FOR THE DISTRICT OF COLUMBIA ENDO PHARMACEUTICALS …

IN THE UNITED STATES DISTRICT COURTFOR THE DISTRICT OF COLUMBIA

ENDO PHARMACEUTICALS INC.,

Plaintiff,

v.

UNITED STATES FOOD AND DRUG ADMINISTRATION, et al.,

Defendants.Civil Action No. ______________

MEMORANDUM OF POINTS AND AUTHORITIES IN SUPPORT OF PLAINTIFF’S MOTION FOR PRELIMINARY INJUNCTION

Introduction

Plaintiff Endo Pharmaceuticals Inc. (“Endo”) seeks a preliminary injunction requiring the

United States Food and Drug Administration, Commissioner Hamburg, and Secretary Sebelius

(collectively, “FDA”) to fulfill FDA’s mandatory duty under 21 U.S.C. § 355(j)(6) and 21 C.F.R.

§ 314.161(a) to determine by December 31, 2012, whether Endo withdrew from sale for safety

reasons the original non-crush-resistant formulation of its extended-release opioid pain reliever,

Opana® ER (“Original Formulation”), a Schedule II drug, and, until FDA has made that

determination, staying the threatened entry into the market, as early as January 1, 2013, of

generic versions of this opioid, in violation of law that prohibits marketing of generic versions of

a reference listed drug (“RLD”) that has been withdrawn for safety reasons.

Endo has a high probability of success on the merits of its claims. By law, FDA has a

clear obligation to suspend approval of any abbreviated new drug application (“ANDA”) for a

generic version of a drug when the RLD on which that application relies to establish the

generic’s safety or effectiveness has been withdrawn for safety reasons. 21 U.S.C. § 355(j)(6);

Case 1:12-cv-01936-RBW Document 5-1 Filed 11/30/12 of 31

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21 C.F.R. § 314.153(a)(3). That is precisely the situation here, but FDA has failed to make its

mandatory determination as to whether Original Formulation Opana® ER was indeed withdrawn

for safety reasons. As a result, entry into the market of a generic drug that relies on a withdrawn

RLD is imminent.

Opana® ER contains oxymorphone, a Schedule II controlled substance that, by

definition, has “a high potential for abuse” that may lead “to severe psychological or physical

dependence.” 21 U.S.C. § 812(b)(2). Unfortunately, many individuals abused Original

Formulation Opana® ER, most commonly by exploiting its vulnerability to crushing; abusers

would crush and snort the pills. In February 2012, after nearly five years of research,

development, and FDA regulatory meetings and filings, Endo introduced Opana® ER Crush

Resistant Formula (“CRF”). The CRF version of the drug makes crushing extremely difficult

and therefore deters potential misuse or abuse.

On May 31, 2012, Endo provided FDA with written notice that Endo had withdrawn

Original Formulation Opana® ER for safety reasons, an action which Endo has supported with

substantial evidence demonstrating the risk of abuse or misuse of the non-crush-resistant version

of the drug. The filing of that notice triggered FDA’s legal obligation to make a determination as

to whether Original Formulation Opana® ER had been withdrawn for reasons of safety because

generic versions of that drug had previously been approved. 21 C.F.R. § 314.161(a). In

December 2010, FDA approved applications from two manufacturers to market generic versions

of non-crush-resistant Original Formulation Opana® ER. Those applications cited the

withdrawn Original Formulation as the RLD. One of those manufacturers, Impax Laboratories,

Inc. (“Impax”), is due to launch the generic version of the drug on January 1, 2013.


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FDA has violated its explicit legal duty to determine in a timely manner whether Original

Formulation Opana® ER was withdrawn for safety reasons, in violation of the Food, Drug and

Cosmetic Act (“FDCA”), 21 U.S.C. § 355(j)(6); FDA’s regulations, 21 C.F.R. § 314.161(a); and

the Administrative Procedure Act (“APA”), 5 U.S.C. 551, et seq., by unlawfully withholding or

unreasonably delaying this mandatory determination.

Equitable considerations strongly support issuance of a preliminary injunction in this

case. Unless the Court intervenes and issues an injunction to preserve the status quo, on January

1, 2013, a generic version of the Original Formulation drug will be released. If this occurs, Endo

will suffer immediate and irreparable injury, including economic harm and harm to its

reputation. Further, and most significantly, the public interest will be substantially and

irreparably injured by release of generic versions of a drug which rely upon a drug that was

withdrawn for safety reasons and that is subject to abuse and misuse that FDA acknowledges and

against which it has long fought.

The scale of opioid prescription drug sales and the related potential for opioid

prescription drug abuse are staggering. More than a quarter billion opioid prescriptions are filled

annually in the United States and, of those, more than 20 million are for extended-release opioids

like Opana® ER.1 FDA has long acknowledged the problem of misuse and abuse of prescription

pain relief drugs, particularly opioids. In less than a decade, the number of deaths associated

with overdoses from prescription pain killers nearly quadrupled. See infra note 6. In response to

this problem, more than six years ago, Congress directed FDA to ensure that health care

1 See Laura Governale, Drug Utilization Data Analysis Team Leader, Division of Epidemiology, Office of Surveillance and Epidemiology, FDA, Outpatient Prescription Opioid Utilization in the U.S., Years 2000-2009, July 22, 2010, at 12, http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndLifeSupportDrugsAdvisoryCommittee/UCM220950.pdf.


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providers understand “the abuse-resistant qualities of safer drugs.”2 In 2010, FDA convened an

Advisory Committee to address the abuse of opioid pain relievers and pressed pharmaceutical

companies to develop “novel interventions” to curb opioid abuse.3

Unless the Court intervenes and issues a preliminary injunction, there is a significant risk

that a readily crushable, and thus admittedly less safe, opioid drug will serve as the RLD for

generic drugs that will then be subject to abuse and misuse. FDA inaction will have facilitated

precisely the type of harm to the public interest against which it has fought for many years. To

avoid this risk, which is attributable to FDA’s failure to comply with its clear legal obligation to

determine whether Original Formulation Opana® ER was withdrawn for safety reasons, this

Court needs to intervene.

The Court should grant Endo’s motion for a preliminary injunction and order FDA to

promptly (no later than December 31, 2012) make the required determination as to whether

Opana® ER was withdrawn for safety reasons. The Court should further order that non-crush-

resistant generic versions of the Original Formulation drug shall be prohibited from entering the

market before FDA has made the legally required withdrawn-for-safety determination.

STATEMENT OF FACTS

A. The Abuse Risks of Original Formulation Opana® ER

Endo introduced Original Formulation Opana® ER, an FDA approved extended-release

pain reliever containing oxymorphone HCl (a semi-synthetic opioid analgesic), in July 2006. The

2 H.R. Rep. No. 109-102 (2006), http://thomas.loc.gov/cgi-bin/cpquery/?&sid=cp109susc7&r_n=hr102.109&dbname=cp109&sel=DOC&.

3 Bob A. Rappaport, Director, Division of Anesthesia and Analgesia Products, Office of Drug Evaluation II, Center for Drug Evaluation and Research, FDA, Memorandum to the Anesthetic and Life Support Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, in advance of the joint committee meeting held on April 22, 2010, at 1 (March 26, 2010), http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndLifeSupportDrugsAdvisoryCommittee/UCM209141.pdf.


