United States Court of Appeals For the First Circuit

No. 00-1158

UNITED STATES,

Appellee,

v.

DAVID W. PRIGMORE,

Defendant, Appellant,

No. 00-1229

UNITED STATES,

Appellee,

v.

LEE H. LEICHTER

Defendant, Appellant,

No. 00-1230

UNITED STATES,

Appellee,

v.

JOHN F. CVINAR,

Defendant, Appellant. APPEALS FROM THE UNITED STATES DISTRICT COURT

FOR THE DISTRICT OF MASSACHUSETTS

[Hon. Joseph L. Tauro, U.S. District Judge]

Before

Selya, Circuit Judge, Coffin, Senior Circuit Judge, and Stahl, Circuit Judge.

Richard G. Taranto, with whom Farr & Taranto, Andrew Good, Harvey A. Silverglate, Silverglate & Good, William H. Kettlewell, Michael B. Galvin, Dwyer & Collora, LLP, Robert D. Keefe, Daniel W. Halston, Jason T. Sherwood, and Hale and Dorr LLP, were on brief, for appellants. David S. Kris, Attorney, Department of Justice, with whom David S. Mackey, Acting United States Attorney, Stephen A. Higginson, Special Assistant United States Attorney, and Michael K. Loucks, Assistant United States Attorney, were on brief, for appellee.

March 16, 2001 STAHL, Circuit Judge. On August 24, 1995, after a

twenty-seven day trial, a jury convicted defendants-appellants

Lee H. Leichter, John F. Cvinar, and David W. Prigmore of

conspiring to defraud and impair the functioning of the United

States Food and Drug Administration (FDA) in connection with its

oversight and regulation of medical devices. See

. The jury simultaneously acquitted George Maloney and

Kenneth Thurston of the same charge. The district court

thereafter sentenced each convicted defendant to 18 months'

imprisonment and two years of supervised release, but stayed

execution of the sentences pending appeals. In these appeals,

Leichter, Cvinar, and Prigmore ("defendants") raise a host of

arguments challenging the legality of their convictions. In

addition, Prigmore claims that insufficient evidence supports

his conviction and that his sentence is unlawful. We vacate the

convictions and remand for further proceedings.

I.

Because we review the trial record primarily to

ascertain whether an error in the district court’s jury

instructions was harmless, see infra Section II, we look at the

evidence as a whole and not in the light most favorable to the

government, see Arrieta-Agressot v. United States,

(1st Cir. 1993). Thus, although we give a detailed account

-3- of the evidence the government relies on to support its case

theory and harmless-error argument, we also provide an overview

of relevant responsive evidence and arguments. See

at 528-

29. We note too that this case has a complicated procedural

history which we describe only insofar as is relevant to these

appeals. Readers interested in additional procedural background

should consult our previous opinion in this matter. See United

States v. Leichter,

(1st Cir. 1998).

A. Statutory and Regulatory Background

In 1976, Congress amended the Food, Drug, and Cosmetics

Act (FDCA),

et seq., by passing what it

denominated the Medical Device Amendments (MDA), 21 U.S.C. §

360c et seq. The amendments made the FDA responsible for

ensuring the safety and effectiveness of medical devices

distributed to the American public. This prosecution proceeded

on the theory that, in testing and marketing medical devices

known as "heart catheters," the defendants conspired to violate

provisions of these statutes and regulations promulgated

thereunder.

A heart catheter is a tiny instrument consisting

primarily of a thin metal wire with a small inflatable balloon

at or near one end. The device is used in a surgical procedure

called angioplasty, which seeks to treat heart disease by

-4- opening clogged coronary arteries. During angioplasty, a

physician inserts a heart catheter into a patient's body,

typically through an artery in the leg or groin area. The

physician then steers the device through the patient's

circulatory system to the site of the blockage and inflates the

balloon with fluid. As it is inflated, the balloon breaks the

"plaque" that is clogging the artery and pushes it against the

artery wall. The physician subsequently withdraws the liquid,

deflates the balloon, and removes it and the catheter, thereby

allowing blood to flow freely through the artery.

Regulations promulgated pursuant to the FDCA and MDA

designate heart catheters as Class III medical devices. See

generally 21 C.F.R. Part 870. Class III medical devices are the

most heavily regulated medical devices in the country. See 21

U.S.C. § 360c(a). Before a manufacturer may market a new Class

III medical device, the manufacturer must apply for and receive

"premarket approval" (PMA) from the FDA. 21 U.S.C. §

360c(a)(C). In connection with its PMA application, the

manufacturer must submit information sufficient to provide the

FDA with "reasonable assurance" that, inter alia, the device is

both "safe" and "effective." 21 U.S.C. § 360e(d)(2).

Under the MDA,

[T]he safety and effectiveness of a [Class III] device are to be determined –

-5- (A) with respect to the persons for whose use the device is represented or intended,

(B) with respect to the conditions of use prescribed, recommended, or suggested in the labeling of the device, and

(C) weighing any probable benefit to health from use of the device against any probable risk of injury or illness from such use.

21 U.S.C. § 360c(a)(2). Regulations promulgated pursuant to

this statute (and others) elaborate:

In determining the safety and effectiveness of a device for purposes of [deciding whether to grant] . . . premarket approval of class III devices, the Commissioner . . . will consider the following, among other relevant factors: (1) The persons for whose use the device is represented or intended; (2) The conditions of use for the device, including conditions of use prescribed, recommended, or suggested in the labeling or advertising of the device, and other intended conditions of use; (3) The probable benefit to health from the use of the device weighed against any probable injury or illness from such use; and (4) The reliability of the device.

(b).

There is reasonable assurance that a device is safe when it can be determined, based upon valid scientific evidence, that the probable benefits to health from use of the device for its intended uses and conditions of use, when accompanied by

-6- adequate directions and warnings against unsafe use, outweigh any probable risks.

§ 860.7(d)(1).

There is reasonable assurance that a device is effective when it can be determined, based upon valid scientific evidence, that in a significant portion of the targeted population, the use of the device for its intended uses and conditions of use, when accompanied by adequate directions for use and warnings against unsafe use, will provide clinically significant results.

Id. § 860.7(e)(1).

Two additional sets of regulations governing Class III

surgical devices are of particular importance to this case, so

we describe them in some detail. The first requires, insofar as

is relevant, that a manufacturer of a previously approved Class

III surgical device "submit a PMA supplement for review and

approval by FDA before making a change affecting the safety or

effectiveness of the device . . . ."

(a). As

with an application for initial PMA, the so-called "PMA

supplement" must contain scientific information that provides a

basis for approval of the modified device. See

§ 814.39(c).

The regulation lists eight "types of changes" for which a PMA

supplement must be filed "if [the changes] affect the safety or

effectiveness of the device," id. § 814.39(a), including the

following: "[n]ew indications for use of the device," id.

-7- § 814.39(a)(1); "[t]he use of a different facility or

establishment to manufacture, process, or package the device,"

id. § 814.39(a)(3); and "[c]hanges in the performance or design

specifications, circuits, components, ingredients, principle of

operation, or physical layout of the device," id.

§ 814.39(a)(7). By operation of § 814.39(c) ("All procedures

and actions that apply to [a PMA] application under § 814.20

also apply to PMA supplements . . ."), the manufacturer also

must "periodically update [a] pending [PMA] application with new

safety and effectiveness information learned about the device

from on-going or completed studies that may reasonably affect an

evaluation of the safety or effectiveness of the device . . . ."

Id. § 814.20(e).

As implied by the regulations just quoted, a

manufacturer need not submit a PMA supplement "if the change

does not affect the device's safety and effectiveness . . .,

e.g., an editorial change in labeling which does not affect the

safety or effectiveness of the device." Id. § 814.39(b). But

where the FDA has required periodic reports as a condition of

approval of the device, the manufacturer must report any changes

to the FDA "in [its] postapproval periodic reports . . . ." Id.

The PMAs of the heart catheters at issue in this case explicitly

-8- required postapproval reports documenting any and all changes to

the catheters.

The second set of regulations underlying this

prosecution arise from the background fact that, prior to

submitting a PMA application or PMA supplement, the manufacturer

of a new or modified Class III medical device may desire to test

the device in humans. To do so lawfully, the manufacturer must

apply to the FDA for an "investigational device exemption"

(IDE). An IDE "permits a device that otherwise would be

required . . . to have premarket approval to be shipped lawfully

for the purpose of conducting investigations of that device."

(a). An IDE thus permits limited use of an

unapproved device for the purpose of collecting human test data.

