State of Wisconsin et al v. Indivior Inc. et al

MOTION TO DISMISS FOR FAILURE TO STATE A CLAIM , MOTION to Dismiss for Lack of Jurisdiction

E.D. Pa.December 12, 2016

IN THE UNITED STATES DISTRICT COURT FOR THE EASTERN DISTRICT OF PENNSYLVANIA STATE OF WISCONSIN By Attorney General Brad D. Schimel; et al., Plaintiffs, v. INDIVIOR INC. f/k/a RECKITT BENCKISER PHARMACEUTICALS, INC.; et al., Defendants. Case No. 2:16-cv-5073-MSG DEFENDANT RECKITT BENCKISER HEALTHCARE (UK) LIMITED’S MOTION TO DISMISS Pursuant to Fed. R. Civ. P. 12(b)(2) and 12(b)(6), Defendant Reckitt Benckiser Healthcare (UK) Limited hereby moves to dismiss with prejudice the First Amended Complaint filed by the Plaintiff States (Docket No. 75). The grounds for this motion are set forth in the accompanying Memorandum. Case 2:16-cv-05073-MSG Document 141 Filed 12/12/16 Page 1 of 2 2 Respectfully submitted, /s/ Mark A. Ford Mark A. Ford Peter A. Spaeth Benjamin N. Ernst Holly A. Ovington Mark S. Gordon WILMER CUTLER PICKERING HALE AND DORR LLP 60 State Street Boston, Massachusetts 02109 T: (617) 526-6000 Nancy J. Gellman Andrew S. Gallinaro CONRAD O’BRIEN PC 1500 Market Street Suite 3900 Centre Square West Tower Philadelphia, PA 19102-2100 T: (215) 864-9600 Counsel for Reckitt Benckiser Healthcare (UK) Limited Dated: December 12, 2016 Case 2:16-cv-05073-MSG Document 141 Filed 12/12/16 Page 2 of 2 IN THE UNITED STATES DISTRICT COURT FOR THE EASTERN DISTRICT OF PENNSYLVANIA STATE OF WISCONSIN By Attorney General Brad D. Schimel; et al., Plaintiffs, v. INDIVIOR INC. f/k/a RECKITT BENCKISER PHARMACEUTICALS, INC.; et al., Defendants. Case No. 2:16-cv-5073-MSG DEFENDANT RECKITT BENCKISER HEALTHCARE (UK) LIMITED’S MEMORANDUM OF LAW IN SUPPORT OF ITS MOTION TO DISMISS Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 1 of 31 -i- TABLE OF CONTENTS I. BACKGROUND .................................................................................................................3 II. PLAINTIFFS’ MONOPOLIZATION AND ATTEMPTED MONOPOLIZATION CLAIMS (COUNTS I & II) DO NOT STATE A CLAIM AS TO RBH ............................5 A. The Complaint Fails To Allege RBH Possessed Monopoly Power ........................5 B. The Complaint Does Not Allege Exclusionary Conduct By RBH ..........................7 III. PLAINTIFFS’ CONSPIRACY CLAIMS (COUNTS III & IV) FAIL TO STATE A CLAIM AS TO RBH ...........................................................................................................9 IV. PLAINTIFFS’ STATE LAW CLAIMS (COUNT V) SHOULD BE DISMISSED..........13 V. PLAINTIFFS FAIL TO ALLEGE SUFFICIENT GROUNDS FOR THE EXERCISE OF PERSONAL JURISDICTION OVER RBH ......................................................................17 A. RBH Is Not Subject To General Jurisdiction .........................................................18 B. RBH Is Not Subject To Specific Jurisdiction ........................................................19 Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 2 of 31 -ii- TABLE OF AUTHORITIES Page(s) Federal Cases Advanced Health-Care Servs. v. Radford Community Hosp., 910 F.2d 139 (4th Cir. 1990) ...................................................................................................13 Apotex, Inc. v. Cephalon, Inc., No. 2:06-CV-2768, 2014 WL 5354243 (E.D. Pa. Aug. 19, 2014) ............................................6 Asahi Metal Indus. Co. v. Superior Court of Cal., 480 U.S. 102 (1987) .................................................................................................................18 Atuahene v. City of Hartford, 10 Fed. Appx. 33 (2d Cir. 2001) ................................................................................................2 In re Auto. Parts Antitrust Litig., No. 2:13-cv-02502, 2015 U.S. Dist. LEXIS 96470 (E.D. Mich. July 23, 2015) .....................20 In re Auto. Refinishing Paint Antitrust Litig., 358 F.3d 288 (3d Cir. 2004).....................................................................................................17 Barq’s Inc. v. Barq’s Beverages, Inc., 677 F. Supp. 449 (E.D. La. 1987) ..............................................................................................7 Bell Atl. Corp. v. Twombly, 550 U.S. 544 (2007) .................................................................................................................11 Berkey Photo Inc. v. Eastman Kodak Co., 603 F.2d 263 (2d Cir. 1979).......................................................................................................8 Borough of Lansdale v. PP & L, Inc., 426 F. Supp. 2d 264 (E.D. Pa. 2006) .......................................................................................13 Brunson Commc’ns, Inc. v. Arbitron, Inc., 239 F. Supp. 2d 550 (E.D. Pa. 2002) .......................................................................................11 In re Burlington Coat Factory Sec. Litig., 114 F.3d 1410 (3d Cir. 1997)...................................................................................................10 California Dental Ass’n v. FTC, 526 U.S. 756 (1999) .................................................................................................................15 Carefirst of Md., Inc. v. Carefirst Pregnancy Ctrs., Inc., 334 F.3d 390 (4th Cir. 2003) ...................................................................................................18 Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 3 of 31 -iii- Cheminor Drugs, Ltd. v. Ethyl Corp., 993 F. Supp. 271 (D.N.J. 1998) ...............................................................................................14 Copperweld Corp. v. Independence Tube Corp., 467 U.S. 752 (1984) ...........................................................................................................12, 13 Crossroads Corp. v. Orange & Utilities, Inc., 159 F.3d 129 (3d Cir.1998)....................................................................................................5, 9 Daimler AG v. Baumann, 134 S. Ct. 746 (2014) .........................................................................................................17, 18 Deutscher Tennis Bund v. ATP Tour, Inc., 610 F.3d 820 (3d Cir. 2010).....................................................................................................12 In re Digital Music Antitrust Litig., 592 F. Supp. 2d 435 (S.D.N.Y.2008).......................................................................................15 In re Digital Music Antitrust Litig., 812 F. Supp. 2d 390 (S.D.N.Y. 2011)........................................................................................2 Dimmitt Agri Indus., Inc. v. CPC Int’l Inc., 679 F.2d 516 (5th Cir. 1982) .....................................................................................................7 Discon, Inc. v. NYNEX Corp., 93 F.3d 1055 (2d Cir. 1996).......................................................................................................6 First Chi. Int’l v. United Exch. Co., 836 F.2d 1375 (D.C. Cir. 1988) ...............................................................................................18 In re Flash Memory Antitrust Litig., 643 F. Supp. 2d 1133 (N.D. Cal. 2009) ...................................................................................17 Fowler v. UPMC Shadyside, 578 F.3d 203 (3d Cir. 2009).......................................................................................................2 General Elec. Co. v. Deutz AG, 270 F.3d 144 (3d Cir. 2001).....................................................................................................17 Helicopteros Nacionales de Colombia, S.A. v. Hall, 466 U.S. 408 (1984) .................................................................................................................17 Hanson v. Denckla, 357 U.S. 235, 253 (1958) .........................................................................................................20 Howard Hess Dental Labs. Inc. v. Dentsply Int’l, Inc., 602 F.3d 237 (3d Cir. 2010).......................................................................................................9 Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 4 of 31 -iv- Indivior Inc. v. Mylan Tech. Inc., 1:15-cv-01016-RGA (D. Del. Nov. 4, 2015) .............................................................................7 Indivior Inc. v. Sandoz, Inc., 1:15-cv-01051-RGA (D. Del. Nov. 13, 2015) ...........................................................................7 Indivior Inc. v. Teva Pharm. USA, Inc., 1:16-cv-0178-RGA (D. Del. Mar. 21, 2016) .............................................................................7 In re Insurance Brokerage Antitrust Litig., 618 F.3d 300 (3d Cir. 2010).............................................................................................3, 9, 11 Luellin v. Gulick, No. 1:10CV203, 2012 U.S. Dist. LEXIS 40281 (N.D. W. Va. Mar. 26, 2012) ......................18 Marten v. Godwin, 499 F.3d 290 (3d Cir. 2007).....................................................................................................19 Mellon Bank (E.) PSFS, N.A. v. DiVeronica Bros., 983 F.2d 551 (3d Cir. 1993).....................................................................................................20 Monsanto Co. v. Spray-Rite Serv. Corp., 465 U.S. 752 (1984) .................................................................................................................11 In re Mushroom Direct Purchaser Antitrust Litig., 514 F. Supp. 2d 683 (E.D. Pa. 2007) .........................................................................................2 Mylan Pharm. Inc. v. Warner Chilcott Pub. Ltd. Co., 838 F.3d 421 (3d Cir. 2016)...................................................................................................8, 9 N. Pac. Ry. Co. v. United States, 356 U.S. 1 (1958) .....................................................................................................................10 In re New Motor Vehicles Canadian Export Antitrust Litig., 350 F. Supp. 2d 160 (D. Me. 2004) .........................................................................................16 Orazi v. Hilton Hotels Corp., No. 09-cv-05959, 2010 WL 4751728 (E.D. Pa. Nov. 22, 2010) ............................................18 Pennzoil Prods. Co. v. Colelli & Assocs., 149 F.3d 197 (3d Cir. 1998).....................................................................................................17 R.J. Reynolds Tobacco Co. v. Philip Morris Inc., 199 F. Supp. 2d 362 (M.D.N.C. 2002) ....................................................................................15 Schering-Plough Corp. v. FTC, 402 F.3d 1056 (11th Cir. 2005) ...............................................................................................15 Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 5 of 31 -v- Segal Co. (Eastern States), Inc. v. Amazon.com, 280 F. Supp. 2d 1229 (W.D. Wash. 2003) ...............................................................................16 Siegel Transfer v. Carrier Express, 54 F.3d 1125 (3d Cir. 1995).....................................................................................................12 United States ex rel. Spay v. CVS Caremark Corp., 913 F. Supp. 2d 125 (E.D. Pa. 2012) .........................................................................................7 In re Suboxone (Buprenorphine Hydrochloride & Naloxone) Antitrust Litig., 64 F. Supp. 3d 665, 713 (E.D. Pa. 2014) .......................................................................2, 4, 5, 8 In re Tamoxifen Citrate Antitrust Litig., 277 F. Supp. 2d 121 (E.D.N.Y. 2003) ...............................................................................14, 15 Toys “R” Us, Inc. v. Step Two, S.A., 318 F.3d 446 (3d Cir. 2003).....................................................................................................20 Vetrotex Certainteed Corp. v. Consol. Fiber Glass Prods. Co., 75 F.3d 147 (3d. Cir. 1996)......................................................................................................20 Walgreen Co. v. AstraZeneca Pharmaceuticals L.P., 534 F. Supp. 2d 146 (D.D.C. 2008) ...........................................................................................8 In re Wellbutrin XL Antitrust Litig., No. CIV. A. 08-2431, 2009 WL 678631 (E.D. Pa. Mar. 13, 2009) ...............................................................................6 State Cases Cheramie Serv. v. Shell Deepwater Prod., Inc., 35 So.3d 1053 (La. 2010) ........................................................................................................16 Desimone v. Barrows, 924 A.2d 908 (Del. Chan. 2007) ................................................................................................2 Messer Griesheim Indus., v. Cryotech of Kingsport, Inc., 131 S.W.3d 457 (Tenn. Ct. App. 2003) ...................................................................................16 Federal Statutes 15 U.S.C. § 1 .......................................................................................................................... passim 15 U.S.C. § 2 .......................................................................................................................... passim 15 U.S.C. § 45 ...............................................................................................................................14 State Statutes Ala. Code § 8-19-5(27) (2016) ......................................................................................................16 Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 6 of 31 -vi- Alaska Stat. § 45.50.471 (West 2016) ...........................................................................................15 Alaska Stat. § 45.50.562 (West 2016) ...........................................................................................14 Ark. Code Ann. § 4-75-301 (2016) ..............................................................................................14 Ark. Code Ann. § 4-88-101 (2016) ..............................................................................................15 Cal. Bus & Prof. Code § 17200 (2016) ............................................................................................5 Cal. Bus. & Prof. Code § 167000 (2016) .......................................................................................14 Colo. Rev. Stat. § 6-4-101 (2016) ..................................................................................................14 Conn. Gen. Stat § 35-44b (West 2016) ..........................................................................................14 Conn. Gen. Stat § 42-110b (West 2016) ........................................................................................15 D.C. Code §§ 28-4502, et seq. (2016) ...........................................................................................14 Del. Code Ann. tit. 6, § 2113 (West 2016) ....................................................................................14 Fla Stat. Ann. § 542.32 (West 2016) .............................................................................................14 Fla. Stat. Ann. § 501.204(2) (West 2016) ......................................................................................15 Ga. Code Ann. § 10-1-391(b) (West 2016) ...................................................................................15 Haw. Rev. Stat § 480-3 (West 2016) .............................................................................................14 Idaho Code Ann. § 48-102(3) (West 2016) ...................................................................................14 Ill. Comp. Stat. 10/1 to 10/11 (2016) .............................................................................................14 Iowa Code Ann. § 553.1 (West 2016) ...........................................................................................14 Iowa Code Ann. § 714.16(1)(n) (West 2016) ................................................................................15 Kan. Stat. Ann. § 50-163 (2016) ....................................................................................................14 Ky. Rev. Stat. Ann. 367.110 (West 2016) .....................................................................................14 Ky. Rev. Stat. Ann. § 367.175 (West 2016) ..................................................................................15 La. Rev. Stat. Ann. § 51:121 (2016) ..............................................................................................14 La. Rev. Stat Ann. § 51-1401 (2016) .............................................................................................16 Mass Gen. Laws ch. 93 § 2 (West 2016) ......................................................................................15 Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 7 of 31 -vii- Md. Code Ann., Com. Law. § 11-202(a)(2) (West 2016) .............................................................14 Me. Rev. Stat. Ann. tit. 10 § 1101 (2016) ......................................................................................14 Me. Rev. Stat. Ann. tit. 5 § 207(1) (2016) .....................................................................................15 Mich. Comp. Laws Ann. § 445.771 (West 2016) ..........................................................................14 Minn. Stat. § 325D.46, et seq. (2016) ............................................................................................14 Minn. Stat. §§ 325D.43, et seq. (2016) ..........................................................................................16 Miss. Code. Ann. § 75-21-1 (West 2016) ......................................................................................14 Miss. Code. Ann. § 75-24-3(c) (West 2016) .................................................................................15 Mo. Code Regs. Ann. tit. 15 § 60-8.020 (2016) ............................................................................15 Mo. Rev. Stat § 407.010 (2016) .....................................................................................................15 Mo. Rev. Stat. § 416.141 (2016) ....................................................................................................14 N.C. Gen. Stat. Ann. § 75-1 (2016) ...............................................................................................14 N.C. Gen. Stat. Ann. § 75-1.1 (2016) ............................................................................................15 N.H. Rev. Stat. Ann. § 356:14 (2016) ...........................................................................................14 N.M. Stat. Ann. § 57-1-15 (West 2016) ........................................................................................14 N.M. Stat. Ann. § 57-12-4 (West 2016) ........................................................................................15 N.Y. Exec. Law § 63(12) (2016) ...................................................................................................16 N.Y. Gen. Bus. Law § 340 (2016) .................................................................................................14 Neb. Rev. Stat. Ann. § 59-829 (2016) ...........................................................................................14 Neb. Rev. Stat. Ann. § 87-301 (2016) ..........................................................................................16 Ohio Rev. Code Ann. § 1331.01 (West 2016) ...............................................................................14 Okla. Stat. Ann. tit. 15 § 752.14 (West 2016) ...............................................................................15 Okla. Stat. Ann. tit.79 § 212 (West 2016) .....................................................................................14 Or. Rev. Stat. Ann. § 646.715(2) (West 2016) ..............................................................................14 73 Pa. Const. Stat. Ann. § 201-2(4) (West 2016) ..........................................................................16 Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 8 of 31 -viii- R.I. Gen. Laws Ann. § 6-13.1-3 (West 2016) ................................................................................15 R.I. Gen. Laws Ann. § 6-36-2(b) (West 2016) ..............................................................................14 S.C. Code Ann. § 39-5-20(b) (2016) .............................................................................................15 Tenn. Code Ann. § 47-25-101 (West 2016) ..................................................................................14 Tenn. Code Ann. § 47-18-101 (West 2016) ..................................................................................16 Utah Code Ann. § 76-10-3118 (West 2016) ..................................................................................14 Va. Code Ann. § 59-1 (West 2016) ...............................................................................................14 Vt. Stat. Ann. tit. 9 § 2453(b) (West 2016)....................................................................................15 W.Va. Code Ann. § 47-18-16 (West 2016) ...................................................................................14 Wash. Rev. Code Ann. § 19.86.920 (West 2016) ..........................................................................14 Wash. Rev. Code Ann. § 19.86.020 (West 2016) ..........................................................................16 Wis. Stat. Ann. § 133.01 (West 2016) ...........................................................................................14 Rules Fed. R. Civ. P. 8(a) ........................................................................................................................11 Other Authorities Phillip E. Areeda & Herbert Hovenkamp, ANTITRUST LAW (4th Ed. 2015) ............................10, 15 Richard A. Posner, ANTITRUST LAW (2d ed. 2001) ........................................................................6 Paul A. Samuelson & William D. Nordhaus, ECONOMICS (17th ed. 2001) .....................................6 Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 9 of 31 - 1 - Defendant Reckitt Benckiser Healthcare (UK) Limited (“RBH”) is a company organized under the laws of England and Wales and based in the United Kingdom. See First Amended Complaint (“Complaint”) ¶ 12 (Dkt. 75). RBH and Defendant Indivior Inc. (“Indivior”) were co-subsidiaries of Reckitt Benckiser Group plc (“RB Group”) until a 2014 demerger in which Indivior-then known as Reckitt Benckiser Pharmaceuticals, Inc.