Court Opinion

ID: 9910168
Source: CourtListenerOpinion
Date Created: 2023-12-14 22:00:27.041406+00
Date Added: 2024-06-11T12:51:13.703134
License: Public Domain

United States Court of Appeals
                     For the First Circuit

No. 21-1080

                    UNITED STATES OF AMERICA,

                           Appellee,

                               v.

                        WILLIAM FACTEAU,

                      Defendant, Appellant.

No. 21-1082

                    UNITED STATES OF AMERICA,

                           Appellee,

                               v.

                        PATRICK FABIAN,

                      Defendant, Appellant.

         APPEALS FROM THE UNITED STATES DISTRICT COURT
               FOR THE DISTRICT OF MASSACHUSETTS

        [Hon. Allison D. Burroughs, U.S. District Judge]

                             Before

                   Gelpí, Lipez, and Thompson,
                         Circuit Judges.

     Reid H. Weingarten, with whom William Hassler, Shannen W.
Coffin, Bruce C. Bishop, Steptoe & Johnson LLP, Michael Pineault,
and Anderson & Krieger LLP were on brief, for appellant William
Facteau.

     Frank A. Libby, Jr., with whom Brian J. Sullivan, and Libby
Hoopes Brooks, P.C. were on brief, for appellant Patrick Fabian.

     Randall E. Kromm, Assistant United States Attorney, with whom
Nathaniel R. Mendell, Acting United States Attorney, was on brief,
for appellee.

     Joel Kurtzberg, Adam S. Mintz, John S. MacGregor, Jason
Rozbruch, Cahill Gordon & Reindel LLP, Cory L. Andrews, John M.
Masslon II, and Washington Legal Foundation on brief for Washington
Legal Foundation, amicus curiae.

     Douglas Hallward-Driemeier, Kelli B. Combs, Joan McPhee,
Ropes & Gray LLP, Paul E. Kalb, Coleen Klasmeier, Erika L. Maley,
and Sidley Austin LLP on brief for Amgen Inc., Biosplice
Therapeutics, Inc., Boehringer Ingelheim Pharmaceuticals, Inc.,
Bristol   Myers   Squibb   Company,  Eli   Lilly   and   Company,
GlaxoSmithKline LLC, Novartis Pharmaceuticals Corporations, and
Pfizer Inc., amici curiae.

     Jeffrey S. Bucholtz, Michael R. Pauzé, John C. Richter,
Alexander Kazam, and King & Spalding LLP on brief for Howard Root,
amicus curiae.

     Jeffrey L. Handwerker, Elisabeth S. Theodore, Samuel F.
Callahan, Arnold & Porter Kaye Scholer LLP, James C. Stansel,
Melissa B. Kimmel, and Kelly Goldberg on brief for Pharmaceutical
Research and Manufacturers of America, amicus curiae.

     Jeffrey L. Handwerker, Elisabeth S. Theodore, Samuel F.
Callahan, Arnold & Porter Kaye Scholer LLP, Daryl Joseffer, Andrew
R. Varcoe, and U.S. Chamber Litigation Center on brief for Chamber
of Commerce of the United States of America, amicus curiae.

                        December 14, 2023
           LIPEZ, Circuit Judge.          After a thirty-day jury trial,

appellants William Facteau and Patrick Fabian, former executives

of the medical device manufacturer Acclarent, Inc., were found

guilty of multiple misdemeanor violations of the Federal Food,

Drug, and Cosmetic Act ("FDCA") for commercially distributing an

adulterated and misbranded medical device. See 21 U.S.C. § 331(a).

The charges related to a device developed and sold by Acclarent

that the government alleged served an intended use different from

the one for which it had been cleared by the U.S. Food and Drug

Administration ("FDA").

           On appeal, appellants assert that their prosecutions

violated their First Amendment rights, relying on an emerging body

of law protecting commercial speech that promotes off-label uses

of medical products.     Appellants also argue that their convictions

violated due process under the Fifth Amendment.            Fabian further

contends that the jury was wrongly instructed about what evidence

it could consider, that the evidence was insufficient to support

his conviction, and that the $500,000 fine the court imposed on

him is excessive under the Eighth Amendment.

           We reject all of these claims and affirm.

                                     I.

           The FDCA strictly limits the ways in which manufacturers

may   market   medical   devices,    including    a   prohibition    on   the

distribution of "adulterated" or "misbranded" devices.              A device

                                    - 3 -
is adulterated or misbranded if its "intended use" -- as determined

objectively by the seller's statements and conduct -- differs from

the use(s) for which the FDA has cleared it.

           Facteau,       former      CEO     of   Acclarent,     and   Fabian,   the

company's former vice present of sales, played prominent roles in

the   marketing    of    a    new   device     for    the   treatment    of   chronic

sinusitis,   the       Relieva      Stratus    Microflow     Spacer     ("Stratus").

Acclarent obtained preliminary approval to market Stratus for use

as a "spacer" that would dispense a saline solution to the ethmoid

sinuses and maintain an opening created by sinus surgery.                     Facteau

and Fabian were convicted of unlawfully marketing Stratus to

dispense a steroid, an "off-label" (i.e. unapproved) use, and fined

$1 million and $500,000, respectively.

A. Legal Framework Governing Medical Devices

           The FDCA has prohibited the distribution of adulterated

or misbranded medical devices since its original enactment in 1938.

With the Medical Device Amendments of 1976 ("MDA"), Pub. L. No.

94-295, 90 Stat. 539, "[i]n response to the mounting consumer and

regulatory concern" over the lack of premarket review of medical

devices, Congress broadened the statute's coverage to regulate the

introduction      of    new   medical       devices    to   the   market   as   well.

Medtronic, Inc. v. Lohr, 518 U.S. 470, 476 (1996).                  This statutory

scheme classifies "devices intended for human use" based on the

level of risk to the public, with Class III devices presenting the

                                        - 4 -
most risk and correspondingly incurring the strictest regulation.

21 U.S.C. § 360c(a)(1)(C); see Lohr, 518 U.S. at 476-77; Buckman

Co. v. Plaintiffs' Legal Comm., 531 U.S. 341, 343-44 (2001).

Devices    not    on   the   market    before    1976    --   and   thus    all      new

devices -- are initially placed by default in Class III. 21 U.S.C.

§ 360c(f)(1).

               1. Premarket Approval and § 510(k) Clearance

               Class III devices       must receive "premarket approval"

("PMA") from the FDA before they can legally be marketed.                            See

§ 360e(a)(2).       The PMA process is "time-consuming," Buckman, 531

U.S. at 348, because it requires the device's manufacturer to

demonstrate a "reasonable assurance" that the device is safe and

effective, id. at 344.          See also Lohr, 518 U.S. at 477.

               A new device can avoid PMA review, however, if the FDA

clears    it    through   the   "premarket       notification"      or    "§ 510(k)"

process,1 which results in the device's reclassification from Class

III to Class I or II.        Lohr, 518 U.S. at 478-79.          A new device can

obtain    § 510(k)     clearance      if   the   FDA    determines       that   it    is

"substantially equivalent" to a predicate device -- that is, a

pre-1976 device or a post-1976 device that previously was moved

from Class III to Class I or II.                 See § 360c(f)(1)(A)(ii); 21

     1 The "§ 510(k)" label for the premarket notification process
reflects the original MDA section number for the process.      See
Lohr, 518 U.S. at 478. That provision of the MDA is now codified
at 21 U.S.C. § 360(k).

                                       - 5 -
C.F.R. § 807.92(a)(3); Buckman, 531 U.S. at 345.            A new device is

"substantially equivalent" to a predicate device if it (1) has the

"same intended use" and (2) either has the same technological

characteristics or the same safety and effectiveness profile.                21

U.S.C. § 360c(i)(1)(A); 21 C.F.R. § 807.100(b).

            At least ninety days before introducing a new device to

the market, a manufacturer seeking § 510(k) clearance must submit

a premarket notification to the FDA.         21 C.F.R. § 807.81(a).       This

premarket notification submission          includes a "510(k) summary"

identifying    the   predicate    device     and   describing      the   device

submitted for clearance, including its "intended use."               21 C.F.R.

§§ 807.87(h), 807.92(a)(3)-(5).2       The submission must also contain

"[p]roposed labels, labeling, and advertisements sufficient to

describe the [device submitted for clearance], its intended use,

and the directions for its use."       Id. § 807.87(e).

            2. "Intended Use"

            If the manufacturer of a device that is being marketed

after    receiving   § 510(k)    clearance    makes   a   "major    change   or

modification" in the device's intended use, the manufacturer must

     2 Instead of a 510(k) summary, the manufacturer may choose to
submit a "510(k) statement" certifying that, if the FDA concludes
that the device submitted for clearance is substantially
equivalent to a predicate device, the manufacturer will provide
safety and effectiveness information to support the FDA's finding
within thirty days of a written request.           See 21 C.F.R.
§§ 807.87(h), 807.93.

                                   - 6 -
submit another premarket notification at least ninety days before

marketing         the    device        for        the        new     use.        21   C.F.R.

§ 807.81(a)(3)(ii).            This new notification must include supporting

data       showing      that     the        manufacturer            has     considered      the

"consequences and effects the . . . new use might have on the

safety and effectiveness of the device."                           Id. § 807.87(g).

                 Whereas the FDA determines the intended use of a new

device based solely on the proposed labeling submitted with its

premarket        notification,        see    21    U.S.C.          § 360c(i)(1)(E)(i),       it

determines the intended use of a device already                                 cleared for

commercial distribution by reference to the "objective intent of

the persons legally responsible for the labeling" of the device

("labelers"),            21      C.F.R.       §      801.4         (2020).3        Labelers'

"expressions" -- such as "labeling claims, advertising matter, or

oral        or     written       statements             by     [labelers]        or       their

representatives" -- are one source of evidence for determining

their "objective intent."              Id.        Labelers' "objective intent" may

also       be    established     by    the        "circumstances            surrounding     the

distribution" of the device.                 Id.

       We refer to the version of the regulation governing the
       3

"intended use" of devices already on the market that was in effect
at the time appellants took the actions underlying their
convictions.   The regulation was revised in August 2021.      See
Regulations Regarding "Intended Uses", 86 Fed. Reg. 41401-02 (Aug.
2, 2021) (codified at 21 C.F.R. § 801.4).

                                             - 7 -
          3. Adulteration, Misbranding, and Off-label Use

          The FDCA prohibits the "introduction or delivery for

introduction             into       interstate            commerce          of

any . . . device . . . that is adulterated or misbranded."                  21

U.S.C. § 331(a).      Violating this prohibition "with the intent to

defraud or mislead" is a felony; a violation absent such intent is

a misdemeanor.       Id. §§ 333(a)(1)-(2).          Misdemeanor offenses of

commercially distributing adulterated or misbranded devices are

strict-liability crimes.        United States v. Dotterweich, 320 U.S.

277, 284 (1943).

          A device is "adulterated" under § 351(f)(1)(B) if, as a

Class III device, it is "required to have in effect an approved

application    for   premarket     approval"   but    moves   in   interstate

commerce without the required PMA.             See also United States v.

Universal Mgmt. Servs., Inc. Corp., 191 F.3d 750, 754 (6th Cir.

1999).   When a device that received an initial § 510(k) clearance

is marketed for an intended use that represents a "major change or

modification" from the cleared use without clearance for that

change, the device is also considered "adulterated."                 21 C.F.R.

§ 807.81(a)(3)(ii).       As relevant here, a device is "misbranded" if

the manufacturer fails to submit a "notice" to the FDA "as required

by . . . section 360(k)."          21 U.S.C. § 352(o).          The "notice"

referenced    by   the   statute   is   the   new   premarket   notification

required when a device that previously received § 510(k) clearance

                                    - 8 -
is about to have a "major change or modification in [its] intended

use."    21 C.F.R. § 807.81(a)(3)(ii).

           In sum, it is unlawful for a manufacturer to commercially

distribute a device for an intended use that represents a "major

change or modification" from the specific use for which the device

received   § 510(k)   clearance.        Such   off-label    marketing   would

amount to the commercial distribution of an "adulterated" and

"misbranded" device. At the same time, however, the FDCA expressly

protects the "authority of a health care practitioner to prescribe

or administer any legally marketed device to a patient for any

condition or disease . . . ."           21 U.S.C. § 396.4      Accordingly,

medical professionals may lawfully prescribe and administer a

device for an off-label use as long as that device has received

§ 510(k) clearance for any intended use.          See Buckman, 531 U.S. at

350; Judge Rotenberg Educ. Ctr., Inc. v. U.S. Food & Drug Admin.,

3 F.4th 390, 395 (D.C. Cir. 2021).         The statutory and regulatory

scheme   governing    medical   devices    thus    limits   the   commercial

distribution of devices to ensure that devices on the market are

reasonably   safe    and   effective,    while    preserving   health   care

     4 We note that this section of the FDCA does contemplate some
limitations on the authority conferred on health care providers
with respect to "legally marketed device[s]." Section 396 states
that the FDA's mandate not to interfere with the practice of
medicine does not limit the agency's authority "to establish and
enforce restrictions on the sale or distribution, or in the
labeling, of a device . . . ." 21 U.S.C. § 396.

                                   - 9 -
professionals' discretion to prescribe and administer devices as

they deem appropriate.      See Buckman, 531 U.S. at 349-50.

B. Factual Background

          Appellants'    various    claims    on    appeal    require   us   to

present the facts from two different perspectives.                 See United

States v. Burgos-Montes, 786 F.3d 92, 99 (1st Cir. 2015).                 When

recounting      the      evidence           relevant          to     Fabian's

sufficiency-of-the-evidence challenges, we take the facts in the

light most favorable to the verdict.          See United States v. Chan,

981 F.3d 39, 45 (1st Cir. 2020).       For the other issues on appeal,

we present the facts in a "balanced" way, taking an "objective[]

view" of the evidence in the record.          Burgos-Montes, 786 F.3d at

99 (first quoting United States v. Felton, 417 F.3d 97, 99 (1st

Cir. 2005); then quoting United States v. Nelson-Rodríguez, 319

F.3d 12, 23 (1st Cir. 2003)).

