Petition for Writ of Certiorari — Efamol, Ltd. v. United States

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Supreme Court, U.S,

rFiLeD

992-173 JUL 28 1992

GFFICE OF THE “p

| No. 92- — c CLERK

come

IN THE

Supreme Court of the United States

OCTOBER TERM, 1992

EFAMOL, LTD.,

Petitioner,

f €titiviieciy,

UNITED STATES OF AMERICA,

Respondent.

ON PETITION FOR WRIT OF CERTIORARI TO THE UNITED

STATES COURT OF APPEALS FOR THE NINTH CIRCUIT

PETITION FOR WRIT OF CERTIORARI

JAMES R. PHELPS

Counsel of Record

ROBERT A. DORMER

A. WES SIEGNER, JR.

MARY BETH NERAAS

HYMAN, PHELPS &

McNAMARA, P.C.

700 Thirteenth Street, N.W.

Suite 1200

Washington, D.C. 20005

(202) 737-5600

July 28, 1992 Attorneys for Petitioners

Balmar Legal Publishing Services, Washington, D.C., (202) 68209800

QUESTIONS PRESENTED

1. Should this Court permit the Ninth Circuit, in conflict

with other circuits and the plain language of the Federal Rules

of Evidence, to use Rule 703 of the Federal Rules of Evidence

and Frye v. United States, 293 F. 1013 (D.C. Cir. 1923), to

exclude from the jury on a motion for summary judgment more

than 300 pages of expert testimony that is based upon facts and

data routinely and reasonably relied upon by experts in the field

to make the type of food safety determination at issue in this

case’

2. Should this Court permit the Ninth Circuit, in conflict

with other circuits, the Federal Food, Drug, and Cosmetic Act

(FDC Act), and the legislative history of the FDC Act, to shift

to manufacturers of food products the burden of proving in a

seizure action that the food in question is “generally recognized

as safe” for its intended use within the meaning of the FDC Act,

21 U.S.C. § 321(s} (1992)?

3. Is there a genuine issue of materia! fact as to whether

the food at issue is “misbranded” within the meaning of the FDC

Act, 21 U.S.C. § 343 (1992)?

TABLE OF CONTENTS

QUESTIONS PRESENTED

OPINIONS BELOW

JURISDICTION

STATUTORY PROVISIONS INVOLVED

STATEMENT OF THE CASE .

1. Statutory And Regulatory Framework

a. Statutory and regulatory requirements

pertaining to general recognition

yf Safety

|) Data from unpublished studies

2) Drug study data

b. Statutory and regulatory requirements

pertaining to misbranding

Proceedings In The District Court... .

WwW

Proceedings In The Court of Appeals

REASONS FOR GRANTING THE WRIT .....

1. This Court Should Resolve The Conflict In

The Circuits Over Fed. R. Evid. 703 And

a. The split in the circuits over Fed. R. Evid.

703 and the Frye test

b. The test that should be used by the

courts

The Supreme Court Should Resolve The

Conflict As To Which Party Bears The

Burden Of Proof On The Issue Of

GRAS Status .....

Pages

3 »~6Efamol’s Fvidence On The Misbranding

Issues Raises Genuine Issues Of Fact

Requiring A Trial Li

CONCLUSION 1

TABLE OF AUTHORITIES

(Cases Pages

Ambrosini 3 Labarraque, No. 90-7 \4¢

ind No. 90-714&,. shi

D.C. Cir. June 12. 1992

Anderson v. Liberty Lobby. J)

5-7-9

ieee ae .

+ S. 242 (19%6 f

Beech Aircraft Corp Raine,

Le ) wat

188 U.S. 153 (198%

Christophersen v. Allied Signal Corp

No. W-®&-CA-09% slip Op (W.D. Tex

October 12, 1989), aff d en han

939 F.2d 1106 (Sth Cir. 1991), cert. denied

U.S 112 S. Ct. 1280 (1992)

(White & Blackmun, J.J., dissenting from

denial of certiorari) passim

Clinchfield R.R. Co. v. Lynch, 7&4 F.2d 545

(4th Cir. 19&6) . . 1%, 23

Daubert v. Merrell Dow Pharmaceuticals. Ine

951 F.2d 1128 (9th Cir. 1991), petition for

cert filed No 92 102 (July 7 1992) Dass m

DeLuca v. Merrell Dow Pharmaceuticals. Ini

911 F.2d 941 (3d Cir. 1990'. summan

judgment granted on remand, No. 87-226

(GEB), 1992 U.S. Dist. LEXIS 6511

(D.N.J. April 29, 1992) 16, 17, 20, 23

Ellis v. Int'l Playtex, In

(4th Cir l 984)

Fmali Herb, Inc. v. Heckler. 715 F.2d 1385

(Oth Cir. 1983) 28

Frvey.l ‘nited States, 293 F 1013 =

(D.C. Cir. 1923 passim

Pages

Head v. Lithonia Corp., Inc., 881 F.2d 941

PH Le. SOY cg ss mace eel es 20

In re “Agent Orange” Prod. Liab. Litig., 611

F. Supp. 1223 (E.D.N.Y. 1985), aff'd on

other grounds, 818 F.2d 187 (2d Cir. 1987),

cert. denied, 487 U.S. 1234 (1988) 14.19

- Int'l Adhesive Coating Co., Inc. v. Bolton Emerson

Int'l, Inc., 851 F.2d 540 (1st Cir. 1988). 17

Japanese Elec. Prod. Antitrust Litig. v. Matsushita

lec. Indus. Co., Ltd.., 723 F.2d 238

(3d Cir. 1983), rev'd on other grounds sub

nom., Matsushita Elec. Indus. Co., Ltd

Zenith Radio Corp., 475 U.S. 574 (1986) 14

Kropinski v. World Plan Executive Council - U.S.,

853 F.2d 948 (D.C. Cir. 1988). ae 20

Mannino vy. Int'l Mfg. Co., 650 F.2d 846

1 2 ae Loo Ze oes are ese 18, 23

Mustafa v. United States, 479 U.S. 953 (1986)

(White & Brennan, J.J., dissenting from

denial of certaOnGMi) ww wk 16

Nat'l Labor Relations Bd. v. Transport.

Management Corp., 462 U.S. 393 (1983) . . . 26

Rogers v. Raymark Indus., Inc., 922 F.2d 1426

‘A ey dt eee eon Ao 1X

Udall v. Tallman, 380 U.S. 1 (1965) ........ 28

United States v.46 Cases, More or Less . ..

“Welch's Nut Caramels * * *,” 204 F. Supp.

S21 (DRL. IFS) 2. es eee ee 26

(/nited States v. 88 Cases, More or Less,

Bireley' s Orange Beverage, 187 F.2d 967 (3d

Cir.), cert. denied, 342 U.S. 861 (1951)

U/nited States v. 119 Cases, More or Less

New Dextra Brand Fortified Cane Suga

231 F. Supp. 551 (S.D. Fla. 1963), aff'd

per curiam, 334 F.2d 238 (Sth Cir. 1964)

(/nited States v. 217 Cases Efamol Evening

Primrose Oil. No Q? BF int. 1B

(D. Utah filed June 1, 1992)

/ } ited States \ A hel. 469 [ S 45 { 1QK4

U/nited States v. Alcon Lab., 636 §.2d &76 (1st ¢

cert. denied, 451 U.S. 10)7 {198]

U/nited States v. An Article of Drug Bentex

Uleerine,” 469 F.2d %75 (Sth Cir. 19

cert. denied, 412 U.S. 93% (1973

United States v. An Article of Food Coco Rico

752 F.2d 11 (1st Cir. 1985) 2t

United States v. An Article of Food FoodScience

Lab., Inc., 678% F.2d 735 (7th Cir. 1982

United States v. An Article of Food 345/50

Pound Bags, 622 F.2d 768 (Sth Cir. 1980

United States v. Articles of Food and Drug

Coli-Trol, 372 F. Supp. 915 (N.D. Ga. 1974

aff d, 518 F.2d 743 (Sth Cir. 1975)

United States v. Dixon, 547 F.2d 1079

(Oth Cir. 1975)

United States v. Downing, 753 F.2d 1224

(3d Cir. 1985)

Vii

United States v. Ewig Bros. Co., Inc.,

502 F.2d 715 (7th Cir. 1974), cert. denied,

oe 3 ty 7 | a eee 28

United States v. General Foods Corp..

446 F. Supp. 740 (N.D.N.Y.), aff d,

591 F208 1332 (2a Cir. 1978) . ww 26

United States v. Grajeda, 570 F.2d 872 (9th Cir. ),

withdrawn and new opinion issued on alternate

ground, 587 F.2d 1017 (9th Cir. 1978) .. . . 24

United States v. Jakobetz, 955 F.2d 786

(2d Cir. 1992), petition for cert. filed,

No. 91-7921 (April 8, 1992) ......... passim

United States v. Kail, 804 F.2d 441

eRe, INN 0 ore aking gk ek aw 18

United States v. Metzger, 778 F.2d 1195

UO | a a Cra ena 19

United States v. Rogers, 918 F.2d 207

Fe ED ere ee ee Fk we Se 24

United States v. Smith, 869 F.2d 348

Po CN 6m ee ace ee eS 16, 19

United States v. © slomon, 753 F.2d 1522

Pee EU a one os ae a ee 20

United States v. Two Bulls, 918 F.2d 56

CR EME 3258 a - G oe bo 3 88s 16, 20

United States v. Tranowski, 659 F.2d 750

(7th Cir. 1981), rev'd on other grounds,

702 F.2d 668 (1983), cert. denied, 468 U.S.

Bre Se ne. a tae ee ek 18

United States v. Western Serum Co., Inc.,

666 F.2d 335 (9th Cir. 1982) .. 2... 29

Weinberger v. Bentex Pharmaceuticals, Inc..,

412 U.S. 645 (1973)

Zuber v. Allen, 396 U.S

Regulations, Statutes and Public Laws

Crk.

a Sh

C.F.R

ot Ok

it FF

Ci.R

Crus

we A

U.S.C

Ly ke

U.S.C

USA...

U.S.C.

OS Be

Lok.

U.S.C

USA.

Part 182 (1991)

torn

wor

Or LQ

ven

Or tr Gr LM

. Part 184 (1991)

101.100(d) (1991)

101.100(d)(2) (1991)

170.3(h) (1991)

170.30(b) (1991)

170.30(d) (1991)

170.35 (1991)

1$2.1(a) (1991)

321(f) (1992)

321(s) (1992)

334 (1992)

334(a) (1992)

334(d) (1992)

334(d)(1) (1992)

342(a)(1) (1992)

342(a)(2)(C) (1992)

342(a)(3) (1992)

§ 343(a) (1992)

uP unr

343(a)(1) (1992)

343(b) ( 1992)

16% { 1969)

gee

QS V4

ISSIUM

+ 4\

5. 27

- 6

343; 1) { 1992)

2i U.S.C.

AY Us

21 U.S.C. § 348 (1992)

21 U.S.C. § 348(a) (1992)

28 U.S.C. § 1254(1) (1992)

28 U.S.C. § 2072-74 (1992)

Pub. L. No. 75-717, 52 Stat. 1050 (1938)

Pub. L. No. 85-929, 72 Stat. 1784 (1958)

Pub. L. No. ‘

3-595. 88 Stat. 1926 (1975)

Rules

Federal Rules of Evidence

Rule 403

Rule 703

Miscellaneous

42 Fed. Reg. 38,609 (July 29, 1977)

42 Fed. Reg. 41,876 (August 19, 1977

343(1)(1) (1992) d.

43 Fed.

48 Fed.

55 Fed.

Reg. 14,064 (April 4, 1978)

Reg. 31,349 (July 21, 1978)

Reg. 239 (January 4, 1983)

Reg. 5716 (February 8, 1983)

Reg. 6384 (February 23, 1990)

Reg. 10,932 (March 23, 1990)

3 Jack B. Weinstein & Margaret A. Berger,

Weinstein’ s Evidence § 703[(01] (1991)

22 C. Wright & K. Graham, Federal Practice and

Procedure § 5169 (1978)

Pages

8, 30

12,13

5 99

}

passim

Pages

Chemical Additives in Foods: Hearings Before a

Subcomm. of the House Comm. on Interstate

and Foreign Commerce, 84th Cong., 2d Sess.

226 (1956) 28

Edward J. Imwinkelreid, The Standard For Admit-

ting Scientific Evidence: A Critique From The

Perspective Of Juror Psychol ey, 28 Vill. L.

Rev. 554 (1982-83)

Edward J. Imwinkelried, The “Bases” Of Expert

Testimony: The Syllogistic Structure Of

Scientific Testimony, 67 N.C.L. Rev. 1

Gok oe ak awe ke wk ee ae a 15,

i”

Faust F. Rossi, Modern Evidence and the Expert

Witness, 12 Litig. 18 (Fall 1985) ....... 22

Food Additives: Hearings Before a Subcomm.

of the House Comm. on Interstate and

Foreign Commerce, 85th Cong., 2d Sess.

Eos hata nee er at Aa tare eth ata a Le 27

Gary Taylor, Expert Witness Opinion Eyed; Circuits

Split on Issue, Nati L.J. (Oct. 21,1991) ... 16

Michael C. McCarthy, Note, “Helpful” Or

“Reasonably Reliable” ? Analyzing The

Expert Witness s Methodology Under

Federal Rules Of Evidence 702 And 703,

77 Cornell L. Rev. 350 (Jan. 1992) ... 14, 16, 19, 20

Recent Case, 105 Harv. L. Rev. 791 (1992) .... 22

S. Rep. No. 93-1277, 93d Cong., 2d Sess. (1974),

reprinted in 1974 U.S. Code Cong. & Admin.

ee ee 4k eS ee ee 24

—————————

OPINIONS BELOW

The decision of the United States Court of Appeals for the

Ninth Circuit affirming the District Court’s grant of summary

judgment for respondent is dated April 7, 1992, is not yet

reported, and is reprinted in the Appendix at A-1. (References

to the appendices bound with this petition are styled “A-__”.)

On June 12, 1992, the Ninth Circuit denied petitioners’ petition

for rehearing and suggestions for rehearing en banc. A-11. On

June 29, 1992, the Ninth Circuit granted petitioners’ motion for

stay of the mandate. A-12. The Order of the United Stutes

District Court for the Central District of California granting

respondent's motion for summary judgment, from which appeal

was taken, is dated November 27, 1989, is unreported, and is

reprinted in the Appendix at A-17.

JURISDICTION

The decision of the Court of Appeals was announced on

April 7, 1992, and the petition for rehearing and suggestions for

rehearing en banc was denied on June 12, 1992. The jurisdiction

of this Court is invoked under 28 U.S.C. § 1254(1) (1992).

STATUTORY PROVISIONS INVOLVED

The Federal Rules of Evidence were enacted by Congress

as a Statute in 1975, Pub. L. No. 93-595, 88 Stat. 1926 (1975),

28 U.S.C. §§ 2072-74 (1992). Rule 703 provides:

Rule 703. Basis of opinion testimony.

The facts or datain the particular case upon which an

expert bases an opinion or inference may be those

perceived by or made known to the expert at or before

the hearing. If of a type reasonably relied upon by

experts in the particular field in forming opinions or

inferences upon the subject, the facts or data need not

be admissible in evidence.

The Federal Food, Drug, and Cosmetic Act (FDC Act),

Pub. L. No. 75-717, 52 Stat. 1050 (1938), amended by The Food

Additives Amendment of 1958, Pub. L. No. 85-929, 72 Stat.

1784 (1958), 21 U.S.C. § 321(s) (1992), A-18, states that:

The term “food additive” means any substance the

intended use of which results or may reasonably be

expected to result, directly or indirectly, in its becom-

ing a component or otherwise affecting the charac-

teristics of any food . . . if such substance is noi

generally recognized, among experts qualified by

scientific training and experience to evaluate its

safety, as having been adequately shown through

scientific procedures . . . to be safe under the ccndi-

tions of its intended use... .

This case also involves the FDC Act’s provisions relating to

“adulteration,” 21 U.S.C. §§ 348(a) and 342(a)(2)(C) (1992), and

“misbranding,” 21 U.S.C. §§ 243(a)(1) and (i)(1) (1992). The

applicable provisions are reproduced in the Appendix, A-i9-21.

STATEMENT OF THE CASE

This is an in rem seizure action brought under the FDC Act

of bulk drums of a vegetable oil, evening primrose oil (EPO).

The primary issue is whether under Rule 703 of the Federal

Rules of Evidence, or the common-law Frye test, the affidavit

testimony of informed experts in the field of food safety may be

disregarded by the trial and appellate courts.

This is also a case in which only one side has been heard.

The district court granted the Food and Drug Administration’s

(FDA’s) motion for summary judgment on a scientific issue that

Congress said was to be determined by qualified experts. The

district court failed even to mention the evidence in over 300 pages

of testimony from eleven internationally recognized experts, includ-

ing a Nobel Prize recipient and a former Deputy Associate FDA

Commissioner.

The Ninth Circuit affirmed, deeming Efamol’s testimony

“contaminated by . . . consideration of unsuitable evidence” and

therefore inadmissible under Rule 703 and under the Frye test.!

United States v. 45/194 Kg. Drums of Pure Vegetable Oil, No.

90-55086, at A-8-9 (9th Cir. April 7, 1992) (hereinafter referred

to as “Opinion at A-__””). The result is the bizarre rejection of

the kind of evidence that all experts, including FDA’s, rely upon

in making food safety evaluations.

The Ninth Circuit’s ruling calls into question a fundamen-

tal aspect of the admissibility of expert testimony and an issue

upon which the circuits are in disagreement: Can Rule 703 of

the Federal Rules of Evidence be used by judges to reject

litigants’ expert opinions, and can courts impose the common-

law Frye test to require that an expert’s methodology be general-

ly accepted within the scientific community?

The Ninth Circuit’s decision raises another issue in which

the circuits are in disagreement: In a seizure action under the

FDC Act, does FDA bear the burden of proving that the sub-

stance at issue is not “generally recognized as safe” and is

therefore a food additive?

1. Statutory And Regulatory Framework.

The government seeks condemnation of bulk drums of

EPO pursuant to the FDC Act, 21 U.S.C. § 334(d)(1) (1992).

The drums of EPO, owned by petitioner, Efamol, Ltd. (Efamol),

remain under seizure. The EPO is intended to be mixed with a

preservative, vitamin E, encapsulated in gelatin capsules, and

sold as a dietary supplement of essential fatty acids.2_ EPO is

sold as a dietary supplement in more than 25 countries, including

Frye v. United States, 293 F. 1013, 1014 (D.C. Cir. 1923), provided

that before a proponent may introduce testimony based on a novel scientific

technique, the proponent must prove that the technique is already generally

accepted within the relevant scientific specialty.