-was spun off. See Am. Compl. ¶¶ 11, 13. Indivior-not RBH-held (and still holds) the NDAs for both Suboxone tablets and Suboxone film. See Ernst Decl. ¶¶ 2, 3; Exs. 1, 2. Indivior-not RBH-sold (and still sells) Suboxone in the United States, and stood to lose market share to generic manufacturers of Suboxone tablets. See Ernst Decl. ¶¶ 2, 3; Exs. 1, 2; see also Am. Compl. ¶ 11. Not surprisingly, then, the Complaint is devoid of a single specific allegation that RBH even participated in the relevant market, much less that it played any role in any of the purportedly unlawful acts alleged in the Complaint, including disparaging the legacy tablet product, filing a sham FDA citizen’s petition, and failing to cooperate with generics during the process for developing a single shared Risk Evaluation and Mitigation Strategy (“REMS”). In their zeal to include RBH as a defendant here, Plaintiffs employ two equally disingenuous pleading artifices. First, they attribute all the conduct in the Complaint to “Reckitt,” which they obfuscate to include RBH as well as Indivior. See Am. Compl. ¶ 13 (defining “Reckitt”); id. ¶ 84 (“. . . Reckitt induced conversion of the market to the Film by raising the price of its Suboxone Tablets before the introduction of the AB-rated generic tablet product into the market.”); ¶ 93 (“. . . Reckitt engaged in multiple delay tactics and made misleading statements to conceal its true intent, which was to prolong the approval of the ANDAs for generic Suboxone Tablets.”); ¶ 102 (“. . . Reckitt filed a citizen petition asking the FDA to withhold approval of the ANDAs for generic Suboxone Tablets . . . .”) (emphases Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 10 of 31 - 2 - added). Second, they allege in the broadest possible terms that RBH is “in whole or in part responsible for some or all of the conduct” in the Complaint. See Am. Compl. ¶ 12. This Court previously rejected these tactics when the class plaintiffs tried them. See In re Suboxone (Buprenorphine Hydrochloride & Naloxone) Antitrust Litig., 64 F. Supp. 3d 665, 713 (E.D. Pa. 2014) (dismissing claims against Reckitt Benckiser Inc., Reckitt Benckiser LLC, and RBH “for failure to identify what role, if any, these entities played in the alleged anticompetitive scheme”); id. at 713-14, n.31 (virtually identical allegation that RBH was “in whole or in part responsible for some or all of the conduct alleged herein and attributed to Reckitt” insufficient). Other courts have done the same where the complaint failed to inform each defendant of the conduct with which it was charged. See, e.g., Fowler v. UPMC Shadyside, 578 F.3d 203, 210 (3d Cir. 2009) (post-Twombly and Iqbal, “conclusory or ‘bare-bones’ allegations will no longer survive a motion to dismiss”); Atuahene v. City of Hartford, 10 Fed. Appx. 33, 34 (2d Cir. 2001) (A plaintiff cannot merely “lump[] all of the defendants together in each claim and provid[e] no factual basis to distinguish their conduct.”); In re Digital Music Antitrust Litig., 812 F. Supp. 2d 390, 417 (S.D.N.Y. 2011) (“The complaint alleges direct involvement of the Parent Companies by way of generic references to ‘defendants.’ This approach is insufficient.”); In re Mushroom Direct Purchaser Antitrust Litig., 514 F. Supp. 2d 683, 699 (E.D. Pa. 2007) (granting motion to dismiss Section 2 claims for failure to plead sufficient elements against each defendant); Desimone v. Barrows, 924 A.2d 908, 939 (Del. Chan. 2007) (dismissing claim premised on “spineless” allegations that defendants “Jewels and/or Smith” breached fiduciary duties by approving illegal backdating of options) (emphasis added). Aside from these defective wholesale allegations, which may not be considered in the 12(b)(6) analysis, all that remains of the Complaint as against RBH is that it allegedly had Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 11 of 31 - 3 - monopoly power, Am. Compl. ¶ 132, that it entered into a contract with Defendant MonoSol Rx, LLC (“MonoSol”) to develop a new film product, id. ¶ 46, and that it “participated” in some unspecified way in “discussions” about a “plan” to convert the market to film, id. ¶ 71. None of this states a claim. To begin with, RBH is not even alleged to have been a participant in the relevant market, and therefore could not have had monopoly power. See infra Part II.A. Second, it is perfectly lawful and pro-competitive to develop a new product, so the agreement with MonoSol cannot form the basis of either a monopolization or a conspiracy claim. See infra Parts II.B, III. Finally, the allegation concerning RBH’s “participat[ion]” in “discussions” is so conclusory as to be meaningless and fails to identify any agreement to carry out an unlawful objective. Nor can any such agreement be inferred, because the obvious inference from the Complaint is that Indivior and RBH did not act in concert with respect to the alleged unlawful conduct, and there is no reason to suppose Indivior would have needed, or asked for, much less received, RBH’s assistance. See infra Part III; see also In re Insurance Brokerage Antitrust Litig., 618 F.3d 300, 322 (3d Cir. 2010) (“[A]llegations of conspiracy are deficient if there are ‘obvious alternative explanation[s]’ for the facts alleged.”) (quoting Bell Atl. Corp. v. Twombly, 550 U.S. 544, 567, (2007)). For these and other reasons set out below, the claims against RBH should be dismissed. I. BACKGROUND RBH is a private limited company incorporated under the laws of England and Wales and based in Slough, United Kingdom. It is a wholly-owned subsidiary of RB Group. See Am. Compl. ¶ 12. RB Group previously owned Reckitt Benckiser Pharmaceuticals, Inc. (“RBP Inc.”)-now known as Indivior-before separating the company from RB Group in a demerger transaction. See Am. Compl. ¶ 13. RBH was the Reckitt manufacturing entity that made, among Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 12 of 31 - 4 - other things, Suboxone tablets, id. ¶ 12, but it was Indivior Inc. (and RBP Inc. before the 2014 demerger) that sold Suboxone “throughout the United States,” id. at ¶ 11. Beginning in 2013, RBH was named as a defendant in suits eventually comprising the multi-district class action litigation brought by private plaintiffs against Indivior. As with this case, the class action complaints alleged a “product hopping” scheme as well as exclusionary tactics to delay approval of generic version of Suboxone tablets. In re Suboxone, 64 F. Supp. 3d at 672. The class plaintiffs alleged that, when faced with impending entry of generic tablets, Indivior sought to convert the market from tablets to film by “falsely disparaging the tablet through fabricated safety concerns” and by threatening to remove the tablet form the market as a result. Id. The class complaint also alleged that FDA approval of generic tablets was stalled because the process of developing a single-shared REMS was intentionally delayed, and because of a sham FDA citizen’s petition claiming safety concerns associated with generic Suboxone tablets. Id. at 672, 676. On December 3, 2014, in a detailed opinion, the Court granted in part and denied in part Indivior’s motion to dismiss. The Court held that while launching Suboxone film was not in and of itself anticompetitive, the class plaintiffs sufficiently stated a claim for unlawful “product hopping” because “[t]he threatened removal of the tablets from the market in conjunction with the alleged fabricated safety concerns could plausibly coerce patients and doctors to switch from tablet to film.” Id. at 682. As to the alleged efforts to delay entry of generic tablets, the Court allowed the case to proceed on the sham citizen’s petition theory, but rejected the failure to engage in developing a single-shared REMS program as a basis for liability. Id. at 688-690. The Court explained that the antitrust laws “do not impose a duty” on branded pharmaceutical companies to aid generics in obtaining speedy FDA approval. Id. at 688. Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 13 of 31 - 5 - While the Court allowed the class actions to proceed against Indivior, it dismissed all claims against RBH. Indeed, when RBH moved to dismiss, the Direct Purchaser plaintiffs did not even oppose the motion, and the End Payors failed to tie RBH to any of the unlawful actions alleged in their complaint. In re Suboxone, 64 F. Supp. 3d at 713-14. The Court-recognizing that it was Indivior “which actually sells Suboxone”-found the complaints did not state claims against RBH. Id. at 713. Nonetheless, on September 22, 2016, plaintiff States filed nearly identical antitrust claims to those in the class actions and insisted on naming RBH as a defendant. In fact, they rely principally on the same pleading obfuscations- defining “Reckitt” to include RBH and alleging cryptically that RBH was “in whole or in part responsible for some or all of the conduct alleged in this Complaint and attributed to Reckitt,” see, e.g., Direct Purchasers’ Consol. Am. Compl. at 1, ¶ 23, In re Suboxone, 64 F. Supp. 3d at 665-that this Court expressly rejected when dismissing RBH the first time. In re Suboxone, 64 F. Supp. 3d at 713-14, n.31. II. PLAINTIFFS’ MONOPOLIZATION AND ATTEMPTED MONOPOLIZATION CLAIMS (COUNTS I & II) DO NOT STATE A CLAIM AS TO RBH Unlawful monopolization requires “(1) the possession of monopoly power in the relevant market and (2) the willful acquisition or maintenance of that power as distinguished from growth or development as a consequence of a superior product, business acumen, or historical accident.” Crossroads Corp. v. Orange & Utilities, Inc., 159 F.3d 129, 141 (3d Cir.1998). Plaintiffs fail to allege either element against RBH. A. The Complaint Fails To Allege RBH Possessed Monopoly Power The Complaint itself undercuts its own defective, conclusory allegation that RBH possessed monopoly power. See Am. Compl. ¶ 132. Plaintiffs define the relevant market as co- formulated buprenorphine/naloxone, including Suboxone and its AB-rated equivalents in the Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 14 of 31 - 6 - United States. See Am. Compl. ¶ 132.1 But Plaintiffs nowhere allege-because they cannot- that RBH ever sold Suboxone in the United States. “[I]t is axiomatic that a firm cannot monopolize a market in which it does not compete.” Discon, Inc. v. NYNEX Corp., 93 F.3d 1055, 1062 (2d Cir. 1996), rev’d on other grounds, 525 U.S. 128 (1998); see In re Wellbutrin XL Antitrust Litig., No. CIV.A. 08-2431, 2009 WL 678631, at *7 (E.D. Pa. Mar. 13, 2009) (dismissing monopolization claims against defendant where plaintiffs failed to allege defendant ever sold drug in the United States). Plaintiffs attempt to avoid this fundamental problem by alleging that RBH (and other defendants) “possessed monopoly power . . . as owners or licensees to use Suboxone intellectual property,” see Am. Compl. ¶ 132, seemingly suggesting that RBH can be deemed a monopolist by virtue of some unspecified intellectual property holdings even if it does not sell the product at issue. This is incorrect as a matter of fundamental antitrust principles. As Judge Posner explained in his oft-cited text, “[a] monopolist is a seller (or group of sellers acting like a single seller) who can change the price at which his product will sell in the market by changing the quantity that he sells.” Richard A. Posner, ANTITRUST LAW 9 (2d ed. 2001). In fact, the word “monopolist” literally means seller. Paul A. Samuelson & William D. Nordhaus, ECONOMICS 169 (17th ed. 2001) (“It is called a ‘monopolist,’ from the Greek work mono for ‘one’ and polist for ‘seller.’”). Not surprisingly then, as this Court has previously observed, monopoly power is shown either directly by demonstrating a defendant’s ability to raise price by restricting its output, or circumstantially by inferring monopoly power from a defendant’s high share of the relevant market. Apotex, Inc. v. Cephalon, Inc., No. 2:06-CV- 1 As set forth in the Memorandum of Law in Support of Monosol Rx, LLC’s Motion to Dismiss the First Amended Complaint (“MonoSol’s Br.”) at Part III.A., Plaintiffs’ alleged relevant product market is implausible. RBH incorporates those arguments herein. Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 15 of 31 - 7 - 2768, 2014 WL 5354243, at *1 (E.D. Pa. Aug. 19, 2014). By definition, having no sales, and thus no market share, precludes a finding of monopoly power. Dimmitt Agri Indus., Inc. v. CPC Int’l Inc., 679 F.2d 516, 529 (5th Cir. 1982) (“[T]here is considerable support for the proposition that low market shares, if undisputed, make monopolization an impossibility as a matter of law.”); Barq’s Inc. v. Barq’s Beverages, Inc., 677 F. Supp. 449, 455 (E.D. La. 1987) (zero percent market share insufficient to show monopoly power). Even if patents could be relevant to the monopoly power analysis here, Plaintiffs do not and could not identify any patent RBH holds covering Suboxone tablets (or film), or how that intellectual property conferred power on RBH. The Complaint references patent enforcement efforts concerning Suboxone film patents, Am. Compl. at ¶¶ 51-52, but Plaintiffs do not allege that those enforcement efforts were undertaken by RBH or explain how those efforts relate to the alleged unlawful scheme at issue. In any event, the relevant court filings-of which the Court may take judicial notice2-show that the enforcement cases were brought by MonoSol and Indivior, not RBH. See, e.g., Indivior Inc. v. Teva Pharm. USA, Inc., 1:16-cv-0178-RGA (D. Del. Mar. 21, 2016); Indivior Inc. v. Sandoz, Inc., 1:15-cv-01051-RGA (D. Del. Nov. 13, 2015); Indivior Inc. v. Mylan Tech. Inc., 1:15-cv-01016-RGA (D. Del. Nov. 4, 2015).3 B. The Complaint Does Not Allege Exclusionary Conduct By RBH Leaving aside the defective wholesale allegations discussed above which do not state a claim, see supra p. 1-3 and cases cited, none of the conduct actually pleaded as to RBH is 2 See United States ex rel. Spay v. CVS Caremark Corp., 913 F. Supp. 2d 125, 139 (E.D. Pa. 2012) (“On a motion to dismiss, courts take judicial notice of documents which are matters of public record such as . . . court-filed documents.”) (citing Rouse v. II-VI Inc., No. Civ.A.06-566, 2008 WL 398788, at *1 (W.D. Pa. Feb. 11, 2008)). 3 The allegation that RBH played a “role in the development [or] manufacture” of Suboxone, see Am. Compl. at ¶ 132, similarly fails to overcome the fact that RBH cannot monopolize a market in which it does not sell any product. Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 16 of 31 - 8 - exclusionary. The Complaint principally alleges that RBH contracted with MonoSol to develop a new film version of Suboxone.4 Rulings in antitrust cases involving a variety of industries, including pharmaceuticals, establish that developing a new product is not in and of itself anticompetitive. As this Court has stated: Even a monopolist may expand its market share and increase demand for its products through technological innovation, ‘and such actions are ‘perfectly consistent with the competitive forces that the Sherman Act was intended to foster…. [W]hat is clear from the case law is that simply introducing a new product on the market, whether it is a superior product or not, does not, by itself, constitute exclusionary conduct. In re Suboxone, 64 F. Supp. 3d. at 679, 682 (citations omitted). Other courts have reached the same result. Berkey Photo Inc. v. Eastman Kodak Co., 603 F.2d 263, 286 (2d Cir. 1979) (“The attempt to develop superior products is … an essential element of lawful competition.”); Mylan Pharm. Inc. v. Warner Chilcott Pub. Ltd. Co., 838 F.3d 421, 440 (3d Cir. 2016) (“Doryx”) (confirming that introduction of a new product could violate the Sherman Act only if, inter alia, coercive conduct is present); Walgreen Co. v. AstraZeneca Pharmaceuticals L.P., 534 F.Supp.2d 146, 152-153 (D.D.C.2008) (granting motion to dismiss ‘product hopping’ antitrust claims because next-generation product supplemented consumer choices rather than eliminating them). The Complaint also alleges-in its description of RBH as a defendant but not in the body of the substantive allegations-that RBH “established the parameters for the timing of the launch and the formulation of Suboxone film, gathers, and investigates all consumer complaints as to 4 See Am. Compl. ¶46 (“. . . MonoSol and Reckitt Benckiser Healthcare UK Ltd. signed an agreement to develop the new Film and bring it to market for the purpose of extending Reckitt’s exclusivity in the co-formulated buprenorphine/naloxone market.”); Am. Compl. ¶150 (“Reckitt Benckiser Healthcare UK, Ltd. and MonoSol entered into a development agreement whereby MonoSol granted Reckitt the right to use its patented sublingual film technology to manufacture Suboxone in a film version.”). Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 17 of 31 - 9 - Suboxone products, trademarked the names for the financial programs to encourage the switch from Suboxone tablets to film, and obtained patents together with MonoSol related to Suboxone film development . . . . [and] monitored the taste and quality of Suboxone film, prepared materials for regulatory approval of Suboxone film, manufactured and supplied the ingredients for Suboxone film, and provided grants for the study of Suboxone.” See Am. Compl. ¶12. However, Plaintiffs never tie this litany of allegations to any of the alleged unlawful conduct at issue. And on its face, none of this alleged conduct is remotely exclusionary, but simply describes pro-competitive actions related to new product development.5 Accordingly, Plaintiffs fail to state a claim for monopolization or attempted monopolization as to RBH.6 III. PLAINTIFFS’ CONSPIRACY CLAIMS (COUNTS III & IV) FAIL TO STATE A CLAIM AS TO RBH To allege a claim under Sherman Act Section 1 (Count IV), or for conspiracy to monopolize under Section 2 (Count III), Plaintiffs must plead an agreement or conspiracy to unreasonably restrain trade or engage in exclusionary conduct. In re Insurance Brokerage, 618 F.3d at 314; Howard Hess Dental Labs. Inc. v. Dentsply Int'l, Inc., 602 F.3d 237, 254 (3d Cir. 2010). An agreement alone is never the target of the antitrust laws; “most agreements are both 5 The only other allegation actually naming RBH-that it “participated in discussions” regarding a “plan” to remove Suboxone tablets from the market, see Am. Compl. ¶ 71-is discussed in Part III immediately below. For the same reasons this allegation fails to state a claim for conspiracy, it necessarily fails to allege exclusionary conduct. Moreover, even the alleged conduct misleadingly attributed to “Reckitt” in the complaint is not exclusionary, particularly under the standard recently announced in Mylan Pharm. Inc. v. Warner Chilcott Public Ltd. Co., 838 F.3d 421 (3d Cir. 2016) (“Doryx”). See Indivior Inc.’s Memorandum in Support of its Motion to Dismiss (“Indivior’s Br.”) at Part III and MonoSol’s Br. at Part I.C., which RBH incorporates herein by reference. 6 For the same reasons, Plaintiffs fall far short of alleging that RBH “engaged in predatory or anticompetitive conduct with . . . a specific intent to monopolize,” as required for their attempted monopolization claim. See Crossroads, 159 F.3d at 141. Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 18 of 31 - 10 - open and lawful.” 