLI’s products. My more than 30 years of experience since receiving an M.B.A. from

Harvard University includes executive leadership of global quality and regulatory matters at Boston

Scientific and Managing Director of Halloran Consulting Group, Inc., a national consultancy to life

sciences companies. The information in this declaration is based on (i) my personal knowledge;


2

(ii) the business records of JLI; and (iii) the personal knowledge of others at JLI from whom I

received the information.

COMPANY BACKGROUND

2. JLI is a San Francisco-based company dedicated to improving the lives of the world’s

one billion smokers by eliminating cigarettes. To further that goal, JLI has developed a nicotine-

delivery system, by pioneering vapor technology, to provide adult smokers with a viable

alternative to combustible cigarettes. JLI is the number one vapor-product manufacturer in the

United States.

3. The Company’s founders, James Monsees and Adam Bowen, both of whom are now

former smokers, conceived the idea that became JLI to provide a real alternative to traditional

combustible cigarettes. Graduates of Stanford University’s Design School in the mid-2000s,

they pioneered groundbreaking technology that aimed to improve the lives of smokers. As

smokers themselves, they saw a gap in the alternative smoking environment for adults who

wanted to switch from combustible cigarettes. Mr. Monsees and Mr. Bowen saw a lack of

development in the tobacco industry, and sought to leverage their own design and scientific

know-how to develop an alternative for adult smokers, one that would provide a nicotine

experience that was similar to cigarettes, was easy to use, and did not involve combustion.

4. The JUUL system is a closed-system vapor platform with three components: (1) an

electronic device that couples with (2) a nicotine-containing liquid pod at one end and (3) a

charger at the other end. The JUUL system generates a nicotine aerosol vapor for inhalation.

The pod is filled with a nicotine and benzoic acid formulation (“e-liquid”) that is designed to

appeal to adult smokers and facilitate their switch away from combustible cigarettes.

5. JLI products have been designed for adult smokers only, for the purpose of

transitioning them from combustible cigarettes.


3

6. Different tobacco products—cigarettes, cigars, smokeless tobacco like dip or snuff,

and ENDS—have different risk profiles. The Food and Drug Administration (“FDA”) has noted

repeatedly that a “key piece of the FDA’s approach is demonstrating a greater awareness that

nicotine—while highly addictive—is delivered through products that represent a continuum of

risk and is most harmful when delivered through smoke particles in combustible cigarettes,” and

is less harmful when delivered through ENDS. News Release, FDA, FDA announces

comprehensive regulatory plan to shift trajectory of tobacco-related disease, death (July 28,

2017) (“FDA News Release”). There is a growing global recognition of the public health benefit

of moving current adult smokers down the continuum of risk from combustible tobacco to

electronic nicotine. For instance, Public Health England, the British government agency

principally responsible for public health, has concluded that e-cigarettes are approximately 95%

less harmful than combustible cigarettes. See Brose, McNeil, et al., E-cigarettes: an evidence

update, A report commissioned by Public Health England 5 (Aug. 2015), available at

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file

/733022/Ecigarettes_an_evidence_update_A_report_commissioned_by_Public_Health_England

_FINAL.pdf.

7. The increase in the sales of JUUL products has corresponded with a significant

population-wide transition away from combustible cigarettes. Cigarette-pack sales volumes have

declined dramatically. Syndicated market data provided by the Nielsen Company’s “Answers in

Demand Services for the Total Store/Tobacco Category” show that in a recent four-week period,

for example, cigarette sales volumes dropped by more than 11% year-over-year. This compares

favorably with the compound annual decline rate of 2.7% from 2011 to 2016 according to the

Alcohol and Tobacco Tax and Trade Bureau. The Nielsen syndicated data show that the trend


https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/733022/Ecigarettes_an_evidence_update_A_report_commissioned_by_Public_Health_England_FINAL.pdf



4

away from combustible cigarettes is most pronounced where JLI has high market penetration: in

New York City, Portland, Oklahoma City, Seattle and Denver, declines accelerated from 3.0%

year-over-year one year ago to 13.9% in a recent reporting period.

8. JLI has reiterated many times, and it continues to maintain, that no youth and no non-

nicotine user should ever use an Electronic Nicotine Delivery System (“ENDS”) product. The

Company does not sell “Juice Box,” “Pop Corn,” or any remotely similar product of the type that

the Court expressed concern about in its May 15, 2019 Memorandum Opinion, D.E. 73. See

Opinion at 3 n.5.

9. The Company has also worked proactively to prevent youth from using its products.

These efforts include, among other things, creating a comprehensive action plan to address youth

access, appeal, and use of JUUL products that it submitted to FDA in November 2018. Some of

the elements of that plan, and some of JLI’s related initiatives, include:

• JLI supports and has advocated for an increase in the minimum age to purchase tobacco products, including vapor, to 21 years old nationwide;

• JLI has ceased selling non-tobacco and non-menthol based flavored JUUL products to more than 90,000 traditional retail outlets;

• JLI has limited the sale of flavored products, other than tobacco and menthol-based, to online sales through JUUL.com, which (i) uses third-party age-verification, two-factor authentication, and facial-recognition technology to help ensure that persons ordering online are at least 21 years of age (even if state law permits tobacco purchases at age 18), and (ii) limits the amount of product that can be purchased;

• JLI has expanded its secret-shopper program that checks 2,000 stores per month to ensure compliance with age-verification and company-specific bulk purchasing requirements;

• JLI has exited U.S. Facebook and Instagram accounts; • JLI is deploying technologically-based solutions to prevent youth access and use,

including establishing full system product traceability to identify where youth are obtaining product illegally;


5

• JLI has developed a standard-based approach for point-of-sale systems, which includes automated scanning of government-issued identification to verify age and validity and an automated block on bulk purchases, and is partnering with retailers to deploy this technology in brick-and-mortar stores to restrict youth access to JUUL products;

• JLI uses only adults in JUUL ads;

• JLI has committed tens of millions of dollars to youth education and prevention, community engagement, and independent research on youth prevention; and

• JLI uses brand slogans that target adult smokers, such as “Make the Switch” and “The Alternative for Adult Smokers.”

PMTA PROCESS

10. The Tobacco Control Act requires manufacturers of “new tobacco products” to seek

FDA premarket authorization for the product to be in interstate commerce. For vapor products,

this generally requires manufacturers to submit a premarket tobacco product application

(“PMTA”) capable of showing that allowing the marketing of such product would be appropriate

for the protection of the public health. The statute requires FDA, when reviewing a PMTA, to

evaluate “the risks and benefits to the population as a whole,” after taking into account (i) “the

increased or decreased likelihood that existing users of tobacco products will stop using such

products” and (ii) “the increased or decreased likelihood that those who do not use tobacco

products will start using such products.” 21 U.S.C. § 387j(c)(4). This standard is not further

defined in the statute.

11. In 2016, FDA released a guidance document, in draft form, regarding PMTAs for

ENDS products. FDA, Draft Guidance for Industry, Premarket Tobacco Product Applications

for Electronic Nicotine Delivery Systems (May 2016) (“Draft PMTA Guidance”). The draft

guidance set forth FDA’s proposed recommendations regarding the contents of an application.

When FDA issues final guidance, it describes “the agency’s interpretation of or policy on a

regulatory issue.” 21 CFR § 10.115(b). Because FDA guidance represents the agency’s views,


6

“FDA employees may depart from guidance documents only with appropriate justification and

supervisory concurrence.” Id. § 10.115(d)(3). Yesterday (June 11, 2019), FDA issued its Final

PMTA Guidance for ENDS products, which replaces the Draft Guidance. FDA, Guidance for

Industry, Premarket Tobacco Product Applications for Electronic Nicotine Delivery Systems

(June 11, 2019), available at http://bit.ly/2XFfWdy (“Final PMTA Guidance”). It will take time

for JLI to review and carefully analyze the Final Guidance (which is 52 single-spaced pages),

including a comparison to the Draft Guidance in order to appreciate fully what has changed,

what still is missing, and how the Final Guidance will affect the work JLI has been doing so far

to prepare PMTAs. In the short amount of time the Final Guidance has been available, our

review has identified a number of areas in which FDA will need to provide further information—

through formal guidance, FDA meetings, public meetings, or otherwise—in order for JLI to

complete and submit PMTAs. The Final Guidance describes an exacting and time-consuming

process that may still take years to complete.

12. As detailed in the Final PMTA Guidance, any PMTA should contain a

comprehensive assessment of each product that includes, among other things, manufacturing

methods and standards, clinical and non-clinical studies, human health surveys, and a population

health model. The Final Guidance confirms that manufacturers are encouraged to include

“detailed technical information and analysis concerning” the product’s manufacturing facilities.