Panel Report on the Status of EPO as “Generally Recognized as Safe,”

excerpts of the record submitted to the Ninth Circuit (hereinafter referred to

as “Exc.”) at 105 n.1 and 116 n.11.

countries such as the United Kingdom, Japan, Germany and

France, which have regulatory systems that are as sophisticated

as FDA’s. Exc. at 376, 387, 1042.

FDA asserts that the EPO should be condemned (1) be-

cause EPO is not generally recognized as safe and is therefore

a “food additive” for which there is no FDA approval, and (2)

because the seized product is “misbranded.”?

a. Statutory and regulatory requirements pertaining

to general recognition of safety.

The Ninth Circuit struck all of Efamol’s expert testimony

based upon the erroneous determination that experts in the field

of food safety are prohibited from considering data from un-

published studies and from studies in which a substance was

used as a drug — rather than as a dietary supplement — in

determining whether the substance is generally recognized as

safe (GRAS). See Opinion at A-8-9. ;

The FDC Act defines the term “food” as “articles used for

food or drink for man. . . [and] articles used for components of

any other such article.” 21 U.S.C. § 321(f) (1992). Under the

FDC Act. a food ingredient intended to become a component or

otherwise affect the characteristics of a food can be used without

prior FDA approval if it is

generally recognized, among experts qualified by

scientific training and experience to evaluate its

3 Whether EPO is generally recognized as safe or whether it is a “food

additive” will determine whether the substance may be sold in the United

States. FDA has recently seized a large quantity of EPO in another action,

United States v. 217 Cases . . . Efamol Evening Primrose Oil, No. 92-C-

0584B (D. Utah filed June 1, 1992), also alleging that EPO is an unapproved

“food additive.” The misbranding issues are peculiar to the particular

product seized in the instant case, and can easily be resolved under the

“reconditioning” provision of the FDC Act. 21 U.S.C. § 334(d) (1992), by

relabeling the product. Efamol maintains that the product is not misbranded.

Efamol is nonetheless willing to stipulate to relabeling the product to comply

with FDA’s wishes.

safety, as having been adequately shown through

scientific procedures . . . to be safe under the condi-

tions of its intended use. . . .

21 U.S.C. § 321(s). Beyond this, the FDC Act does not specify

any other requirements for establishing the GRAS status of a

particular food ingredient.

Food ingredients that are “generally recognized as safe” are

referred to by food safety experts as “GRAS” substances. Many

foods similar to EPO, including vegetable oils such as corn oil.

soybean oil, and safflower oil, are GRAS and are marketed

without FDA approval. FDA’s regulations contain a partial list

of substances the agency regards as GRAS. 21 C.F.R. Parts 182

and 184 (1991). FDA recognizes that, because the number of

GRAS substances is so large, “{iJt is impracticable to list all

substances that are generally recognized as safe for their in-

tended use.” 21 C.F.R. § 182.1(a) (1991): see also id. at

§ 170.30(d) (1991).

FDA’s primary basis for condemnation is that EPO is not

GRAS and is therefore a “food additive” within the meaning of

21U.S.C. §321(s). Because FDA has not published a regulation

permitting its use, 21 U.S.C. § 348 (1992), FDA argues that EPO

is an “adulterated food” pursuant to 21 U.S.C. § 342(a)(2)(C).

Adulterated foods are subject to seizure under 21 U.S.C. § 334

(1992).

1) Data from unpublished studies.

FDA’s regulations, similar to the FDC Act, provide broad

standards for GRAS status. The courts below took no notice of

the fact that FDA’s regulations define the term “scientific pro-

cedures,” as used in the FDC Act, 21 U.S.C. § 321(s), as “human,

animal, analytical, and other scientific studies, whether publish-

ed_ or unpublished, appropriate to establish the safety of a

substance.” 21 C.F.R. § 170.3(h) (1991) (emphasis added).

FDA’s regulations further state that “[g]eneral recognition of

safety through scientific procedures shall ordinarily be based

upon published studies which may be corroborated by un

published studies and other data and information.” 21 C.F.R

§ 170.30(b) (1991) (emphasis added).

FDA’s regulations therefore specifically contemplate con

sideration of unpublished studies in GRAS evaluations. FDA’s

regulations do not define what studies are ~appropriate” to

GRAS evaluations, or what “other data and information” may

or may not be considered. However, food safety experts, both

within and outside FDA, routinely rely on unpublished studies

as well as data from drug studies for the purpose of GRAS

evaluations.

FDA’s own published GRAS “affirmations” establish that

the agency itself has relied extensively on unpublished data in

GRAS evaluations.4 In its GRAS affirmation of corn syrup

made from bacteria, 48 Fed. Reg. 5716 (February 8, 1983),

A-71, FDA stated that “[u]npublished pathogenicity studies . . .

show that these organisms are neither pathogenic nor

toxicogenic . . . .” A-74, 78.5 FDA also considered “un

published animal feeding studies” for this GRAS evaluation.

Id.° More recently, FDA has relied on unpublished data to

corroborate the agency’s GRAS affirmations for Simplesse®, a

fat substitute, and chymosin, an enzyme used to clot milk.”

Although the FDC Act does not require FDA approval of GRAS food

ingredients, companies may request that FDA “affirm” a company’s GRAS

determination. 21 C.F.R. § 170.35 (1991). FDA publishes its proposed and

final regulations pertaining to such GRAS affirmations in the Federal Revis-

ter as well as the final in the Code of F ederal Regulations. 21 C.F.R. Part 184

The Federal Register announcements cited here were included in an

addendum to Efamol’s appellate brief. The announcements are duplicated.

and the applicable portions underlined, in the Appendix to this Petition for

the Court’s convenience.

See also 48 Fed. Reg. 239, 240 (January 4, 1983), A-86, 89.

' §5 Fed. Reg. 6384, 6386-87, 6390 (February 23, 1990), A-48-51, 59.

62-63; 55 Fed. Reg. 10,932 (March 23, 1990), A-24, 33.

FDA’s former Deputy Associate Commissioner for Health Af

fairs, Dr. Joseph V. Rodricks, further establishes that e Xperts

engaged in GRAS evaluations routine ly consider unpublished

data as part of the evaluation. Exc. at 1057-&. © 16.2

2) Drug study data.

FDA’s published record of GRAS evaluations establishes

unequivocally that food safety experts depend on data from dru

studies to perform GRAS evaluations Examples of such

reliance include FDA’s GRAS affirmation of beeswax (used in

food as a flavoring agent and for other uses). 42 Fed. Reg. 3% 609

(July 29, 1977), A-138, 141-42, papain (an enzyme used in beer

processing, cooking, and meat tenderizing ), 43 Fed. Reg. 31,349

(July 21, 1978), A-93, 98-99, agar-agar (a polysaccharide ex

tracted from algae used to make candy), 42 Fed. Reg. 41.876

(August 19, 1977), A-125, 131, and ammonium compounds

(used a agen ong purpose food substances), 43 Fed. Reg. 14.064

(April 4, 1978), A-107, 114. In addition, the te sumony of

Efamol’s experts establishes that drug studies provide v aluable

safety information and therefore should be considered in any

GRAS evaluation of EPO used as a dietary supplement. Exc. at

687-9, 4 10; Exc. at 1056-7, 94 12-15; and Exc. at 1041-2. 9 16.

b. Statutory and regulatory requirements pertaining

to misbranding.

FDA has alleged, as alternative grounds for condemnation

of the seized product, that the product is misbranded within the

meaning of 21 U.S.C. §§ 343(aj(1) and (ij(1) because it is

labeled “Pure Vegetable Oil” rather than “Evening Primrose

Oil.” Section 343(a)(1) states that a food is misbranded if its

labeling is “false or misleading in any particular.” Section

343(1)(1) requires that the label of most foods bear “the common

While at FDA, Dr. Rodricks had special responsibility for risk and

safety assessment of foods. Exc. at 394, 4 1. He has also served as a member

and has chaired several committees of the National Academy of Sciences.

and has testified before the United States Congress as an expert on issues

relating to food safety and risk assessment. /d

or usual name of the food... .° FDA has promulgated

regulations exempting under specified conditions foods that are

intended for further processing from the “common or usual

name” requirement. 21 C.F.R. § 101.100(d) (1991). A-22.

2. Proceedings In The District Court.

The bulk drums of EPO at issue in this case were seized on

January 31, 1989. Efamol submitted a claim requesting a jury

trial on February 13, 1989. FDA submitted a motion for sum-

mary judgment on May 22, 1989. In support of FDA’s allega-

tion that evening primrose oil is not GRAS, FDA submitted 48

pages of testimony consisting of the declarations of two FDA

employees and four outside scientists. Exc. at 33-80. FDA also

submitted a declaration and documentary evidence to support

its allegation that the seized product is misbranded pursuant to

21 U.S.C. §§ 343(a) and (i)(1).?

On August 22, 1989, Efamol submitted a cross motion for

summary judgment in opposition to FDA’s motion for summary

judgment. Efamol argued that FDA-had the burden of proving

that EPO is not GRAS, that the published literature as reviewed

and analyzed by Efamol’s experts established that EPO is

GRAS, and that the product was not misbranded. Efamol

argued that at a minimum it was entitled to a jury tral.

Prior to responding to FDA’s summary judgment motion,

Efamol convened a panel of experts to consider the GRAS status

of EPO. The panel included:

Uno O. Barcelli, M.D., Associate Professor of Clinical

Medicine, University of Cincinnati Medical Center.

David J. Everett, B.Sc.; Head of Rodent and Reproductive

Toxicology and Study Director at Inveresk Research Inter-

national, Scotland.

° Efamol does not contest that the common or usual name of the seized

product is evening primrose oil, but maintains that the seized product is

exempt from the “common or usual name” requirement, as discussed below.

Robert S. Fisher, M.D., Ph.D., Associate Professor of

Neurology/Neurosurgery, and Co-director, Epilepsy Cen-

ter, The Johns Hopkins University.

Ralph T. Holman, Ph.D., Emeritus Professor of

Biochemistry, University of Minnesota, Minneapolis:

Professor in Mayo Medical School, Rochester, Minnesota.

Loren D. Koller, Ph.D., D.V.M., Professor and Dean.

College of Veterinary Medicine, Oregon State University,

Corvallis, Oregon.

Asaf A. Qureshi, Ph.D., Senior Scientist at the Wisconsin

Analytical and Research Services, Ltd. and President of

Advanced Medical Research, Madison. Wisconsin.

Adrianne E. Rogers, M.D., Professor of Pathology, As-

sociate Chairman of Pathology for Academic Affairs, and

Director of Graduate Studies in Pathology, Boston Univer-

sity School of Medicine.

Robert G. Tardiff, Ph.D., Director, Riskfocus, Versar Inc..

Springfield, Virginia.

Stephen Wright, M.D., Consultant Senior Lecturer in Der-

matology, The Royal Free Hospital School of Medicine,

London.

Exc. at 105-6. Efamol’s evidence on the issue of EPO’s GRAS

status consisted of a joint declaration by the expert panel, Exc.

at 105-53, individual declarations from each of the panel ex-

perts, Exc. at 154-325, additional declarations from four of the

panel members, Exc. at 495-709, 1030-46, and declarations

from Dr. Joseph V. Rodricks and Sir James Black, a 1988 Nobel

Prize laureate in Medicine. Efamol’s experts specifically tes-

tified that the facts and data they relied on in making their

determination that EPO is GRAS are of the type reasonably

relied upon by experts in the field.!° All of these experts

The petitioners’ experts testified that, for example: EPO “satisfied

the . . . scientific criteria” in establishing the safety of EPO, Declaration of

Robert G. Tardiff, Ph.D., Exc. at 283-84, § 9: methods “generally recognized

—

concluded from their review of the published scientific data,

corroborated by unpublished studies, that EPO is GRAS within

the meaning of 21 U.S.C. § 321(s). Exc. at 105-53. Efamol’s

expert panel summarized its reasons for concluding that EPO is

GRAS as follows:

The necessary information to determine the safety of

EPO is published in the scientific literature, and is

therefore available to any scientist interested in

evaluating the safety of EPO. The published literature

contains information on the consumption and meta-

bolism of EPO and its constituents, and contains

information on the consumption of chemically related

substances. The published literature contains... the

most crucial animal studies performed on EPO,

{which} show that EPO is not toxic or carcinogenic.

The published literature also contains extensive

reports of clinical studies which also support the

safety of EPO.

by toxicologists” were used in testing the carcinogenic potential of EPO, id

at 288-89, § 17(a); “EPO has been subjected to a battery of toxicity and

carcinogenicity tests consistent with that required by FDA for a new food

additive,” id. at 299, § 28 (emphasis in original); “[t}he necessary information

to determine the safety of EPO is published in the scientific literature,” id. at

302. 4 31; the “highly desirable procedure” of “conven[ing] an Expert Panel

of qualified and experienced experts” was used in making the GRAS deter-

mination for EPO, Declaration of Joseph V. Rodricks, Exc. at 397,47; FDA

cntena were used “in an analysis of whether the use of [EPO] .. . can be

considered as GRAS,” id. at 398-99, ¥¥ 10-11; “[t}he safety factors obtained

from the dog and rat studies substanuate the safety of EPO .. .: the safety of

EPO is assured beyond the level normally required by FDA.” id. at 301,

€ 30: experts engaged in GRAS evaluations routinely use unpublished data

as part of their evaluations, Second Declaration of Joseph V. Rodricks, Exc.

1057. ¢ 16; “[f}rom a scientific standpoint, it makes no sense to disregard

such published [drug study] information,” Third Declaration of Loren D.

Koller, D.V.M., Ph.D., Exc. at 1042, J 16; “it is clearly apparent that

documented human experience with [EPO] exists, that the data relating to

this experience exceed FDA’s normal requirements to show safety and GRAS

Status .. .,” Second Declaration of Joseph V. Rodricks, Exc. at 1057, § 15.

Exc. at 132 (emphasis added).!!

The conclusion of the expert panel that EPO is GRAS for

its intended use as a dietary supplement was confirmed by

Dr. Rodricks, Exc. at 394-414, and Sir James Black, M.D.. Exc

at 386-93. Sir James concluded that “based on my knowledge

of the scientific information and on the review of the expert

panel [report on the GRAS status of EPO], I am satisfied that

any scientist with the appropriate expertise and an open mind

would conclude that EPO is GRAS for use as a dietary supple-

ment....° Exc. at 392,416. Based on his food safety experience

both at FDA and in private industry, Dr. Rodricks concluded

that:

[T]he necessary information to determine the safety

of Evening Primrose Oil is published in the peer

reviewed scientific literature, and is therefore avail

able to any scientist interested in evaluating the safety

of Evening Primrose Oil.... [T]he safety information

available for Evening Primrose Oil far exceeds that

normally required by FDA for vegetable oils such as

Evening Primrose Oil.

Exc. at 405, 4 21.

On the misbranding issues, Efamol submitted the declara-

ion of a consumer behavior expert who reviewed the labels on

the seized product. The expert stated that, in his view, the labels

The expert panel reviewed and analyzed 162 published articles before

reaching its conclusion that EPO is GRAS. Exc. at 109 n.3 and 341-52. As

directed by FDA’s regulations, 21 C.F.R. §§ 170.3(h) (1991) and 170.30(b).

the panel also reviewed data from unpublished studies to corroborate the

panel’s GRAS determination and to make certain that the unpublished data

did not raise safety concerns about EPO. Exc. at 124-26. The panel's report

establishes the panel's understanding that GRAS status according to FDA's

regulations shall “ordinarily be based upon published studies which may be

corroborated by unpublished studies and other data and information.” Exc.

at 111, quoting 21 C.F.R. § 170.30(b); see also Exc. at 124 (“the safety and

general recognition of safety of EPO are corroborated by unpublished

studies”).

a ——

would not mislead consumers.!* Efamol also submitted tes-

timonial and documentary evidence that a written agreement

existed between Efamol and the company to whom the bulk EPO

was sent, exempting the seized EPO from the common or usual

name requirement of the FDC Act, 21 U.S.C. § 343(i)(1).

pursuant to FDA’s regulation, 21 C.F.R. § 101.100(d)(2)

(1991). Exc. at 988-1900.

The district court granted FDA’s motion for summary

judgment on November 27, 1989, without addressing the burden

of proof issue and, with no analysis, adopted FDA’s findings of

fact verbatim. Compare FDA’s Statement of Uncontroverted

Facts at @§ 12, 14, 15 and 16, Exc. at 10-11, with District Court’s

Findings of Fact at §§ 12, 13, 14 and 16, A-14-15. The district

court found that EPO is not GRAS because FDA’s experts did

not view it as such. A-15,§ 16. The district court did not even

acknowiedge Efamol’s extensive expert testimony, let alone

articulate why it believed the testimony inadequate to establish

a genuine issue of material fact. /d.

3. Proceedings In The Court Of Appeals.

Efamol appealed to the Ninth Circuit, arguing again that

FDA bears the burden of proof on the GRAS issue, and that

Efamol’s expert testimony established that EPO is GRAS, or at

a minimum raised a genuine issue of fact. Without analysis, the

Ninth Circuit quoted one of several conflicting burden-of-proof

cases and held that the burden of proving GRAS status “is placed

on the proponent of the food substance in question.” Opinion

at A-7 (citation omitted).

The Ninth Circuit then rejected Efamol’s testimony in total,

Stating that

[s]cientific studies which would support a finding that

EPO is generally recognized as safe must be based on

12 m Aas

He stated further that no definitive conclusion on this issue could be

reached without empirical data, in the form of a consumer survey, evidence

which FDA did not present. Exc. at 1003-5, 99 8-13.

human, animal, analytical and other scientific studies.

21 C.F.R. § 170.3(h). This data must be collected and

analyzed with regard to EPO’s use as a dietary sup-

plement. Furthermore, the information must be

generally available to the community of experts and

Subjected to peer evaluation, criticism and review

appropriate to establish such safety. 21 C.F.R.

§ 170.30(b); Weinberger v. Bentex Pharmaceuticals.

Inc., 412 U.S. 645, 652 (1973).

The evidence submitted by Efamol or used by

Efamol’s experts to evaluate EPO fails to meet the

above criteria. Some of the data considered by

Efamol’s experts concerns EPO’s use as a drug and

not as a dietary supplement. Other data was based on

unpublished materials, which were not subjected to

peer evaluation. Thus, the opinions of Efamol’s ex-

perts were contaminated by their consideration of

unsuitable evidence.

Opinion at A-8-9 (footnote omitted).

The Ninth Circuit identified two grounds for its wholesale

rejection of Efamol’s expert testimony. First, the court found

that the “data relied on by Efamol is insufficient under Rule 703

of the Federal Rules of Evidence.” Jd. at A-9 n.4. Second. the

court cited two cases, Daubert v. Merrell Dow Pharmaceuticals.