          1. Development and Design of Stratus

          Acclarent   was    founded   in    2004   as    a   medical   device

manufacturer focusing on devices for use in ear, nose, and throat

("ENT") care.   Facteau served as Acclarent's CEO from November

2004 to December 2011, and Fabian was the company's vice president

of sales from August 2007 to November 2011.              Since its founding,

Acclarent's core products have been devices for use in balloon

                                 - 10 -
sinuplasty, a surgical technique to treat chronic sinusitis by

dilating the sinus openings with a small balloon.5

          However,   sinusitis    in   the   ethmoid   sinuses   is   not

treatable with balloon sinuplasty.        As early as 2005, therefore,

the members of Acclarent's Scientific Advisory Board ("SAB"), led

by Facteau, discussed the possibility of developing a device that

could provide relief for ethmoid sinusitis by delivering Kenalog-

40 ("Kenalog") -- a topical steroid commonly used to reduce sinus

inflammation -- directly to the ethmoid sinuses. These discussions

culminated in the January 2006 approval by Facteau and other

Acclarent officers of a project aimed at developing an "Ethmoid

Sinus Stent" that, in the words of the project specification

prepared as a roadmap for the design process, would be able "to

deliver . . . Kenalog 40 for a duration of 14 days" "to the ethmoid

[sinuses]."

          This project led to the design of a device that was

ultimately marketed as Stratus.           The device featured a small

balloon that was perforated with many tiny pores and was attached

to a catheter.   The device would be inserted, with the balloon

     5 Sinusitis is the inflammation of the mucus membranes of the
paranasal sinuses, see Stedman's Medical Dictionary 1777 (28th ed.
2006), which are paired air-filled cavities in the bones of the
face lined by mucous membranes, id. at 1776. Balloon sinuplasty
is offered as a less invasive surgical treatment for sinusitis
than traditional endoscopic sinus surgery, which involves removal
of tissue and bone.

                                 - 11 -
uninflated, into the ethmoid sinus cavity by means of an access

probe.   Once in situ, the balloon could be inflated by injecting

a substance into it through the catheter.     When the balloon was

filled in this way with Kenalog, the steroid would gradually

diffuse out of the pores and bathe the ethmoid cavity over a

roughly two-week period. The size of the pores had been calibrated

to Kenalog's viscosity to achieve this result.     Indeed, the SAB

discussed the importance of fine-tuning the pore size to ensure

that, when inflated with Kenalog specifically, the steroid would

not leak out of the balloon too quickly.

          2. Regulatory history of Stratus

          Although the Stratus device was designed for use in

treating ethmoid sinusitis by delivering Kenalog to the ethmoid

sinuses, the SAB and the project team, with Facteau's approval,

decided to pursue a regulatory strategy of first gaining § 510(k)

clearance for the device for use as a post-surgical spacer capable

of releasing saline, and later seeking a second § 510(k) clearance

for use as a system to deliver Kenalog to the ethmoid sinuses.

          In line with this strategy, Acclarent filed a premarket

notification in August 2006, seeking § 510(k) clearance to market

Stratus for use "as a postoperative spacer to maintain an opening

to the ethmoid sinus within the first 14 days following surgery"

and to "help[] to prevent obstruction."      Acclarent's submission

identified the Rains Frontal Sinus Stent as the predicate device.

                              - 12 -
That device, which Acclarent stated was "substantially equivalent"

to   Stratus      "in    indications      for        use     and   technological

characteristics," is a spacer designed to minimize the post-

operative    formation      of   adhesions      in    the    frontal    sinus   by

maintaining an opening in the frontal sinus in the days following

surgery.    In addition to use as a similar post-operative spacer in

the ethmoid sinuses, Acclarent's submitted "Instructions for Use"

for Stratus contemplated that, after the device had been inserted

into the patient's ethmoid sinuses, the user would inject saline

through    the   catheter    into   the   perforated        balloon    and,   after

trimming away the catheter shaft, leave the device in place for up

to fourteen days to "allow[] saline to moisten the [surrounding]

area."     In September 2006, the FDA cleared Stratus for the use

indicated in Acclarent's premarket notification.

            Although Acclarent's § 510(k) submission specifically

contemplated that Stratus would be used with saline to moisten the

ethmoid sinuses, it was understood by the SAB that the pores in

the balloon were too large to allow saline -- a much less viscous

fluid than Kenalog -- to gradually seep out over a two-week period.

Rather, when injected, saline would rapidly flow out.                  The amount

of saline that could fit in the Stratus balloon was also too small

to be of much therapeutic value.

            Consistent      with     Acclarent's           two-step    regulatory

strategy, it wrote to the FDA in April 2007 seeking to change

                                    - 13 -
Stratus's labeling to add an indication to use Stratus "to irrigate

the   sinus    space   for   diagnostic   and   therapeutic   procedures."

Acclarent also sought to modify the instructions for use to state

that the user could inject either saline or some "other therapeutic

agent" into the catheter to inflate the balloon.

              The following month, the FDA denied Acclarent's request.

The FDA sent a letter to Acclarent communicating that the proposed

use of Stratus with a therapeutic agent might render it a drug-

device "combination product" under 21 C.F.R. § 3.2(e), and hence

subject to review both as a drug and as a device.         The letter also

made clear that, even if the use of Stratus with a therapeutic

agent did not render it a combination product, the proposed changes

to the device's indications for use signaled a significant change

or modification in the intended use of the device such that

Acclarent would "need to submit a new 510(k)" and receive FDA

clearance "prior to marketing [Stratus]" with the proposed changes

in intended use.

              Notwithstanding this setback, in September 2007, with

Facteau and Fabian in attendance, the steering committee tasked

with developing and commercializing Stratus approved a proposal to

market Stratus as a product to deliver Kenalog to the ethmoid

sinuses, with plans for a commercial launch in the third or fourth

quarter of 2008.       The committee recognized that for a commercial

launch, Acclarent needed -- but lacked -- regulatory approval for

                                   - 14 -
Stratus's use with a drug delivery indication.                 To that end, the

committee made plans to submit a premarket notification seeking

§ 510(k) clearance to market Stratus for drug-delivery use, with

the first quarter of 2008 as an optimistic target timeline.

            By   November    2007,     Acclarent     had     concluded    that   a

successful § 510(k) submission for Stratus to be used for drug

delivery    purposes    would   need   to     be   supported    by   appropriate

clinical studies.       But the clinical study Acclarent was conducting

had to be halted when, in December 2007, the FDA determined that

it posed a significant risk to its subjects. To proceed, Acclarent

needed to submit a proposal for a new study for the FDA's approval.

Although the FDA approved a new study in August 2008, it too was

halted -- in     July    2009 -- after      reports     of     adverse    events.

Ultimately, Acclarent never completed an approved study to support

Stratus's use with Kenalog and thus never filed a premarket

notification for that intended use.

            3. Stratus Enters the Market

            Despite the lack of § 510(k) clearance for Stratus to be

used with Kenalog, Acclarent proceeded with the plan to begin

marketing the device for that use in the second half of 2008.                  With

Facteau's    approval,     Acclarent    promoted     Stratus     for     use   with

Kenalog at the July 2008 meeting of the Sinus Forum, an annual

conference fully sponsored at the time by Acclarent, which Facteau

and Fabian both attended.        One panel session featured, via video

                                     - 15 -
feed, live demonstrations of Stratus by two surgeons, Dr. Douglas

Hoisington    and   Dr.     Michael    Friedman,       whose   display    included

filling the balloon with Kenalog.          The panel members explained how

Stratus was designed to allow Kenalog to escape gradually into the

ethmoid cavity while the device was in situ.               Hoisington, a member

of Acclarent's SAB, also indicated that Stratus was not suited for

its   cleared    use   by   demonstrating        how    saline     solution   would

immediately run out of the device upon injection.                       Hoisington

explained that the perforations in the balloon were designed to be

small enough so that Kenalog, a more viscous fluid, would seep out

slowly.    This live demonstration of Stratus was included in the

2008 Sinus Forum at Facteau's direction.                 Facteau's goal was to

showcase    Stratus's     use   with    Kenalog,       although    Hoisington   and

Friedman themselves made the ultimate decisions to go ahead with

their demonstrations.

            Around this time, Acclarent                also began commercially

distributing Stratus on a limited market release, selling the

device on a trial basis within a small number of sales territories

and to a select group of doctors.               The limited launch of Stratus

was   a   commercial    success.        Acclarent's       management     therefore

decided to      expand the      marketing of Stratus to all potential

customers.      Leading up to this full commercial launch, Facteau

emailed several members of the SAB with a slide presentation on

how Stratus would be commercially positioned.                     The presentation

                                       - 16 -
described Stratus as "simply a way to obtain sustained drug

delivery to [a] targeted sinus or sinus complex."               In this period,

Facteau and Fabian also participated in a conference call with

some of Acclarent's sales and training personnel, during which

Facteau spoke about presenting Stratus to ENT surgeons as a way of

delivering Kenalog to the ethmoid sinuses.

             Acclarent     launched       Stratus       for   full     commercial

distribution at the 2008 meeting of the American Academy of

Otolaryngologists        and     American        Rhinologic    Society         ("AAO

conference"), which took place in September 2008.                As the annual

meeting of the major professional organization for ENT surgeons,

the    AAO    conference       provides     an     opportunity       for   device

manufacturers to set up booths to exhibit their products and share

information     about    these    products       with    potential     customers.

Acclarent's booth was divided into two sides, one staffed by sales

representatives focused on selling to the U.S. market, the other

by    representatives    focused    on    the    international       market.      As

directed by Acclarent regulatory officers, representatives on the

U.S. side refrained from discussing off-label uses for Stratus,

although the U.S.-side representatives also did not discuss or

demonstrate Stratus for use as a spacer with saline.                    U.S.-side

representatives were instructed to send attendees who asked about

the uses for Stratus to the international side. The international-

                                    - 17 -
side representatives would then share information about using

Stratus for delivering Kenalog.

          4. Internal Training of Sales Representatives

          Acclarent required newly hired sales representatives to

complete a month-long training program, including two weeks of

on-site training, where they would learn how to promote Stratus

and other Acclarent products.     Fabian led some of the training

sessions and generally attended throughout to supervise.   Facteau

also spoke and gave a presentation at some of these sessions.

Trainees were taught how to present Stratus to ENT surgeons who

were potential customers for the product by describing Stratus's

features and benefits and how to operate it.

          The sales training staff and other presenters repeatedly

conveyed to new hires that Stratus was designed to be used, and

was expected to be used by most surgeons, to deliver Kenalog.

Trainees were not taught about any clinical benefit that Stratus

could provide when used as a spacer with saline, and they were

trained to tell surgeons that although Stratus was cleared for use

in the United States only as a spacer with saline, it was approved

for use with Kenalog in Europe.       In addition, new hires were

advised to ask surgeons "probing" or leading questions that would

                             - 18 -
prompt the surgeons to inquire about Stratus's potential use for

steroid delivery to the sinuses.6

           Acclarent also provided sales representatives with a

document -- reviewed and approved by Acclarent officers including

Fabian -- to   guide    them   in    discussing   Stratus    with    potential

customers and to "help them understand what they can and can't say

about . . . Stratus"     and   its    intended    use.      This    "physician

discussion guide"      recommended that      sales representatives        tell

surgeons that, although Stratus was cleared only for use with

saline, Acclarent "expect[ed]" that some surgeons "may want to

infuse the device with a therapeutic fluid, steroid, antibiotic,

antifungal, instead of saline."          The guide also noted that "the

only agent that works optimally with [Stratus] is [Kenalog]."               By

contrast, the guide provided no suggestions on how to explain the

clinical benefit of using Stratus to deliver saline.                The guide

also included "probing questions" that sales representatives might

use to invite inquiries from surgeons about using Stratus with

Kenalog.

     6 Facteau maintains that this training was properly designed
to allow sales representatives to discuss using Stratus with
Kenalog while remaining within the FDA's safe-harbor policy, which
excludes manufacturer communications about off-label use of
products from being considered evidence of a new intended use if
those communications occur in response to unsolicited inquiries
from health care professionals. See infra Section II.A.

                                    - 19 -
               Particularly       successful        sales    representatives       were

invited by the sales team management, including Fabian, to share

their    sales      techniques       and     marketing      materials    with   other

representatives.           The promotional slide presentation for Stratus

used    by    one   such      top-performing        sales   representative,     Jason

Elmore, was widely shared in this way. This presentation described

Stratus as "designed to elute Kenalog-40," that is, designed to

allow the steroid to diffuse gradually out of the device.

               5. Promoting Stratus for Sale

               The Acclarent sales representatives who testified at

trial reported that they were never given marketing materials for

Stratus that described benefits from using the device as a spacer

with saline.        By contrast, Acclarent made available a video for

representatives to use in their pitches that depicted a surgeon

implanting Stratus and filling the balloon with Kenalog. Acclarent

also     provided         "sell    sheets" -- reviewed          and     approved     by

Fabian -- that           sales    representatives       could    use    in   pitching

Stratus.       These sell sheets included a picture of Stratus that

appeared to show the balloon filled with Kenalog.

               The Acclarent sales representatives who testified about

how they promoted Stratus to their customers uniformly stated that

their pitches positioned Stratus as a device to deliver Kenalog,

rather       than   as    a   spacer   with    saline.        This     testimony   was

corroborated by testimony from multiple ENT surgeons who had been

                                           - 20 -
approached by Acclarent sales representatives about Stratus.    The

surgeons testified that the sales pitches they received positioned

Stratus as a device for delivering Kenalog, not for use as a spacer

with saline.

           These sales pitches bore abundant fruit.      From 2008,

when Stratus was brought to market, until 2011, the final year

appellants were employed at Acclarent, the gross revenue Acclarent

earned from sales of Stratus totaled $33.5 million.