See

But the testing regulations themselves specify a number

of situations in which an IDE is not a prerequisite to the

investigational use of unapproved Class III medical devices in

humans. See

§ 812.2(a), (c). Such “exempted

investigations” include "consumer preference testing" and the

"testing of a modification" to an approved Class III medical

device, so long as "the testing is not for the purpose of

determining [the unapproved device's] safety or effectiveness

and does not put subjects at risk." Id. § 812.2(c)(4).

-9- B. Relevant Factual Background

Defendants had leadership positions at United States

Catheter and Instrument, Inc. (USCI), a division of C.R. Bard,

Inc. (Bard), for most or all of the alleged conspiracy period,

which ran from 1987 to 1990. Defendant Leichter was USCI's head

of regulatory affairs and quality assurance; defendant Cvinar

was USCI's president; and defendant Prigmore, who previously had

been president of USCI, was until September 1989 a vice

president at Bard with authority over USCI's operations. All

three defendants had offices in Billerica, Massachusetts, where

USCI operated a manufacturing plant and maintained its corporate

headquarters.

USCI's chief decision-making body was its Management

Board. Cvinar presided over the Board and Leichter was a

member. Cvinar reported to Prigmore. Representatives from

middle management at USCI made up an organization known as the

"Breakfast Club." The Breakfast Club reported regularly to the

Board and provided the Board with the minutes of its meetings.

The Breakfast Club had no authority to make decisions without

the Board's approval. Leichter was not a member of the

Breakfast Club, but he sometimes attended its meetings.

The conspiracy alleged in this case involved two lines

of heart catheters manufactured by USCI. In 1987, USCI

-10- introduced the first line, which we shall call the "Probe Line,"

with a catheter known as "Probe A." In 1988, USCI modified

Probe A and renamed it "Probe B." In early 1989, USCI began

distributing Probe B commercially. Later in 1989, USCI modified

Probe B and renamed it "Probe C." At trial, the government's

conspiracy theory with respect to the Probe Line was that, under

defendants' leadership and with defendants' knowledge and

approval, USCI tested Probe B and Probe C in humans in violation

of the Class III medical device testing regulations; marketed

Probe B and Probe C in violation of the Class III medical device

marketing regulations; and otherwise deceived the FDA in order

to avoid the agency's oversight.

In 1987, the second line of heart catheters, which we

shall call the "Miniprofile Line," featured a catheter called

the "Simplus.” In 1988, the Simplus evolved into a catheter

called the "Miniprofile,” which, in 1989, evolved into a

catheter called the "Solo." In 1989, USCI also filed a PMA

supplement for a catheter called the "Solo Sr.," but the company

never manufactured the Solo Sr. and ultimately withdrew the

filing. With respect to the Miniprofile Line, the government's

conspiracy theory once again was that, under defendants'

leadership and with defendants' knowledge and approval, USCI

committed a number of violations of the Class III medical device

-11- testing and marketing regulations and otherwise lied to the FDA

to avoid the agency's oversight. The following is a summary of

the evidence supporting the government's conspiracy theories.

1. The Probe Line

In the early 1980s, when angioplasty first became

available in this country, USCI controlled 100% of the market

for heart catheters. By the late 1980s, however, USCI's market

share had declined by about half and the market had become very

competitive. When USCI introduced the FDA-approved Probe A in

1987, the device initially sold very well. But the device had

a significant limitation. Although USCI marketed Probe A with

a label warning that it should not be rotated more than one full

turn (360 degrees) in the same direction, physicians performing

angioplasties sometimes saw it as necessary to rotate the device

beyond its warned-against limitation. When this occurred, the

device's balloon had a tendency to wrap itself around the wire,

which prevented deflation. This, in turn, blocked blood flow

through the artery and complicated efforts to remove the device

from the body.

USCI's solution to Probe A's wrapping problem was Probe

B, a redesigned version of the same catheter. In Probe A, the

balloon attached at the end of the wire, but in Probe B, the

balloon attached to a polymer tube threaded over the wire. The

-12- result was that Probe B could be rotated more than once in the

same direction without the balloon becoming entangled.

Unfortunately, however, the new design created different

problems.

There was evidence that, in actual use in humans, Probe

B's wire broke 25 times more frequently than Probe A's wire.

There also was evidence that, when compared to Probe A, these

breaks were far more likely to occur when the device was rotated

more than once in the same direction. Moreover, the

consequences of a Probe B wire break tended to be more serious.

In the relatively unlikely event of a Probe A wire break, the

catheter's metal tip typically would not detach and could be

removed with the wire and balloon. By contrast, when Probe B

broke, the broken tip frequently could not be removed with the

rest of the catheter. In such a situation, the physician either

had to leave the tip in the patient or remove it by invasive

surgery. Evidence of these problems poured into USCI in early

1989, but, contrary to the urgings of certain USCI "Crisis Team"

members appointed by Cvinar to handle the situation, USCI, and

then Bard, declined to order a voluntary recall of Probe B.

The government contends that this disastrous state of

affairs was a direct result of USCI violating the regulations

governing the testing and marketing of Class III medical devices

-13- in connection with bringing Probe B to market. We start with a

synopsis of the evidence of unlawful testing in connection with

Probe B.

a. Misconduct Involving the Probe B

On November 11, 1988, one of Leichter's subordinates

filed a PMA supplement for Probe B asserting that it should be

approved without being tested in humans. Upon receipt of the

supplement, the FDA questioned USCI's assertion and asked for

proof that clinical testing was unnecessary. In a December 13,

1988 letter and in a December 15, 1988 meeting, certain of

Leichter's subordinates explained to FDA representatives that

Probe B's safety and effectiveness had been established by

laboratory "bench" testing and that the FDA could rely on data

submitted in connection with Probe A's PMA application because

the two devices were similar. The December 13 letter also

explained that clinical testing was not necessary because bench

testing had showed that Probe B "allows for more independent

rotation of the core wire and balloon" than Probe A. Leichter

sent the Management Board a copy of the December 13 letter and

a memorandum summarizing the December 15 meeting. On these

documents he handwrote "Excellent work." On January 19, 1989,

the FDA approved Probe B for commercial distribution without

requiring testing in humans.

-14- In fact, however, notwithstanding its representations

to the FDA and without having applied for an IDE, in late

October 1988, USCI began shipping Probe B catheters for purposes

of gathering feedback as to how they performed in humans.

Documentary evidence suggests that this feedback gathering,

which USCI called "disaster checking," was for purposes of

ascertaining Probe B's rotational capabilities, steerability,

and "performance characteristics . . . as compared to the [Probe

A]." The government contends that testing for such purposes was

safety or effectiveness testing, and thus violated a negative

implication to be found in the Class III medical device testing

regulations: that an unapproved Class III medical device may not

be tested in humans for safety or effectiveness without an IDE.

See generally 21 C.F.R. Part 812. With the exception of

Prigmore, who explicitly challenges the sufficiency of the

government's proof linking him with this evidence, defendants do

not dispute that they were aware of and approved of this course

of conduct. Rather, pointing to testimonial evidence supporting

their case theory, they (joined by Prigmore arguing in the

alternative) take the position that this "testing" was solely

for purposes of establishing consumer preferences; was not for

purposes of determining safety or effectiveness as defendants

reasonably understood the regulations to define those terms; and

-15- did not pose risks to humans beyond those associated with Probe

A. Defendants thus understood the testing to be exempted from

Part 812's IDE requirements by § 812.2(c)(4). We shall have

considerably more to say on the defendants' understanding of

Part 812 and the terms "safety" and "effectiveness" later in

this opinion.

The government also argues that, in bringing Probe B

to market, USCI violated the Class III medical device marketing

violations in two ways. First, USCI failed to report to the FDA

that it was conducting clinical tests in humans in several

documents: the Probe B PMA supplement (which was filed after

clinical tests in humans began in October 1988); the December

13, 1988 letter to the FDA; the December 15, 1988 meeting with

FDA representatives; and the subsequent updates required by the

FDA when it approved Probe A. See

(c),

814.20(e). Moreover, USCI failed to report that, in Probe B's

clinical tests, the device experienced breakage rates far beyond

those reported with respect to Probe A as marketed. See

Here too, only Prigmore disputes the sufficiency of the evidence

that he was aware of Probe B's test results and the subsequent

failure to share those results with the FDA; the other

defendants take the position that, under their understanding of

-16- the regulatory mandates and the typical circumstances of a Probe

B tip break, no reporting was required.

Second, USCI representatives were marketing Probe B

with the claim that it could be rotated more than once in the

same direction even though Probe B’s PMA supplement represented

that the device would retain Probe A's label warning against

more than a single revolution. There was evidence that, despite

the label warning, the device was presented to USCI sales staff

as the solution to Probe A's rotational limitations.

