F I L E D
United States Court of Appeals
Tenth Circuit
PUBLISH
August 17, 2006
UNITED STATES CO URT O F APPEALS Elisabeth A. Shumaker
Clerk of Court
TENTH CIRCUIT
N U TRAC EU TIC AL C OR PO RATION;
SOLARAY, IN C.,
Plaintiffs-Appellees,
v. No. 05-4151
A N D REW V O N ESC HEN BA CH,
Acting Commissioner, U.S. Food and
Drug Administration; UN ITED
STA TES FO O D A ND D RU G
A D MIN ISTR ATIO N ; M IC HA EL O.
LEAVITT, Secretary of the Department
of H ealth and H uman Services;
D EPA RTM EN T O F H EA LTH AND
HU M AN SERVICES; UN ITED
STA TES O F A M ER IC A,
Defendants-Appellants.
A PPE AL FR OM T HE UNITED STATES DISTRICT COURT
FOR T HE DISTRICT OF UTAH
(D .C . No. 2:04-CV-00409-TC)
Christine N. Kohl, Attorney (Peter D. Keisler, Assistant Attorney General, Paul
M . W arner, United States Attorney, Jeffrey Bucholtz, Deputy Assistant Attorney
General, and Douglas N. Letter, Attorney, Department of Justice, W ashington,
D .C ., and Paula M . Stannard, A cting General Counsel, Sheldon T. Bradshaw,
Associate General Counsel, Eric M . Blumberg, Deputy Chief Counsel, and
Claudia J. Zuckerman, Associate Chief Counsel, Office of General Counsel, U.S.
Department of Health & Human Services, Food and Drug Division, Rockville,
M aryland, with her on the briefs), for Defendants-Appellants.
Jonathan W . Emord (Andrea G. Ferrenz with him on the brief), Emord &
Associates, P.C., Reston, Virginia for Plaintiffs-Appellees.
Before K ELL Y, T YM KOV IC H, Circuit Judges and EAGAN, * District Judge.
E AG A N, District Judge.
Defendants-appellants, Andrew von Eschenbach, M .D., Acting
Commissioner of the U.S. Food and Drug Administration, the United States Food
and Drug Administration (“FDA” or “the agency”), M ichael O. Leavitt, Secretary
of the Department of Health and Human Services, the Department of Health and
Human Services, and the United States, appeal from a judgment of the district
court denying their motion for summary judgment and granting the cross-motion
of plaintiffs-appellees for summary judgment. Nutraceutical Corp. v. Crawford,
364 F. Supp. 2d 1310 (D. Utah 2005). Plaintiffs-appellees, Nutraceutical
Corporation and its wholly-owned subsidiary, Solaray Corporation (collectively,
*
The Honorable Claire V. Eagan, District Judge, United States District Court for
the Northern District of Oklahoma, sitting by designation.
2
“Nutraceutical”), manufacture and sell Ephedra, a product containing ephedrine-
alkaloid dietary supplements (“ED S”). In 2004, the FDA issued a regulation
which banned all EDS sales in the United States market. Nutraceutical brought
this action challenging the regulation as unlaw ful. The district court agreed with
Nutraceutical. Id. at 1321. Our jurisdiction arises under 28 U.S.C. § 1291, and
we reverse.
Background
In its published decision, the district court determined that the risk-benefit
analysis employed by the FDA to support an ED S ban was contrary to the intent
of Congress and that the FDA had failed to prove by a preponderance of the
evidence that EDS pose an unreasonable risk of illness or injury at 10 milligrams
(“mg”) or less a day. Nutraceutical, 364 F. Supp. 2d 1310. It accordingly entered
summary judgment in favor of Nutraceutical, enjoined the FDA from enforcing its
proscription against Nutraceutical for the sale of products with a recommended
daily dosage of 10 mg or less of ED S, 1 and remanded to the FDA for new rule-
making.
The issues raised by this appeal are: (1) w hether the FDA correctly
interpreted the relevant statute to require a risk-benefit analysis in determining if
a dietary supplement presents an “unreasonable risk of illness or injury”; and (2)
1
To the extent that we recognize Nutraceutical’s product as recommending less
than 10 mg of ephedrine alkaloids per day, Nutraceutical’s Motion to Correct Oral
Argument Record, filed on May 11, 2006, is granted.