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drug was initially available in 5 mg, 10 mg, 20 mg, and 40 mg strengths and, in February 2008

Endo received approval for 7.5mg, 15mg, and 30mg strengths. FDA approved Original

Formulation Opana® ER for prescription use for the relief of moderate to severe pain in patients

requiring continuous around-the-clock opioid treatment for an extended period of time. See

Declaration of Frank Casty (“Casty Dec.”), ¶ 5, attached as Exhibit 1. Original Formulation

Opana® ER was safe and effective when used according to the indications on its label; however,

Original Formulation Opana® ER, like other extended-release opioid-based pain relievers,

proved to be subject to abuse and, sadly, attractive to abusers. Id., ¶¶ 6, 9. The National

Addictions Vigilance Intervention and Prevention Program (“NAVIPPRO”), an entity that

collects data on drug abuse reporting at substance abuse centers, reported that more than 75% of

abusers of Original Formulation Opana® ER chose to crush and snort the drug.4 Declaration of

Mark Collins (“Collins Dec.”), ¶ 6, attached as Exhibit 2.

The drug also posed the potential for misuse by caregivers who might crush pills for

insertion into feeding tubes, or by children who might chew the pills. Crushing and/or chewing

extended-release opioids is particularly risky because manipulating the drug may cause the active

ingredient to rapidly release (rather than release over an extended period of time, as intended).

This rapid-release effect, sometimes called “dose dumping,” may cause an overdose. See Casty

Dec., ¶ 10. Snorting these drugs also adds an additional element of danger because, when

inhaled, a much larger percentage of the active ingredient enters the body. Thus, crushing and

snorting the drug is significantly more dangerous than taking the whole pill orally. See id.

4 NAVIPPRO is a national program that includes surveillance of substance abuse as well as prevention and intervention educational programs for substance abuse. NAVIPPRO surveillance involves analyses of multiple data sources for indicators of prescription medication abuse. Continuous examination of these data streams allows monitoring of trends over time for drug abuse at a product-specific level.


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Over the last decade, the misuse and illicit abuse of extended-release prescription opioids

such as Original Formulation Opana® ER and OxyContin®5 have resulted in a serious public

health crisis of addiction, overdose, and death. Indeed, the number of deaths associated with

overdoses from prescription pain killers nearly quadrupled from 1999 to 2008.6 This prompted

the Centers for Disease Control and Prevention (“CDC”) to characterize the abuse of opioid pain

relievers as “a growing, deadly epidemic.”7

FDA, the federal agency responsible “for protecting the public health by assuring the

safety, efficacy and security” of drugs, and “for advancing the public health by helping to speed

innovations” that make medicines safer,8 has taken a series of actions aimed at curbing abuse and

misuse of extended-release opioids such as Opana® ER. In 2009, for example, FDA worked

with stakeholders to develop a class-wide Risk Evaluation and Mitigation Strategy (“REMS”) for

all extended-release opioid medications. According to FDA: “The REMS is part of a multi-

agency Federal effort to address the growing problem of prescription drug abuse and misuse

[and] introduces new safety measures to reduce risks and improve safe use of ER/LA [extended-

release/long acting] opioids while continuing to provide access to these medications for patients

in pain.”9

5 OxyContin®, a market leader of Schedule II opioid pain relief drugs, has six-fold the market share (by prescription volume) of Opana® ER. Collins Dec., ¶ 9.

6 See Centers for Disease Control and Prevention. Prescription Painkiller Overdoses in the U.S., Vital Signs, Nov. 2011, at 2, http://www.cdc.gov/VitalSigns/pdf/2011-11-vitalsigns.pdf.

7 CDC, Policy Impact: Prescription Painkiller Overdoses, http://www.cdc.gov/homeandrecreationalsafety/rxbrief/.

8 FDA, What We Do, http://www.fda.gov/aboutfda/whatwedo/default.htm.

9 “On July 9, 2012, FDA approved the class-wide REMS.” FDA, Risk Evaluation and Mitigation Strategy (REMS) for Extended-Release and Long-Acting Opioids, Drugs, http://www.fda.gov/drugs/drugsafety/informationbydrugclass/ucm163647.htm.


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In April 2010, FDA convened a meeting of its Anesthetic and Life Support Drugs

Advisory Committee and its Drug Safety and Risk Management Advisory Committee, to address

the abuse of prescription opioid pain relievers. At that time, i.e., more than two-and-a-half years

ago, FDA stated that it was seeking “novel interventions” to prevent opioid abuse, “while

maintaining the availability of these important drug products for the millions of patients in this

country who suffer from chronic pain.”10

B. Endo’s Responsible Effort to Address the Abuse Risks of Original FormulationOpana® ER While Preserving an Important Pain Relief Medication – Development of Opana® ER CRF

Recognizing the abuse risks of the Original Formulation Opana® ER, Endo sought to

reformulate the drug to strengthen its safety profile by making it less susceptible to tampering.

Declaration of Tara Chapman, ¶ 4, attached as Exhibit 3. To that end, Endo entered into a

product development agreement with a German company, Grunenthal GmbH, in December

2007. Id. In May 2009, before Endo filed an Investigational New Drug (“IND”) Application for

Opana® ER CRF, Endo met with FDA to discuss Endo’s goals of reformulating the drug.11

Endo’s goals included developing a formulation that would better protect against medical errors

by caregivers and potentially fatal accidental ingestions by children and that would thwart

potential abusers’ attempts to defeat Opana® ER’s controlled-release mechanisms. Id. FDA had

not previously provided any guidelines or criteria to gauge or quantify crush resistance and, at

10 Bob A. Rappaport, Director, Division of Anesthesia and Analgesia Products, Office of Drug Evaluation II, Center for Drug Evaluation and Research, FDA, Memorandum to the Anesthetic and Life Support Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, in advance of the joint committee meeting held on April 22, 2010, at 1 (March 26, 2010), http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndLifeSupportDrugsAdvisoryCommittee/UCM209141.pdf.

11 Before the meeting, Endo provided FDA with voluminous “Pre-IND Meeting Background/Briefing Materials,” which included data on the safety benefits of Opana® ER CRF. See Chapman Dec., ¶ 5


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the May 2009 meeting, FDA acknowledged that even an incremental improvement over the non-

crush-resistant formulation could be beneficial. Id.

On July 7, 2010, Endo submitted New Drug Application (“NDA”) No. 201655 to FDA

for Opana® ER CRF, seeking a priority review of the application. In the cover letter that

accompanied its submission, Endo stated:

As a pharmaceutical company with a focus on pain management, Endo Pharmaceuticals Inc. strives to improve the treatment of pain in patients while at the same time safeguarding against potential misuse, abuse, overdose, and addiction associated with use of its products. Improving pain management includes the development of new effective analgesics and also supporting the proper and appropriate use of its medication.

R. Barto, Letter to B. Rappaport (July 7, 2010), attached as Exhibit A to Chapman Dec. Endo

advised FDA that Opana® ER CRF was designed to “reduce accidental misuse (ie, breaking,

and/or crushing for patient convenience) and to deter certain methods of intended abuse (ie,

crushing for snorting and/or injection).” Id. Opana® ER CRF is bioequivalent12 to the Original

Formulation, but the CRF version embeds the active ingredient, oxymorphone, in a polyethylene

oxide matrix that makes the pill much harder than the Original Formulation. Thus, the CRF

version is resistant to crushing (and is also difficult to manipulate into a soluble form that could

be easily drawn up in a syringe and subsequently injected). See Collins Dec., ¶¶ 7-8.