Presentations to sales staff at the company's annual national

meeting held at Lake Tahoe, California, from January 15-17,

1989, left at least one salesman with the impression that "Probe

B could be torqued more than once, and that was the whole idea

of freeing the wire [from the balloon]." Also, written

promotional materials for Probe B explained that "[t]his new

device allows increased torque delivery because of the new

design" and that "with every rotation, it's the wire you're

steering and not the balloon." In addition, a USCI videotape

designed to instruct doctors on use of Probe B contained remarks

from a doctor suggesting that the device could be rotated two or

three times.

USCI's sales force, which had been instructed to warn

physicians against overrotation of Probe A, were not so

-17- instructed with respect to Probe B. Indeed, USCI sales staff

informed physicians that, although there would be no labeling

change, Probe B contained improvements "that should prevent the

twisting problem" that occurred with overrotation of Probe A.

One USCI representative told a doctor that he could rotate Probe

B as many as 10 times, and another told several doctors at a

physicians' conference that they could rotate the device up to

15 times (although the second representative subsequently was

admonished not to advocate such extreme use).

Defendants do not contest that USCI representatives in

fact told physicians that they could rotate Probe B more than

once, and that USCI promotional materials might have given the

same impression. Defendants vigorously contest, however, that

they themselves knew of and condoned promotion of Probe B

contrary to its label warning. The evidence as to defendants’

knowledge and condonation was thin; Cvinar and Prigmore attended

the January 1989 Lake Tahoe conference, but no witness placed

them at the presentation in question. All promotional materials

relating to use of a Class III device were approved by the

regulatory affairs department (which Leichter headed), but there

was evidence that the doctor’s remarks on the videotape were

added after regulatory affairs had approved it. In any event,

no witness or document ever directly tied defendants to the

-18- promotional materials in question. Finally, there was evidence

that Leichter insisted that label warnings be followed when he

learned that some USCI salespeople had been promoting Probe B

contrary to its label warnings.

b. Misconduct Involving the Probe C

The government asserts that USCI committed similar

regulatory infractions with respect to the testing and marketing

of Probe C. In early 1989, at the same time the Crisis Team was

reacting to the problems with Probe B, USCI was working urgently

on modifications designed to rectify those problems. The result

was Probe C. USCI bench tested eight Probe C prototypes and,

without having secured an IDE from the FDA, shipped two or three

of the prototypes for use in humans to see whether the changes

improved the strength of the catheter's tip and thus reduced the

chance of breakage. Some of the prototypes used in humans did

not perform as well as Probe B, but, by March 1989, USCI had

settled on a final version. In this version, USCI increased the

diameter of the device's core wire by 30% and eliminated a

solder joint used to attach the wire to a spring. USCI also

modified the device's assembly process.

USCI then marketed Probe C without filing a PMA

supplement. In fact, the company took steps that can be taken

to evince an intent to conceal Probe C’s changes and thus to

-19- blur the differences between Probe C and its predecessor. For

example, USCI basically retained the Probe B label for the new

device but placed on the label an inconspicuous dot or small

letter "C" so that USCI, and USCI alone, would know the model's

identity. In the government's view, the unapproved testing and

marketing of Probe C was unlawful because the testing was for

purposes of establishing the device's safety or effectiveness,

see 21 C.F.R. Part 812, and because the new product contained

design changes affecting its safety or effectiveness, see

§ 814.39(a), (b). Once more, Prigmore contests the sufficiency

of the evidence establishing his knowledge and approval of

USCI's conduct with respect to Probe C, and the other defendants

assert that their conduct was perfectly lawful under their

understanding of the applicable regulations.

c. Additional Deceptions

In the spring of 1989, the FDA learned that USCI had

modified Probe B so as to create Probe C without filing a PMA

supplement. At the same time, the FDA came into possession of

information that caused it to become concerned about Probe B tip

breaks. On April 25, 1989, an FDA reviewer met with Leichter

and informed him that she was concerned whether Probe B was

sufficiently safe. Leichter denied that there were safety

concerns and failed to reveal the tip breaks that had occurred

-20- during the investigational use of Probe B in humans. The next

day, Prigmore sent Leichter a memo conveying a "personal 'job

well done' with regard to your recent dealings on the Probe, and

particularly your meeting with the FDA."

The FDA later requested explanations for both Probe B's

failure rates and USCI's failure to file a PMA supplement with

respect to Probe C. On May 15, 1989, USCI responded to the

FDA's concerns by letter. All three defendants spent several

hours reviewing the contents of the letter. The letter

explained that, following field observation and analysis of

broken catheters, it had become clear to USCI that Probe B's

breakage problems were attributable to "overtorque[ing] during

clinical use while the tip was restricted." In other words, the

device was only breaking when it was being used contrary to its

label warning against more than a single revolution in either

direction. The letter also took the position that Probe B was

sufficiently safe because the device's actual breakage rate was

statistically identical to the breakage rate of Probe A observed

in clinical testing and reported to the FDA before the agency

acted favorably on the Probe A PMA application. But the letter

did not reveal that the tip of Probe B had a tendency to remain

in the patient following a break. Nor did it acknowledge that,

in actual use, Probe B in fact broke 25 times more frequently

-21- than did Probe A, and that, during what defendants call the

"consumer preference testing" of Probe B, the device broke many

times more frequently than did Probe A in actual use.

Defendants contend that, under their understanding of the

regulations and the circumstances of Probe B tip breaks, none of

the foregoing representations or omissions was fraudulent.

The letter also explained that, although the design

modifications in Probe C "substantially reduced the risk of

critical tip failure," these modifications did not affect the

device's safety or effectiveness. The asserted basis for these

seemingly contradictory assertions was a tripartite argument:

(1) the regulations only require the filing of a PMA supplement

when a design modification affects the safety or effectiveness

of the device when it is used in accordance with its labeling;

(2) the modifications to Probe B inhering in Probe C only

affected (by improving) the safety and effectiveness of the

device when it was used in a manner contrary to its labeling

(i.e., when, contrary to its label warning, the device was

rotated more than a single revolution in the same direction);

and (3) the modified catheter that became Probe C thus could be

marketed without a PMA supplement. This argument presaged

defendants' trial position in the dispute about the meaning of

the regulations at the core of this case.

-22- On June 9, 1989, the FDA ordered a recall of Probes B

and C and directed USCI to file a PMA supplement before

marketing Probe C in the future. In August 1989, USCI submitted

such a supplement. In the supplement, USCI asserted that the

Probe C was in fact safe and effective and cited in support of

this claim the data gathered during its earlier investigational

use of the device in humans, along with additional follow-up

data collected at the direction of the FDA. The PMA supplement

stated without limitation that Probe C had been "distributed

from March 1989 until August 1989" in order "to determine the

safety and efficacy of the device."

2. The Miniprofile Line

During the conspiracy period, the Miniprofile line was

USCI's second most profitable line of catheters, ranking just

behind the Probe line in sales. At trial, the government

introduced evidence tending to show that, with defendants'

knowledge and approval, USCI engaged in four courses of conduct

with respect to the Miniprofile line that the government sees as

fraudulent: (1) in late 1987, USCI changed the manufacturing

location for the Miniprofile line and then marketed catheters

manufactured at the new location without obtaining the FDA's

prior approval; (2) in 1988, USCI modified the design of the

Miniprofile, tested the modified catheter in humans without

-23- having secured an IDE, marketed the modified version without

having filed a PMA supplement, and adopted complex inventory

sorting and labeling methods designed to conceal the change; (3)

in 1989, in PMA supplements filed in connection with several

additional changes to the Miniprofile, USCI (a) represented that

clinical testing was not necessary to evaluate the safety or

effectiveness of the changes at the same time it allegedly was

conducting such testing, and (b) failed to reveal the 1988

design change; and (4) in August 1989, USCI filed a PMA

supplement crafted to "legitimize" the 1988 design change. We

elaborate briefly on each of these four blocs of evidence.

a. The Change in Manufacturing Location

As previously detailed, the first catheter in the

Miniprofile line was called the "Simplus." Until the end of

1987, USCI manufactured the Simplus at a plant in Billerica,

Massachusetts. In September 1987, USCI acquired a factory

building in Haverhill, Massachusetts, and began preparations to

move its Simplus manufacturing operations there. The move

required approximately six weeks of work from a 25-person crew,

structural changes to the buildings, and the installation of

filters and purifiers to de-ionize the air and water. The idea

was essentially to "replicate" the Billerica Simplus

-24- manufacturing operations, although only some Billerica machines

and workers were transferred to the new plant.