           6. Training for Surgeons Who Bought Stratus

           Acclarent provided training on how to use Stratus for

the surgeons who    ordered the device.     The training sessions

featured both slide presentations and a laboratory-based segment

where participating surgeons had the opportunity to practice using

the technology with cadaver heads or anatomically correct model

heads.   Although the Acclarent trainers would inform participating

surgeons that Stratus was cleared for use as a spacer with saline,

the slide presentations did not describe how to use Stratus for

its cleared use.    They did, however, tell surgeons how to use

Stratus with Kenalog.   For example, one slide in the standard deck

used for these training presentations featured a depiction of

Stratus with the balloon filled with Kenalog.   Fabian reviewed and

approved this slide deck.   During the laboratory-based segment of

the training sessions, participating surgeons would usually learn

                               - 21 -
to use Stratus by filling the balloon with Kenalog or coffee

creamer, a substance that looks like the steroid.7

             In line with this training and the sales pitches they

received from Acclarent's sales representatives, the surgeons who

bought Stratus predominantly used it off-label to deliver Kenalog

or   some   other   drug.         Acclarent    was   aware   that   Stratus   was

predominantly being used off-label since it notified the FDA of

this fact in a March 2010 letter.8

C. Procedural History

             In April 2015, a grand jury returned an eighteen-count

indictment against Facteau and Fabian.                 In addition to counts

alleging     conspiracy,     securities       fraud,   and   wire   fraud,    the

indictment     included     ten    counts     specifically   directed   to    the

unlawful off-label promotion of Stratus.                 Five counts charged

appellants with commercially distributing an adulterated device

with the intent to defraud and mislead in connection with five

shipments of Stratus between October 2009 and February 2011.                  See

      7   Saline solution, by contrast, is clear.
      8 The Acclarent sales representatives who testified all
reported that they only knew of surgeons who used the device with
Kenalog and were aware of no surgeons who used it with saline.
The record, however, does contain evidence of at least one doctor
who used Stratus for its cleared use. Dr. Hoisington, a member of
the Acclarent SAB, testified that he used Stratus as a post-
operative spacer with saline in about 15 percent of the procedures
he performed with the device. At other times, he used Stratus with
an antifungal solution, an antibiotic solution, or Kenalog.
Hoisington's most common use for Stratus was to deliver Kenalog.

                                      - 22 -
21 U.S.C. §§ 331(a), 333(a)(1)-(2), 351(f)(1)(B).            Another five

counts charged them with commercially distributing a misbranded

device with the intent to defraud and mislead in connection with

five other shipments of Stratus between December 2009 and May 2011.

See id. §§ 331(a), 333(a)(1)-(2), 352(a), 352(f), 352(o).                The

charges    for   distributing   a    misbranded   device    alleged   three

theories    of   misbranding:   false    and   misleading    labeling,    in

violation of § 352(a); inadequate directions for use, in violation

of § 352(f); and failure to file a required premarket notification,

in violation of § 352(o).       The securities fraud charges and one

wire-fraud count were dismissed on the government's motion before

trial.

            After a thirty-day trial spanning June and July 2016,

the jury acquitted      Facteau and Fabian        of the conspiracy      and

remaining wire fraud counts but returned guilty verdicts on all

ten counts charging them with distribution of an adulterated and

misbranded device.9     However, the jury found that appellants had

not committed those violations with the intent to defraud or

mislead, thus finding them guilty only of the misdemeanor form of

the offenses.

     9 With regard to the misbranding counts, the jury found that
the government had proven misbranding for lack of regulatory
clearance but had not proven its theories based on false or
misleading labeling or inadequate directions for use.

                                    - 23 -
           In August 2016, appellants jointly moved for judgments

of acquittal.      See Fed. R. Crim. P. 29(c).             In challenging their

convictions,     appellants     raised     five    claims     relevant    to   this

appeal:   (1) their       convictions     were     based     on   truthful,    non-

misleading speech, thereby infringing their rights under the First

Amendment;      (2) the    regulatory     scheme     under    which     they   were

convicted is unconstitutionally vague; (3) the jury was improperly

instructed on the evidence that may be considered in determining

a device's intended use; (4) they lacked fair notice of the case

against them, and thus were denied                 due process,       because the

government proceeded on a novel prosecutorial theory and relied on

internal company communications as evidence of intended use; and

(5) the government presented insufficient evidence of statements

promoting off-label use made by them or by Acclarent employees

with respect to the ten shipments of Stratus that grounded their

convictions.

           Rejecting these and other claims, the district court

denied    appellants'       motion   in    September       2020.       The     court

subsequently imposed a $1 million fine on Facteau and a $500,000

fine on Fabian.     Appellants' timely appeals followed.

                                        II.

           On     appeal,    Facteau      and     Fabian    reiterate     numerous

objections to their convictions, with some claims of error raised

                                     - 24 -
jointly and others raised only by one of them.10             Fabian also

challenges the amount of his fine. We begin with appellants' First

Amendment   claims   and   then   consider   in   turn   their   arguments

concerning the statutory concept of "intended use."11           Finally, we

address Fabian's remaining claims, which challenge the sufficiency

of the evidence and -- based on the Eighth Amendment's Excessive

Fines Clause -- his $500,000 penalty.

A. First Amendment Claim

            Facteau's First Amendment attack on his conviction takes

the form of an instructional challenge.             He argues that the

district     court   improperly      refused      appellants'     proposed

instruction, which would have prevented the jury from considering

any truthful, non-misleading promotional speech as evidence of the

intended use of Stratus.     Instead, the court instructed the jury

that it could consider such speech.          Facteau maintains that the

court erred for two reasons.       First, using promotional speech as

evidence of intended use in effect criminalizes that speech, in

     10Fabian incorporated by reference the arguments asserted in
Facteau's brief. See Fed. R. App. P. 28(i). Hence, although for
clarity's sake we discuss certain arguments as made by Facteau,
our discussion of those arguments applies to both appellants. On
the other hand, because Facteau did not join Fabian's brief, our
discussion of issues raised by Fabian alone applies only to him.
     11 Fabian argues that as a matter of text and precedent,
"intended use" encompasses only promotional speech, and thus the
district court's instruction to the contrary was error.       Both
appellants argue that the government's interpretation of "intended
use" violates due process.

                                  - 25 -
contravention of a growing body of law in the Second Circuit

holding that truthful, non-misleading speech promoting off-label

use is protected.   Second, because the FDA has adopted a policy

that shields certain non-promotional speech from evidentiary use,

allowing speech outside of this safe harbor to serve as evidence

imposes an impermissible content-based burden on           "disfavored"

speech, especially off-label promotional statements.

          After reviewing the district court's instructions and

important background First Amendment principles, we consider each

of these arguments in turn.

          1. Background

          At   trial,     appellants     proposed   that   the   court's

instructions on the adulteration and misbranding charges include

the statement that "truthful, non-misleading statements cannot

give rise to a new intended use."      The court declined to give that

instruction.   Instead, it told the jurors that, because "[i]t is

not illegal in and of itself for a device manufacturer to provide

truthful, not misleading information about an off-label use," they

may not find a defendant guilty "based solely on truthful, non-

misleading statements promoting an FDA-cleared or approved device,

even if the use being promoted is not a cleared or approved use."

Nevertheless, the court continued, jurors could consider truthful,

non-misleading speech promoting off-label use as "evidence" in

determining "whether the government has proved each element" of

                                - 26 -
the charged adulteration and misbranding offenses, "including the

element of intent."       Appellants objected to the court's "failure

to instruct the jury that truthful speech cannot be considered as

evidence of intended use."

             2. Legal Analysis

             Facteau appears to take issue both with the district

court's rejection of appellants' proffered instruction, as well as

the instruction the court ultimately delivered to the jury. Where,

as here, we consider a preserved claim that the trial court's

instruction misstated the law, we review the court's instruction

de novo.     United States v. Florentino-Rosario, 19 F.4th 530, 534

(1st Cir. 2021).      We test whether the district court's refusal to

give   appellants'      requested   instruction     constituted   reversible

error by asking if that instruction was "(1) substantively correct

as a matter of law, (2) not substantially covered by the charge as

rendered, and (3) integral to an important point in the case so

that   the   omission    of   the   instruction   seriously    impaired   the

defendant's ability to present his defense."               United States v.

McLellan, 959 F.3d 442, 467 (1st Cir. 2020) (quoting United States

v. Baird, 712 F.3d 623, 628 (1st Cir. 2013)).                 We review the

instruction     the   trial    court   did   give    for   whether   it   was

"(1) misleading, unduly complicating, or incorrect as a matter of

law; and (2) adversely affected the objecting party's substantial

rights."     United States v. Figueroa-Lugo, 793 F.3d 179, 191 (1st

                                    - 27 -
Cir. 2015) (quotation marks omitted) (quoting United States v.

Stark, 499 F. 3d 72, 79 (1st Cir. 2007)).    In the present appeal,

the question    under both inquiries    boils down to whether the

district court erred because it should have instructed the jurors

that they could not consider promotional statements as evidence of

Stratus's intended use, rather than instructing the jurors that

they could.

          To answer that question, we must note at the outset that,

as a general matter, the First Amendment does not apply to the

"evidentiary use of speech to establish the elements of a crime or

to prove motive or intent."    Wisconsin v. Mitchell, 508 U.S. 476,

489 (1993). In Mitchell, the Court held that an aggravated battery

defendant's First Amendment rights were not violated by using his

statements to prove the racial motive that made him eligible for

a sentence enhancement.     See id. at 489-90.    In reaching that

conclusion, the Court did not analyze whether this evidentiary use

of the defendant's speech could satisfy some heightened standard

of scrutiny.    Rather, the Court concluded that there was no First

Amendment violation because the use of a defendant's speech as

proof of his motive or intent simply does not implicate the First

Amendment.    Id. at 489.

          Facteau's First Amendment argument is in obvious tension

with the Court's holding in Mitchell.        For the crux of his

instructional error claim, he argues that because a manufacturer's

                               - 28 -
truthful, non-misleading speech promoting the off-label use of a

device is protected under the First Amendment, the district court

should have instructed the jury that, in effect, it may not

consider any such speech as evidence of the device's intended use.

To do otherwise, the court's instruction would need to withstand

heightened scrutiny, which Facteau argues it could not.              But, as

indicated, Mitchell makes clear that the First Amendment offers no

protection against using otherwise protected speech as evidence of

intent or to establish the elements of a crime.              Facteau offers

two explanations for why the Court's holding in Mitchell does not

reach this case, and hence appellants' proposed instruction was

compelled by the First Amendment.

          i.   Whether Using Promotional Speech as Evidence of
Intended Use De Facto Criminalizes That Speech

             Facteau first argues that the First Amendment does not

permit   the   factfinder    here   to   consider    off-label   promotional

speech as evidence of intended use by pointing to the Second

Circuit's decision in United States v. Caronia, 703 F.3d 149 (2d

Cir. 2012), and its progeny in Amarin Pharma, Inc. v. FDA, 119 F.

Supp. 3d 196 (S.D.N.Y. 2015).       In a significant decision limiting,

for the first time, the use of off-label promotional speech in the

context of misbranding prosecutions, the court in Caronia held

that   the   defendant's    conviction    violated    the   First   Amendment

because the prosecution "repeatedly argued that [he] engaged in

                                    - 29 -
criminal conduct by promoting and marketing the off-label use

of . . . an FDA-approved drug," leaving "the jury to understand

that [his] speech was itself the proscribed conduct."             703 F.3d at

161.        Because it found that the defendant "was prosecuted [for]

precisely his speech in aid of pharmaceutical marketing," id. at

162, the court applied heightened scrutiny under Central Hudson

Gas & Electric Corp. v. Public Service Commission of New York, 447

U.S. 557 (1980), and concluded that the prosecution did not survive

that standard, Caronia, 703 F.3d at 164-69.12

               Taking   his   cue   from   Caronia,   Facteau   contends   that

permitting the jury to consider his off-label promotional speech

in assessing his guilt under the FDCA amounts to the de facto

criminalization of his protected speech, creating a "backdoor"

through which the government may sneak past the First Amendment's

reach and punish appellants simply for the things they said about

Stratus.       In Caronia, the government argued, as it does here, that

it was merely relying on the defendant's speech as evidence of his

intended use for the drug, rather than punishing him for his

        Applying Caronia as binding precedent, the district court
       12

in Amarin sided with a drug manufacturer in its pre-enforcement
challenge against the FDA, declaring that the manufacturer had a
First Amendment right to "engage in truthful and non-misleading
speech promoting the off-label use of [its product]" and that "such
speech may not form the basis of a prosecution for misbranding."
119 F. Supp. 3d at 237.

                                      - 30 -
speech.13 See 703 F.3d at 160-62. While stressing that its opinion

did not question the general principle that speech can constitute

evidence of intended use, the Caronia majority was not persuaded

that the government's use of speech was limited to evidentiary

purposes in that case.      Id.   It pointed, among other things, to

the government's sole reliance on the defendant's statements to

establish his criminal liability, the government's profligate use

of his statements in its summation to the jury, and the court's

jury instructions, which "flatly stated . . . that pharmaceutical

representatives     are   prohibited   from   engaging   in   off-label

promotion" and "left the jury to understand that Caronia's speech

was itself the proscribed conduct."        Id. at 161.   It also bears

emphasis that the defendant in Caronia was a sales representative,

whose sole job function was to make promotional statements about

the product.      Moreover, the government's theory of misbranding

focused on the defendant's statements promoting off-label uses and

the consequence that the drug's labeling did not bear "adequate

directions for use."      See 21 U.S.C. § 352(f)(1).

     13 Likewise, in dissent, Judge Livingston posited that the
government's reliance on the defendant's speech served no purpose
other than as evidence of the drug's intended use, and she pondered
whether, under the majority's rule, any prosecution could rely on
off-label promotional speech as evidence of the defendant's
intended use for a potentially misbranded product. Caronia, 703
F.3d at 172-77.

                                  - 31 -
            Though Facteau's reliance on Caronia is understandable,

that case is meaningfully different from the one at hand and

provides us with no basis to depart from the rule in Mitchell that

the evidentiary use of speech does not violate the First Amendment.

Unlike in Caronia, the government's case here relied on a wide

array of evidence, which included not only promotional speech about

off-label    uses    but    also     internal   communications         regarding

regulatory   and    marketing      strategy   and    the   product's    physical

design.     It is not the case, as it was in Caronia, that the

government set out to punish appellants for what they said about

the product; rather, what appellants said about Stratus simply

shed light on how they intended it to be used.                   The district

court's instructions made as much clear, specifying that "[i]t is

not illegal in and of itself for a device manufacturer to provide

truthful, not misleading information about an off-label use" and

that the jury may not find a defendant guilty "based solely on

truthful, non-misleading statements promoting an FDA-cleared or

approved device, even if the use being promoted is not a cleared

or approved use."