6 Phillip E. Areeda & Herbert Hovenkamp, ANTITRUST LAW ¶ 1400 (4th Ed. 2015) (hereinafter AREEDA); N. Pac. Ry. Co. v. United States, 356 U.S. 1, 5 (1958) (holding that the Sherman Act “preclude[es] only those contracts or combinations which ‘unreasonably’ restrain competition”). Here, Plaintiffs allege that RBH entered into an agreement with MonoSol to develop Suboxone film, Am. Compl. ¶ 12, but as explained above, it is perfectly legal to develop a next generation product. See supra Part II.B and cases cited. A fortiori, it is perfectly legal to enter into an agreement to develop such a product.7 The Complaint does not allege any facts showing any broader, coercive “product hopping” agreement (or agreement to delay generic competition) to which RBH was a party, or from which such an agreement can be plausibly inferred. To begin with, Plaintiffs do not plead any express agreement or promise involving RBH to engage in any of the acts involved in the alleged strategy to switch the market to film or to delay generic entry. The contract between RBH and MonoSol, which the Court may consider,8 is devoid of any such terms. It provides only that MonoSol would develop a “pharmaceutical film” for RBH. See Ernst Decl. ¶ 4; Ex. 3. Plaintiffs do not allege any agreement at all between RBH and Indivior. The absence of any express agreement should end the inquiry. As the leading antitrust treatise states, when the alleged participants in a conspiracy are not competitors, non-conspiracy should normally be inferred in the absence of an unambiguously express promise on the point of the challenged action . . . .” 6 AREEDA ¶ 1402b. (“speculative possibility” of 7 RBH incorporates herein by reference the arguments set forth in MonoSol’s Br. at Part I.B and Indivior’s Br. at Part IV.B.. 8 See In re Burlington Coat Factory Sec. Litig., 114 F.3d 1410, 1426 (3d Cir. 1997) (courts may consider on a motion to dismiss a “document integral to or explicitly relied upon in the complaint . . . . Plaintiffs cannot prevent a court from looking at the texts of the documents on which its claim is based by failing to attach or explicitly cite them.”) (internal quotations omitted) (emphasis in original). Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 19 of 31 - 11 - concerted action cannot be assumed in the absence of concerted action when the parties involved are non-competitors); see also United States v. Sargent Elec. Co., 785 F.2d 1123, 1127 (3d Cir. 1986) (holding that “[a]n agreement among persons who are not actual or potential competitors in a relevant market is for Sherman Act purposes brutum fulmen”). The vague allegation that “[e]mployees of [RBH] participated in discussions regarding the plan to remove Tablets from the market” is also insufficient to identify any express agreement or promise with respect to any of the alleged unlawful conduct. See Am. Compl. ¶ 71. For example, Plaintiffs do not identify the other parties to these “discussions,” or who from RBH participated, or what anyone from RBH (or anyone else) said, or what the participants agreed to do, or even whether RBH agreed with whatever “plan” was under discussion. Even under Rule 8(a), this is not enough to plead a conspiracy involving RBH. See Twombly, 550 U.S. at 556 (holding that “bare assertion[s] of conspiracy” are insufficient to survive a motion to dismiss); Brunson Commc’ns, Inc. v. Arbitron, Inc., 239 F. Supp. 2d 550, 563 (E.D. Pa. 2002) (conclusory allegation that defendant participated in “many meetings” insufficient to state antitrust claim). Nor do Plaintiffs plead facts from which any broader conspiracy to which RBH was a party can be inferred in the absence of an express agreement. To infer a conspiracy in these circumstances, even between competitors, a plaintiff must allege facts that plausibly “tend[] to exclude the possibility that [the defendants] were acting independently.” Monsanto Co. v. Spray- Rite Serv. Corp., 465 U.S. 752, 764 (1984); see also Ins. Brokerage, 618 F.3d at 322 (“[A]llegations of conspiracy are deficient if there are ‘obvious alternative explanation[s]’ for the facts alleged.”) (quoting Twombly, 550 U.S. at 567). Here, despite Plaintiffs’ pleading artifices, Indivior-not RBH-was responsible for and sold Suboxone tablets and film. See Ernst Decl. ¶¶ Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 20 of 31 - 12 - 2, 3; Exs. 1, 2. Indivior-not RBH-filed the citizen’s petition. See Ernst Decl. ¶ 5; Ex. 4. Plaintiffs nowhere allege that RBH participated in these allegedly unlawful actions, and there is no plausible reason that Indivior would have needed RBH’s assistance or participation. Thus, nothing in the Complaint tends to negate the possibility that Indivior acted independently of RBH, and in fact the record that the Court may consider shows that Indivior did exactly that.9 Finally, even if the Complaint somehow adequately alleged RBH’s involvement, the type of coordination the States allege is not actionable under Copperweld Corp. v. Independence Tube Corp., 467 U.S. 752 (1984), and its progeny, which limit Section 1 to agreements involving “independent centers of decision making.” Id. at 769. As the Third Circuit explained, “[t]he focus of the inquiry under § 1 of the Sherman Act centers on diminution of competition that would otherwise exist.” Deutscher Tennis Bund v. ATP Tour, Inc., 610 F.3d 820, 835 (3d Cir. 2010). That is because Section 1 of the Sherman Act seeks to prevent the accumulation of market power that occurs when actors, “previously pursuing divergent interests and goals,” act in concert. Siegel Transfer v. Carrier Express, 54 F.3d 1125, 1137 (3d Cir. 1995). Under these principles, any coordination among RBH, Indivior, and MonoSol could not violate Section 1. As a preliminary matter, RBH and RBP Inc. (now Indivior) were, at the relevant times, sister companies under RB Group, and under the Copperweld doctrine two wholly-owned subsidiaries of the same parent cannot conspire with each other for purposes of the antitrust laws. See Copperweld, 467 U.S. at 755 (holding that a corporation and its wholly owned subsidiaries “are incapable of conspiring with each other for purposes of § 1 of the Sherman Act”); Borough of 9 As set forth above, the alleged “product hopping” and generic delay allegations do not constitute anticompetitive conduct anyway for the reasons set forth in Indivior’s Br. at Parts III, V, and MonoSol’s Br. at Part I, which RBH incorporates by reference herein. Furthermore, the alleged anticompetitive conduct did not proximately cause Plaintiffs’ claimed injury, as set forth in Monosol’s Br. at Part II, which RBH incorporates by reference herein. Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 21 of 31 - 13 - Lansdale v. PP & L, Inc., 426 F. Supp. 2d 264, 293 (E.D. Pa. 2006) (applying Copperweld in the context of sister companies); see also Advanced Health-Care Servs. v. Radford Community Hosp., 910 F.2d 139, 146 (4th Cir. 1990) (“[T]wo subsidiaries wholly owned by the same parent corporation are legally incapable of conspiring with one another for purposes of § 1 of the Sherman Act.”). Similarly, for the reasons detailed in the briefs submitted by Indivior and MonoSol, the Copperweld doctrine also extends to any coordination among Indivior, RBH, and Monosol, because-as the Complaint alleges-those entities did not compete with each other or pursue separate economic interests in the relevant market.10 Siegel Transfer, 54 F.3d at 1137. Consequently, any agreement among them could not have “deprive[d] the marketplace of the independent centers of decision making that competition assumes and demands.” Copperweld, 467 U.S. at 769. Indeed, the Complaint offers no reason to believe MonoSol would have participated at all in the relevant market but for its “joint venture” with “Reckitt.” See Am. Compl. ¶ 12. Accordingly, Plaintiffs’ conspiracy allegations against RBH fail to state a claim. IV. PLAINTIFFS’ STATE LAW CLAIMS (COUNT V) SHOULD BE DISMISSED Plaintiffs’ state law antitrust and consumer protection claims arise from the same conduct as their federal claims, and thus fail for the same reasons their federal claims do. Moreover, certain state consumer protection claims fail because Plaintiffs have not alleged the type of fraudulent or deceptive conduct those statutes require. 10 See Indivior’s Br. at Part IV.A.; MonoSol’s Br. at Part I.A.; see also Am. Compl. ¶ 12 (alleging RBH and MonoSol engaged in a “joint venture”). Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 22 of 31 - 14 - First, each of the state antitrust laws at issue are either explicitly aligned with the Sherman Act or interpreted consistently with federal antitrust law. 11 See In re Tamoxifen Citrate Antitrust Litig., 277 F. Supp. 2d 121, 139 (E.D.N.Y. 2003) aff’d, 466 F.3d 187 (2d Cir. 2006) (“[S]ince [p]laintiffs fail to state a claim under the Sherman Act, and since the state antitrust law claims are based on the same allegations, those claims are also dismissed.”);12 Cheminor Drugs, Ltd. v. Ethyl Corp., 993 F. Supp. 271, 281, n.23 (D.N.J. 1998) (“To the extent that plaintiffs allege a separate antitrust claim pursuant to state law, courts have consistently found that the failure to state viable federal antitrust claims is fatal to state antitrust claims.”), aff’d, 168 F.3d 119 (3d Cir. 1999). Next, each of the unfair trade practices/consumer protection statutes asserted (save for those addressed separately below) mirror and are construed consistently with Section 5 of the 11 See Alaska Stat. § 45.50.562 (West 2016); Ark. Code Ann. § 4-75-301 (2016); Cal. Bus. & Prof. Code § 167000 (2016); Colo. Rev. Stat. § 6-4-101 (2016); Conn. Gen. Stat § 35-44b (West 2016); Del. Code Ann. tit. 6, § 2113 (West 2016); D.C. Code §§ 28-4502, et seq. (2016); Fla Stat. Ann. § 542.32 (West 2016); Haw. Rev. Stat § 480-3 (West 2016); Idaho Code Ann. § 48- 102(3) (West 2016); 740 Ill. Comp. Stat. 10/1 to 10/11 (2016); Iowa Code Ann. § 553.1 (West 2016); Kan. Stat. Ann. § 50-163 (2016); Ky. Rev. Stat. Ann. 367.110 (West 2016); La. Rev. Stat. Ann. § 51:121; Me. Rev. Stat. Ann. tit. 10 § 1101 (2016); Md. Code Ann., Com. Law. § 11- 202(a)(2) (West 2016); Mich. Comp. Laws Ann. § 445.771 (West 2016); Minn. Stat. § 325D.46, et seq. (2016); Miss. Code. Ann. § 75-21-1 (West 2016); Mo. Rev. Stat. § 416.141 (2016); Neb. Rev. Stat. § 59-829 (West 2016); N.H. Rev. Stat. Ann. § 356:14 (2016); N.M. Stat. Ann. § 57-1- 15 (West 2016); N.Y. Gen. Bus. Law § 340 (2016); N.C. Gen. Stat. Ann. § 75-1 (2016); Ohio Rev. Code Ann. § 1331.01 (West 2016); Okla. Stat. Ann. tit.79 § 212 (West 2016); Or. Rev. Stat. Ann. § 646.715(2) (West 2016); R.I. Gen. Laws Ann. § 6-36-2(b) (West 2016); Tenn. Code Ann. § 47-25-101 (West 2016); Utah Code Ann. § 76-10-3118 (West 2016); Va. Code Ann. § 59-1 (West 2016); Wash. Rev. Code Ann. § 19.86.920 (West 2016); W.Va. Code Ann. § 47-18-16 (West 2016); Wis. Stat. Ann. § 133.01 (2016). 12 The state antitrust statutes at issue both here and in Tamoxifen are: California, the District of Columbia, Florida, Kansas, Louisiana, Maine, Michigan, Minnesota, New York, North Carolina, West Virginia, and Wisconsin. Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 23 of 31 - 15 - FTC Act.13 In turn, anticompetitive conduct claims under the FTC Act (the “unfair” prong) are analyzed under the same principles as Sherman Act claims. See, e.g., Schering-Plough Corp. v. FTC, 402 F.3d 1056, 1072-76 (11th Cir. 2005) (in overturning FTC’s cease-and-desist order, applying Sherman Act cases and analysis); California Dental Ass’n v. FTC, 526 U.S. 756 (1999) (same); 2 AREEDA ¶ 302h (“[I]nsofar as sound policy condemns or permits given conduct under the Sherman or Clayton Acts, then sound policy requires the same result under the Federal Trade Commission Act.”). As a result, courts in antitrust cases have dismissed tagalong claims based on the same factual allegations under state unfair trade practices/consumer protection statutes where the complaint failed to state a federal antitrust claim. See, e.g., Tamoxifen, 466 F.3d at 198 (affirming district court’s dismissal of state consumer protection claims upon district's court conclusion that plaintiffs failed to state a federal antitrust claim); R.J. Reynolds Tobacco Co. v. Philip Morris Inc., 199 F. Supp. 2d 362, 396 (M.D.N.C. 2002) (“Because Plaintiffs do not allege any facts that suggest that Defendant's conduct is unlawful beyond the conduct that is the basis for their failed federal [antitrust] claims, Plaintiffs' state common law and statutory claims fail as well.”); see also In re Digital Music Antitrust Litig., 592 F. Supp. 2d 435, 450-51 (S.D.N.Y. 2008) (dismissing state consumer protection claims and finding that “[the court’s] conclusion that Plaintiffs have not adequately alleged [a federal antitrust] violation necessarily precludes 13 See Alaska Stat. § 45.50.545 (2016); Ark. Code Ann. § 4-88-101 (2016); Cal. Bus & Prof. Code § 17200 (2016); Conn. Gen. Stat § 42-110b (West 2016); Fla. Stat. § 501.204(2) (West 2016); Ga. Code Ann. § 10-1-391(b) (West 2016); Iowa Code § 714.16(1)(n) (West 2016); Ky. Rev. Stat. Ann. § 367.175 (West 2016); Mass. Gen. Laws ch. 93A § 2 (West 2016); Me. Rev. Stat. Ann. tit. 5 § 207(1) (2016); Miss. Code. Ann. § 75-24-3(c) (West 2016); Mo. Rev. Stat § 407.010 (2016); 15 Mo. Code Regs. Ann. tit. 15 § 60-8.020 (2016); N.M. Stat. Ann. § 57-12-4 (West 2016); N.C. Gen. Stat. Ann. § 75-1.1 (2016); Okla. Stat. Ann. tit. 15 § 752.14 (West 2016); R.I. Gen. Laws Ann. § 6-13.1-3 (West 2016); S.C. Code Ann. § 39-5-20(b) (2016); Vt. Stat. Ann. tit. 9 § 2453(b) (West 2016). Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 24 of 31 - 16 - their attempt to recast that violation as an unfair business practice”), vacated and remanded on other grounds, sub nom. Starr v. Sony BMG Music Entm't, 592 F.3d 314 (2d Cir. 2010). Finally, the consumer protection claims under the laws of Alabama, Louisiana, Massachusetts, Minnesota, Nebraska, New York, Pennsylvania, Tennessee, and Washington should be dismissed for the additional reason that all require fraudulent or deceptive conduct in connection with a consumer transaction.14 Plaintiffs do not allege that RBH (or any other defendant for that matter) engaged in any such conduct. As discussed in detail in the preceding sections, RBH is only alleged to have executed a contract to develop a new product and to have “participated” in “discussions” concerning tablet removal. See Am. Compl. ¶ 12, 71. Therefore, these allegations do not state a claim for fraud or deceptive conduct under these state statutes. See, e.g., In re New Motor Vehicles Canadian Export Antitrust Litig., 350 F. Supp. 2d 160, 178, 14 See Ala. Code § 8-19-5(27) (2016) (forbidding certain acts or practices relating to deceptive advertisement, representation, and quality of consumer goods or services); La. Rev. Stat Ann. § 51-1401 (2016); Cheramie Serv. v. Shell Deepwater Prod., Inc., 35 So.3d 1053, 1059 (La. 2010) (finding an “extremely narrow” range of prohibited unfair activities and requiring a showing of “fraud, misrepresentation, deception, or other unethical conduct”) (citation omitted); Minn. Stat. §§ 325D.43, et seq. (2016) (listing enumerated prohibited acts involving fraud or deceit); In re New Motor Vehicles Canadian Export Antitrust Litig., 350 F.Supp. 2d 160, 189-90 (D. Me. 2004) (“Minnesota’s Uniform Deceptive Trade Practices Act prohibits a variety of acts, but all involve deception or misrepresentation.”); Neb. Rev. Stat. Ann. § 87-301 (West 2016) (prohibiting specific enumerated actions, all of which involve the misrepresentation of goods or services); N.Y. Exec. Law § 63(12) (2016) (declaring unlawful “persistent fraud or illegality” in the course of conducting business); 73 Pa. Const. Stat. Ann. § 201-2(4) (West 2016) (prohibiting “fraudulent or deceptive conduct which creates a likelihood of confusion or misunderstanding”); In re New Motor Vehicles, 350 F. Supp. 2d at 200 (finding the Pennsylvania consumer protection statute “requires fraud or deception” and allegations of conspiracy to prevent less expensive Canadian vehicles from entering the American market insufficient to state a claim); Tenn. Code Ann. § 47-18-101 (West 2016); Messer Griesheim Indus., v. Cryotech of Kingsport, Inc., 131 S.W.3d 457, 469 (Tenn. Ct. App. 2003) (“[T]here must be a deceptive act by the defendant before the defendant can be liable under the [Tennessee Consumer Protection Act.]”); Wash. Rev. Code Ann. § 19.86.020 (West 2016); Segal Co. (Eastern States), Inc. v. Amazon.com, 280 F.Supp.2d 1229, 1232 (W.D. Wash. 2003) (“[F]or conduct to be an unfair or deceptive practice under the [Washington] Consumer Protection Act (CPA), it must have the capacity to deceive a substantial portion of the public.”). Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 25 of 31 - 17 - 189-90, 196-98, 202-03 (D. Me. 2004) (where plaintiffs alleged a conspiracy among automobile manufacturers and dealers to prevent Canadian vehicles from entering the American market, dismissing claims under, inter alia, Michigan, Minnesota, New York, and Tennessee consumer protection statutes for failure to allege required fraudulent, deceptive, or unconscionable conduct); In re Flash Memory Antitrust Litig., 643 F. Supp. 2d 1133, 1160-63 (N.D. Cal. 2009) (dismissing New York and West Virginia consumer protection claims in case involving alleged horizontal price fixing conspiracy). For these reasons, the state law claims should be dismissed. V. PLAINTIFFS FAIL TO ALLEGE SUFFICIENT GROUNDS FOR THE EXERCISE OF PERSONAL JURISDICTION OVER RBH Although the Court did not reach the issue in the context of dismissing RBH from this litigation the first time, the vague allegations directed at RBH, a UK company, are insufficient grounds on which to base personal jurisdiction. A court may not exercise jurisdiction over a defendant unless that party had sufficient “minimum contacts” with the forum (here, the United States15) to satisfy the due process requirements of the Fifth Amendment. Pennzoil Prods. Co. v. Colelli & Assocs., 149 F.3d 197, 201 (3d Cir. 1998) (citing Int’l Shoe Co. v. Washington, 326 U.S. 310, 316 (1945)). Personal jurisdiction may be either general (if the defendant is “essentially at home” in the forum and thus subject to jurisdiction for any claim) or specific (if “the episode-in-suit occurred in the forum or the defendant purposefully availed itself of the forum”). Daimler AG v. Baumann, 134 S. Ct. 746 (2014); Helicopteros Nacionales de Colombia, S.A. v. Hall, 466 U.S. 408, 414 (1984); General Elec. Co. v. Deutz AG, 270 F.3d 144, 150 (3d Cir. 2001). As the Supreme Court has stressed, when considering jurisdiction over 15 In a federal antitrust case such as this, “the relevant forum to assess the defendant’s contacts is the United States as a whole.” In re Auto. Refinishing Paint Antitrust Litig., 358 F.3d 288, 291- 92 (3d Cir. 2004). Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 26 of 31 - 18 - foreign entities like RBH, courts must exercise particular restraint. Asahi Metal Indus. Co. v. Superior Court of Cal., 480 U.S. 102, 114 (1987) (“The unique burdens placed upon one who must defend oneself in a foreign legal system should have significant weight in assessing the reasonableness of stretching the long arm of personal jurisdiction over national borders.”). Just as it fails to state a claim, Plaintiffs’ woefully insufficient allegation that RBH is “in whole or in part responsible for some or all of the conduct alleged in [the] complaint” is too conclusory to plausibly establish the requisite contacts with the forum. The same holds for the wholesale allegations of conduct attributed to “Reckitt” purporting to encompass RBH. See First Chi. Int’l v. United Exch. Co., 836 F.2d 1375, 1378 (D.C. Cir. 1988) (“Conclusory statements such as these, however, [do] not constitute the prima facie showing necessary to carry the burden of establishing personal jurisdiction.”) (internal quotations omitted); Luellin v. Gulick, No. 1:10CV203, 2012 U.S. Dist. LEXIS 40281, at *14 (N.D. W. Va. Mar. 26, 2012) (“A plaintiff cannot establish personal jurisdiction by relying solely on the basis of his own conclusory, speculative assertions.”); see also Carefirst of Md., Inc. v. Carefirst Pregnancy Ctrs., Inc., 334 F.3d 390, 402 (4th Cir. 2003) (“When a plaintiff offers only speculation or conclusory assertions about contacts with a forum state, a court is within its discretion in denying jurisdictional discovery.”). And the remaining allegations specific to RBH fall well short of establishing grounds for either general or specific jurisdiction. A. RBH Is Not Subject To General Jurisdiction A corporation is subject to general jurisdiction only if the contacts between the corporation and the forum are so pervasive that the corporation can be said to be “essentially at home” there. Daimler, 134 S. Ct. at 749; Orazi v. Hilton Hotels Corp., No. 09-cv-05959, 2010 WL 4751728 at *2 (E.D. Pa. Nov. 22, 2010) (general jurisdiction is a “demanding” standard). RBH is not alleged to have a corporate presence in the United States. See Am. Compl. ¶ 12 Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 27 of 31 - 19 - (“[RBH] is a British corporation incorporated under the laws of England and Wales, with its registered office located at 103-105 Bath Road, Slough, Berkshire, SL1 3UH.”); Daimler, 134 S. Ct. at 760 (“With respect to a corporation, the place of incorporation and principal place of business are ‘paradig[m] ... bases for general jurisdiction.’”) (citing Goodyear Dunlop Tires Operations, S.A. v. Brown, 564 U.S. 915, 922-24 (2011)). While RBH is alleged to be “engaged in the development and manufacture of pharmaceuticals, including Suboxone, and health care products and services made and sold subject to FDA approval,” Am. Compl. ¶ 12, the Complaint does not allege that these activities took place within the United States, much less that they are so regular that RBH is “at home” here. See Lewis v. Cabana Coaches, LLC, No. 2:11-CV-2507, 2012 WL 246390, at *2 (E.D. Pa. Jan. 26, 2012) (finding no general jurisdiction where plaintiff “failed to allege or provide evidence to suggest that Cabana does any business in [the forum], let alone that its contacts are ‘systematic and continuous’”).16 B. RBH Is Not Subject To Specific Jurisdiction Specific jurisdiction is present only when: (1) the defendant purposely directed her activities at the forum state (purposeful availment); (2) the plaintiff’s claim arises out of and relates to those specific activities; and (3) the exercise of jurisdiction comports with fair play and substantial justice. See Marten v. Godwin, 499 F.3d 290, 296 (3d Cir. 2007). The allegations that RBH entered into a contract with MonoSol to develop Suboxone film and engaged in other 16 The allegations that RBH “investigates all consumer complaints as to the Suboxone products, trademarked the names for the financial programs to encourage the switch from Suboxone tablets to film, [] obtained patents together with MonoSol related to Suboxone film development …. monitored the taste and quality of Suboxone film, prepared materials for regulatory approval of Suboxone film, manufactured and supplied the ingredients for Suboxone film, and provided grants for the study of Suboxone” also are insufficient. See Am. Comp. ¶ 12. The States never say that any of these activities took place within the United States, and in any case, even if domestic, none is so regular and pervasive as to show RBH is “essentially at home” in the forum. Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 28 of 31 - 20 - action in connection with developing film, Am. Compl. ¶ 12, are insufficient to show purposeful availment. Plaintiffs never allege where the contract was executed or performed. In any case, a single contract within the forum would not justify the exercise of specific jurisdiction. See Mellon Bank (E.) PSFS, N.A. v. DiVeronica Bros., 983 F.2d 551, 557 (3d Cir. 1993) (“Contracting with a resident of the forum state does not alone justify the exercise of personal jurisdiction over a non-resident defendant . . . .”); Vetrotex Certainteed Corp. v. Consol. Fiber Glass Prods. Co., 75 F.3d 147, 152-153 (3d. Cir. 1996) (holding that defendant’s two in-state contracts did not support the conclusion that the defendant “purposefully availed itself of the privilege of doing business” in the state where the contract was fulfilled). The vague allegation that RBH “participated in discussions” at an unspecified location, Am. Compl. ¶ 71, is similarly deficient, as it does not show contact with the United States at all, much less activities “specifically directed” here. Finally, while the Complaint does allege conduct by Indivior in the United States (i.e., the removal of tablets from the market, the allegedly sham FDA citizen’s petition, and the alleged disparagement of tablets), Plaintiffs cannot impute Indivior’s actions in the forum to RBH for the purpose of establishing jurisdiction, even if they adequately plead a conspiracy between them. Hanson v. Denckla, 357 U.S. 235, 253 (1958) (“The unilateral activity of those who claim some relationship with a nonresident defendant cannot satisfy the requirement of contact with the forum State.”); In re Auto. Parts Antitrust Litig., No. 2:13-cv-02502, 2015 U.S. Dist. LEXIS 96470, at *59 (E.D. Mich. July 23, 2015) (“The Court has no basis for imputing the actions of one [conspiracy] defendant to another in analyzing jurisdiction . . . .”). Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 29 of 31 - 21 - Thus, Plaintiffs have failed to allege a relationship between RBH and the forum that would justify the exercise of personal jurisdiction.17 VI. CONCLUSION For the reasons set forth above, each of Plaintiffs’ claims against RBH should be dismissed with prejudice. 17 For all the same reasons, the exercise of jurisdiction over RBH, a foreign defendant, would not comport with notions of fair play and substantial justice. Toys “R” Us, Inc. v. Step Two, S.A., 318 F.3d 446, 451 (3d Cir. 2003) (citing World-Wide Volkswagen Corp. v. Woodson, 444 U.S. 286, 297 (1980)). Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 30 of 31 - 22 - Respectfully submitted, /s/ Mark A. Ford Mark A. Ford Peter A. Spaeth Benjamin N. Ernst Holly A. Ovington Mark S. Gordon WILMER CUTLER PICKERING HALE AND DORR LLP 60 State Street Boston, Massachusetts 02109 T: (617) 526-6000 Nancy J. Gellman Andrew S. Gallinaro CONRAD O’BRIEN PC 1500 Market Street Suite 3900 Centre Square West Tower Philadelphia, PA 19102-2100 T: (215) 864-9600 Counsel for Reckitt Benckiser Healthcare (UK) Limited Dated: December 12, 2016 Case 2:16-cv-05073-MSG Document 141-1 Filed 12/12/16 Page 31 of 31 IN THE UNITED STATES DISTRICT COURT FOR THE EASTERN DISTRICT OF PENNSYLVANIA STATE OF WISCONSIN By Attorney General Brad D. Schimel; et al., Plaintiffs, v. INDIVIOR INC. f/k/a RECKITT BENCKISER PHARMACEUTICALS, INC.; et al., Defendants. Case No. 2:16-cv-5073-MSG DECLARATION OF BENJAMIN N. ERNST IN SUPPORT OF DEFENDANT RECKITT BENCKISER HEALTHCARE (UK) LIMITED’S MEMORANDUM OF LAW IN SUPPORT OF ITS MOTION TO DISMISS Mark A. Ford Peter A. Spaeth Benjamin N. Ernst Holly A. Ovington Mark S. Gordon WILMER CUTLER PICKERING HALE AND DORR LLP 60 State Street Boston, Massachusetts 02109 T: (617) 526-6000 Counsel for Reckitt Benckiser Healthcare (UK) Limited OF COUNSEL: Nancy J. Gellman Andrew S. Gallinaro CONRAD O’BRIEN PC 1500 Market Street, Suite 3900 Centre Square, West Tower Philadelphia, PA 19102-2100 T: (215) 864-9600 Dated: December 12, 2016 Case 2:16-cv-05073-MSG Document 141-2 Filed 12/12/16 Page 1 of 3 I, Benjamin N. Ernst, declare as follows: 1. I am an associate at the law firm of Wilmer Cutler Pickering Hale and Dorr LLP, counsel for Defendant Reckitt Benckiser Healthcare (UK) Limited (“RBH”). I am a member in good standing of the Bar of the Commonwealth of Massachusetts and am admitted to this Court pro hac vice. I make this declaration in support of RBH’s Memorandum of Law in Support of its Motion to Dismiss. 2. Attached hereto as Exhibit 1 is a true and accurate copy of a printout from the Food and Drug Administration’s website showing information regarding the New Drug Application for Suboxone Tablets, printed from the web address: http://www.accessdata.fda.gov/scripts/cder/ob/results_product.cfm?Appl_Type=N&Appl_No=0 20733#. 3. Attached hereto as Exhibit 2 is a true and accurate copy of a printout from the Food and Drug Administration’s website showing information regarding the New Drug Application for Suboxone Film, printed from the web address: http://www.accessdata.fda.gov/scripts/cder/ob/results_product.cfm?Appl_Type=N&Appl_No=0 22410#. 4. Attached hereto as Exhibit 3 is a redacted copy of a 2006 product development agreement between RBH and Defendant MonoSol Rx, LLC. The document is designated Confidential and an unopposed motion to seal this document has been filed with the Court. A true and accurate unredacted copy of this document is being provided to counsel of record. In consideration of EU data privacy laws, the name and signature of an RBH employee has been permanently redacted from this document. 2 Case 2:16-cv-05073-MSG Document 141-2 Filed 12/12/16 Page 2 of 3 Case 2:16-cv-05073-MSG Document 141-2 Filed 12/12/16 Page 3 of 3 Exhibit 1 Case 2:16-cv-05073-MSG Document 141-3 Filed 12/12/16 Page 1 of 3 Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations http://www.accessdata.fda.gov/scripts/cder/ob/results_product.cfm?Appl_Type=N&Appl_No=020733#[12/9/2016 12:07:52 PM]  Home  Drug Databases  Orange Book Home Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations Home | Back to Search Results Product Details for NDA 020733 Collapse All Active Ingredient: BUPRENORPHINE HYDROCHLORIDE; NALOXONE HYDROCHLORIDE Proprietary Name: SUBOXONE Dosage Form; Route of Administration: TABLET; SUBLINGUAL Strength: EQ 2MG BASE;EQ 0.5MG BASE Reference Listed Drug: No TE Code: Application Number: N020733 Product Number: 001 Approval Date: Oct 8, 2002 Applicant Holder Full Name: INDIVIOR INC Marketing Status: Discontinued Patent and Exclusivity Information Active Ingredient: BUPRENORPHINE HYDROCHLORIDE;  SHARE  TWEET  LINKEDIN  PIN IT  EMAIL  PRINT Marketing Status: Discontinued SUBOXONE (BUPRENORPHINE HYDROCHLORIDE; NALOXONE HYDROCHLORIDE) EQ 2MG BASE;EQ 0.5MG BASE Marketing Status: Discontinued SUBOXONE (BUPRENORPHINE HYDROCHLORIDE; NALOXONE HYDROCHLORIDE) EQ 8MG BASE;EQ 2MG BASE Case 2:16-cv-05073-MSG Document 141-3 Filed 12/12/16 Page 2 of 3 Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations http://www.accessdata.fda.gov/scripts/cder/ob/results_product.cfm?Appl_Type=N&Appl_No=020733#[12/9/2016 12:07:52 PM] NALOXONE HYDROCHLORIDE Proprietary Name: SUBOXONE Dosage Form; Route of Administration: TABLET; SUBLINGUAL Strength: EQ 8MG BASE;EQ 2MG BASE Reference Listed Drug: No TE Code: Application Number: N020733 Product Number: 002 Approval Date: Oct 8, 2002 Applicant Holder Full Name: INDIVIOR INC Marketing Status: Discontinued Patent and Exclusivity Information Note: If you need help accessing information in different file formats, see Instructions for Downloading Viewers and Players. Accessibility Careers FDA Basics FOIA No FEAR Act Site Map Transparency Website Policies U.S. Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993 1-888-INFO-FDA (1-888-463-6332) Contact FDA       FDA Archive Combination Products  Advisory Committees  Regulatory Information  Safety  Emergency Preparedness  International Programs  News & Events  Training & Continuing Education  Inspections & Compliance  Federal, State & Local Officials  Consumers  Health Professionals  Science & Research  Industry  Case 2:16-cv-05073-MSG Document 141-3 Filed 12/12/16 Page 3 of 3 Exhibit 2 Case 2:16-cv-05073-MSG Document 141-4 Filed 12/12/16 Page 1 of 4 Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations http://www.accessdata.fda.gov/scripts/cder/ob/results_product.cfm?Appl_Type=N&Appl_No=022410#[12/9/2016 12:06:56 PM]  Home  Drug Databases  Orange Book Home Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations Home | Back to Search Results Product Details for NDA 022410 Collapse All Active Ingredient: BUPRENORPHINE HYDROCHLORIDE; NALOXONE HYDROCHLORIDE Proprietary Name: SUBOXONE Dosage Form; Route of Administration: FILM; BUCCAL, SUBLINGUAL Strength: EQ 2MG BASE;EQ 0.5MG BASE Reference Listed Drug: No TE Code: Application Number: N022410 Product Number: 001 Approval Date: Aug 30, 2010 Applicant Holder Full Name: INDIVIOR INC Marketing Status: Prescription Patent and Exclusivity Information Active Ingredient: BUPRENORPHINE HYDROCHLORIDE;  SHARE  TWEET  LINKEDIN  PIN IT  EMAIL  PRINT Marketing Status: Prescription SUBOXONE (BUPRENORPHINE HYDROCHLORIDE; NALOXONE HYDROCHLORIDE) EQ 2MG BASE;EQ 0.5MG BASE Marketing Status: Prescription SUBOXONE (BUPRENORPHINE HYDROCHLORIDE; NALOXONE HYDROCHLORIDE) EQ 4MG BASE;EQ 1MG BASE Case 2:16-cv-05073-MSG Document 141-4 Filed 12/12/16 Page 2 of 4 Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations http://www.accessdata.fda.gov/scripts/cder/ob/results_product.cfm?Appl_Type=N&Appl_No=022410#[12/9/2016 12:06:56 PM] NALOXONE HYDROCHLORIDE Proprietary Name: SUBOXONE Dosage Form; Route of Administration: FILM; BUCCAL, SUBLINGUAL Strength: EQ 4MG BASE;EQ 1MG BASE Reference Listed Drug: No TE Code: Application Number: N022410 Product Number: 003 Approval Date: Aug 10, 2012 Applicant Holder Full Name: INDIVIOR INC Marketing Status: Prescription Patent and Exclusivity Information Active Ingredient: BUPRENORPHINE HYDROCHLORIDE; NALOXONE HYDROCHLORIDE Proprietary Name: SUBOXONE Dosage Form; Route of Administration: FILM; BUCCAL, SUBLINGUAL Strength: EQ 8MG BASE;EQ 2MG BASE Reference Listed Drug: No TE Code: Application Number: N022410 Product Number: 002 Approval Date: Aug 30, 2010 Applicant Holder Full Name: INDIVIOR INC Marketing Status: Prescription Patent and Exclusivity Information Active Ingredient: BUPRENORPHINE HYDROCHLORIDE; NALOXONE HYDROCHLORIDE Proprietary Name: SUBOXONE Dosage Form; Route of Administration: FILM; BUCCAL, Marketing Status: Prescription SUBOXONE (BUPRENORPHINE HYDROCHLORIDE; NALOXONE HYDROCHLORIDE) EQ 8MG BASE;EQ 2MG BASE Marketing Status: Prescription SUBOXONE (BUPRENORPHINE HYDROCHLORIDE; NALOXONE HYDROCHLORIDE) EQ 12MG BASE;EQ 3MG BASE Case 2:16-cv-05073-MSG Document 141-4 Filed 12/12/16 Page 3 of 4 Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations http://www.accessdata.fda.gov/scripts/cder/ob/results_product.cfm?Appl_Type=N&Appl_No=022410#[12/9/2016 12:06:56 PM] SUBLINGUAL Strength: EQ 12MG BASE;EQ 3MG BASE Reference Listed Drug: Yes TE Code: Application Number: N022410 Product Number: 004 Approval Date: Aug 10, 2012 Applicant Holder Full Name: INDIVIOR INC Marketing Status: Prescription Patent and Exclusivity Information Note: If you need help accessing information in different file formats, see Instructions for Downloading Viewers and Players. Accessibility Careers FDA Basics FOIA No FEAR Act Site Map Transparency Website Policies U.S. Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993 1-888-INFO-FDA (1-888-463-6332) Contact FDA       FDA Archive Combination Products  Advisory Committees  Regulatory Information  Safety  Emergency Preparedness  International Programs  News & Events  Training & Continuing Education  Inspections & Compliance  Federal, State & Local Officials  Consumers  Health Professionals  Science & Research  Industry  Case 2:16-cv-05073-MSG Document 141-4 Filed 12/12/16 Page 4 of 4 Exhibit 3 (Under Seal) (Motion Pending) Case 2:16-cv-05073-MSG Document 141-5 Filed 12/12/16 Page 1 of 1 Exhibit 4 Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 1 of 49 September 25, 2012 BY HAND DELIVERY Division of Dockets Management Food and Drug Administration 5630 Fishers Lane, Room 1061 (HF A-305) Rockville, Maryland 20852 0 1 0 7 1="Reckitt 1z SEP 25 Benckiser 'P~dtHlaceuticols Inc. Re: Safety Concerns Regarding Buprenorphine For Opioid Dependence CITIZEN PETITION Reckitt Benckiser Pharmaceuticals Inc. (HRBP") submits this petition pursuant to Section 505(b), 5050), and 505(q) of the Federal Food, Drug, and Cosmetic Act ("FDC Act"), among other provisions of law, to request that the Commissioner of Food and Drugs ("Commissioner") refrain from approving any buprenorphine drug application (whether New Drug Application ("NDA") or Abbreviated New Drug Application ("ANDA")) for opioid dependence treatment until the Food and Drug Administration ("FDA") considers whether such application includes adequate measures to ensure the safe use of buprenorphine, and require all approved applications to contain the same safeguards. As described further below, use ofbuprenorphine products without these safeguards puts opioid dependent patients and their families at risk. The approval ofSubutex® (buprenorphine HC1) and Suboxone® (buprenorphine HCl-naloxone HCl) for opioid dependence treatment created a pathway to treatment for a historically underserved patient population. However, as a partial ~-opioid agonist, buprenorphine poses risks of diversion, abuse and dependence, especially when prescribed to patients with a history of addiction. Due to these concerns, Suboxone's and Subutex's sponsor, RBP, implemented a comprehensive risk mitigation program ("RiskMAP"). Reckitt Benckiser Pharmaceuticals, Inc. 10710 Midlothian Turnpike, Suite 430 Richmond. VA 23235 USA T 804 379 1090 F 801\ 379 1215 www.suboxone.com ~OS<')_ '}G'~- e,? Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 2 of 49 Division of Dockets Management September 25, 2012 Page2 RBP launched its extensive RiskMAP when Suboxone and Subutex were approved by FDA in 2002. Although the RiskMAP was effective in meaningfully reducing the risks of abuse and diversion, an alarming trend regarding pediatric safety emerged in 2006-2007. Poison control data showed an increasing rate of young children being accidentally exposed to Subutex and Suboxone. RBP took action to address this trend, implementing targeted educational interventions on the risk of pediatric exposure to buprenorphine. RBP also developed Suboxone Film with child-resistant unit-dose packaging to reduce the likelihood of pediatric exposure as well as the number of dosage units exposed if the child-resistant packaging were defeated. After RBP commenced its pediatric exposure education initiative, the rates of pediatric exposure plateaued. After introduction of buprenorphine film, those rates steeply declined. A recent study by independent experts at the Researched Abuse, Diversion and Addiction-Related Surveillance ("RADARS") System and Venebio Group, LLC further explored the observed association between these measures and the risk of pediatric exposure. Across the study period (fourth quarter 2009 to first quarter 2012) 2,380 unique cases of pediatric exposure in children under the age of 6 were identified, including 536 serious adverse events. The risk of unintentional pediatric exposure in children under 6 years to single entity and combination buprenorphine tablets was 2.5 and 7.8 times greater, respectively, than for buprenorphine combination film. Further, for the most recent quarter measured in 2012, the risk of unintentional pediatric exposures to combination tablets was 8.5 times greater than it was for combination film. RBP now urges the FDA to recognize the pediatric safety risks posed by buprenorphine marketed for opioid dependence that lacks these safeguards. RBP asks that FDA not approve any buprenorphine application for opioid dependence Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 3 of 49 Division of Dockets Management September 25,2012 Page 3 without targeted educational interventions on the risk of pediatric exposure because such interventions are important to ensuring pediatric safety. Moreover, RBP asks that FDA not approve any buprenorphine application for opioid dependence without child-resistant unit-dose packaging because evidence shows that such products would be unsafe to young children. Finally, RBP requests FDA not to approve any buprenporhine/naloxone ANDA for opioid dependence treatment until FDA determines whether the reference listed drug ("RLD") for those drugs was discontinued for reasons of safety. Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 4 of 49 Division of Dockets Management September 25, 2012 Page4 I. ACTION REQUESTED ............................................................................. 6 II. STATEMENT OF GROUNDS .................................................................. 6 A. FACTUAL BACKGROUND ................................................................. 6 1. Background and Approval of Buprenorphine ..................................... 6 a. Approval of Buprenorpltine for Opioid Dependence Significantly Expanded Access to Addiction Treatment ................................................... 6 b. Suboxone and Subutex Are Associated With Serious Health Risks. 9 c. RBP Adopts a Robust RiskMAP to Address Risks Posed by Subutex and Suboxone ............................................................................................. 12 i. RBP Monitors B11prenorphine Use .................................................. 12 ii. RBP's Comprehensive Education Materials and Interventions .. 13 iii. RBP Develops Subutex and Suboxone REMS ............................. 16 2. RBP Responds to an Alarming Trend in Pediatric Exposure Rates 18 3. RBP Develops Buprenorphine Film .................................................... 21 4. Recent Study Reveals Decreased Risk of Pediatric Exposure to Buprenorphine in Child-Resistant Unit-Dose Packaging .................. 24 5. RBP Discontinues Marketing of Suboxone Sublingual Tablets Due to Safe-ty Concerns ..................................................................................... 26 B. LEGAL BACKGROUND ..................................................................... 26 C. ANALYSIS ............................................................................................. 29 1. FDA Should Refrain from Approving any Buprenorphine NDA or ANDA That Does Not Include A Targeted Pediatric Exposure Education Program Because Those Applications Are Not Approvable Pursuant to Sections 505(b) and (j) of the FDC Act ..... 