Final PMTA Guidance at 25. FDA also continues to recommend in its new Final PMTA

Guidance validation and accreditation to ensure that a company manufactures a consistent

product over time and meets the specifications listed in the application. Id. at 26, 30-31. The

Final PMTA Guidance, like the Draft Guidance, states that FDA will provide “tobacco product

manufacturing practices, which will be set forth in a future rulemaking,” to help manufacturers


7

satisfy various criteria. Id. at 11. FDA has not stated when it expects to complete the

rulemaking that sets forth these recommended tobacco product manufacturing practices. It

appears from the Final Guidance, though, that FDA may apply future requirements that result

from such rulemaking to a PMTA that is begun before, but submitted after, the rulemaking is

completed. Id. at 11 n.18.

13. FDA also recommends that manufacturers undertake non-clinical studies. Id. at 31.

Non-clinical studies include, for example, in vitro (outside of a living organism, such as in a

culture dish) studies that test cytotoxicity (whether the components are toxic to cells) and

genotoxicity (whether the components affect genetic material). Final PMTA Guidance at 34-35.

The Final PMTA Guidance also refers to in vivo (inside a living organism, such as a mouse)

studies to determine toxicity levels. Id. at 35. These tests, which FDA traditionally expects for

non-tobacco products, should be performed by accredited laboratories, which is usually

accomplished by hiring a third-party laboratory inspected and approved by FDA.

14. The Final PMTA Guidance confirms that the manufacturer must include in its

application “a full statement of the components, ingredients, additives, and properties, and of the

principle or principles of operation” of the product. Final PMTA Guidance at 26. “FDA

interprets this requirement” from the Tobacco Control Act “to mean that [an applicant] should

provide a complete list of uniquely identified components, ingredients, and additives by quantity

in the new product, as well as the applicable specifications and a description of the intended

function for each.” Id. The new Final Guidance also recommends that any testing “reflect the

range of operating conditions,” such as different temperatures and settings, as well as different

“use patterns (e.g., intense and non-intense use conditions) within which consumers are likely to

use” the product, and the “types of products that consumers are likely to use in conjunction with”


8

applicant’s products. Id. at 27-28. The practical effect is that manufacturers will need to test the

product’s components under a wide range of use and operating condition assumptions, not only

at the time that the product is created, but also after 3, 6, 9, and 12 months to determine whether

the product’s characteristics (such as their chemical composition) are stable or, instead, change

over time.

15. FDA’s Final Guidance also states that when a product “has not yet been sufficiently

reviewed, new nonclinical and clinical studies may be necessary.” Final PMTA Guidance at 46.

FDA says it does not expect “long-term” clinical or non-clinical studies, where “long-term” is

defined as lasting six months or longer, to be included in PMTAs. Id. at 13, 31, 37. But the

Final Guidance further states: “To evaluate the acute and chronic health effects associated with

the product, FDA recommends including studies, other scientific evidence, or both, that identify

biomarkers of exposure, biomarkers of harm, and health outcome measurements or endpoints.”

Id. at 37, 40. In a section about “[h]ealth outcomes” FDA recommends data measuring changes

to “heart rate and blood pressure” as well as longer-term effects such as “changes in lung,

cardiac, and metabolic function. Id. at 40-41. Under the Final PMTA Guidance, FDA interprets

the Tobacco Control Act to require inclusion of “a full narrative description of the way in which

a consumer will use the new tobacco product, including a description of how a consumer

operates the product, how the manufacturer reasonably believes a consumer could change the

product characteristics, adjust the performance, or add or subtract ingredients.” Id. at 30.

16. The Final PMTA Guidance also suggests that an evaluation of product use patterns

consider, among other things, “the trends by which users consume the product over time.” Final

PMTA Guidance at 38-39. “FDA recommends that information and data on product use,

including use in conjunction with other tobacco products, be assessed, when possible, by factors


9

that may be expected to influence such patterns, such as age group (including youth and young

adults), sex, race, ethnicity, and education.” Id. at 39. The Final PMTA Guidance recommends,

when conducting studies, to “ensure, to the extent possible, that the study findings are

generalizable to the population of U.S. users and nonusers of” the new tobacco product. Id. at

41. Evaluations of consumer perception should identify consumer perceptions of the product,

both in an absolute sense and in comparison to other categories of tobacco products or quitting

tobacco use. Id. at 38. Evaluations should also address the likelihood of initiation and cessation

by both users and nonusers of tobacco products. Id.

17. As alluded to above, the Tobacco Control Act requires that the manufacturer make a

“showing that permitting such tobacco product to be marketed would be appropriate for the

protection of the public health.” 21 U.S.C. 387j(c)(2)(A). This suggests that manufacturers may

need to create a population health model to assess the net-population impact of their products,

including use by current and new users of tobacco products. FDA’s Final PMTA Guidance does

not offer insight into how to construct a proper population health model for ENDS products.

18. FDA asserts that “[t]he recommendations made in [the Final] guidance document are

substantially similar to those set forth in the draft guidance issued on May 5, 2016” and that if a

manufacturer has “taken measures consistent with the draft guidance, they will generally be

consistent with the recommendations herein.” Final PMTA Guidance at 2. Yet there are some

material changes in FDA’s position in the Final PMTA Guidance, including the agency’s

expectations on the duration and form of the studies required to support a PMTA. Compare,

e.g., Final PMTA Guidance at 14 with Draft PMTA Guidance at 14 (regarding the specific

comparisons recommended for the assessment of health risks between a new tobacco product

and marketed products); Final PMTA Guidance at 13, 31, 37 with Draft PMTA Guidance at 44


10

(regarding the agency’s position on “long-term” studies in such contexts as clinical studies of

biomarkers of exposure). Moreover, FDA repeatedly acknowledged that its draft guidance

provided insufficient information for regulated entities to prepare a compliant PMTA. In July

2017, FDA stated that an extended compliance policy was necessary “to issue foundational rules

to make the product review process more efficient, predictable, and transparent for

manufacturers,” “to issue regulations outlining what information the agency expects to be

included in Premarket Tobacco Applications,” and to “finalize guidance on how it intends to

review PMTAs.” See FDA News Release. The Commissioner at that time explained during a

November 2017 speech that FDA “pushed off product application deadlines for certain of the

newly deemed products in particular to allow the ENDS to continue to advance while we got in

place foundational reg[ulation]s that would define how we would require product applications to

come into FDA.” Scott Gottlieb, Address at National Press Club, at 32:16-34 (Nov. 3, 2017).1

He explained that FDA intended to advance regulations that “are going to lay out what that

product application process is. The foundational regulations for the tobacco program were never

put in place, and so we are going to take the time to put those in place.” Id. at 33:08-20. In

August 2018, FDA repeated that “foundational proposed rules” were needed “regarding the basic

‘rules of the road,’ especially when it comes to what’s expected in premarket applications.”

FDA, Advancing Tobacco Regulation to Protect Children and Families: Updates & New

Initiatives from the FDA on the Anniversary of the Tobacco Control Act & FDA’s

Comprehensive Plan for Nicotine (Aug. 2, 2018).

1 Available at https://www.c-span.org/video/?436197-1/fda-commissioner-scott-gottlieb-addresses-national-

press-club


11

19. The new deadlines that FDA set in August 2017 for submitting a PMTA have

significantly affected JLI’s planning for various studies and other work that the Company is

performing, and will be performing, for use in connection with PMTAs. In order to prepare a

high-quality PMTA – one that contains the quantity and quality of information most helpful to

FDA’s review process – the durations of the studies and other work that the Company is

performing, and will be performing, were chosen in line with having the application completed

and submitted by August 2022 (the date set forth in the August 2017 guidance for ENDS

products). For example, as explained more below, the Company’s human health surveys and

nonclinical stability testing were designed to fit within a timetable under which the application

would be submitted in August 2022 or earlier.

20. The brief filed by Plaintiffs on May 29, 2019, states that no further PMTA guidance

was needed from FDA, but FDA’s subsequent release of Final Guidance, which differs from the

Draft Guidance, shows otherwise. Plaintiffs’ brief gives the example of products manufactured

for the IQOS Tobacco Heating System that recently received an FDA marketing order based on a

PMTA. Pl’s Opening Br. On Remedies, D.E. 78, at 10-12 & n.11. The IQOS Tobacco Heating

System products are not ENDS products. Instead, as the FDA release cited in footnote 11 of

Plaintiffs’ brief describes them, they are part of a device that heats tobacco-filled sticks wrapped

in paper to generate a nicotine-containing aerosol. See News Release, FDA, FDA permits sale of

IQOS Tobacco Heating System through premarket tobacco product application pathway (Apr.

30, 2019), available at https://www.fda.gov/news-events/press-announcements/fda-permits-sale-

iqos-tobacco-heating-system-through-premarket-tobacco-product-application-pathway. Because

of this composition, IQOS products “meet the definition of a cigarette in the Federal Food, Drug

and Cosmetic Act.” Id. The manufacturer of the IQOS products did not need guidance from


12

FDA for PMTAs for ENDS products, because they are not ENDS products. Moreover, it took

FDA more than two years to complete its review of the application for the IQOS products. FDA

announced its decision on April 30, 2019. Although, as just noted, FDA review did not involve

an ENDS product, FDA made a number of statements in connection with issuing its IQOS

marketing order that JLI is considering in an effort to understand how FDA might approach its

review of PMTAs for ENDS products. These statements are apart from, and in addition to, the

new Final Guidance.