Inc., 951 F.2d 1128, 1130 (9th Cir. 1991), petition for cert. filed,

No. 92-102 (July 7, 1992), and Christophersen vy. Allied-Signal

Corp., 939 F.2d 1106, 1114 (Sth Cir. 1991) (en banc). cert.

denied, __U.S.__, 112 S. Ct. 1280 (1992). both of which rejected

expert tesumony on the basis of the test enunciated in F rye.}3

Moreover, the Ninth Circuit rejected Efamol’s expert testimony on

the issue of whether labeling the seized oil “Pure Vegetable Oil” rather than

“Evening Primrose Oil” was false or misleading within the meaning

of 21 U.S.C. § 343(a) (1992). Opinion at A-5. The court also rejected

Efamol’s evidence of a written agreement exempting the seized product from the

“Common or usual name” requirement of 21 U.S.C. § 343(1)(1). Opinion at A-6-7.

REASONS FOR GRANTING THE WRIT

A sharp conflict and much confusion exist in the circuits

over the proper role and interpretation of Rule 703 of the Federal

Rules of Evidence, and whether the enactment of Rule 703

eliminated the common-law Frye test. This is the fourth time

in recent months that this Court has been asked to resolve the

Frye issue. See note 22 infra. Many courts, including the Ninth

Circuit in this case and in Daubert and the Fifth Circuit in

Christophersen, are moving farther and farther away from the

plain meaning of Rule 703 and are making up rules of evidence

tor individual cases in an apparent attempt to resolve complex

cases by excluding one party’s expert testimony, thereby dis-

posing of the cases on summary judgment. This case is an

extreme consequence of the restrictive approach, rejecting the

kind of scientific data that all scientists, in and out of FDA, use

to make food safety evaluations.

1. This Court Should Resolve The Conflict In The

Circuits Over Fed. R. Evid. 703 And Frye.

The controversy over Rule 703 involves whether courts

“can impose an independent reasonableness standard on the

expert s reliance, or whether it is enough that experts in the field

customarily rely on the type of data upon which the expert

intends to rely.” Michael C. McCarthy, Note, “Helpful” Or

“Reasonably Reliable”? Analyzing The Expert Witness's

Methodology Under Federal Rules Of Evidence 702 And 703,

77 Cornell L. Rev. 350, 356 n.34 (Jan. 1992).!4_ To complicate

In Japanese Elec. Prod. Antitrust Litig. v. Matsushita Elec. Indus. Co.,

Lid., 723 F.2d 238, 276 (3d Cir. 1983), for example, the Third Circuit reversed

the trial court’s ruling that it was obliged to determine the reasonableness of

the expert's reliance. The court stated that “[t]he proper inquiry [under Rule

703] is not what the court deems reliable, but what experts in the relevant

discipline deem it to be.” Rev'd on other grounds sub nom., Matsushita Elec.

Indus. Co., Ltd. v. Zenith Radio Corp., 475 U.S. 574 (1986). A more

. Testrictive approach was taken in Jn re “Agent Orange” Prod. Liab. Litig.,

611 F. Supp. 1223, 1244 (E.D.N.Y. 1985): “The more restrictive view

matters further, some courts — including the Ninth Circuit in

this case — use the common-law Frye test, which has no textual

basis in the Federal Rules of Evidence, asa ground for excluding

expert testimony. Professor Imwinkelried has provided a

detailed explanation of this conflict:

At the time of the adoption of the Federal Rules of

Evidence, the overwhelming majority of jurisdictions

subscribed to the Frye standard for determining the

admissibility of scientific testimony. . . .

Against this backdrop, Congress enacted the Federal

Rules, including rule 703. Rule 703 permits an expert

to base an opinion on information only “[i]f [it is] of

a type reasonably relied upon by experts in the par-

ticular field.” At least one line of authority holds that

by virtue of the rule’s use of the term “reasonably,”

the judge may bar an expert from relying on a type of

information even when it is the Customary practice

within the expert’s specialty to rely on that type of

data, if the judge finds that reliance objectively un-

reasonable. If that interpretation of rule 703 is correct.

rule 703’s application to the expert’s major premise

could result in a more conservative test for admis-

sibility than the Frye standard; even when the

proponent of the testimony can prove generai accep-

tance, the judge could second-guess the scientific

community and bar the testimony.!5

As to the status of the Frye test, Justice White. dissenting from

this Court’s denial of the petition for writ of certiorari of the

requires the trial court to determine not only whether the data are of a type

reasonably relied upon by experts in the field, but also whether the underlying

data are untrustworthy for hearsay or other reasons.” Aff don other grounds,

818 F.2d 187 (2d Cir. 1987), cert. denied, 487 U.S. 1234 (1988).

'S Edward J. Imwinkelried, The “Bases” Of Expert Testimony: The

Syllogistic Structure Of Scientific Testimony, 67 N.C.L. Rev. 1, 18-19 (Nov.

1988) (citations omitted) (foomotes omitted).

Fifth Circuit's decision in Christophersen v. Allied-Signal

(orp, Summarized the division in the courts

As the Fifth Circuit is divided, so the Courts of

Appeals are in disagreement. Some continue to apply

the approach set forth in Frye in deciding whether

expert evidence 1s admissible. F.g., Daubert v. Mer

rell Dow Pharmaceuticals, Inc., 951 F.2d 1128 (CA9

1991): United States v. Two Bulls, 918 F.2d 56 (CA®

1990): United States v. Smith, 869 F.2d 348 (CA7

1989). But courts in other circuits have concluded

that Frve was superseded in 1975 by the Federal Rules

of Evidence, which they maintain established a lower

threshold for determining the admissibility of expert

evidence. F£.g.. United States v. Jakobetz, 60

U.S.L.W. 2470, ___ F.2d (CA2 1992); DeLuca

v. Merrell Dow Pharmaceuticals, inc., 911 F.2d 941

(CA3 1990). Because this is an important and recurring

issue, | would grant certiorari to resolve the conflict.

Christophersen v. Allied-Signal Corp., 112 S. Ct. at 12%1 (1992)

(White & Blackmun, J.J., dissenting from denial of certiorari).

As early as 1986, two Justices indicated the need for granting

ceruoran to resolve the circuit split over Frye. Mustafa v.

United States, 479 U.S. 953, 953 (1986) (White & Brennan, J.J.,

dissenting from denial of certiorari) (““] would grant certiorari to

resolve the conflict on an obviously recurring and important

issue,”’),16

the circuits on the admissibility of expert tesumony under Rules 702 and 703

and the continuing questions regarding Frye’ s viability in light of the Federal

Rules... . {t]he ume may be npe for the Supreme Court to grant certiorari

on these issues.”); Gary Taylor, Expert Witness Opinion Eyed; Circuits Split

on Issue, Nat | LJ., at 3-4 (Oct. 21, 1991) (*Tnal Lawyers for Public Justice

Says that the [Christophersen) opinion places the 5th Circuit at odds with the

3d Circuit on the expert witness issue, and only the high court can sort things

i ee 3

a. The split in the circuits over Fed. R. Evid. 703 and

the Frye test.

Some courts of appeals properly interpret the expert tes

timony provisions of the Federal Rules of Evidence and recog

nize that Rule 703 is not a tool for judges to weigh conflicting

expert testumony. These same courts also recognize that the

Frye test has been superseded by the Federal Rules of

Evidence.!’ The Third Circuit has provided particularly help

ful commentary in this area. In United States v. Downing, 753

F.2d at 1232-37, the court surveyed the history of Frye’'s

serious flaws,” notably “its vagueness and its conservatism

and concluded that Frye “should be rejected as an independent

controlling standard of admissibility” because it “reflects a

conservative approach to the admissibility of scientific evidence

that 1s at odds with the spirit, if not the precise language, of the

Federal Rules of Evidence.” /d. at 1236-37. In DeLuca

Merrell Dow Pharmaceuticals, Inc., 911 F.2d 941 (3d Cir

1990), the Third Circuit also recognized that

Rule 703 is satisfied once there is a showing that an

expert s testimony 1s based on the type of data a

reasonable expert in the field would use in rendering

an opinion on the subject at issue; it does not address

\S2e2"

)

FIRST CIRCUIT: Int’! Adhesive Coating Co., In Boltan Emerson In

Inc., 851 F.2d 540, 544-45 (ist Cir. 1988) (“As noted in Rule 703

reasonableness is measured against the facts or data upon which experts in

the particular field normally rely When the factual underpinning of an

expert s opinion is weak, it is a matter affecting the weight and credibility of

the tesumony — a question to be resolved by the jury.”) (citations omitted)

SECOND CIRCUIT: United States v. Jakobetz, 955 F.2d 786, 794 (2d Cir

1992) (“[T]he Frye standard [has] been superseded by the Federal Rules of

Evidence, which stress{es] a permissive method for determining admis-

sibility.”), petition for cert. filed, No. 91-7921 (April 8, 1992).

THIRD CIRCUIT: United States v. Downing, 753 F.2d 1224, 1237 (3d Cir

1985)

the reliability or general acceptance of an expert's

methodology.

Id. at 953. summary judgment granted on remand, No. 87-226

(GEB), 1992 U.S. Dist. LEXIS 6511 (D.N.J. April 29, 1992).

Some circuits have also refused to use Rule 703 as a vehicle

for judges to take away the jury function of weighing expert

testimony.!* Yet strangely these same circuits insist on con-

tinuing to apply the Frye test.. See note 21 infra.

1S ‘

See:

FOURTH CIRCUIT: ClinchfieldR R. Co. v. Lynch, 784 F.2d 545, §54 (4th

Cir. 1986) (“[I}t is better to admit relevant scientific evidence in the same

manner as other expert tesumony and allow its weight to be attacked by cross

examinauion and refutation.) (citation omitted).

SIXTH CIRCUIT: Mannino v. Int'l Mfg. Co., 650 F.2d 846, 853 (6th Cir.

1981) (2Great liberality is allowed the expert in determining the basis of his

opinions under Rule 703. Whether an opinion should be accepted is not for

the tnal judge.”).

SEVENTH CIRCUIT: United States v. Tranowski, 659 F.2d 750, 755 n.10

(7th Cir. 1981) (“Rule 703 permits a court to admit an expert opinion based

on hearsay, if reliance on such factual bases is ure normal practice of experts

in the field in reaching their conclusions.”) (emphasis added), rev'd on other

grounds, 702 F.2d 668 (1983), cert. denied, 468 U.S. 1217 (1984).

EIGHTH CIRCUIT: United States y. Kail, 804 F.2d 441, 448 (8th Cir.

1986) (“[Q]juestions as to the reliability of the experts’ judgments go to the

weight to be given . . . to the testimony, and not toe the admissibility of the

tesumony. We therefore conclude that the district court did not err in

admitung the expert testumony to the jury under Rule 703.”).

NINTH CIRCUIT: Rogers v. Raymark Indus., Inc., 922 F.2d 1426, 1429-

30 (9th Cir. 1991) (“an expert opinion may be based on any type of evidence

commonly used by experts in the field.”) (citation omitted).

D.C. CIRCUIT: Ambrosini v. Labarraque, No. 90-7146 and No. 90-7148,

slip op. at 5 (D.C. Cir. June 12, 1992) (“Rule 703 broadens the acceptable

bases for expert tesumony by allowing an expert to base an opinion on

hearsay and other evidence not admissible in court.”).

In other circuits, however, a “disturbing trend” exists for

reading Rule 703 very restrictively and excluding evidence

under that rule. McCarthy, supra page 14, at 366 n.96. This

trend arose out of Judge Weinstein’s opinion in In re “Agent

Orange,” 611 F. Supp. 1223.'? As one commentator noted,

‘“[w]hen the Court is unconvinced. it grants defendants’ motions

for summary judgment. Rather rare before Weinstein’s [/n re

Agent Orange] decision, this movement is gathering momen-

tum."” McCarthy, supra page 14, at 367 n.96.2°

The Ninth Circuit in this case cited Daubert, 951 F.2d at

1130, and Christophersen, 939 F.2d at 1114, in its holding that

Efamol’s expert opinions were “contaminated.” Opinion at

A-9. These Fifth and Ninth Circuit opinions are representative

of two of the eight circuits that have employed a restrictive

reading of Rule 703 and/or have invoked the Frye test to exclude

expert testimony.*! “Whatever degree of clarity the Third

In In re “Agent Orange,” the court decided not to allow the cases of

almost 300 individuals who had opted out of a class settlement to survive

summary judgment. The decision hinged on a restrictive reading of Rule 702

and a finding that the plaintiffs’ expert testimony was inadmissible under

both Federal Rules of Evidence 703 and 403. 611 F. Supp. at 1256.

For an extended iliustration of cases in which courts have used Rule

703 as a basis for granting summary judgment, see McCarthy supra page

14, at 358 nn.41-42.

See:

FOURTH CIRCUIT: Ellis v. Int'l Playtex, inc., 745 F.2d 292. 304 n.15

(4th Cir. 1984) (“Although this court has expressed concern over the Frye

rule, we have continued to recognize its validity in certain circumstances.”).

SIXTH CIRCUIT: United States v. Metzger, 778 F.2d 1195. 1203 (6th Cir.

1985) (“[a]lthough ‘[a] number of the federal courts have responded to the

enactment of Rule 702 by rejecting the Frye standard, [this circuit] still

predicate[s] the admission of scientific evidence on general acceptance in the

community’) (citations omitted), cert. denied, 477 U.S. 906 (1986).

SEVENTH CIRCUIT: United States v. Smith, 869 F.2d 348, 351 (7th Cir.

1989) (“[T]his circuit has continued to affirm (and to apply) the Frye

standard.”).

——————————

Circuit brought to Rule[] . . . 703 in DeLuca was shattered by

the Fitth Circuit’s most recent pronouncements on scientific

expert testimony in Christophersen...” McCarthy, supra page

ld. at 381.

In Christophersen, the district court struck the plaintiff’ s

expert's testimony “as it is not based upon the type of evidence

usually relied upon by experts in the field of cancer research.”

Christophersen, No. W-88-CA-098, slip op. (W.D. Tex. Ox

tober 12, 1989), reprinted in Petition for Writ of Certiorari at

A74, No. 91-785 (filed November 12, 1991). Summary judg

ment was issued for the defendants. The Fifth Circuit voted en

banc to affirm the judgment of the district court, stating that “the

inquiry into the . . . ‘facts and data’ underlying an expert's

tesumony is not limited to the admissibility of that data,” but

extends to the sufficiency and accuracy of underlying facts.

939 F.2d at 1114. The Frye test, the court explained, requires

a court to determine “whether the methodology or reasoning that

the expert uses to connect the facts to his conclusions is generally

accepted within the relevant scientific community.” /d. at 1115.

The court in Daubert affirmed a summary judgment ruling

with similar reliance on the Frye test. The court stated:

Expert opinion based on a scientific technique “‘is

admissible if it is generally accepted as a reliable

technique among the scientific community.” United

States v. Solomon, 753 F.2d 1522, 1526 (9th Cir.

EIGHTH CIRCUIT: United States v. Two Bulls, 918 F.2d 56, 60 n.7 (8th

Cir. 1990) (Federal Rules of Evidence do not supersede Frye.).

TENTH CIRCUIT: Head v. Lithonia Corp., Inc., 881 F.2d 941, 944 (10th

Cir. 1989) (“Because the record does not sufficiently establish the trustwor-

thiness of topographical brain mapping or its acceptance in the relevant scientific

community” court vacated the judgment and remanded for a new trial.).

D.C. CIRCUIT: Kropinski v. World Plan Executive Council - U.S., 853

F.2d 948, 956-57 (D.C. Cir. 1988) (expert opinion was excluded because it

did not have a “significant following in the scientific community, let alone

general acceptance.”).

1985) (citing Frye v. United States, 293 F. 1013. 1014

(D.C. Cir. 1923)

YS1 F.2d at 1129-31 (citing Christophersen, 939 F.2d at 1109).

In Daubert and now in this case, the Ninth Circuit has

refused to join the circuits that recognize that the Frye test has

been displaced by the Federal Rules of Evidence. Certiorari was

recently sought in Christophersen and Daubert to resolve the

Frye issue. Jakobetz is the other petition for certiorari.“* In

response to that petition, Solicitor General Kenneth W. Starr

acknowledged that the courts of appeals are divided over

whether Frye is still good law.2? The Solicitor General argued

however, that Jakobetz “is not an appropriate case in which to

resolve the issue in which the courts of appeals are in conflict.’

Id. at 12.4

In contrast, this case is a particularly appropriate one for

the Court to resolve the conflict and confusion over Rule 703

and the Frye test. This case turns squarely on whether the Ninth

See United States v. Jakobetz, 955 F.2d 786 (2d Cir. 1991). Petition

for Wnit of Certiorari (pending), No. 91-7921 (filed April 6, 1992) (petition

seeks review of the Second Circuit's refusal to follow other circuits in

requiring prosecutors to meet Frye’s heightened standard for admissibility

when seeking to introduce new forms of forensic evidence): Daubert y

Merrell Dow Pharmaceuticals, Inc., Petition for Writ of Certiorari | pending)

No. 92-102 at 9-10 (filed July 7, 1992) (petition requested that this Court

resolve whether the judge-made rule of Frye “was eliminated as a ground for

excluding evidence by Congress’s enactment of uniform Federal Rules of

Evidence.”). See also Christophersen v. Allied Signal Corp., Petition for

Wnt of Certiorari, No. 91-785 at 20 (filed November 7, 1991. denied March

2. 1992) (certiorari petition requested the Court's prompt intervention to

resolve the Frye issue).

732

Jakobetz v. United States, Brief For The United States In Opposition

(To The Petition For Wnit Of Certiorari], No. 91-7921 (filed June 10. 1992)

at 8-10.

*4 The issue in Jakobetz is whether DNA profiling is admissible under

the Federal Rules of Evidence. According to the Solicitor General. the DNA

profiling technique is admissible even under the restrictive Frye test. /d.

iii ieee

ht hw

Circuit applied the correct test under Rule 703, and whether the

outdated Frye rule should have been invoked in assessing

Efamol’s expert testimony. Moreover, this Court’s review is

necessary to address Christophersen, which “breathes new life

into the Frye rule and counters ‘the movement away from the

general acceptance test’” of Rule 703.29 The fact that another

circuit — the Ninth Circuit— has now boarded the Christopher-

sen bandwagon in two recent decisions only heightens the

conflict and confusion in the federal courts over the admis-

sibility of expert testimony under Rule 703 and whether Frye is

still good law.

If this Court grants review of Daubert and/or Jakobetz, it

should also grant review of the instant petition or hold it pending

disposition of the other(s). Even if this Court denies review of

Daubert and Jakobetz, it should grant this petition because,

unlike the Daubert and Jakobetz petitions, the instant petition

also presents the opportunity for this Court to resolve the conflict

and confusion in the circuits over Rule 703 of the Federal Rules

of Evidence.

b. The test that should be used by the courts.