29 a. FDA may not approve a buprenorplline NDAfor opioid dependence treatment witlwut educational interventions targeted to pediatric exposure risk because the labeling of drugs subject to those NDAs is misleading . .................................................................................................. 3 0 b. FDA should not approve a buprenorphine NDA for opioid dependence treatment witlwut targeted educational interventions on Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 5 of 49 Division of Dockets Management September 25, 2012 Page 5 pediatric exposure risks, because the risk-benefit profiles of drugs subject to tltose NDAs does not favor approval . .................................................... 33 c. FDA must deny any buprenorphine ANDA for opioid dependence treatment that lacks targeted educational interventions on pediatric exposure risks because such applications fail to contain the same labeling as tl1e RLD . ................................................................................................. 34 d. FDA must deny any buprenorpltine ANDA for opioid dependence treatment that lacks educational interventions adopted to reduce the risk of pediatric exposure, because such ANDAs lack the same risk-benefit profile as the RLD .•..............•...........•......•••............•.................................... 36 2. FDA Should Refrain from Approving Applications for Buprenorphine for Opioid Addiction that Lacks Child-Resistant Unit-Dose Packaging ............................................................................. 38 a. FDA may not approve any buprenorphine NDA for addiction treatment that lacks child-resistant unit-dose packaging because FDA It as insufficient information to determine the safety of those drugs ............... 39 b. FDA may not approve any buprenorphine NDA for addiction treatment that lacks child-resistant unit-dose packaging because the risk- benefit profile of those drugs does not favor approval .............................. 42 3. FDA may not approve any buprenorphine/naloxone ANDA for addiction treatment until FDA determines whether the RLD for those drugs was discontinued for reasons of safety ................................................................ 43 III. ENVIRONMENTAL IMPACT ............................................................... 46 IV. ECONOMIC IMP ACT ............................................................................. 47 V. CERTIFICATION .................................................................................... 48 Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 6 of 49 Division of Dockets Management September 25 ~ 20 12 Page 6 I. ACTION REQUESTED A. That FDA refrain from approving any buprenorphine NDA or ANDA for the treatment of opioid addiction that does not include a targeted pediatric exposure education program because those applications are not approvable pursuant to sections 505(b) and (j) of the FDC Act. B. That FDA refrain from approving applications for buprenorphine for opioid addiction that lacks child-resistant unit-dose packaging. C. That FDA not approve any buprenorphine/naloxone ANDA for addiction treatment until FDA determines whether the RLD for those drugs was discontinued for reasons of safety. II. STATEMENT OF GROUNDS A.FACTUALBACKGROUND 1. Background and Approval of Buprenorphine a. Approval of Buprenorphine for Opioid Dependence Significantly Expanded Access to Addiction Treatment Opioid addiction and abuse is a pervasive public health problem that plagues patients~ families, and communities. 1 In 2010, the Substance Abuse and Mental Health Services Administration ("SAMHSA") reported in the National Guide to Drug Abuse Epidemiology, Department of Mental Health and Substance Dependence, Noncommunicable Diseases and Mental Health Cluster, World Health Organization (2000), available at http://whqlibdoc.who.int/hq/2000/a58352_PartA.pdf. Buprenorphine. Center for Substance Abuse Treatment, Substance Abuse and Mental Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 7 of 49 Division ofDockets Management September 25, 2012 Page7 Survey on Drug Use and Health, that over 1.9 million Americans suffer from opioid dependence or abuse. 2 Prior to 2000, patients who suffered from opioid addiction were primarily referred to a narcotic treatment program ("NTP") for opioid maintenance treatment using methadone. Methadone is a Schedule II controlled substance3 and a full J!-opioid receptor agonist similar to other highly abused opiates such as heroin.4 To mitigate the risk of diversion associated with prescribing methadone to opioid addicted patients, methadone may only be administered to treat addiction in a facility specially registered by the U.S. Drug Enforcement Administration ("DEA") as a NTP.5 Many opioid dependent patients avoided NTPs due to privacy concerns and the perceived stigma attached to those programs rendering methadone an incomplete answer to the demand for opioid addiction treatment.6 Accordingly, in 2000, Congress sought to improve access to opioid addiction treatment via the Drug Addiction Treatment Act ("DATA"). DATA enabled practitioners who 2 3 4 5 6 Substance Abuse and Mental Health Services Administration, Results from the 2010 National Survey on Drug Use and Health: Summary ofNational Findings, NSDUH Series H-41, ffiiS Publication No. (SMA) 11-4658, available at http://www.samhsa.gov/data/NSDUH/2k I ONSDUH/2k 1 OResults.htm. 21 U.S.C. § 812(c) (2010). The U.S. Drug Enforcement Administration ("DEA") places drugs and other substances in a respective schedule according to their relative abuse potential and accepted medical use. For example, Schedule I controlled substances have no currently accepted medical use and a high potential for abuse and, and Schedule II controlled substances have a currently accepted medical use but a higher potential for abuse than Schedule III, IV, or V controlled substances. /d. at (b). About Buprenorphine Therapy, U.S. Dep't of Health and Human Services, http://buprenorphine.samhsa.gov/about.html. 21 C.P.R.§ 1306.07 (2012). Elisa F. Cascade et al., Prescribing/or Buprenmphine in the Treatment ofOpioid Addiction, 4(1) Psychiatry 15, 15-16 (2007). Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 8 of 49 Division of Dockets Management September 25, 2012 Page 8 obtained special training to administer Schedule III, IV, or V controlled substances to a certain number of patients in an office-based setting. 7 RBP had developed two buprenorphine products for the treatment of opioid addiction: a single-entity buprenorphine product, Subutex, intended for a brief induction stage, and Suboxone, a buprenorphine-naloxone combination drug for post-induction maintenance treatment. Suboxone posed less risk of diversion and abuse than Subutex, because naloxone's J.t-opioid antagonist properties will precipitate withdrawal symptoms if used parenterally by a full opioid agonist dependent patient.8 Suboxone is thus less attractive to drug abusers than Subutex.9 Prior to these drugs being approved in 2002 by FDA, 10 buprenorphine was rescheduled from Schedule V to Schedule III 1 1 and they became the first opioid addiction treatments available outside an NTP pursuant to DATA 2000. The approval of Subutex and Suboxone broke barriers in addiction treatment. 12 For the first time, patients could obtain opioid addiction treatment from their family physicians and take their medication inside the privacy of their own home. Patients who previously avoided treatment due to the stigma and lack of privacy attached to NTPs, finally sought and obtained treatment. 13 Given the 8 9 10 II 12 13 Drug Addiction Treatment Act of2000, Pub. L. No. 106-310, § 3502, 114 Stat. 1222-7 (2000). Buprenorphine, Center for Substance Abuse Treatment, Substance Abuse and Mental Health Services Administration, US Department of Health and Human Services, About Buprenorphine Therapy, available at http://buprenorphine.samhsa.gov/about.html. Id Drugs@FDA, available at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. 67 Fed. Reg. 62,354 (Oct. 7, 2002). Cynthia G. McConnick et al., Case histories in pharmaceutical risk management, 1 OS (Suppl. I) Drug and Alcohol Dependence S42, S50 (2009). Elisa F. Cascade et al., supra n. 6. Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 9 of 49 Division of Dockets Management September 25,2012 Page9 devastating impact of opioid addiction on patients and families, the approval of Suboxone and Subutex was a critical step in the advancement of addiction medicine. 14 b. Suboxone and Subutex Are Associated With Serious Health Risks Because both Subutex and Suboxone have opioid agonist properties and are indicated to treat opioid addicted patients, these drugs are associated with serious risks of diversion and abuse. Reports indicate that buprenorphine is attractive to drug users and may be abused parenterally. 15 The medical risks ofbuprenorphine parenteral abuse are similar to the risks associated with other injected substances to include "soft tissue infections, emboli, acute limb ischemia, endocarditis, sepsis, and HIV and Hepatitis C infection."16 A significant societal risk associated with buprenorphine diversion is abuse by individuals who are experimenting with illicit drugs, potentially contributing to the occurrence of concomitant drug abuse. 17 Further, as aptly noted by DEA in its rescheduling of buprenorphine, "providing an abusable substance to known drug abusers imparts enhanced risks."18 Buprenorphine overdose poses medical risks 14 15 16 17 18 Guide to Drug Abuse Epidemiology, Department of Mental Health and Substance Dependence, Noncommunicable Diseases and Mental Health Cluster, World Health Organization (2000), available at http://whqlibdoc.who.int/hq/2000/a58352_PartA.pdf. Michael A. Yokell, et. al., Buprenorphine and Buprenorphine/Naloxone Diversion, Misuse, and Illicit Use: An International Review, 4(1) Curr. Drug Abuse Rev. 28,32 (2011). Id Id 67 Fed. Reg. 62,354,62,357. (Oct. 7, 2002). Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 10 of 49 Division of Dockets Management September 25, 2012 Page 10 comparable to other opioids. 19 Significant r~spiratory depression and death have occurred in association with buprenorphine, particularly when taken by intravenous route in combination with benzodiazepines or other CNS depressants (including alcohol).20 Further, as addressed in Subutex's and Suboxone's labeling, the effects of exposure are particularly acute in young children and can be severe.21 Similar to other opioids, they include CNS respiratory depression and death.22 There has also been one case report of onset of acute leukoencephalopathy after buprenorphine intoxication in a two-year-old child.23 The most serious effects have been reported in children less than two years of age at doses greater than or equal to four milligrams.24 Because, prior to August 10, 2012, both Subutex and Suboxone were only distributed in 2 mg and 8 rng dosage units, exposures to greater than 2 mgs and less than 8 mgs could only result from the child ingesting multiple 2 mg dosage units. According to American Association of Poison Control Centers ("AAPCC") data25 measuring single substance exposures to buprenorphine, meaning no other 19 20 21 22 23 24 25 See Subutexsublingual tablet, NDA 20-732, Risk Evaluation and Mitigation Strategy, Important Safety Information I, 6 (approved Dec. 20 I I) (hereinafter "Suboxone Tablet REMS"). !d. !d. Bryan D. Hayes, PharmD et al., Toxicity of Buprenorphine Overdoses in Children, 121 Pediatrics e782, e784 (2009). B. Bellot eta!., Acute leukoencephalopathy after buprenorphine intoxication in a 2-year- old child, 15(4) Eur. J. Pediatr. Neural. 368 (2011). !d. The American Association of Poison Control Centers (AAPCC; http://www.aapcc.org) maintains the national database of information logged by the country's 61 Poison Control Centers (PCCs). Case records in this database are from self-reported calls: they reflect only information provided when the public or healthcare professionals report an actual or Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 11 of 49 Division of Dockets Management September 25, 2012 Page 11 drugs were detected, from 2006 through June 2011, 37% of all exposures involved moderate effect or major effect, including four deaths.26 In addition, during that same time period, 34% of all exposures to children under 6 resulted in a major or moderate effect, including death.27 In August 2010, the first pediatric death attributed solely to buprenorphine was reported to AAPCC.Z8 As of June 30, 2011, 3 other deaths had been reported to AAPCC for children under the age of six. 29 In October 20 II , the New York Times reported the death of a thirteen-month-old boy who opened a bottle of buprenorphine tablets and ingested them while in his crib.30 More recently, in 26 21 28 29 30 potential exposure to a substance (e.g., an ingestion, an inhalation, or a topical exposure, etc.), or request information/educational materials. Exposures do not necessarily represent a poisoning or overdose. The AAPCC is not able to completely verify the accuracy of every report made to member centers. Additional exposures may go unreported to PCCs and data referenced from the AAPCC should not be construed to representthe complete incidence of national exposures to any substance(s). Data submitted to NDA 22-410, NDA 20-733, and NDA 20-732. !d. AAPCC defines "death" as only death that "was a direct complication of the exposure." Major effect means that the "person exhibited symptoms that were life- threatening or resulted in significant residual disability." Moderate effects means the "exposure was not life-threatening, but some form oftreatment was indicated." Minor effect means that "the person exhibited some symptoms, but were minimally bothersome and usually resolved rapidly." American Association of Poison Control Centers, National Poison Data System Report, available at http://www .aapcc.orgldnn/LinkCI ick.aspx?fileticket=WFdNF2cwrMI%3 D&tabid=31 0& mid=728. Data submitted to NDA 22-410, NDA 20-733, and NDA 20-732. ld Baby Boy Dies; Was Given Pills as a Toy, N.Y. Times (Oct. 14, 2011), available at http://www.nytimes.com/2011/I0/15/nyregion/baby-boy-dies-of-Suboxone- overdose.html. See also, Kerry A. Schwartz, et. al., Suboxone (Buprenorphine/Naloxone) Toxicity in Pediatric Patients A Case Report, 23 Pediatric Emergency Care 651, 651-652 (Sept. 2007) (a report of case studies of pediatric exposures to buprenorphine in young children). It should be noted that AAPCC estimates that it detects only 56%, or just slightly more than half, of poison exposures that occur annually and only 3.5% of poisoning fatalities. Bronstein, A.C., et al., 2007 Annual Report of the American Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 12 of 49 Division of Dockets Management September 25, 20 12 Page 12 August 2012, a local news source reported the hospitalization of a two-year-old child for suspected exposure to Suboxone, after the child's mother reportedly stored the medication in a breath mint container.31 c. RBP Adopts a Robust RiskMAP to Address Risks Posed by Subutex and Suboxone RBP recognized the need to balance the public health benefit of expanded access to addiction treatment and the unique diversion and abuse concerns and medical risks posed by Suboxone and Subutex. Thus, prior to FDA approval, RBP worked closely with FDA, Substance Abuse and Mental Health Services Administration ("SAMHSA"), and DEA to appropriately manage these risks. This collaboration resulted in a comprehensive FDA-approved RiskMAP, which included extensive monitoring, education, and surveillance measures.32 RBP later adjusted and improved this RiskMAP to address the emergence of pediatric safety concerns stemming from an unanticipated spike in pediatric exposures to buprenorphine. i. RBP Monitors Buprenorphine Use As part of its RiskMAP, RBP undertook an expansive monitoring and reporting initiative. RBP monitored and reported instances of individuals who were primarily addicted to buprenorphine, abuse ofbuprenorphine by opioid-naive individuals, death due to overdose of buprenorphine, and neonatal withdrawal 31 32 Association of Poison Control Centers' National Poison Data System (NPDS), 45 Clinical Toxicology 815 (2007). See Police: 2-Year-Old Overdosed on Narcotics, Rtv6theindychannel, (Aug. 22, 2012), available at http://www.theindychannel.com/news/31376335/detail.html. Cynthia G. McCormick et al., supra n. 12. Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 13 of 49 Division of Dockets Management September 25, 2012 Page 13 from buprenorphine.33 This monitoring kept RBP apprised of changes in buprenorphine abuse, diversion, misuse and other important safety trends. Further, as part of its effort to monitor and investigate suspicious orders by customers, RBP established a single distribution center for Subutex and Suboxone.34 RBP created a new function within the company that focused solely on assisting the distribution facility to establish parameters for detecting, evaluating, and canceling suspicious orders.35 The Medication Utilization Manager, who performs this function, is further apprised when safety concerns, such as increased incidence of diversion or pediatric exposures arise in geographic regions of the country, so that RBP can target and address those trends. ii. RBP 's Comprehensive Education Materials and Interventions RBP developed educational materials to emphasize the safe and effective use ofbuprenorphine for providers, patients, counselors and families. 36 Those materials focused on reinforcing the matrix of care model for addiction treatment and provided information that supported best medical practices.37 The matrix model emphasizes the importance of integrating all aspects of addiction treatment including relapse prevention, family and group therapy, motivational interviewing, 33 34 35 36 37 !d. !d. Wholesale distributors are required to report to DEA suspicious orders of controlled substances. Suspicious orders include orders of an unusual size, frequency, and orders deviating from a normal pattern. 21 C.F.R. § 1301.74(b). Cynthia G. McCormick et al., supra n. 12. /d. !d. Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 14 of 49 Division of Dockets Management September 25, 2012 Page 14 I 2-step involvement, and psychological and social support. 38 In addition, RBP emphasized the important role of counseling and other behavioral treatment as a supplement to opioid maintenance to achieve successful outcomes. By educating providers on these important aspects of addiction therapy, RBP contributed to ensuring that patients successfully completed treatment. RBP ensured that education on proper prescribing and the risks of abuse and diversion was a standard component of all promotional materials. 39 RBP also provided unrestricted grants to professional associations authorized by DATA 2000 to train providers on becoming DATA-certified.40 RBP utilized several critical educational interventions to ensure risk messages and strategies reached the treatment community. RBP sent teams of field representatives into the community to educate physicians, pharmacists, and counselors on the proper use of Suboxone and Subutex. RBP ensured these field representatives, a.k.a. Clinical Liaisons, were properly trained on the risks of buprenorphine use for opioid maintenance treatment and the role that Suboxone and Subutex treatment play in the overall treatment regimen. RBP also developed websites to reinforce educational messages about the risks of misuse and abuse associated with Subutex and Suboxone, and the importance of treatment being more than just the prescription of a medication.41 38 39 40 41 See Ahndrea Weiner, M.S., LMFT, Matrix Model of Outpatient Treatment for Substance Dependence (May 19, 2003), available at http://www .ag.state.nd.us/MethSummit/MethTreatment-Ahndrea Weiner.pdf Cynthia G. McCormick et al., supra n. 12. !d. Jd By 2011, over 2.6 million unique visitors accessed www.Suboxone.com and www.turntohelp.com. Through these websites, patients and caregivers contemplating or committed to treatment can sign up to receive ongoing treatment support via email Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 15 of 49 Division ofDockets Management September 25, 2012 Page 15 RBP created a Medical Information Unit to field caJJs from patients and providers about safety issues regarding buprenorphine, including misuse or accidental exposure. These calls are answered by a registered nurse trained on appropriate steps to take in a safety emergency. RBP also established a team of Field Medical Advisors ("FMAs") to educate providers on best medical practices and ways to decrease risks of diversion and abuse.42 FMAs have significant experience and/or clinical education in addiction medicine and ensure providers receive important safety information. FMAs' key messages included the importance of early and frequent patient assessments; patient medication dosage limits; the need to educate patients to refrain from misusing, abusing or diverting their medication; and the importance of proper storage of medication. The FMAs also worked closely with the Medication Utilization Manager to evaluate signs of abuse and actively intervene through education and field contact where there was suspected misuse of Suboxone or Subutex. 