On December 15, 1987, USCI filed a PMA supplement

requesting FDA approval to manufacture the Simplus at its

Haverhill facility. On March 3, 1988, the FDA sent inspectors

to the Haverhill plant. After a five-day inspection, the

inspectors identified a number of problems with various pieces

of equipment at the new plant. On March 23, 1988, Cvinar wrote

to the FDA and promised to correct the problems. On June 7,

1988, the FDA approved the PMA supplement for the Haverhill

facility, stating in a cover letter that "[y]ou may begin

marketing of the device manufactured at this facility upon

receipt of this letter." But by that time, USCI already had

marketed several thousand catheters manufactured at the

Haverhill plant.

As noted above, the regulations for Class III medical

devices require the filing of a PMA supplement when an approved

device is manufactured at "a different facility and

establishment" and the change in location affects the device's

safety or effectiveness. See

(a)(3). The

government takes the position that the move from Billerica to

Haverhill was one that affected safety or effectiveness and thus

required FDA approval prior to the marketing of any catheters

-25- assembled in Haverhill. Defendants respond that, because the

Haverhill operations were designed to replicate the Billerica

operations, the move was "safety neutral" and the PMA supplement

USCI filed was in fact unnecessary. Defendants also contest the

sufficiency of the evidence linking them with the decision to

market Haverhill-manufactured catheters prior to FDA approval.

b. The 1988 Design Change

On May 24, 1988, the FDA approved the marketing of the

Miniprofile catheter, which evolved from the Simplus. As

approved, the Miniprofile contained three "lumens," which are

the tiny tubes used to inflate and deflate the balloon.

Originally, USCI intended to manufacture the Miniprofile with a

"fast purge" system that facilitated quick elimination of air

from the lumens prior to filling them with the liquid that would

inflate the balloon. The fast purge system was patented,

however, and USCI ultimately could not use it in the

Miniprofile.

Following its commercialization, the Miniprofile

developed a reputation for having a deflation problem. There

was evidence that the problem was largely traceable to end users

not preparing and purging the catheter in accordance with the

-26- instructions in its labeling. But there also was evidence that

the round shape of the Miniprofile's lumens may have been a

contributing factor. In any event, the perception that the

Miniprofile had a deflation problem affected sales, and USCI

began investigating the possibility of an ameliorative

modification.

Eventually, USCI decided that a reduction in the number

of lumens from three to two would positively affect Miniprofile

deflation issues. The company created a two-lumen prototype

and, after bench testing, shipped it for investigational use in

humans. USCI did not secure an IDE prior to its investigation

of the device, the objective of which (as stated in an internal

USCI document) was "[t]o evaluate the 2 Lumen Mini/Simplus

catheter for improved inflation/deflation times; and to verify

that non-deflation of the balloon will not occur." On November

3, 1988, a USCI employee sent the Management Board and Breakfast

Club a memorandum summarizing the results of the company's

testing. On November 7, 1988, Cvinar informed Prigmore in

writing that testing of the two-lumen Miniprofile had been

completed, that the testing revealed "significantly better

inflation/deflation times with latest 2 lumen version," and

that USCI would be changing to the two-lumen design "post

haste." On November 17, 1988, Cvinar sent the Management Board

-27- a memo explaining that the changeover to a two-lumen Miniprofile

was a "safety issue" and linking the decision with the need to

"remain competitive in key market areas."

USCI did not file a PMA supplement prior to marketing

the two-lumen Miniprofile. Moreover, the company took steps

that tend to evince an intent to conceal the change from the

FDA. For example, Leichter would not permit USCI's vice

president of marketing to issue a brochure with a diagram of the

modified catheter because the diagram was "inconsistent with

what had been submitted to the FDA . . . ." Leichter also

rejected a subordinate’s suggestion that the label of the

modified device reflect the decreased number of lumens,

explaining that "[w]e don't want it to be evident to the FDA, so

I would rather have something different that would not be so

obvious." Instead, USCI adopted more complicated inventory-

sorting and labeling methods. The government takes the now-

familiar position that the testing and marketing of the two-

lumen Miniprofile violated the Class III medical device

regulations because the testing was for purposes of determining

the modified device's safety or effectiveness yet was performed

without an IDE, see 21 C.F.R. Part 812, and because the change

from three to two lumens affected the device's safety or

effectiveness yet was implemented without a PMA supplement, see

-28-

§ 814.39(a). Here again, Prigmore asserts evidentiary

insufficiency and all defendants contend that, under their

understanding of the regulations, neither an IDE nor a PMA

supplement was required in connection with the testing and

marketing of the two-lumen Miniprofile.

c. The 1989 PMA Supplements

Throughout 1989, USCI modified the Miniprofile by

creating versions of the device with (1) a silicone coating, (2)

a balloon bond cured by ultraviolet light, (3) longer and

thicker balloons, and (4) a thinner shaft (the so-called "Solo"

model). USCI filed PMA supplements for these modifications,

asserting that clinical testing was not required to verify the

continued safety and effectiveness of the device. In fact,

however, USCI investigated how each of these models performed in

humans without having secured an IDE from the FDA. The plans

for and results of these tests were documented in various

memoranda sent to Leichter and Cvinar. In addition, with the

exception of the Solo submission (which in one section mentioned

that the device had two lumens), the PMA supplements for these

modifications did not reveal that the Miniprofile was, by 1989,

a two-lumen catheter. This apparently was not an accident.

There was evidence that Leichter directed that a draft of the

PMA supplement for the Miniprofile with the new balloon sizes be

-29- altered to remove a passage describing the catheter as having

two lumens because "right now it wasn't a good time" to mention

the change in light of "what had happened with the Probe."

Defendants' response to the government's argument that

this evidence suggests a conspiracy to defraud is basically the

same as that with respect to the three-to-two lumen change.

Prigmore asserts that there is insufficient evidence that he

knew or approved of these events. The other defendants do not

disclaim the necessary knowledge and approval. Rather, they

assert that the "testing" of these modifications without an IDE

and the failure to reveal the three-to-two lumen change were not

unlawful given their understanding of the regulatory

requirements.

d. The "Legitimizing" 1989 PMA Supplement

In August 1989, USCI allegedly conceived a plan to

obtain post hoc FDA approval of the two-lumen Miniprofile. The

company decided to file a PMA supplement for a new catheter in

the Miniprofile line called the "Solo Sr." The supplement would

disclose and seek approval for the three-to-two lumen change as

if it were not already a done deed. As explained in a

memorandum summarizing an August 30, 1989 Regulatory Affairs

Meeting attended by Leichter and Prigmore, USCI would

"'legitimize' the changes [it] ha[d] already made (3 lumen to 2

-30- . . .)" by submitting a PMA supplement "within a month."

Leichter told a subordinate that the Solo Sr. PMA supplement was

designed as a "cleanup" filing to secure FDA approval of a

product already being shipped. As noted previously, the PMA

supplement submitted for the Solo Sr. was eventually withdrawn.

During the late summer of 1989, Leichter walked into

a Management Board meeting carrying a group of files on the

Miniprofile line and announced that the files were problematic

and "not clean." William Longfield, the Chief Operating Officer

of Bard, replied by asking whether the records could be

"purged." In response, Cvinar halted the meeting and sent the

participants out of the room. After a break, the meeting

resumed and the subject of purging the files did not arise

again.

Despite his presence at the meeting where it was

decided that USCI would attempt to “legitimize” already-made

changes to the Miniprofile, Prigmore again argues that there is

insufficient evidence to prove that he knew of or condoned

USCI's actions with respect to the Solo Sr. The other

defendants contend that the Solo Sr. was not in fact the then-

extant Miniprofile, pointing to evidence that the device was to

have a blood-pressure monitoring capability not then present in

the Miniprofile. In other words, defendants take the position

-31- that the Solo Sr. PMA supplement was not fraudulently filed in

an attempt to legitimize already made changes to the

Miniprofile; rather, it was filed "in order to seek approval of

changes and features other than the number of lumens."

Defendants additionally contend that the Solo Sr. PMA supplement

was filed at the direction and under the supervision of David

Thomas, USCI's Vice President of Regulatory Affairs and an

immunized government witness.

C. Relevant Procedural History

As indicated above, the primary defense theme at trial

was that, under defendants' understanding of the applicable

statutory and regulatory requirements, the testing and marketing

efforts at the root of the charged conspiracy were not

fraudulent. This theme had two components pressed by defendants

in the alternative: (1) defendants' understanding of the legal

requirements was correct; or (2) defendants' understanding of

the legal requirements, even if incorrect, was objectively

reasonable and therefore foreclosed a fraud prosecution based on

a stricter reading of the law. See, e.g., United States v.

Rowe,

(1st Cir. 1998) (applying the rule

that, in a fraud prosecution premised on an alleged violation of

ambiguous positive law, the defendant is entitled to have his

culpability assessed against the interpretation of the law that

-32- most tends to rebut the charge of intentional deceit so long as

the interpretation is objectively reasonable).