The Ninth Circuit’s decision in this case illustrates how far

federal courts are diverging from Rule 703. Having decided

Daubert, the Ninth Circuit cited that decision and Christopher-

sen to reject more than 300 pages of detailed scientific tes-

timony. Congress plainly intended through the adoption in 1975

of the Federal Rules to liberalize the admissibility of expert

testimony, thereby eliminating the common-law Frye test.?°

The Ninth Circuit shuts the door that Congress attempted to open

— in this case, with the spectacular result of denying useful

Recent Case, 105 Harv. L. Rev. 791, 794-95 (1992) (citation omitted).

The Advisory Committee’s note to Rule 703 provides specifically

that “[t]he rule is designed to broaden the basis for expert opinions beyond

that current in many jurisdictions and to bring the judicial practice into line

with the practice of experts themselves when not in court.” See also Faust

F. Rossi, Modern Evidence and the Expert Witness, 12 Litig. 18, 18 (Fall

evidence routinely used by experts, even those within FDA, to

make GRAS determinations.

The Supreme Court should define the proper test under

Fed. R. Evid. 703. This Court should clarify that “[t]he proper

inquiry [under Rule 703] is not what the court deems reliable.

but what experts in the relevant discipline deem it to be... . [I]f

an expert avers that his testimony is based upon data in the field

that experts rely upon, then Rule 703’s requirements are generally

satisfied.”?7

This Court should also make clear that the common-law

Frye test has been displaced by the Federal Rules of Evidence.28

As this Court has emphasized, “[b]Jecause the Federal Rules of

Evidence are a legislative enactment, we turn to the ‘traditional

tools of statutory construction,’ in crder to construe their

provisions.” Beech Aircraft Corp. v. Rainey, 488 U.S. 153, 163

(1988) (citation omitted). Citing Beech Aircraft, then-Judge

1985) (“The welcome mat was rolled out in 1975, when Congress enacted

Federal Evidence Rules 702 through 705. These four provisions, comprising

only six sentences, confirmed the judicial trend toward expanded admis-

sibility of expert testimony.”)

*7 DeLuca, 911 F.2d at 952 (citations omitted). See also Mannino,

650 F.2d at 851 (“[t]he purpose of Rule 703 is to make available to the expert

all of the kinds of things that an expert would normally rely upon in forming

an opinion, without requiring that these be admissible in evidence”: through

it “the law is catching up with the realities of professional life.”): Clinchfield

R.R. Co., 784 F.2d at 553-54 (Rule 703 satisfied with a showing that data are

“reasonably relied upon by experts in the particular field” — questions going

to weight should be “attacked by cross examination and refutation.”) (cita-

tions omitted).

See 3 Jack B. Weinstein & Margaret A. Berger, Weinstein’ s Evidence

§ 703[01), at 702-36 (1991) (“Elimination of the Frye test is consistent with

the underlying policy of Article VII” of the Federal Rules of Evidence)

(footnote omitted); 22 C. Wright & K. Graham, Federal Practice and

Procedure § 5169, at 108 (1978) (Frye did not survive the enactment of the

Federal Rules of Evidence).

(now Justice) Thomas emphasized that on evidence questions a

court must “begin as... with any statute, with the language of

the rules themselves.” United States v. Rogers, 918 F.2d 207.

209 (D.C. Cir. 1990).

Furthermore, in a decision citing an opinion issued by

then-Judge (now Justice) Kennedy. the Ninth Circuit recog

nized that the Federal Rules of Evidence “supersede the rules

of evidence based on common-law principles,” and that “the

courts are not free to establish rules of evidence independent of

the Federal Rules.” United States y. Grajeda, 570 F.2d 872. 874

(9th Cir. 1978) (citing United States v. Dixon. 547 F.2d 1079,

1082 (9th Cir. 1976) (Kennedy, J.) (footnote omitted), Grajeda,

570 F.2d 872, withdrawn and new opinion issued on alternate

ground, 587 F.2d 1017 (9th Cir. 1978). Although the Ninth

Circuit has chosen to ignore Justice Kennedy’s opinion, his view

was endorsed by this Court, which recognized that “[bJefore the

present Rules were promulgated, the admissibility of evidence

in the federal courts was governed in part by statutes or Rules,

and in part by case law.” The Court then agreed that “in

principle, under the Federal Rules no common law of evidence

remains.” United States v. Abel, 469 U.S. 45. 50-52 (1984)

(citations omitted).

The Frye test appears nowhere in the text of the Federal

Rules of Evidence. As such, this common-law rule of evidence

no longer remains. The Senate Report accompanying the

Federal Rules of Evidence cited the need for “a comprehensive

code of evidence intended to govern the admissibility of proof

in all trials before the Federal courts beeause of the lack of

uniformity and clarity in the present law of evidence on the

Federal level.” S. Rep. No. 93-1277, 93d Cong., 2d Sess.

(1974), reprinted in 1974 U.S. Code Cong. & Admin. News

7054. In order to maintain a uniform rule of evidence, this Court

Should make clear that Frye is no longer good law.

Roughly one-third of all cases in federal courts depend on

expert testimony.*? Professor Imwinkelried summarized why

Frye presents a “formidable” and unreasonable barrier in cases

involving such testimony:

Even if the world’s leading scientific authority on a

subject attests to a new theory, even if the Nobel prize

winner in a specific field conducts a thorough. wel]

designed experiment to validate the technique, the

courts Cannot admit the evidence until most of the

scientists in that specialized field know and approve

the theory.”

The same logic applies to Rule 703. Courts should not

substitute their judgment for the judgment of experts

2. The Supreme Court Should Resolve The Conflict As

To Which Party Bears The Burden Of Proof On The

Issue Of GRAS Status.

This case presents a second conflict among the circuits

Whether FDA or the manufacturers of food products bear the

burden of proving GRAS status in a seizure action. This is an

issue of fundamental importance to the food industry. Inde-

pendently determining that a food ingredient is GRAS and

marketing it without undergoing the lengthy delays of the FDA

food additive approval process is a major route by which food

ingredients come to the market. See 21 C.F.R. § 182. 1(a).

After rejecting all of Efamol’s testimony on the GRAS

issue, the Ninth Circuit held that summary judgment was ap-

propriate because “Efamol failed to make a showing sufficient

to establish the existence of an element essential to its case. and

Imwinkelried, supra page 15, at |

Edward J. Imwinkelreid, The Standard For Admitting Scientific

Evidence: A Critique From The Perspective Of Juror Psychology, 28 Vill.

L. Rev. 554, 557 (1982-83) (footnote omitted).

on which it bears the burden of proof at trial.” Opinion at A-9,3!

As the basis for this crucial allocation of the burden of proof,

the Ninth Circuit quoted dictum in United States v. An Article

of Food . . . Coco Rico, 752 F.2d 11, 15 (1st Cir. 1985) and,

without analysis of the issue, placed the burden of proof of

GRAS status on Efamol. Opinion at A-7, 9.

The FDC Act authorizes the government to proceed against

adulterated or misbranded products on libel of information in

any federal district court. 21 U.S.C. § 334(a) (1992). The FDC

Act contains numerous grounds upon which a food can be

deemed to be adulterated or misbranded.32 It is clear that in all

enforcement actions under the FDC Act for adulteracion or

misbranding, FDA must prove each element of its case by a

preponderance of the evidence.33 In this case, however. the

Ninth Circuit heid that the burden is different where FDA seizes

a food product alleging that it is not GRAS and is therefore an

unapproved food additive. Had Congress intended to make the

The Ninth Circuit also erred because Efamol was only required to

show a genuine issue of material fact to be entitled to a trial. Efamol was not

required to prove that it would prevail at trial to overcome a motion for

summary judgment. Anderson v. Liberty Lobby, Inc., 477 U.S. 242. 248-49

(1986).

2 For example, a food may be deemed “adulterated” if it “contains any

poisonous or deleterious substance which may render it injurious to health,”

or “if it consists . . . of any filthy, putrid, or decomposed substance. . . .”

21 U.S.C. § 342(a)(1), (3) (1992). A food may be deemed “misbranded”

under the FDC Act if, for example, “its labeling is false or misleading in any

particular, . . .” or if “it is offered for sale under the name of another food.”

21 U.S.C. § 343(a)(1), (b) (1992).

Nat'l Labor Relations Bd. v. Transport Management Corp., 462 U.S.

393, 401 (1983) (government carries the burden of proving the elements of

a4 Statutory violation). See also United States v. General Foods Corp

446 F. Supp. 740, 753 (N.D.N.Y.), aff'd, 591 F.2d 1332 (2d Cir. 1978);

United States v. 119 Cases, More or Less .. . “New Dextra Brand Fortified

Cane Sugar * * *,” 231 F. Supp. 551, 558 (S.D. Fla. 1963). aff d per curiam,

334 F.2d 238 (Sth Cir. 1964); United States v. 46 Cases. More or Less .

“Welch's Nut Carameis * * *,” 204 F. Supp. 321, 322 (D.R.I. 1962)

burden different in GRAS cases, it would have made its intent

clear. Cf. United States v. 88 Cases, More or Less, .. . Bireley’s

Orange Beverage, 187 F.2d 967 (3d Cir.), cert. denied, 342 U.S.

861 (1951). There is nothing in the language of the statute that

even suggests there is a different burden of proof when a seizure

action is brought under 21 U.S.C. § 342(a)(2)(C), as opposed to

any other subsection of § 342.

The legislative history is unequivocal that Congress in-

tended, consistent with all other FDC Act enforcement actions,

that FDA bear the burden of proving that a substance is not

GRAS. The Food Additives Amendment of 1958 added the

term “food additive” to the FDC Act, 21 U.S.C. § 321(s). The

Department of Health, Education, and Welfare (now the Depart-

ment of Health and Human Services, of which FDA is a part)

issued a statement that all of the various bills

contain a “generally recognized” clause in one form

or another .... It is important to note that under all

the bills, as drawn, the burden would be on the

Government, in an enforcement proceeding, to prove

that a substance is not generally recognized by experts

as safe and is therefore within the scope of the bill.54

The chief counsel of FDA at the time agreed:

We have the burden, no matter how this bill goes, of

proving that a product is not generally recognized as

safe among experts in the courts. Let us assume that

this bill came out as we recommended it and company

X had a chemical which had not been adequately

tested, we thought it was not generally recognized as

safe, the applicant thought it was generally recognized

as safe. We would have the burden of going to court

34 Food Additives: Hearings Before a Subcomm. of the House Comm.

on Interstate and Foreign Commerce, 85th Cong., 2d Sess. 455 (1958)

(supplemental statement of the Department of Health, Education, and

Welfare’s views to accompany the statement of George P. Larrick, FDA

Commissioner) (emphasis added).

was not generally recognized as safe.35

These contemporaneous interpretations of the statute by those

charged with its enforcement are entitled to great deference.

See, e.g., Udall v. Tallman, 380 U.S. 1, 16 (1965): Zuber v.

Allen, 396 U.S. 168, 192-93 (1969). The district court and the

Ninth Circuit ignored this legislative history.

The circuits are split on the issue of who bears the burden

of proof on the GRAS issue. Without much discussion. some

circuits have required FDA to prove that a substance is not

GRAS. United States v. An Article of Food . . . 345/50-Pound

Bags, 622 F.2d 768, 771 (Sth Cir. 1980)(“‘the government had

the burden of demonstrating that no genuine issue of material

fact existed” as to general recognition of safety): United States

v. Articles of Food and Drug .. . Coli-Trol, 518 F.2d 743. 746

(Sth Cir. 1975)(FDA bears burden of proof on the GRAS issue):

United States v. Ewig Bros. Co., Inc., 502 F.2d 715, 719 (7th

Cir. 1974)(the government “need only prove that ‘such sub-

stance is not generally recognized . . . to be safe under .. .’

21 U.S.C. § 321(s)”) (footmote omitted), cert. denied. 420 U.S.

945 (1975).36

Other courts of appeals appear to place the burden on the

manufacturer to prove GRAS status.37_ None of these cases.

Chemical Additives in Foods: Hearings Before a Subcomm. of the

House Comm. on Interstate and Foreign Commerce. 84th Cong., 2d Sess.

226 (1956) (statement of Mr. William W. Goodrich) (emphasis added).

On the similar question of general recognition of safety and efficacy

of drugs, courts have stated that the government has the burden of proof.

United States v. Alcon Lab., 636 F.2d 876, 888 (1st Cir.), cert. denied,

451 U.S. 1017 (1981); United States v. Articles of Food and Drug ...

Coli-Trol, 372 F. Supp. 915, 917 (N.D. Ga. 1974), aff d, 518 F.2d 743 (5th

@ir. 1975); United States v. An Article of Drug ... “Bentex Ulcerine,” 469

F.2d 875, 878-79 (5th Cir. 1972), cert. denied, 412 U.S. 938 (1973).

*T An Article of Food . . . Coco Rico, 752 F.2d at 15 (Ist Cir, 1985):

F mali Herb, Inc. v. Heckler, 715 F.2d 1385. 1390-91 (9th Cir. 1983): United

however, focused on the burden of proof issue because it was

not central to the decision. The court in Coco Rico, on whose

dictum the Ninth Circuit chose to rely, appears to have confused

the burden of proving GRAS status, which Congress placed on

FDA, with the burden of proving safety for a food additive when

one seeks FDA approval to market the additive. In the latter

case Congress clearly put the burden of proving safety on the

proponent of the food additive. 21 U.S.C. § 348.

The Ninth Circuit’s decision dramatically alters the playing

field by erroneously shifting the burden of proof. The Ninth

Circuit said that Efamol’s failure to meet the burden of proof on

the GRAS issue warranted summary judgment. Therefore, the

Ninth Circuit’s misallocation of the burden of proof by itself

warrants the grant of certiorari in this case.

3. Efamol’s Evidence On The Misbranding Issues Raises

Genuine Issues Of Fact Requiring A Trial.

The Ninth Circuit’s holding on the misbranding issues is

based on a misreading of Dr. Ross’ testimony, which clearly

raises a genuine issue of fact as to whether the descriptor “Pure

Vegetable Oil” on drums of oil is misleading,*® and a misread-

ing of the documents Efamol submitted to support its claim of

an exemption under 21 C.F.R. § 101.100(d)(2) from the ““com-

mon or usual name” requirement of 21 U.S.C. § 343(i).39

States v. An Article of Food . .. FoodScience Lab., Inc., 678 F.2d 735, 739

(9th Cir. 1982).

* The Ninth Circuit rejected Dr. Ross’ testimony because it claimed he

“based his opinion on the encapsulated version of EPO.” Opinion at A-5.

Dr. Ivan Ross’ declaration demonstrates just the opposite; his opinion was

based on the labels on the seized drums. Exc. at 1003-5, 9§ 9-13. In

Dr. Ross’ opinion, whether the labels on the seized products are misleading

cannot be determined without a consumer survey, which FDA did not

produce. Exc. at 1005, 4 13. FDA therefore failed to meet its burden.

3 . ‘. . . .

*° ‘There is no disagreement that the intent of this regulation, to assure

that processing of the bulk oil does not result in adulteration or misbranding,

The misbranding issues are unimportant, as contrasted to the

others in the case. Efamol has repeatedly stated its willingness

to stipulate to relabeling of the seized product as contemplated

under 21 U.S.C. § 334(d) to dispose of these issues.

CONCLUSION

For the foregoing reasons, certiorari should be granted.

Respectfully submitted,

JAMES R. PHELPS

Counsel of Record

Hyman, Phelps & McNamara, P.C.

700 Thirteenth Street, N.W.

Suite 1200 ‘

Washington, D.C. 20005

(202) 737-5600

July 28, 1992

was met. The aocuments on which Efamol relies to establish an agreement,

Exc. at 994-1000, do not raise “unresolved questions,” Opinion at A-6, but

Clearly resolve questions necessary for further processing, as contemplated

by 21 C.F.R. § 101.100(d)(2). At a minimum. these documents raise a

genuine issue of material fact requiring a trial.

APPENDIX

A-i

TABLE OF CONTENTS

Page

Ninth Circuit Opinions and Orders (No. 90-55086):

Opinion and Order filed April7,1992 ..... A-]

Order filed June 12,1992 ............ A-11

Order filed June 29,1992 ............ A-12

District Court Opinions and Orders

(No. CV 89-73 MRP):

Findings of Fact and Conclusions

of Law filed November 27,1989 ........ A-13

Order and Judgment filed

POET 21, Eee wk ee A-17

eh Gls BD ake eee ee ee ee A-18

ai Usk. Sema emege) tk cs és oY A-19

21 U.S.C. § 343(a)(1) and(@)Q1) . 2 ee ee A-20

A ae Se oh A-2]

oe se NS) fk ee ak eee - A-22

PA ee Pee ee ee ee eee A-23

55 Fed. Reg. 10,932 (March 23,1990) ........ A-24

55 Fed. Reg. 6384 (February 23,1990) ....... A-4]

48 Fed. Reg. 5716 (February 8, 1983) ........ A-71

. 48 Fed. Reg. 239 (January 4,1983) ......... A-86

F 43 Fed. Reg. 31,349 (July 21,1978) ......... A-93

4 43 Fed. Reg. 14,064 (April 4, 1978) ......... A-107

: 42 Fed. Reg. 41,876 (August 19,1977) ....... A-125

42 Fed. Reg. 38,609 (July 29,1977) ......... A-138

A-1

FOR PUBLICATION

United States Court Of Appeals

FOR THE NINTH CIRCUIT

UNITED STATES OF AMERICA,

Plaintiff-Appellee,

45/194 KG. DRUMS OF PURE

VEGETABLE OIL, et al.,

Defendant,

EFAMOL, LTD.

Claimant-Appellant.

No. 90-55086

D.C. No.

CV-89-0073-MRP

OPINION

| Appeal from the United States District Court

for the Centra! District of California

Mariana R. Pfaelzer, District Judge, Presiding

Argued and Submitted

April 5, 1991—Pasadena, California

Filed April 7, 1992

Before: Alex Kozinski and Diarmuid F. O’Scannlain,

Circuit Judges, and Stephen M. McNamee,” District Judge.

Opinion by District Judge McNamee

The Honorable Stephen M. McNamee, United States District Judge

for the District of Arizona, sitting by designation.

A-2 ‘

SUMMARY

Health and Safety

Affirming a district court grant of summary judgment, the

court of appeals held that the labeling of bulk EPO (evening

primrose oil) as “Pure Vegetable Oil” is misbranding under 2]

U.S.C. § 343.

Appellant Efamol, Ltd. engaged in the export to the United

States of evening primrose oil (EPO). Efamol sold EPO as a

dietary supplement of fatty acids. Despite Efamol’s assertion

that it would not export EPO to the U.S.. it put the mixture into

soft gelatin capsules for shipment to this country in barrels

labeled ‘‘Pure Vegetable Oil.” A U.S. Marshall [sic] seized the

oil. The district court held that EPO Was misbranded and was an

unsafe food additive in violation of federal law. The district

court granted summary judgment for the government on its

forfeiture action.