C. When Manufacturers Produce Crush-Resistant Opioid Products, Abusers Move to Non-Crush Resistant Alternatives – the “Squeezing-the-Balloon Effect”.

Later in the summer of 2010, before FDA approved Endo’s NDA for Opana® ER CRF,

and thus before Endo could produce and market Opana® ER CRF, Purdue Pharma L.P. launched

12 21 C.F.R. § 320.1 defines “bioequivalence” as

the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.


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a crush-resistant formulation of OxyContin® and discontinued its non-crush-resistant

formulation of the drug. See Chapman Dec., ¶ 6. FDA acknowledged that the crush-resistant-

formulation of OxyContin® made it “more difficult for people to defeat the controlled-release

properties of the drug by cutting or crushing the tablets,” which was, according to FDA, “a step

in the right direction.”13

When non-crush-resistant OxyContin® became increasingly difficult to procure, abusers

turned to other opioid drugs that were easier to crush, including Original Formulation Opana®

ER. This phenomenon is called the “squeezing-the-balloon effect.” Collins Dec., ¶ 9. In May

2011, the Drug Enforcement Administration commented that misusers and abusers were

“reportedly switching from Oxycontin to Oxymorphone [e.g., Opana® ER] for ease of use

(crushable).”14 As Endo described to FDA in an August 13, 2012 Citizen Petition, abuse of

Original Formulation Opana® ER had increased approximately 140% after the introduction of

abuse-deterrent OxyContin®.15 See August 13, 2012 Citizen Petition at 7, attached to Chapman

Dec. as Exhibit C. The following charts illustrate this effect:

13 FDA Patient Safety News, New Formulation for OxyContin, Show No. 99, http://www.accessdata.fda.gov/psn/transcript.cfm?show=99.

14 Drug Enforcement Agency, Philadelphia Division Intelligence Program, Drug Intelligence Brief: Opana (Oxymorphone) Abuse, May 2011, http://www.docstoc.com/docs/83651887/DRUG-INTELLIGENCE-BRIEF.

15 The reformulation of OxyContin® was the subject of an extensive FDA Advisory Committee review and hearings. In 2008, FDA stated that “Availability of a ER oxycodone product with reduced abuse liability is desirable.” History of OxyContin: Labeling and Risk Management Program, Anjelina Pokrovnichka, M.D., FDA Medical Officer Division of Anesthesia, Analgesia, and Rheumatology Products Office of Drug Evaluation II (November 2008),http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndLifeSupportDrugsAdvisoryCommittee/UCM248776.pdf.

On July 13, 2012, Purdue filed a Citizen Petition asking FDA to, inter alia, announce guidance detailing the in vitro and in vivo tests that must be performed to demonstrate that generic forms of OxyContin® “can be expected to perform as well as reformulated OxyContin when subjected to known and anticipated forms of tampering.” Citizen Petition No. FDA-2012-P-0760 (July 13, 2012), resubmitted as Citizen Petition No. FDA-2012-P-0939 (August 18, 2012).


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Reports of abuse of OxyContin®16 v. Reports of abuse of Opana® ER17

The data demonstrate that, after crush-resistant OxyContin®--referred to in the charts

above as “ORF” – was introduced in the third quarter of 2010, abuse of OxyContin® decreased

significantly (as demonstrated by several measures in the first graph), while abuse of non-crush-

resistant Original Formulation Opana® ER spiked in that time frame. This spike is demonstrated

in the second graph by the change in the average rate of abuse of Original Formulation Opana®

ER before introduction by Purdue of its tamper-resistant formulation of OxyContin® (“ORF”),

represented by the first dashed horizontal line, to the rate of abuse after ORF introduction,

represented by the second dashed horizontal line. The second graph also shows the steep drop

(44%) in abuse of Opana® ER that occurred after Endo introduced its crush-resistant-

formulation in the first quarter of 2012.

16 This chart incorporates data collected by Researched Abuse, Diversion and Addiction-Related Surveillance system (“RADARS”) from Drug Diversion and Poison Centers, from NAVIPPRO from substance abuse treatment centers, and from NPDS Poison Centers (Source: Purdue Pharma). See Collins Dec., ¶ 9.

17 This chart incorporates RADARS data on the intentional exposure rates per 100,000 population by year/quarter for Opana® ER in the Poison Control Center program. See Id.


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D. The Approval and Introduction of the CRF Product; Endo’s Notification of Withdrawal of Original Formulation; and Endo’s Persistent Requests to FDA to Make the Required “Withdrawn-for-Safety” Determination

Endo received FDA approval to market the reformulated version of Opana® ER on

December 9, 2011. Chapman Dec., ¶ 7. Shortly thereafter, in February 2012, Endo stopped

manufacturing Original Formulation Opana® ER after the plant that produced the pills (run by

Novartis AG) encountered production problems. Id.18 Endo did not recall the Original

Formulation Opana® ER that already had been produced because of its concerns (which were

shared by FDA) that an abrupt recall would cause a shortage and place patients who had been

legitimately prescribed the drug at risk of severe withdrawal symptoms and/or other negative

consequences associated with switching to another drug, such as side effects and

underdosing/overdosing. Id., ¶ 8. Accordingly, Endo coordinated with FDA to allow the

existing supply of Original Formulation Opana® ER to be drawn down while Endo undertook an

accelerated effort to quickly bring the crush-resistant-formulation to market. Id. Endo began

shipping Opana® ER CRF in February 2012. Id.

On May 31, 2012, Endo wrote to FDA, providing notice that Endo had discontinued

marketing Original Formulation Opana® ER (NDA 21-610). Endo stated:

While the original formulation of OPANA ER (under NDA 21-610) was deemed by the FDA to be safe and effective when taken according to the prescribing information, the original formulation was subject to both intentional and inadvertent abuse and misuse. Endo believes that the new formulation of OPANA ER (under NDA 201655), which is designed to be crush resistant, offers safety advantages over the original formulation (NDA 21-610) and that the original formulation (under NDA 21-610) should be discontinued for safety reasons.

18 The last batch of Original Formulation Opana® ER was released in March 2012. Chapman Dec., ¶7. Previously, in March 2011, Endo had made a business decision to discontinue the sale and distribution of Original Formulation Opana® ER in the 7.5 and 15 mg strengths. These low dosage forms, which were used primarily used for titration purposes (e.g., increasing dosages gradually) were abused less often than the higher strength dosages. Id., ¶ 9.


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May 31, 2012 e-mail from Tara Chapman of Endo to FDA’s Director of Drug Information (a

copy of which is attached to the Chapman Dec. as Exhibit B) (emphasis added).

On or about June 14, 2012, FDA moved the Original Formulation of Opana® ER to the

discontinued drugs list. Also on June 14, 2012, FDA acknowledged separately that “the status

quo is not acceptable” and stated: “[W]e must stem this tide of misuse, abuse, and death before it

imperils future access to essential therapies for pain.”19 Notwithstanding this unequivocal

statement, FDA did not then issue, nor has it since issued, the determination it is statutorily

required to make – i.e., whether Original Formulation Opana® ER was withdrawn for safety

reasons. See 21 U.S.C. § 355(j)(6) (requiring FDA, on its own initiative, to withdraw or suspend

approval of any ANDA with an RLD that “has been withdrawn from sale for safety . . .

reasons”); 21 C.F.R. §§ 314.153(a)(3), 314.161(a) (requiring FDA to make a safety

determination before approving any ANDA that refers to the listed drug or whenever an ANDA

referring to the withdrawn drug is withdrawn from sale).