JLI’S PMTA EFFORTS BEFORE THE RELEASE OF FINAL GUIDANCE

21. Notwithstanding a lack of finalized PMTA guidance for ENDS products before

yesterday, JLI had already been at work on the necessary studies, and had gathered the required

information, to the extent possible. To that end, JLI has dedicated 87 full-time employees to

conducting the work necessary to, and to preparing, its PMTAs. The number of employees

working on the PMTA process is expected to grow to more than 150 by the end of this year. JLI

has already dedicated more than $50 million to preparing the applications, and it plans to spend a

total of more than $125 million by the end of 2019. The absence of sufficient information from

FDA on what specifically those applications must include has caused JLI to be conservative in

its preparations in order to guard against FDA penalizing it for a lack of thoroughness. This

necessarily means that progress has been slower, and will take longer, than if JLI had more

specific instructions.

Meetings with FDA for Information on Survey and Test Design

22. In an effort to address the issues and questions left unresolved by the Draft PMTA

Guidance, JLI availed itself of an FDA process for submitting questions about the preparation

and review of PMTAs for ENDS products. For example, JLI used the feedback at one of the


13

earlier meetings, in January 2018, to help inform its understanding of FDA’s expectations for its

PMTA.

23. Further meetings have been necessary. FDA’s process for requesting, planning,

participating in, and receiving feedback following such meetings is involved. For example,

another meeting with FDA occurred in February 2019. A total of four months passed between

the date JLI requested the meeting (in November 2018) and FDA’s written feedback following

the meeting. Before JLI could attend the meeting it needed to submit, at least 45 days before the

meeting date, a detailed “briefing document,” known as a Meeting Information Package for

Premarket Tobacco Product Application. The document, 29 pages plus attachments, contained

required product information and a list of 13 detailed, multi-part questions for the agency. JLI’s

stated purpose for this meeting was to receive FDA feedback on the specific questions it had

about preparing JLI’s PMTA submission.

24. JLI received written feedback from FDA in March 2019. That feedback was

important to JLI on a number of fundamental issues. For example, FDA responded to questions

with factors and approaches that JLI should consider in determining how many permutations of

product flavors and nicotine concentrations it should subject to a number of different types of

clinical, nonclinical, and analytical chemistry testing. FDA also suggested that, in identifying

the physical characteristics of each e-liquid subject to the PMTA, JLI should add at least five

metrics to the list that was proposed by JLI. As another example, FDA advised JLI that, before

undertaking a particular type of toxicology study, it should request a follow-up meeting with the

agency to discuss specific design parameters to be incorporated into such a study. FDA also

referenced its May 2016 draft PMTA guidance, and explained that, when finalized, it would

represent the Agency’s current thinking on this issue.


14

25. On another topic at the February 2019 meeting, FDA stated that, while it does not

have specific requirements governing the types of experimental models and toxicity endpoints to

be measured in a PMTA for tobacco products, JLI should consider a number of specific things to

include in the PMTA relevant to those tests, and FDA identified four non-FDA guidance

documents that may be useful. FDA also provided responses on important questions about how

to determine, under the Draft PMTA Guidance at the time, when “batches” used in sampling are

“different,” and what constitutes a “replicate” for each batch. This information was needed to

satisfy the proposed recommendation in the Draft PMTA Guidance that data sets span “a

minimum of three different batches with a minimum of ten replicates per batch, with date and

time sampling points.” Draft PMTA Guidance at 24; see also Final PMTA Guidance at 25-26

(changing the number of suggested replicates to “generally seven or more”). FDA responded by

explaining, with examples, that the answers vary according to the purpose of each test. FDA

also clarified that, while the sampling protocol described in the relevant section of the Draft

PMTA Guidance operates as a minimum, a number of factors which it set forth at the meeting

could raise or lower the numbers. FDA also suggested how to go about justifying the choice and

clarified that, in the absence of FDA guidance regarding replicate and batch testing for tobacco

products at this time there are multiple ways to conduct batch testing. This was all information

that FDA provided for the first time in connection with the February 2019 meeting.

26. This need for meetings to gain clarification and further guidance still exists even now

that Final PMTA Guidance has been published. In fact, the Final Guidance recommends

requesting such a meeting in multiple circumstances. See, e.g., Final PMTA Guidance at 36

(suggesting a meeting before conducting non-animal based tests); 37 (suggesting a meeting if

planning to conduct any computational modeling); 13 (suggesting a meeting to discuss


15

alternatives to well-controlled investigations); 26 (same, specific to demonstrating

appropriateness for human health); 22 (suggesting a meeting to discuss product samples before

submitting them); 28 (suggesting a meeting to consult on which harmful and potentially harmful

constituents (HPHC) testing is appropriate to a particular application).

Validation of Manufacturing Machines and Facilities

27. In addition to JLI meeting with FDA about its study designs and other aspects of the

PMTA, the Company has taken extensive steps to validate its manufacturing lines. As explained

above, FDA recommends that companies manufacture their tobacco products through validated

machines (also referred to as “qualified lines”). Qualified lines are necessary so that JLI can

demonstrate that the facility produces a consistent product, which is necessary to ensure that the

pods it tests share the characteristics of pods that consumers use. If pods are produced on

machines that do not create a consistent product, then the different samples will vary, and the

results of the testing may differ between batches.

28. For other (i.e., non-tobacco) products that FDA regulates, the agency has published

“good manufacturing practice” requirements that inform manufacturers of the Agency’s view

about how to create qualified lines and ensure consistent and quality-controlled product

manufacturing. As noted above, FDA stated in its Draft PMTA Guidance document that it will

set forth tobacco product manufacturing practice requirements for ENDS in a future rulemaking.

See Draft PMTA Guidance at 12. In November 2017, FDA requested comments on “updated

recommendations for regulations on good manufacturing practice for [ENDS],” see 82 Fed. Reg.

55,613, 55,613 (Nov. 22, 2017), but it has yet to initiate a rulemaking. Furthermore, because

ENDS are a new product, there are no readily identifiable standards for manufacturing or

production. JLI therefore does not know the agency’s view about what is necessary to create a


16

qualified line. JLI expected that the recently released Final Guidance would include

recommendations on product manufacturing to support a PMTA, but the Final Guidance states

that “tobacco product manufacturing practices . . . will be set forth in a future rulemaking.” Final

PMTA Guidance at 11. Thus, no discernible clarity on manufacturing requirements will be

known until FDA finalizes that rulemaking.

29. To fill this gap, JLI has looked at how manufacturers in other areas regulated by

FDA, such as the pharmaceutical and medical device industries, have set up their manufacturing

process. JLI also evaluated whether its manufacturing procedures comport with what other

ENDS manufacturers are doing, and based on a “best guess” about what FDA will want. Due to

the lack of clarity from FDA, however, JLI has been forced to take extra precautions that have

delayed qualifying the lines.

30. In addition to manufacturing facilities, JLI needs to establish controls over supplier

quality systems and product specifications to verify the raw materials and facilities of suppliers,

because supply variations could lead to an inconsistent product used in the PMTA process.

31. Despite the lack of final guidance on the topic, JLI went ahead with validating its

facilities and qualifying its lines, using its best estimate of what FDA will require. This was a

time-intensive process, still under way across the entire supply chain base, with specific lines

used to manufacture PMTA test samples to be completed later this month (June 2019). In

choosing when and how to qualify its lines, JLI relied on FDA’s extended compliance policy to

ensure that JLI could comply with the August 2022 deadline.

JLI’s Extensive Nonclinical Studies

32. JLI has also designed non-clinical studies to gather required data on the products’

chemical attributes and components. Designing an effective study is a labor intensive and


17

challenging process that frequently requires time consuming back-and-forth with FDA. For

example, as explained above, JLI added to the attributes it tests after FDA recommended adding

to the list during the February 2019 meeting. The proper definition of a “different batch,” also

clarified at the February 2019 meeting, was needed before JLI could begin some of the required

nonclinical testing.

33. As another example, JLI has been in dialogue with FDA over the proper inhalation

profile for its toxicological studies. An inhalation profile measures the length of inhalation, how

long the vapor is held, and the volume of vapor. FDA has not informed regulated entities what

inhalation profile should be used during testing. JLI originally proposed to FDA that it use a

standard puff – one representative of how consumers use the product. After extensive

communication, FDA recommended using a different inhalation profile. Again, determining the

proper inhalation profile is a prerequisite to conducting certain nonclinical tests, yet even the

Final PMTA Guidance does not provide concrete guidance on this foundational point.

34. JLI’s nonclinical testing has been hampered by the lack of concrete guidance in other

ways as well. For most products that FDA regulates, the product formulations and test methods

are well established. The pharmaceutical industry, for example, has international standards that

inform regulated industries how to perform certain tests, and how to interpret those test results.