3
whether the FDA satisfied its burden of proving that dietary supplements
containing EDS present an unreasonable risk of illness or injury when doses of 10
mg or less per day are suggested or recommended in labeling.
Nutraceutical alleges that the FDA lacked statutory authority to promulgate
and enforce a ban of all EDS. The FDA argues that it acted pursuant to the broad
authority delegated to it by the Food, Drug and Cosmetic Act (“FDCA”), 21
U.S.C. §§ 301, et seq., to regulate dietary supplements for safety. The FDCA
provides the FDA with broad authority to regulate food, drug, and dietary
supplement products in order to ensure public health and safety. Id. In 1994,
Congress amended the FDCA with the Dietary Supplement Heath and Education
Act (“DSH EA”), Pub. L. No. 103-417, 108 Stat. 4325 (1994). Under DSH EA, the
FDA regulates vitamins, minerals, herbs, amino acids, and other dietary
substances. Dietary supplements are generally regulated in a manner similar to
food and the FDA is authorized to prevent adulterated products from entering the
market. See 21 U.S.C. § 331(a), (b), (c), (k) (adulteration and distribution of
adulterated food are prohibited acts). Congress declared that a dietary
supplement is “adulterated”:
If it is a dietary supplement or contains a dietary ingredient that--
(A) presents a significant or unreasonable risk of illness or injury
under--
(i) conditions of use recommended or suggested in labeling, or
(ii) if no conditions of use are suggested or recommended in
the labeling, under ordinary conditions of use; . . .
4
21 U.S.C. § 342(f)(1). The FDA argues that EDS are adulterated and points to the
“unreasonable risk of illness or injury” provision of D SHEA as the primary
source of statutory authority for its EDS ban. 21 U.S.C. § 342(f)(1)(A).
Ephedrine alkaloids are a class of structurally-related chemical stimulants
that occur naturally in some botanicals. In the 1980s and 1990s, manufacturers
promoted the sale of EDS for w eight loss and athletic performance enhancement.
In the 1990s, the FDA received numerous Adverse Event Reports (“AERs”) which
documented harmful side effects, including heart attacks, strokes, seizures, and
death, associated with EDS intake. 2 Based on the circumstantial evidence of the
AERs, the FDA began to investigate the effects of ED S. The investigation
included a literature review of scientific studies and a Food Advisory Committee
on Dietary Supplements Containing Ephedrine A lkaloids M eeting held on A ugust
26-27, 1996 (“1996 Food Advisory Committee”). In 1997, the agency proposed a
regulation which would have required specific warnings and established a dosage
regimen. 62 Fed. Reg. 30,678 (June 4, 1997).
The FDA’s 1997 proposed regulation of ED S faced substantial opposition,
including from the General Accounting Office (“GAO”). The GAO determined
that the FDA had not been thorough in its investigation and requested further
2
The FDA established the MedWatch program to monitor AERs associated with
nutritional products, including dietary supplements. This program relies on voluntary
reporting from public health agencies, health professionals, and consumers. See FDA
MedWatch Home Page, http://www.fda.gov/medwatch/.
5
research. See GAO, Dietary Supplements: Uncertainties in Analyses Underlying
FD A’s Proposed Rule on Ephedrine Alkaloids 11 (1999). Responding to the
GAO’s concerns, the FDA withdrew the 1997 proposed regulation. 65 Fed. Reg.
17,474 (A pr. 3, 2000).
The FDA continued to receive AERs and compile scientific literature
regarding EDS. Given the fact that dietary supplement manufacturers are not
required to submit scientific data on their products, the body of scientific
literature on EDS was limited. Among the studies on w hich the FDA relied w as a
report commissioned by the National Institutes of Health. To further supplement
the record, the agency hired M ario A. Inchiosa, Jr., Ph.D., 3 to conduct further
research on the health effects of ED S in 1999. During the public notice and
comm ent period, Nutraceutical submitted to the FDA several requests for an
exemption of low-dosage EDS, to no avail. The administrative record grew to
over 130,000 pages, approximately 19,000 AERs were collected, 4 and extensive
public notice and comment resulted in over 48,000 comments.
After seven years of investigating EDS, the FDA adopted a regulation
which banned EDS at all dosage levels from the national market. Final Rule
3
Professor of Pharmacology, New York Medical College.
4
The AERs which were voluntarily submitted to the FDA were supplemented with
16,000 complaints received by Metabolife, one of the largest distributors of EDS. 364 F.