Because Endo knew that Impax would be coming to market on January 1, 2013 with a

generic, which relies on the Original Formulation as its RLD, Endo did not stop with its May

2012 notice of withdrawal. In a blunt effort to prod FDA into action and to draw attention to the

need for a timely withdrawn-for-safety determination (meaning before December 31, 2012),

Endo filed in August a Citizen Petition under FDCA §§ 505(j) and 505(q), and 21 C.F.R. §§

10.30 and 314.161 (“August 13 Citizen Petition,” a copy of which is attached to the Chapman

Dec. as Exhibit C). In its Citizen Petition, Endo requested that FDA:

19 Douglas C. Throckmorton, Deputy Director, Center for Drug Evaluation and Research, FDA, FDA and Opioids: What’s a Regulator to Do?, June 14, 2012, at 24, http://www.fda.gov/downloads/AboutFDA/Centers Offices/CDER/ UCM309381.pdf.


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1. Determine that the discontinued, non-crush-resistant version of Opana® ER approved under NDA 021610 was discontinued for reasons of safety and can no longer serve as an RLD for an ANDA applicant;

2. Refuse to approve any pending ANDA for a generic version of the non-crush-resistant version of Opana® ER approved under NDA No. 02160; and

3. Suspend and withdraw the approval of any ANDA referencing Opana® ER approved under NDA No. 021610 as the RLD.

August 13 Citizen Petition at 1 (emphasis added).

Endo’s petition reiterated information it had submitted to FDA through its 2010 NDA,

e.g., Opana® ER CRF provides resistance to crushing, which could be expected to deter abuse

by recreational and experienced abusers, misuse by patients or other healthcare providers who

attempt to crush tablets to facilitate swallowing or gastric tube administration, and chewing (and

attendant potentially fatal “dose dumping”) by children. Id. at 4-5; Casty Dec., ¶¶ 7, 8, 16, and

18. Endo reminded FDA that it expected Impax to come to market with a non-crush-resistant

generic formulation of Opana® ER (in all strengths) as early as January 1, 2013, and explained

that permitting the generic non-crush-resistant form of the drug to enter the market “would allow

abuse or diversion to continue, limiting the potential benefits that can be provided by Opana®

ER CRF.” August 13 Citizen Petition at 8.20

Hearing nothing in response from FDA, on August 31, 2012, Endo filed a second Citizen

Petition (the “August 31 Citizen Petition,” a copy of which is attached to the Chapman Dec. as

Exhibit D). The August 31 Petition requested that FDA: (1) require any ANDA referencing

Opana® ER CRF to demonstrate that the proposed product is similarly crush-resistant to

Opana® ER CRF; (2) classify crush-resistant extended-release opioids, such as Opana® ER

CRF, as a new dosage form; and (3) confirm that any ANDA referencing the Original

20 Under a patent license agreement with Endo, the earliest time by which Impax could come to market with its non-crush-resistant formulation is January 1, 2013.


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Formulation of Opana® ER will not be identified as therapeutically equivalent to Opana® ER

CRF. See August 31 Citizen Petition at 1-2. As with its first Petition, Endo also received no

response from FDA.

Endo’s August 31 Petition again stated Endo’s rationale for discontinuing the Original

Formulation of Opana® ER, i.e., for safety reasons, and provided additional information (again,

derived from the data that Endo had submitted to FDA in support of its NDA for Opana® ER

CRF) demonstrating that Opana® ER CRF is more resistant to crushing, and thus less attractive

to abusers who administer drugs by snorting. Id. at 6-7. The data showed that, whereas 96% of

research subjects were willing to snort the Original Formulation (which could be crushed into a

powder), only 11% of subjects were willing to attempt to snort the larger pieces of tablets that

were produced when they attempted to crush Opana® ER CRF. Id. at 7-8; see also id. at 9-15;

Casty Dec., ¶ 16. Thus, Endo submitted that, although the two formulations are bioequivalent,

they do not have the same safety profile and, accordingly, should not be considered

therapeutically equivalent. Id. at 24-25, citing Approved Drug Products with Therapeutic

Equivalence Evaluations (“Orange Book”) Preface at viii.

On November 13, 2012, Endo submitted a Supplement to its August 13 Citizen Petition

(the “Supplement,” a copy of which is attached to the Chapman Dec. as Exhibit E). In the

Supplement, Endo provided surveillance data, gathered after the February 2012 introduction of

Opana® ER CRF, which demonstrated that the introduction of Opana® ER CRF has

significantly reduced the abuse and misuse of the drug. Specifically, six months’ worth of data

collected by NAVIPPRO after the introduction of Opana® CRF demonstrated a 59% reduction

in abuse from a baseline level of Original Formulation Opana® ER. Data from RADARS

showed that, after Endo introduced the crush-resistant formulation, reports of abuse and


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diversion of Opana® ER in poison control centers and diversion programs dropped by 44% and

58%, respectively. See Casty Dec., ¶ 18; Collins Dec., ¶ 10. Thus, Endo submitted, the data

“indicates that the reformulated Opana® ER is having the desired effect on the rates and routes

of abuse of the product.” See November 13 Supplement at 1.

Endo again stressed the need for FDA to make a safety determination before Impax

launches its generic version of Original Formulation Opana® ER on or about January 1, 2013:

“Because of the urgency of the matter and the significant impact on public health, FDA must not

delay any further in issuing its determination that the original formulation Opana ER was

withdrawn from sale for safety reasons.” Id. (emphasis added). Based on Endo’s own recent

experience with Opana® ER CRF and its 2010 experience with a spike in the misuse of Original

Formulation Opana® ER when Purdue introduced a tamper-resistant form of OxyContin®, Endo

posited with considerable confidence that introduction of non-crush-resistant generic versions of

Opana® ER “will result in increases in drug abuse, misuse and diversion. Serious and

predictable public health harm would flow from the entry and continued sale of additional non-

tamper-resistant versions of Opana ER.” Id. at 2. Put differently, the “squeezing-the-balloon

effect” can be expected to begin soon after Impax’s January 1, 2013, launch with predictable,

devastating consequences for opioid misusers and abusers. Thus, Endo again urged FDA to act

immediately, i.e., make a determination as to whether Original Formulation Opana® ER was

withdrawn for safety reasons and can no longer serve as a RLD for any ANDA applicants. See

id. at 2.

Notwithstanding (a) Endo’s notice of withdrawal, (b) follow-on Petitions and

Supplement, (c) Impax’s imminent market entry, and (d) the clear mandate of 21 C.F.R. §

314.161(a) requiring FDA to determine whether Endo discontinued Original Formulation


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Opana® ER for reasons of safety, FDA has failed to act. Out of options and out of time, Endo

brings this action and the present motion for preliminary injunctive relief.

ARGUMENT

Endo has a strong likelihood of success on the merits of its claims that FDA has violated

the law. FDA’s legal duty is clear. FDA is required to make a determination as to whether

Original Formulation Opana® ER was voluntarily withdrawn by Endo for safety reasons. 21

C.F.R. § 314.161(a)(2). FDA has breached this clear duty by failing to make such a

determination in a timely manner. Further, the equitable considerations involved here strongly

support the issuance of preliminary injunctive relief. This Court should order FDA to determine

expeditiously and, in any event, by December 31, 2012, whether Original Formulation Opana®

ER was withdrawn for safety reasons. The Court should further order that, until that

determination is made, FDA must maintain the status quo by suspending approval of any

ANDAs that refer to Original Formulation Opana® ER.