Although defendants took a number of different legal

positions based on the specific language of the pertinent

regulations, the foundation supporting their primary defense

theme tracked USCI's earlier argument, set forth in the May 15,

1989 letter to the FDA, that a Class III medical device

manufacturer is only required to file a PMA supplement when it

modifies an approved device and the modification affects the

device's safety or effectiveness when the device is used in

accordance with its "intended conditions of use" – i.e., the

conditions of use prescribed in the labeling. Thus, the

argument ran, modifications affecting the device's safety or

effectiveness only during "unlabeled," and thus unintended,

conditions of use, such as overrotation with respect to the

Probe line and improper preparation and purging with respect to

the Miniprofile line, did not affect the device's safety or

effectiveness within the meaning of the applicable regulations.

In support of their argument, defendants relied heavily

upon 21 U.S.C. § 360c(a)(2) and

, which by

their terms define for the FDA when a device is to be regarded

as safe and effective. These provisions combine to suggest that

-33- the safety and effectiveness of a device are to be determined

by, inter alia, weighing its benefits to health against the

probable risks from use of the device for its intended

conditions of use. See

In a nutshell, defendants' position

was that, if the FDA determines a device's safety and

effectiveness within the context of the device's intended

conditions of use, it was at least reasonable for them to assume

that modifications which affect a device's safety or

effectiveness only during unintended conditions of use do not

affect "safety" or "effectiveness" within the meaning the

applicable law.1

1 As to the claim that the clinical testing described above violated 21 C.F.R. Part 812 because it was done without an IDE "to determine [the] safety and effectiveness" of the various device modifications, § 812.2(a), defendants in part relied on a derivative of their argument responding to the government's claims of illegal marketing. With respect to modifications for which, in defendants' view, no PMA supplement was required, defendants reasonably understood that an IDE also was not required because an IDE is nothing more than an "exemption permit[ting] a device that otherwise would be required . . . to have premarket approval to be shipped lawfully," id. § 812.1(a). With respect to the preapproval testing conducted on modified devices for which a PMA supplement admittedly was required (e.g., Probe B), defendants asserted that they regarded the testing to be consumer preference testing exempted from the IDE requirements by § 812.2(c)(4). In their submissions to this court, defendants also hint at an all-encompassing argument that they reasonably did not regard any of the allegedly unlawful clinical "testing" charged by the government to violate Part 812. According to this argument, as we understand it, defendants reasonably read Part 812 as merely prescribing the protocols for the gathering of the "valid scientific evidence" upon which the FDA will assess the safety

-34- The government did not agree with defendants' asserted

understanding of the crucial statutory and regulatory

provisions, or with defendants' alternative argument that, even

if not correct, defendants' understanding was objectively

reasonable and therefore the appropriate benchmark against which

criminal liability should be judged. Rather, the government

took the position that any modification known by the

manufacturer to affect the safety or effectiveness of an

approved Class III device – even a modification only affecting

safety or effectiveness during unlabeled and warned-against

conditions of use – triggers the obligation to file a PMA

supplement. The government supported this so-called "plain" or

"dictionary" meaning of the phrase "affecting the safety or

effectiveness of the device" in

(a) with the

testimony of two FDA experts and a Bard executive, all of whom

and effectiveness of new and modified devices pursuant to § 860.7(d)(1) and (e)(1). The testing at issue in this case was not for purposes of gathering this type of "valid scientific evidence"; it was more in the way of informal feedback gathered on the front lines by USCI sales representatives and passed back to corporate headquarters. Thus, the argument concludes, while the prior shipment of the catheters in question might have violated § 814.39(a), their actual use in humans did not independently violate Part 812. Whatever merits this alternative argument might have, we disregard it for present purposes because defendants did not sufficiently develop and preserve it as a defense theory in the district court. See United States v. Zannino,

(1st Cir. 1990).

-35- shared with the jury their understandings of the crucial Class

III medical device regulations. Although the experts gave

testimony that generally tended to support the government's

case, defendants were able to elicit on cross-examination of the

FDA witnesses that a manufacturer attempting to divine the

meaning of the phrase "affecting the safety or effectiveness of

the device" reasonably might cross-reference § 860.7, and that

this regulation does indeed circumscribe the concepts of

"safety" and "effectiveness" in terms of "intended . . .

conditions of use."

Consistent with their position on the meaning of the

phrase "affecting the safety or effectiveness of the device,"

defendants requested that the district court instruct the jury

to construe the phrase in the light cast by

.

Accordingly, defendants asked the court to quote § 860.7(d)(1)

and (e)(1) verbatim and to instruct the jury to "seek the

definition[s] of 'safe' and 'effective'" in these provisions.

Defendants further asked that the court instruct the jury "to

determine the safety and effectiveness of a device or of a

change to a device, not under any conditions of use, but in

light of the conditions of use, directions for use, and warnings

against unsafe use contained in the manufacturer's labeling for

that device." Finally, defendants asked the court to instruct

-36- the jury that "the defendants' interpretation of the standard

they were to use in determining safety and effectiveness was

reasonable."

The government, by contrast, opposed defendants'

attempt to link

to the phrase "affecting the

safety or effectiveness of the device" in § 814.39(a). The

government argued that § 860.7 is intended only to guide the FDA

as to whether a device is safe and/or effective; it is not

intended to advise the manufacturers of Class III medical

devices in connection with their PMA supplement filing

obligations. Accordingly, the government asked that, in

instructing the jury, the district court (1) simply quote the

relevant portions of § 814.39 (but not § 860.7); (2) define the

terms "safety" and "effectiveness" according to "their plain

ordinary meaning," – i.e., "freedom from danger or risks" and

"having a definite or desired effect," respectively; and (3)

state that there is no exemption from the relevant filing

requirements "based upon a misuse of the device by users of the

device," and that "a PMA supplement must be filed . . . for a

change that affects safety and efficacy regardless of the reason

for the change" – i.e., even if the change affects safety or

effectiveness of the device only in the event of unlabeled or

warned-against conditions of use.

-37- The district court did not adopt either approach.

Instead, the court advised counsel on the day before closing

arguments that, although it would permit defendants and the

government to argue to the jury their respective interpretations

of the applicable Class III medical device statute and

regulations, it would only instruct on conspiracy to defraud.

The court thus would not instruct on either the meaning of the

underlying statute and regulations or objectively reasonable

interpretations thereof.

Accordingly, counsel for Leichter and Cvinar stressed

in their closing arguments that, as the relevant statute and

regulations were reasonably understood by their clients, a

modification to an approved Class III medical device affected

the device's safety or effectiveness (and triggered the PMA

supplement filing requirement) only when the modification

impacted safety or effectiveness during the device's intended

conditions of use. Counsel for Leichter and Cvinar also

emphasized that the intended conditions of use were to be found

in the device's labeling instructions and warnings. Counsel for

Prigmore primarily focused on whether there was sufficient

evidence to tie his client to the conspiracy, but also joined in

Leichter and Cvinar's legal arguments to the district court.

The government, for its part, prominently argued that "safety"

-38- and "effectiveness" should be given their plain or dictionary

meanings, and that modifications affecting safety or

effectiveness during unlabeled or warned-against uses were

subject to the regulatory filing requirements. The government

also suggested that

is intended only to guide

the FDA in making its safety and effectiveness assessments, and

has no bearing on a manufacturer's obligation to file a PMA

supplement.

Subsequently, as promised, the district court declined

to instruct the jury on the meaning of the statute and

regulations. Rather, the court instructed on the elements of

conspiracy to defraud, and specified that defendants were

accused of conspiring to defraud the FDA in three respects: (1)

"knowingly and willfully, and with an intent to defraud, failing

to submit applications for product approval and testing [to] the

FDA, which allegedly they were required to submit"; (2)

"concealing or failing to report material facts which allegedly

they were required to report"; and (3) "making false statements

in documents that they submitted to the FDA."

The district court also gave detailed state-of-mind

instructions, emphasizing that the government was required to

prove beyond a reasonable doubt that defendants had knowledge of

their legal duties (on this point, the court simply provided the

-39- jury with copies of the applicable Class III medical device

statutory and regulatory provisions); that defendants

specifically intended to agree to violate these duties and thus

defraud the FDA; and that defendants "did not act in good faith

or by mistake, accident, or neglect." Defendants timely

objected to the court's refusal to instruct that the terms

"safety" and "effectiveness" in the provisions spelling out

defendants' legal duties must be understood as described and

confined by

and, alternatively, to the court's

refusal to instruct that defendants' interpretation of the

regulatory requirements was at the very least reasonable. On

the sixth day of its deliberations, the jury convicted

defendants. These appeals eventually ensued.

-40- II.