[1] The facts in this case failed to support Efamol’s argu-

ment tl. t labeling the bulk EPO as “Pure Vegetable Oil” was

not misbranding within the meaning of 21 U.S.C. § 343, [2] The

record showed that the condemned substance was commonly

sold and referred to as “evening primrose oil” or “oil of evening

primrose” and not “pure vegetable oil.” [3] In addition, Efamol

had no simple, concise document Satisfying the exemption

requirements of 21 C.FR. § 101.100(d)(2). [4] Rather than

indicatiig an express intent to package the EPO capsules in a

particular manner and ensure their purity, the documents

revealed nothing more than a series of negotiations for the

encapsulation of EPO. [5] No regulatory approval existed for

the sale of EPO as a “food additive.” [6] Thus. summary

judgment was appropriate because Efamol failed to make a

showing sufficient to establish the existence of an element

essential to its case, and on which it bears the burden of proof

at trial.

A-3

COUNSEL

James R. Phelps, Hyman, Phelps & McNamara, | ee

Washington, D.C., for the claimant-appellant.

Mary K. Pendergast, Associate Chief Counsel, Food and Drug

Administration, Rockville, Maryland, for the plaintiff-appellee.

OPINION

McNAMEE, District Judge:

FACTS

Appellant, Efamo] Ltd., Surrey, England, researches, ex-

ports and markets evening primrose oil (EPO). EPO is made

from the crushed seeds of the evening primrose plant. Efamol

sells EPO as a dietary supplement of fatty acids.

In February 1979, the Food and Drug Administration

(FDA) informed Efamol representatives that EPO was not

generally recognized as safe for use as a dietary supplement. If

Efamol wanted to export EPO to the United States, it would have

to file a Food Additive Petition with the FDA, pursuant to 21

C.F.R. section 171, or an affirmation petition in accordance with

21 C.F.R. section 170.35. Efamol informed the FDA it would

no longer export EPO to the United States. !

Despite Efamol’s assertion that it would not export EPO to

the United States, Efamol has been shipping bulk EPO from the

United Kingdom to Banner Gelatin Products (Banner) in

In 1985 the FDA issued Import Alert 66-04 for Evening Primrose Oil.

The FDA revised the alert in June 1985. The alert instructs FDA officials to

detain evening primrose oil labeled for food use because the agency considers

it an unsafe food additive. However, Alert 66-04 provides that the oil may

be sold as a food or drug if: (1) when sold as a drug, it is considered a new

drug and the responsible person hold{s] an approved new drug application

or (2) when sold as a food, it is considered a food additive, and prior to

marketing a food additive petition is submitted to FDA in accordance with

21 C.F.R. sections 170.35 and 17i.1 and is approved by the FDA. Efamol

did not submit a new drug application or a food additive petition to the FDA.

A-4

Chatsworth, California since 1985. Banner mixes EPO with

vitamin-E and puts the combined mixture into soft gelatin

capsules. The capsules are then shipped to distributors, who

market them as a dietary supplement.

On January 6, 1989, the FDA filed a Complaint for Forfei-

ture under 21 U.S.C. section 334(a)(1). seeking the seizure and

condemnation of forty-five barrels of EPO, labeled “PURE

VEGETABLE OIL.” Pursuant to a district court order the

United States Marshal seized the oil on January 31, 1989.

The parties filed cross motions for summary judgment. The

district court granted the government’s motion for summary

judgment, finding: (1) EPO was misbranded under 21 U.S.C.

section 343; and (2) EPO is an unsafe food additive pursuant to

21 U.S.C. section 321. Efamol appeals the district court’s

decision. For the reasons set forth below we affirm the district

court's decision.

We review the granting of a motion for summary judgment

de novo. Jung v. FMC Corp., 755 F.2d 708, 710 (9th Cir. 1985).

Summary judgment is appropriate when there is no genuine

issue of any material fact and the moving party is entitled to

judgment as a matter of law. Fed. R. Civ. P. 56(c): Anderson v.

Liberty Lobby, Inc., 477 U.S. 242, 250 (1986). When a party

“fails to make a showing sufficient to establish the existence of

an element essential to that party’s case, and on which that party

will bear the burden of proof at trial,” Summary judgment is

appropriate. Celotex Corp. v. Catrett, 477 U.S. 317, 322 (1986).

[1] Food shall be deemed misbranded unless its label ee

the “common or usual name” of the product. 21 U.S.C. § 343(

It is not iuecessary to show that anyone was actually das or

deceived, or that there was any intent to deceive. “The statute .

A-5

condemn{[s] every statement, design and device which may

mislead or deceive.” United States v. 95 Barrels-Cider Vinegar,

265 U.S. 438[,] 442-43 (1924). The facts fail to support

Efamol’s argument that labeling the bulk EPO as “Pure

Vegetable Oil” was not misbranding within the meaning of

section 343.

[2] Efamol sold the oil using the name “evening primrose

oil,” and Efamol’s documents, advertising and expert witnesses

all referred to the substance as “evening primrose oil.” Thus, the

record shows that the condemned substance was commonly sold

and referred to as “evening primrose oil” or “oil of evening

primrose” and not “pure vegetable oil.”

in granting the government’s motion for summary judg-

ment, the district court also relied on the testimony of the

government's expert witness, Dr. Kassarjian. Dr. Kassarjian

testified that labeling the drums of oil as “PURE VEGETABLE

OIL” implied that the oil was for cooking or salads, and not part

of a dietary supplement. Efamol’s expert, Dr. Ross, stated that

[the] labels were not misleading because it was extremely un-

likely that a reasonable consumer who saw gelatin capsules,

labeled or not, would assume the product was intended as a

cooking or salad oil. Plainly, Dr. Ross based his opinion on the

encapsulated version of EPO. Such testimony ignores the facts

presented in this case. The government is alleging that the oil as

seized was misbranded. It is undisputed that when the oil was

seized, it was in its bulk form. Thus, Dr. Ross’ testimony does

not raise a genuine issue of material fact on the misbranding

issue presented in this case and the district court properly

disregarded his testimony.?

We also consider the extent to which the label fails to reveal facts

material in light of Efamol’s representations. 21 U.S.C. § 321(n). Conse-

quently we find it important that the FDA had issued an import alert for EPO.

The FDA cannot accurately track EPO labelled as “pure vegetable oil.”

A-6

Efamol contends that even if EPO was misbranded, it is

exempt from the labelling requirements under 21 C.F.R. section

101.100(d)(2). This regulation exempts manufacturers from

labeling their products with the usual or common name when

the food is being shipped to another area for processing, repack-

aging and labeling if a written agreement exists: (1) between the

shipper and the establishment that covers the shipment; (2) is

signed by both parties; (3) contains the post office address of

both parties; and (4) sets our [sic] specifications that will ensure

that food will not be adulterated or misbranded when the

processing, labeling, or repacking is completed. Jd. All four

elements must be present and both parties must keep copies of

the agreement and make it available for inspection by the FDA.

The exemption cannot be claimed if the food will be adulterated

after processing.

[3] Efamol had no single, concise document satisfying the

requirements of section 101.100. Instead, Efamol relies on a

collection of several letters and facsimile transmissions. arguing

that when read together, an agreement was formed which con-

formed with the labeling exemption. We disagree. A simple

reading of the documents demonstrates that each party had

unresolved questions on the vitamin E content of the capsules,

the use of preservatives, packaging requirements, the ap-

pearance of EPO, Efamol’s order number, and “micro testing.”

[4] The Food, Drug, and Cosmetic Act is a remedial

measure. United States v. Dotterweich, 320 U.S. 277, 280-81

(1943). Misbranding was one of the chief evils Congress sought

to stop when it enacted this legislation. 62 Cases of Jam v. United

States, 340 U.S. 593, 596 (1951). Given Congress’ concern for

proper labeling, we cannot find that the documents constitute an

agreement. Rather than indicating an express intent to package

the EPO capsules in a particular manner and ensure their purity,

the documents reveal nothing more than a series of negotiations

between Efamol and Banner for the encapsulation of EPO.

—————EEEEE—eEeE————E

A-7

Nowhere do the documents reflect a clear agreement that satis-

fies the four requirements of 21 C.F.R. section 101.100(d)(2).

Efamol has the burden of proving that the seized EPO was

exempt from the labeling requirements under the Food, Drug{[,]

and Cosmetic Act. United States v. Article of Device *** Toft-

ness, 731 F.2d 1253, 1262 (7th Cir.), cert. denied, 469 U.S. 882

(1984). Because the communications submitted by Efamol fail

to make a showing sufficient to establish the existence of an

agreement under 21 C.F.R. section 101.100(d)(2), summary

judgment was appropriate, Celotex, 477 U.S. at 322.

ITT.

Under the Food, Drug, and Cosmetic Act, a substance is a

“food additive” when (1) it is intended for use as a component

of a food; and (2) it is not generally recognized by qualified

experts as safe under the conditions of its intended use. 21

U.S.C. § 321(s). “[A] food additive is presumed to be unsafe

unless the Secretary of Health and Human Services has promul-

gated a regulation ‘prescribing the conditions under which such

additive may be safely used’ or providing for ‘investigational

use by qualified experts.”” United States v. An Article of Food,

678 F.2d 735, 737 (7th Cir. 1982) (quoting 21 U.S.C. § 348(a)

and (1)).

[5] No such regulatory approval exists for EPO. Rather,

Efamol contends that the sale of EPO is lawful because EPO is

not a “food additive” at all, as defined by the FDA, and hence

needs no regulatory approval. In particular, Efamol argues that

EPO is generally recognized as safe, and hence does not fit the

regulatory definition of “food additive.” “The burden of proving

general recognition of safe use is placed on the proponent of the

food substance in question.” United States v. An Article of Food,

752 F.2d 11, 15 (1st Cir. 1985) (citing 21 U.S.C. § 348(a) and

(i)).

‘s

A-8

To prove that EPO is generally recognized as safe, Efamol

must (1) submit evidence establishing that scientifically trained

experts qualified to evaluate EPO believe EPO is generally

recognized as safe and (2) show that there is scientific data

establishing the safety of EPO for use as a food supplement. Cf.

Weinberger v. Bentex Pharmaceuticals, Inc., 412 U.S. 645. 652

(1973).3

Scientific studies which would support a finding that EPO

is generally recognized as safe must be based on human. animal.

analytical and other scientific studies. 21 C.F.R. § 170.3(h). This

data must be colJected and analyzed with regard to EPO’s use

as a dietary supplement. Furthermore, the information must be

generally available to the community of experts and subjected

to peer evaluation, criticism and review appropriate to establish

such safety. 21 C.F.R. § 170.30(b); Bentex Pharmaceuticals.

412 US. at 652.

The evidence submitted by Efamol or used by Efamol’s

experts to evaluate EPO fails to meet the above criteria. Some

of the data considered by Efamol’s experts concerns EPO’s use

as a drug and not as a dietary supplement. Other data was based

on unpublished materials, which were not subjected to peer

evaluation. Thus, the opinions of Efamol’s experts were con-

Subsequent to oral argument, Efamol submitted a “motion to vacate

and remand for further proceedings” based on new precedent. Efamol’s

motion is denied. First, the opinion cited by Efamol, United States v. Two

Plastic Drums ... of an Article of Food ... Blackcurrant oil, No. 88-2398. slip

op. (C.D. Ill. April 10, 1991) (hereinafter BCO), is from a district court and.

therefore, is not binding precedent on this court. Second, the facts of BCO

are distinguishable.

In BCO the government seized two drums of bulk black currant oil. The

district court foun< that other than a preservative, black currant oil was

generally the sole ingredient of the capsule. Consequently, the court held that

a single ingredient cannot be a food additive. In the present case, however,

the evidence has shown that EPO is mixed with Vitamin E when encapsu-

lated. Therefore, EPO is not a single ingredient and is properly considered a

food additive.

EEE

A-9

taminated by their consideration of unsuitable evidence.‘ Cf.

Daubert v. Merrell Dow Pharmaceuticals, Inc., 951 F.2d 1128,

1130 (9th Cir. 1991); Christophersen v. Allied-Signal Corp.,

939 F.2d 1106, 1114 (Sth Cir. 1991) (en banc), petition for cert.

filed, 60 U.S.L.W. 3406 (U.S. Dec. 3, 1991) (No. 91-785). In

comparison, the government’s witnesses testified that there is

insufficient published scientific literature showing that EPO is

safe and there is insufficient animal or human testing of EPO’s

use as a dietary supplement.

[6] Thus, summary judgment was appropriate because

Efamol failed to make a showing sufficient to establish the

existence of an element essential to its case, and on which it

bears the burden of proof at trial. Celotex, 477 U.S. at 322;

United States v. Articles of Food and Drug ..., 518 F.2d 743,

747 (Sth Cir. 1975) (no genuine issue of material fact on the

issue of general recognition of safety where evidence considered

by plainuff’s experts was inappropriate).

BV.

We hold that the district court properly found that the

labeling of bulk EPO as “PURE VEGETABLE OIL” is

misbranding pursuant to 21 U.S.C. section 343. We also find

that EPO is a “food additive” within 21 U.S.C. section 321 and

that Efamol has failed to show that EPO is generally recognized

as safe; therefore, summary judgment was appropriate.

Efamol’s conduct comes four-square within the type of activity

Congress sought to prohibit.

AFFIRMED.

During oral argument, Efamol conceded that in opposing the

government's motion for summary judgment, (1) its experts relied on infor-

mation never furnished to the government, despite the government’s dis-

covery request; and (2) it had not previously relied on this information to

establish that EPO was generally recognized as safe. We make no findings

on the proprietary [sic] of Efamol’s actions. However, we do find, for the

previously mentioned reasons, the additional data relied on by Efamol is

insufficient under Rule 703 of the Federal Rules of Evidence.

A-10

PRINTED FOR

ADMINISTRATIVE OFFICE—U.S. COURTS

BY BARCLAYS/ELECTROGRAPHIC

SAN FRANCISCO—(415) 588-1155

The summary, which does not constitute a part of the

Barclays Law Publishers.

A-1]

Not for Publication

United States Court Of Appeals

FOR THE NINTH CIRCUIT

UNITED STATES OF AMERICA,

Plaintiff-Appellee,

45/194 KG DRUMS OF PURE

VEGETABLE OIL, et al,

Defendant,

EFAMOL, LTD..,

Claimant-Appellant.

NO. 90-55086

D.C. No. CV-89-0073-MRP

ORDER

Before: KOZINSKI and O’SCANNLAIN, Circuit Judges,

and McNAMEE,.” District Judge.

The petition for rehearing is denied. The full court has been

advised of the suggestion for en banc rehearing and no judge

has requested a vote thereon. The suggesiiun for rehearing en

banc is therefore rejected. Fed. R. App. P. 35(b).

The Honorable Stephen M. McNamee, United States District Judge

for the District of Arizona, sitting by designation.

A-12

Not for Publication

United States Court MOF Appeals

FOR THE NINTH CIRCUIT

\ UNITED STATES OF AMERIC ‘A,

| Plaintiff-Appellee,

45/194 KG DRUMS OF PURF

VEGETABLE OIL. et al.

Defendant.

EFAMOL, LTD..

Claimant-Appellant

NO. 90-55086

D.C. No. CV-89-0073-MRP

ORDER

Before: KOZINSKI and O'SCANNLAIN, Circuit Judges,

and McNAMEE, District Judge.

The motion to stay the mandate is GRANTED. The man-

date will issue 30 days from the date of this order.

The Honorable Stephen M. McNamee. United States District Judge

for the District of Arizona, sitting by designation.

United States Histrict Court

CENTRAL DISTRICT OF CALIFORNIA

UNITED STATES OF AMERICA,

Plaintiff.

15/194 kg. drums ... “PURE VEGETABLE OIL ...’

Defendant

CASE NO. CV 89-73 MRP

FINDINGS OF FACT AND

CONCLUSIONS OF LAW

Plaintiff's Motion for Summary Judgment and Claimant’s

Cross Motion for Summary Judgment came on for hearing

before the Honorable Mariana R. Pfaelzer on October 23, 1989.

The Court, having considered the memoranda, affidavits, and

exhibits filed by the parties and heard oral argument, makes the

following Findings of Fact and Conclusions of Law

FINDINGS OF FACT

1. This action was filed by the United States of America

pursuant to the Federal Food, Drug, and Cosmetic Act, 21

U.S.C. § 301 et seg., to have seized and condemned, pursuant

to 21 U.S.C. § 334, 45/194 kg. drums, one/130 kg. drum, and

one/45 kg. drum of an article of food labeled in part “PURE

VEGETABLE OIL”. The 47 drums contained oil pressed from

the evening primrose plant (hereafter called evening primrose

oil).

2. The complaint for forfeiture was filed on January 6,

1989.

A-14

3. The evening primrose oil was seized by the United

States Marshal on January 31, 1989 at Banner Gelatin Products

in Chatsworth, California (“Banner”)

4. Thereafter, on February 13, 1989. Efamol Ltd.

(“Efamol’) intervened in this action and filed a claim and an

ANnSWeT

\. The evening primrose oil had been shipped in interstate

commerce prior to the seizure.

6. Atthe time the evening primrose oil was seized. it was

being held for the purpose of further processing and sale.

—

The seized evening primrose oil was intended for use

ds a component of a nutritional or dietary supplement.

8. When introduced into and while in interstate com

merce, and while held for sale after shipment in interstate

commerce, the seized drums of evening primrose oil were

labeled “PURE VEGETABLE OIL”.

Y. When introduced into and while in interstate com-

merce, and while held for sale after shipment in interstate

commerce, the seized drums of evening primrose oil were not

labeled “evening primrose oil” or “oil of evening primrose”.

10. When evening primrose oil is promoted, marketed,

and discussed in the public and scientific literature in the United

States, it is called “evening primrose oil”.

11. Evening primrose oil is commonly and usually

referred to as “evening primrose oil”.

12.

With regard to the seized evening primrose oil, there

1S NO written agreement between Efamol and Banner that was

signed by both parties, contains the post office addresses of both

parties, and sets out specifications that ensure that the evening

primrose oil would not be adulterated or misbranded when its

processing is completed.

A-15

13. Labeling oil as “PURE VEGETABLE OIL” without

further qualification in effect represents to consumers that the

product ts intended for use as a cooking or salad oil rather than

as a nutritional or dietary supplement.

14. Drs. Robert E. Olson, Garret A. FitzGerald, William

A. Sibley, Howard W. Sprecher, John E. Vanderveen, Hilteye

lrausquin, and Gloria J. Troendle-—experts qualified by scien

tific training and experience to evaluate the safety of evening

primrose oil—do not consider evening primrose oil to be

generally recognized as safe for use as a nutritional or dietary

supplement.

16. Drs. Olson, FitzGerald, Sibley, Sprecher, Vander

veen, lrausquin, and Troendle do not recognize evening prim

rose oil as having been shown through scientific procedures to

be safe for use as a nutritional or dietary supplement.

