Nuvaring Class Action | Nuva Ring Issues

by Steve Fields on January 25th, 2009

UNITED STATES DISTRICT COURT
EASTERN DISTRICT OF MISSOURI
(St. Louis)

IN RE NUVARING PRODUCTS LIABILITY : 4:08 MDL 1964 RWS
LITIGATION

ALL CASES
Honorable Rodney W. Sippel

MEMORANDUM OF LAW IN SUPPORT OF
\ DEFENDANTS' MOTION FORSUMMARY JUDGMENT
OR, IN THE ALTERNATIVE, MOTION FORPARTIAL SUMMARY JUDGMENT,
BASED ON THE DEFENSE OF FEDERAL PREEMPTION;
STATEMENT OF UNCONTROVERTED MATERIAL FACTS

Fed. R. Civ. Proc. 56
TABLE OF CONTENTS
Page
I INTRODUCTION 1
II STATUTORY AND REGULATORY FRAMEWORK .4
A. The FDA's Statutory Authority For Regulating Prescription Drugs 4
B. The FDA's Regulation OfDrug Labeling 5
III FACTUAL BACKGROlJND 8
A. The FDA Has Carefully And Deliberately Regulated Combined Hormonal
Contraceptives For Decades 8
1. The FDA Has Long Evaluated The Risk ofVTE for All Combined
Hormonal Contraceptives 8
2. The FDA Carefully Reviewed And Approved The NDA for
NuvaRing®, and Mandated the VTE Warnings for Its Label .lO
3. Following Approval ofthe NuvaRing® NDA, the FDA Has
Continued Careful Monitoring ofThromboembolic Risks
Associated With Combination Hormonal Contraceptives 12
IV ARGUMENT 13
A. Organon is Entitled to Summary Judgment Because Plaintiffs' State Law
Claims Are Preempted By Federal Law 13
1. Plaintiffs' Claims Are Preempted Because It Is Impossible for
NuvaRing® to Comply With Both The Federal Mandates and the
Standards that Plaintiffs Seek To Impose Through Their State Law
Based Tort Claims 15
2. Plaintiffs' Claims Are Preempted Because They Obstruct the
Objectives and Purposes ofthe FDCA and Its Implementation by
the FDA 20
B. Plaintiffs Cannot Avoid Preemption By Arguing Defendants Misled The
FDA, Because Such Claims Also Are Preempted .22
V CONCLUSION 24
STATEMENT OF UNCONTROVERTED MATERIAL FACTS PER LOCAL RULE 7-
4.01(E) 1
I INTRODUCTION
Defendants Organon USA, Inc., Organon Pharmaceuticals USA, Inc. LLC (flkla Organon
Pharmaceuticals USA, Inc.), Organon International, Inc. and Schering-Plough Corporation
(collectively, "defendants" or "Organon") move for summary judgment on the ground that the
MOL plaintiffs' lawsuits are preempted by federal law.
The MDL plaintiffs assert product liability claims relating to NuvaRing®, a prescription
pharmaceutical consisting ofa flexible, transparent vaginal ring containing a combined
honnonal contraceptive, estrogen (ethinyl estradiol) with a "third generation" progestin
(etonogestrel). More specifically, plaintiffs assert causes of action for negligent failure to warn;
strict liability design defect; fraud and misrepresentation; breach ofexpress and implied
warranty; manufacturing defect; and "[v]iolation ofconsumer protection laws in various states."
See Affidavit ofMelissa A. Geist ("Geist Aff."), Exhibit A (Oct. 22, 2008 Letter from Blau
Brown & Leonard LLC identifying the "causes of action and facts common to" all the MDL
plaintiffs' claims) at 3-4.
In support ofthese causes ofactio~ plaintiffs assert that: (1) NuvaRing® "is defective in
that it contains too much progestin" and "an unduly dangerous form ofthird generation
progestin"; and (2) NuvaRing®'s labeling fails to adequately warn ofa potential association
between hormonal contraceptives and blood clots, venous thromboembolism ("VIE"), stroke,
and/or other conditions. See id. I
1See also lenn First Amended Complaint, ~ 14 ("Defendants Organon failed to warn ofthe
extent of the risk ofvenous thromboembolism, including Deep Vein 1brombosis (OVT) and
Pulmonary Embolism (PE) and death associated With the use ofthe novel combined
contraceptive vaginal route ofadministration, the NuvaRing®."); Mecca (Blau Brown)
Complaint, ~ 23 ("Defendants failed to warn prescribing physicians and the public that the
Continued on following page
1
These allegations, however, fail to account for the regulatory role ofthe Food and Drug
Administration which has the sole authority, by statute and by regulation, to determine whether a
drug is safe and efficacious and what can be contained in a drug's labeling. Here, moreover, the
record is uncontradicted that, after exhaustive review and analysis, the FDA approved
NuvaRing® as safe and effective and, after a similar exhaustive and ongoing review, approved
NuvaRing's® labeling.
Indeed, the regulatory history ofNuvaRing® demonstrates that the FDA engaged in a
considered and deliberate risk-benefit analysis concerning the very aspects ofthe NuvaRing®
design and labeling challenged in this litigation: the alleged propensity ofcombined hormonal
contraceptives to increase VTE and similar risks. This regulatory history demonstrates that the
FDA has been aware of issues pertaining to thromboembolic risks allegedly associated with
combined hormonal contraceptive products, has stayed abreast ofthe relevant scientific data
concerning products in the class, and has mandated labeling revisions when deemed appropriate.
Under these circumstances, plaintiffs' product liability claims are preempted because
those claims directly conflict with the FDA's regulatory actions, decisions and objectives. The
only circuit to directly address the effect ofpreemption on tort claims involving prescription
drugs has so held on a record analogous to the one before this Court. See Colacicco v. Apotex,
Inc., 521 F.3d 253, 269 (3d Cir. 2008) (implied preemption defense barred state law product
Continued from previous page
NuvaRing was associated with increased risk ofcardiovascular thromboembolic complications
than the pill.").
-2-
liability lawsuit where plaintiff faulted suicide warning on prescription drug but FDA had
carefully mandated the suicide warning based on its evaluation of scientific data.).2
There is every reason to conclude that the Eighth Circuit would recognize the preemptive
effect ofthe FDA's regulatory decision-making as applied to this record. In Brooks v.
Howmedica, Inc., 273 F.3d 785, 796-98 (8th Cir. 2001) (en bane), the Eighth Circuit found a
failure to warn claim preempted where, as here, FDA had the exclusive responsibility for the
substance ofthe product's labeling and where, as here, it exercised its judgment concerning the
contents ofthe label with knowledge ofthe alleged safety issue. Although Brooks involved
express preemption and a prescription medical device, instead ofimplied preemption and a
prescription pharmaceutical, its reasoning and rationale safeguarding the primacy ofFDAdecision-
making apply with equal force here as well. See Ehlis v. Shire Richwood, Inc., 233 F.