            Moreover,      the   government's       successful   theories    for

misbranding and adulteration did not turn on whether Acclarent's

statements left Stratus without adequate directions for use, as

was the case in Caronia.         Though the government did present that

theory of misbranding to the jury, the jury rejected that approach

                                     - 32 -
and instead found appellants guilty of misbranding because Stratus

lacked the proper regulatory clearance -- a theory of misbranding

less   intertwined   with    appellants'   speech.     And,   unlike   the

defendant in Caronia, both Facteau and Fabian were high-level

executives at Acclarent responsible not just for what was said

about Stratus publicly but also for internal decisions on product

design and regulatory strategy (in the case of Facteau), as well

as sales strategy (in the case of both).

            In short, Caronia does not render appellants' proposed

instruction an accurate statement of law that properly captured

the nuances of the First Amendment interests at stake in this case.

Calculated to cut off any evidentiary use of off-label promotional

speech, appellants' preferred instruction would have removed this

case from the teachings of Mitchell and placed it within the domain

of Caronia without the facts to justify such a move.          We discern

no error in the district court's refusal to take that step, nor in

the instructions it ultimately handed down, which better respected

the    sensitive   balance   between   protecting    promotional   speech

without shielding such speech from evidentiary value.

            In so holding, we note that we are in alignment with our

sister circuits -- including the Second.        The courts to consider

the issue have uniformly concluded that using speech merely as

evidence of a misbranding offense under the FDCA does not raise

First Amendment concerns.       See, e.g., Whitaker v. Thompson, 353

                                 - 33 -
F.3d     947,     953     (D.C.    Cir.       2004)      (holding           that     it    is

"constitutionally         permissible"        to   use     a    seller's       claims      as

evidence of intended use, even when                      doing so       "renders      [the]

otherwise       permissible   act       [of   selling      the       product       with   FDA

approval] unlawful"); Nicopure Labs, LLC v. FDA, 944 F.3d 267, 282

(D.C. Cir. 2019) (reaffirming Whitaker);                  United States v. LeBeau,

654 F. App'x 826, 830-31 (7th Cir. 2016).                        Indeed, as we have

noted, the Caronia court assumed that evidentiary use of statements

to prove FDCA violations would be permissible under the First

Amendment but concluded on the facts that the prosecution did not

use speech in that way.           See 703 F.3d at 161.                See also U.S. ex

rel. Polansky v. Pfizer, Inc., 822 F.3d 613, 615 n.2 (2d Cir. 2016)

("Caronia left open the government's ability to prove misbranding

on a theory that promotional speech provides evidence that a drug

is intended for a use that is not included on the drug's FDA-

approved label.").

            We     find    relevant       and      persuasive         this     consistent

authority from other circuits that the First Amendment is not

implicated by the evidentiary use of truthful, non-misleading

promotional speech to establish a drug's intended use to obtain a

conviction under the FDCA.              Appellants' convictions fall soundly

within    that     domain.        The    trial     court       did    not     criminalize

appellants'      speech    itself,      instructing        the       jury    to    consider

promotional speech only insofar as it shed light on appellants'

                                        - 34 -
intended use for Stratus.           Accordingly, Facteau's reliance on

Caronia fails.

          ii. Whether the FDA's Safe Harbor               Policy    Subjects
Promotional Speech to a Discriminatory Burden

           Facteau's additional First Amendment argument targets

FDA   guidance    explaining    when   truthful,     non-misleading   speech

regarding off-label uses will not be considered evidence of a

product's intended use.        In Facteau's telling, this "safe harbor"

draws content-based distinctions between favored and disfavored

speech, burdening speech that affirmatively promotes an off-label

use of a device -- by considering it as evidence of intended use

-- while excluding evidentiary uses of science-based responses to

unsolicited questions from physicians regarding off-label use and

the distribution of certain scientific literature.              He contends

further that, because these burdens are content- and viewpoint-

based,   they    cannot   survive   heightened     scrutiny   and   therefore

violate the First Amendment.

           Facteau's argument draws upon Supreme Court precedent

recognizing      that   policies    singling   out    certain   speech   for

regulatory burdens -- based on the content of that speech -- are

subject to heightened judicial scrutiny.             See, e.g., Sorrell v.

IMS Health Inc., 564 U.S. 552, 565 (2011) (holding that a law

"designed to impose a specific, content-based burden on protected

expression" is subject to "heightened judicial scrutiny"); United

                                    - 35 -
States v. Playboy Ent. Grp., Inc., 529 U.S. 803, 812 (2000)

("[C]ontent-based burdens must satisfy the same rigorous scrutiny

as . . . content-based bans.").        In Sorrell, for instance, the

Court   held    unconstitutional   a    Vermont    law   that   required

pharmaceutical marketers to obtain a physician's consent before

they could use data about his prescribing practices to inform their

marketing strategy but imposed no similar requirement on using

that data for other purposes, such as for research or patient

education.     See 564 U.S. at 559-60, 565.       Facteau contends that

the FDA's safe harbor operates in similar fashion by using the

content of a medical product manufacturer's speech to determine

whether that speech will bear the burden of potentially being used

as evidence of intended use.

           We understand Facteau's theory to fit into his First

Amendment instructional error claim by supplying another rationale

for the correctness of appellants' rejected instruction, even

though seemingly out of step with Mitchell, in the context of this

case.   Although it is generally permissible for a jury to consider

promotional speech as evidence of intent, any evidence so presented

to the jury because it is not protected by the safe harbor would

be the product of a government policy that unequally foists the

burden of potential evidentiary use upon certain speech based on

its content.    Thus, the court should have instructed the jury to

                               - 36 -
exclude all evidence derived from appellants' promotional speech,

as appellants requested.

            The government asserts that this argument is forfeited

because it was not raised below.         We agree.     Although appellants

made general First Amendment objections to the court's instruction

that the jurors may consider promotional speech as evidence of

intent, and at times couched their arguments in terms of content-

and viewpoint-based discrimination, they never suggested that the

FDA's     safe-harbor    guidance    constituted     such   discrimination.

Indeed, Facteau's trial counsel insisted -- over the government's

objection -- that the court adopt an instruction modeled on one of

the guidance documents, hardly suggesting that appellants viewed

the safe harbor as odious to protected speech.14            Because "a party

is not at liberty to articulate specific arguments for the first

time on appeal simply because the general issue was before the

district court,"        United States v. Slade, 980 F.2d 27, 31 (1st

     14 We recognize that Facteau's counsel requested this
instruction as a "fallback" after the trial court rejected
appellants' view that any consideration of truthful, non-
misleading statements to show improper intent violated the First
Amendment. Nonetheless, Facteau's counsel expressly agreed that
appellants were "not objecting to this instruction as-is over and
beyond the views they already have of the First Amendment in this
case," thereby disclaiming any First Amendment argument beyond
their objection rooted in Caronia.

                                    - 37 -
Cir. 1992), we will apply plain error review to assess Facteau's

unpreserved argument.15

             Under that standard, Facteau "must show '(1) that an

error occurred (2) which was clear or obvious and which not only

(3) affected [his] substantial rights, but also (4) seriously

impaired the fairness, integrity, or public reputation of judicial

proceedings.'"      United States v. Nieves-Meléndez, 58 F.4th 569,

579 (1st Cir. 2023) (quoting United States v. Merced-García, 24

F.4th 76, 79-80 (1st Cir. 2022)).              An error is only clear or

obvious when it is "'indisputable' in light of controlling law."

Merced-García, 24 F.4th at 80 (quoting United States v. Rabb, 5

F.4th 95, 101 (1st Cir. 2021)); see also United States v. Grullon,

996   F.3d   21,   33   (1st   Cir.    2021)   ("[P]lain   error   cannot   be

found . . . absent clear and binding precedent." (quoting United

States v. Marcano, 525 F.3d 72, 74 (1st Cir. 2008) (per curiam))).

      15At times, Facteau's briefing regarding this additional
First Amendment argument appears to stray from the framing of an
instructional challenge, engaging instead in a more fundamental
and broad-based attack on the FDA's safe harbor policy.       But
Facteau never presented any such argument to the district court
and does not suggest before us how the safe harbor policy
concretely affected his prosecution beyond the conclusory
assertion that "[t]he government's . . . enforcement approach
improperly affected every aspect of the trial here." Accordingly,
we would deem any such theory waived.       See United States v.
Zannino, 895 F.2d 1, 17 (1990) ("[I]ssues adverted to in a
perfunctory manner, unaccompanied by some effort at developed
argumentation, are deemed waived."). Instead, we construe
Facteau's argument as part of his primary instructional error
challenge, reviewable for plain error.

                                      - 38 -
             Facteau principally points to two guidance documents

issued by the FDA -- a draft document from 2011 ("2011 guidance")

and a revised draft from 2014 ("2014 guidance") -- as the source

of the safe harbor policy that, he urges, results in a burden on

the speech excluded from the safe harbor by subjecting only such

"disfavored" speech to the peril of being used as evidence of

intended use.16        The 2011 guidance sets out standards for how

manufacturers        should     respond   to     unsolicited     requests     for

information about off-label uses for their devices.               See U.S. Food

&    Drug    Admin.,    Draft     Guidance     for   Industry    Responding   to

Unsolicited Requests for Off-Label Information About Prescription

Drugs and Medical Devices (2011).            For example, the 2011 guidance

recommended that manufacturers respond to such requests with "non-

biased information or data" concerning the off-label use.                Id. at

8.     The    2011     guidance    also   recommended     that    responses    to

unsolicited requests be generated by scientific personnel rather

       Facteau also cursorily mentions, as among the safe harbor
      16

guidance that he claims imposes a First Amendment-violative burden
on speech, a 2009 FDA guidance document on recommended practices
for the distribution of medical or scientific publications
discussing off-label uses of drugs or devices, as well as a notice
by the FDA regarding Washington Legal Foundation v. Henney, 202
F.3d 331 (D.C. Cir. 2000). See U.S. Food & Drug Admin., Guidance
for Industry: Good Reprint Practices for the Distribution of
Medical Journal Articles and Medical or Scientific Reference
Publications on Unapproved New Uses of Approved Drugs and Approved
or Cleared Medical Devices (2009); U.S. Food & Drug Admin.,
Decision in Wash. Legal Found. v. Henney, 65 Fed. Reg. 14,286 (Mar.
16, 2000).

                                      - 39 -
than   by   sales    or    marketing    personnel.            Id.     at   8-9.        If   a

manufacturer       abided    by   these       standards,        the    2011       guidance

announced, the FDA would not use the manufacturer's response as

evidence of a new intended use.               Id. at 9.

             The    2014    guidance      articulated         standards          governing

manufacturers'        dissemination           of     scientific            and     medical

publications        discussing       off-label         uses      to        health       care

professionals and entities.            See U.S. Food & Drug Admin., Revised

Draft Guidance for Industry: Distributing Scientific and Medical

Publications on Unapproved New Uses — Recommended Practice (2014).

The 2014 guidance stated that, if a manufacturer follows these

standards, the FDA would not use its distribution of scientific

and medical publications discussing off-label use of a device as

evidence of a new intended use.               Id. at 6.

             Facteau devotes much of his briefing to establishing

that the FDA's safe harbor amounts to content-based discrimination

that cannot withstand heightened scrutiny.                       But this argument

depends     upon    the    premise     that    speech      outside         of    the   safe

harbor -- and thus subject to potential evidentiary use -- suffers

a "burden" raising First Amendment concerns in the first place.

On plain error review we must satisfy ourselves that this threshold

assertion     is    "'indisputable'       in       light   of    controlling           law."

Merced-García, 24 F.4th at 80 (quoting Rabb, 5 F.4th at 101).                           That

is a tall order, considering the clarity with which Mitchell

                                       - 40 -
establishes that using speech as evidence ordinarily does not run

afoul of the First Amendment.   Because Facteau's argument fails to

clear the threshold hurdle of demonstrating that the safe harbor

policy "burdens" protected speech within the meaning of the First

Amendment, we need not analyze whether the safe harbor policy

imposes such a burden by drawing content-based distinctions or

whether those distinctions would satisfy heightened scrutiny.

          To start, Facteau's argument fundamentally misconstrues

the nature of the FDA's safe harbor.        Far from burdening what

device manufacturers may say, the safe harbor guidance expands,

rather than contracts, the domain of speech that the government

shields from being used as evidence.     If, as a general matter, the

evidentiary use of speech discussing off-label use does not raise

First Amendment concerns, then presumably a policy that limits the

consideration of such speech as evidence of intended use does not

raise First Amendment concerns either.17

          Neither of the cases upon which Facteau relies persuades

us otherwise.   See Sorrell, 564 U.S. 552; Playboy, 529 U.S. 803.

While these cases certainly establish the general principle that

     17We note, moreover, that it is far from clear that the FDA's
safe harbor policies make content-based distinctions on speech.
In many cases, such as the 2011 guidance on unsolicited questions
about off-label use, it is the circumstances under which a
statement arises, and not the content of the statement itself,
that determine whether the FDA deems that statement open for
evidentiary use.

                                - 41 -
some regulations on speech impose burdens sufficient to raise First

Amendment concerns, they fall far short of the "clear and binding

precedent" necessary on plain error review to sustain Facteau's

argument that the FDA's safe harbor fits that mold.             Grullon, 996

F.3d at 33.

           The regulations found to impermissibly burden speech in

both Sorrell and Playboy took much more direct aim at protected

speech -- and imposed far more onerous restrictions on it -- than

does the FDA's safe harbor, even in Facteau's telling.                The law

challenged     in   Sorrell   prohibited     pharmaceutical    sellers    from

using, or even receiving, information about doctors' prescribing

practices to inform their sales pitches.            564 U.S. at 564-66.      In

Playboy, a regulation aimed at preventing broadcasts of adult

entertainment from reaching children produced a sweeping partial

ban of such programming except during late evening hours.                   529

U.S. at 811-15.