As we stated at the outset, defendants raise a number

of issues. All three defendants press various arguments that

the underlying convictions should be reversed and the conspiracy

charge dismissed. All three defendants also assert a number of

alternative arguments that their convictions should be vacated

and the matter remanded for further proceedings. Prigmore

additionally contends, again in the alternative, that his

sentence was unlawful. In the end, we are not persuaded by

defendants' arguments for reversal and dismissal. Yet we are

convinced that the convictions should be vacated and the case

remanded for further proceedings. To simplify our analysis, we

shall begin by explaining why vacatur is warranted and then

proceed to explain why reversal and dismissal is not. We do not

reach the merits of any arguments for vacatur beyond the one we

regard as dispositive because, in any retrial, the issues giving

rise to these other arguments are either not likely to arise

again or likely to arise in materially different contexts. For

the same reason, we do not address the merits of Prigmore's

sentencing challenge.

A. The Dispositive Issue

Defendants contend, inter alia, that the district court

committed reversible error in refusing to instruct the jury that

-41- defendants' asserted understanding of when a change should be

regarded as "affecting the safety or effectiveness" of a Class

III medical device, and thus trigger the PMA supplement filing

requirement, was at least reasonable and therefore the measure

against which defendants' criminal culpability should be

assessed. In defendants' view, the trial record and the logic

of the rule we applied in Rowe, see

, entitled

them to such an instruction as a matter of law. We do not

believe that the court was obliged to discuss the concept of

reasonableness in its instructions; an instruction that the jury

should simply apply a definition of the applicable phrase

informed by the limitations of

and tailored to

the evidence in this case would have covered the point just as

well. Nonetheless, on the facts of this case, we agree that the

court erred in not instructing the jury to determine defendants'

guilt against the backdrop of such a definition.

We begin by acknowledging that the district court has

considerable discretion in how it formulates, structures, and

words its jury instructions. See, e.g., United States v.

Woodward,

, 68 n.14 (1st Cir. 1998). Moreover, the

court often acts within its discretion in refusing to elaborate

the meaning of even an important legal term or phrase that falls

short of being self-explanatory. Indeed, we have recognized

-42- that, in some instances, attempts to clarify inherently nebulous

concepts can do more harm than good. Cf. United States v.

Andujar,

(1st Cir. 1995) (explaining our repeated

warnings that district courts within this circuit should avoid

defining the phrase "reasonable doubt" in their jury

instructions). The applicable standard, informed in part by

these principles, is that a court's refusal to give a requested

instruction is reversible error only if the requested

instruction was (1) substantively correct; (2) not substantially

covered elsewhere in the charge; and (3) concerned a

sufficiently important point that the failure to give it

seriously impaired the defendant's ability to present his or her

defense. See, e.g., United States v. Rose,

(1st Cir. 1997). In our view, this is the relatively rare case

where all three of these requirements are met.

As an initial matter, defendants are plainly correct

in asserting that, under settled circuit law, they were entitled

to have their intent assessed in the light of the interpretation

of the underlying filing requirements that is most congenial to

their case theory and yet also objectively reasonable. See

Rowe,

(bankruptcy fraud case) (applying this

principle to hold that an allegedly false statement was not

fraudulent because it was not in fact false under an objectively

-43- reasonable interpretation of the underlying disclosure

requirement); United States v. Migliaccio,

(10th Cir. 1994) (applying the rule in a mail fraud

prosecution); cf. United States v. Bradstreet,

(1st Cir. 1998) (securities fraud case) (endorsing such a rule

in dicta). This rule, rooted in the due process-based "fair

warning requirement," see United States v. Lanier,

(1997), recognizes that, in a prosecution based on the

theory that a defendant has defrauded the government by making

false statements in information defendant was duty-bound to

divulge to the government (or by failing to divulge information

defendant was duty-bound to divulge), there has been no crime if

the statements were not false (or if there was no duty to

divulge) under an objectively reasonable interpretation of the

law imposing the duty. See Rowe,

. The

government does not take issue with this general principle; in

fact, it makes no mention at all of Rowe or Bradstreet despite

defendants' significant reliance on them.

We also think it apparent that, if the evidence at

trial gives rise to a genuine and material dispute as to the

reasonableness of a defendant's asserted understanding of

applicable law, the judge, and not the jury, must resolve the

dispute. See United States v. Cheek,

(1991)

-44- (tax fraud case) (observing that the objective reasonableness of

defendant's view of the law is a legal question); Rowe,

(treating the reasonableness question raised in

that case as a matter of law). 2 On this general point, the

government's agreement is explicit.

Indeed, despite its position at trial, the government

no longer affirmatively takes issue with the general proposition

that it was reasonable for defendants to have regarded the

definition of the phrase "affecting the safety or effectiveness

of the device" in

(a) as properly informed by

2 To be sure, a reasonableness determination sometimes requires preliminary resolution of underlying factual disputes, and the court almost certainly acts within its rights in asking the jury to resolve these disputes. Cf. Bradstreet,

(suggesting in dicta that, had there been a genuine dispute as to which of several "revenue recognition policies" defendant had been "booking" revenue under, and had an allegedly fraudulent booking of revenue been appropriate under an objectively reasonable interpretation of one such policy, then the court would have been obliged to instruct the jury to assess culpability in the light of that reasonable interpretation so long as it first found defendant to have been using that policy in booking the revenue in question); St. Hilaire v. City of Laconia,

, 24 n.1 (1st Cir. 1995) (civil rights damages action) (observing in a discussion of the qualified immunity defense and its "objective reasonableness" criterion that it is an open question whether the judge may decide underlying factual disputes bearing on reasonableness or must ask the jury to resolve such disputes). But as a legal question, the reasonableness of defendants' understanding is ultimately a question for the judge. See Nieves-Villanueva v. Soto-Rivera,

(1st Cir. 1997) (noting that, in our legal system, purely legal questions are exclusively within the domain of the judge).

-45- the context-providing qualifications set forth in § 860.7.

Although at oral argument the government declined to disavow the

"plain meaning" or "dictionary" definitions of the terms

"safety" and "effectiveness" that it pressed at trial and in its

closing arguments, the government makes no real effort to defend

those definitions in its brief to this court. Perhaps this is

because the Supreme Court recently recognized that "virtually

every drug or device poses dangers under certain conditions,"

FDA v. Brown & Williamson Tobacco Corp.,

(2000), and repeatedly emphasized that a drug or device is safe

within the meaning of the FDCA when, in connection with its

intended uses and conditions of use, see generally

at 1301-

06, its "therapeutic benefits outweigh the risk of harm,"

. Perhaps this is because, on cross-examination, the FDA

experts who testified concerning the meaning of the applicable

regulations conceded that it was reasonable to refer to the

phrase "intended . . . conditions of use" in § 860.7(d)(1) and

(e)(1) in ascertaining the meaning of the phrase "affecting the

safety or effectiveness of the device" in § 814.39(a).3 Perhaps

3 In referring to the experts' testimony regarding the meaning of the applicable laws, we do not wish to be understood as more generally endorsing the use of expert testimony on legal meaning. Neither side contests the appropriateness of the expert testimony that took place in this case, so we do not address its admissibility. We feel it important to note, however, that expert testimony proffered solely to establish the

-46- the government has simply changed its position because it now

agrees with defendants' argument that terms and phrases repeated

throughout a given law generally carry the same meaning. See,

e.g., United States v. Nippon Paper Indus. Co., Ltd.,

(1st Cir. 1997). In any event, to the extent that the

government may have tacitly conceded the general point, we

regard the concession as proper. For the reasons just stated,

and regardless how the phrase "affecting the safety or

effectiveness of the device" in § 814.39(a) ultimately ought to

be understood, it was objectively reasonable for defendants to

regard the phrase as definitionally circumscribed by the

"intended . . . conditions of use" qualification found in, among

other places, § 860.7(d)(1) and (e)(1).

That said, the government does not concede that the

district court committed reversible error in declining to give

the instruction defendants requested. Put in the language of

the three-part test under which we review the court's refusal to

instruct, see Rose,

, the government's argument,

meaning of a law is presumptively improper. See Nieves- Villanueva v. Soto-Rivera,

; see also Benjamin J. Vernia, Annotation, Admissibility of Expert Testimony Regarding Questions of Domestic Law,

(1999) (detailing how, despite the inroads courts have made into the rule against expert testimony on questions of law, such testimony is still usually excluded).

-47- in essence, is that there has been no error because the

instruction defendants requested was neither substantively

correct nor concerned a sufficiently important point that the

court's failure to give it seriously impaired defendants'

ability to present their defense, see id.4 We disagree.