Supp. 2d 1189,1198 (D.N.D. 2002) (holding preemption barred product liability claim over
2 Many other courts have applied principles ofimplied preemption to foreclose claims made
against drug manufacturers. See also Buckman Co. v. Plaintiffs' Legal Committee, 531 U.S. 341,
348 (2001) (implied preemption barred claims that defendant misled the FDA into approving its
prescription device); Pennsylvania Employees Benefit Trust Fund v. Zeneca, Inc., 499 F.3d 239,
253 (3d Cir. 2007) (consumer fraud and false advertising claims preempted by FDA regulation
ofdrug label and advertising); O'Neal v. Smithkline Beecham Corp., 551 F. Supp. 2d 993,100203
(B.D. Cal. 2008) (implied conflict preemption barred injury tort claim over prescription
antidepressant warnings); Longs v. Wyeth, 536 F. Supp. 2d 843, 847 (N.D. Ohio 2008) (implied
preemption barred plaintiff's product liability claim that FDA never should have approved
prescription diet drug); Dobbs v. Wyeth Pharm., 530 F.Supp.2d 1275, 1280-81 (W.D. Okla.
2008) (implied preemption barred product liability claim over prescription antidepressant
warnings); Masterson v. Apotex Corp., 2008 WL 3262690 (S.D. Fla. Aug. 7, 2008) (implied
preemption barred product liability failure to warn claim over prescription generic drug's birth
defect warning); Mensing v. Wyeth, 2008 WL 2444689 (D. Minn. June 17,2008) (implied
preemption barred product liability failure to warn claim involving prescription generic drug);
Mason v. Smithkline Beecham Corp., 2008 WL 1835350 (C.D. Ill. Apr. 23,2008) (implied
conflict preemption barred injury tort claim over prescription antidepressant warnings); Horne v.
Novartis Pharmaceuticals Corp., 2008 WL 818819 (W.D.N.C. March 25,2008) (implied
preemption barred failure to warn and other claims involving prescription drug). In addition, the
United States Supreme Court will hear oral argument in a case raising these issues, Wyeth v.
Levine, No. 06-1249, on November 3, 2008.
- 3 -
prescription ADHD drug; "plaintiffs' claims in this case mirror those brought by Brooks, and
although plaintiffs in oral argument attempted to distinguish the FDA from the MDA, the court is
not convinced that preemption would not apply in this case").
In the end, plaintiffs are attempting to use their various tort claims to second-guess the
FDA's regulatory judgments and to penalize defendants for their compliance with the FDA's
regulatory mandates. Principles ofimplied preemption are intended to foreclose both results.
The FDA made its evaluations and decisions with awareness ofthe alleged risks plaintiffs
identify, and that is dispositive of plaintiffs' lawsuit. Summary judgment is warranted and
respectfully urged.
II STATUTORY AND REGULATORY FRAMEWORK
A. The FDA's Statutory Authority For Regulating Prescription Drugs
The FDA is the federal health agency charged by Congress with ensuring that drugs are
safe and effective and that drug labeling adequately infonns users ofthe risks and benefits ofthe
product. See generally 21 U.S.C. § 201 et seq. The Food, Drug and Cosmetic Act ("FDCA")
prohibits the marketing ofa new prescription drug until the FDA detennines the drug is safe and
effective for its intended use, and mandates the language that must be contained in the product
label. See 21 U.S.C. §§ 355(d), 505.
When evaluating a New Drug Application ("NDA"), the FDA must weigh the potential
safety risks associated with the new drug against the therapeutic benefits to patients. The FDA
strikes a balance between those often competing considerations by regulating "the conditions
prescribed, recommended, or suggested in the proposed labeling." See 21 U.S.C. § 355(d); see
also 21 C.F.R. § 314.50(d)(5)(viii) (requiring NDAs to include a "summary ofthe benefits and
-4-
risks ofthe drug, including a discussion ofwhy the benefits exceed the risks under the conditions
stated in the labeling"); FDA, Guidance for Industry, Development and Use ofRisk
Minimization Action Plans 4 (Mar. 2005) (describing the FDA's risk-benefit assessment as
measuring whether, under labeled conditions of use, "the clinical significance and probability of
[a drug's] beneficial effects outweigh the likelihood and medical importance of its harmful or
undesirable effects"»)
In this way, the FDA fulfills its dual mission to "protect the public health" by barring
access to unsafe or ineffective drugs, and to "promote the public health" by ensuring prompt
access to effective and beneficial medicines. 21 U.S.C. § 393(b).
B. The FDA's Regulation OfDrug Labeling
Because prescription drugs carry unavoidable, and often serious, risks for some patients,
"drug labeling serves as the standard under which FDA determines whether a product is safe and
effective" [50 Fed. Reg. 7452, 7470 (Feb. 22, 1985)], and it is "[t]he centerpiece ofrisk
management" [71 Fed. Reg. 3922,3934 (Jan. 24,2006)]. FDA-approved drug labeling
"communicates to health care practitioners the agency's fonnal, authoritative conclusions
regarding the conditions under which the product can be used safely and effectively." 71 Fed.
Reg. at 3934.
A drug's labeling must include "a summary ofthe essential scientific information needed
for the safe and effective use ofthe drug." 21 C.F.R. § 201.56(a)(1). To achieve this result, the
FDA reviews the labeling proposed with each NDA and may approve an NDA only if it finds:
(1) that the drug is "safe for use under the conditions prescribed, recommended, or suggested in
3 Available at http://www.fda.gov/cder/guidance/6358fnl.pdf.
-5-
the proposed labeling thereof'; (2) that there is "substantial evidence that the drug will have the
effect it purports or is represented to have under the conditions ofuse prescribed, recommended,
or suggested in the proposed labeling thereof'; and (3) that the proposed labeling is not "false or
misleading in any particular." 21 U.S.C. § 355(d). Further, the FDA can withhold NDA
approval until the manufacturer makes changes to the labeling that the Agency deems necessary.
21 C.F.R. § 314.105(b); see also id. § 314.110(a).
Once the FDA approves an NDA, a manufacturer can distribute the drug only with FDAapproved
labeling. See id. § 314.105(b) ("[A]pproval will be conditioned upon the applicant
incorporating the specified labeling changes exactly as directed, and upon the applicant
submitting to FDA a copy ofthe final printed labeling prior to marketing."); see also Colacicco,
521 F.3d at 257-60. A manufacturer may not change a drug's FDA-approved labeling without
obtaining the FDA's prior approval ofa supplemental NDA. See 21 U.S.C. § 355(a), (b)(I)(F),
(c)(I)(A), (d); see also 21 C.F.R. § 314.70(b)(2)(v)(A), (b)(3).4
A narrow regulatory exception to this rule pennits a manufacturer, who has filed a
supplemental NDA, to implement a labeling change before FDA has acted on the application if
the change is intended "[t]o add or strengthen a contraindication, warning, precaution, or adverse
4 Similar features of the FDA's premarket approval of Class III medical devices recently led the
Supreme Court to find preemption ofstate-law tort claims in that analogous context. Riegel v.