Similar standards do not exist in the ENDS industry. There is no consensus about how to set up

sample units, what tests to use to measure chemical components, or how to interpret the results.

Furthermore, because test results may vary depending on the test method used, the absence of

standardized methods makes it difficult to compare products. Although JLI is not waiting before

it conducts nonclinical testing, JLI expected that the Final PMTA Guidance would include

standardized testing methods, but it does not. In addition, the Final Guidance recommends


18

considering a list of more than 30 constituents or chemicals in the analysis of potential health

risks, with a dozen added to the list that appears in the Draft Guidance. Compare Final PMTA

Guidance at 28-29 with Draft PMTA Guidance at 26-27. The Final Guidance also states that this

list is only FDA’s “current thinking” on which constituents or chemicals to consider. Final

PMTA Guidance at 28 n.35. “FDA intends to establish a revised list of harmful and potentially

harmful constituents (HPHCs) that include HPHCs in ENDS products and publish it in the

Federal Register.” Id. The Final Guidance gives no expected publication date.

35. Another factor that affects the timing to complete nonclinical testing is the

availability of space at accredited laboratories. Qualified laboratory space is severely limited,

however, both because relatively few accredited laboratories perform work on ENDS products

and because manufacturers are competing for the limited space.

36. Notwithstanding these challenges, and even before receiving the Final PMTA

Guidance, JLI has (1) set up testing parameters that it believes FDA will accept, (2) arranged for

the delivery of product from qualified lines, and (3) secured laboratory space.

37. These efforts have been made in reliance on the timeline the FDA announced in 2017.

The tests of other remaining work will still take a significant amount of time, and there are

serious limitations on shortening the process. For example, one critical component of a PMTA is

stability testing. Stability testing is akin to determining a use-by date for groceries. JLI must test

whether and how the product changes over various time periods (3, 6, and 12 months, for

example) and under various conditions (such as various temperatures or exposure to light). By

definition, these tests take time. The only way to determine, for example, how its product

changes over a one-year period is to test it a year after it was manufactured on a qualified line.


19

Furthermore, neither the Draft nor the Final PMTA Guidance explains whether the stability

testing should account for 6 months, 12 months, or some other duration.

JLI’s Clinical Studies

38. JLI is already conducting clinical, human-based studies in support of its PMTA. Five

clinical studies that it began in April 2018 concluded in February 2019.

39. The clinical studies that JLI has conducted to date are helpful for test-design

purposes, and will assist in planning and carrying out studies for use in the PMTA. (These

concluded trials pre-dated the existence of a qualified line.)

40. Similar to the process for nonclinical studies, JLI has met with FDA to attempt to

ascertain whether its planned clinical studies would comport with FDA’s expectations. During

those meetings, FDA has told JLI that it expects certain types of clinical studies that do not

appear in the Draft PMTA Guidance and that JLI did not have reason to believe were necessary

for a PMTA.

41. For example, during the meeting process FDA requested clinical research on “third-

hand” exposure. (First-hand exposure is when a consumer uses the product directly; second-

hand exposure is similar to the phenomenon of second-hand smoke for combustible tobacco

products; and third-hand exposure refers to vapor that a non-user might come into contact with

after it condenses on a surface). Neither the Draft PMTA Guidance nor the Final Guidance

mentions this type of exposure. To JLI’s knowledge, there also is no research in the literature

about third-hand exposure testing and no other party has ever submitted research on third-hand

exposure as part of a PMTA. Based on FDA’s statements outside of the formal written guidance

process, JLI plans to design and conduct third-hand exposure clinical trials.


20

JLI’s Long-Term Adult Survey

42. JLI is also engaged in surveys to determine how adults use its products, as well as

their use of other tobacco products. Among other things, these surveys cover frequency of use of

JLI’s products, use concurrently with other tobacco products, use as an alternative to other

tobacco products, and changes in usage over time.

43. JLI began designing these surveys more than a year ago. Due to the dearth of

experience conducting significant behavioral research on ENDS products, these surveys needed

to be designed with minimal guidance from past practice. That lack of experience has slowed

the entire process down, from engaging research firms that could conduct preliminary testing and

design a proper survey, to obtaining institutional review board approval, to implementing the

survey.

44. Because a well-designed survey must be representative of the United States

population, the sample size must be large. These surveys, which began in May 2018, currently

have roughly 70,000 participants who have signed up over time.

45. In addition to needing a proper methodology and a large sample size, these surveys

must take place over a sufficient length of time. Especially when evaluating behavior relating to

an addiction, results—such as whether a person has switched from combustible cigarettes to

ENDS products—are more reliable the further out they are measured. JLI therefore intends to

follow survey participants for at least one year to determine rates of cigarette abstention and

regression. Because survey participants have enrolled over time, results will continue to come in

over the course of this year. As discussed below, there will be more to do after the survey data

are compiled.


21

JLI’s Youth Surveys

46. The PMTA process requires information about youth usage and perceptions. JLI has

therefore also commissioned youth surveys. In addition to questions about usage, the surveys

attempt to determine prevalence, patterns of use, and perceptions regarding the addictiveness of

ENDS and other tobacco products. The surveys are conducted by an independent provider.

47. Youth surveys differ from adult surveys in important ways and raise special

challenges. JLI did not want to commission a youth study until it could meet with FDA to

ensure that any youth surveys were conducted in a manner that FDA would approve. Before the

youth surveys were started, JLI therefore met with FDA in August 2018. FDA provided

feedback in October 2018, and the first round of surveys was launched the following month.

48. For ethical reasons, dual consent is required for these surveys—consent of the

participant and a parent. The logistics of a youth survey also make the process more time-

consuming, in part because of the need to find a survey provider experienced in and capable of

locating a representative sampling of participants.

49. The youth surveys that JLI commissioned are cross-sectional and conducted at six-

month intervals. Each survey is conducted with a new cohort of participants, and the answers are

compared to the results of previous surveys.

50. Although cross-sectional youth surveys will have been conducted by the end of 2019,

JLI needs additional information to support a PMTA. Youth perceptions of ENDS products are

highly dynamic, in part because of the recent increased emphasis on initiatives to prevent usage

by youth, including through educational outreach. This makes the results of only two or three

surveys (for example) more difficult to use as a predictive device.


22

JLI’s Efforts To Create A Population Health Model

51. JLI is also developing a population health model. Such a model is important in

preparing the PMTA because, as noted earlier, the standard for approving an application is

whether there is a showing that permitting the product to be marketed would be appropriate for

the protection of the public health.

52. In contrast with combustible tobacco products, because ENDS products are relatively

new JLI has not been able to look to prior studies to develop a population health model.

Creating a public health model requires balancing benefits and costs without any clear guidance

on how either should be measured. For example, by statute the model must weigh the cost of a

person who had never previously used tobacco products becoming addicted to ENDS against the

benefit of a cigarette smoker transitioning to non-combustible products. See 21 U.S.C.

§ 387j(c)(4). There is no established, accepted model informing regulated parties how to

measure and compare those or other possible effects.

53. Importantly, even with the issuance of Final PMTA Guidance, FDA has not

provided guidance or insight into how it intends to construct or evaluate a population model that

accounts for the relevant costs and benefits of ENDS products. This is a foundational component

of the PMTA, yet regulated entities have little insight into how FDA intends to evaluate whether

a product is appropriate for the protection of the public health.

54. Even if FDA were to inform regulated entities about how it plans to evaluate a

population health model, a reasonably situated applicant like JLI could not complete the model

until its non-clinical, clinical, and survey results are complete.

55. In sum, JLI has already devoted substantial resources to the preparation of a PMTA.

It embarked on the process without clear guidance from FDA, as the industry waited for the


23

Agency to finalize a draft from 2016. FDA has finally issued its Final PMTA Guidance, but it

leaves important questions unanswered and amends recommendations made in the Draft PMTA

Guidance. Even with Final Guidance, a number of the remaining steps for completing a PMTA

will require time to conduct and complete studies and other work. By their nature, these studies

and other analyses will take time. In addition, under FDA’s submission rules a manufacturer

must submit a “fileable” application. This means that if FDA decides the application should

have contained additional elements or information, it can reject (decline to file) the application.

With all of this in mind, JLI has designed studies and other work in reliance on FDA’s guidance

stating that JLI has until August 2022 to complete its PMTA. Although JLI will endeavor to

meet an earlier deadline, the many factors set forth above will limit the ability of JLI to submit

an application more quickly.


24


EXHIBIT D



FOR THE DISTRICT OF MARYLAND

Greenbelt Division

AMERICAN ACADEMY OF

PEDIATRICS, et al.,

Plaintiffs,

v.

FOOD AND DRUG ADMINISTRATION,

et al.,

Defendants.

Civil Action No. 8:18-cv-00883-PWG

DECLARATION OF CAROLE B. FOLMAR

I, Carole B. Folmar, declare as follows:

1. I have personal knowledge of the facts set forth in this declaration and, if called to

testify as a witness, would testify competently under oath.