           By contrast, at most, the FDA's safe harbor puts the

sellers   of   medical   products    on    notice    about   which   of   their

statements the government deems most probative of that product's

intended use.18     That is no different than how a defendant's speech

     18Facteau assumes that all off-label speech, whether within
the safe harbor or otherwise, has equal potential to be probative
of intended use.    But that assumption defies the common sense
behind the FDA's safe harbor policy, which reflects the agency's
judgment about the circumstances in which a device seller's off-
label speech is more indicative of its state of mind than other

                                    - 42 -
may be probative of the racial animus behind an assault, see

Mitchell, 508 U.S. at 489, or soldiers "announcing their sexual

orientation" was probative of whether they had violated "Don't

Ask, Don't Tell" prior to its repeal, see Cook v. Gates, 528 F.3d

42, 62-64 (1st Cir. 2008).      As we have noted, if the FDA's safe

harbor marks a departure from the Mitchell baseline at all, it is

only because it removes certain speech from government scrutiny,

rather than heaping more scrutiny upon the speech that falls

outside the safe harbor.

            It is of course true that medical device sellers, aware

that their speech may become evidence          of intended use, will

necessarily choose their words carefully when promoting their

products.    But such efforts do not amount to a "burden" on free

expression   when   it   is   conduct -- in   this   case,   introducing

misbranded or adulterated devices into commerce -- and not speech

that the law aims to control.      We have said that such "incidental

effects" on speech arising from laws directed at non-speech conduct

"do[] not . . . implicate the First Amendment."          Wirzburger v.

Galvin, 412 F.3d 271, 278 (1st Cir. 2005) (citing Arcara v. Cloud

instances of speech. For instance, the FDA's 2011 draft guidance
distinguishes between requests for off-label information that are
"solicited" versus "unsolicited."   When a physician or patient
comes to a manufacturer unbidden and asks about the off-label
application of a product, nothing about a manufacturer responding
truthfully inherently suggests that it intends the product to be
used off-label.

                                 - 43 -
Books, Inc., 478 U.S. 697, 698 (1986)).              See also Cook, 528 F.3d

at 63 (use of speech as evidence of violation of law "aimed at

eliminating certain conduct . . ., not at restricting speech,"

does not burden speech).

            We thus find no merit in Facteau's apparent contention

that, because the FDA's safe harbor policy shields some speech

from evidentiary use, the jury should have been instructed to

disregard all promotional speech as evidence of intended use. And,

having rejected the Caronia argument as well, we conclude that

Facteau's First Amendment arguments fail to support departing from

Mitchell's longstanding rule that using speech as evidence of

intent does not implicate the First Amendment.                        Accordingly,

neither the district court's rejection of appellants' proposed

instruction nor its decision to instead instruct the jury that it

could consider speech for evidentiary purposes was in error.

B. Instructional Error Claim Regarding "Intended Use"

            Having     decided    that     the    First   Amendment        poses   no

obstacle    to   the   government's      evidentiary      use    of    appellants'

off-label    promotional         speech,     we    turn    now        to    Fabian's

countervailing argument that the jury should have been instructed

that it may consider only such evidence to determine a product's

intended use.

                                     - 44 -
           1. Background

           At the pre-trial charge conference, appellants' counsel

objected   to    the   district     court's     proposed   instructions     on

"intended use" on the ground that those instructions did not convey

to the jury that when the government alleges that a medical device

serves an intended use for which it has not been approved, that

"intended use must be based only on external promotional conduct."

Appellants asked the court to instead instruct the jury that only

statements made to potential customers bear on a device's "intended

use" and that the jurors therefore should not consider internal

company    documents      and   communications,      responses   to    doctor-

initiated inquiries, and scientific information disseminated in

academic and educational venues in evaluating the question of

"intended use."

           The    court    declined    to     give   appellants'      requested

instruction and rejected their challenge to its own instruction.

It thus instructed the jury as follows on how a device's "intended

use" is to be determined outside of the § 510(k) process:

           The term "intended use" refers to the
           objective intent of the manufacturer or seller
           of the device.   The intent is determined by
           such person's expressions or may be shown by
           the     circumstances      surrounding     the
           distribution of the device.     This objective
           intent may, for example, be shown by labeling
           claims, advertising matter, or oral or written
           statements   by   such    persons   or   their
           representatives.    It may be shown by the
           circumstances that the device is, with the

                                    - 45 -
          knowledge   of    such persons   or   their
          representatives, offered and used for a
          purpose for which it is neither labeled nor
          advertised. . . .

          Mere knowledge that doctors are using a device
          for purposes other than its labeled use does
          not give rise to a new intended use.      Off-
          label promotional statements can constitute
          evidence   of  an   intended   use,   although
          truthful, non-misleading speech alone cannot
          be the basis for a criminal conviction. . . .

          After the court charged the jury, appellants objected to

the court's "failure to instruct the jury that in determining

intended use, the jury must look solely to the external promotional

activities surrounding the distribution of a device."            Appellants

renewed this instructional challenge in their motion for judgments

of acquittal.

          In ruling on appellants' motion, the district court gave

two reasons for rejecting this instructional challenge.                 First,

the instruction as given was consistent with the plain language of

the description of "intended use" set out in 21 C.F.R. § 801.4.

Second,   the   position      stated        in   appellants'         requested

instruction -- that   the   only    relevant     evidence   of   a    device's

intended use is the manufacturer or seller's external promotional

statements -- finds no support in caselaw.

          2. Legal Analysis

          On appeal, Fabian reiterates his claim that the district

court's instruction was legally erroneous and that the court should

                                   - 46 -
have instead instructed the jury that only external promotional

statements could be considered in determining whether Stratus was

being improperly marketed for a new intended use.          Fabian relies

first on the definition of "intended use" in § 801.4, which refers

to the "objective intent" of the labelers of the device.        He claims

that reference necessarily limits the focus to external marketing

and promotional statements.      Fabian also relies on what he asserts

are prior judicial interpretations of "intended use" that define

that term to encompass only promotional statements communicated to

potential customers.

          This preserved instructional claim thus requires us to

determine whether Fabian's proposed instruction or the contrary

instruction   given   by   the   district   court   properly   stated   the

relevant law. Accordingly, our review is de novo. See Florentino-

Rosario, 19 F.4th at 534.19

          Fabian's argument based on the definition of "intended

use" in 21 C.F.R. § 801.4 is easily dispatched.          As the district

court persuasively reasoned, the concept of "objective intent"

simply means that there must be "outward expressions" of such

     19 The government argues that we should apply plain error
review because Fabian did not specifically object to the district
court's failure to give his requested instruction after the court
charged the jury. See United States v. Pérez-Rodríguez, 13 F.4th
1, 16 (1st Cir. 2021).     The government, however, is mistaken.
Fabian did object to the court's refusal to instruct the jury that
intended use is to be determined solely by reference to external
promotional statements.

                                  - 47 -
intent and not merely "unexpressed thoughts" within the mind of an

individual.      United States v. Facteau, No. 15-cr-10076-ADB, 2020

WL 5517573, at *17 (D. Mass. Sept. 14, 2020).                        This notion of

intent,     which judges a person's mental state by its outward

manifestations through speech and conduct, is a familiar concept

in the law.          See, e.g., Restatement (Second) of Contracts § 18

cmt. a (Am. L. Inst. 1981) ("Assent to the formation of an informal

contract is operative only to the extent that it is manifested.").

Communications and conduct internal to Acclarent's operations were

not   any     less    "objective"    because     they       were    not   directed      at

potential customers for Stratus or at the public in general.

              Moreover, as the district court noted, the plain text of

the   then-current         version   of   § 801.4      did    not    limit      relevant

manifestations        of   "objective     intent"      in    the    way   that    Fabian

suggests. The regulation stated that objective intent may be shown

by "expressions" such as "oral or written statements by [labelers]

or    their     representatives,"         with   no     indication         that    these

statements must be directed to individuals outside the company.

The regulation also embraced, as a manifestation of "objective

intent," "the circumstances surrounding the distribution" of a

device -- including          evidence     that   the    device      was,       "with   the

knowledge of [labelers] or their representatives, offered and used

for a purpose for which it is neither labeled nor advertised."

Thus,   the    regulation      expressly     contemplated          that    a   labeler's

                                        - 48 -
"objective intent" -- and hence a device's intended use -- could

be proven with evidence beyond the external promotional statements

of a device manufacturer's officers and employees.

             Fabian's argument from precedent is equally unavailing.

Neither of the out-of-circuit cases he highlights stand for the

principle on which he relies, namely that only public-facing

promotional statements can provide evidence of a device's intended

use.    Indeed, in United States v. Articles of Drug for Veterinary

Use, 50 F.3d 497 (8th Cir. 1995), the Eighth Circuit expressly

held that a seller's "intended application" of a product -- in

that case, a suspected adulterated new animal drug -- may be

determined by reference to evidence from "any relevant source,"

including, but not limited to, external promotional statements.

Id.    at   499-500.   To    be   sure,   promotional   statements   proved

exceptionally relevant in that case as the facts centered on

literature accompanying the product, see id. at 499-500, but the

court did not purport to hold that only such promotional material

is probative of the intended use of a product regulated by the

FDCA.

             The Fourth Circuit's decision in Brown & Williamson

Tobacco Corp. v. FDA, 153 F.3d 155 (4th Cir. 1998), is similarly

unhelpful to Fabian.        Although the panel observed that "no court

has ever found that a product is 'intended for use' [as a drug or

device] . . . absent manufacturer claims as to that product's

                                   - 49 -
use," id. at 163 (quoting Coyne Beahm, Inc. v. FDA, 966 F. Supp.

1374, 1390 (M.D.N.C. 1997)), the decision does not support Fabian's

view that a court may not consider other sources of evidence.

Rather, the case merely reinforces the obvious point that labeling

and external statements are important sources to consider.

            Moreover, Fabian's position is contradicted by other

precedent, including from our own court.       We long ago stated that,

in   determining   a   product's    intended   use   for   purposes   of   a

misbranding conviction, courts are "free to look to all relevant

sources in order [to] ascertain . . . 'intended use.'" V.E. Irons,

Inc. v. United States, 244 F.2d 34, 44 (1st Cir. 1957) (emphasis

added).     While the specific sources we relied on in V.E. Irons

were the literature distributed and the oral representations made

in connection with the sale of the misbranded drugs, we did not

thereby imply any limitation on the "all relevant sources" standard

we announced.

            This broad standard has been endorsed by multiple other

circuits.    For instance, the Federal Circuit, in Allergan, Inc. v.

Athena Cosmetics, Inc., 738 F.3d 1350 (Fed. Cir. 2013), stated

that the intended use of a product "may be 'derived or inferred

from labeling, promotional material, advertising, or any other

relevant source.'"     Id. at 1357 (quoting United States v. Storage

Spaces Designated Nos. 8 and 49 Located at 277 East Douglas, 777

F.2d 1363, 1366 (9th Cir. 1985)). The court expressly "disagree[d]

                                   - 50 -
with [the defendant] that the only relevant evidence is labeling

and marketing," and it considered the company's internal "training

of resellers" when analyzing the question of objective intent. Id.

Similarly, in United States v. An Article of Device, 731 F.2d 1253,

1257 (7th Cir. 1984),    the Seventh Circuit determined that a

chiropractic instrument was intended to be used as a medical device

by examining the instructions that accompanied the device, the

"financial arrangements through which chiropractors were trained

in the use of the [device]," and testimony from chiropractors about

how they used it.   See also Action on Smoking & Health v. Harris,

655 F.2d 236, 239 (D.C. Cir. 1980) ("[I]t is well established that

the 'intended use' of a product, within the meaning of the [FDCA],

is determined from its label, accompanying labeling, promotional

claims, advertising, and any other relevant source."     (Internal

quotation marks omitted) (emphasis added)); United States v. An

Article . . . Consisting of 216 Cartoned Bottles, More or Less,

Sudden Change, 409 F.2d 734, 739 (2d Cir. 1969) ("It is well

settled that the intended use of a product may be determined from

its   label,   accompanying   labeling,    promotional   material,

advertising and any other relevant source."   (Emphasis added)).

          In sum, we do not find Fabian's proposed understanding

of "intended use" under § 801.4 persuasive, and we discern no error

in the district court's interpretation of that term as stated in

                              - 51 -
its instruction to the jury.     Accordingly, Fabian's instructional

challenge fails.

C. Due Process Claims Regarding "Intended Use"

          Both Facteau and Fabian contend that their convictions

were obtained in violation of the Fifth Amendment's Due Process

Clause because "intended use," as that term is used in the relevant

FDCA    provisions      and      accompanying        regulations,        is

unconstitutionally vague.       Facteau makes a further due process

claim that, because the government and courts at the time of his

conduct took the position that only external marketing statements

promoting off-label use can be considered as evidence of a new

intended use, his prosecution under a novel and more expansive

interpretation of intended use denied him the fair notice required

by due process.

          Appellants   raised    both     due   process   claims   in   the

district court, and we therefore review them de novo.          See United

States v. Silva, 794 F.3d 173, 177 (1st Cir. 2015).

          1. Unconstitutional Vagueness Claim

          The government violates the Due Process Clause if it

"tak[es] away someone's life, liberty, or property under a criminal

law so vague that it fails to give ordinary people fair notice of

the conduct it punishes, or so standardless that it invites

arbitrary enforcement."   Johnson v. United States, 576 U.S. 591,

595 (2015) (citing     Kolender v. Lawson, 461 U.S. 352, 357-58

                                 - 52 -
(1983)); accord Frese v. Formella, 53 F.4th 1, 6 (1st Cir. 2022)

(identifying "lack of notice" and the prospect of "discriminatory

enforcement"   as    the   hallmarks     of    an   unconstitutionally         vague

statute).      In   most   contexts,     the    test      for    unconstitutional

vagueness is whether the challenged law is so indefinite that it

"fails to provide a person of ordinary intelligence fair notice of

what is prohibited."       Frese, 53 F.4th at 6 (quoting United States

v. Williams, 553 U.S. 285, 304 (2008)).                   For provisions that

concern   economic    regulation,      however,     the    test    is   whether    a

"business person of ordinary intelligence would understand" what

conduct is prohibited -- a "less strict vagueness test."                  Vill. of

Hoffman Ests. v. Flipside, Hoffman Ests., Inc., 455 U.S. 489, 499,

501 (1982) (emphasis added).20

            Appellants     offer   two    rationales        to    support      their

contention   that    the   legal    framework       under       which   they   were

     20 Courts are less likely to conclude that statutes and
regulations   "addressed   to   sophisticated   businessmen   and
corporations" are unconstitutionally vague because of an
assumption that, given the "complexity" of economic regulation,
such parties "necessarily consult counsel in planning their
activities," and some "administrative process" will often be
available "to secure advisory interpretations of the statute [or
regulation]" at issue. United States v. Lachman, 387 F.3d 42, 57
(1st Cir. 2004). By contrast, vagueness review is more stringent
when the challenged laws implicate the First Amendment's
protections for speech. See FCC v. Fox Television Stations, Inc.,
567 U.S. 239, 253-54 (2012) (noting that a more "rigorous"
vagueness inquiry is appropriate "to ensure that ambiguity does
not chill protected speech"). As explained above, however, the
adulteration and misbranding offenses underlying appellants'
convictions do not raise First Amendment concerns.