Medtronic, Inc., 552 U.S.-' 128 S. Ct. 999, 1008 (2008). In Riegel, the Court held that once a
Class III medical device receives premarket approval, the FDCA (as amended by the Medical
Device Amendments of 1976 (MDA» forbids the manufacturer to make any change without
FDA permission, including a change to the approved labeling, that would "affect safety or
effectiveness." ld. at 1005. Any change must be submitted by supplemental application for FDA
approval before implementation. ld. The Supreme Court thus held that the FDA's detailed,
individualized review ofthe safety and effectiveness of each Class III medical device imposed a
federal-law "requirement" that an approved device be made "with almost no deviations from the
specifications in its approval application," and pr.eempted conflicting state-law requirements
applicable to the device. ld. at 1006-1007. The same holds true for prescription drugs, which
are subject to an approval process that is very similar to the MDA's premarket approval process.
-6-
reaction," or "[t]o add or strengthen an instruction about dosage and administration that is
intended to increase the safe use of the drug product" ifpremised on new information not already
known to the Agency. 21 C.F.R. § 314.70(c)(6)(iii)(A), (C); see also Brief for the United States
as Amicus Curiae in Wyeth v. Levine, No. 06-1249, at 23-24 (S. Ct. June 2007)5 (CBE regulation
does not allow manufacturers to reassess the same risks and benefits already accounted for by the
FDA, but rather "must be based on new information"); cf Riegel v. Medtronic, Inc., 552 U.S.
-' 128 S. Ct. 999, 1005 (2008) (discussing analogous CBE regulation for medical devices).6
Even where the CBE exception might be applicable, however, the FDA retains the
ultimate authority to decide whether the additional warning language can be utilized. As the
FDA has expressly acknowledged, the over inclusion ofrisk information in product labeling is
not necessarily protective of patients as such information can distort the risk versus benefit
analysis that is critical to a prescriber's ability to make appropriate judgments about product use.
71 Fed. Reg. 3934,3935 ("Exaggeration of risk could discourage appropriate use ofa beneficial
drug."). Thus, "the determination ofwhether labeling revisions are necessary is, in the end,
squarely and solely FDA's under the act." Id. at 3934.
5 Available at http://www.abanetorglpubliced/preview/briefs/pdfs/07-08/061249
PetitionerAmCuUSA.pdf.
6 FDA also recently published a proposed change to the CBE provision "to codify" this
longstanding view and to "reaffirm that a CBE supplement is appropriate to amend the labeling
for an approved product only to reflect newly acquired information and to clarify that a CBE
supplement may be used to add or strengthen a contraindication, warning, precaution or adverse
reaction only if there is sufficient evidence ofa causal association with the drug, biologic or
medical device." 73 Fed. Reg. 2848,2849 (Jan. 16,2008).
-7-
OJ FACTUAL BACKGROUND
A. The FDA Has Carefully And Deliberately Regulated Combined Hormonal
Contraceptives For Decades
1. The FDA Has Long Evaluated The Risk of VTE for All Combined Hormonal
Contraceptives.
The FDA has regulated - and mandated - warnings regarding the potential risk ofVTE
associated with the use ofhormonal contraceptives for decades. Beginning in 1970, the FDA
published a Final Rule requiring "uniform labeling" for hormonal contraceptives ("class
labeling''), stressing that the "most important complication" to be communicated to the patient
"is abnormal blood clotting which can have a fatal outcome." See Geist Aff., Exhibit D at 9002.
This regulation further required manufacturers to include inserts to be dispensed to patients with
the same warning. Id. at 9002-03.7
In 1976, the FDA issued revised physician and patient labeling for all combined
hormonal contraceptives based on "[s]ignificant new information" regarding thromboembolic
disorders and other risks associated with such product use. Geist MI., Exhibit E at 53633. The
FDA mandated that all manufacturer labels contain contraindications for any woman with
"[t]hrombophlebitis or thromboembolic disorderst' or a "past history ofdeep vein
7 With respect to prescription drugs, "labeling" or "professional labeling" is "a compilation of
information about the product, approved by FDA, based on the agency's thorough analysis ofthe
new drug application (NDA) .... This labeling contains information necessary for safe and
effective use. It is written for the health care practitioner audience." 71 Fed. Reg. at 3922. The
term "patient insertst' or "patient labeling't means special labeling distributed directly to patients
and "refers to any labeling that has been reviewed and approved by the agency that provides
information for patients and is for distribution to patients who are prescribed a drug. This term
includes approved printed patient information specifically required by regulation (e.g., for oral
contraceptives (21 CFR 310.501) and estrogens (21 CFR 310.515»." 71 Fed. Reg. at 3954.
-8-
thrombophlebitis or thromboembolic disorders," and it required that all labeling contain several
new thromboembolism warnings, including the following language: "use oforal contraceptives
is associated with increased risk of several serious conditions including thromboembolism,
stroke ...." Id. at 53634. The FDA specified at that time that "[a]bnormal blood clotting" be
described first under "The Dangers of Oral Contraceptives" in a patient insert as well as the
physician labeling. Id. at 53640.
Similarly, the FDA has closely regulated hormonal contraceptive products containing
third-generation progestins for thromboembolic risks, long before NuvaRing® was approved.
See Declaration ofTitia M.T. Mulders ("Mulders Decl."), Exhibit Bat 10. In August 1994, the
FDA issued its "Guidance for Industry on Combined Oral Contraceptives - Labeling for
Healthcare Providers and Patients" (the "COC Guidance"), as well as several draft amendments
thereto (issued June 2000 and March 2004), in order to impose uniform labeling among
combined oral contraceptive products. The 2004 draft version ofthe COC Guidance,
specifically directed the inclusion ofwarnings for thromboembolic risks like VTE in the
Contraindications and Warnings sections, including the following warning:
For desogestrel containing products: Several epidemiologic studies
indicate that OCs containing desogestrel are associated with a higher
risk of venous thromboembolism than OCs containing other
progestins. In general, these studies indicate an approximate 2-fold
increased risk, which corresponds to an additional 1 to 2 cases of
venous thromboembolism per 10,000 women-years of use. However,
data from other studies have not shown this 2-fold increase in risk.
Geist Aff., Exhibit B at 5.
In 1995, the FDA issued a statement entitled "Oral Contraceptives and Risk ofBlood
Clots" in response to inquiries about oral contraceptives containing third generation progestins.
Geist Aff., Exhibit F. Although the FDA stated that some studies suggested an approximate twofold
increase in the risk ofVTE for third generation contraceptives as compared to products
-9-
containing older progestins, it also stated that the risk did not require women to stop using the
product and was "not great enough to justify switching to other products." See id At the same
time, the FDA indicated that it would work with manufacturers to further update the labeling. Id
2. The FDA Carefully Reviewed And Approved The NDA for NuvaRing®, and
Mandated the VTE Warnings for Its Label
NuvaRing® is the first and only contraceptive vaginal ring approved for delivering
combined hormones. See Mulders Decl., Exhibit D at NDA-0127486, NDA-0127490. When
placed in the vagina, the ring releases continuous levels ofetonogestrel and an estrogen over a
three-week period. Id at NDA-0127490.