43 In addition, RBP initiated an innovative Treatment Advocate Training Program, through which it recruited and trained individuals with prior experience in addiction medicine, called Treatment Advocates ("TAs"). T As facilitate one- on-one and small group discussions with physicians, pharmacists and other providers on the appropriate use and risks of misuse, abuse, and diversion of buprenorphine. RBP conducts a large number ofT A small group discussions each year throughout the country (4,000 between July 2011 and June 2012, alone). 42 43 messages to improve their knowledge of the disease of addiction and steps that can be taken to ensure successful treatment. Cynthia G. McCormick et al., supra n. 12, at SSO. ld. at S50-S51. Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 16 of 49 Division of Dockets Management September 25,2012 Page 16 RBP contracted with an independent monitoring organization to, among other things, actively survey DATA-qualified physicians and persons enrolled in substance abuse treatment programs on the prevalence of buprenorphine abuse; monitor emergency department visits related to buprenorphine; analyze poison control center and emergency room data for reported buprenorphine exposure cases; monitor internet newsgroups, chat rooms, and blogs discussing buprenorphine in the context of misuse and abuse; and utilize a network of key informants to monitor trends in illegal drug use in their locales and provide street- level surveillance.44 This monitoring alerted RBP of changes in diversion and abuse trends, new issues of misuse, and other important safety trends so that RBP could appropriately respond and implement new safety initiatives as necessary. iii. RBP Develops Subutex and Suboxone REMS In 2007, Congress amended the FDC Act to require Risk Evaluation and Mitigation Strategies ("REMS") for new and existing drugs that posed certain public health risks.45 FDA required that applicants for drugs subject to RiskMAPs develop a REMS program that included the RiskMAP elements. In response, RBP developed REMS for Suboxone and Subutex while continuing to maintain and improve implementation of its RiskMAP. Suboxone's and Subutex's REMS are now in place with clear goals and mechanisms to mitigate the risks of unintentional pediatric exposures, accidental overdose, misuse, and abuse, and inform patients of the serious risks associated with use of Suboxone and Subutex. The REMS requires a Medication Guide to be 44 4S Id at SSt. Food and Drug Administration Amendments Act (FDAAA) of2007, Pub. L. No. 110-85, Title IX, Subtitle A, Section 901, 121 Stat. 823 (2007), (codified at 21 U.S.C. § 355-1 ). Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 17 of 49 Division ofDockets Management September 25, 2012 Page 17 dispensed with each Suboxone/Subutex prescription, certain Elements to Assure Safe Use ("ETASU"), and certain monitoring and implementation requirements.46 The Subutex and Suboxone REMS Medication Guide educates patients on risks related to use, such as physical dependence and the onset of withdrawal when Suboxone is used parenterally. 47 The ET ASU include, among other things, requiring patients to meet certain diagnostic criteria prior to prescribing those medications, the use of an "Appropriate Use Checklist" by providers, and the mailing of educational materials to DATA -certified providers and retail pharmacies.48 Subutex and Suboxone's REMS ask providers, inter alia, to monitor patients' use of their medication through weekly or more frequent visits depending on patient stability and progression in treatment, to assess and reinforce patients' compliance with their medication regimen, and to assess whether the patients' are receiving the appropriate psychosocial support.49 As part of the REMS implementation, RBP monitors provider compliance with the REMS program through surveys of providers and patients, and monitors health care utilization databases and conducts ongoing surveillance. 5° RBP's risk mitigation strategies have been successful in improving education on safety risks ofbuprenorphine use as an opioid maintenance medication. Initial results from RBP's assessments reveal high levels of provider 46 47 48 49 50 Subutex sublingual tablet, NDA 20~ 732, Risk Evaluation and Mitigation Strategy (approved Dec. 20 II) (hereinafter "Subutex REMS"); Suboxone Tablet REMS; Suboxone sublingual film, NDA 22-4 I 0, Risk Evaluation and Mitigation Strategy (approved Aug. 2010) (hereinafter "Suboxone Film REMS"). Suboxone Tablet REMS, Medication Guide at 2. Suboxone Tablet REMS; Suboxone Film REMS; Subutex REMS. Id Id Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 18 of 49 Division of Dockets Management September 25, 2012 Page 18 understanding of the serious risks of misuse and abuse ofSuboxone and Subutex, the importance of appropriate use ofbuprenorphine products for successful opioid dependence treatment, and the role of psychosocial support for safe and effective opioid addiction treatment with buprenorphine.51 It is not possible to determine what part of these impressive results are attributable to RBP's REMS, and what part are attributable to RBP's other risk- mitigation efforts. RBP's monitoring, educational initiatives, and interventions surely play a large role and RBP's view has always been that the appropriate management of abuse, misuse, and diversion risks since Subutex's and Suboxone's approval is largely attributed to those efforts, including the RiskMAP and REMS, as a whole. 2. RBP Responds to an Alarming Trend in Pediatric Exposure Rates Despite having a robust RiskMAP in place that successfully reduced the risk of diversion and abuse of Suboxone and Subutex, RBP noticed a disturbing buprenorphine-related safety trend. A report based on data from AAPCC showed 53 exposures to buprenorphine in children under six in 2004.52 By 2006, the number reported by AAPCC had jumped to 204 exposures among children under the age of six. 53 RBP responded to this important public safety concern. By June of2007, RBP had developed materials for an education campaign to inform patients and 51 52 53 See e.g. Suboxone sublingual film REMS assessment, submitted to NDA 22-410, (August 2011). Edward W. Boyer, MD, PhD, et al., Methadone and Buprenmphine Toxicity in Children, 19 The A mer. Journal on Addictions 89 -95 (Figure I) (2009). Data submitted to NDA 20-732,20-733, and 22-410. Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 19 of 49 Division of Dockets Management September 25, 2012 Page 19 providers of the unique risks of pediatric exposure to buprenorphine. Using RBP's educational resources, discussed above, over subsequent months, patients and providers were educated about the increased risks of pediatric exposure, the need for patients to properly store their medication, and the need to seek immediate emergency intervention if an exposure occurred. RBP utilized all available resources in its targeted educational campaign, including outreach by Clinical Liaisons, Field Medical Advisors, and Treatment Advocates. These individuals informed providers of the pediatric safety risks of Suboxone and Subutex and promoted best practices to ensure patients properly stored their medication away from children, and these messages were repeated frequently. Further, in March of 2008, RBP amended its labeling for Suboxone to inc1ude a warning that patients should "always store buprenorphine-containing medications safely and out of the reach of children, and destroy any unused medication appropriately. "54 Even as those targeted educational interventions persisted, rates of pediatric exposure to buprenorphine continued to rise between 2008 and 2009. The number of children under six exposed to buprenorphine products had risen to 431 in 2007, 866 in 2008, and 1318 in 2009 (Figure 1 ). 55 54 55 See FDA, Drugs@FDA, Suboxone Labeling (2008), available at http://www.accessdata.fda.gov/scripts/cder/drugsatfda. This rise could be explained by the fact that passive educational interventions such as mailings are generally ineffective alone at creating changes in provider behavior and require reinforcement over time through active interventions like RBP's targeted outreach. See JM Grimshaw, et al., Changing Provider Behavior: An Overview of Systematic Reviews of Interventions, 39 Med. Care IJ2, 45 (Aug. 2001 ). In RBP's experience, genuine change in provider and patient behavior requires multiple active interventions. Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 20 of 49 Division of Dockets Management September 25, 20 12 Page 20 1600 1400 Figure 1: Trend in Pediatric Exposure to Buprenorphine 2006-2011 --.----------------------------·-· ···-·····----· Number of 1200 Pediatric Exposures 1000 in Children 800 Age<6 600 400 200 0 2006 Source: Data from AAPCC, submitted to NDA 20-732, NDA 20-733, and NDA 22-410) This alarming trend was unforeseen by RBP and FDA. Indeed, the rise in pediatric exposures to buprenorphine was disproportionate to buprenorphine sales. (Figure 2). Figure 2: Pediatric Exposures to Subutex and Suboxone per Million Dosage Units Distributed e ;t= ~ ~ :§10.0 8.. Q., u ~ 'fJ ~ 7.5 ..... 5 0 0 .... 0 t ::g s:: 5.0 ..0 ·- 0 s ..&:: ·- ~ u ~ 2.5 0.0 8.5 4.7 2006 2007 2009 Source: Data Submitted to NDA 20,732, NDA 20·733, and NDA 22-410) 8.7 2010 L Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 21 of 49 Division of Dockets Management September 25,2012 Page 21 RBP continued its educational campaign on the risk of pediatric exposures. RBP' s educational efforts finally stemmed the rising tide of pediatric exposures. As shown in Figures 1 and 2, the number of exposures in 2010 was only slightly higher than 2009. In August of2009, RBP began monitoring AAPCC data on a monthly basis to more closely track pediatric exposure rates. This more granular data confirmed that pediatric exposures to buprenorphine had begun to stabilize at the 2009 level (Figure 3). 350 300 250 Exp Figure 3: Plateau in Pediatt·ic Exposures Post Education Initiatives lll 6or0lcler •Uncle · osur 200 es l50 JOO • 50 - 0 ,1'"--l.""!"-.-...'1"'- ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ \~~ ~~<: ~"'4,' \~ '?~<:f ~o·'' \~~ ~'~><: ~'!>";' \~ '?t~,<:f ~o·'' rvronlh Source: Data frol)l AAPCC, (submitted to NDA 20-732, NDA 20-733, and NDA 22·410 3. RBP Develops Buprenorphine Film During the time period of the rise in pediatric exposure rates, RBP had begun development of a buprenorphine product with the potential to decrease the risk of pediatric exposure: Suboxone Film. A primary reason that such a product -- --- --- --- Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 22 of 49 Division of Dockets Management September 25, 2012 Page 22 was attractive from a risk management standpoint is that each individual Suboxone Film product would be placed inside a child-resistant foil package. 56 This child-resistant unit-dose packaging would inherently reduce the number of dosage units of exposure if a child defeated the child-resistant packaging. That is, it eliminated the risk posed by tablet-bottle packaging that a child, having defeated the child-resistant packaging, would have access to multiple doses of buprenorphine. In addition, packaging Suboxone Film in unit-dose packaging reduced the risk that patients would otherwise repackage their Suboxone in a manner that eliminated its child-resistant feature. 57 As the New Drug Application ("NDA") for Suboxone Film was being reviewed in May of2009, RBP proposed to FDA that the labeling should include a strong risk message related to pediatric exposure possibly resulting in death. Specifically, RBP proposed: "Keep out of the reach and sight of children because of the risk of respiratory depression which may potentially be fatal." FDA agreed 56 57 Another way that Suboxone Film contributes to mitigating risk is that as a film dosage form, it can not be crushed and injected, thus reducing the risk of abuse and diversion. In addition, in August 2012, FDA approved two additional strengths of the film product 12mg and 4mg). See FDA, Drugs@FDA, available at: http://www.accessdata.fda.gov/scriptslcder/drugsatfdalindex.cfm?fuseaction=Search.Lab el_ApprovaiHistory#apphist. Because the dose of buprenorphine is titrated, the availability of additional strengths will help prevent the possibility of a patient opening the child-resistant packaging and removing only part of the dose, leaving the remainder in a place that may not prevent pediatric exposure. This was not the first time that RBP recognized the value of unit-dose packaging of buprenorphine. RBP had been working to develop unit-dose packaging for Suboxone tablets since before the product was first approved for marketing. However, initial efforts to develop unit-dose packaging for Suboxone tablets using peel-push blisters were met with limited success due to technical issues involving the integrity of the tablet when attempting to remove it from the packaging. RBP proceeded with these efforts, but encountered other technical issues, primarily related to the stability of naloxone in certain unit-dose packaging configurations. Although later studies revealed unit-dose packaging of Suboxone may be feasible, RBP focused its resources on the development of Suboxone Film. Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 23 of 49 Division of Dockets Management September 25, 2012 Page 23 that a risk message was needed and required: "Children who accidentally take Suboxone will need emergency medical care. Keep Suboxone out of the reach of children." FDA approved Suboxone Film in August of20l0. In September of that year, RBP began distribution of Suboxone film with unit-dose child-resistant packaging. 58 By 2011, data from AAPCC had demonstrated a precipitous decline in the number of pediatric exposures to buprenorphine products, even from 2009 levels (Figure 4). tl .... = Ill 0 Q, 1-f ~ 58 Figure 4: Trend Line of exposures to Suboxone over Time 200 180 - -under6 160 -6orolder 140 ffhn I)Jsu lbottou begins 120 100 80 60 40 20 0 r--r-r--'T---r---, Source: Data from AAPCC, submitted to NDA 20-732, NDA 20-733, and NDA 22-410 The Consumer Product Safety Commission does not require testing in children who are less than 48 months in age to meet the minimum child-resistant packaging standards. See 16 C.F.R. § 1700.20(a)(2). However, RBP conducted special child-resistant packaging testing of Suboxone Film in children ages eighteen to thirty-six months, in part because I 00% of child patient deaths due to buprenorphine exposure came from this population. That testing revealed a 0% success rate for children in this age group in defeating the unit-dose child-resistant packaging ofSuboxone Film. Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 24 of 49 Division of Dockets Management September 25, 2012 Page 24 4. Recent Study Reveals Decreased Risk of Pediatric Exposure to Buprenorphine in Child-Resistant Unit-Dose Packaging A recent study by independent experts at the Researched Abuse, Diversion and Addiction-Related Surveillance ("RADARS") System and Venebio Group, LLC further explored the risk of pediatric exposure (hereinafter, "pediatric exposure analysis"). Specifically, that study estimated and compared the frequency of reports of unintentional exposure among children under six to single entity buprenorphine tablets, Suboxone tablets, and Suboxone film; attempted to identity, using a root cause analysis, factors influencing the unintentional pediatric exposure and assessed causality of reported adverse events associated with unintentional pediatric exposure to buprenorphine via an expert physician panel. 59 The study estimated the relative risk (rate ratio) of unintentional pediatric exposure for the following two comparisons: 1) single-ingredient tablet (generic/Subutex) vs. combination ingredient film (Suboxone film) and 2) combination ingredient only analysis (Suboxone tablet vs. Suboxone film). A root cause analysis was performed on each of the eligible cases. All potential root causes were recorded, but the Executive Summary focused on causes related to physician/patient education and packaging. Further results related to these and other root cause factors are being reviewed by the expert clinical panel and will be submitted to FDA when complete. 59 See Exhibit I: Venebio, Accidental Exposure to Buprenorphine in Children: Focus on the Impact of Product Packaging and Patient/Physician Education: Executive Summary, (Sept. 14, 2012). Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 25 of 49 Division of Dockets Management September 25, 2012 Page 25 A total of 2,380 unique cases of exposure meeting the inclusion criteria were identified (2,337 from the RADARS System Poison Control Program, 40 from RBP Pharmacovigilance Database, and three duplicate cases for which data were merged from the two sources). Of these, 154 (6.5%) cases were associated with single-ingredient tablets, 2,107 (88.5%) cases were associated with combination-ingredient tablets, 118 (5.0%) cases were associated with combination-ingredient film, and one case ( <0.1%) was an unspecified buprenorphine exposure. Across the study period (fourth quarter 2009 through first quarter 20 12), mean rates of accidental pediatric exposure to single- and combination-ingredient tablets per 10,000 unique recipients of a dispensed drug (URDD) were 2.51 cases/10,000 URDD (95% CI: 2.12 -2.98) and 6.25 cases/10,000 URDD (95% CI: 5.90- 6.63), respectively, and mean rates for combination-ingredient film were 0.71 cases/10,000 URDD (95% CI: 0.59- 0.87). The risk of unintentional pediatric exposure to single- and combination tablets was 2.5 and 7.8 times higher, respectively, than the risk for combination film. For the most recent quarter (January-March 2012) the risk of unintentional pediatric exposures to single- and combination ingredient tablets was 3.2 and 8.5 times greater than for combination film, respectively. The case reports reviewed did not provide sufficient information regarding physician/patient education or medication packaging to draw definitive conclusions. However, further analysis is ongoing to ascertain why the rates of pediatric exposure to child-resistant unit-dose packaged buprenorphine film (Suboxone Film) are significantly less than the rates of exposure to buprenorphine Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 26 of 49 Division of Dockets Management September 25, 2012 Page 26 packaged as loose tablets in a bottle, and these data will be submitted to FDA as soon as it is available. 5. RBP Discontinues Marketing of Suboxone Sublingual Tablets Due to Safety Concerns Review of the pediatric exposure analysis revealed significant safety risks posed by buprenorphine products for opioid dependence in multi-dose packaging. It revealed that the risk of accidental exposure to children under six is 2.5 and 7.8 times greater for multi-dose packaged buprenorphine and buprenorphine/naloxone, respectively, than tor unit-dose packaged buprenorphine/naloxone. Based on the ready availability of safer alternatives for opioid dependence treatment through Suboxone Film, on September 18, 2012, RBP notified FDA of its intent to discontinue marketing Suboxone Tablet (NDA 20-733). B. LEGALBACKGROUND One of FDA's most important missions is to ensure the availability of drugs that are both effective and safe. All drugs, whether approved under an NDA or an ANDA, must be shown to be safe. An NDA may not be approved if"upon the basis of the infonnation submitted ... as part of the application, or upon the basis of any other infonnation ... with respect to such drug, [there is] insufficient information to determine whether such drug is safe for use .... "6° FDA's regulations indicate that an ANDA product is unsafe, and may not be approved, if there is a "reasonable basis" to conclude that the ANDA raises serious questions 60 See FDC Act§§ 505(d)(4); 21 U.S.C. 505(d)(4). Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 27 of 49 Division of Dockets Management September 25, 2012 Page 27 of safety. 