2. I have been the Director of Regulatory and Scientific Affairs and Associate General

Counsel of ITG Brands, LLC (“ITG”) since June 2015. In that capacity I oversee ITG’s

preparation of regulatory submissions to the U.S. Food and Drug Administration (“FDA”).

3. ITG is the third-largest tobacco company in the United States and offers a broad

range of cigar brands, including Dutch Masters, Backwoods, Phillies, White Cat, Antonia y

Cleopatra, El Producto, and Hav-A-Tampa cigars.

4. In 2009, Congress passed the Family Smoking Prevention and Tobacco Control

Act (“Tobacco Control Act”), which permits FDA to regulate cigarettes, smokeless tobacco, and

other products FDA “deems” to be tobacco products. 21 U.S.C. § 387a(b). Except as to covered

products commercially marketed as of February 15, 2007 (grandfathered products), the Tobacco

Control Act generally requires manufacturers of new tobacco products to obtain premarket


2

authorization from FDA by submitting a premarket tobacco application (“PMTA”) before their

products may be marketed or sold. Id. § 387j(a). Manufacturers need not submit PMTAs,

however, for new products that are “substantially equivalent” to either products that were on the

market as of February 15, 2007, or that FDA has previously approved. Id. § 387e(j). Such a

manufacturer must instead demonstrate in a report (an “SE Report”) that its product has the “same

characteristics” as an earlier predicate product or that its product has “different characteristics” but

does not “raise different questions of public health.” Id. § 387j(a)(3)(A).

5. In May 2016, well after all of ITG’s cigars became available to consumers, FDA

deemed cigars to be tobacco products subject to the Tobacco Control Act (the “Deeming Rule”).

81 Fed. Reg. 28,974 (May 10, 2016). All of ITG’s cigar products were either on the market prior

to February 15, 2007, and thus are grandfathered products, or are “substantially equivalent” ( “SE”)

to products on the market at that time. Therefore, ITG does not anticipate filing PMTAs for its

cigar products, and is entitled instead to rely on the SE pathway created by Congress for

substantially equivalent products.

6. FDA has not yet published regulations governing the SE process for “deemed”

tobacco products, but has been reviewing SE Reports for cigarettes since March 2011. Based on

publicly available data, FDA received approximately 3,517 provisional SE Reports, and through

September 2015, had received an additional 1,926 regular SE Reports—for a total of 5,443. As of

April 2018, FDA announced that it had issued final orders for 191 products. Accounting for SE

Report withdrawals and cancellations, FDA appears to have issued final orders on only

approximately 5.1 percent of known SE Reports in the over eight years since those SE submissions

began. Thus, FDA retains a backlog of thousands of SE Reports, including approximately 1,500

SE Reports that the Agency has announced in 2018 that it would indefinitely remove from review.


3

7. ITG has extensive experience with FDA’s “SE” process, having navigated that

process for cigarette products since 2011. ITG has found that demonstrating “substantial

equivalence” is an exacting, and resource-intensive process, with multiple supplemental FDA

requests for information, that takes years to complete. Indeed, several ITG submissions originally

filed by the March 2011 deadline for provisional products still remain unresolved.

8. Successfully demonstrating substantial equivalence has required ITG to show in

very significant detail that the product at issue has the same characteristics as an earlier predicate

product (sold over a decade ago) or that its product has different characteristics than that predicate

but does not raise different questions of public health. This showing has required ITG to develop

thousands of pages of comparative manufacturing, chemistry, toxicological, and social science

data and literature. In order to facilitate such a comparison, testing data and detailed manufacturing

documentation must be collected for a grandfathered predicate product that typically has not been

manufactured or distributed for several years (manufacturers were not on notice that any such data

would ever be needed, so it typically was not collected). As a practical matter, manufacturers are

frequently required to conduct comparative testing on a “surrogate” tobacco product, which refers

to a product manufactured for the purposes of supporting an SE Report that is intended to replicate

the grandfathered predicate product as it existed as of February 15, 2007. In such circumstances,

in order to “bridge” the surrogate product data and predicate product, manufacturers are required

to submit information to support three comparisons: (1) surrogate product to predicate product; (2)

surrogate product to new tobacco product; and (3) predicate product to new tobacco product.

9. Once an SE Report has been submitted, FDA first conducts a compliance review to

ensure that the predicate product is a valid predicate (i.e., on the market as of February 15, 2007

or a provisional product subject to an SE Marketing Order). Next, an SE Report enters scientific


4

review, sometimes years after the SE Report was submitted, and is assigned for review to Office

of Science staff from up to eight scientific disciplines (chemistry, microbiology, engineering,

toxicology, environmental science, social science, addiction, and medical). FDA may then issue

Advice/Information Request letters soliciting additional information, or a Preliminary Finding

letter containing deficiencies requiring additional information from the applicant. After a

Preliminary Finding letter, FDA will issue an SE Marketing Order or Not Substantially Equivalent

(“NSE”) Order. Applicants may request supervisory review, a form of administrative appeal, of

NSE Orders.

10. ITG has been deeply engaged with FDA on scientific and regulatory issues

regarding the SE process since the enactment of the Tobacco Control Act. ITG has filed multiple

comments regarding the SE review process, both in the context of cigarettes and deemed products.

These comments have offered suggestions for ways in which FDA can most efficiently and

appropriately conduct SE review, consistent with FDA’s public health mission. Further, ITG has

shared cigar leaf data and provided FDA information on the current state of cigar science in

anticipation of future cigar SE submissions for its products.

11. Importantly, although FDA has now defined in some detail the requirements for SE

Reports for cigarettes, FDA has not yet fully defined any single standard as to the information

required to initiate the substantial equivalence process for cigars. Standards set for cigarette SE

applications do not translate to cigars. Cigar tobaccos are selected and controlled in a different

manner than cigarette leaf varieties, and available data indicate that cigar tobacco leaf naturally

displays a much higher degree of variability than cigarette tobacco. Thus, there is no reliable way

to know what will be accepted by FDA in a cigar SE Report, and no way to ensure in advance that

the effort, time, and money spent preparing an SE application will produce an acceptable


5

submission. Among the issues left unaddressed by FDA guidance and/or rulemaking are: (1)

which specific harmful and potentially harmful constituents (“HPHCs”) should be analyzed in any

tests run and submitted for a cigar product and its predicate; (2) the technical methodology for

conducting testing for those HPHCs and performing risk assessments for oral or inhalation

exposures; (3) the definition of, and how to identify, a product’s “characterizing flavor”; and (4)

the information required in the application to describe and compare flavors for purposes of

demonstrating substantial equivalence. Indeed, FDA has separately postponed issuing guidance

on HPHC testing and reporting for cigars under Section 904(a)(3) of the Act.

12. As FDA has recognized, it is not feasible for cigar manufacturers to simply guess

what is required to demonstrate substantial equivalence because of the unique features of cigars.

To that end, FDA’s previous extensions of the compliance deadlines for deemed products

recognized “the amount of time needed for firms to prepare” SE Reports, and FDA has recently

issued a notice of proposed rulemaking intended to provide “clarity to industry about the

requirements for” SE Reports. The proposed rule instead “invite[d] comments and information

[regarding] the parameters that may be needed to support an SE Report,” and ITG and other

stakeholders have announced their intent to provide further comments regarding these issues.

Those comments are due on July 17, 2019.

13. Given the lack of guidance, the significant cost of performing testing, and FDA’s

specific instruction that cigar SE Reports need not be filed until 2021 after “foundational rules and

guidances” are put in place by FDA,1 ITG had no practical option but to follow FDA’s lead and

1 FDA, Advancing Tobacco Regulation to Protect American Children and Families: Updates and

New Initiatives from the FDA on the Anniversary of the Tobacco Control Act and FDA’s

Comprehensive Plan for Nicotine, Aug. 2, 2018, available at https://www.fda.gov/news-

events/fda-voices-perspectives-fda-experts/advancing-tobacco-regulation-protect-children-and-

families-updates-and-new-initiatives-fda.


6

await more specific instruction before filing cigar SE Reports. In the meantime, ITG has not sat

on its hands—it has expended thousands of man hours and millions of dollars anticipating what

FDA might require. And based on the type of technical requirements FDA has imposed for SE

Reports in other contexts, many months may be needed to submit SE Reports here despite ITG’s

preparation. Indeed, SE Reports for cigarettes have previously been rejected by FDA if they lack

sufficiently detailed information.

14. Any order rendering cigars illegally marketed because FDA has not approved an

SE could have very serious consequences for a number of ITG’s key brands that have been on the

market for decades and should qualify as SE under the Act. Congress intended that these products

can be lawfully marketed and specified that the SE process would be available for that purpose;

any remedy that has the practical effect of preventing that outcome is starkly inconsistent with the

statute. Indeed, if the Court’s remedy appears to render these products illegal, retailers could

erroneously conclude that ITG’s cigars are not compliant with the Tobacco Control Act and

prematurely pull them from their shelves.