As to the first Rose factor, substantive correctness,

the government points out that defendants requested that the

court instruct the jury not only that it should link the phrase

"affecting the safety or effectiveness of the device" in

(a) with the phrase "intended . . . conditions of

use" in § 860.7(d)(1) and (e)(1), but that it also should

understand "intended . . . conditions of use" in terms of the

device's labeling. Such a definition was too narrow, according

to the government, because there was evidence that, with respect

to Probe B, defendants knew of and acquiesced in USCI's on-the-

side promotion of the overrotation against which the device's

label warned. As the government sees it, all actual conditions

of use that the manufacturer intends or even knows of are

relevant to the safety-or-effectiveness inquiry, and

modifications affecting a device's safety or effectiveness

4 It is undisputed that the instruction defendants requested was not substantially covered elsewhere in the charge. See Rose,

. Thus, we address only the first and third prongs of the Rose standard.

-48- during such conditions of use trigger the PMA supplement-filing

requirements even if they are specifically warned against on the

label. In making this argument, the government points out that

§ 860.7(b)(2) specifies that "[t]he conditions of use for [a]

device[] includ[e] conditions of use prescribed, recommended, or

suggested in the labeling or advertising of the device, and

other intended conditions of use." (emphasis supplied).5

Given the explicit references to intention in

(d)(1) and (e)(1), and in the absence of some clarifying

regulatory or judicial gloss to support the government's

position, see Lanier,

(recognizing that

"uncertain" laws can be clarified by authoritative

construction), we are not persuaded that a criminal fraud

5The government also draws support for this argument from

, which was neither the subject of trial argument nor given to the jury. In relevant part, § 801.4 states:

The words "intended uses" or words of similar import in [three regulations not relevant to this case] refer to the objective intent of the persons legally responsible for the labeling of devices. The intent is determined by such persons' expressions or may be shown by the circumstances surrounding the distribution of the article. The 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 article is, with the knowledge of such persons or their representatives, offered and used for a purpose for which it is neither labeled nor advertised . . . .

-49- prosecution can be premised upon a failure to file a PMA

supplement in connection with a modification to an approved

device that affects the device's safety or effectiveness only

with respect to a sincerely unintended and warned-against,

albeit known, condition of use. 6 Yet we think that the

regulatory text does accommodate the government's argument that

a manufacturer must take into account unlabeled, though promoted

(and thus “intended”), conditions of use in determining whether

a modification affects safety or effectiveness. Moreover, given

the evidence of USCI's promotion of Probe B overrotation, such

a jury instruction might well be necessary at any retrial if

there is sufficient evidence that defendants knew of or

acquiesced to such promotion.

6 We of course recognize that, if a modification makes an approved device more dangerous in the event of a condition of use that sometimes occurs despite the manufacturer's best efforts to prevent it, there may be sound policy reasons for requiring the manufacturer to file a PMA supplement. But we are concerned here not with the most socially useful interpretation of the relevant regulations; we are concerned with whether those regulations gave fair warning that a failure to file a PMA supplement in such a circumstance is a felony under federal law. See Lanier,

. Because the most relevant regulation defines device safety in terms of "intended . . . conditions of use," § 860(d)(1) (emphasis supplied), and because there has been no authoritative judicial or regulatory pronouncement clarifying that a sincerely warned-against but known condition of use should be regarded as "intended," see Lanier,

, we reject the government's argument on this narrow point.

-50- But under the circumstances of this case, we do not

think it appropriate to hold that the defendants' reference to

labeling in their requested instruction effectively waived their

right to an instruction that, for purposes of this prosecution,

the "intended . . . conditions of use" qualification in

(d)(1) and (e)(1) limits the meaning of the phrase

"affecting safety or effectiveness" in § 814.39(a). Although

defendants' proposed instruction did request that the jury be

instructed in terms of labeling, it more generally requested

(over the government's objection) that the jury be instructed in

the specific language of § 860.7(d)(1) and (e)(1), both of which

state broadly, without specific reference to labeling, that

"intended . . . conditions of use" are relevant to safety and

effectiveness determinations. In other words, but for a

proposed refinement suggesting that the label instructions

reveal the manufacturer’s intended conditions of use (as in most

cases they would), defendants' request was sufficiently close to

the mark. Moreover, and more to the point, we think it evident

that the government's promotion at trial of an overly broad (at

least for purposes of assessing criminal liability) definition

of the relevant statutory and regulatory terms had as much, if

not more, to do with this issue not emerging in sharp relief as

did any lapse on defendants' part. Defendants' requested

-51- instruction was thus adequate to preserve the issue. Cf. United

States v. Sanborn,

(1st Cir. 1977)

(vacating a conviction on the basis of a rule of law slightly

different, and less defendant-friendly, than that sought by the

defendant in his requested instruction).

As to the third Rose factor, whether the requested

instruction concerned a sufficiently important point that the

district court's failure to give it seriously impaired

defendants' ability to present their defense, the government

appears to make two arguments. First, the government makes a

halfhearted claim that the court's good-faith instructions

"adequately articulated" the no-mens-rea defense theory and thus

rendered unimportant the court's failure to define the disputed

underlying regulatory requirements. See Gov’t Br. at 111. We

disagree. While the court's good-faith instructions were

comprehensive, articulate, and beyond reproach insofar as they

generally described the concept of good faith, the jury's good-

faith finding may well have been affected by its view of what

the underlying law required. The trial evidence, closing

arguments, and the jury instructions might well have left the

jury with an erroneous belief that manufacturers face criminal

liability for failing to file a PMA supplement when they make a

modification to an approved device that has an effect only

-52- during a sincerely unintended and specifically warned-against

condition of use. This erroneous belief, in turn, might well

have been the basis upon which the jury rejected the good-faith

defense. The good-faith instruction thus did not undo the harm

caused by the court’s failure to give the requested instruction

in and of itself. See Migliaccio,

.

Second, the government in substance contends that, even

if erroneous, the district court's failure to define the

underlying regulatory terms was unimportant because it was

harmless beyond a reasonable doubt within the meaning of Neder

v. United States,

(1999) (holding harmless the

trial court's erroneous failure to instruct the jury to

determine whether a failure to report taxable income was

"material" where the failure to report involved over $5 million,

the evidence regarding the failure to report was not

controverted, and defendant did not argue to the jury that his

failure to report was immaterial). The government suggests

that, as in Neder, it is here "clear beyond a reasonable doubt

that a rational jury would have found" defendants guilty even if

properly instructed.

(emphasis supplied).7

7 In arguing that any error here was harmless “beyond a reasonable doubt,” the government appears to take the position that instructional error of the type we have identified is constitutional in dimension. See Chapman v. California,

(1967) (holding that, “before a federal

-53- Indeed, in the government's view, "[t]his case . . .

presents a stronger candidate for a finding of harmlessness"

than did Neder because the legal error in Neder affected the

jury's consideration with respect to all of defendant's

allegedly illegal acts. Gov’t Br. at 80. In contrast to Neder,

the government asserts, the error in this case only affected the

jury's deliberations with respect to those acts pertaining to

the failure to obtain a PMA supplement; the error did not affect

the jury's consideration of the evidence of the testing

violations, the evidence that defendants failed to disclose the

three-to-two lumen change in the 1989 Miniprofile PMA

supplements, the evidence regarding deceptive intentions with

respect to the filing of the Solo Sr. PMA supplement, the

constitutional error can be held harmless, the court must be able to declare a belief that it was harmless beyond a reasonable doubt”). One member of the panel, however, believes that the error likely was not constitutional, and that the applicable harmless-error standard therefore comes from Kotteakos v. United States,

(1946) (interpreting the predecessor to the federal harmless-error statute,

, to require reversal only when the error “had substantial and injurious effect or influence in determining the jury’s verdict”). See Brecht v. Abrahamson,

(1993) (noting that the Chapman standard applies to direct review of constitutional errors and that the Kotteakos standard applies to direct review of non- constitutional errors). Because the panel unanimously agrees that the error we discern cannot be said to be harmless under either test, we do not decide which test applies or, concomitantly, whether the error deprived defendants of a constitutional right.

-54- evidence of USCI's failure to report modifications in mandatory

follow-up reports, or the evidence of other assorted deceit and

trickery (e.g., promoting Probe B contrary to its label warnings

and adopting complicated inventory and labeling methods designed

to conceal device modifications from the FDA). And, the

argument concludes, the evidence with respect to these matters

was "overwhelming."

In our view, the evidence of guilt in this case is

quite substantial; certainly, it is more than sufficient to

permit a retrial on a properly formulated theory that defendants

conspired to defraud the FDA with respect to its oversight and

regulation of medical devices. We do not believe, however, that

the evidence is so one-sided as to render harmless the

underlying instructional error we have identified. Unlike the

government, we do not see this as a case, like Neder, where it

is far-fetched to conclude that a properly instructed jury might

have returned different verdicts than those returned. In

explaining, we follow the government's lead and focus upon the

nature and weight of the evidence asserted to have been

unaffected by the instructional defect.