Supp. 2d at 1315; see GAO, Dietary Supplements: Review of Health-Related Call
Records for Users of Metabolife 356 (GAO-03-494) (2003).
6
Declaring Dietary Supplements Containing Ephedrine Alkaloids Adulterated
Because They Present an Unreasonable Risk, 69 Fed. Reg. 6788 (Feb. 11, 2004)
(“Final Rule”). In the Final Rule, the FDA concluded that “[t]he best clinical
evidence for a benefit . . . supports only a modest short-term weight loss,
insufficient to positively affect cardiovascular risk factors or health conditions
associated with being overweight or obese.” Id. at 6789. Based on this risk-
benefit analysis, the FDA determined that all EDS present an “unreasonable risk
of illness or injury” under all ordinary or recommended conditions of use. Id. at
6788. As such, the Final Rule classified ED S adulterated within the meaning of
DSHEA.
The district court held that “the FDA’s requirement that EDS demonstrate a
benefit is contrary to the clear intent of Congress” and found the agency’s
definition of “unreasonable” as entailing a risk-benefit analysis to be improper.
364 F. Supp. 2d 1310, 1319. The district court also found that the FDA failed “to
prove by a preponderance of the evidence that a dosage of 10 mg or less of
ephedrine alkaloids presents a significant or unreasonable risk of illness or
injury.” Id. at 1321. Based on these findings, the district court granted summary
judgment for plaintiffs and denied summary judgment for defendants.
7
Discussion
Standard of Review
The district court’s conclusions as to whether the FDA had acted pursuant
to congressionally delegated authority in promulgating a rule is reviewed de novo.
However, the parties dispute the appropriate standard of review of the
administrative decision. DSH EA provides that: “The court shall decide any issue
under this paragraph on a de novo basis.” 21 U.S.C. § 342(f). The district court
did “not reach the question of whether the FDA’s statutory construction should be
reviewed de novo.” 364 F. Supp. 2d at 1317. In the interest of clarity and
consistency, we now reach this question.
Courts are to review agency actions under DSH EA using the “traditional
tools of statutory construction.” Pharmanex v. Shalala, 221 F.3d 1151, 1154
(10th Cir. 2000). The de novo standard, under section 342(f), applies to
enforcement actions by the U nited States against manufacturers of dietary
supplements. Such enforcement actions may result in imprisonment or monetary
fines. 21 U.S.C. § 333; see United States v. Park, 421 U.S. 658 (1975). Reading
the statute as a whole, it is clear that the de novo standard applies when courts
“decide” matters rather than w hen they “review” administrative decisions. As
such, it is appropriate to limit the de novo standard of review, which affords the
FDA no deference, to enforcement proceedings. Challenges by private parties to
FD A rules promulgated under DSH EA are reviewed pursuant to the
8
Administrative Procedure Act (“APA ”), 5 U.S.C. § 706, and “the normal rules for
judicial deference regarding agency action apply.” NVE, Inc. v. HHS, 436 F.3d
182, 196 (3rd Cir. 2006). “H ad Congress intended to supplant the well-
established procedures for APA challenges, it would have been clearer about its
objective.” Id. at 194.
Chevron Analysis
A court reviewing the FDA’s construction of the FDCA must determine:
whether Congress has directly spoken to precise question at issue; and if not, then
whether agency's construction of statute is permissible one. Chevron U.S.A., Inc.
v. Natural Res. Def. Council, Inc., 467 U.S. 837, 842-43 (1984). In reviewing the
FDA’s interpretation of D SHEA under Chevron, we ask two questions:
First, alw ays, is the question whether Congress has directly spoken to
the precise question at issue. If the intent of Congress is clear, that is
the end of the matter; for the court, as well as the agency, must give
effect to the unambiguously expressed intent of Congress [Chevron
step 1]. But if the statute is silent or ambiguous with respect to the
specific issue, the question for the court is whether the agency's
answer is based on a permissible construction of the statute. If
Congress has explicitly or implicitly delegated authority to an
agency, legislative regulations are given controlling weight unless
they are arbitrary, capricious, or manifestly contrary to the statute
[Chevron step 2].
Seneca-Cayuga Tribe of Oklahoma v. National Indian Gaming Com'n, 327 F.3d
1019, 1037 (10th Cir. 2003) (citations omitted).