FDA’s unlawful inaction seriously undermines longstanding efforts to curb the national

health epidemic of opioid abuse and misuse, which ruins lives, costs Americans billions of

dollars, and accounts for thousands of deaths a year. In the absence of preliminary injunctive

relief, it is a virtual certainty that generic versions of Original Formulation Opana® ER will

come to market beginning January 1, 2013. Those generic drugs rely upon the withdrawn

Original Formulation to ostensibly establish their safety. Before Americans are exposed to the

risks of a non-crush-resistant generic version of Original Formulation Opana® ER, FDA should

determine, as it is required to do, whether the Original Formulation was withdrawn for safety

reasons. And, pending FDA’s determination, FDA should be ordered not to allow generics on

the market which rely upon the Original Formulation as their RLD.


17

I. Preliminary Injunction Standard.

“A plaintiff seeking a preliminary injunction must establish [1] that he is likely to

succeed on the merits, [2] that he is likely to suffer irreparable harm in the absence of

preliminary relief, [3] that the balance of equities tips in his favor, and [4] that an injunction is in

the public interest.” Sanofi-Aventis U.S. LLC v. FDA, 733 F. Supp. 2d 162, 167 (D.D.C. 2010);

CollaGenex Pharms, Inc. v. Thompson, 2003 U.S. Dist. LEXIS 12523, *36 (D.D.C. 2003).21

These four factors are evaluated on a sliding scale and are balanced against each other. See

Serono Labs., Inc. v. Shalala, 158 F.3d 1313, 1318 (D.C. Cir. 1998); Leitner v. United States,

679 F. Supp. 2d 37, 41 (D.D.C. 2010); Merriweather v. Lappin, 680 F. Supp. 2d 142, 143

(D.D.C. 2010).22 In other words, if the arguments for one factor are particularly strong, as is the

case here with respect to the public interest factor, in particular, an injunction may issue even if

the district court considers arguments in other areas to be weaker. CSX Transp., Inc. v. Williams,

406 F.3d 667, 670 (D.C. Cir. 2005). Here, although each of the four factors weighs heavily in

favor of preliminary injunctive relief, Endo makes an especially compelling public interest

21 Where, as here, the agency has not acted or has not explained its action, and the plaintiff is able to make a strong showing on the other three preliminary injunction prongs, a colorable claim (rather than likely success on the merits) constitutes a sufficient showing of likelihood of success. This Court has defined “colorable,” to mean a “claim that is legitimate and that may reasonably be asserted given the facts presented and the current law.” CollaGenex Pharms, Inc. v. Thompson, 2003 U.S. Dist. LEXIS 12523, *23 (citing Black’s Law Dictionary 240 (7th ed. 1999)); see also Cuomo v. United States Nuclear Regulatory Comm’n , 772 F.2d 972, 974 (D.C. Cir. 1985). Although Endo satisfies the “likely to prevail” standard, because Endo makes a strong showing on the other three preliminary injunction prongs, it need only show that it has a colorable claim to satisfy the rule set forth in CollaGenex.

22 The Supreme Court’s 2008 decision, Winter v. Natural Def. Council, 129 S. Ct. 365, 375 (2008), has raised questions whether the sliding scale approach still applies. See Davis v. Pension Ben. Guar. Corp., 571 F.3d 1288, 1292 (D.C. Cir. 2009) (“the analysis in Winter could be read to create a more demanding burden, although the decision does not squarely discuss whether the four factors are to be balanced on a sliding scale.”); but see, e.g.,Tyndale House Publishers, Inc. v. Sebelius, 2012 U.S. Dist. LEXIS 163965, 12 (D.D.C. Nov. 16, 2012) (“The District of Columbia Circuit has applied a ‘sliding scale’ approach in evaluating the preliminary injunction factors.”).

No decision by the D.C. Circuit has explicitly overturned the long standing four-part sliding scale test. In any event, because all four factors weigh strongly in favor of Endo, preliminary relief is warranted under either standard.


18

showing. Injunctive relief is necessary given: the imminent market entry of a non-crush-resistant

generic version of Original Formulation Opana® ER, the fact that the generic relies upon a

withdrawn drug as its RLD, and the years’ worth of data reflecting the propensity of opioid

abusers to crush and snort non-crush resistant formulations of these powerful drugs. These are

drugs that have “a high potential for abuse” that may lead “to severe psychological or physical

dependence.” 21 U.S.C. § 812(b)(2). Endo’s compelling showing that the injunction requested

would promote the public interest warrants entry of a preliminary injunction.

II. Endo Is Likely To Prevail on the Merits.

A. FDA has Violated its Duties under Governing Statutory Provisions and FDA Regulations.

Endo is highly likely, if not absolutely certain, to prevail on its claim that FDA’s failure

to carry out its non-discretionary duty to make a withdrawn-for-safety determination is unlawful.

The facts are undisputed: FDA has not made the required determination as to whether Endo

withdrew the Original Formulation for safety reasons. The FDCA requires FDA, on its own

initiative, to withdraw or suspend approval of any ANDA that refers to an RLD that “has been

withdrawn from sale for safety . . . reasons.” 21 U.S.C. § 355(j)(6). The duty imposed on FDA

by this provision is mandatory. The statute, in explicit terms, provides that, if the approved

application for a drug refers to a drug that the agency determines “has been withdrawn from sale

for safety or effectiveness reasons,” then the approval of that drug “shall be withdrawn or

suspended” by FDA. Id. (emphasis added).

Consistent with this mandate, FDA’s regulations provide that, whenever a listed drug has

been voluntarily withdrawn from sale, as Endo did here, FDA must determine whether the drug

was withdrawn for safety or effectiveness reasons:


19

(a) A determination whether a listed drug that has been voluntarily withdrawn from sale was withdrawn for safety or effectiveness reasons may be made by the agency at any time after the drug has been voluntarily withdrawn from sale, but must be made: . . . .(2) Whenever a listed drug is voluntarily withdrawn from sale and

abbreviated new drug applications that referred to the listed drug have been approved; . . . .

21 C.F.R. § 314.161(a)(2) (emphasis added). The statute and regulations thus create

unambiguous legal duties requiring FDA to make a determination and, depending upon the

determination, to take further action. FDA has defaulted in all respects. Where, as here, an

agency’s failure to follow its own regulations is prejudicial, that failure constitutes arbitrary and

capricious action in violation of the Administrative Procedure Act. See, e.g., Way of Life

Television Network, Inc. v. FCC, 593 F.2d 1356, 1359-60 (D.C. Cir. 1979).

When Endo provided FDA with Endo’s notice of withdrawal on May 31, 2012, FDA had

approved two ANDAs for generic versions of Original Formulation Opana® ER (filed by Impax

and Actavis South Atlantic LLC). Accordingly, FDA’s duty under § 314.161(a)(2) was

triggered, and that duty was mandatory, not optional. Nevertheless, some six months have

passed since Endo formally notified FDA that it had withdrawn Original Formulation Opana®

ER, and only one month remains until Impax is scheduled to launch a generic version of Original

Formulation Opana® ER. Yet FDA still has not made the required “withdrawn-for-safety”

determination.