Organon submitted the NuvaRing® NDA (No. 21-187) on December 28, 1999. Mulders
Decl., Exhibit A. Organon's submission included the results of"two large Phase 3 studies"
(Study 068003 and Study 034219) regarding the "contraceptive efficacy, vaginal bleeding
patterns, and safety ofthe NuvaRing regimen," as well as other studies including those
comparing NuvaRing® with second-generation oral contraceptives and thromboembolic events
reported during the studies. Mulders Decl., Exhibit B. These studies provided information on
contraceptive efficacy and cycle control, risk ofserious adverse events including VTE, lipid and
carbohydrate metabolism, coagulation and fibrinolysis (the body's clotting and clot dissolving
mechanism), and pharmacokinetic effects ofNuvaRing®. Id
After reviewing the data and information submitted, the FDA Medical Officer's Review8
stated "there is a solid database of safety information" concerning NuvaRing®, and that there
were "no major changes ofconcern in the hemostasis [blood clotting] parameters." Mulders
8 The role ofan FDA Medical Officer is to review all ofthe information about a new drug to
ensure that it is safe and effective and contains accurate product labeling. Mulders Decl. '10.
- 10-
Decl., Exhibit Bat 4,6. The FDA's Medical Officer's Review further stated that the FDA's
"primary concern [was] the increased risk ofVTE associated with combination hormonal
contraceptives containing a third-generation progestin, such as the etonogestrel in NuvaRing®."
Id. at 2.
Almost two years later, on October 3, 200 I, the FDA approved the NuvaRing® NDA.
Mulders Decl., Exhibit D. Again, the FDA addressed safety issues potentially associated with
the alleged increased risk ofVTEs in desogestreVetonogestrel containing combined hormonal
contraceptives by requiring that "[t]he final printed label ... reflect the increased risk ofvenous
thromboembolism (VTE) associated with combination hormonal contraceptives containing a socalled
third generation progestin such as desogestrel." Mulders Decl., Exhibit B at 2.
The FDA provided substantive comments and instructions to Organon concerning the
NuvaRing® labeling, including the following:
• October 6, 2000 - the FDA stated it would require a warning about the increased risk of
VTE associated with combined hormonal contraceptives containing third generation
progestins. See Mulders Decl., Exhibit B at 2.
• November 2000 - the FDA considered label language regarding epidemiology studies of
third generation oral contraceptives and VTE risks as follows: "There is evidence of an
association between the following conditions and the use ofcombination hormonal
contraceptives, although additional confirmatory studies are needed"; "[m]esenteric
thrombosis"; and "[r]etinal thrombosis"; "[c]ombination hormonal contraceptives may
increase the tendency to develop strokes (blockage or rupture ofblood vessels in the
brain) and angina pectoris (chest pain)"; and risks of side effects like blood clots "may be
greater with etonogestrel-containing combination hormonal contraceptives, such as
NuvaRing®, than with certain other low-dose pills." See Mulders Decl., Exhibit Cat
NDA-0125666, NDA-0125672.
• December 2000 - the FDA directed that the NuvaRing® label "include the text that is
required for all desogestrel-containing OCs regarding an approximate 2-fold increased
risk ofVTE with third generation OCs compared with certain second generation OCs."
The FDA noted that "[t]he potential increased incidence ofvenous thromboembolism
(VTEs) associated with third generation OCs, including those containing desogestrel ...
remains the major safety concern." Mulders Decl., Exhibit Eat 5,2, respectively.
- 11 -
• December 2000 - the FDA directed that the NuvaRing® label should include a statement
that "it is unknown whether NuvaRing® is distinct from combination oral
contraceptives" when comparing the risk ofNuvaRing® to other combined honnonal
contraceptives. ld. at 7.
When the FDA approved the NuvaRing® NDA in October, 2001, Organon incorporated
the FDA's ultimate directives regarding label language into the final version ofthe printed label.
See Mulders Decl., Exhibit D.
3. Following Approval of the NuvaRing® NDA, the FDA Has Continued
Careful Monitoring of Thromboembolic Risks Associated With Combination
Hormonal Contraceptives
After product approval, the FDA remained engaged in monitoring the safety and efficacy
ofNuvaRing® and regulating the product labeling. Such regulatory oversight resulted in revised
labeling, including:
• July 20,2005 - Changes to the Contraindications section ofthe NuvaRing® label
regarding thromboembolism, along with changes to the Patient Information section
regarding the risk of cigarette smoking and stroke. Mulders Decl., Exhibit F at NDA0129785,
NDA-0129823;
• March 2007 - Changes to the NuvaRing® label, including changes to the "Warnings"
section ofthe physician labeling regarding arterial thromboembolic events, hypertension
and risk of stroke. See Affidavit ofJune Bray ("Bray Aff."), , 13 & Exhibit A.
• March 2007 - Changes to the patient labeling regarding use ofNuvaRing® prior to
surgery because ofthe risk of blood clots. Bray Aff., Exhibit A at 14.
In addition, the FDA has received VTE adverse events reported to Organon [see 21
C.F.R. section 314.80(a), (c)(2)] and requested additional information when necessary in the
Agency'sjudgment. See, e.g., Bray Mf.,,~ 15-16 & Exhibit B.
- 12-
IV ARGUMENT
A. Organon is Entitled to Summary Judgment Because Plaintiffs' State Law Claims
Are Preempted By Federal Law
The uncontradicted record demonstrates that the FDA carefully exercised its expert
regulatory judgment regarding NuvaRing®, based on more than 30 years of expertise with all
known data regarding hormonal contraceptives and thrombogenicity. Plaintiffs' tort causes of
action, and the allegations that underlie them, directly conflict with the FDA's explicit
judgments. Congress has made the decision, however, that paramount FDA authority over drug
safety and labeling is the best way to protect patient health. The FDA's federal requirements
trump conflicting state requirements like plaintiffs seek to impose. Principles of federal
preemption accordingly bar this lawsuit.
Rule 56(c) ofthe Federal Rules of Civil Procedure requires that summary judgment be
granted when, as in this case, "there is no genuine issue as to any material fact and the moving
party is entitled to ajudgment as a matter oflaw.n Anderson v. Liberty Lobby, Inc., 477 U.S.
242,247 (1986); see also Cameo Homes v. Kraus-Anderson Const. Co., 394 F.3d 1084, 1087
(8th Cir. 2005). Through Rule 56, courts may summarily resolve all or part ofa claim. Fed. R.
Civ. Proc. 56(b).
The party opposing summary judgment bears the burden ofcoming forward with specific
facts to show there is a genuine issue for trial. See Forrest v. Kraft Foods, Inc., 285 F.3d 688,
691 (8th Cir. 2002). A fact issue is considered "genuinen only if there is sufficient evidence on
which a reasonable jury could base a fmding in favor ofthe non-moving party. Anderson, 477
U.S. at 249. Conclusory statements, speculation, unsubstantiated allegations, or merely
- 13-
colorable evidence will not suffice. See, e.g.• Banovetz v. King, 66 F. Supp. 2d 1076, 1079 (D.