9
The APA reflects the principles of Chevron and “provides that agency
action must be set aside if the action was ‘arbitrary, capricious, an abuse of
discretion, or otherwise not in accordance with law’ or if the action failed to meet
statutory, procedural, or constitutional requirements.” Valley Cmty. Pres.
Comm’n v. M ineta, 373 F.3d 1078, 1084 (10th Cir. 2004) (internal quotation
omitted) (citing 5 U.S.C. § 706). “W hen we review an agency’s decision under
the arbitrary, capricious or abuse of discretion standard [of the APA ], our review
is narrow and deferential; we must uphold the agency’s action if it has articulated
a rational basis for the decision and has considered relevant factors.” Slingluff v.
Occupational Safety & Health Review Comm’n, 425 F.3d 861, 866 (10th Cir.
2005) (citing M ountain Side M obile Estates P’ship v. Sec’y of HUD, 56 F.3d
1243, 1250 (10th Cir. 1995)). Under the APA , regulations are presumed to be
valid, and review is deferential to the government agency.
“U nreasonable Risk”
In this case, we must determine whether Congress unambiguously
manifested its intent to restrict the FDA from weighing benefits when determining
the risk posed by a dietary supplement. The district court was correct to proceed
under Chevron step one in deciding the question of whether the FDA properly
used a risk-benefit analysis in determining whether EDS pose an “unreasonable
risk.” Chevron, 467 U.S. at 843. W e nevertheless reverse the district court after
10
finding that Congress unambiguously required the FDA to conduct a risk-benefit
analysis under D SHEA.
In 1994, Congress enacted DSHEA to clarify that dietary supplements,
absent declarations promoting the supplements as drugs, would be regulated in a
manner similar to food products. Accordingly, in the interest of public health,
Congress imposed a duty on the FDA to keep adulterated dietary supplements off
the market. 108 Stat. at 4326 (instructing the FDA to “take swift action against
[dietary supplements] that are unsafe or adulterated.”). DSHEA classifies a
dietary supplement as adulterated if it “presents a significant or unreasonable risk
of illness or injury.” 21 U.S.C. § 342(f)(1). The FDA understood “[t]he plain
meaning of ‘unreasonable’ . . . [to] connote[] comparison of the risks and benefits
of the product.” 69 Fed. Reg. 6788, 6823 (2004). W e agree. The plain language
of the statute directs the FDA to restrict distribution of dietary supplements which
pose any risk that is unreasonable in light of its potential benefits. See M erck
KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (2005) (unanimously finding
that “unreasonable risk,” as used in another FDCA provision, 21 U.S.C. §
355(i)(3)(B)(I), “involves a comparison of the risks and the benefits . . . .”).
Congress enacted D SHEA in an effort to improve public access to dietary
supplements based on the belief that there may be a positive relationship between
dietary supplement use, reduced health-care expenses, and disease prevention.
See Pharmanex, 221 F.3d at 1158-59 (“It is true that DSHEA was enacted to
11
alleviate the regulatory burdens on the dietary supplement industry, allowing
consumers greater access to safe dietary supplements in order to promote greater
wellness among the American population.”) (citation omitted). The FDCA should
not be read too restrictively but in manner consistent with the statute’s overriding
purpose to protect public health. See 21 U.S.C.A. § 301 et seq.; United States v.
Rx Depot, Inc., 438 F.3d 1052, 1061 (10th Cir. 2006) (“The FDCA’s primary
purpose is to protect the public health.”) (citing United States v. An Article of
Drug . . . Bacto-Unidisk, 394 U.S. 784, 798 (1969)). Accordingly, DSHEA
should receive a liberal construction where the FDA has taken remedial steps in
response to a perceived public health problem.
A ccording to the district court, by injecting a risk-benefit analysis, the FD A
required Nutraceutical to make a showing of the benefits of its product.
However, at no time has the FDA required manufacturers of EDS to provide data
on the benefits of their products. Rather, the FDA has assumed its responsibility
of gathering data, soliciting comments, and conducting the risk-benefit analysis. 5
5
The district court compared the language of DSHEA to the statutory language
governing medical devices and drugs and concluded that, unlike manufacturers of
medical devices and drugs, manufacturers of dietary supplements do not need to prove
effectiveness prior to taking their product to market. 364 F. Supp. 2d at 1318 (“A brief
look at the legislative history of the DSHEA indicates that Congress generally intended to
harmonize the treatment of dietary supplements with that of foods when it added the
dietary supplement subsection to the food adulteration provision.”). The district court is
correct. However, the district court confused effectiveness with safety. The FDA did not
ban EDS for failing to deliver promised health gains or for ineffectiveness; the FDA
banned EDS because they were determined to be unsafe.