FDA cannot reasonably dispute that it is required to make a determination regarding the

reason for Opana® ER’s withdrawal. The only potential point of dispute involves the narrow

issue of timing. When is FDA required to make such a determination? Although the regulatory

and statutory provisions do not establish a deadline, per se, FDA is under an obligation to make

its determination within such period of time as may be reasonable under the circumstances. See


20

Hamandi v. Chertoff, 550 F. Supp .2d 46, 50 (D.D.C. 2008) (where agency has a clear duty, it

must act on that duty within a reasonable amount of time, and the fact that the governing statute

does not specify a timeframe for action is immaterial. “The APA’s requirement of action within

a reasonable time applies.”); In re Barr Labs., Inc., 930 F.2d 72, 74 (D.C. Cir. 1991) (“delays

that might be reasonable in the sphere of economic regulation are less tolerable when human

health and welfare are at stake”). Given the facts of this case, it simply would make no sense to

say that FDA has fulfilled its legal obligations if it fails to make the required “withdrawn-for-

safety” determination before Impax launches its non-crush-resistant generic version of Opana®

ER on January 1, 2013.

Lest there be any doubt, Endo is not asking the Court to make a determination as to

whether Original Formulation Opana® ER was withdrawn for safety reasons. That is a

judgment to be made in the first instance by FDA. For present purposes, Endo simply notes that

there is ample evidence before FDA – evidence which Endo submitted and additional evidence

of which the agency is aware because of its long-standing concerns over prescription drug opioid

abuse – to support a “withdrawn for safety” determination. That evidence includes information

which Endo submitted to FDA in advance of a May 2009 a pre-IND Application meeting with

FDA concerning the development of Opana® ER CRF. Endo submitted substantive “Pre-IND

Meeting Background/Briefing Materials” which provided plans for studies Endo intended to

conduct on the physiochemical properties of Opana® ER CRF that could lead to safety benefits

with the CRF formulation. See Chapman Dec., ¶ 5. In July 2010, Endo filed its NDA for

Opana® ER CRF and presented FDA with a substantial amount of data to demonstrate the

improved safety properties of the new formulation. Id.23

23 As noted, Endo was not the first company to conduct such discussions with FDA. In August 2010, Purdue Pharmaceuticals launched a crush-resistant formulation of OxyContin® and discontinued its non-crush-resistant


21

As FDA recently stated: “[T]he Agency may, in certain circumstances, determine that a

previous drug formulation was withdrawn for reasons of safety following the introduction of a

safer alternative.”24 FDA recognized that “withdrawn for reasons of safety” determinations “are

made on a case-by-case basis and depend on the circumstances of the specific drug product.”25

Here, in a Schedule II narcotic drug circumstance, where Opana® ER CRF plainly is a “safer

alternative” to Original Formulation Opana® ER, Endo firmly believes that the only reasonable

outcome would be for FDA to determine that Original Formulation Opana® ER was withdrawn

for reasons of safety. FDA, however, needs to make this determination.

FDA is required to make the “withdrawn for safety” determination in a timely manner (by

December 31, 2012). Based upon FDA’s record to date, however, there is no reason to believe

that will occur unless the Court orders FDA to do so. Accordingly, the limited relief sought in

this action is an order that FDA do as it is obligated to do. There is a substantial likelihood that

Endo will prevail on that claim. The focus of the requested preliminary injunctive relief is that

FDA be ordered to perform its duty to decide by December 31.

B. FDA’s Determination Has Been Unreasonably Delayed.

This court may compel FDA to act because of the agency’s unreasonable delay. 5 U.S.C.

§ 706(1) (“The reviewing court shall compel agency action unlawfully withheld or unreasonably

delayed.”). Further, agency inaction may constitute “final agency action” that is subject to

judicial review under the APA. See Lauderhill Hous. Auth. v. Donovan, 818 F. Supp. 2d 185,

195 (D.D.C. 2011); Sierra Club v. Thomas, 828 F.2d 783, 793 (D.C. Cir. 1987). Indeed, the

formulation of the drug. This prior experience provided FDA with a good precedent for understanding how Endo’s withdrawal of Opana® ER, in May 2012, and introduction of Opana® ER CRF, in February 2012, would promote public safety. Chapman Dec., ¶ 6.

24 See November 7, 2012 Letter from FDA RE: Docket Nos. FDA-2011-P-0339 and FDA-2012-P-0507, at 5 n.11, http://www.regulations.gov/#!documentDetail;D=FDA-2012-P-0507-0008.

25 See id.


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United States Court of Appeals for the District of Columbia Circuit has identified six principles

to guide judges in this District in determining whether mandamus is an appropriate remedy for

agency delay:

(1) [T]he time agencies take to make decisions must be governed by a “rule of reason”; (2) where Congress has provided a timetable or other indication of the speed with which it expects the agency to proceed in the enabling statute, that statutory scheme may supply content for this rule of reason; (3) delays that might be reasonable in the sphere of economic regulation are less tolerable when human health and welfare are at stake; (4) the court should consider the effect of expediting delayed action on agency activities of a higher or competing priority; (5) the court should also take into account the nature and extent of the interests prejudiced by the delay; and (6) the court need not find any impropriety lurking behind agency lassitude in order to hold that agency action is unreasonably delayed.

In re Barr Labs., Inc., 930 F.2d 72, 74-75 (D.C. Cir. 1991) (emphasis added) (internal quotation

marks omitted) (citing Telecomms. Research. & Action Ctr. v. FCC, 750 F.2d 70, 80 (D.C. Cir.

1984)).

The single most salient and undisputed fact here is the scheduled January 1, 2013

introduction of a non-crushable generic version of Original Formulation Opana® ER. FDA is

aware of this launch date. FDA has long been aware of the leading role that crushable drugs

have played in the public health crisis relating to extended relief opioids. FDA has long

encouraged the development of innovations in drug manufacturing to reduce opioid abuse.

Where, as in this case, a generic has been approved, but is not yet on the market, the agency has

unreasonably delayed when it has not made the required determination prior to the generic’s

introduction to the market.


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In the face of FDA’s prior dealings with drug withdrawals,26 its prior initiatives

concerning opioids, the information in the Opana® ER CRF NDA, Endo’s notice of withdrawal

of Original Formulation Opana® ER, and the information submitted in the two Citizen Petitions

and the Supplement, it is simply unreasonable, and therefore a violation of the FDCA and FDA’s

own rules, for the agency to have delayed this long in making the mandatory determination as to

whether Original Formulation Opana® ER was withdrawn for safety reasons.27

III. Endo Will Suffer Irreparable Harm if the Court Does Not Grant its Motion for Preliminary Injunction and Mandamus Relief.

Although the irreparable harm prong is typically plaintiff-specific, given the unique and

extremely serious circumstances of this case, the substantial irreparable harm to the public in the

absence of preliminary injunctive relief must be emphasized. If a preliminary injunction is not

granted, the introduction on January 1, 2013, of readily crushable generic versions of Original

Formulation Opana® ER will result in increases in drug abuse, misuse, and diversion with a

predictable upsurge in serious injuries and overdose deaths. See supra at 5-10. This harm

cannot and will not be undone, corrected, or remedied even if Endo ultimately prevails on the

26 Making a determination on whether a drug should be withdrawn from the market because of safety concerns relating to the drug’s off-label use is not a question of first-impression for FDA. For example, in July 2005, FDA suspended marketing of Palladone (hydromorphone HC1) Extended-release Capsules due to the "potential for severe side effects" when Palladone is taken with alcohol. See FDA, Public Health Advisory: Suspended Marketing of Palladone (hydromorphone hydrochloride, extended-release capsules) (July 13, 2005),http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm051743.htm.