15. I am not aware of any allegation in this case that there has been an uptick in youth

cigar usage, and multiple sources report a significant decline in youth cigar usage over recent

years. See, e.g., CDC, Vital Signs: Tobacco Product Use Among Middle and High School

Students – United States, 2011-2018, Feb. 15, 2019, available

at https://www.cdc.gov/mmwr/volumes/68/wr/mm6806e1.htm?s_cid=mm6806e1_w (significant

decline in youth usage of cigars observed from 2011 to 2018); Lloyd D. Johnston, et al.,

Monitoring the Future National Survey Results on Drug Use 1975-2018, Jan. 2019, at 45, available

at http://www.monitoringthefuture.org/pubs/monographs/mtf-overview2018.pdf (significant

declines in youth usage of small cigars since 2010).


https://www.cdc.gov/mmwr/volumes/68/wr/mm6806e1.htm?s_cid=mm6806e1_w

EXHIBIT E


EXHIBIT F


1




Plaintiffs,

v.

FOOD AND DRUG ADMINSTRATION, et al.,

Defendants.


DECLARATION OF MARK ANTON, PRESIDENT, WHAT A SMOKE, LLC, AND

EXECUTIVE DIRECTOR, SMOKE-FREE ALTERNATIVES TRADE ASSOCIATION

1. I am the President of What a Smoke, LLC, a small Electronic Nicotine Delivery

Systems (ENDS) manufacturer, distributor and retailer based in Flanders, New Jersey. What a

Smoke was established in 2008 as one of the country’s first ENDS businesses. In my capacity, I

manage the day-to-day operations of the company, but also engineer ENDS devices and e-liquid

formulations. We market 138 unique ENDS products, all of which will have to go through FDA

premarket review.

2. Since 2017, I have also served as the Executive Director of the Smoke-Free

Alternatives Trade Association (SFATA), one of the largest national trade associations of U.S.

ENDS businesses. Our membership includes hundreds of manufacturers, retailers and

distributors, both large and small, located in all 50 States. Our members employ thousands of

individuals across the country.


2

3. Based on my experiences with What a Smoke and SFATA, I have an extensive

knowledge of the industry and the related actions taken by the Food and Drug Administration

(FDA) under the Tobacco Control Act (TCA).

4. In May 2016, when the final Deeming Rule was published, FDA extended the

TCA’s requirements to all deemed products, including ENDS that contain tobacco-derived

nicotine. Now, ENDS manufacturers are subject to a host of regulatory requirements, including

registration, product listing, ingredient reporting, harmful constituent testing, warning labels and,

most critically, premarket authorization for any new tobacco products.

5. Since the Deeming Rule went into effect, FDA has consistently moved regulatory

deadlines to give the ENDS industry a reasonable amount of time to comply, as well as

accommodate FDA’s own needs, technical issues and capacity. For example, the initial

registration and product listing deadline for U.S. manufacturing establishments was moved

several times from December 31, 2016 to October 12, 2017. The ingredient reporting deadline

was moved from February 8, 2017 for large manufacturers, and August 8, 2017 for small-scale

manufacturers, to May 8, 2018 and November 8, 2018, respectively. The harmful and potential

harmful constituent (HPHC) reporting deadline, which was originally set for August 8, 2019, has

been moved indefinitely to either six or nine months after FDA’s final guidance on HPHC

testing is published (depending on whether the reporting company is large or small). As a

practical matter, it would not have made sense to require PMTAs even before much less-

involved ingredient reports were due.

6. The most critical requirement for ENDS companies is premarket authorization for

new products. A “new” tobacco product is one that was either introduced to the U.S. market

after the February 15, 2007 “grandfather date” or, if it was already on the market as of that date,


3

had any modifications made to the product other than to its label. Although my company has

been in business for 11 years, none of my products – nor any ENDS on the market – are

grandfathered, and all will have to go through “premarket” review.

7. More specifically, while the TCA offers several pathways for premarket approval

to combustible tobacco products (i.e., substantial equivalence), the only approval route available

to lower risk products such as ENDS is through the most onerous of these pathways, the PMTA.

8. The PMTA is the most extensive pre-market review pathway and, according to

the statute, requires tobacco product manufacturers to submit information for each product

showing that marketing the product is “appropriate for the protection of the public health” with

respect to both users and nonusers of tobacco products. This has become known as the

“population effects” standard, which requires FDA, when deciding whether a product may be

commercialized, to consider the product’s impact on the population as a whole, including the

likelihood that people will stop using tobacco products (i.e., cessation), as well as start using

them (i.e., initiation).

9. Since the Deeming Rule was published in May 2016 and until yesterday (June 11,

2019), only a draft guidance has been published by FDA on the PMTA process for ENDS. The

fact that the guidance was not finalized for over three years has made it very difficult for

companies like mine, and hundreds of SFATA members, to understand what information would

satisfy this population effects standard. Such understanding, of course, is necessary for

companies to plan and invest in the appropriate level of resources. Unlike well-established

regulations for drugs and medical devices, which require demonstration of safety and

effectiveness, the more burdensome public health or population effects standard is brand new for


4

both industry and FDA – making the need for clear guidance so critical, especially for small

ENDS businesses.

10. Beyond the PMTA guidance itself, FDA has also so far failed to provide any

guidance or initiate rulemaking in other critical areas necessary to complete PMTAs. For

example, FDA has not yet established Tobacco Product Manufacturing Practices (TPMP),

although a proposed TPMP rulemaking has been on FDA’s regulatory agenda for several years.

Section 910(b)(1)(C) of the TCA requires that PMTAs include “a full description of the methods

used in, and the facilities and controls used for, the manufacture, processing, and, where relevant,

packing and installation of the new tobacco product.” The recently finalized PMTA guidance

summarizes information about manufacturing processes that will need to be included in an

application, but does not itself provide any guidance on what practices or procedures are

appropriate for the protection of the public health when, for example, manufacturing e-liquids.

11. Another example is the lack of guidance on how to assess the levels of HPHCs in

ENDS products. This is a particular concern for “open-tank” (i.e., refillable) products. There are

no standardized test methods for aerosol produced from open-tank ENDS, unlike for cigarettes

which have established smoke testing regimes. In the recently finalized PMTA guidance, FDA

indicates that, in lieu of testing, “it might be acceptable to provide the quantity [of an ingredient]

added to an e-liquid,” but still does not provide any guidance on testing procedures, sample sizes,

validation methods, limits of detection, or how to conduct exposure assessments.

12. Another major concern for smaller companies that market open-tank products, of

which FDA records indicate there are millions, is the lack of available third-party laboratory

space to conduct HPHC and other analytical testing necessary for PMTAs. Small companies like

mine do not have their own laboratory capabilities and so must rely on third-party labs and


5

consultants. Based on our research and outreach, there are only handful of establishments in the

country that would be able to conduct this research.

13. Another challenging aspect of the PMTA process for ENDS companies is

developing an Environmental Assessment (EA), which applicants must submit so that the agency

can assess the environmental impact of issuing a marketing order for a new product, as required

by the National Environmental Policy Act (NEPA). Significant clarity on what an EA requires

for an ENDS manufacturer is needed. For example, it is not clear if and how companies need to

assess the potential greenhouse gas emissions that result from the manufacture, use and disposal

of ENDS products. This is particularly concerning for ENDS companies whose devices and

other components are produced by contract manufacturers in China. The time and expense to

prepare EAs for PMTAs that meet FDA standards is expected to be significant.

14. In addition, as the final PMTA guidance makes clear (page 51), pre-PMTA

meetings are essentially required with FDA. FDA specifically recommends applicants meet with

them “well in advance of the planned premarket applications so that the applicant has the

opportunity to consider CTP feedback prior to preparing the application and to help ensure the

application will be complete at the time of submission and likely to provide the data and

information required for the Agency to make a final authorization decision.” Moreover, FDA

states that to ensure a successful pre-submission meeting, applicants are “expected to have a

fully developed approach to meet the regulatory requirements for its planned application(s)”

before the meeting with FDA. Thus, given the large number of PMTAs that are expected to be

filed, it is likely that even scheduling a meeting with FDA could take months or more. In the

end, FDA still needs time, even with the final guidance, to flesh out parameters and solve hard

technical questions for individual applications.


6

15. While we are encouraged that FDA has finally published a final PMTA guidance,

significant time and expense will be needed to complete this process.

16. Based on the recently finalized PMTA guidance, the expected cost to complete a

PMTA is exorbitant – potentially millions of dollars per application. Literature reviews alone,

the backbone of any PMTA, are estimated to cost over $500,000 to generate according to

consultants. This far exceeds the $300,000 per application FDA estimated in the Deeming Rule.

17. My business has over 138 ENDS products. Even if I can realize some economies

of scale in filing multiple applications, it is easy to see that my costs would sky-rocket, at a

minimum, into the tens of millions of dollars.

18. There are thousands of small businesses like mine, many of them “Mom and Pop”

type businesses. In fact, we understand FDA has over 3 million different products registered.