Minn. 1999).
Federal preemption of state law arises from the Supremacy Clause of the U.S.
Constitution, which states:
This Constitution, and the Laws of the United States which shall be made in
pursuance thereof . . . shall be the supreme Law of the Land; and the Judges in
every State shall be bound thereby, any Thing in the Constitution or Laws of any
State to the Contrary notwithstanding.
U.S. Const. art. VI, cl. 2. 9
Even when Congress has not expressly declared its intent to have federal law preempt
state law, "implied conflict preemption" may result. l0 Congress is understood to imply a
preemptive effect for federal law when state laws either (a) "make it 'impossible' for private
parties to comply with both state and federal law" or (b) "prevent or frustrate the
accomplishment ofa federal objective." Geier v. Am. Honda Motor Co., 529 U.S 861, 873
(2000).
9 The implied conflict preemption issue in this case is a defense to liability and a matter of
"ordinary preemption," because it is concerned only with whether plaintiffs' state law tort claims
impermissibly conflict with federal law. This motion does not involve the jurisdictional issues
of"complete preemption," which relate to whether Congress intended to convert all nominally
state law claims into federal claims sufficient to create federal question jurisdiction. It thus is
unlike the complete preemption issues discussed in St. John~ Mercy Health System v.
Healthlink, Inc., 2008 WL 4204721 (B.D.Mo. Sept. 9,2008) (Sippel, J.) (on motion for remand,
issue was whether ERISA created "complete preemption" converting a state claim into a federal
question) and in Gillenwater v. Burlington Northern & Santa Fe Ry. Co., 481 F. Supp. 2d 998
(B.D. Mo. 2007) (Sippel, J.) (on reconsideration ofmotion for remand, issue was "complete
preemption" and whether Congress intended the Federal Railroad Safety Act to convert a state
claim into a federal question).
10 Implied conflict preemption is one oftwo types of"ordinary preemption," the other being
express. Express preemption requires a court to look to the text and structure ofa federal statute
to discern Congress' intent with respect to the scope ofpreemption. See Brooks v. Howmedica.
Inc., 273 F.3d 785, 792 (8th Cir. 2001) (en bane). Implied preemption differs from express
preemption "in that it turns on the identification of 'actual conflict'" rather than interpretation of
statutory language. Geier v. American Honda Motor Co., 529 U.S. 861,884 (2000).
- 14-
Because the FDA is vested with the exclusive authority to make the determination that a
particular prescription drug is "safe and effective" when used in accordance with the approved
labeling, product liability suits based upon a contrary assessment of the adequacy ofa drug's
label pose an obstacle to the FDA's ability to carry out its congressionally-mandated
responsibilities. In addition, because manufacturers must comply with FDA mandates, it is
impossible for them to, at the same time, comply with contrary directions imposed by juries
applying their understanding of state law tort duties. Tort claims such as those at issue in this
lawsuit thus are preempted.
1. Plaintiffs' Claims Are Preempted Because It Is Impossible for NuvaRing® to
Comply With Both The Federal Mandates and the Standards that Plaintiffs
Seek To Impose Through Their State Law Based Tort Claims
The FDA's review ofNDAs is a rigorous process that focuses on whether the drug is safe
and effective under the labeled conditions of use and whether its labeling complies with
extensive and detailed regulations. FDA approval ofa drug's labeling is thus part and parcel of
its approval of the drug itself. If the FDA finds anything it judges to be deficient in the proposed
labeling during its review ofan NDA, the FDA will specify exactly how those deficiencies
should he corrected and final approval ofthe NDA is "conditioned upon the applicant
incorporating the specified labeling changes exactly as directed." 21 C.F.R. § 314.105(b).
The FDCA required that Organon incorporate the FDA-mandated language regarding
thromboembolic events. No deviation was permitted without FDA approval. By contrast,
plaintiffs seek to impose state law obligations which would require Organon to deviate from
those established by the expert agency charged with responsibility for making determinations
- 15 -
concerning the safety, efficacy and labeling of combined honnonal contraceptives. 11 Because
these two directives are in direct conflict, plaintiffs' claims are preempted as a matter oflaw.
In Colacicco, the Third Circuit recognized the fundamental problem with state court
actions that challenge FDA approval and labeling decisions when Congress sought to assign
exclusive authority over prescription drugs to the FDA:
State standards of care undoubtedly differ from state to state. Absent a
determination that the FDA-approved labeling and the FDA's refusal to require
the warnings suggested by plaintiffs in this case preempt state tort actions, the
manufacturers may be subjected to considerable liability based on varying
standards, with no benclunark that they should follow.
521 F.3d at 267-68; see also Pennsylvania Employees Benefits Trust Fund, 499 F.3d at 251 ("the
purpose of protecting prescription drug users in the FDCA would be frustrated if states were
allowed to interpose consumer fraud laws that pennitted plaintiffs to question the veracity of
statements approved by the FDA.").
Comparing the FDA's regulation ofNuvaRing® with its regulation of the anti-depressant
in Colacicco is instructive regarding the effect ofthose actions on preemption. The facts in this
MDL parallel those in Colacicco, and implied conflict preemption is the result in each. In
Colacicco, the FDA was acutely aware that anti-depressants known as SSRIs potentially posed a
risk of increased suicidality in some patients. Colacicco, 521 F.3d at 269-270. The Agency
reviewed the scientific studies and carefully deliberated on the issue time and again, each time
concluding that stronger suicide warnings were not scientifically justified and did not pennit
label changes on the issue. ld at 269. Because the FDA's actions established federal law that
controlled how the drug had to be labeled, the Third Circuit concluded that those FDA drug-
11 See Riegel, 129 S. Ct. at 1007-1008 ("[C]ommon-law liability is premised on the existence of
a legal duty, and a tort judgment therefore establishes that the defendant has violated a state-law
obligation." (internal quotation marks omitted)).
- 16-
labeling requirements preempted tort claims that sought to impose liability on the manufacturer
despite its compliance with federal law. Id at 267, 269.. 12 Just as the FDAwas aware ofthe
potential suicide risk with SSRI, so too was the FDA aware ofthe potential VTE risk with
combined hormonal contraceptives, including NuvaRing®. Just as the FDA carefully (and
repeatedly) weighed the scientific data regarding SSRIs and instructed the manufacturer about
the language it had to include on the drug label, so too did the FDA carefully (and repeatedly)
weigh the scientific data regarding VTEs and instructed defendants about the language to be
included on the NuvaRing® label.
Notably, the Third Circuit based its decision in Colacieco, in part, on the FDA's
awareness and detailed scrutiny of safety risks and its control over whether and how the
prescription product label would warn about those potential risks. Id at 269. In Brooks, an en
bane panel of the Eighth Circuit employed this same rationale in upholding express preemption
involving a prescription medical device. Brooks, 273 F.3d at 796-98 (failure to warn claim
preempted where FDA had authority and responsibility to mandate prescription device warnings,
the FDA knew of alleged safety issue and mandated warning language).