12
Congress expressly placed the burden of proof on the government to determine
whether a dietary supplement is adulterated. Accordingly, EDS were allowed to
enter the market without findings of safety or effectiveness. The FDA did not
impose a pre-market requirement for the sale of EDS. For example, Nutraceutical
has been selling ED S since 1988. As dictated by the statutory scheme, the FDA
assumed the duty of post-market surveillance and imposed the ED S ban following
numerous AERs, public notice and comment, and significant scientific review.
See 69 Fed. Reg. 6788. Based on the record, we disagree with the district court
and find that the FDA did not shift the burden of proof to manufacturers. The
risk-benefit analysis is conducted by, and at the expense of, the agency. Id. at
6798 (“the agency performs a risk/benefit analysis to ascertain whether the risks
of the product outweigh its benefits.”). Despite Nutraceutical’s characterization
of the process, the agency did not “require[] proof of a substantial benefit to
counterbalance risk as a condition precedent to lawful sale of EDS.” A ppellee’s
Brief, at 5. The burden remains on the agency to show that risks associated with
a dietary supplement outweigh benefits and are, therefore, unreasonable. Thus, a
risk-benefit analysis does not undermine congressional intent by improperly
shifting the burden of proof onto manufacturers of dietary supplements.
Under the rules of statutory construction, courts consider the whole act and
evaluate terms in context. Pharmanex, 221 F.3d at 1154 (“we examine the
statutory provision in context.”). The rule against surplusage encourages courts
13
to give meaning to every word used in a statute to realize congressional intent. In
effect, this rule embodies the belief that Congress would not have included
superfluous language. Thus, in DSH EA, an “unreasonable risk” has a meaning
independent from a “significant risk.” The plain meaning of a “significant risk”
is a great danger. “Unreasonable risk” is a distinct term and requires more than
evaluation of the significance of risk. “A risk could be significant but reasonable
if the benefits were great enough to outw eigh the risks.” 69 Fed. Reg. at 6823.
In other words, an “unreasonable risk” is relative to the circumstances; the
potential risk is more “unreasonable” if the potential benefit is smaller. See
Castrignano v. E.R. Squibb & Sons, Inc., 900 F.2d 455, 459 (1st Cir. 1990)
(upholding jury instructions which define “unreasonable” as the “balance between
the expected beneficial effects of the [product] as opposed to its harmful effects,
if any.”). The district court erred by conflating the terms “significant” and
“unreasonable,” thereby rendering “unreasonable” superfluous. In contrast to
“significant risk,” “unreasonable risk” accounts for whether the benefits justify
the risks. The use of “unreasonable” to qualify risk in addition to “significant”
makes it clear that Congress intended to integrate a risk-benefit analysis in the
former. Thus, because w e find the statute is clear, we now review the FDA’s
absolute prohibition of EDS under the APA.
14
“Conditions of Use”
Under DSHEA, the government bears the burden of proof to show that,
“under conditions of use recommended or suggested in labeling,” a dietary
supplement is adulterated. 21 U.S.C. § 342(f)(1)(A)(i). It is undisputed that the
FD A must consider the dosage recommended in a dietary supplement’s labeling
when making an adulteration determination under section 342(f)(1)(A). The
district court held that the FDA failed “to prove by a preponderance of the
evidence that a dosage of 10 mg or less of ephedrine alkaloids presents a
significant or unreasonable risk of illness or injury, [and] has failed to give effect
to the dose-specific language of [] § 342(f)(1)(A)(I).” 364 F. Supp. 2d at 1321.
In determining that EDS pose an “unreasonable risk of illness or injury,”
the FDA found that the w eight loss and other health benefits possible from the use
of ED S w ere dwarfed by the potential long-term harm to the user’s cardiovascular
system. The agency went on to enact a complete ban on the product after making
a finding that any amount of ED S had negative ramifications on the
cardiovascular system and, based on the FDA’s analysis, EDS provided no
benefits so great as to justify such risk.
The preponderance of the evidence standard 6 requires the party with the
burden of proof to support its position with the greater w eight of the evidence.