                                    - 53 -
convicted -- and particularly the term "intended use" -- is so

vague as to violate the Due Process Clause.     First, they argue

that the broad scope of evidence that § 801.4 allows to determine

intended use makes the term unconstitutionally vague.      Second,

they argue that there is a history of inconsistent agency and

judicial interpretations of "intended use" that indicates that the

term is impermissibly vague.   We address each of these arguments

in turn.

           i. Evidence of "Intended Use" Under § 801.4

           Appellants contend that the government's position that

a device manufacturer's "intended use" for a device may take into

account "'all circumstances' from 'any relevant source' relating

to the [device]" -- an interpretation adopted by the district

court in its jury instructions -- renders the FDCA provisions

underlying their convictions unconstitutionally vague.21      They

argue that, when such a wide array of evidence may be used to

     21 The government does not dispute appellants' depiction of
its interpretation of the regulation and, indeed, the record
reflects the broad construction they posit.        In its closing
argument, for example, the government told the jurors that they
could "look at all of the circumstances surrounding the
distribution of the device to figure out what would be the intended
use of the device." As recounted above, the district court's jury
instructions also reflected this interpretation. The court told
the jurors that the intended use for a device "refers to the
objective intent" of the device manufacturer or seller, which
intent   is  "determined   by"   the   manufacturer   or   seller's
"expressions" and "the circumstances surrounding the distribution
of the device."

                               - 54 -
support    a   finding   of   "intended     use" -- and          thus    criminal

liability -- manufacturers       lack    fair    notice     of     the    conduct

prohibited under the adulteration and misbranding offenses, and

the   government's   authority    to    prosecute   violations           of   those

offenses improperly lacks any limiting standards.

           The   vagueness    doctrine    is    primarily    concerned         with

whether the language of a legal provision is sufficiently clear.22

Necessarily, then, appellants must show that § 801.4's definition

of "intended use" -- which looks to the "objective intent" of the

seller as determined by his "oral or written statements" and "the

circumstances surrounding the distribution" of the device -- is so

unclear that it does not give fair warning of when the seller will

be found to have an intended use for their device that differs

from the use for which it has been cleared.

       The vagueness doctrine's focus on the language of a penal
      22

law is evident from the earliest cases developing the doctrine.
See, e.g., Connally v. Gen. Constr. Co., 269 U.S. 385, 391 (1926)
("That the terms of a penal statute creating a new offense must be
sufficiently explicit to inform those who are subject to it what
conduct on their part will render them liable to its penalties is
a well-recognized requirement, . . . and a statute which either
forbids or requires the doing of an act in terms so vague that men
of common intelligence must necessarily guess at its meaning and
differ as to its application violates the first essential of due
process of law." (Emphases added)); McBoyle v. United States, 283
U.S. 25, 27 (1931) ("[I]t is reasonable that a fair warning should
be given to the world in language that the common world will
understand, of what the law intends to do if a certain line is
passed. To make the warning fair, so far as possible the line
should be clear." (Emphasis added)).

                                  - 55 -
             Appellants fail to explain how, as a textual matter, the

law lacked sufficient clarity to apprise them of when they would

be criminally liable for distributing a device with an unapproved

intended use. The FDCA and its implementing regulations make clear

that manufacturers must submit a new premarket notification before

they commercially distribute a device for an intended use that

represents a "major change or modification in the intended use of

the device" from the cleared use.             21 C.F.R. § 807.81(a)(3)(ii).

And, as noted in our discussion of Fabian's instructional-error

claim,    "objective   intent,"      which    § 801.4    relies   upon    in      its

definition of "intended use," is a familiar and well-established

concept in the law.      Indeed, the Supreme Court has indicated that

the objective intent standard is sufficiently determinate for

purposes of the vagueness doctrine.           See Williams, 553 U.S. at 306

(holding that "[w]hether someone . . . had an intent is a true-

or-false     determination,    not    a   subjective     judgment"     and    hence

specifies      a   sufficiently      determinate       standard   of     criminal

culpability).      Moreover, the regulation goes on to explain that

such objective intent may be reflected in a seller's "statements"

or   other    "circumstances   surrounding       the    distribution"        of   the

device.      To be sure, the provision casts a wide net.             It does so,

however, in language that fairly apprises the reader of the broad

range of conduct that may reasonably reflect a device's intended

use.

                                     - 56 -
          Especially given the less stringent vagueness test that

applies to economic regulation, appellants have failed to show

that "intended use," as that term is defined in § 801.4, is

unconstitutionally vague.    At most, there may be some uncertainty

under § 801.4 about when, in a close case, there will be sufficient

evidence to prove that a manufacturer marketed a device for an

off-label intended use.     That type of uncertainty, however, does

not give rise to a valid vagueness claim.   As the government points

out, a penal law is impermissibly vague when it fails to give "fair

notice of what is forbidden," United States v. Morosco, 822 F.3d

1, 5 (1st Cir. 2016), not simply when it may be difficult to

determine whether, given the evidence in a particular case, the

elements of the offense defined in the law have been proved, see

Williams, 553 U.S. at 306 ("What renders a statute vague is not

the possibility that it will sometimes be difficult to determine

whether the incriminating fact it establishes has been proved; but

rather the indeterminacy of precisely what that fact is.").

          Moreover, we think it worth noting that this was not a

close case.   The government produced copious evidence from a wide

range of sources -- from the design of Stratus, to the history of

its product development within Acclarent, to how it was promoted

to potential customers -- that established an objective intent by

Acclarent's management that Stratus be used for delivering Kenalog

rather than for its cleared use as a postoperative spacer with

                               - 57 -
saline.     Whatever indeterminacy there might be about how much and

what kinds of evidence would be sufficient to prove a new intended

use in a close case, appellants cannot rely on that hypothetical

indeterminacy to make a vagueness claim here.               Cf. McCoy v. Town

of Pittsfield, 59 F.4th 497, 509 (1st Cir. 2023) ("[A] 'plaintiff

who engages in some conduct that is clearly proscribed cannot

complain of the vagueness of the law as applied to the conduct of

others.'"    (Quoting Holder v. Humanitarian L. Project, 561 U.S. 1,

18-19 (2010))).

            ii. Inconsistent Agency and Judicial Interpretations

            The   Supreme   Court    recognized   in    Johnson        that   one

powerful indication that a law is unconstitutionally vague is when

the law has "proved nearly impossible to apply consistently,"

engendering "pervasive disagreement" among courts about even "the

nature of the inquiry [a court applying the law] is supposed to

conduct and the kinds of factors [the court] is supposed to

consider."     576 U.S. at 601 (internal quotation marks omitted).

We   have    similarly   suggested    that   where     an     agency    "issues

contradictory or misleading public interpretations" of its own

regulation, "there may be sufficient confusion for a regulated

party to justifiably claim a deprivation of fair notice." Lachman,

387 F.3d at 57.

            Appellants raise an inconsistent interpretation argument

along these lines by alleging that both the FDA and the courts

                                    - 58 -
have shifted in their interpretation of the FDCA, demonstrating

that the term "intended use" is unconstitutionally vague because

it has proven subject to varying interpretations.                  On appellants'

telling, the courts and the FDA have at times embraced the narrow

view that a medical product's "intended use," is revealed only by

promotional    statements.      At    other    times,       however,   they    have

endorsed the more expansive view that evidence of a product's

intended use can come from any relevant source, including not just

promotional speech but internal communications, product design,

and other conduct.

            Appellants suggest that perhaps Caronia is to blame for

this shift.    To be sure, as we have already observed, Caronia was

a significant opinion, articulating a limit on the government's

use of off-label promotional speech as the basis of a conviction

under the FDCA.    It is reasonable to think that the government, as

well   as   courts,   may    have    grown     more    cautious     about     using

promotional speech alone as the basis of a conviction following

Caronia.      However,   that   caution       does    not   mean    that    Caronia

fundamentally altered the way the government or courts construe

the applicable law and regulations, opening a door to using non-

promotional statements and other conduct as evidence of intended

use that was previously (in appellants' telling) closed.

            Upon our examination of judicial and agency precedent,

we are unpersuaded that there has been such a sea change in the

                                     - 59 -
interpretation of the FDCA that appellants were deprived of fair

notice of what the law prohibited.           We begin with the caselaw.

            Appellants misread the precedent in claiming that courts

have exhibited pervasive disagreement about how to understand the

determinants of "intended use."         Neither of the cases appellants

cite exemplify, as they suggest, courts narrowing permissible

evidence of intended use to external manufacturer claims only.

See Brown & Williamson, 153 F.3d 155; Am. Health Prods. Co. v.

Hayes, 574 F. Supp. 1498, 1505 (S.D.N.Y. 1983), aff'd per curiam,

744 F.2d 912 (2d Cir. 1984).

            As we explained with regard to Fabian's instructional

challenge, the Brown & Williamson court observed that courts

typically   do    not   determine   intended     use   without    considering

manufacturers' external claims, but it did not endorse the distinct

notion that only such claims may be considered as evidence of

intended use.     See 155 F.3d at 163.        The court in American Health

Products    Co.    v.   Hayes   likewise      endorsed   the     unremarkable

proposition that "marketing representations" are                 important   in

determining intended use but did not say that they alone may be

considered.      See 574 F. Supp. at 1505.

            In fact, as noted above, multiple federal courts of

appeal, in decisions stretching back decades, have taken the

position that finders of fact may determine "intended use" by

considering evidence from a broad range of sources, including

                                    - 60 -
evidence   other   than    promotional    claims    and    other      externally

directed manufacturer claims.         See, e.g., V.E. Irons, 244 F.2d at

38; Allergan, 738 F.3d at 1357; Article of Device, 731 F.2d at

1257; Action on Smoking, 655 F.2d at 239; Article of 216 Cartoned

Bottles, 409 F.2d at 739.

           As   for   appellants'      suggestion        that   the    FDA     has

previously   interpreted    the   determinants      of    "intended     use"    as

encompassing only external promotional claims, the main example

they cite comes from a 2002 letter from Daniel E. Troy ("Troy

letter"), then Chief Counsel of the FDA.             The letter contained

Troy's response to requests for information from Applied Digital

Systems, see 21 U.S.C. § 360c(g), regarding whether a device the

company planned to market was a "medical device" under the FDCA

because it was "intended for use in the diagnosis of disease or

other   conditions,   or   in   the   cure,   mitigation,       treatment,      or

prevention of disease," see 21 U.S.C. § 321(h)(1)(B). In analyzing

two intended uses that the company proposed for the device, Troy

stated that "[i]t is well settled that intended use is determined

with reference to marketing claims."

           The Troy letter does not show that the FDA previously

embraced the narrow interpretation of "intended use."                 First, the

Troy letter does not say that external promotional claims are the

exclusive source of permissible evidence.                As with the caselaw

discussed above, a statement that marketing claims are essential

                                  - 61 -
in determining intended use does not foreclose reliance on other

factors.23    Second, per regulation, the views expressed in the Troy

letter cannot be attributed to the agency itself, but only to an

FDA employee.     The letter did not offer an advisory opinion under

21 C.F.R. § 10.85, and it was therefore an "informal communication"

that "[did] not necessarily represent the formal position of FDA,

and [did] not bind or otherwise obligate or commit the agency to

the views expressed."    Id. at § 10.85(k).   More fundamentally, the

fact that the Troy letter was an informal communication to a

private regulated entity means that the principle we articulated

in Lachman, discussed above, does not apply here. As we emphasized

there, "non-public statements" by agency employees do not "create

the kind of confusion that supports a finding of a due process

violation."    387 F.3d at 58.

     23The other FDA guidance documents that appellants point to
as examples of the FDA adopting the narrow interpretation of the
determinants of "intended use" are inapposite for the same reason.
Thus, while one guidance document explained that the "FDA has
consistently prohibited the promotion of . . . unapproved uses of
approved products," nowhere does the document suggest that such
promotional claims are the sole permissible evidence of intended
use.   See Final Guidance on Industry-Supported Scientific and
Educational Activities, 62 Fed. Reg. 64074, 64081 (Dec. 3, 1997).
Similarly, while another guidance document mentioned product
labeling and information about the product disseminated by
manufacturers among the "materials [that] can create new intended
uses," the document does not state that these two types of
materials are the only permissible determinants of intended use.
See Citizen Petition Regarding the FDA's Policy on Promotion of
Unapproved Uses of Approved Drugs & Devices, 59 Fed. Reg. 59820,
59821 (Nov. 18, 1994).

                                 - 62 -
           2. Fair Warning Claim

           Facteau presses an additional due process argument along

similar lines.       He suggests that in the wake of Caronia, the

government has undertaken an interpretive pivot in its enforcement

of the FDCA, expanding its definition of intended use to account

for the fact that post-Caronia it may be more difficult to carry

a   conviction    based    on   promotional        statements        alone.      Since

appellants' conduct occurred before Caronia but their prosecution

came after that decision, Facteau argues that he was convicted by

retroactive      application     of        a    novel    and     more       expansive

interpretation     of     the   relevant         FDCA   provisions       and     their

accompanying regulations and thus lacked "fair warning" of what

the law requires.

           A defendant may not be convicted under a penal law that,

"either   standing      alone   or    as       construed,"     did    not     make   it

"reasonably clear at the relevant time that the defendant's conduct

was criminal."     United States v. Lanier, 520 U.S. 259, 267 (1997).

Thus, a defendant has been deprived of "the right of fair warning"

when he is convicted under a novel judicial construction of a

statute or other law that works "an unforeseeable and retroactive

judicial expansion" of the law's scope. Bouie v. City of Columbia,

378 U.S. 347, 352 (1964); see also Lanier, 520 U.S. at 266 ("[D]ue

process bars courts from applying a novel construction of a

criminal statute to conduct that neither the statute nor any prior

                                      - 63 -
judicial decision has fairly disclosed to be within its scope.").