In Brooks, the FDA "heavily regulated" a bone cement known as Simplex, through the
NDA process for prescription drugs, evaluating all scientific data and reviewing the label "word
for word." Id at 788. After an amendment to the FDCA granted the FDA regulatory authority
over medical devices, Simplex was reclassified from a drug to a device although the Agency's
12 The Third Circuit has rejected the contention that the FDA must "formally" deny a drug
manufacturer's request to add the specific contested warning in order for preemption to result.
Colacicco, 521 F.3d at 272 (rejecting the "notion that, in order to rise to the level ofa conflict in
this situation, the FDA's rejection ofa warning must be imbued with the formality proposed by
plaintiffs."). Federal law results when an agency acts with '''fairness and deliberation' which
would suggest that Congress intended the agency's action to be a binding and exclusive
application of federal law." See Fellner v. TriUnion, 539 F.3d 237, 245 (3rd Cir. 2008).
- 17 -
regulatory activity remained constant. Id at 789. Upon learning of information suggesting a risk
posed from vapors from Simplex, the FDA mandated warnings about that risk, and mandated
additional changes to the label language as the data warranted. Id. at 789-90. The Eighth Circuit
thus concluded that tort claims that depended on a duty to give warnings different from what the
FDA required were preempted:
The failure to warn claim asserted by [plaintifl] would interfere or
conflict with the specific federal requirements imposed during the
regulation of Simplex. A jury finding of negligent failure to warn
would be premised on the fact that the label for Simplex was not
written in a particular way or did not contain certain information.
This would be equivalent to a state regulation imposing specific
label requirements.
****
The effect of a jury finding of negligent failure to warn would be
that state law would require Howmedica to change the label and
package insert for Simplex, but Howmedica may not unilaterally
make such changes under federal law.
Id at 796.
The Brooks decision makes clear that in the Eighth Circuit, as in the Third, a conflict
between what the FDA requires and what a plaintiff's tort claims necessarily demand results in
preemption - regardless of whether a drug or device is at issue. See Ehlis, 233 F. Supp. 2d at
1198 (in holding that preemption barred product liability claim over prescription ADHD drug,
the district court stated "plaintiffs' claims in this case mirror those brought by Brooks, and
although plaintiffs in oral argument attempted to distinguish the FDA from the MDA, the court is
not convinced that preemption would not apply in this case").
- 18 -
This conclusion is buttressed by the FDA's own position on the preemptive effect ofits
labeling mandates - one deserving ofdeference from the courts. 13 In the January 2006 new drug
labeling rules, the FDA reiterated its longstanding view that lawsuits seeking to impose duties in
conflict with FDA requirements, as these cases do, obstruct the Agency's ability to ensure that
prescribing physicians receive accurate and helpful information about the proper use of
prescription drugs:
FDA believes that under existing preemption principles, FDA approval of
labeling under the act, whether it be in the old or new format, preempts
conflicting or contrary state law. The discussion that follows, therefore,
represents the government's long standing views on preemption, with a particular
emphasis on how that doctrine applies to State laws that would require labeling
that conflicts with or is contrary to FDA-approved labeling.
71 Fed. Reg. 3934 (Jan. 24, 2006) (codified at 21 C.F.R. §§ 201.56-201.58, 201.80, 201.100,
314.70,601.12).
Here, in particular, the FDA's safety and efficacy determination for NuvaRing® and its
substantive input into the NuvaRing® labeling was informed by decades ofexperience with
hormonal contraceptives. Both before and after approval ofNuvaRing®, the FDA took
deliberate positions concerning the VTE risks associated with NuvaRing®, and other combined
hormonal contraceptives, that had the force of federal law and dictated what the label had to say
13 It is well-settled that an agency's interpretation ofits own regulations is entitled to substantial
deference and that a court can reject the agency's stated position only if it is "plainly erroneous
or inconsistent with the regulation." Auer v. Robbins, 519 U.S. 452,461 (1997) (quoting
Robertson v. Methow Valley Citizens Council, 490 U.S. 332, 359 (1989»; see also Geier, 529
U.S. at 883 (deference to agency determination of preemptive effect of its regulations). Such
deference is appropriate here because the FDA "is uniquely qualified to determine whether a
particular form of state law stands as an obstacle to the accomplishment and execution ofthe full
purposes and objectives of Congress and, therefore ... should be preempted." Medtronic v.
Lohr, 518 U.S. 470, 496 (1996) (citations and internal quotation marks omitted) (preemption
under the Medical Device Amendments).
-19 -
with no discretion left to the manufacturer. The FDA's oversight and regulation thus extended to
the very risks now at issue in this litigation and that places this case squarely within the ambit of
Colacicco, Brooks, and Ehlis. The manifest conflict between the FDA's federal requirements for
NuvaRing® and the standards plaintiffs demand in this litigation leads to the same result:
application ofpreemption and dismissal ofthe lawsuits.
2. Plaintiffs' Claims Are Preempted Because They Obstruct the Objectives and
Purposes ofthe.FDCA and Its Implementation by the FDA
Plaintiffs' lawsuits are subject to implied preemption for an additional reason as well: "it
is now established that lawsuits based on state tort law, as well as on state statutes, may be
viewed as presenting obstacles to federal objectives and hence barred as preempted." Colacicco,
521 F.3d at 267; see also id at 276 (commenting that "[w]e are not scientists and we do not
purport to have any expertise on [the alleged drug risk]. That is within the FDA's authority.").
For prescription drugs like NuvaRing®, Congress's objective in passing the FDCA was
to assign "comprehensive scientific evaluation ofthe product's risks and benefits" exclusively to
the FDA. 71 Fed. Reg. 3934; see also Brief for the United States as Amicus Curiae, Wyeth v.
Levine, No. 06-1249, at 7 (Dec. 2007) (contrary tort claims are "implied[ly] preempted by the
FDCA because they challenge labeling that FDA approved after being informed ofthe relevant
health risk, based on its expert weighing ofthe risks and benefits ofrequiring additional or
different warnings."). As Colacicco concluded, tort litigation poses a distinct obstacle to that
federal objective, and implied conflict preemption again is the result.
For example, plaintiffs' design defect claims essentially allege that NuvaRing® should
not have been marketed at all despite the FDA's determination that NuvaRing® was safe and
effective for marketing. Plaintiffs' label-based claims allege that the label language the FDA
mandated was inadequate. But through the FDCA, Congress established a drug approval regime
- 20-
in which an expert scientific agency makes uniform, national judgments about the safety and
effectiveness of prescription drugs by balancing therapeutic benefits against safety risks ex ante,
taking into account the interests ofall potential patients. FDA struck precisely that type of
balance in approving NuvaRing® after reviewing data regarding potential thromboembolic
issues, and in mandating the specific label language it did.
As the FDA has explained, claims demanding the withdrawal ofan FDA-approved
medication (on pain oftort liability), or advocating warnings that conflict with FDA standards,
interfere with the agency's intricate and intensive regulation ofprescription drug labeling, and
interfere with purposes behind the federal regulatory scheme in several ways:
• "State law requirements can undermine safe and effective use." 71 Fed. Reg.