CONCLUSIONS OF LAW

1. Evening primrose oil is a food within the meaning of

21 U.S.C. § 321(f).

2. The seized evening primrose oil was being held for sale

after shipment in interstate commerce within the meaning of 21

U.S.C. § 334(a)(1).

3. The seized evening primrose oil is misbranded within

the meaning of 21 U.S.C. § 343(1)(1) because its labeling fails

to bear the common or usual name of the article.

4. The seized evening primrose oi! is misbranded within

the meaning of 21 U.S.C. § 343(a)(1) because the labeling on

the drums states that the productis “PURE VEGETABLE OIL”

which is misleading.

5. Evening primrose oil is not generally recognized as

safe by qualified experts, and is therefore a food additive within

the meaning of 21 U.S.C. § 321{s).

A-16

6. There is no regulation in effect permitting the use of

evening primrose oil as a food additive or exempting evening

primrose oil from the food additives requirements of the Federal

Food, Diug, and Cosmetic Act:

7. Evening primrose oil is an unsafe ys additive and

adulterated within the meaning of 21 U.S.C. §§ 342(a)(2)(C)

and 348.

5. The evening primrose oil is subject to condemnation

and destruction pursuant to 21 U.S.C. §§ 331 (a). 331(b), and

334(a)(1).

9. Claimant has failed to show the existence of a genuine

issue of material fact, and plaintiff is therefore entitled to judg-

ment as a matter of law.

DATED:

/s/ Mariana R. Pfaelzer

Mariana R. Pfaelzer

United States District Judge

A-17

United States Histrict Court

CENTRAL DISTRICT OF CALIFORNIA

UNITED STATES OF AMERICA,

Plaintiff,

Vv.

45/194 kg. drums ...“PURE VEGETABLE OIL ...”

Defendant.

CASE NO. CV 89-73 MRP

ORDER AND JUDGMENT

Plaintiff's Motion for Summary Judgment and Claimant’s

Cross Motion for Summary Judgment came on for hearing

before the Honorable Mariana R. Pfaelzer on October 23, 1989.

The Court, having heard oral argument and considered the

memoranda, affidavits, and exhibits filed by the parties, and in

accordance with the Findings of Fact and Conclusions of Law

filed herewith,

IT IS ORDERED, ADJUDGED AND DECREED that,

1. Summary judgment be, and the same hereby is, entered

in favor of the United States of America, and against the defen-

dants, condemning and forfeiting the defendants herein to the

United States of America; and

2. Claimant’s Motion for Summary Judgment be denied.

DATED: November 27, 1989

/s/ Mariana R. Pfaelzer

Mariana R. Pfaelzer

United States District Judge

A-18

21 U.S.C. § 321(s)

§ 321. Definitions; generally

For the purpose of this chapter —

(s) The term “food additive” means any substance the

intended use of which results or may reasonably be expected tc

result, directly or indirectly, in its becoming a component or

otherwise affecting the characteristics of any food (including

any substance intended for use in producing, manufacturing,

packing, processing, preparing, treating, packaging, transport-

ing, or holding food; and including any source of radiation

intended for any such use), if such substance is not generally

recognized, among experts qualified by scientific training and

experience to evaluate its safety, as having been adequately

shown through scientific procedures (or, in the case of a sub-

stance used in food prior to January 1, 1958, through either

scientific procedures or experience based on common use in

food) to be safe under the conditions of its intended use; except

that such term does not include—

(1) a pesticide chemical in or on a raw agricul-

tural commodity; or

(2) a pesticide chemical to the extent that it is

intended for use or is used in the production, storage,

or transportation of any raw agricultural commodity;

(3) acolor additive: or

(4) any substance used in accordance with a

sanction or approval granted prior to September 6,

1958 pursuant to this chapter, the Poultry Products

Inspection Act (21 U.S.C. 451 and the following) or

the Meat Inspection Act of March 4, 1907. as

amended and extended; or

(5) anew animal drug.

A-19

21 U.S.C. § 342(a)(1) and (2)

§ 342. Adulterated food

A food shall be deemed to be adulterated—

Poisonous, insanitary, etc., ingredients

(a) (1) If it bears or contains any poisonous or deleterious

substance which may render it injurious to health: but in case

the substance is not an added substance such food shall not be

considered adulterated under this clause if the quantity of such

substance in such food does not ordinarily render it injurious to

health; or (2) (A) if it bears or contains any added poisonous or

added deleterious substance (other than one which is (i) a

pesticide chemical in or on a raw agricultural commodity; (ii) a

food additive; (iii) a color additive; or (iv) a new animal drug)

which is unsafe within the meaning of section 346 of this title,

or (B) if it is a raw agricultural commodity and it bears or

contains a pesticide chemical which is unsafe within the mean-

ing of section 346a(a) of this title, or (C) if it is, or it bears or

contains, any food additive which is unsafe within the meaning

of section 348 of this title: Provided, That where a pesticide

chemical has been used in or on a raw agricultural commodity

in conformity with an exemption granted or a tolerance

prescribed under section 346a of this title and such raw agricul-

tural commodity has been subjected to processing such as

canning, cooking, freezing, dehydrating, or milling, the residue

of such pesticide chemical remaining in or on such processed

food shall, notwithstanding the provisions of sections 346 and

348 of this title, not be deemed unsafe if such residue in or on

the raw agricultural commodity has been removed to the extent

possible in good manufacturing practice and the concentration

of such residue in the processed food when ready to eat is not

greater than the tolerance prescribed for the raw agricultural

commodity. .. .

A-20

21 U.S.C. § 343(a)(1) and (i)(1)

§ 343. Misbranded food

A food shall be deemed to be misbranded

(a) If (1) its labeling is false or misleading in any

particular

(1) Unless its label bears (1) the common ol!

usual name of the food, if any there be... .

A-2]

21 U.S.C. § 348

§ 348. Food additives—Unsafe food additives; exception

for conformity with exemption or regulation

(a) A food additive shall, with respect to any particular use

or intended use of such additives, be deemed to be unsafe for

the purposes of the application of clause (2) (C) of section 342(a)

of this title, unless—

(1) it and its use or intended use conform to the

terms of an exemption which is in effect pursuant to

subsection (i) of this section; or

(2) there is in effect, and it and its use or intended

use are in conformity with, a regulation issued under

this section prescribing the conditions under which

such additive may be safely used.

While such a regulation relating to a food additive is in effect,

a food shall not, by reason of bearing or containing such an

additive in accordance with the regulation, be considered adul-

terated within the meaning of clause (1) of section 342(a) of this

title.

A-22

21 C.F.R. § 101.100(d)(2)

§ 101.100 Food; exemptions from labeling.

(d) Except as provided by paragraphs (e) and (f) of thi:

section, a shipment or other delivery of a food which is. it

accordance with the practice of the trade. to be processed

labeled, or repacked in substantial quantity at an establishmen

other than that where originally processed or packed, shall be

exempt, during the time of introduction into and movement ir

interstate commerce and the time of holding in such estab-

lishment, from compliance with the labeling requirements ot

section 403(c), (e), (g), (h), (i), (j), and (k) of the act if:

(2) Incase such person is not such operator, such shipment

or delivery is made to such establishment under a written

agreement, signed by and containing the post office addresses

of such person and such operator, and containing such specifica-

tions for the processing, labeling, or repacking, as the case may

be, of such food in such establishment as will ensure. if such

specifications are followed, that such food will not be adul-

terated or misbranded within the meaning of the act upon

completion of such processing, labeling, or repacking. Such

person and such operator shall each keep a copy of such agree-

ment until 2 years after the final shipment or delivery of such

food from such establishment, and shall make such copies

availabie for inspection at any reasonable hour to any officer or

employee of the Department who requests them.

ss, eimai lai

A-23

21 C.F.R. § 170.30

§ 170.30 Eligibility for classification as generally

recognized as safe (GRAS).

(a) General recognition of safety may be based only on the

views of experts qualified by scientific training and experience

to evaluate the safety of substances directly or indirectly added

to food. The basis of such views may be either (1) scientific

procedures or (2) in the case of a substance used in food prior

to January 1, 1958, through experience based on common use

in food. General recognition of safety requires common

knowledge about the substance throughout the scientific com-

munity knowledgeable about the safety of substances directly

or indirectly added to food.

(b) Genera! recognition of safety based upon scientific

procedures shall require the same quantity and quality of scien-

tific evidence as is required to obtain approval of a food additive

regulation for the ingredient. General recognition of safety

through scientific procedures shall ordinarily be based upon

published studies which may be corroborated by unpublished

Studies and other data and information.

A-24

FEDERAL REGISTER

Vol. 55, No. 57, at 10932

Friday, March 23, 1990

RULES AND REGULATIONS

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 184

[Docket Nos. 87G-0418 and 87F-0416]

Direct Food Substances Affirmed as Generally

Recognized as Safe; Chymosin Enzyme Preparation

Derived From Escherichia Coli K-12

AGENCY: Food and Drug Administration.

ACTION: Final rule.

SUMMARY: The Food and Drug Administration (FDA) is

amending its regulations to affirm that the use of chymosin

preparation derived by fermentation from Escherichia coli K-12

is generally recognized as safe (GRAS). This action is in

response to a petition filed by Pfizer Central Research. Pfizer,

Inc.

EFFECTIVE DATE: March 23, 1990. The Director of the

Office of the Federal Register approves the incorporation by

reference in accordance with 5 U.S.C. 552(a) of a certain pub-

lication in 21 CFR 184.1685(b) effective on March 23, 1990.

FOR FURTHER INFORMATION CONTACT: Eric L.

Flamm, Center for Food Safety and Applied Nutrition (HFF-

334), Food and Drug Administration, 200 C Street SW..

Washington, DC 20204, 202-426-8950.

A-25

SUPPLEMENTARY INFORMATION:

I. Background

In accordance with the procedures described in § 170.35

(21 CFR 170.35), Pfizer Central Research (Pfizer) submitted a

petition (GRASP 8G0337) requesting that its chymosin prepara-

tion (referred to as “chymosin” in the petition’s filing notice that

FDA published in the Federal Register of February 9, 1988 (53

FR 3792)), which is derived from the fermentation of a geneti-

cally modified FE. coli K-12, be affirmed as GRAS as a direct

human food ingredient. Chymosin is the principal enzyme in

rennet, a GRAS food ingredient used for its milk-clotting ac-

tivity, and is primarily responsible for that activity. Chymosin

preparation is intended for use as a substitute for rennet.

To avoid confusion between chymosin the enzyme and

chymosin the enzyme preparation (in which chymosin is the

principal active component but which may also contain im-

purities), this document will henceforth use the term

“chymosin” when referring to the enzyme and “chymosin

preparation” when referring to the fermentation-derived

chymosin enzyme preparation.

Pfizer submitted two petitions concerning chymosin

preparation. In addition to GRASP 8G0337, it submitted a

petition (FAP 8A4048) requesting that the food additive regula-

tions be amended to provide for the safe use of genetically

modified E. coli K-12 as a source of chymosin preparation

(referred to as “chymosin” in the petition’s filing notice that

FDA published in the Federal Register of February 9, 1988 (53

FR 3792)), for use in food. The regulation that is the subject of

this final rule is in response to the GRAS affirmation petition.

Published elsewhere in this issue of the Federal Register is a

document (Docket No. 87F-0416) announcing that Pfizer has

withdrawn its food additive petition without prejudice to a future

filing.

A-26

FDA gave interested parties an opportunity to submit cor

ments concerning the GRAS affirmation petition to the Docke

Management Branch (HFA-305), Food and Drug Administr

tion, Rm. 4-62, 5600 Fishers Lane, Rockville, MD 20857. FD

received two comments in response to the notice. Both cor

ments address whether the dairy industry needs new sources |

chymosin. Neither comment contains any information releva:

to the safety, functionality, environmental impact, or GRA

Status of the food use of the subject chymosin preparation. Thu

the comments are not relevant to the agency's evaluation «

chymosin preparation. FDA’s authority in reviewing food add

tive and GRAS affirmation petitions is limited to questior

about the safety and functionality of the substance at issue an

does not include questions about the need for a new foo

ingredient (21 U.S.C. 348).

II. Standards for GRAS Affirmation

Pursuant to § 170.30 (21 CFR 170.30), general recognitio

of safety may be based only on the views of experts qualifie

by scientific training and experience to evaluate the Safety

substances. The basis of such views may be either (1) scientifi

procedures or (2) in the case of a substance used in food prio

to January 1, 1958, experience based on common use in fooc

General recognition of safety based upon scientific procedure

requires the same quantity and quality of scientific evidence a

is required to obtain approval of a food additive regulation an

ordinarily is to be based upon published studies, which may b

corroborated by unpublished studies and other data and infor

mation (§ 170.30(b)). In its petition, Pfizer has relied upo!

scientific procedures to establish that chymosin preparation i

GRAS.

Rennet is an animal-derived enzyme preparation that i

GRAS as specified in § 184.1685 (21 CFR 184.1685). There

fore, if published information shows that the principal active

component of chymosin preparation is the same as that of rennet

A-27

and that the other components (i.e., impurities) of the chymosin

preparation, which may differ from the other components (i.e.,

impurities) of rennet, do not render the use of the substance

unsafe, then chymosin preparation derived from E. coli would

present no more safety concern than rennet. If this is the case,

FDA can affirm chymosin preparation derived from E. coli as

GRAS for use as a replacement for rennet.

II. Safety

A. Introduction

Chymosin, also known as rennin, is the principal milk-clot-

ting enzyme present in rennet (Ref. 1). Rennet is an enzyme

preparation that will clot milk, forming it into curds and whey

(Refs. 1 and 2). It is used to make cheese and other dairy

products. It has a long and extensive history of safe use in food

and has been affirmed by FDA as GRAS in § 184.1685 (48 FR

51151; November 7, 1983).

Food-grade rennet is an enzyme preparation that is derived

from the fourth stomach of calves, kids, or lambs. Commercial-

ly, it is generally derived from unweaned calves by aqueous

extraction. The aqueous extraction step is followed by purifica-

tion steps and an acidification step to cleave prochymosin (the

inactive precursor of chymosin) in the rennet into chymosin

(Ref. 1).

There are two predominant forms of calf chymosin,

chymosin A and chymosin B (Ref. 1). Foltmann et al. have

shown thatchymosin A and chymosin B differ by a single amino

acid (Ref. 3). In this document FDA is using the terms

“chymosin” to refer to either, or both, chymosin A and chymosin

B. mt

Techniques developed in the last 15 years (frequently

termed “recombinant DNA technology” or “cloning techni-

ques’’) enable scientists to locate and to obtain a segment of

deoxyribonucleic acid (DNA) containing a gene of interest.

A-28

They are able to move that DNA segment into a vector (a

self-replicating DNA molecule that is easy to manipulate) and

then introduce it into a new host organism where it can be

correctly expressed (that is, produce the protein that it would

produce in the original organism). These techniques are well-

known to molecular biologists. (see e.g., Refs. 4 and 5).

B. The Chymosin Component

Using cloning techniques, scientists in a number of dif-

ferent laboratories have identified the gene in the calf from

which the chymosin in rennet is produced, the prochymosin

gene (Refs. 6 through 8). Scientists have moved the calf

prochymosin gene into E. coli (Refs. 6 through 10) as well as

into other microorganisms (Refs. 11 through 13).

They have used a variety of techniques to demonstrate that

they have cloned full-length copies of the correct gene. Such

techniques include: (1) DNA sequencing, whereby the cloned

putative prochymosin gene was shown to have the nucleotide

sequence that encodes the amino acid sequence of prochymosin

(Refs. 6 through 8); (2) nucleic acid hybridization, whereby the

cloned DNA fragments or the ribonucleic acid (RNA) molecules

made from the DNA fragments were shown to hybridize (i.e.,

specifically bind) with complementary DNA in the

prochymosin gene (Refs. 7 through 12); and (3) physical map-

ping, whereby the cloned DNA fragments were shown to be

large enough to contain the prochymosin gene and, when

digested with appropriate DNA-cutting enzymes and run on gels

that separate DNA fragments by size, were shown to yield the

pattern of DNA fragments expected for prochymosin (Refs. 7

through 13).

The published evidence establishes that the new host or-

ganisms are able to use the prochymosin gene to produce

prochymosin that has the same molecular weight as

prochymosin found in calf rennet (Refs. 9 through 11 and 13

through 15). It also establishes that the prochymosin that is

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produced (cloned prochymosin) can be cleaved into chymosin

(cloned chymosin) that has the same molecular weight and the

same functional activity as chymosin found in calf rennet (Refs.

9, 10, and 12 through 15).

The molecular weights of prochymosin and chymosin were

assayed using sodium dodecyl sulfate-polyacrylamide gel

electrophoresis, a technique that enables one to determine the

comparative molecular weight of proteins based on their rate of

migration through the gel. Cloned prochymosin was found to

migrate through these gels at the same rate as the prochymosin

derived from calves (Refs. 9 through 11 and 13 through 15).

Cloned chymosin was found to migrate through these gels at the

same rate as the chymosin found in rennet (Refs. 9, 10, and 12

through 15).

The functional activity of chymosin that was measured was

milk-clotting activity. Cloned chymosin was found to clot milk

at the same rate as the chymosin in rennet under various tempera-

tures, salt concentrations, and pH conditions (Refs. 9 through

15).

One safety concern raised by cloning is whether extraneous

DNA, particularly DNA flanking the gene of interest, that could

potentially encode extraneous harmful proteins may be cloned

along with the gene of interest (i.e., prochymosin). However,

the regulation stipulates that the substance being affirmed as

GRAS is one that is produced using a production strain that is

nontoxigenic (see § 184.1685(a)(2)). If the cloned DNA encodes

a harmful substance that could render the enzyme preparation

unsafe, the production strain would be toxigenic, and the sub-

stance produced would not be GRAS under § 184.1685(a)(2).

Therefore, the agency finds that there is no basis for concern that

the safety of the chymosin preparation will be compromised by

contaminating proteins encoded by extraneous uncharacterized

DNA cloned along with the prochymosin gene.

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FDA notes that as a matter of good manufacturing practice,

manufacturers using recombinant DNA technology should as

sure themselves that they have not inadvertently cloned ex-

traneous protein-encoding DNA along with the prochymosin

gene. Such assurance can come from reviewing the details of

the cloning steps, such as the origin and sequence of the DNA

fragments used in the cloning, and from full characterization of

the final genetic constructs via techniques such as DNA se

quencing. The agency points out that Pfizer’s petition contains

information demonstrating that it conducted these steps.

Based on the fact that published information demonstrates

that chymosin produced from the cloned prochymosin gene has

the same molecular weight and the same functional activity as

the chymosin derived from calves, FDA concludes that the

chymosin enzyme in chymosin preparation is the same as the

chymosin enzyme in calf rennet. Therefore, FDA concludes that

the chymosin enzyme in chymosin preparation is as safe as the

chymosin enzyme in rennet.