This means an industry that is estimated at $6 billion annually in sales would have to spend far in

excess of that figure to just keep the products we currently have on the market.

19. There will be many unintended economic consequences of the PMTA process as

outlined by FDA. Small businesses investing in a PMTA will struggle to pay their bills and

overhead, to invest in new inventory and equipment and extend their leases. Beyond

manufacturers, many of whom will go out of business because of the PMTA process, there are

over 15,000 small “vape shops” that focus on selling open-tank devices and e-liquids whose

businesses will be severely impacted by a shortage of approved products, and will likely have to

shut down, putting thousands of employees out of jobs.

20. This will cause economic hardship on multiple levels for small business owners.

Many have invested their life savings into their vapor business, mortgaged their homes, and

personally guaranteed leases and SBA loans. If we are forced out of business, we will also lose


7

the significant resources we spent on outfitting our labs to incorporate clean rooms and advanced

production equipment.

21. In short, the FDA needs sufficient time to work with the industry to develop a fair

and streamlined PMTA process that takes into account the lower risk profile of ENDS products

and provide additional, and much needed, guidance on manufacturing standards and other PMTA

requirements.

22. As a business owner I believe I am doing a public good by helping adult smokers

transition to products that studies show are at least 95% less harmful than combustible cigarettes.

We would like to continue to help millions of addicted smokers reduce or eliminate their harm

from tobacco smoke.

23. The youth issue is of paramount importance and our industry members strive to

operate under the laws to prevent youth access. However, it is important to consider the

devastation the PMTA process will have on the thousands of U.S. businesses and workers, as

well as the millions of smokers who have made the switch and have seen their health

dramatically improve, if the compliance period effectively results in millions of products being

arbitrarily removed from the market.

It is with great honor and thanks to the court in taking into consideration the points and

concerns of a citizen, industry member and leader. I thank you.

I declare under penalty of perjury that the foregoing is true and correct. Executed on

June 12, 2019.

Mark Anton


EXHIBIT G


1




Plaintiffs,

v.

FOOD AND DRUG ADMINSTRATION, et al.,

Defendants.


DECLARATION OF STACEY M. BENSON, Ph.D.

1. I am an epidemiologist with over 15 years of professional experience conducting,

analyzing, and interpreting scientific data using well-accepted scientific methodology.

2. I currently serve as a Supervising Health Scientist and Epidemiology Practice

Area Lead at Cardno ChemRisk, a global scientific consulting firm specializing in, among other

areas, product health and safety. Cardno ChemRisk is a consulting firm that provides scientific

advice to the government, corporations, law firms and various scientific/professional

organizations.

3. My areas of expertise include environmental epidemiology, occupational

epidemiology, respiratory protection, and clinical research. I received my undergraduate degree

(B.S.) in physics from St. Lawrence University, my master’s degree (M.S.) in the field of

exercise physiology from the University of Pittsburgh, and my Ph.D. in Epidemiology from the

University of Pittsburgh.


2

4. Prior to joining Cardno ChemRisk, I held teaching positions at Carnegie Mellon

University and Point Park University, and served an Associate Service Fellow at the National

Institute for Occupational Safety and Health, where I conducted human subject experiments at

the National Personal Protective Technology Laboratory. I have published over 30 scientific

articles, presented 28 papers at both national and international conferences, and have been cited

in the scientific literature over 400 times.

5. Cardno ChemRisk has been providing consulting services to electronic nicotine

delivery systems (ENDS) clients for over five years and is currently supporting clients through

the Premarket Tobacco Application (PMTA) process. As such, we are familiar with the PMTA

procedures, at least as they stand today, as well as the many challenges and uncertainties facing

stakeholders attempting to meet the requirements set forth by FDA.

6. In 2016, the Food and Drug Administration (FDA) released a draft guidance

document regarding PMTAs for ENDS. While the draft discussed many aspects of the PMTA

process, including several types of non-clinical and clinical studies that must be completed, there

remained many unanswered questions about, among other issues, various testing protocol

requirements. It was not surprising that many manufacturers, and especially smaller companies

with limited financial resources, were hesitant to start the PMTA process, at least beyond the

early planning stages, based on only a draft guidance.

7. Given FDA’s statements regarding the draft guidance and PMTA process, this

hesitancy was understandable. The FDA Center for Tobacco Products indicated on their website

that the draft PMTA guidance document is “[n]ot for implementation” and “[c]ontains non-

binding recommendations” (FDA, 2018). According to the FDA, once the guidance document is

finalized it “will represent FDA’s current thinking on submitting PMTAs for ENDS products.”


3

(FDA, Accessed June 2019). In August 2018, Commissioner Gottlieb acknowledged that “[a]

key part of achieving [FDA’s] goals is issuing foundational rules and guidances to help industry

better understand what is needed to submit product applications.” He explained further that “in

the coming months,” FDA would “propose new rules to help industry on topics including

Substantial Equivalence, Premarket Tobacco Applications, Modified Risk Tobacco Product

Applications, and Tobacco Product Manufacturing Practices” that would “lay out a transparent,

modern, and science-based framework for manufacturing practices and the development of

tobacco product applications that meet the legal requirements.” (Gottlieb, 2018).

8. It was not until three years later, on June 11, 2019, that FDA released the finalized

PMTA guidance document (FDA, 2019). This document describes on some level the types of

data and information that must be submitted in order to meet the Tobacco Control Act’s (TCA)

requirement that a new tobacco product be protective of public health. As discussed in the

guidance, a comprehensive assessment of each product requires an evaluation of the short and

long-term human health effects of ENDS on the population. These investigations include

product testing, environmental assessments, toxicological studies, and human subject research.

The findings must be generalizable to the U.S. population and include impacts on both users and

non-users of the product (FDA, 2019).

9. Although the final guidance provides some additional insight into how FDA is

going to evaluate the PMTAs, there are still many issues that have not been resolved. For

example, the PMTA applicant must demonstrate high standards for product quality through good

manufacturing practices (GMP), supply chain assessment, and product testing. Applicants must

also demonstrate through an environmental assessment that their products do not have significant

impacts on the environment. Stakeholders, however, are in a tenuous position, because FDA has


4

not issued guidance on GMPs or methods/assumptions that need to be incorporated in the

environmental assessment.

10. To add to the continued uncertainty, the final guidance does not provide

manufacturing or testing standards for devices or e-liquids. For instance, the FDA does not

provide a standard device or device settings for e-liquid manufacturers. The guidance also does

not recommend a standard liquid or set of liquids for open-tank device manufacturers. Instead,

the FDA recommended that applicants conduct tests that reflect a “reasonable range” of

conditions (FDA, 2019 p. 28). Without further direction, however, the applicant runs the risk of

falling short of what FDA expects to see in a PMTA.

11. These details are extremely important as the study design and number of variables

to test in non-clinical and clinical studies can greatly influence the costs and time to execute and

perform these studies. By way of example, there are several variables that could influence

toxicological and clinical study design, execution, and findings regarding product testing: e.g.,

power settings, airflow settings, humectant composition, flavors, nicotine concentrations, and

nicotine type (free base v. nicotine salts). Thus, under one possible interpretation of the final

guidance, a clinical study of a closed device with one power setting, one airflow setting, two

nicotine concentrations, one PG/VG ratio, and three flavors would result in having to test six

potential ENDS use scenarios with the study participants. This type of study design would likely

take 12 to 18 months to plan, perform, analyze and summarize for the PMTA.

12. Further, a clinical study of an open-tank device with two power settings, two

airflow settings, three flavors, three PG/VG ratios, and three nicotine concentrations would be

even more involved and result in 108 possible ENDS use scenarios. This type of study would

likely take several years to complete.


5

13. It is clear that as the number of use scenarios increases, the costs to conduct

clinical studies also increases and, particularly for smaller companies, could easily become

prohibitive. Therefore, having an understanding, before developing and filing the PMTA, of

what the FDA considers adequate for the range of appropriate testing conditions would be

invaluable to the FDA and the applicant in at least two ways: ensuring FDA gets the information

it needs to fairly evaluate the product and to set reasonable limitations on the required research

so that both parties can optimize the use of limited resources.

14. For those of us who are working to complete PMTAs, this means that FDA will

be required to spend a significant amount of time with each applicant (and the consultants and

technicians who are helping them) leading up to the PMTA’s submission to work through

numerous issues so that the application is appropriately robust and complete for a substantive

review by FDA. I was not surprised at all when I reviewed the final guidance to see FDA

repeatedly urging applicants to meet with the agency to discuss particular issues. As just one

example, the finalized guidance recommends that applicants “meet with the FDA to discuss the

approach prior to preparing and submitting an application.” (FDA, 2019 p. 13). This back and

forth will take months, at a minimum, to get the applicant in a place where it can actually

conduct the required studies and research knowing that their efforts will provide useful

information to FDA and satisfy the PMTA requirements.