The government first asserts that the trial evidence

showed conclusively that defendants tested their device

modifications for the purpose of determining safety and

-55- effectiveness with respect to intended conditions of use and in

such a way as to put patients at prohibited risks. In

responding to this argument, we limit ourselves to the factual

nature of the evidence presented and put to the side defendants'

legal argument that, because an IDE is an exemption permitting

the clinical testing of unapproved devices that otherwise could

not lawfully be shipped without premarket approval, the

lawfulness of most of the testing at issue in this case turns in

the first place on whether the modification at issue was subject

to the PMA supplement requirement. See supra note 1.

As to the nature of the testing evidence, we think

that, while the factual inference the government would have us

draw surely would be permissible on the present record, see,

e.g., supra at 13, 20, 23-24 (summarizing documentary evidence

suggesting that the testing was for purposes of evaluating

safety and/or efficacy during intended conditions of use), it is

not the only rational inference. Unlike Neder, the government's

evidence as to the purpose of the testing was contested by

defendants; as we have stated, defendants introduced testimonial

evidence that the purposes of this testing were to determine

whether the modifications were ameliorating safety concerns

during unintended conditions of use and/or to establish consumer

preferences within the meaning of

(c)(4). See

-56- supra at 13-14. Given Neder's repeated emphasis on the

"uncontested" nature of the evidence of materiality in that

case, see

, 17 n.2, & 19, the contested nature

of the testing evidence in this case might well suffice to

distinguish it from Neder in and of itself.

In any event, while the government's evidence of the

purpose behind the testing was strong, the competing evidence

was not inherently incredible. That effectively ends the

matter. As an appellate court, we are not equipped to make the

credibility determinations that must be made in choosing between

these clashing blocs of evidence, each of which is sufficient to

render rational a finding in favor of its proponent. See Neder,

. We also are mindful that, in denying

defendants' motions for judgments of acquittal, the trial court

thought it a very "close" call whether the motions should be

granted, and that, in overruling defendants’ objections to its

failure to give the requested safety-and-efficacy instruction,

the court opined that instructing the jury as the defendants

requested would be tantamount to directing a verdict for them.

In sum, we do not regard the government's evidence of the

purpose of the testing, alone or combination with the other

-57- evidence discussed below, to be of such a nature as to render

the court's instructional error harmless.

Our analysis with respect to the other evidence

mentioned by the government in support of its harmless-error

argument follows a similar path. As we have observed,

defendants explained the failure to file a PMA supplement with

respect to the three-to-two lumen change in the Miniprofile with

evidence and argument that a filing was unnecessary because the

change was designed to ameliorate safety issues caused by

unintended preparation and purging techniques by end users. See

supra at 23. The evidence on this point was not inherently

incredible. If a correctly instructed jury were to have

accepted this evidence and line of defense (as it might have),

we think it might well also have regarded the subsequent failure

to report the three-to-two lumen change in the 1989 Miniprofile

PMA supplements as inconsequential. So too with the Solo Sr.;

we think it possible that the jury might have accepted

defendants' supported and argued contention that USCI filed the

Solo Sr. PMA supplement in order to seek approval of changes

other than those pertaining to lumen number and/or at the

direction and under the supervision of David Thomas, and not

defendants.

-58- Finally, with respect to the evidence of failure to

submit follow-up reports and the evidence of other assorted

deceptions and trickery, it suffices to note that such evidence

was either largely tangential to the primary trial themes or not

particularly probative of any of the principal fraud theories as

to which the jury was instructed. See supra at 34. As we have

explained, instructional error and the absence of one-sided and

overwhelming evidence of guilt combine to prevent us from

affirming defendants' convictions on the basis of the primary

criminal liability theories advanced at trial: fraudulent

marketing and fraudulent testing. Moreover, the experienced

trial judge who presided over the case stated on the record that

he was not sure he was correct in even sending the case to the

jury. Given this state of affairs, it would be improper to

affirm defendants' convictions on the basis of evidence that, on

the whole, played a supporting rather than a starring role at

trial.

B. Other Issues

As noted, defendants press various arguments for

reversal and dismissal of the conspiracy charge. These

arguments do not merit extended discussion.

First, all three defendants argued in their initial

briefs that the regulations under which they were prosecuted did

-59- not give fair warning of the "dictionary" or "plain language"

interpretation that the government relied upon in pressing this

prosecution. Then, when defendants perceived in the

government's brief a shift in position towards (if not all the

way to) the interpretation of the regulations they have advanced

all along (and we herein confirm as objectively reasonable), all

three defendants suggested in their reply briefs that the

conspiracy charge should be dismissed outright because the

government's "switch . . . confirms the . . .

unconstitutionality of this prosecution." Defendants do not,

however, place this argument within the context of a recognized

legal theory; nor do they cite authority which supports the

drastic remedy they seek. We therefore reject the argument as

insufficiently elaborated. See Zannino,

.

Second, defendants Cvinar and Prigmore contend that

they are entitled to dismissal of the conspiracy charge because

the FDA did not provide them with notice and an opportunity to

present to the FDA their "views" as to the events underlying

this case prior to reporting their alleged violations of the

FDCA to a United States Attorney for prosecution.

. But even assuming that Cvinar and Prigmore were entitled

to such notice and opportunity, the Supreme Court has made it

clear that they are not entitled to dismissal of the

-60- prosecution. See United States v. Dotterweich,

(1943).

Third, and finally, Prigmore asserts that there was

insufficient evidence to link him to the conspiracy charged and

thus to sustain his conviction. Frankly, in reviewing those

portions of the record the government points to in response to

Prigmore's sufficiency argument, we are not particularly

impressed by the strength of the case against him. Nonetheless,

mindful that "in a criminal conspiracy, culpability may be

constant even though responsibilities are divided," United

States v. Sepulveda,

(1st Cir. 1993), and

that a successful sufficiency claim requires a showing that "no

rational jury could have found [defendant] guilty beyond a

reasonable doubt," United States v. Scharon,

(1st Cir. 1999) (emphasis supplied), we are persuaded that there

was sufficient evidence to tie Prigmore to the conspiracy.

As we have noted, there was evidence that, on November

7, 1988, Cvinar informed Prigmore that testing of the modified

two-lumen Miniprofile had been completed, that the testing

revealed "significantly better inflation/deflation times" in the

new model, and that USCI would be adopting the two-lumen design

"post haste." See supra at 23-24. There thus was evidence to

ground a conclusion that Prigmore knew that the three-to-two

-61- lumen change was a change affecting the safety and/or the

effectiveness of the Miniprofile – at least with respect to its

unintended conditions of use.

Further, there was evidence that Prigmore reviewed for

several hours the May 15, 1989 letter in which USCI took the

position that the modifications to Probe B that became Probe C

did not require a PMA supplement because they did not affect the

safety or effectiveness of the catheter during its intended uses

and conditions of use. See supra at 18-20. There thus was

evidence to ground a conclusion that, by May 1989, Prigmore knew

that USCI was under a regulatory obligation to file a PMA

supplement with respect to all changes affecting the safety or

effectiveness of its approved heart catheters during their

intended uses and conditions of use prior to marketing the

altered product.

Moreover, there was evidence that, on August 30, 1989,

Prigmore participated in the meeting where it was decided that

USCI, according to a memorandum memorializing the meeting, would

file a PMA supplement for the Solo Sr. designed to "'legitimize'

the changes [it] already ha[d] made (3 lumen to 2 . . .)" to the

Miniprofile by submitting to the FDA a cleanup PMA supplement.

See supra at 26. There is no indication that Prigmore, who then

was a Bard vice president with authority over USCI operations,

-62- dissented from the proposed course of conduct, which eventually

was implemented. In our view, the memorandum describing the

August 30 meeting suggests that Prigmore acquiesced in an

unlawful plan to conceal from the FDA a dubious course of

conduct, particularly in light of Prigmore's authority, his

knowledge of the three-to-two lumen change, and his awareness of

the relevant regulatory requirements. This evidence is

sufficient to implicate Prigmore in the conspiracy of which he

was convicted.

III.

As we have stated, there was substantial evidence that

defendants in fact committed the serious crime of which the jury

convicted them. But there is too great a possibility that the

jury’s verdicts were affected by an erroneous failure to define

crucial and disputed regulatory terms for us to affirm the

convictions under the harmless-error doctrine. We thus vacate

defendants' convictions and remand for further proceedings

consistent with this opinion.

Vacated and remanded.

-63-