C. Sources of Impurities

Enzyme preparations used in food-processing are usually

not chemically pure but contain extraneous source (cellular) and

processing material. The nature and amounts of these impurities

in the finished enzyme preparation depend on the organism from

which the enzyme is produced (the source or production or-

ganism), the fermentation materials and methods used to grow

the production organism, and the materials and methods used to

generate the finished enzyme preparation.

Both the source material and the manufacturing methods

for producing chymosin preparation differ from those used to

produce animal rennet. Therefore, the impurities in chymosin

preparation will differ from those in rennet. The question thus

is whether the source material or manufacturing methods for

chymosin preparation will introduce impurities that would raise

concems about the safety of the preparation.

|. Processing steps

Researchers in a number of laboratories have published

papers containing descriptions of methods that they used for

producing chymosin preparation from microorganisms contain

ing the calf prochymosin gene (e.g., Refs. 9 through 15). The

methods described in these publications and in Pfizer’s petition

do not differ from each other in any significant way. The key

steps in the methods, as described by Marston et al. (Ref. 15)

and by Pfizer, are summarized below.

E. coli is grown in a liquid nutrient medium, then pelleted

by centrifugation. The pelleted cells are resuspended in a small

volume of buffer and burst open, releasing the prochymosin in

the form of densely packed insoluble aggregates. The aggregates

are recovered by a second centrifugation step, while most of the

rest of the cellular protein and debris remain in suspension. The

prochymosin is thus rapidly purified from the bulk of cellular

material. Pfizer treats the aggregates with acid to kill residual

cells and to degrade residual DNA. The prochymosin aggregates

are solubilized by denaturation in an alkaline urea solution. The

prochymosin is renatured by decreasing the alkalinity and dilut-

ing out the urea and further purified by ion-exchange

chromatography. The prochymosin is converted to chymosin,

the active form of the enzyme, by suspension in a pH 2 acid

solution for an hour. The final chymosin preparation is a clear

solution. ;

FDA finds that the manufacturing method does not require

the use of any processing materials that are not GRAS or

approved food additives. Accordingly, it is specifying in the

regulation that the substance being affirmed as GRAS is one that

is-produced using only processing materials that are GRAS

substances or food additives approved for use in this type of

process (see § 184.1685(a)(2)). Therefore, the agency concludes

that the manufacturing steps will not introduce impurities into

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the enzyme preparation that will adversely affect the safety of

the preparation.

2. Production organism

The source material for the chymosin in chymosin prepara-

tion is FE. coli K-12. E. coli’s natural habitat is the large intestine

of humans and animals, where it is found at 1 million to 100

million organisms per gram of intestinal contents (Ref. 16). E.

coli K-12 is a laboratory strain that, through longtime propaga-

tion in the laboratory, has lost a number of the traits necessary

for colonization of, and therefore survival in, the intestinal tract

(Ref. 17).

E. coli K-12 is one of biology’s most extensively studied

microorganisms. It has been shown to be nonpathogenic and

nontoxigenic in studies in which it has been fed to humans and

laboratory animals (see, e.g., Refs. 16 and 17) and in detailed

studies of its phenotypic and genotypic traits (see, e.g., Refs. 16

through 18). For example, Gorbach (Ref. 16), Curtiss (Ref. 17),

and Smith (Ref. 18) have reported their own and others’ failed

attempts to implant E. coli K-12 in the human intestine, an initia!

step for pathogenicity. In none of the experiments were re-

searchers able to isolate the strain from the feces of volunteers

1 to 6 days after they were fed high doses (10°-10'° live

organisms) of various strains of E. coli K-12. In none of the

experiments did the volunteers become sick as a result of their

ingestion of the organisms.

Gorbach (Ref. 16) discussed six factors necessary for an

organisms to be pathogenic: (1) Survival in the environment, (2)

a mechanism for penetrating the skin or mucosal surface, (3)

multiplication within the host, (4) systemic spread within the

host, (5) resistance to host defense mechanisms, and (6) produc-

tion of a toxin or some other mechanism to damage the host to

produce disease symptoms. He noted that a lack of any one of

these characteristics will render the microorganisms non-

pathogenic, and that, based on the available evidence, E. coli

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K-12 is deficient in every one of these factors (Ref. 16). Gorbach

also noted that in the 30 years that E. coli K-12 has been used

in genetics research, there have been no reported cases of

laboratory-acquired infections from this organism (Ref. 16).

As corroborative evidence of the safety of chymosin

preparation, Pfizer submitted two unpublished short-term in

vivo studies conducted on its enzyme preparation, a 5-day

feeding study in dogs and a 1-month gavage study in rats (Ref.

19). No adverse effects were observed in these studies at any

dose fed.

Some E. coli K-12 strains, such as those that are used by

Pfizer and others (e.g., Refs. 9, 10, and 14) to produce chymosin

preparation, do contain marker genes that encode resistance to

clinically useful antibiotics. Such genes potentially could be

transferred to other microorganisms with which the production

strain or its DNA comes into contact. However, as previously

described, the isolation of the enzyme as an intracellular in-

soluble aggregate results in the destruction of the microorganism

and in the elimination of most cellular material, including these

marker genes (Ref. 15). Additionally, the two acid treatment

steps in the manufacturing process inactivate residual cells and

degrade residual DNA, including marker genes, that remain in

the enzyme preparation (Ref. 20).

_ As corroborative evidence that the enzyme preparation

does not contain gene-size DNA fragments or transformable

DNA (that is, DNA that a microorganism can take up from its

surroundings and functionally incorporate into its own DNA),

Pfizer submitted data from several unpublished experiments,

including a gel electrophoresis/DNA hybridization assay and a

transformation assay. In the electrophoresis experiment, DNA

fragments were sized based on their differential rates of migra-

tion through the gel and quantified based on their level of

hybridization with labeled complementary DNA. No DNA frag-

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ments large enough to contain an intact gene encoding antibiotic

resistance were detected in the enzyme preparation (Ref. 19).

In the transformation assay, bacterial cells were mixed with

DNA under optimized conditions and assayed to see if they had

picked up the antibiotic resistance encoded by the DNA. Cells

mixed with the enzyme preparation did not become antibiotic

resistant (Ref. 19).

Based on the above discussion, FDA concludes that

chymosin preparation manufactured in conformity with §

184.1685(a)(2) will not contain DNA encoding resistance to

antibiotics at levels that would provide any safety concern. FDA

concludes that EF. coli K-12 is safe for use as a source of

food-grade chymosin preparations, and that impurities resulting

from its use in the production of chymosin preparation will not

affect the safety of the chymosin preparation.

IV. Specifications

The agency finds that, because the principal active in-

gredient of chymosin preparation and rennet are the same, and

because the impurities in chymosin preparation do not provide

any basis for concern that the use of the preparation may not be

safe, the general and additional requirements given for rennet

and other enzyme preparations in the “Food Chemicals Codex,”

3d Ed. (1981), pp. 107-110, are adequate for defining minimum

criteria for a food-grade chymosin preparation derived from E.

coli K-12. FDA is amending § 184.1685(b) to reference pp. 109

and 110 of the “Food Chemicals Codex,” 3d Ed. (1981), as well

as pp. 107 and 108.

Vv. Conclusions

The agency has evaluated all available information and

finds, based upon the published and corroborative evidence

discussed above, that the active principal ingredient in the

chymosin preparation is the same as that in rennet, and that when

the preparation is manufactured in accordance with §

A-35

184.1685(a)(2), the source organism and manufacturing process

will no[t] introduce impurities into the preparation that would

provide a basis for concern that the use of the preparation may

not be safe. Therefore, the agency concludes, based upon scien-

tific procedures, that the chymosin preparation derived by fer-

mentation from E. coli K-12 and described in the regulation

below is GRAS for use as a replacement for rennet.

VI. Environmental Effects

The agency has carefully considered the potential environ-

mental effects of this action and has concluded that the action

will not have a significant impact on the human environment

and that an environmental impact statement is not required. The

agency’s finding of no significant impact and the evidence

supporting that finding, contained in an environmental assess-

ment, may be seen in the Dockets Management Branch (address

above).

VII. Economic Effects

FDA, in accordance with the Regulatory Flexibility Act,

has considered the effects that this regulation would have on

small entities, including small businesses, and has determined

that the effect of this regulation is to provide for the use of

fermentation-derived chymosin for both large and small busi-

nesses. Therefure, FDA certifies in accordance with section

605(b) of the Regulatory Flexibility Act that no significant

economic impact on a substantial number of small entities will

derive from this action.

In accordance with Executive Order 12291, the agency has

analyzed the economic effects of this final rule and has deter-

mined that this rule will not be a major rule as defined by that

Order.

The agency’s finding of no major economic impact and no

significant impact on a substantiai number of small entities, and

the evidence supporting these findings, are contained in a

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threshold assessment which may be seen in the Dockets

Management Branch (address above).

VII. References

The following references have been placed on display in

the Dockets Management Branch (address above) and may be

seen by interested persons between 9 a.m. and 4 p.m., Monday

through Friday.

1. Foltmann, B., “Prochymosin and Chymosin (Prorennin

and Rennin),” Methods in Enzymology, 19:421-436, 1970.

2. Burgess, K., and M. Shaw, “Dairy,” in “/ndustrial

Enzymology,’ T. Godfrey and J. Reichelt, eds., The Nature

Press, New York, pp. 260-265, 1983.

3. Foltmann, B. et al., “The Primary Structure of Calf

Chymosin,” Journal of Biological Chemistry, 254:8447-8456,

1979.

4. Watson, J.D. et al., “Molecular Biology of the Gene,”

Benjamin/Cummings Publishing Co., Inc., Menlo Park, CA, pp.

65-94, 202-213, 1987.

5. Murray, K., “Genetic Engineering and its Applica-

tions,” in “Basic Biotechnology,” J.D. Bu’ Lock and B. Kristian-

sen, eds., Academic Press, London, pp. 483-508, 1987.

6. Harris, T.J.R. et al., “Molecular Cloning and Nucleotide

Sequence of cDNA Coding for Calf Preprochymosin,” Nucleic

Acids Research, 10:2177-2187, 1982.

7. Hidaka, M. et al., “Cloning and Structural Analysis of

the Calf Prochymosin Gene,” Gene, 43:197-203, 1986.

8. Moir, D. et al., “Molecular Cloning and Charac-

terization of Double-stranded cDNA Coding for Bovine

Chymosin,” Gene, 19:127-138, 1982.

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9. Emtage, J.S. et al., “Synthesis of Calf Prochymosin

(Prorennin) in Escherichia coli,” Proceedings of the National

Academy of Sciences, 80:3671-3675, 1963.

10. McCaman, M.T., W.H. Andrews, and J.G. Files, “En-

zymatic Properties and Processing of Bovine Prochymosin Syn-

thesized in Escherichia coli,” Journal of Biotechnology,

2:177-190, 1985.

11. Goff, C.G. et al., “Expression of Calf Prochymosin in

Saccharomyces cerevisiae,” Gene, 27:35-46, 1964.

12. Cullen, D. et al., “Controlled Expression and Secretion

of Bovine Chymosin in Aspergillus nidulans,” Bio/Technology,

5:369-376, 1987.

13. Mellor, J. et al., “Efficient Synthesis of Enzymatically

Active Calf Chymosin in Saccharomyces cerevisiae,” Gene,

24:1-14, 1983.

14. Kawaguchi, Y. et al., “Production of Chymosin in

Escherichia coli Cells and its Enzymatic Properties,” A gricul-

tural and Biological Chemistry, 51:1871-1877, 1987.

15. Marston, F.A.O. et al., “Purification of Calf

Prochymosin (Prorennin) in Escherichia coli,” Bio/Technology,

2:800-804, 1984.

16. Gorbach, S.L., “Recombinant DNA: An Infectious

Disease Perspective,” Journal of Infectious Diseases, 137:615-

623, 1978.

17. Curtiss, R., “Biological Containment and Cloning

Vector Transmissibility,” Journal of Infectious Diseases,

137:668-675, 1978.

18. Smith, H.W., “Is It Safe to Use Escherichia coli K-12

in Recombinant DNA Experiments?,” Journal of Infectious

Diseases, 137:655-660, 1978.

19. Petition 8C0337.

A-38

20. Lehninger, A.L., “Biochemistry,” Worth Publishers,

New York, p. 256, 1970.

List of Subjects in 21 CFR Part 184

Food ingredients, Incorporation by reference.

Therefore, under the Federal Food, Drug, and Cosmetic

Act and under authority delegated to the Commissioner of Food

and Drugs, 21 CFR part 184 is amended as follows:

PART 184—DIRECT FOOD SUBSTANCES

AFFIRMED AS GENERALLY RECOGNIZED

AS SAFE

1. The authority citation for 21 CFR part 184 continues to

read as follows:

Authority: Secs. 201, 402, 409, 701 of the Federal Food,

Drug, and Cosmetic Act (21 U.S.C. 321, 342, 348, 371).

2. Section 184.1685 is revised to read as follows:

§ 184.1685 Rennet (animal-derived) and

chymosin preparation (fermentation-derived).

(a)(1) Rennet and bovine rennet are commercial extracts

containing the active enzyme rennin (CAS Reg. No. 9001-98-3),

also known as chymosin (International Union of Biochemistry

Enzyme Commission (E.C.) 3.4.23.4). Rennet is the aqueous

extract prepared from cleaned, frozen, salted, or dried fourth

stomachs (abomasa) of calves, kids, or lambs. Bovine rennet is

the product from adults of the animals listed above. Both

products are called rennet and are clear amber to dark brown

liquid preparations or white to tan powders.

(2) Chymosin preparation is a clear solution containing the

active enzyme chymosin (E.C. 3.4.23.4). It is derived, via

fermentation, from a nonpathogenic and nontoxigenic strain of

Escherichia coli K-12 containing the prochymosin gene. The

prochymosin is isolated as an insoluble aggregate that is acid-

treated to destroy residual cellular material and, after solubiliza-

A-39

tion, is acid-treated to form chymosin. It must be processed with

materials that are generally recognized as safe, or are food

additives that have been approved by the Food and Drug Ad-

ministration for this use.

(b) Rennet and chymosin preparation meet the general and

additional requirements for enzyme preparations of the “Food

Chemicals Codex,” 3d Ed. (1981), pp. 107-110, which is incor-

porated by reference in accordance with 5 U.S.C. 552(a). Copies

are available from the National Academy Press, 2101 Constitu-

tion Avenue NW., Washington, DC 20418, or are available for

inspection at the Office of the Federal Register, 1100 L Street

NW., Washington, DC.

in food with no limitation other than current good manufacturing

practice. The affirmation of this ingredient as generally recog-

nized as safe as a direct human food ingredient is based upon

the following current good manufacturing practice conditions

of use:

(1) The ingredient is used as an enzyme as defined in §

170.3(0)(9) of this chapter; a processing aid as defined in §

170.3(0)(24) of this chapter; and a stabilizer and thickener as

defined in § 170.3(0)(28) of this chapter.

(2) The ingredient is used in the following foods at levels

not to exceed current good manufacturing practice: In cheeses

as defined in § 170.3(n)(5) of this chapter; frozen dairy desserts

and mixes as defined in § 170.3(n)(20) of this chapter; gelatins,

puddings, and fillings as defined in § 170.3(n)(22) of this

chapter; and milk products as defined in § 170.3(n)(31) of this

chapter.

(d) Prior sanctions for this ingredient different from the

uses established in this section do not exist or have been waived.

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Dated: March 14, 1990.

Alan L. Hoeting.

Acting Associate Commissioner for

Regulatory Affairs.

[FR Doc. 90-6600 Filed 3-22-90; 8:45 am]

BILLING CODE 4160-91-M

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FEDERAL REGISTER

Vol. 55, No. 37, at 6384

Friday, February 23, 1990

RULES AND REGULATIONS

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 184

[Docket No. 88G-0371]

Direct Food Substances Affirmed as

Generally Recognized as Safe;

Microparticulated Protein Product

AGENCY: Food and Drug Administration

ACTION: Final rule.

SUMMARY: The Food and Drug Administration (FDA) is

amending its regulations for substances that are generally recog-

nized as safe (GRAS) to affirm as GRAS the use of micropar-

ticulated protein product in frozen dessest-type products. This

action is in response to a petition filed by The NutraSweet Co.

requesting that a microparticulated egg white and milk protein

product be affirmed as GRAS for use as a direct food ingredient.

EFFECTIVE DATE: February 23, 1990.

FOR FURTHER INFORMATION CONTACT: JoAnn

Ziyad, Center for Food Safety and Applied Nutrition (HFF-

334), Food and Drug Administration, 200 C Street SW..

Washington, DC 20204, 202-426-9463.

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SUPPLEMENTARY INFORMATION:

I. Background

A. Regulatory History

In accordance with the procedures described in § 170.35

(21 CFR 170.35), The NutraSweet Co., Box 1751 Lake Cook

Rd., Deerfield, IL 60015, submitted a petition (GRASP

8G0345) proposing that microparticulated egg white and milk

protein product be affirmed as GRAS asa direct food ingredient.

FDA published a notice of the filing of this petition in the Federal

interested persons an Opportunity to submit comments to the

Dockets Management Branch (HFA-305), Food and Drug Ad-

ministration, Rm. 4-62, 5600 Fishers Lane, Rockville, MD

20857. The five comments received in response to the filing

notice are discussed below.

B. Standards for GRAS Affirmation

Pursuant to 21 CFR 170.30, general recognition of safety

may be based only on the views of experts qualified by scientific

training and experience to evaluate the safety of substances.

The basis of such views may be either (1) scientific proce-

dures or (2) in the case of a substance used in food prior to

January 1, 1958, experience based on common use in food.

General recognition of safety based upon scientific procedures

requires the same quantity and quality of scientific evidence as

is required to obtain approval of a food aclditive regulation and

ordinarily is to be based upon published studies, which may be

corroborated by unpublished studies and other data and infor-

mation (21 CFR 170.30(b)). General recognition of safety

through experience based on common use in food prior to

January 1, 1958, may be determined without the quantity or

quality of scientific procedures required for approval of a food

additive regulation but ordinarily is to be based upon generally

A-43

available data and information concerning its pre-1958 history

of use.

II. Manufacturing Process/Use/Exposure

A. Manufacturing Process

According to the information in the petition, microparticu-

lated protein product is manufactured from egg whites or milk

protein or a combination of egg whites and milk protein. The

protein-containing mixture is high-shear heat processed to

produce particles of protein that are microscopic in size. Accord-

ing to the petition, these microparticles are roughly spheroidal

in shape. The particles are basically nonaggregated when

formed, although aggregation does occur upon heating. High-

shear heat processing is followed by a series of steps that may

include ultrafiltration, dry-blending of ingredients, hydration

with water, and pH adjustment with food-grade acids, bases, or

both. Other steps may include deaeration and heat pasteuriza-

tion. Safe and suitable ingredients may be added to the egg

whites and milk proteins to aid in accomplishing the desired

technical effect before or after the high-shear heat processing.