Likewise, where an agency expands its interpretation of a statute

or regulation to cover conduct not previously covered, it may not

penalize a regulated party for engaging in the newly covered

conduct prior to that change in interpretation. See Fox Television

Stations, 567 U.S. at 254-58; cf. United States v. Anzalone, 766

F.2d 676, 681-82 (1st Cir. 1985) (concluding that defendant's

conviction violated due process because he lacked fair notice of

a   newly   expanded    interpretation       of    the   Currency   Transaction

Reporting Act).

            Facteau cannot avail himself of this doctrine.                      As

indicated    in   our   earlier   discussion       of    appellants'   vagueness

claim, neither the FDA nor the courts, prior to Caronia, espoused

an interpretive approach that limited the determinants of intended

use   to     manufacturers'       external        claims,    and    thus     their

interpretation of the law has not broadened following that decision

in the way Facteau claims.            Beyond those discussed above in

connection with appellants' vagueness claim, Facteau cites four

cases as examples of decisions where courts have adopted a narrow

interpretation of the determinants of "intended use."                      None of

these cases, however, suggests that a product's intended use must

be determined exclusively by reference to external promotional

claims.     Moreover, we find it telling that though Facteau cites

all of these cases as examples of the supposed pre-Caronia rule,

                                    - 64 -
some were decided after that case, refuting the suggestion that

Caronia spurred a change in how the law is interpreted.                 Rather,

the authority consistently shows, before Caronia and since, that

relevant evidence of intended use can come from many sources.

            As we have explained, the Eighth Circuit did not hold in

Articles of Drug, 50 F.3d 497, that the intended use of a medical

product    may    be    determined   only   by    reference   to    promotional

materials.    Indeed, the court expressly affirmed that the seller's

intended use for a product "may be derived from any relevant

source."   Id. at 500.      Similarly, in United States v. US Stem Cell

Clinic, LLC, 998 F.3d 1302, 1311 (11th Cir. 2021), the court

suggested that the government must produce marketing materials

that support its allegations of a drug's intended use but nowhere

stated that only marketing materials are permissible.                 Likewise,

the district court's statement in U.S. ex rel. Modglin v. DJO

Global Inc. that a device manufacturer "can only be liable for

violating the FDCA if it markets or promotes the device for [an

off-label use]," does not limit the range of evidence to such

statements.       48 F. Supp. 3d 1362, 1371 (C.D. Cal. 2014) (citing

Carson v. Depuy Spine, Inc., 365 F. App'x 812, 815 (9th Cir.

2010)).    Whether we agree with these latter two cases that the

government       must   produce   evidence       of   promotional   speech   to

establish a product's intended use is not at issue in this appeal.

For the purposes of this case, it is sufficient that we have found

                                     - 65 -
no    authority   indicating   that    only   promotional   statements    are

relevant to intended use.24

            We thus discern no interpretive pivot following Caronia.

Accordingly, the interpretation of the determinants of "intended

use" under which Facteau was prosecuted was not a novel and more

expansive interpretation of which he lacked fair warning.

            Facteau's fair warning claim fails for a further reason.

As the Seventh Circuit has explained, the "uncertainty that is

inevitable in legal standards . . . often is offset by [actual]

notice, so that people need not guess what is required of them."

United States v. Caputo, 517 F.3d 935, 941 (7th Cir. 2008).            Hence,

where an agency has "alerted [regulated parties] to its view of

their legal obligations," and the regulated parties nonetheless

choose "to go their own way," they are thereby "[taking] a risk

and [cannot] then say 'we didn't know' or 'the regulation left us

scratching our heads.'"        Id.     Here, Acclarent received actual

notice.    In May 2007, in response to Acclarent's request to add to

Stratus's labeling an indication for the delivery of diagnostic

and    therapeutic   substances   to    the   sinuses,   the   FDA   notified

Acclarent that the proposed change appeared to be a change in

24 Facteau's fourth case, Association of American Physicians &
Surgeons, Inc. v. FDA, is irrelevant as it did not concern intended
use at all.     See 226 F. Supp. 2d 204, 216-18 (D.D.C. 2002)
(explaining that the question of intended use was not at issue and
that the case concerned "a different section of the FDCA
entirely").

                                  - 66 -
intended use requiring Acclarent to "submit a new 510(k) and

receive Food and Drug Administration clearance prior to marketing

[Stratus] with [the proposed] changes."25   Having been notified of

the government's view, Facteau's complaint of unfair surprise at

being prosecuted for marketing Stratus to deliver Kenalog despite

Acclarent's failure to obtain such approval rings hollow.

D. Fabian's Remaining Arguments

          Finally, we turn to several issues that Fabian raises

separately: that the evidence is insufficient in the absence of

promotional statements specifically pertaining to the ten Stratus

shipments underlying the convictions; that Fabian's conviction is

improper absent any evidence that he personally participated in

submitting Stratus's § 510(k) filings, which he characterizes as

the actus reus of the crime; and that his $500,000 fine is

excessive under the Eighth Amendment.

          1. Sufficiency of the Evidence Arguments

          Fabian makes two arguments to challenge the sufficiency

of the evidence. Although the government argues that Fabian failed

     25 Facteau argues that because the May 2007 letter indicated
that Stratus must receive § 510(k) clearance for use with Kenalog
prior to its "marketing" for that use, it did not provide actual
notice that Acclarent could not commercially distribute Stratus
with that intended use as opposed to making promotional statements
about that intended use. We do not agree. In context, "marketing"
was a reference to placing Stratus on the market, not to promoting
Stratus.    In any event, Acclarent did not receive additional
clearance before its sales representatives began promoting Stratus
for use with Kenalog.

                              - 67 -
to preserve one of them -- the inadequacy of the evidence on the

crime's actus reus -- we disagree and, accordingly, apply de novo

review to both sufficiency claims.26          See United States v. Cadden,

965 F.3d 1, 10 (1st Cir. 2020).        Our task is therefore to "assess

the   record   evidence   'in   the     light    most     favorable     to   the

prosecution' and affirm so long as the 'body of proof, as a whole,

has sufficient bite to ground a reasoned conclusion that the

government proved each of the elements of the charged crime beyond

a reasonable doubt.'"     Id. at 10 (quoting United States v. Lara,

181 F.3d 183, 200 (1st Cir. 1999)).

           i. Evidence of Intended Use Accompanying Each Shipment

           Fabian   argues   that    the     government   needed   to    adduce

evidence -- in the form of commercial expression -- accompanying

each of the ten shipments of Stratus underlying the conviction to

      26The government asserts that Fabian is not entitled to de
novo review of the actus reus claim because he did not specifically
brief that claim in the district court. We have held, however,
that a Rule 29 motion raising a "general challenge to the adequacy
of the evidence preserves for de novo review 'the full range of
challenges, whether stated or unstated.'"        United States v.
Marston, 694 F.3d 131, 134 (1st Cir. 2012). Only if a defendant
"give[s] specific grounds for a Rule 29 motion" is there a waiver
of "all grounds not specified." Id. Although appellants' Rule
29(c) motion specifically challenged only the evidence pertaining
to the ten shipments of Stratus, their Rule 29(a) motion
"assert[ed] a general challenge to the sufficiency of the
Government's evidence on all counts." We consider this statement
adequate to generally preserve the issue of sufficiency of the
evidence. See id. at 135 (urging "in case of doubt to treat an
ambiguous motion . . . as 'general'" to avoid "penaliz[ing] the
giving of examples" or "creat[ing] a trap for the unwary defense
lawyer").

                                    - 68 -
establish the intended use of that particular shipment.                   The

government having failed to carry this burden, Fabian argues, his

conviction stands on insufficient evidence.          We disagree.

          To start, Fabian's argument as presented seems to depend

upon his theory that only outward promotional speech is probative

of a product's intended use.      Accordingly, Fabian asserts that the

government   needed   to,   but   did   not,   put   forward   evidence    of

statements accompanying each shipment of Stratus promoting that

shipment for use with Kenalog rather than saline.               As we have

explained, Fabian is incorrect that only promotional statements

can establish a product's intended use, and his argument thus

falters out of the gate.

          In any case, we do not agree with Fabian's underlying

premise that the government must always put forward evidence

establishing the intended use of each individual shipment, even

when the evidence shows that the whole point of the enterprise was

to market an adulterated and/or misbranded device.             Fabian seems

to suggest that it is the act of shipping, itself, that renders a

device adulterated or misbranded, such that the circumstances of

each shipment are essential to the status of the device.            But that

is not so.     We have long said that § 331(a) "prohibit[s] the

introduction into interstate commerce of [products] which at the

time of introduction" are adulterated or misbranded.              Penobscot

Poultry Co. v. United States, 244 F.2d 94, 97 (1st Cir. 1957).

                                  - 69 -
In other words, a device must in its "present state" at the time

of shipping be adulterated or misbranded, but the circumstances of

the shipment need not render it so.    Id.

          To be sure, the immediate circumstances accompanying a

device's shipment may provide evidence of its intended use, but so

may all sorts of evidence from before (or after) the shipment that

establish the essential fact under § 331(a): that the device was

misbranded or adulterated when shipped.      Here, the record evidence

reflects a scheme that from the beginning was aimed at marketing

Stratus to deliver Kenalog rather than saline, including evidence

that Stratus did not even work to deliver saline, was specifically

designed with Kenalog in mind, and was promoted with a sales

strategy devised to get physicians to associate Stratus with

Kenalog and consider using it for drug delivery.     As the Acclarent

executive in charge of sales, Fabian oversaw much of this activity.

A reasonable juror could examine this evidence and find that any

Stratus shipped by Acclarent in the midst of that scheme had an

intended use of delivering Kenalog.

          In arguing that the evidence needed to establish the

intended use of each shipment, Fabian largely relies on Kordel v.

United States, 335 U.S. 345 (1948), and, once again, on the Eighth

Circuit's decision in Articles of Drug, 50 F.3d 497.     Neither case

lends Fabian the support he claims.     Kordel does not, as Fabian

suggests, stand for the broad principle that any conviction for

                              - 70 -
violating the FDCA by marketing an unapproved product requires

evidence (of promotional statements or otherwise) accompanying

that specific shipment to establish the intended use of the shipped

product.    The defendant in Kordel was convicted of misbranding a

drug by marketing it with an inadequate or false label.                   Whether

promotional       statements     had    to    directly    accompany    individual

shipments of a product to establish liability was a relevant issue

in that case because the statute defined a drug label to include

"written,       printed,    or   graphic      matter . . . accompanying      such

article."       Kordel, 335 U.S. at 347 (citing 21 U.S.C. § 201(m))

(emphasis added).          Here, by contrast, Fabian is not accused of

mislabeling a drug product, and thus the scope of the statutory

requirement      that   statements       or   other   materials   "accompany"     a

product    to    be   considered       part   of   the   product's    labeling   is

irrelevant.      The statutory and regulatory scheme at hand speaks of

no similar requirement that materials or other evidence must

"accompany" the individual product unit to shed light on its

intended use.27

            Nor does Articles of Drug lend any persuasive force to

Fabian's argument.          The court did express that "[p]romotional

     27Our decision in Nature Food Centres, Inc. v. United States,
310 F.2d 67 (1st Cir. 1962), is similarly inapposite. That case,
too, discussed the requirement that materials "accompany" shipped
products in the specific context of labeling, drawing that
requirement directly from the statutory and regulatory scheme.
Id. at 70-71.

                                        - 71 -
materials are relevant to intent so long as they are currently

being distributed with the product . . . ."            Articles of Drug, 50

F.3d at 500.     But nothing in the court's analysis suggests that

the caveat that promotional material be "current" -- which also

harkened to the requirement that drug labeling "accompany" the

product, see 21 U.S.C. § 201(m) -- should extend to other forms of

evidence.    To the contrary, the court expressly recognized that

"intended application for a product may be derived from                   any

relevant source."      Articles of Drug, 50 F.3d at 500 (emphasis

added).     Indeed, it even held that past promotional efforts not

tied to a particular shipment can be probative of a product's

intended use in appropriate cases.          Id.   As we have discussed, the

evidence in this case may not be contemporaneous with individual

shipments, but it provided ample reason for jurors to conclude

that the intended use of Stratus, generally, was to deliver

Kenalog, and thus that each shipment of Stratus underlying Fabian's

conviction shared that intended use.

            ii. Evidence of Actus Reus

            In his second sufficiency challenge, Fabian argues that

the government failed to produce evidence that would allow a

rational jury to conclude that he participated in the actus reus

of the crime, which, in his telling, was Acclarent's § 510(k)

filings with the FDA.        Fabian asserts that, because no record

evidence    showed   that   he   participated     in   preparing   regulatory

                                   - 72 -
filings for the company, he could not have committed what he argues

is the criminal act underlying the conviction.             Nor, as vice

president of sales, could he have been considered a responsible

corporate agent for that act.       See United States v. Dotterweich,

320 U.S. 277, 284 (1943); United States v. Park, 421 U.S. 658,

673-74 (1975).    The government counters that the true actus reus

of   violating   § 331(a)   is   "caus[ing]    the   introduction    of   an

adulterated or misbranded article into interstate commerce."              The

government insists that a rational jury could conclude from the

evidence that Fabian, the company's chief salesman, participated

in introducing Stratus -- which the jury otherwise concluded was

a misbranded and adulterated device -- into interstate commerce.

           We agree with the government's assessment, starting with

how to properly characterize the actus reus of the crime.           Section

331(a), upon which Fabian's conviction stands, prohibits "[t]he

introduction or delivery for introduction into interstate commerce

of any . . . device . . . that is adulterated or misbranded."              21

U.S.C. § 331(a).     Plainly enough, the prohibited act under the

statute is causing a misbranded or adulterated device to be

introduced into interstate commerce.          To be sure, the fact that

the device is misbranded or adulterated (and that the article is

a device to begin with) is a separate element of the offense, which

the government must prove to carry a conviction.         But it does not

                                  - 73 -
follow -- and nothing in § 331(a) suggests -- that the government

must prove that the defendant caused it to be misbranded.

            Our recent analysis in United States v. Stepanets, 989

F.3d 88, 95 (1st Cir. 2021), is instructive.                     As relevant here,

Stepanets concerned an appeal from a conviction under 21 U.S.C.