6
Congress did not prescribe the quantum of proof required under DSHEA.
Accordingly, the standard traditionally applied in administrative cases, the preponderance
of the evidence standard, governs. See Steadman v. SEC, 450 U.S. 91, 95, 102 (1981).
15
See M etropolitan Stevedore Co. v. Rambo, 521 U.S. 121, 137-38 n.9 (1997)
(explaining that the preponderance of the evidence standard “simply requires the
trier of fact to believe that the existence of a fact is more probable than its
nonexistence . . . .”) (citation omitted); Vesper Const. Co., Inc. v. Rain for Rent,
Inc., 602 F.2d 238, 242 (10th Cir. 1979) (“by the greater weight of the evidence
or, as it is sometimes called, the preponderance of the evidence.”). The evidence
relied on by the FDA to enact its ban of ED S covers over seven years of agency
review, public notice and comment, peer-reviewed literature, and scientific data.
It is the purview of the FDA to weigh the evidence, including the evidence
submitted by Nutraceutical and other manufacturers during public notice and
comment.
It is notew orthy that Nutraceutical relies on the 1999 GAO report to
support its contention that the Final Rule lacks support. However, the GAO has
since updated its findings and arrived at conclusions in support of the Final Rule.
See GAO, Dietary Supplements: Review of H ealth-Related Call Records for Users
of M etabolife 356 (GAO-03-494) (2003). Based on scientific data and AERs, the
GAO concluded that EDS pose a significant risk of cardiovascular and nervous
system effects among consumers who are young to middle-aged. See GAO,
Dietary Supplements Containing Ephedra, Testimony before the Subcomm ittee on
Oversight and Investigations, Committee on Energy and Commerce, House of
Representatives (July 23, 2003); 69 Fed. Reg. at 6818 (GAO found that AERs
16
“were consistent with . . . the scientifically documented pharmacological and
physiological effects of ephedrine alkoids.”).
The FDA hired Dr. Inchiosa to study the effects of EDS on human health in
1999. Dr. Inchiosa used principles of pharmacokinetics 7 to examine the effects of
ingestion of ED S on the human cardiovascular system. Dr. Inchiosa found that
ephedrine would be expected to produce the same adverse cardiovascular effects
(increased heart rate and blood pressure) as a comparable dose of the
pharmacologically-related drug, epinephrine, 8 and that, consequently, no dose of
ephedrine can be considered safe. Nutraceutical raises objections to D r.
7
A pharmacokinetic analysis is one which examines the bodily absorption,
distribution, metabolism, and excretion of drugs. Merriam Webster’s Collegiate
Dictionary 871 (10th ed.1994).
8
To reach his conclusions, Dr. Inchiosa relied on a peer-reviewed study of the
effect of epinephrine in humans. William E. Clutter, et al., Epinephrine Plasma
Metabolic Clearance Rates and Physiologic Thresholds for Metabolic and Hemodynamic
Actions in Man, 66 J. Clin. Invest. 94 (July 1980). The Clutter study revealed significant
increases in heart rate and blood pressure from epinephrine infusion at the rate of 0.5
µg/minute.
17
Inchiosa’s study and methodology which it did not raise during the rulemaking. 9
N utraceutical argues that D r. Inchiosa’s work is irrelevant to the effect of its low -
level dosage EDS product because his study examined the impact of continuous
injection of epinephrine into the bloodstream rather than ingestion of pills
containing 10 mg or less of ED S. 10 The district court rejected the “mathematical
model used [by Dr. Inchiosa] to compare doses of epinephrine to ephedrine.” 364
9
Although Nutraceutical did not specifically object to Dr. Inchiosa’s study and
methodology during rulemaking, it did not thereby waive its objection. In a review of the
decision of an administrative agency, a party waives its right to appeal an issue if it fails
to object through comments or documents in the record. New Mexico Environmental
Imp. Div. v. Thomas, 789 F.2d 825, 835 (10th Cir. 1986) (when agency solicited
comments on the very issue being challenged, party “was obligated to make its record
before the agency.”); American Frozen Food Institute v. Train, 539 F.2d 107, 134 (D.C.
Cir. 1976) (“What the industry failed to present to the Administrator during rulemaking
procedures when specifically asked to comment cannot now be urged [as] a basis for
invalidation [of the rule].”); see also Fuel Safe Washington v. F.E.R.C., 389 F.3d 1313
(10th Cir. 2004); Kennecott Copper Corp. V. E.P.A., 612 F.2d 1232, 1245 (10th Cir.