27 FDA may take the position that this dispute is not ripe because it has yet to make a determination about thereason for Endo’s withdrawal of Original Opana® ER. However, such an argument would fail because at least twogenerics are not awaiting final approval from FDA, and one is scheduled to come to market on January 1. Thus,there plainly is imminent foreseeable harm to Endo. Further, if FDA makes a determination adverse to Endo, finding that the Original Formulation was withdrawn for reasons other than safety, Endo is entitled to challenge that determination by seeking judicial review. For that right to have any meaning, FDA must make its determination –whatever it may be – in advance of January 1 so that Endo has sufficient opportunity to challenge it. FDA should not be allowed to thwart Endo’s right to timely judicial review (thereby making FDA’s determination the truly final and effectively unreviewable determination) by delaying its determination.


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merits of its claims. Preliminary injunctive relief is called for in this case to prevent harm for

which there will be no remedy.

In addition, in the absence of preliminary relief, Endo itself will suffer irreparable harm.

Opana® ER was Endo’s second largest grossing product in 2011, generating $384,339,000 in

revenues. See Endo Pharmaceuticals 2011 Form 10-K at 40.28 If Impax and other generics were

permitted to launch their less-safe generic versions of Original Formulation Opana® ER, prior to

FDA’s making the required safety determination, a significant portion of Endo’s sales of

Opana® would be lost as purchasers will buy the less-expensive generic Opana® product in

spite of (and in some cases because of) its diminished safety properties. Moreover, the owner of

the branded version of a drug typically loses more than half of its market share in the first year

following the entry of generics onto the market. See FDA Says It May Tighten Standards for

Generic Drugs, Bloomberg.com (Oct. 20, 2010) (“By the end of their first year, generics can

capture nearly 60 percent of market share”);29 because, for example, certain third-party payers

for prescription drugs insist upon the use of the less expensive generic drugs instead of the brand

name drugs. See CollaGenex Pharms, Inc. v. Thompson, 2003 U.S. Dist. LEXIS 12523, *33

(D.D.C. 2003) (“[I]nsurers [often] insist on cheaper, generic drugs as soon as they are available

unless a physician can demonstrate a medical need for the pioneer drug.”).

A brand-name drug manufacturer’s unrecoverable loss of sales to a generic and the

resulting harm constitutes irreparable injury sufficient to justify entry of a preliminary injunction.

See Serono Labs., Inc. v. Shalala, 158 F.3d 1313 (D.C. Cir. 1998) (assuming that the plaintiff

28 http://www.sec.gov/Archives/edgar/data/1100962/000119312512089641/d264698d10k.htm

29 http://www.bloomberg.com/news/2010-10-20/fda-says-it-may-tighten-standards-for-generic-drugs-update2-.html; see also IMS Institute for Healthcare Informatics, The Use of Medicines in the United States: Review of 2010, April 2011, at 1, http://www.imshealth.com/deployedfiles/imshealth/Global/Content/IMS%20Institute/Static%20File/IHII_UseOfMed_report.pdf (“Within six months of patent loss, patients received the generic form of the molecule 80% of the time in 2010”).


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would be irreparably injured if FDA were not enjoined from approving an ANDA where the

plaintiff would suffer an unrecoverable loss of sales to the generic manufacturer). Similarly, the

price erosion that is caused by the entry of a generic into the market is typically irreversible and

therefore supports granting a preliminary injunction. See Sanofi-Synthelabo v. Apotex, Inc., 488

F. Supp. 2d 317, 342-44 (S.D.N.Y. 2006) (describing this sequence of events, and holding that

“irreversible price erosion [from introduction of generics] is a legitimate basis for a finding of

irreparable harm”) (rev’d in part on other grounds by Sanofi-Aventis v. Apotex, Inc., 659 F.3d

1171 (Fed. Cir. 2011)); Purdue Pharma L.P. v. Boehringer Ingelheim GmbH, 237 F.3d 1359,

1368 (Fed. Cir. 2001) (“Given the testimony of the likelihood of price erosion and loss of market

position . . . , we see no deficiency in the district court's finding of irreparable harm.”).

In addition to the unrecoverable loss of sales, if an injunction is not granted and the non-

crush-resistant versions of Opana® ER are allowed to come onto the market starting on January

1, 2013, Endo would – in practical effect – suffer unrecoverable losses in terms of the millions of

dollars it invested to bring the safer crush-resistant formulation to market. For example, apart

from the significant time and resources Endo devoted to a tamper-resistant formulation over the

past five years, Endo has paid Grunenthal three $4.9 million milestone payments (one in 2010,

one in 2011, and one in August 2012), $26.9 million in payments based on net sales, and an

additional estimated $65.3 million may become due if future milestones are met. See Endo

Health Solutions Inc., 3d Quarter 2012, Form 10-Q at 22 (Nov. 5, 2012).30

This Court has found irreparable injury sufficient to warrant injunctive relief when the

plaintiff lacks, as Endo does here, an adequate remedy at law to recover its losses. See Smoking

Everywhere v. FDA, 680 F. Supp. 2d 62, 77 n. 19 (D.D.C. 2010) (“Where a plaintiff cannot

30 http://phx.corporate-ir.net/phoenix.zhtml?c=123046&p=irol-SECText&TEXT=aHR0cDovL2lyLmludC53ZXN0bGF3YnVzaW5lc3MuY29tL2RvY3VtZW50L3YxLzAwMDExMDA5NjItMTItMDAwMDI5L3htbA%3d%3d


26

recover damage, from an agency because the agency has sovereign immunity ‘any loss of

income suffered by [the] plaintiff is irreparable per se.’” (quoting Feinerman v. Bernardi, 558 F.

Supp. 2d 36, 51 (D.D.C. 2008)); Bracco Diagnostics, Inc. v. Shalala, 963 F. Supp. 20, 29

(D.D.C. 1997) (finding irreparable harm where, although injury is “‘admittedly economic,’ there

is ‘no adequate compensatory or other corrective relief’ that can be provided at a later date,

tipping the balance in favor of injunctive relief.”) (quoting Hoffmann-LaRoche, Inc. v. Califano,

453 F. Supp. 900, 903 (D.D.C. 1978)).

IV. The Balance of Equities Heavily Favors Endo.

FDA will not be harmed if mandamus and a preliminary injunction are granted. To the

contrary, FDA will simply be ordered to perform its clear duty and to “do no harm” until it

performs its duty. On the other hand, the public and Endo would be substantially and irreparably

harmed if a preliminary injunction is not granted. See supra, 5-10; 24-26; Elzie v. Aspin, 841 F.

Supp. 439, 443 (D.D.C. 1993) (holding that the balance of equities favored the plaintiff because

“[g]ranting a preliminary injunction . . . will result in no discernible injury to defendants”).

Further, although no generic manufacturer is presently a party to this lawsuit, any harm

that the first generic ANDA applicant (Impax) might suffer if a preliminary injunction is granted

is far outweighed by the certain, substantial, and irreparable harm that will be suffered by the

public and Endo in the absence of an injunction. Impax or another generic manufacturer with an

approved ANDA will suffer no significant harm if FDA suspends approval of its ANDA for a

short period of time while FDA makes its required withdrawn for safety decision. By contrast, if

one or more generics are permitted to come onto the market, and FDA later determines that

Original Formulation Opana® ER was withdrawn for safety reasons, the public will certainly be

harmed: Recalling non-crush-resistant generic versions of Original Formulation Opana® ER


27

from countless wholesaler and retail pharmacy shelves, to say nothing of innumerable home

medicine cabinets, would be a monumental, if not literally impossible, task. See Chapman Dec.