§ 331(a)    for     delivering       a    misbranded      drug    into   interstate

commerce.        The government's theory on misbranding turned on 21

U.S.C. § 353(b)(1), which provides that "the act of dispensing a

drug" absent a proper prescription "shall be deemed to be an act

which results in the drug being misbranded while held for sale."

The defendant urged us to overturn the conviction on the ground

that the record contained no evidence that she, personally, had

dispensed the drug improperly, thereby misbranding it.                     While we

ultimately found it unnecessary to reach that issue, we expressed

doubt that the statutory scheme required such a showing.                          See

Stepanets, 989 F.3d at 95.               After all, the prohibited act under

the statute is "causing . . . [t]he introduction or delivery for

introduction into interstate commerce of any" such drug. 21 U.S.C.

§ 331(a). Section 353(b)(1) explained why the drug was misbranded,

but, as we pointed out, nothing in § 331, under which Stepanets

was   charged,     required    the       government    to   prove   that    she   had

personally caused the drug to become misbranded, so long as she

caused     the    misbranded     drug       to    enter     interstate     commerce.

Stepanets, 989 F.3d at 95.

                                         - 74 -
          Likewise, here, Fabian was convicted under § 331(a) for

causing an adulterated or misbranded device to be introduced into

interstate commerce.     The government's theory on adulteration or

misbranding turns on different FDCA provisions from those at issue

in Stepanets, but our analysis there is equally applicable here.

That is, the jury in this case needed to determine that the device

was adulterated or misbranded (or both), but it did not need to

conclude that Fabian caused the adulteration or misbranding.               As

we observed in Stepanets, § 331(a) speaks of no such requirement,

but only of "causing . . . [t]he introduction or delivery for

introduction          into          interstate           commerce          of

any . . . device . . . that is adulterated or misbranded."

          Accordingly,       we   reject    Fabian's   assertion    that   the

government needed to prove that he participated in the Stratus

§ 510(k) filings.28     Evidence that Fabian caused the device to

     28 Fabian claims that the district court's order denying
appellants' motion for acquittal characterized the actus reus as
he does on appeal. That claim is mistaken. In its order, the
court stated that the actus reus for marketing a misbranded device
was "Defendants' failure to submit a premarket notification for
the intended use" of the drug. Facteau, 2020 WL 5517573, at *14
(emphasis added). In other words, the district court described
the actus reus as marketing a device that lacked the proper
regulatory clearance, which rendered it misbranded and adulterated
under the FDCA.      See 21 U.S.C.A. § 352(o).      For both the
adulteration and misbranding counts, the court's instructions on
the second element of the crimes further made clear the actus reus
by appellants that the jury needed to find: "caus[ing]" an
adulterated or misbranded device "to be introduced into interstate
commerce."

                                   - 75 -
enter into interstate commerce was sufficient -- assuming, as the

jury   found    here,      that   the    device    was   indeed      adulterated    or

misbranded.

            Fabian does not specifically challenge the sufficiency

of the government's evidence to establish that he caused Stratus

to enter interstate commerce, nor could he.                 As we have discussed,

the record is replete with evidence showing that Fabian, as

Acclarent's vice president of sales, had a hand in marketing

Stratus   and    thereby     caused      it   to   enter    interstate      commerce.

Moreover, even in the absence of evidence specifically tying Fabian

to the strategy of marketing Stratus to deliver Kenalog, the jury's

verdict would stand under Dotterweich, 320 U.S. 277, and Park, 421

U.S. 658.      These cases -- both concerning violations of § 331 of

the FDCA -- stand for the proposition that the statute is violated

by anyone who has "a responsible share in the furtherance of the

transaction which the statute outlaws, namely, to put into the

stream of interstate commerce adulterated or misbranded drugs."

Dotterweich, 320 U.S. at 284.             Thus, the government's evidence is

sufficient to sustain a conviction under § 331 of an individual

who    "had,    by   reason       of    his   position      in   the    corporation,

responsibility       and    authority     either    to     prevent     in   the   first

instance, or promptly to correct, the violation complained of, and

[who] failed to do so," even absent direct evidence tying the

defendant to the act.             Park, 421 U.S. at 673-74.             Charged with

                                        - 76 -
spearheading Acclarent's sales and marketing strategy for Stratus,

Fabian was well-situated to prevent or correct the marketing of

adulterated and misbranded Stratus, and it was reasonable for the

jury to find him culpable for failing to do so.

          2. Excessive Fines Clause

          Fabian challenges the $500,000 fine the district court

imposed on him.   He asserts that this fine, which is 2.5 times the

recommended   guidelines   amount   but   well   within   the   statutory

maximum, is excessive in violation of the Eighth Amendment.           The

government counters that Fabian has waived any such argument, and,

regardless, his challenge fails the test laid out in United States

v. Bajakajian, 524 U.S. 321 (1998), and our cases applying it.

          The government's argument for waiver is not without

merit.   Not only did Fabian fail to lodge an Eighth Amendment

objection to the fine at sentencing, but he also acknowledged that

the court could depart from the guidelines up to the statutory

maximum. Nonetheless, we choose to deem the Eighth Amendment claim

forfeited rather than waived and, as in similar cases, we will

review the district court's judgment for     plain error.       See, e.g.,

United States v. Sepúlveda–Hernández, 752 F.3d 22, 36 (1st Cir.

2014); United States v. Aguasvivas-Castillo, 668 F.3d 7, 16 (1st

Cir. 2012); United States v. Beras, 183 F.3d 22, 28 (1st Cir.

1999).   See also Fed. R. Crim. P. 52(b) ("A plain error that

affects substantial rights may be considered even though it was

                               - 77 -
not brought to the court's attention.").                   Fabian therefore "must

show '(1) that an error occurred (2) which was clear or obvious

and which not only (3) affected [his] substantial rights, but also

(4) seriously     impaired        the    fairness,        integrity,     or    public

reputation of judicial proceedings.'"                   Nieves-Meléndez, 58 F.4th

at 579 (quoting Merced-García, 24 F.4th at 79-80).29

            Fabian has not made that showing.                   For a fine to be

excessive    under     the   Eighth      Amendment,        it   must   be     "grossly

disproportional      to    the    gravity   of     the     defendant's      offense."

Bajakajian, 524 U.S. at 337.             We have distilled from the Supreme

Court's     guidance      three   factors        that    courts   must      consider:

"(1) whether the defendant falls into the class of persons at whom

the criminal statute was principally directed; (2) other penalties

authorized by the legislature (or the Sentencing Commission); and

(3) the harm caused by the defendant."              United States v. Heldeman,

402 F.3d 220, 223 (1st Cir. 2005) (citing Bajakajian, 524 U.S. at

     29 The government further contends that Fabian waived plain
error review by failing to apply this four-factor test in his
opening brief. While that is true, his arguments make apparent
his theory of the district court's plain error, and he did squarely
address the plain error factors in his reply brief. See United
States v. Serrano-Delgado, 29 F.4th 16, 27 (1st Cir. 2022) (citing
United States v. Pabon, 819 F.3d 26, 33–34 (1st Cir. 2016))
("[P]lain error review is waived if its four-part test is not
argued at least in reply."). Moreover, "'[w]here a defendant's
claim would fail even if reviewed for plain error, we have often'
simply proceeded to the merits."        Grullon, 996 F.3d at 32
(alteration in original) (quoting United States v. Brake, 904 F.3d
97, 99 (1st Cir. 2018)). As we explain, Fabian's Eighth Amendment
claim fails under plain error review.

                                        - 78 -
337-40).30    Nothing from this guidance suggests that the fine the

district court imposed was in error.

             First,     as     an   executive     of   a      medical   device

company -- and        one    specifically    tasked    with    marketing   its

products -- Fabian falls squarely within "the class of persons at

whom    [§ 331(a)]     [is]   principally     directed."      Id.31     Second,

comparison to the "other penalties authorized by the legislature

(or the Sentencing Commission)" shows that the fine the district

court imposed is not excessive.             Id.   Notably, Fabian's fine is

only half of the maximum fine authorized by the statute.                See 18

U.S.C. § 3571(b)(5). Indeed, Facteau, Fabian's co-defendant, was

       Bajakajian and Heldeman both concerned forfeitures rather
       30

than literal fines like the one at issue in this case. However,
both cases considered those forfeitures to be fines within the
meaning of the Excessive Fines Clause. See Bajakajian, 524 U.S.
at 328 ("Forfeitures -- payments in kind -- are thus 'fines' if
they constitute punishment for an offense.").        Hence, the
principles announced in Bajakajian and distilled in Heldeman are
equally relevant when considering actual fines rather than
forfeitures.
       Fabian suggests, without citation, that the first Heldeman
       31

factor is relevant only to cases involving forfeitures and
therefore does not apply to the fine here. We do not agree. In
Bajakajian, the Supreme Court considered whether the defendant
fell within the class of people at whom the statute was directed
not because the penalty at issue was a forfeiture but to determine
if the penalty corresponded to the defendant's conduct. In that
case, the statute was "principally designed" to stop the activity
of "money launderer[s], drug trafficker[s], [and] tax evader[s],"
but the defendant was none of these things -- he was carrying the
forfeited cash to pay off a lawful debt. Bajakajian, 524 U.S. at
338. By contrast, § 331(a) is principally directed at those, like
Fabian, who sell medical devices (among other products covered by
the FDCA).

                                    - 79 -
convicted of the same ten counts as Fabian but received the

statutory maximum fine of $1 million.     Where a fine falls below

the statutory maximum, we have suggested that "a defendant who

purposes to challenge its constitutionality faces an especially

steep uphill climb."   Sepúlveda–Hernández, 752 F.3d at 37.

           Fabian emphasizes that his fine is more than twice the

maximum amount stated in the sentencing guidelines, which at the

time of Fabian's offense was $200,000.   See U.S.S.G. § 5E1.2(c)(3)

(2014) (maximum fine of $20,000 per count for level 10 offenses).

True, we have inferred from Bajakajian that "the maximum penalties

provided under the Guidelines should be given greater weight than

the statute because the Guidelines take into consideration the

culpability of the individual defendant."    Beras, 183 F.3d at 29

n.5 (citing Bajakajian, 524 U.S. at 339 n.14).    But that caution

does not mean that any fine exceeding the Guidelines, yet within

the statutory maximum, becomes per se unconstitutional.   In United

States v. Carpenter, for example, we observed that the Guidelines

were calibrated to the "gain or loss resulting from the offense,"

sanctioning an upward departure when necessary to achieve that

aim.   941 F.3d 1, 11 n.8 (1st Cir. 2019) (quoting U.S.S.G. § 5E1.2

cmt. n.4).     There, we ultimately upheld a forfeiture of $14

million, which dwarfed the maximum guideline sentence of $100,000.

Here, the district court reasoned that Fabian's crime warranted a

hefty financial penalty because "[t]his was a crime about money"

                              - 80 -
and "in the corporate environment in which we live," the "best

way" to "accomplish general deterrence" is by "financial penalty."

The district court thus justified its decision to exceed the

Guidelines with a thoughtful explanation that reveals no error.

           Finally, while the record does not show injury to others

or financial harm, damage to the government's regulatory interests

is also an important consideration.                 See, e.g., United States v.

Jose, 499 F.3d 105, 112 (1st Cir. 2007) (choosing to "adhere to

Congress's     view    that    defendant's         violation    of    the    bulk   cash

smuggling statute constitutes a significant harm," without noting

any   direct    harm   to     individuals         resulting    from    his   actions);

Aguasvivas-Castillo,          668   F.3d     at    17   (stating      that   harm   from

defendant's food stamp fraud included "introduc[ing] waste into

the program," undermining efforts to "reduce opportunities for

fraud,"   and    subverting         Puerto    Rico's     judgment      about   how   to

administer its food stamp program).

           Here, the district court noted the regulatory harm of

Fabian's conduct, remarking:

           I feel [it] is critically important to
           protect . . . the integrity of the regulatory
           process.   . . .  I think that the FDA is
           important. I think that they try very hard to
           do what is a very difficult job, and it is
           important to maintain the integrity of this
           process for them.

           And again as I noted [in Facteau's sentencing
           hearing], particularly in the time of COVID,
           it's become just starkly clear how important

                                       - 81 -
           it is that the public have confidence in what
           the FDA does.

           The district court's conclusion that these harms to the

government's regulatory prerogatives warranted serious punishment,

even in the absence of recorded harm to any individual, is well-

founded.   After all, the FDCA reflects Congress's longstanding

view that marketing unadulterated or misbranded medical devices is

a serious offense, the violation of which endangers public health

and harms the government's interests in ensuring public confidence

in the market for products overseen by the FDA.32

           Because we conclude that the district court's sentence

was not in error, much less plain error, we find that Fabian's

fine of $500,000 passes muster under the Eighth Amendment.

                                   III.

           To   briefly   recap   our      holdings,   we   conclude   that

appellants' convictions did not violate the First Amendment or

     32 See, e.g., POM Wonderful LLC v. Coca-Cola Co., 573 U.S.
102, 108 (2014) ("The FDCA statutory regime is designed primarily
to protect the health and safety of the public at large."); Brown
& Williamson Tobacco Corp., 529 U.S. at 133 ("[O]ne of the Act's
core objectives is to ensure that any product regulated by the FDA
is 'safe' and 'effective' for its intended use. . . . This
essential purpose pervades the FDCA."); In re Zofran (Ondansetron)
Prod. Liab. Litig., 57 F.4th 327, 330 (1st Cir. 2023) ("Congress
enacted the Food, Drug, and Cosmetic Act (FDCA) in 1938 'to bolster
consumer protection against harmful products.'" (quoting Wyeth v.
Levine, 555 U.S. 555, 574 (2009))). See also 21 U.S.C. § 393(b)(2)
(defining the FDA's mission as "protect[ing] the public health by
ensuring that . . . there is reasonable assurance of the safety
and effectiveness of devices intended for human use").

                                  - 82 -
constitutional due process, that the district court's instruction

to the jury that it may consider evidence of intended use from any

relevant source was proper, that Fabian's conviction was supported

by sufficient evidence, and that Fabian's fine did not violate the

Eighth Amendment.   We therefore affirm appellants' convictions and

Fabian's fine.

           So ordered.

                               - 83 -