1979) (“it is well settled that industry must first utilize the opportunity for comment [on
an agency regulation] before it may raise issues on appeal.”). While Nutraceutical did not
object to Dr. Inchiosa’s study on the record, it did advance dissatisfaction with the
scientific evidence relied on by the FDA during the rulemaking. Appellee’s App., at 159-
60 (“Nutraceutical submits these comments to show that there is absolutely no basis for
concluding that [] whole-herb ephedra supplement products present a significant or
unreasonable risk . . . .”). The FDA solicited comments on “new scientific evidence . . .
concerning health risks associated with the use of dietary supplements containing
ephedrine alkaloids.” 68 Fed. Reg. 10417 (March 5, 2003). Dr. Inchiosa’s study was not
among the evidence referenced in the FDA’s March notice. Id. Given that the FDA did
not specifically ask for comments on Dr. Inchiosa’s study and Nutraceutical did object to
the new scientific evidence generally, it is appropriate for us to consider Nutraceutical’s
objections to Dr. Inchiosa’s study in particular.
10
Nutraceutical’s conclusory allegation that there is insufficient science to support
the FDA’s conclusion that increased heart rate and blood pressure correlate to increased
risk of cardiovascular disease is contrary to the vast scientific evidence in the
administrative record.
18
F. Supp. 2d at 1315. To account for the different potency levels of ephinephrine
and ephedrine, Dr. Inchiosa factored the greater potency of ephinephrine into his
calculations. Dr. Inchiosa’s work indicates that he exaggerated margins of error
in order to come to a conservative conclusion that the cardiovascular effects
produced by a dose of 9 mg of EDS daily may be dangerous.
19
Further, the FDA did not rely on Dr. Inchiosa’s work alone. 11 The FDA’s
11
The FDA relied on multiple studies which demonstrated that EDS raise blood
pressure and increase heart rate. The agency considered evidence from the well-known,
scientifically established pharmacology of ephedrine alkaloids; peer-reviewed scientific
literature on the effects of ephedrine alkaloids; and AERs of occurrences following
consumption of EDS. 69 Fed. Reg. 6788. In its call for comments, the FDA specifically
cited to the following peer-reviewed studies: Stephen Bent, et al., The Relative Safety of
Ephedra Compared with Other Herbal Products, 138 Ann. Intern. Med. 468-72 (March
2003) (finding that EDS accounted for 64% of all adverse reactions to herbs in the United
States, despite representing only 0.82% of herbal product sales); Paul G. Shekelle, et al.,
U.S. Dep’t of Health & Human Servs., Agency for Healthcare Research & Quality,
Assessment No. 76, Ephedra and Ephedrine for Weight Loss and Athletic Performance
Enhancement: Clinical Efficacy and Side Effects (Feb. 2003) (concluding that the use of
ephedrine and/or the use of ephedra or ephedrine plus caffeine is associated with two to
three times the risk of nausea, vomiting, psychiatric symptoms such as anxiety and
change in mood, autonomic hyperactivity, and palpitations); Lewis B. Morgenstern, et al.,
Use of Ephedra-Containing Products and Risk for Hemorrhagic Stroke, 60 J. Neurology
132-35 (2003) (concluding that ephedra is not associated with increased risk for
hemorrhagic stroke, expect possibly at higher doses); David Samenuk, et al., Adverse
Cardiovascular Events Temporally Associated With ma huang, an Herbal Source of
Ephedrine, 77 Mayo Clinic Proceedings 12 (2002) (concluding that ephedra use is
temporally related to stroke, myocardial infarction, and sudden death; underlying heart or
vascular disease is not a prerequisite for ephedra-related adverse events; and the
cardiovascular toxic effects associated with ephedra were not limited to massive doses);
Christine Haller, et al., Pharmacology of Ephedra Alkaloids and Caffeine After
Single-dose Dietary Supplement Use, 71 Clinical Pharmacology and Therapeutics 421-32
(June 2002) (after assessing the pharmokinetic effects of a single dose of EDS plus
caffeine in eight healthy adults and finding that the mean heart rate response reached a
maximum change of 15 beats/minute above the baseline, the authors concluded that
dietary supplements that contain ephedra and caffeine can produce significant
cardiovascular responses after a single dose); C. Boozer, et. al. Herbal Ephedra/Caffeine
for Weight Loss: a 6-month Randomized Safety and Efficacy Trial, 26 Int’l J. Obesity
Related and Metabolic Disorders 593-604 (2002) (concluding that dietary supplements
that contain ephedra and caffeine promote weight and fat loss without the expected
decrease in blood pressure); C. Boozer, et al., An Herbal Supplement Containing Ma
Huang-Guarana for Weight Loss: A Randomized, Double-blind Trial, 25 Int’l J. Obesity
and Related Metabolic Disorders, 316-24 (2001) (concluding that dietary supplements
that contain ephedra and caffeine promote short-term weight and fat loss, but that safety
with long-term use requires further investigation). The FDA also relied on an
(continued...)