15. The risks associated with incomplete information and any uncertainties regarding

the PMTA process can even be seen when a sophisticated company is involved. Recently, Philip

Morris became only the second manufacturer to successfully get a tobacco product (in this case,

a heat-not-burn product called IQOS) through the PMTA process. Philip Morris still conducted

studies that ultimately did not weigh into FDA’s evaluation and marketing authorization of the


6

IQOS product. This is a testament to just how complicated and time-consuming PMTA issues

can be for both FDA and the applicants.

16. Philip Morris provided its initial PMTA submission on May 15, 2017. Over the

course of the FDA’s evaluation, the agency communicated and requested additional information

and/or corrected reports 12 times. FDA provided a decision on the IQOS products on April 30,

2019. The process that was undertaken for the IQOS PMTA illustrates two points. First, it took

approximately two years for the FDA to review, provide feedback, and ultimately issue a

marketing authorization for the IQOS product.

17. Second, even with likely communications between the FDA and Philip Morris

throughout the entire application process, there was information included in the PMTA that the

FDA did not consider relevant. For instance, the FDA indicated that the pharmacokinetic studies

conducted in rats were not relevant for informing on human health effects. Philip Morris

conducted a 90-day nose only inhalation study of Sprague-Dawley rats to compare the effect of

exposure to the IQOS Heatsticks, a reference cigarette, and filtered air. The FDA stated “[i]n

vivo studies, such as the 90-day inhalation study, can provide important information about non-

cancer toxicology endpoints, but are not generally sensitive enough to determine systemic

toxicities from chronic tobacco product use.” (CTP IQOS, 2019 p. 38).

18. Philip Morris also conducted several in vitro systems toxicology studies with

human organotypic tissues; the FDA stated the following:

“The experimental approach taken in these studies included using methods that are

exploratory, have not been independently validated, and have unknown utility for

regulatory use. The applicant attempts to extrapolate from acute exposure studies with

naïve tissues that have little or no genetic variability to predict toxicity in a diverse


7

population with a history of cigarette smoking. This limits the use of these data. Thus,

this data does not significantly contribute to the overall toxicological profiles of the

products under review in these applications.” (CTP IQOS, 2019 p. 58).

19. The FDA also provided comments on studies that were not conducted but that

could have, according to FDA, been relevant to determining whether the IQOS product is

appropriately protective of public health. For example:

“No biomarker studies of secondhand exposure to these products were conducted by the

applicant. This type of study could have helped to better understand potential risks to

non-users. There were also no comparisons between IQOS and other tobacco products

(e.g., e-cigarettes). Given that IQOS and e-cigarettes may both be considered by

consumers to be a substitute for cigarettes, a comparison of the differences in exposure

would be useful.” (CTP IQOS, 2019 p. 56).

20. FDA’s comments on the IQOS PMTA are informative, but also lead to

questions/concerns for future PMTA submissions regarding the types of non-clinical and clinical

studies FDA will consider pertinent and informative to evaluate the public health impacts of

newly deemed tobacco products, including ENDS.

21. Further complicating matters, the final guidance recommends that applicants

conduct systematic reviews of “all relevant publications.” (FDA, 2019). New research on these

products is published daily. The National Academy of Science released their report on “Public

Health Consequences of E-Cigarettes” which evaluated over 4,000 publications from the peer-

reviewed literature published prior to February or August of 2017 (depending on topic area)

(NAS, 2018). Since the release of the NAS report, hundreds to thousands of papers have been


8

published in the peer-reviewed literature (Briganti et al. 2019) and the current publication rate

for articles that include the key word “e-cigarette” is over 100 articles per month.

22. These preliminary literature reviews are encouraged by the FDA. Due to the

abundance of available literature, systematic reviews require the applicant to review and evaluate

hundreds of articles for their specific product. Toxicology reviews include in vitro and in vivo

summaries for the following topic areas: carcinogenesis, genotoxicity, mutagencitiy, reactive

oxygen species, inflammation, cytotoxicity, cardiovascular effects, respiratory effects, and

reproductive and developmental toxicity. Epidemiology reviews include the following topic

areas: trends in usage, factors that influence ENDS usage (susceptibility, perception, initiation,

and transition), cessation, respiratory health, cardiovascular disease, biomarkers of harm and

exposure, pharmacokinetics, abuse liability, topography, and population health. These

systematic reviews allow applicants to identify bridging opportunities and data gaps, and informs

the strategic planning for product testing, toxicological evaluations, and human clinical subject

study designs. Needless to say, these reviews will take a significant amount of time and money

to complete, spanning weeks or more as the applicant puts its PMTA together.

23. In addition, even if publicly available studies can be located that are relevant to

the product at issue, it is likely that many product-specific studies will need to be conducted due

to all of these numerous and product-specific variables. For instance, devices contain different

types of components to aerosolize the e-liquid. The e-liquids may also contain any range of

humectant combinations between propylene glycol (PG) and vegetable glycerin (VG). E-liquids

may also consist of free-base nicotine or nicotine salts, with very different nicotine delivery

efficiency. Regardless of the protocols involved, testing all of these variables is expensive and

takes weeks, months, and potentially years to complete (Benson Affidavit, 2018).


9

24. Finally, lab capacity for product testing, in vitro tests, and clinical tests is also a

major concern for potential applicants. The labs should be accredited, follow good laboratory

practices, and have the research capabilities to conduct the necessary tests to demonstrate that an

e-cigarette is appropriately protective of public health. Not all laboratories have the capabilities

to perform all of the necessary testing. There are only a handful of laboratories across the

various research categories that have the experience and expertise to conduct these experiments.

As more and more applicants move forward with the PMTA process, laboratory capacity will

reach critical mass, making it impossible for future applicants to move forward with their

submissions in a timely fashion.

25. In the final analysis, we expect the typical PMTA application process – from the

initial planning stages to completion of FDA’s substantive review – to span at least 2 years, if not

more, depending on the tobacco products at issue. The estimated costs are anticipated to be in

the millions. All of this places a high premium on FDA providing predictability for the applicant

in terms of what is required in the PMTA process so that the company can manage risk, as well

as financial and time demands.

26. The process applicants must go through to demonstrate that their new tobacco

product (a device and/or e-liquid) is appropriate for the protection of public health is complex.

Both FDA and companies will need sufficient time to resolve complicated issues associated with,

among other things, protocols for testing and research. Providing rationale to and receiving

feedback from the FDA during the initial phase of the process will hopefully lead to high quality

PMTAs, but will nevertheless expand the timelines for the application process. For these

reasons, the current deadlines need to remain in effect (August 2021 and August 2022).


10

I declare under penalty of perjury that the foregoing is true and correct. Executed on

June 12, 2019.

STACEY M. BENSON, Ph.D.

References

Benson Affidavit, Am. Academy of Pediatrics v. FDA, Case No. 8:18-cv-883-PWG (Aug. 14,

2018) (Dkt. 37-4).

Briganti, M., Delnevo, C.D., Brown, L., Hastings, S.E. and Steinberg, M.B., 2019. Bibliometric

Analysis of Electronic Cigarette Publications: 2003–2018. International journal of

environmental research and public health, 16(3), p.320.

CTP IQOS. (2019). Center for Tobacco Control. Food and Drug Administration. Technical

Project Lead Review. Philip Morris New Tobacco Product PMTA Submission. Marlboro

Heatsticks, Marlboro Smooth Menthol Heatsticks, Marlboro Fresh Menthol Heatsticks, IQOS

System Holder and Charger. April 30, 2019. Accessed June, 2019.

https://www.fda.gov/media/124247/download.

Gottlieb, S. 2018. Advancing Tobacco Regulation to Protect Children and Families: Updates

and New Initiatives (August 2, 2018), https://www.fda.gov/news-events/fda-voices-perspectives-

fda-experts/advancing-tobacco-regulation-protect-children-and-families-updates-and-new-

initiatives-fda.

National Academies of Sciences Engineering and Medicine (NAS). (2018). Public Health

Consequences of E-Cigarettes. A Consensus Study Report. Accessed: June, 2019.

https://www.nap.edu/catalog/24952/public-health-consequences-of-e-cigarettes.

US Food and Drug Administration (FDA). (2016). Premarket Tobacco Product Applications for

Electronic Nicotine Delivery Systems. Guidance for Industry. Accessed: June, 2019.

https://www.fda.gov/media/97652/download.

US Food and Drug Administration (FDA). Draft Guidance: Premarket Tobacco Product

Applications for Electronic Nicotine Delivery Systems. Presentation by Paul Hart and Li-Lun

Chen. Accessed June 2019. https://www.fda.gov/media/97881/download.

US Food and Drug Administration (FDA). (2018). Guidance Document. Premarket Tobacco

Product Applications for Electronic Nicotine Delivery Systems (ENDS) Guidance for Industry.

May 2016. Accessed: June, 2019. https://www.fda.gov/regulatory-information/search-fda-

guidance-documents/premarket-tobacco-product-applications-electronic-nicotine-delivery-

systems-ends.


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