3922,3935.
• "State law attempts to impose additional warnings can lead to labeling that does
not accurately portray a product's risks, thereby potentially discouraging safe and
effective use of approved products or encouraging inappropriate use and
undermining the objections ofthe [FDCA]." Id
• "State law actions ... threaten FDA's statutorily prescribed role as the expert
Federal agency responsible for evaluating and regulating drugs." Id
• "State actions are not characterized by centralized expert evaluation ofdrug
regulatory issues. Instead, they encourage, and in fact require, lay juries to
second-guess the assessment ofbenefits versus risks ofa specific drug to the
general public... That individualized reevaluation ofthe benefits and risks ofa
product can result in relief- including the threat ofsignificant damages awards or
penalties - that creates pressure on manufacturers to attempt to add warnings that
the FDA has neither approved nor found to be scientifically required." Id
This sort ofinterference too triggers implied preemption principles. In Longs v. Wyeth,
536 F. Supp. 2d 843, 847 (N.D. Ohio 2008), for example, the court concluded that implied
preemption barred plaintiff's product liability contention that the FDA should not have approved
prescription diet drug, because the drug was defectively designed. The court concluded that such
a claim "directly conflicts with the FDA's authority to determine which drugs are sufficiently
- 21 -
safe and effective to be marketed." ld The court noted "although plaintiff asserts that she
alleges only that [Wyeth] should not have marketed Redux, and that she does not argue that the
FDA did anything wrong, the court finds that her claim that Redux should never have been
placed on the market interferes with the FDA's objectives." ld
As in Longs, plaintiffs here likewise contend that the FDA never should have approved
NuvaRing®, and that it should not be sold to patients because third generation oral
contraceptives are unsafe. But a jury cannot reach this conclusion without fundamentally
interfering with the regulatory scheme established by Congress, and its delegation ofexclusive
authority to the FDA to decide which drugs are sufficiently safe and effective to be sold. This
unquestionable interference with federal objectives requires dismissal on preemption grounds.
B. Plaintiffs Cannot Avoid Preemption By Arguing Defendants Misled The FDA,
Because Such Claims Also Are Preempted
Apparently anticipating this preemption motion, some plaintiffs have sought to avoid it
by alleging that defendants misled the FDA in securing and maintaining approval for the
NuvaRing® NDA.14 Confronting similar allegations (brought directly as claims for "fraud on
the FDA"), the Supreme Court concluded such claims are preempted. In Buckman Co. v.
Plaintiffs'Legal Committee, 531 U.S. 341,343 (2001), the plaintiffs contended that the
defendant company ""made fraudulent representations to the [FDA] in the course ofobtaining
approval to market [bone] screws." The plaintiffs further claimed that "[h]ad the representations
14 See Jenn First Amended Complaint, ~ 47 ("Defendants failed to provide proper and full
information as to the safety ofthe NuvaRing to the U.S. Food and Drug Administration, which
regulates the sale ofthe NuvaRing."); Mecca (Blau Brown) Complaint, ~ 25 ("Defendants failed
to provide proper and full information as to the safety ofthe NuvaRing to the U.S. Food and
Drug Administration, which regulates the sale ofthe NuvaRing.").
- 22-
not been made, the FDA would not have approved the devices, and plaintiffs would not have
been injured." Id. The court held "such claims are pre-empted by the Federal Food Drug and
Cosmetic Act." Id (citations omitted).
The Buckman Court noted that the FDCA creates a comprehensive regulatory scheme and
confers upon the FDA power to police the behavior ofregulated entities, including fraud
committed on the agency. Id at 348. The Court thus reasoned that permitting state courts to
adjudicate whether the FDA was defrauded or its rules complied with would "inevitably conflict
with the FDA's responsibility to police fraud consistently with the [FDA's] judgment and
objectives." Id. at 350. Therefore, allowing ajury to determine, under state law, whether a
company withheld material information from FDA would "cause applicants to fear that their
disclosures to the FDA, although deemed appropriate by the Administration, will later be judged
insufficient in state court. Applicants would then have an incentive to submit a deluge of
information that the Agency neither wants nor needs." Id at 351.
Consistent with Buclanan's reasoning, the Third Circuit held that claims alleging that a
manufacturer withheld or manipulated data presented to the FDA "border on" claims for fraud on
the FDA and "should be brought before the FDA." Colacicco, 521 F.3d at 272; see also Garcia
v. Wyeth-Ayerst Labs., 385 F.3d 961 (6th Cir. 2004) (holding that federal law preempts any effort
to assess fraud on the FDA except where the FDA itselfhas found such fraud); O'Neal, 551 F.
Supp. 2d at 996 (same); In Re Aredia and Zometa Products Liability Litigation, 2008 WL
913087 (M.D. Tenn. April 2, 2008) (implied preemption barred plaintiffs effort to prove up
"fraud on the FDA" exception to Michigan's FDA regulatory compliance defense). Further, the
FDA's continued monitoring of a particular risk and approval of a drug after all ofthe allegedly
"withheld" or "manipulated" information is before the agency, lays to rest any claim that an
- 23 -
earlier or more prominent presentation ofthe information would have made any difference in
FDA rejection ofthe need for a warning. Colacicco, 521 F.3d at 273-274.15
V CONCLUSION
NuvaRing® received regulatory approval after the FDA's expert evaluation, conducted
with an acknowledged awareness ofthe alleged risks plaintiffs raise as the basis for their tort
claims. It is difficult to imagine a more direct conflict with the FDA's regulatory authority than
tort claims that would contravene the very efficacy and labeling decisions FDA has made
principle ofimplied preemption are intended to foreclose that result. Defendants therefore
respectfully request that the Court dismiss, with prejudice, each and every claim for failure to
warn; strict liability design defect; fraud and misrepresentation; breach of express and implied
warranty; manufacturing defect; and violation ofstate consumer protection laws because they are
preempted by federal law.
IS The Supreme Court's decision in Warner-Lambert Co., LLC v. Kent, 128 S. Ct. 1168 (2008)
has no precedential value and thus does not affect the validity of Colacicco or Garcia.