¶14.31 Moreover, generic manufacturers, including Impax, have known for months of Endo’s

notice to FDA that Endo had withdrawn the Original Formulation for safety reasons. Endo’s

position that the Original Formulation has been withdrawn for safety reasons is thus no mystery

nor is a surprise sprung on the eve of Impax’s planned product launch.

V. The Public Interest Strongly Favors Granting Preliminary Injunctive Relief.

The public interest is served by requiring FDA to comply with the law and its own

regulations. See, e.g., Fund for Animals v. Espy, 814 F. Supp. 142, 152 (D.D.C. 1993) (“[T]here

is a strong public interest in meticulous compliance with law by public officials.”); see also

Mova Pharm. Corp. v. Shalala, 140 F.3d 1060, 1066 (D.C. Cir. 1998) (discussing the district

court’s determination that “the public’s interest in the ‘faithful application of the laws’

outweighed its interest in immediate access to [the] generic product”). Moreover, because Endo

has shown a likelihood of success on the merits, the public interest weighs in favor of injunctive

relief. See Serono Laboratories, Inc. v. Shalala, 158 F.3d 1313, 1326 (D.C. Cir. 1998).

In this case, the public interest is furthered by ensuring that powerful opioid pain

medications are as safe as practicable. Ensuring that drugs are safe, of course, is a principal

reason for FDA’s existence. Here, there is a particularly strong interest – an interest long

acknowledged and promoted by FDA – in curtailing the abuse and misuse of powerful Schedule

II drugs like Opana® ER.

31 See also U.S. Has Drug Recall Problem, Study Says, ABC News.com (June 4, 2012), http://abcnews.go.com/blogs/health/2012/06/04/u-s-has-drug-recall-problem-study-says/.


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As the non-profit Center for Lawful Access and Abuse Deterrence (“CLAAD”)32 warned

recently, if generic opioids without safety features are permitted to come to market, “parents,

healthcare providers, and law enforcement must be prepared to confront the resurgence of more

readily abused pain medications and the overdoses that could follow.” Press Release, CLAAD,

CLAAD Warns of Increase in Prescription Drug Overdoses, Nov. 12, 2012.33

An additional and significant public interest concern is at stake here. If generic versions

of Original Formulation Opana® ER are allowed to come to market before FDA has made its

safety determination, that action will discourage all pharmaceutical companies (not only Endo)

from investing time and money in researching and developing safer formulations of their

medications.34 As this Court has previously pointed out, “the countervailing public interest in

the marketing of less expensive generic drugs is outweighed by the public’s interest in the initial

development of new drugs.” CollaGenex Pharms, Inc. v. Thompson, 2003 U.S. Dist. LEXIS

12523, *36 (D.D.C. 2003). Reducing the incentive for manufacturers to develop future solutions

to real problems, including the problems of prescription drug misuse and abuse, is clearly

contrary to the public interest.

32 CLAAD is a not-for-profit organization that coordinates a comprehensive national effort to prevent the diversion, misuse, and abuse of prescription medications by fostering collaboration among multiple sectors of society to address the growing national concern for prescription drug abuse.

33 The misuse and abuse of prescription pain killers is not just harmful to those ingesting the drug, but according to a study conducted by the CDC, “Nonmedical use of prescription painkillers costs health insurers up to $72.5 billion annually in direct health care costs” – a cost that is no doubt being passed on to the public. See Centers for Disease Control and Prevention. Prescription Painkiller Overdoses in the U.S., Vital Signs, Nov. 2011, at 1, http://www.cdc.gov/VitalSigns/pdf/2011-11-vitalsigns.pdf.

34 As Congressman Harold Rogers of Kentucky recently stated to FDA personnel and others in a July 16, 2012, Capitol Hill briefing sponsored by the Congressional Caucus of Prescription Drug Abuse: “Obvious issues with diversion and abuse could arise if [non-crush-resistant OxyContin®] is available in a cheaper, generic form, and I’m afraid we’ll experience a new wave of overdose deaths . . . Aside from the human toll, this would be a tremendous setback to companies developing other tamper-resistant pain medications. If generic OxyContin is available on the market for a low price, there is little financial incentive for these companies to invest in the development of tamper-resistant drugs.” See Summary of Rep. Rogers’ comments at:http://halrogers.house.gov/news/documentsingle.aspx?DocumentID=303856 (emphasis added).


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In requesting preliminary injunctive relief, Endo is seeking to ensure that, before any

non-crush-resistant generic version of Original Formulation Opana® ER is marketed and sold,

FDA has first carried out its mandatory duty to make a determination as to whether Original

Formulation Opana® ER (the generic’s RLD) was withdrawn for safety reasons. It is plainly in

the public interest for FDA to make this determination. It is plainly not in the public interest for

agency inaction to result in less safe, readily crushable opioid drugs reaching the market.


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CONCLUSION

For the reasons stated, the Court should grant Endo’s motion for a preliminary

injunction. The Court should determine that there is a substantial likelihood that Endo will

prevail on its claims that FDA violated its mandatory obligations under the FDCA and FDA’s

regulations and unlawfully withheld or unreasonably delayed its determination whether Original

Formulation Opana® ER was withdrawn for safety reasons; that the public and Endo will suffer

irreparable harm in the absence of preliminary relief; and that the balance of the equities and the

public interest strongly favor granting preliminary injunctive relief. The Court should order

FDA to make a determination on an expedited basis and by no later than December 31, 2012, as

to whether Endo’s Original Formulation Opana® ER was withdrawn for safety reasons and,

pending that determination, the Court should order FDA to suspend approval of ANDAs for

generic versions of the drug that reference Original Formulation Opana® ER. A proposed Order

is submitted herewith.

Respectfully submitted,

s/ David W. Goewey________________ Ralph S. Tyler (D.C. Bar No. 357087)David W. Goewey (D.C. Bar No. 414257)Meredith L. Boylan (D.C. Bar No. 978088)VENABLE LLP575 7th St., NWWashington, D.C.Tel. 202.344.4000Fax 202.344.8300Attorneys for Plaintiff Endo Pharmaceuticals Inc.

November 30, 2012


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CERTIFICATE OF SERVICE

I HEREBY CERTIFY that on this 30th day of November 2012, a true and complete copy

of the foregoing Memorandum of Points and Authorities In Support of Motion For Preliminary

Injunction was served via hand-delivery on the following:

U.S. Food and Drug Administrationc/o Elizabeth Dickinson, Esq.Office of Chief Counsel10903 New Hampshire AvenueWhite Oak Building 31, Rm 4536Silver Spring, MD 20993

Margaret A. Hamburg, M.D.Commissioner of Food and DrugsU.S. Food and Drug Administration10903 New Hampshire AvenueWhite Oak Building 1Silver Spring, MD 20993

Kathleen SebeliusSecretary of Health and Human Services200 Independence Avenue, S.W.Washington, DC 20201

Eric HolderAttorney General for the United StatesUnited States Department of Justice950 Pennsylvania Avenue, N.W.Washington, DC 20530-0001

Ronald C. Machen Jr.United States Attorney for the District of ColumbiaUnited States Attorney's Office555 4th Street, N.W.Washington, DC 20530

/s/Meredith L. Boylan


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