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investigation also considered the findings of the National Institutes of Health, the
GAO, and the 1996 Food Advisory Committee, among others. See also 364 F.
Supp. 2d at 1320-21 (“Dr. Inchiosa . . . states that he cannot determine a safe
level of ED S intake. This sentiment is echoed throughout the transcript of the
[1996 Food Advisory Committee]. Several of the meeting’s attendees made
comm ents that a safe level could not be determined. There was, apparently, not
enough evidence to support the conclusion that there is a safe level of intake for
EDS.”). The review of scientific literature is properly in the province of the
FD A, to which this Court grants deference based on its expertise. See
W einberger v. Bentex Pharms., Inc., 412 U.S. 645, 653-54 (1973) (The FDA is
“peculiarly suited” to evaluate conflicting scientific reports, a matter “not . . .
well left to a court without chemical or medical background,” because it
“necessarily implicates complex chemical and pharmacological considerations.”).
The majority of data in the administrative record suggests that EDS pose an
unreasonable threat to the public’s health. The FDA:
11
(...continued)
investigation by the GAO which withdrew its earlier criticism of the FDA’s 1997
proposed regulation of EDS after linking EDS use with heart attacks, strokes, seizures,
death, and cardiac arrest. In addition, Dr. Inchiosa’s study discussed the relationship
between EDS and epinephrine in a transparent manner. Ephedrine alkaloids are
members of a family of pharmacological compounds called sympathomimetics, which
mimic the effects of epinephrine in the human body. 69 Fed. Reg. at 6789. Dr. Inchiosa
extrapolated data on epinephrine to draw conclusions about EDS, but he did so using
peer-reviewed data and generally accepted principles of pharmacology.
21
looked at the seriousness of the risks and the quality and
persuasiveness of the totality of the evidence to support the presence
of those risks. [It] then weighed the risks against the importance of
the benefits and the quality and persuasiveness of the totality of the
evidence to support the existence of those benefits . . . giv[ing] more
weight to benefits that improve health outcomes, especially in the
long term, than to benefits that are temporary or rely on subjective
measures such as feeling or looking better.
69 Fed. Reg. at 6799. The agency expressed that it would not deem EDS
adulterated based on “risks that are insignificant and reasonable in light of the
benefits from the supplement . . . .” Id. at 6825. The evidence in the
administrative record was sufficiently probative to demonstrate by a
preponderance of the evidence that EDS at any dose level pose an unreasonable
risk. The greater weight of the evidence supports the FDA’s ban on ED S, thus
satisfying the agency’s burden.
The FDA’s extensive research identified the dose level at which ephedrine
alkaloids present unreasonable risk of illness or injury to be so minuscule that no
amount of EDS is reasonably safe. The FDA reasonably concluded that there is
no recommended dose of EDS that does not present an unreasonable risk. Id. at
6829 (“dose limitations cannot change the unfavorable risk-benefit ratio of
[ED S]”). The FDA was not arbitrary or capricious in its Final Rule; the FDA met
its statutory burden of justifying a total ban of ED S by a preponderance of the
evidence.
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W e find that the FDA correctly followed the congressional directive to
analyze the risks and benefits of ED S in determining that there is no dosage level
of EDS acceptable for the market. Summary judgment for plaintiffs was therefore
improper, and summary judgment for defendants should have been entered.
Accordingly, the district court’s decision is reversed, and we remand for entry of
judgment in favor of defendants. As noted above, Nutraceutical’s M otion to
Correct O ral Argument Record is granted.
REVERSED AND REM ANDED.
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