- 24-
DATED: November 4, 2008
Respectfully submitted,
REED SMITH LLP
/s/ Melissa A. Geist
Melissa A. Geist
REED SMITH LLP
Princeton Forrestal Village
136 Main Street
Suite 250
Princeton, NJ 08540
(609) 987 0050
Barbara R. Binis
REED SMITH LLP
2500 One Liberty Place
1650 Market Street
Philadelphia, PA 19103-7301
(215) 851-8100
Sonja S. Weissman
REED SMITH LLP
1999 Harrison Street
Suite 2400
Oakland, CA 94612-3572
(510) 763 2000
Lisa M. Baird
REED SMITH LLP
355 South Grand Avenue
Suite 2900
Los Angeles, CA 90071
(213) 457-8000
Counsellor Defendants Organon USA, Inc.,
Organon Pharmaceuticals USA, Inc. LLC (f/k/a
Organon Pharmaceuticals USA, Inc.), Organon
International, Inc. andSchering-Plough
Corporation
- 25-
CERTIFICATE OF SERVICE
I hereby certify that on this 4th day ofNovember, 2008, I caused the foregoing to be
presented to the Clerk ofCourt for filing and uploading to the CMlECF system, which will send
notification ofsuch filing to all counsel who registered with the CMlECF system consistent with
the Court's order.
lsi Melissa A. Geist
Melissa A. Geist
- 26-
UNITED STATES DISTRICT COURT
EASTERN DISTRICT OF MISSOURI
(St. Louis)
IN RE NUVARING PRODUCTS LIABILITY : 4:08 MDL 1964 RWS
LITIGATION
ALL CASES
Honorable Rodney W. Sippel
ATTACHMENT
SEPARATE STATEMENT OF UNCONTROVERTED MATERIAL FACTS IN
SUPPORT OF MEMORANDUM OF LAW IN SUPPORT OF DEFENDANTS'
MOTION FOR SUMMARY JUDGMENT BASED ON THE DEFENSE OF FEDERAL
PREEMPTION
STATEMENT OF UNCONTROVERTED MATERIAL FACTS
PER LOCAL RULE 7-4.01(E)
1. Organon submitted the NuvaRing® NDA (No. 21-187) on December 28, 1999.
• Declaration ofTitia M. T. Mulders ("Mulders DecL '" ExhibitA (transmittal letter
dated Dec. 28, 1999 submitting NuvaRing® NDA, application No. 21-187, to the
FDA).
2. In it, Organon provided the results of"two large Phase 3 studies" (Study 068003 and
Study 034219) regarding the "contraceptive efficacy, vaginal bleeding patters, and safety ofthe
NuvaRing regimen", as well as other studies including those comparing NuvaRing® with
second-generation oral contraceptives and thromboembolic events reported during the studies.
These studies provided information on contraceptive efficacy and cycle control, risk ofserious
adverse events including VTE, lipid and carbohydrate metabolism, coagulation and fibrinolysis
(the body's clotting and clot dissolving mechanism), and pharmacokinetic effects with
NuvaRing®.
• Mulders DecL, Exhibit B (description ofstudies in FDA Medical Officer's Review,
NDA 21-187, October 6,2000);
• Mulders DecL, ~ 9.
4. The October 6, 2000 FDA Medical Officer's Review stated: "there is a solid database of
safety information" on NuvaRing®, "[t]he agency goal ofa total ofat least 10,000 evaluable
cycles was easily achieved" (the two large clinical studies alone provided over 23,000 cycles of
safety data), and "there were no major changes ofconcern in the hemostasis [blood clotting]
parameters."
• Mulders DecL, Exhibit Bat 3-4,6 (FDA Medical Officer's Review, NDA 21-187,
October 6, 2000).
5. This FDA Medical Officees Review further stated that the FDA's "primary concern
[was] the increased risk ofVTE associated with combination hormonal contraceptives containing
a third-generation progestin, such as the etonogestrel in NuvaRing®."
• Id. at 2.
6. This FDA's Medical Officer's Review stated the Agency would require a warning about
the increased risk ofVTE associated with combined hormonal contraceptives containing third
generation progestins.
• It!. at 2,6,60.
1.A
7. In November 2000, correspondence from the FDA regarding label language about
epidemiology studies ofthird generation oral contraceptives and VTE risks stated: "There is
evidence ofan association between the following conditions and the use of combination
hormonal contraceptives, although additional confrrmatory studies are needed"; "[m]esenteric
thrombosis"; and "[r]etinal thrombosis" and "[c]ombination hormonal contraceptives may
increase the tendency to develop strokes (blockage or rupture ofblood vessels in the brain) and
angina pectoris (chest pain)."
• Mulders Decl., Exhibit C at NDA-0125666, NDA-0125672 (Organon's Point-byPoint
Responses to FDA Labeling Comments ofNovember 22, 2000 and
NuvaRing® Package Insert with FDA Comments).
8. In December 2000, the FDA directed that the NuvaRing® label "include the text that is
required for all desogestrel-containing DCs regarding an approximate 2-fold increased risk of
VTE with third generation OCs compared with certain second generation Des." The FDA noted
that "[t]he potential increased incidence ofvenous thromboembolism (VTE) associated with
third generation OCs, including those containing desogestrel ... remains [the] major safety
concern. No safety data exists on long-term use (>13) cycles ofNuvaRing®)."
• Mulders Decl., Ex/dbit Eat 5, 2, respectively (December 18, 2000Addendum to
Original Medical Officer's Review).
9. In December 2000, the FDA directed that the NuvaRing® label should include a
statement that "it is unknown whether NuvaRing® is distinct from combination oral
contraceptives" when comparing the risk ofNuvaRing to other combined hormonal
contraceptives.
• Mulders DecL, Exhibit E at 7.
10. The FDA specified that "[t]he Final Printed Label (FPL) should reflect the increased risk
ofvenous thromboembolism (VTE) associated with combination hormonal contraceptives
containing a 'third-generation progestin' such as desogestrel."
• Mulders DecL, Exhibit Eat 7.
11. On October 3,2001, the FDA approved the NuvaRing® NDA.
• Mulders DecL, ExhibitD (FDA's October 3, 2001 Approval Letter andFinal
Printed Labeling);
• Affidavit ofMelissa A. Geist ("Geist Aff.'" Exhibit A at 1 (October 22, 2008 letter
from Blau Bown & Leonard LLC).
2.A
12. Organon incorporated the FDA's ultimate directives regarding label language into the
fmal version ofthe printed label, including the FDA-specified language about studies showing a
two-fold risk, contraindications for women at higher risk for thromboembolism; warnings about
thromboembolism and stroke; and adverse reactions including thromboembolism, stroke, VTE,
and arterial thromboembolism.
• Mulders DecL, Exhibit D.
13. By email dated July 20, 2005, the FDA approved changes to the Contraindications
section of the NuvaRing® label regarding thromboembolism, along with changes to the Patient
Information section regarding the risk ofcigarette smoking and stroke.
• Mulders DecL, Exhibit Fat NDA-0129785, NDA-0129823.
14. The FDA approved changes to the NuvaRing® label, proposed by Organon in March
2007, including changes to the "Warnings" section ofthe physician labeling regarding arterial
thromboembolic events, hypertension and risk of stroke.
• Affidavit ofJune Bray (1lBray Aff. '" ~ 13 & ExhibitA (March 30, 2007 letterfrom
Organon to FDA).
15. The FDA also approved changes to the NuvaRing® patient labeling, including regarding
use ofNuvaRing® prior to surgery because ofthe potential risk of blood clots.
• Id.
16. At no time has the FDA ever found or declared the NuvaRing® label to be out of
conformance with the FDA labeling requirements, and at no time has the FDA ever withdrawn
approval for NuvaRing®.
• Mulders Decl., ~ 25.
3.A