The use of these ingredients must be in accordance with the

regulations in 21 CFR parts 172, 182, or 184.

B. Uses

The proposed use of the substance is as a thickener or

texturizer in frozen dessert-type products at levels not to exceed

Current good manufacturing practice. The petition states that a

typical use level would be 32 percent by weight of product, with

a range of 25 to 53 percent. The petition also states that there is

no technical limitation on either the minimum or maximum

amount of microparticulated protein product that can be added

to a frozen dessert-type product. The desired sensory qualities

determine the level of use of the substance in the finished

product. The petitioner found that the oral sensation produced

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by the hydrated microparticles of gelled product is one of

smoothness and is much the same as that produced by fat.

C. Consumer Exposure

The only proposed use for microparticulated protein

product requested in the petition is as a fat replacer to perform

the technical effects of fat in frozen dessert-type products.

FDA based its daily intake calculations for the petitioned

ingredient on the food intake values for frozen desserts of the

Market Research Corp. of America (MRCA) Survey of Fre-

quency of Food Consumption, 1977-1978, using the U.S.

Department of Agriculture- National Food Consumption Survey

(USDA-NFCS), 1977-1978, for portion size. The frozen dessert

intake values (eaters-only) are as follows: 2 to 5 year age group,

29.5 grams per person per day (g/p/d) (mean) and 61.1 g/p/d

(90th percentile); for the 2+ years age group, the values are 38.5

g/p/d (mean) and 80 g/p/d (90th percentile). At a use level of 53

percent, and assuming that all frozen desserts consumed contain

the petitioned products, the microparticulated protein product

daily intake would be 15.6 g/p/d (2 to 5 years, mean), 32.4 g/p/d

(2 to 5 years, 90th percentile), 20.4 g/p/d (2+ years, mean), and

42.4 g/p/d (2+ years, 90th percentile). Because no product-

specific use levels were available, and because there are no

known technologically self-limiting use levels, FDA used the

maximal likely use level (53 percent) to calculate a conservative

estimated daily intake of microparticulated protein product.

Because microparticulated protein product will replace a

portion of fat in the diet of people that consume frozen desserts,

the petitioner estimated that the proposed use of the product will

increase the protein intake of the consumer by 3.5 g/p/d (90th

percentile). Based on the information provided in the petition

and the above referenced data bases (MRCA and USDA-

NFCS), FDA estimated the mean and the 90th percentile in-

creases in protein intake from the maximal proposed use of

microparticulated protein product in frozen dessert-type product

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to be 2.3 and 4.9 g/p/d for 2- to S-year-old children and 3.1 and

6.4 g/p/d for the 2+ year-old group, respectively. Assuming that

there is no change in the amount of protein contributed by other

ingredients, this additional protein intake represents an increase

in the average protein intake of the two age groups of 4 percent

for average consumers of microparticulated protein-containing

products and of about 9 percent for heavy consumers. After

adjusting for expected decreases in fat intake, the protein intake

estimates represent an increase in dietary energy (calorie) con-

tribution from protein for all age groups and intake categories

of about 0.5 to 1.5 percent. Based on calculations derived from

the above data, the agency finds that this amount does not

represent a significant increase in dietary protein (Ref. 41).

III. Evaluation of the Microparticulation Process

The major constituents of microparticulated protein

product, egg whites and milk protein, have been safely con-

sumed by humans as sources of food protein throughout

recorded history and, therefore, are GRAS (§170.30(d)). In

evaluating the petition to determine whether the use of micropar-

ticulated protein product as a fat replacer in frozen dessert-type

products can be affirmed as GRAS, the agency focused on the

steps that make up the microparticulation process. FDA dis-

covered that these steps were nothing more than commonly used

food processing steps that have been shown through published

studies not to change the nutritional value and, therefore, the

safety of food, including egg whites and milk protein. Thus,

based on published data, for the reasons discussed below, FDA

concludes that egg whites and milk protein treated by micropar-

| ticulation processing can be affirmed as GRAS.

A. Homogenization/Microparticulation

Published studies show that commonly used food process-

ing techniques that reduce the size of food particles, such as

homogenization and high-speed, high-shear mixing, modify the

A-46

sensory properties (viscosity, texture, mouthfeel) of the food

that is processed (Ref. 23). To maintain these modified sensory

properties, it is routinely necessary to use gums (such as xanthan

gum) to stabilize the particles (Refs. 23 and 24). The reduction

in particle size produced by these techniques often increases the

digestibility of the food. For example, Renner reports that in rat

Studies, homogenized milk produced a better utilization of

protein compared with whole milk (Ref. 20). Although these

processing techniques produce some reduction in vitamin con-

centration, they generally do not change the nutritional value of

the food (Ref. 23).

Based on its evaluation of these published studies, the

agency finds that these techniques do not affect the safety of

milk and egg protein. In addition, these studies demonstrate that

microparticulated egg and milk protein products will act as

thickeners and texturizers and therefore can serve to replace the

fat ordinarily used for these purposes (Refs. 23 and 24).

Bb. Heating

Eggs and milk have been heat-processed for probably as

long as humans have cooked food. A rather extensive literature

exists on heat processing of raw food ingredients. In summariz-

ing much of our knowledge concerning the heating of milk, FDA

notes the following facts:

1. Heat induced denaturation of milk proteins is not

detrimental to nutrition (Ref. 20).

2. Heating changes the secondary and tertiary structure!

of proteins, increasing accessibility to digestive enzymes and

thus increasing utilization of the protein-(Ref. 20).

| The secondary structure of a protein refers to the regular structural

arrays found in proteins, principally helices, which are formed by folding a

single segment of polypeptide chain, and B structures or pleated sheets,

formed by two or more chains. The tertiary structure is the total conformation

of the molecule, that is, its disposition in three dimensions (Ref. 43).

A-47

3. Milk proteins undergo chemical reactions during the

heating of milk. The products of these reactions have been

consumed without adverse effects since milk was first cooked

in food preparation. Therefore, the normal heating of milk-con -

taining foods is not harmful (Ref. 20).

Other reports show that heat sterilization of milk has little

effect on levels of vitamins and virtually no effect on lipids,

carbohydrates, and minerals (Ref. 21).

Concerning the effects of cooking on eggs, studies show

that some loss of vitamins occurs. The loss is dependent on the

method of cooking (Ref. 22). With respect to protein quality,

Froning (Ref. 22) reports a study showing a slightly lower

protein efficiency ratio (PER) value for hard-boiled eggs than

for dried eggs. (Dried eggs have a PER value identical with fresh

eggs.) Therefore, the effects of heat on egg protein may differ

slightly depending on the extent and method of heating. How-

ever, the agency finds based on the foregoing data that within

the temperature ranges employed, the level of heat has no

adverse effect on the safety of the food.

C. pH Modification

Food-grade acids and bases are commonly used to adjust

the pH of foods and food formulations. The available informa-

tion indicates that pH modification does not adversely affect the

quality and utility of food protein. Acidification is extensively

used in cooking; for flavor, color, and texture modification; for

preservation; and for aiding in the gelling of proteins (especially

in baked products) (Ref. 25). Additionally, acidification is used

to denature proteins (e.g. curdling milk or making cottage

cheese). Ingested foods are subjected to acid conditions in the

stomach. Under these physiological conditions proteins are

denatured and rendered more accessible to attack by digestive

enzymes. Alkali is used to modify proteins, to enhance emul-

sification properties of proteins, and to increase the solubility,

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elasticity, and resistance to heat-induced aggregation of proteins

(Ref. 26).

D. Ultrafiltration

Ultrafiltration is a process by which water is removed from

a solution by passing the solution through a semi-permeable

membrane. It is routinely used in food processing because the

food being filtered is not heated, resulting in little loss of

nutrients or volatile flavor components (Ref. 27). In addition, it

is very energy efficient compared with other methods of con-

centration (Ref. 27). Ultrafiltration is commonly used to con-

centrate whey proteins from cheese manufacture and to

concentrate milk products before the manufacture of dairy

products.

As stated above, ultrafiltration has little effect on the nutri-

tional quality of foods (Ref. 27). Some low molecular weight

sugars, vitamins, and amino acids may be lost during ultrafiltra-

tion, but fats, proteins, and carbohydrates are retained without

loss of sensory or nutritional qualities (Ref. 27).

E. Conclusion

Based on the summaries above, it is clear that there is

adequate published information for experts to conclude that the

processes used in the microparticulation of egg and milk protein

are commonly used food processing techniques that do not

materially change the quality, utility, functionality, or safety of

food products. The use of these techniques is just as common in

the home as it is in the food industry, and it is generally known

by experts and laypersons alike that these techniques do nothing

except make food more palatable or appealing. Therefore, FDA

concludes on the basis of the published data discussed above

that microparticulated egg and milk protein is safe.

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IV. Corroborating Evidence of No Adverse

Effect on Protein Quality and of Safety

A. Microparticles in Other Foods

Protein microparticles occur in many foodstuffs, such as in

milk from humans, cows, goats, and camels and in the cheeses

made from some of these milks (Refs. | through 4). The forma

tion of microparticles also occurs during the normal processing

of foods, e.g., blending, mixing, pasteurizing, pH-modification,

and baking (Ref. 42). As discussed above, the petitioner has

incorporated established food processing techniques into a dis-

tinct process that consistently yields a product containing

protein microparticles that are roughly uniform in size, quality,

and distribution (GRASP &G0345).

B. Structure of Microparticles

The petition contains unpublished studies on the morphol-

ogy of the microparticles using scanning electron microscopy

and transmission electron microscopy to look for changes in the

microparticulated protein product before and_after freezing

(GRASP 8G0345, pp. 559-596). These studies show the

product’s microparticle stability through several freeze-thaw

cycles such as might be encountered by the product in transit

through the food-distribution system. The studies found no

significant differences in protein structure before and after freez-

ing.

The petition also includes the results of studies using

transmission electron microscopy and scanning electron micros-

copy that investigated the microstructures of the constituent, and

of the final, microparticulated protein product. These studies

showed that the high-shear heat treatment of the mixture of milk

and egg white protein yields casein micelles (predominantly

spheroidal in shape) surrounded by flocculated egg white

protein.

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Further characterization of the proteins by one- and two-

dimensional gel electrophoresis showed “marked similarity (to

one another) among all gels in which all the protein bands could

be identified as either milk or egg white proteins” (Ref. 18).

Therefore, these studies demonstrate that the microparticulation

process does not change the egg and milk protein into new or

novel substances that do not have a history of safe use.

C. Amino Acid Profiles

The amino acid profile can be used to characterize proteins

(Ref. 43). Recognizing this, the petitioner submitted data that

provide evidence that the amino acid profiles of the egg white

and milk proteins used as test materials and those of the

processed product are not significantly different. Because there

are no significant differences between the amino acid profiles

of the source protein and of the processed protein, the agency

changes in the amino acid composition of the egg and milk

protein product that would affect its safety.

D._ Protein Efficiency Radio (PER)

To provide additional evidence of the safety of micropar-

ticulated protein products, the petitioner submitted data from

unpublished studies that compare the PER’s of the source

proteins and of the processed product. In these studies, rats were

fed either of the following diets: (1) Casein (standard reference

protein for PER bioassay); (2) casein plus 15 percent sucrose;

(3) mixture of unprocessed starting ingredients for the product

(premix); (4) premix exposed to gentle heat (325 °F for 1 hour);

(5) premix exposed to severe heat for 15 minutes; (6) premix

processed to contain microparticulated egg white and condensed

milk proteins; and (7) processed product with 20 percent sucrose

(weight/weight) to potentially enhance the stability of the

product during long-term storage at freezer temperatures. The

rats were fed the diets for 28 days. There were no statistically

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significant differences between the PER’s of the processed and

the unprocessed materials. These studies provide evidence that

the_microparticulation process does not change the nutritive

value of the egg white and milk protein.

E. ¢ llergenicity Studies

Published studies show that both eggs and milk produce

allergic reactions in sensitive individuals (Ref. 45). To test what -"

effect the microparticulated protein product would have on such

individuals, the petitioner submitted an unpublished in vitro

allergenicity/antigenicity study of the product with sera from 13

people with an allergy to either milk or egg proteins or to both.

The test employed the sodium dodecyl] sulfate-polyacrylamide

gel electrophoretic [SDS-PAGE] analysis of the test materials.

The test materials included. (1) Premix containing a mixture of

unprocessed starting materials; (2) premix gently heated (cus-

tard-like); (3) premix severely heated (scrambled egg-like); (4)

properly prepared microparticulated protein product; (5) proper-

ly prepared product with extra sugar; (6) ultrafiltered egg white

and condensed milk; (7) fresh egg whites; and (8) fresh cow’s

milk.

If antibodies to proteins in the test material are present in

human sera, they can react with the SDS-PAGE-separated

proteins to form antibody-antigen complexes. Seven patients

who were clinically symptomatic (allergic) to both eggs and

cow’s milk were chosen for the study. The study also included

three patients symptomatic to eggs only, three symptomatic to

milk only, and two controls. The results of these studies

produced no evidence of novel proteins in the test materials and

no evidence of increased immunologic activity when the final

product was compared with the premix of unprocessed starting

materials and discrete ingredients (Ref. 19).

The agency concludes, however, that patients clinically

allergic to either eggs or cow’s milk, or to beth, have antibodies

to protein fractions in eggs, cow’s milk, and the five test

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materials at approximately equal levels of binding. If an in-

dividual who is allergic to either egg or cow’s milk, or both,

ingested microparticulated protein product test materials, it 1s

likely that he/she would experience an allergic reaction similar

to that produced by egg or cow’s milk or both.

Under section 409(c)(1) of the act (21 U.S.C. 348(c)(1)),

FDA is authorized, in approving the use of a food additive, to

list the conditions under which the additive may be safely used.

These conditions may include any labeling requirements that the

agency finds necessary to ensure the safe use of the additive.

Similarly, under 21 CFR 184.1(b)(2), in affirming a sub-

stance as GRAS, FDA is authorized to set forth, by means of

specific limitations, the particular conditions, including label-

ing, under which there is general recognition among qualified

experts that use of a substance is safe. After careful review of

the information on the allergenicity of egg and milk protein,

given the fact that the microparticulated protein products will

continue to produce allergic-type reactions, FDA has concluded

that the use of microparticulated egg and milk protein product

is GRAS only (except in the restaurant-type setting) when the

conditions of its use include a declaration on the label or labeling

of the presence of the egg and milk protein in the food. This

specific limitation is set forth below in new § 184.1498(b)(3).

Persons who know that they are sensitive to the protein used in

the product are likely to be selective in the types of foods that

they use and, with appropriate label declaration, will be able to

avoid the potential hazard from allergic-type reactions to the

proteins in the product by reading the label.

F. Biotin/Avidin Binding

The agency has considered the possible effect of increased

egg white consumption on biotin deficiencies. Biotin, a water-

and alcohol-soluble vitamin essential for the activity of many

enzyme systems, may be inactivated by avidin, a glycoprotein

found in egg whites. Avidin has a high affinity for biotin, and

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the prolonged ingestion of very large quantities of raw eggs may

result in a biotin deficiency. However, because biotin is widely

distributed in the food supply and 1s formed by the intestinal

flora, biotin deficiencies occur very infrequently, only with

abnormal diets low in biotin or very high in avidin (200 g of

dried egg whites per day (Ref. 5)) or a combination of these

conditions (Ref. 6). Heat processing, such as the high-shear heat

treatment used in microparticulation, readily denatures avidin

and prevents its binding to biotin (Ref. 7). For this reason, the

agency finds that there is no basis for concern that a biotin

deficiency will develop in people consuming microparticulated

protein product.

V. Comments

FDA received five comments in response to the published

notice. One comment was from a nutrition consultant, one from

a physician, one from a consumer, one from a consumer interest

group, and one from a law firm. The specific comments and the

agency’s responses are discussed below.

1. The comment from the nutrition consultant questioned

whether there was breakdown of protein in the microparticulated

product into amino acids, particularly glycine, and if so, whether

the level is less than the 0.2 percent limitation specified in the

food additive regulation for the use of glycine in § 172.812 (21

CFR 172.812).

The agency finds that there is no basis for the concerns

expressed in this comment. Based on published information

about the effects of processing techniques on food protein (Refs.

20, 21, 22, and 46), the agency finds that under the conditions

used in the processing of the egg whites and milk proteins to

form microparticulated egg white and milk protein products, the

proteins would not break down into the component amino acids,

including glycine, during the processing. Further, § 172.812 (21

CFR 172.812) establishes a 0.2 percent limit for the food addi-

tive use of the free amino acid glycine in certain foods to produce

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* limited and specific technical effects. This limit on an added

amino acid has no relationship to consumer exposure to the

amino acids that are present in intact food proteins such as those

found in the egg whites and milk protein in microparticulated

protein product at physiologically safe levels. Thus, the com-

ment is irrelevant to the exposure to the amino acids derived

from microparticulated protein product.

2. Citing five specific references (Refs. 9, 10, 14, 15, and

16), the comment from the physician identified six issues that

he believes should be addressed in the evaluation of the safety

of microparticulated protein product. However, the comment

did not provide copies of these five references or of others

identified in his letter (see GRASP 8G0345—comment 3) (Refs.

8, 11, 12, and 13). The agency has evaluated the available

references as reflected in the responses provided below. The

physician did not present any conclusion on whether the use of

microparticulated protein product is GRAS.

The first issue identified by the comment is whether par-

ticle size and homogenization influence the absorption and

metabolism of the component amino acids. The comment stated

that “it is known * * * for example, that such alteration of milk

or whole eggs increases the absorption of free cholesterol and

* * * that particle size significantly alters the physical charac-

teristics of aspartame.”

The agency has evaluated the relevant references cited by

the comment and finds that the references document a controver-

sy regarding the subject of absorption of cholesterol as a func-

tion of homogenization of milk or eggs that contain both protein

and fat. The studies referred to in the references submitted in the

comment were designed to measure fat absorption, which would

include cholesterol absorption, but were not designed to

measure amino acid/protein absorption. Amino acids/proteins

are absorbed by a different mechanism than cholesterol. There-

fore, the comment and references are not relevant to the absorp-

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tion of the microparticulated protein product, which consists of

only the protein from milk and eggs.

Although the references cited in the comment address the

absorption of a different macromolecule (cholesterol) that is

absorbed by a different mechanism than that by which protein

and amino acids are absorbed, it is true that modification of

amino acid/protein absorption may be influenced by

homogenization (Ref. 20). Studies have shown that

homogenization of milk produces a better utilization of the —

protein in milk (Ref. 20) as compared with nonhomogenized

milk.

Also, as discussed in section IV, protein quality (PER) data

show that there were no significant differences between the

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