61 FDA has also indicated that the ANDA disapproval standards are consistent with the ANDA withdrawal standards, and FDA may withdraw an ANDA "whenever there is a reasonable basis to conclude that a drug is unsafe even if the agency lacks proof that the drug is unsafe."62 To ensure safety, the FDC Act requires FDA not to approve a NDA for a new drug, if, "the [proposed] labeling is false and misleading in any particular."63 The FDC Act further restricts the introduction of drugs into the marketplace whose labeling is misleading or lacks adequate safety warnings by deeming those drugs misbranded.64 In addition, FDA may not approve a NDA if"upon the basis of information submitted to him as part of the application, or upon the basis of any other information before him with respect to such drug, he has insufficient information to determine whether such drug is safe for use under the "conditions prescribed recommended, or suggested in the [drug's] proposed 1abeling."65 61 62 63 64 6S 21 C.P.R. § 314.127(a)(8)(ii) (stating FDA may not approve an ANDA when "there is a reasonable basis to conclude that one or more ofthe inactive ingredients ofthe proposed drug or its composition raises serious questions of safety or efficacy.") 57 Fed. Reg. 17950, 17969 (April28, 1992). Approval ofan NDA or ANDA may be withdrawn if"new evidence of clinical experience, not contained in the application or not available to FDA until after the application or abbreviated application was approved, or tests by new methods, or tests by methods not deemed reasonably applicable when the application or abbreviated application was approved, evaluated together with the evidence available when the application or abbreviated application was approved, reveal that the drug is not shown to be safe for use under the conditions of use upon the basis of which the application or abbreviated application was approved." 21 C.F.R. § 314.l50(a)(2)(ii). FDC Act§ 505(dX7), 21 U.S.C. 355(d)(7); See also 21 C.F.R. § 314.125(a)(6}. FDC Act§ 301 (a), 21 U.S.C. § 331 (a) {prohibiting the introduction or the delivety for introduction into interstate commerce of any food, drug, device, tobacco product, or cosmetic that is adulterated or misbranded");§ 502(f) {defining misbranded to include inadequate safety warnings). FDC Act§ 505(dX4); 21 U.S.C. 355(d)(4); See also 21 C.F.R. § 3 14.125{a){4). Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 28 of 49 Division of Dockets Management September 25, 20 12 Page 28 Moreover, the FDC Act now requires FDA to "implement a structured risk-benefit assessment" in determining whether to approve a "new drug. ''66 To ensure the safety of generic drugs, FDA may not approve a generic drug application ("ANDA") if the generic drug lacks "sameness'' to the reference listed drug ("RLD").67 As FDA has summarized the applicable statutory and regulatory standards: "The ANDA applicant must identity the listed drug on which it seeks to rely, and, with limited exceptions, the drug product described in the ANDA must contain the same active ingredient, conditions of use, route of administration, dosage form, strength, and (with certain permissible differences) labeling as the listed drug it references."68 Following the U.S. Supreme Court's decree that the FDC Act "must be given the most harmonious comprehensive meaning possible in light of legislative policy and purpose" FDA has held in the context of ANDA approval, "that the FDC Act could not impose a burden on the agency ... that would require approval of potentially unsafe drugs."69 66 67 68 69 See Food and Drug Administration Safety and Innovation Act, Pub. L. No. 112-144, § 905, 126 Stat. 993, 1092 (2012) (amending FDC Act§ 505(d))). Notwithstanding this mandate, FDA has historically employed such an analysis in the approval process. See International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Periodic Benefit-Risk Evaluation Report (PBRER) (Feb. 20, 2012) (stating "[w]hen a drug is approved for marketing, a conclusion has been reached that, when used in accordance with approved product information, its benefits outweigh its risks."), available at http://www.ich.org/fileadmin/Public_ Web_Site/ICH_Products/Guidelines/Efficacy/E2C/ E2C_R2_Step2.pdf. See FDC Act§ 5050); 21 U.S.C. § 3550); 21 C.F.R. § 314.127. FDA Response to Perrigo Company's Citizen Petition, Docket No. FDA-2011-P-0840, at 2 (May 16, 2012) (emphasis added) (citing FDC Act§ (j)(2)(A) and (j)(4), and 21 C.F.R. § 314.94(a)). 57 Fed. Reg. 17950, 17969 (April28, 1992). Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 29 of 49 Division of Dockets Management September 25, 2012 Page 29 Moreover, FDA may not approve an ANDA, if"the reference listed drug has been voluntarily withdrawn from sale and the agency has not determined whether the withdrawal is for safety or effectiveness reasons."70 In making this determination, FDA will consider the risk benefit profile of the withdrawn drug, including whether the withdrawn drug has any material efficacy advantage over comparable safer drugs.71 C. ANALYSIS 1. FDA Should Refrain from Approving any Buprenorphine NDA or ANDA That Does Not Include A Targeted Pediatric Exposure Education Program Because Those Applications Are Not Approvable Pursuant to Sections 505(b) and (j) of the FDC Act. In response to the rise in accidental pediatric exposures to buprenorphine, RBP implemented a comprehensive pediatric exposure education campaign with specific interventions targeted to educate providers on pediatric exposure risks and the importance of instructing patients to safeguard their buprenorphine. RBP sent teams of personnel into the field to communicate these messages to providers. RBP reinforced these messages through educational materials it mailed directly to providers. RBP further utilized specially trained instructors to hold educational sessions with providers that focused on pediatric exposure risks and the importance of patients' safeguarding their medication. Through their constant persistence and targeted delivery, RBP's measures were critical to ensuring that 70 71 21 C.P.R. § 314.127(a)(I 1 ). See Response to Citizen Petition, FDA to 1ST A Pharmaceuticals, FDA Docket No. 2008- p-0368 at 16 (May 11, 2011) (stating, "[e]ven if Bromday were shown to be safer than Xibrom that would not necessarily mean that Xibrom should no longer be considered sufficiently safe. Rather, the Agency would evaluate Xibrom's risks in light of its benefits, including any evidence that showed that Xibrom offers any material efficacy advantage over Bromday"). Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 30 of 49 Division of Dockets Management September 25, 2012 Page 30 providers understood risks and took appropriate action. Subsequently, the risks of pediatric exposure to buprenorphine plateaued and eventually declined. RBP has since continued, expanded, and enhanced those efforts. There is certainly more than a reasonable basis to question the safety of a buprenorphine product that is marketed without any of these interventions. The data indicate that without such interventions, unintentional pediatric exposures are very likely to rise. Accordingly, FDA should not approve any NDA or ANDA for buprenorphine for opioid dependence treatment that fails to commit to comparable interventions. a. FDA may not approve a buprenorphine NDA for opioid dependence treatment without educational interventions targeted to pediatric exposure risk because the labeling of drugs subject to those NDAs is misleading. The FDC Act makes clear that FDA shall not approve any NDA if, based on the information available to the Agency, the NDA's proposed labeling is false or misleading in any particular.72 The FDC Act defines labeling broadly to include "all labels and other written, printed, or graphic matter (1) upon any article or any of its containers or wrappers, or (2) accompanying such article."73 Based on a series of court cases originating in 1948 with Kordel v. United States, 335 U.S. 345 (1948) and United States v. Urbuteit, 335 U.S. 355 (I 948), FDA considers aU textuaUy related product information disseminated by the manufacturer to be "labeling" within the meaning ofFDC Act§ 20l(m), even if the product is not distributed with the information. 72 73 Brochures, booklets, mailing pieces, detailing pieces, file cards, bulletins, calendars, price lists, catalogs, house organs, letters, motion picture films, film strips, lantern slides, sound recordings, exhibits, FDC Act§ 505(d)(7); 21 U.S.C. § 355(d)(7); 21 C.F.R. § 314.125(b)(6). FDC Act§ 201(m), 21 U.S.C. § 321(m). Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 31 of 49 Division of Dockets Management September 25, 2012 Page 31 literature, and reprints and similar pieces of printed, audio, or visual matter descriptive of a drug and references published (for example, the "Physicians Desk Reference") for use by medical practitioners, pharmacists, or nurses, containing drug information supplied by the manufacturer, packer, or distributor of the drug and which are disseminated by or on behalf of its manufacturer, packer, or distributor are hereby determined to be labeling as defined in section 20l(m) of the act.74 Under this standard, there can be little question that RBP's educational campaign would be considered to be part of the labeling for its buprenorphine products. FDA considers a drug's labeling to be misleading if it omits material facts. 75 Here, a buprenorphine NDA sponsor who fails to ensure the adequate dissemination ofthe pediatric safety risks ofbuprenorphine for opioid dependence, omits material information from its labeling that would ensure patients properly safeguard their medication. This renders the labeling of such a drug misleading. This omission further renders those drugs misbranded. 76 To be sure, in &aguiv. Dow Chem. Corp., 598 F.2d 727,733-36 (2d Cir. 1979), the court found that the failure of Park-Davis "to provide adequate warnings of known risks associated with normal use" of Quadrigen, namely the risk of harm posed to infants, rendered the company's labeling in violation of the FDC Acfs misbranding provisions.77 74 75 76 77 21 C.F.R. § 202.1(1)(2). FDC Act§ 20l(n); 21 U.S.C. § 321(n). FDC Act§ 502(f)(2); 21 U.S.C. § 352(f)(2) (rendering a drug misbranded if the drug has inadequate safety warnings). !d. Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 32 of 49 Division of Dockets Management September 25, 2012 Page 32 FDA has not required conclusive evidence of causation to take action in response to other pediatric safety concerns. In 2006, FDA published its intent to take enforcement action against all drugs containing carbinoxamine that were labeled for use in children less than 2 years of age or marketed as drops for oral administration. 78 In so doing, it noted The agency is aware of 21 deaths since 1983 in children under 2 years of age associated with carbinoxamine-containing products. However, in most of those incidents, other active ingredients in the drugs or other factors aside from the drug could have been responsible for the death a causative relationship between exposure to carbinoxamine and death in these infants has not been established. Nevertheless, there is scientific support for the proposition that infants and young children may be more susceptible to experiencing drug-related adverse events, in part due to the normal immaturity of their metabolic pathways. 79 Likewise, FDA should find that RBP's continuous implementation of targeted educational interventions on pediatric exposure is certainly associated with, and likely contributed to, the plateau and subsequent decline in accidental pediatric exposures. Conclusive proof of causation is not the appropriate standard. Thus, to ensure appropriate safe use of buprenorphine for opioid dependence, FDA should not approve any NDA that does not include these targeted interventions. 78 79 Carbinoxamine Products; Enforcement Action Dates, 71 Fed. Reg. 33462-33465, 33463 (June 9, 2006). Id Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 33 of 49 Division of Dockets Management September 25,2012 Page 33 b. FDA should not approve a buprenorphine NDA for opioid dependence treatment without targeted educational interventions on pediatric exposure risks, because the risk-benefit profiles of drugs subject to those NDAs does not favor approval. FDA must refuse to approve a NDA if the drug presents unreasonable safety risks. 80 As noted above, Congress recently amended section 505( d) of the FDC Act to require FDA to "implement a structured risk-benefit assessment framework in the new drug approval process to facilitate the balanced consideration of benefits and risks, a consistent and systematic approach to the discussion and regulatory decision-making, and the communication of the benefits and risks of new drugs."81 The public health benefits of buprenorphine when used for opioid maintenance are significant. Without buprenorphine, many patients would not have access to addiction treatment. These key benefits must be viewed in light of evidence showing that prior to and during the initial stages ofRBP's pediatric exposure educational campaign, pediatric exposures to buprenorphine increased unexpectedly. Moreover, given the vulnerability of the affected population, FDA must give additional weight to the risk of pediatric exposure in the risk-benefit analysis. As FDA recently explained: 80 81 [FDA] is mindful of risks posed to certain vulnerable populations, such as pediatric patients, older patients, and pregnant women. FDC Act§ 505(b); 21 U.S.C. § 355(b). See Food and Drug Administration Safety and Innovation Act, Pub. L. No. 112-144, § 905, 126 Stat. 993, 1092 (2012) (amending FDC Act§ 505(d))). http://www.ich.org/fileadmin/Public_ Web_Site/ICH_Products/Guidelines!Efficacy/E2C/ E2C_R2_Step2.pdf. Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 34 of 49 Division of Dockets Management September 25, 2012 Page 34 Evidence that a drug poses a risk to such populations would more likely weigh in favor of making the safety issue a priority.82 FDA should recognize the observed association between RBP's initiatives and improvements in pediatric safety. RBP urges FDA to ensure that the appropriate balance of risk to benefit is achieved for buprenorphine, and not approve any buprenorphine NDA for opioid addiction that fails to include these interventions. c. FDA must deny any buprenorphine ANDA for opioid dependence treatment that lacks targeted educational interventions on pediatric exposure risks because such applications fail to contain the same labeling as the RLD. With certain exceptions, FDA may not approve an ANDA if the ANDA fails to include the same labeling as the RLD.83 The FDC Act allows labeling differences that are necessary "because the new [generic] drug and the listed [pioneer] drug are produced or distributed by different manufacturers."84 The FDA has interpreted this exception to permit changes in labeling because of "differences in expiration date, formulation, bioavailability, or pharmacokinetics, [or] labeling revisions made to comply with current FDA labeling guidelines or other guidance. "85 Given the association between the decreased rate of pediatric exposures and RBP's campaign on pediatric exposure risks, FDA should not approve a 82 83 84 8S Food and Drug Administration, Draft Guidance, Classifying Significant Postmarketing Drug Safety Issues, 7 (Mar. 2012). FDC Act§ 505G)(4)(G), 21 U.S.C. § 355(j)(4)(G); 21 C.F.R. § 314.127(a)(4). FDC Act§ 505(j)(2)(A)(v); 2 I U.S.C. § 355(jX2)(A)(v). 21 C.F.R. § 314.94(a)(8)(iv). Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 35 of 49 Division of Dockets Management September 25, 2012 Page 35 buprenorphine ANDA without these important safeguards. The risks of CNS suppression and death of children are too grave to justifY such approval. In FDA's response to a citizen petition of Accutane, FDA explained that all generic manufacturers of Accutane must adopt all of the essential elements of Accutane's risk- management measures.86 In particular, CDER Director, Janet Woodcock, stated that "the documents in the [risk management program] are part of the product labeling," and "all generic [Accutane] manufacturers, as part of their labeling for ANDA approval, will have the same educational materials."87 If FDA were to permit buprenorphine ANDA sponsors to forgo certain educational interventions on pediatric exposure, to ensure comparable safety profiles of those drugs and the RLD, FDA would then have to consider imposing heightened labeled warnings on the generic drugs. But, FDA has explained that imposing such a requirement frustrates the purpose of the FDC Act.88 86 87 88 Letter from Janet Woodcock, FDA, COER to Accutane at 4 (Nov. 8, 2002). /d. In that case, Roche had submitted certain educational materials for its risk management program for Accutane as part of a labeling supplement. RBP's REMS requires it to "take reasonable steps to improve implementation of these elements to meet the goals of the REMS." Suboxone Tablet REMS at 4. RBP's educational efforts are undoubtedly reasonable steps to further the goals of the REMS, but to date, FDA has not specifically made them a part of the REMS. See also Transmucosallmmediate Release Fentanyl (TIRF) REMS (June 2012) (initially approved in December 2011 and specifically containing an education program for prescribers and phannacists that includes education on pediatric exposure), available at http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetylnformationforP atientsandProviders/UCM289730.pdf. Abbreviated New Drug Applications; Proposed Rule, 54 Fed. Reg. 28872, 28884 (July I 0, 1989) (stating "FDA does not believe that it would be consistent with the purpose of section 5050) of the act, which is to assure the marketing of generic drugs that are as safe and effective as their brand-name counterparts, to interpret section 505G)(2)(a)(v) of the act as permitting the marketing of generic drugs with diminished safety or effectiveness and concomitantly heightened labeled warnings"). Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 36 of 49 Division of Dockets Management September 25,2012 Page 36 Accordingly, FDA must deny any buprenorphine ANDA that fails to include educational interventions comparable to those adopted by RBP to reduce the risk of pediatric exposure to buprenorphine, as such AND As lack the same labeling as the RLD. d. FDA must deny any buprenorphine ANDA for opioid dependence treatment that lacks educational interventions adopted to reduce the risk of pediatric exposure, because such AND As lack the same risk- benefit profile as the RLD. In determining whether to approve a new drug, FDA will consider whether the risks posed by the drug outweigh its potential benefit. 89 FDA has indicated that an ANDA sponsor must demonstrate that the generic drug has the same risk- benefit profile as the RLD, by stating that those drugs have comparable safety risks.90 The benefits ofbuprenorphine as an opioid dependence medication are clear: both Suboxone and Subutex expanded access to addiction treatment for a significantly underserved population ofpatients.91 In addition, compared to a full opioid receptor agonist, buprenorphine has reduced diversion concerns due to its partial opioid-receptor agonist properties. Combining buprenorphine and 89 90 91 Food and Drug Administration Safety and Innovation Act, Pub. L. No. 112-144, § 905, 126 Stat. 993, 1092 (2012) (amending FDC Act§ 50S( d))). See Generic Drugs: Questions and Answers?, available at http://www .fda.gov/Drugs/ResourcesForYou/Consumers/QuestionsAnswers/ucm 100100. htm. (stating "a generic drug is the same as a brand-name drug in dosage, safety, strength, quaJity, the way it works, the way it is taken and the way it should be used"). Gregory B. Collins, MD et al., Buprenorphine maintenance: a new treatment for opioid dependence, 74(7) Cleve. Clin. J. Med. 514 (2007). Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 37 of 49 Division of Dockets Management September 25, 2012 Page 37 naloxone in Suboxone provides further public benefit by reducing the risk that the drug will be abused parenterally.92 Buprenorphine is, however, a serious drug. It is an opiate that is associated with risks of abuse and diversion. In some cases, particularly when injected and when used in combination with alcohol or benzodiazepines, buprenorphine can be associated with significant adverse events including respiratory failure and death. That risk is even more acute in exposed children due to their lower body weight. FDA must consider the data presented here showing an alarming increase in the rates of pediatric exposure during the five-years following approval, which has only recently reached a plateau and subsequent decline. The plateau and decline are clearly associated with specific interventions RBP took with respect to pediatric safety, thus the most prudent course is to attribute that success to those measures as a whole. If the safety risks of a generic and innovator must be the same as the RLD, then FDA cannot conclude that buprenorphine marketed without targeted interventions concerning pediatric exposure is the same as buprenorphine marketed with such interventions. The rate of pediatric exposures was increasing before RBP's targeted education campaign took effect, and has only recently plateaued and begun to decline, thus demonstrating the greater safety risks posed by buprenorphine marketed for addiction treatment without educational interventions. FDA cannot permit the marketing of a drug with equal therapeutic 92 See Buprenorphine, Center for Substance Abuse Treatment, Substance Abuse and Mental Health Services Administration, US Department of Health and Human Services, About Buprenorphine Therapy, available at http://buprenorphine.samhsa.gov/about.html. Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 38 of 49 Division of Dockets Management September 25, 2012 Page 38 effect, but a substantially greater safety risk, than an otherwise identical competitor, especially where those risks threaten the safety and lives of children. 2. FDA Should Refrain from Approving Applications for Buprenorphine for Opioid Addiction that Lacks Child-Resistant Unit-Dose Packaging. As summarized above, the pediatric exposure analysis revealed a highly significant statistical difference between the rates of pediatric exposure to multi- dose packaged buprenorphine versus child-resistant, unit-dose packaged buprenorphine for opioid addiction. Indeed, the risk of unintentional pediatric exposures to multi-dose packaged buprenorphine and buprenorphine/naloxone tablets was 2.5 to 7.8 times greater, respectively, than for child-resistant, unit dose packaged buprenorphine/naloxone film. For the most recent quarter measured in 2012, the risk of unintentional pediatric exposure to buprenorphinelnaloxone tablet is 8.5 times greater than for buprenorphine/naloxone film. These findings fundamentally alter the inherent risk-benefit profile of certain buprenorphine drugs marketed for opioid dependence treatment. The child-resistant unit-dose packaging used by RBP may help to reduce pediatric exposure in several ways. First, it could be more difficult for a child to open the foil wrappers than a bottle. Second, even if a child does defeat the unit- dose packaging, the child is only exposed to one dose of the product. Third, adults may be less likely to open multiple unit-doses packages and improperly store several doses together, such as in a container that is not child-resistant.93 93 Additionally, it is hoped that the recent approval by the FDA of two new strengths of the film product will reduce the likelihood of a patient opening the foil pouch to extract a partial dose, leaving any remaining drug available for unintentional exposures. Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 39 of 49 Division of Dockets Management September 25,2012 Page 39 a. FDA may not approve any buprenorphine NDA for addiction treatment that lacks child-resistant unit-dose packaging because FDA has insufficient information to determine the safety of those drugs. As set forth above, the FDC Act requires FDA to refrain from approving an NDA if "upon the basis of information submitted to [it, FDA] has insufficient information to determine whether [the] drug is safe for use" under the conditions set forth in the drug's proposed labeling. 94 Not surprisingly, FDA has considered abuse and misuse, to include accidental pediatric exposure, part of a drug's conditions of use in ascertaining safety. For example, in 1977 FDA withdrew trichloroethane aerosol due to concerns of"potential CV toxicity" and "deaths from misuse [and] abuse."95 Later, in 1982, FDA withdrew camphorated oil due to "infant (and] child poisonings"96 More recently, FDA requested that Purdue voluntarily cease marketing ofPalladone® (hydromorphone HCl extended-release) Capsules, because pharmacokinetic data revealed that co-ingestion ofPalladone with alcohol results in an increase in the peak plasma of hydromorphone. Despite having strong labeling warning patients against the risks of taking Palladone with alcohol, 94 95 96 FDC Act§ 50S(d)(4); 21 U.S.C. § 355(d)(4); See also 21 C.F.R. § 314.12S(a)(4). Diane K. Wysowski, Ph.D., et al., Adverse Drug Event Surveillance an Drug Withdrawals in the United States, 1969-2002, The Importance of Reporting Suspected Reactions, 175 Archives Internal Medicine 1363, 1366 (June 27, 2005). /d. ----------------------------·------ Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 40 of 49 Division of Dockets Management September 25, 2012 Page 40 including a black box warning, FDA found that the likelihood of patients' misuse of the drug altered its risk/benefit profile and ordered the drug's suspension.97 Even more directly relevant here, FDA has found that withdrawal of a drug product was necessary because the drug's dosage form rendered it more subject to abuse than effective alternative drugs with different dosage forms. In 1973, FDA withdrew approval of all drug applications for parenteral methamphetamine. The Agency concluded that "the well documented history of abuse of parenteral methamphetamine, together with the severe risks of dependence and the presence of effective alternative drugs, creates an unfavorable balance of risk to benefit."98 Here, the conditions of use of buprenorphine that pose serious questions of safety include the failure of patients or family members to safeguard that medication from children. That failure has contributed to many accidental exposures to children, some causing severe adverse events including hospitalization and death. However, the new pediatric exposure analysis indicates that unit-dose packaging 97 98 See Food and Drug Administration, Press Release, FDA Asks Purdue Pharma to Withdraw Palladone for Safety Reasons (July 13, 2005), available at http://www .fda.gov/NewsEvents/Newsroom/PressAnnouncements/2005/ucm 1 08460.htm ' http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafety[nformationforPatientsandP roviders/ucm l29288.htm; Public Health Advisory: Suspended Marketing of Palladone (hydromorphone hydrochloride, extended-release capsules) (July 13, 2005), available at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetylnformationforPatientsandP roviders/DrugS afetyinformationforHeathcareProfessionals/PublicHealthAdvisories/UCMOS 1 743; Palladone Package Insert and Medication Guide (Feb. ll, 2005), available at http://dailymed.nlm.nih.gov/dailymed/druglnfo.cfm?id=894. Opportunity for a Hearing on Proposal to Withdraw Approval of New Drug Applications, 3 8 Fed. Reg. 4282 (Feb. 12, 1973); Amphetamines for Human Use; Notice of Withdrawal of Approval ofNew Drug Applications, 38 Fed. Reg. 8290 (Mar. 30, 1973). Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 41 of 49 Division of Dockets Management September 25, 20 12 Page 41 may reduce those risks. Specifically, Suboxone Film in child-resistant foil unit- dose packaging was significantly less likely to be exposed to children than Suboxone tablets in standard child-resistant bottles. Thus, FDA should refrain from approving any buprenorphine NDA without unit- dose packaging, or where the NDA sponsor otherwise fails to submit data demonstrating the drug does not pose comparable safety risks to multi-dose packaged buprenorphine. 99 Without such packaging or data, FDA would have 99 RBP recognizes that in Nutritional Health Alliance v. FDA, 318 F.3d 92 (2nd Cir. 2003), the court held that FDA lacked the regulatmy authority to promulgate a rule requiring unit-dose packaging of a dietary supplement for the sole purpose of reducing the risk of pediatric exposure. ld. at 95. The Nutritional Health court also opined, in dicta, that FDA lacked regulatory authority from the FDC Act's adulteration and cGMP provisions to require unit-dose packaging for pharmaceutical drugs. ld at I 00. The court explained that Congress transferred FDA's authority to regulate child-resistant packaging to the Consumer Product Safety Commission through the Poison Prevention Packaging Act. ld. However, several factors distinguish Nutritional Health from the present case. First, buprenorphine is a drug, not a dietruy supplement, and the requested action is not a rulemaking. Second, that case considered FDA's authority pursuant to entirely distinct statutory sections, section 402 and 351, finding adulteration is "simply unrelated" to "the risk that a product will be used or be misused in an unintended fashion." ld. at lOl. In contrast, FDA has broad authority to consider a wide range of public health risks pursuant to sections 505 and 505-1. To be sure, FDA has since considered pediatric exposure risks in making that determination. See Letter from Gita A. Akhavan Toyserkani, CDER, FDA, to RBP (Aug. 6, 2010) (requiring RBP to include an analysis of pediatric exposure in its REMS assessments); (Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) I, 2 (Dec. 20 II), available at http://www .fda.gov/down loads/Drugs/DrugSafety/PostmarketDrugSafetylnformationforP atientsandProviders/UCM289730.pdf (including "preventing accidental exposure to children" as an express goal); See also FDA, Questions and Answers About Onsolis (fentanyl buccal soluble film) (noting the requirement ofOnsolis REMS was to "reduce . . . accidental exposure in children.") FDA has required specific packaging for drugs, most notably for Actiq (oral transmucosal fentanyl citrate; NDA 02-747), to help prevent pediatric exposure. Actiq is provided in "a foil pouch composed of PET, Veleron, foil, polyethylene ... consumer tested for child resistance and requires scissors to open." CDER, Medical Review, Actiq, NDA 20747, 1.4 (1997). In addition, an "ACTIQ Child Safety Kit" is provided "to patients and their caregivers who have children in the home or visiting." Actiq Package Insert 1, I 0 available at Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 42 of 49 Division of Dockets Management September 25, 2012 Page 42 insufficient information to determine whether approval of those drugs would result in a spike in pediatric exposures, similar to that which occurred for Suboxone and Subutex, after those products were approved. b. FDA may not approve any buprenorphine NDA for addiction treatment that lacks child-resistant unit-dose packaging because the risk-benefit profile of those drugs does not favor approval. As set forth above, the FDC Act requires FDA to consider the risk-benefit profile of a drug prior to its approval. 10° FDA has explained that it will consider a broad range of safety risks and benefits in conducting this risk-benefit analysis. 101 FDA cannot approve an application for a drug that poses heightened safety risks unless the drug also provides a meaningful and significant benefit to the public health. The pediatrics exposure analysis demonstrates the safety risks of buprenorphine for opioid addiction packaged in multi-dose versus unit-dose packaging. It demonstrates that pediatric exposures to buprenorphine soared while Subutex and Suboxone were packaged and marketed in multi-dose packaging. 100 101 http://www. actiq. comlpdf/actiq_package _insert_ 4 _5 _ 07.pdf, . The Child Safety Kit includes: A child-resistant lock used to secure the storage space where ACTIQ is kept, a portable locking pouch, and a child-resistant temporary storage bottle. ACTIQ Medication Guide at 14, available at http:llwww.actiq.com/pdflactiq_package _insert_ 4 _5 _ 07.pdj. Thus, special packaging, such as unit-dose packaging of buprenorphine for opioid addiction can be required by FDA to protect the public safety. However, to the extent that FDA disagrees, RBP asks that FDA at least require all buprenorphine applications for opioid dependence include data demonstrating that the drug does not pose unreasonable pediatric safety risks, to adequately ensure safe use of those drugs. Food and Drug Administration Safety and Innovation Act, Pub. L. No. 1 12-144, § 905, 126 Stat. 993, 1092 (2012) (amending FDC Act§ SOS(d))). Response to Citizen Petition, FDA to ISTA Pharmaceuticals, FDA Docket No. 2008-p- 0368 at 3 (May II, 2011). Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 43 of 49 Division of Dockets Management September 25, 2012 Page 43 FDA must consider this safety risk in assessing the risks of buprenorphine for opioid dependence that is similarly packaged. Moreover, FDA must also consider the public health benefits of any buprenorphine drug subject to an NDA that poses these risks. In determining those benefits, FDA must consider whether safer alternative treatment exists for the same indication through currently approved drugs. Thus, FDA must consider the fact that Suboxone Film, which is currently approved for opioid addiction treatment, poses a significantly lower risk of pediatric exposure than comparable drugs in unit-dose packaging. In light of these considerations, the risk-benefit profile of any buprenorphine NDA for opioid addiction treatment without child- resistant unit-dose packaging likely renders those NDAs not approvable by FDA. 3. FDA may not approve any buprenorphine/naloxone ANDA for addiction treatment until FDA determines whether the RLD for those drugs was discontinued for reasons of safety. FDA may refuse to approve an ANDA if the agency determines the RLD was withdrawn from sale for reasons of safety or effectiveness. 102 Before FDA can approve an ANDA, the FDC Act and implementing regulations require the agency to determine whether the RLD has been voluntarily withdrawn from sale for safety or effectiveness reasons. 103 In this case, there have been thousands of accidental exposures to children causing severe adverse events including hospitalization and death. RBP now has evidence showing that when buprenorphine for opioid addiction is packaged in child-resistant unit-dose, versus multi-dose packaging, the risks of pediatric 102 103 21 C.F.R. § 314.127(a)(ll); FDC Act§ SOSG)(4)(I). 21 C.F.R. § 314.161(A)(l). Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 44 of 49 Division of Dockets Management September 25, 2012 Page 44 exposure are significantly reduced. In response to these findings, RBP discontinued marketing of Suboxone tablets (NDA 20-733). RBP concluded that the balance of risk to benefit, in light of readily available safer alternatives (Suboxone Film) justified that discontinuance. FDA must employ a comparable analysis in determining whether ANDAs that list the discontinued drugs are approvable. FDA recently employed that analysis in determining that Chloromycetin (chloramphenicol) was withdrawn from sale for reasons of safety or efficacy. Specifically, FDA found that "with the approval of additional therapies with less severe adverse drug effects, FDA has determined that the risks associated with Chloromycetin ... as currently labeled, outweigh the benefits. Most importantly, Chloromycetin may cause a number of adverse reactions, the most serious being bone marrow depression (anemia, thrombocytopenia, and granulocytopenia temporally associate with treatment)."104 The comparative safety of formulation and packaging differences can also be considered. 105 In addition, a risk-benefit comparison to alternative products can inform FDA's determination of the reasons a product has been discontinued for sale. For example, in response to a recent citizen petition filed by IST A Pharmaceuticals, Inc., arguing that its once-a-day 104 105 FDA, Determination that Chloromycetin (chloramphenicol) Capsules, 250 Milligrams were withdrawn from sale for reasons of safety or effectiveness, 77 Fed. Reg. 135,135 (July 13, 2012). See also FDA, Determination That Halflytely and Bisacodyl Tablets Bowel Prep Kit (Containing Two Bisacodyl Delayed Release Tablets, 5 Milligrams) Was Withdrawn from Sale for Reasons of Safety or Effectiveness, 76 Fed. Reg. 51037 (Aug. 17, 20 II) (the 5 mg product had "a safety advantage over the 1 0 mg product because there is less abdominal fullness and cramping .... "). FDA, Determination That BREVffiLOC (Esmolol Hydrochloride) Injection, 250 Milligrams/Milliliter, I 0-Milliliter Ampule, Was Withdrawn from Sale for Reasons of Safety or Effectiveness, 75 Fed. Reg. 24710 (May 5 201 0) (taking into account "alternative presentations ofthe product" in assessing the risk of medication errors). Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 45 of 49 Division of Dockets Management September 25,2012 Page 45 formula (Bromday) for bromfenac ophthalmic solution was safer than its then withdrawn twice-a-day formula (Xibrom), and thus any ANDA referencing Xibrom must be denied, FDA stated, "[e]ven ifBromday were shown to be safer than Xibrom that would not necessarily mean that Xibrom should no longer be considered sufficiently safe. Rather, the Agency would evaluate Xibrom's risks in light of its benefits, including any evidence that showed Xibrom offers any material efficacy advantage over Bromday."106 Suboxone Tablet offers no efficacy advantage over Suboxone Film, but is associated with a significantly higher risk of pediatric exposure. Suboxone Tablet is thus less safe than Suboxone Film, and RBP discontinued marketing it for that reason. FDA must refuse to approve any ANDA referencing Suboxone Tablet (NDA 20-733) until it determines whether RBP's decision was based on reasons of safety. CONCLUSION FDA cannot approve an application for a drug if the drug poses unreasonable safety risks. In administering this important responsibility, FDA considers a broad panoply of factors, each ofwhich is aimed at ensuring that unsafe products do not reach the public. In response to concerns regarding the potential misuse and abuse of buprenorphine for opioid dependence, RBP adopted a robust RiskMAP. Moreover, when pediatric exposure concerns emerged, RBP adjusted its RiskMAP to address those concerns. Today, the risks of accidental pediatric exposure to 106 Response to Citizen Petition, FDA to ISTA Pharmaceuticals, FDA Docket No. 2008-p- 0368at 16(May 11,2011). Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 46 of 49 Division of Dockets Management September 25, 2012 Page 46 buprenorphine have diminished. FDA should consider the observed association of these events and recognize the importance of all ofRBP's risk management interventions. Accordingly, to ensure the future safe use of buprenorphine for opioid addiction treatment, FDA should refrain from approving any buprenorphine application for opioid addiction that lacks risk-management interventions comparable to RBP's. Further, buprenorphine drugs for opioid dependence that fail to contain child-resistant unit-dose packaging pose an unreasonable risk that those products will be exposed to children, potentially causing permanent injury or even death. This reason alone merits denial of any application for those products. In addition, in light of a readily available safer alternative for opioid addiction treatment with buprenorphine, and FDA's historic treatment of products that pose unique risks of misuse, FDA should deny buprenorphine applications for opioid addiction without child-resistant unit-dose packaging that is associated with a reduction in the risk of pediatric exposure to those drugs. In light of findings from the recent pediatric exposure analysis, RBP has concluded that it is appropriate to discontinue marketing of Suboxone tablet. Accordingly, FDA may not approve any buprenorphine/naloxone ANDA for addiction treatment that references Suboxone tablet (NDA 20-733) until FDA determines whether that drug was discontinued for reasons of safety. III. ENVIRONMENTAL IMPACT RBP claims a categorical exclusion from the requirements for an Environmental Assessment under 21 C.F.R. § 25.3l(a) because the grant of this Citizen Petition would not have an effect on the environment. Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 47 of 49 Division of Dockets Management September 25, 2012 Page 47 IV. ECONOMIC IMPACT Information on the economic impact of the action requested by this Citizen Petition will be submitted if requested by FDA. Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 48 of 49 Division of Dockets Management September 25, 2012 Page48 V. CERTIFICATION RBP makes the following certification pursuant to FDC Act § 505(q)(l)(H): I certify that, to my best knowledge and belief: (a) this petition includes all information and views upon which the petition relies; (b) this petition includes representative data and/or information known to the petitioner which are unfavorable to the petition; and (c) I have taken reasonable steps to ensure that any representative data and/or information which are unfavorable to the petition were disclosed to me. I further certify that the information upon which I have based the action requested herein first became known to the party on whose behalf this petition is submitted on or about the following date: September 15, 2012. If I received or expect to receive payments, including cash and other forms of consideration, to file this information or its contents, I received or expect to receive those payments from the following persons or organizations: RBP. I verify under penalty of perjury that the foregoing is true and correct as of the date of the submission of this petition. Respectfully submitte ,/¥ Tim Baxter _- Global Medical Director Reckitt Benckiser Pharmaceuticals, Inc. Case 2:16-cv-05073-MSG Document 141-6 Filed 12/12/16 Page 49 of 49 IN THE UNITED STATES DISTRICT COURT FOR THE EASTERN DISTRICT OF PENNSYLVANIA STATE OF WISCONSIN By Attorney General Brad D. Schimel; et al., Plaintiffs, v. INDIVIOR INC. f/k/a RECKITT BENCKISER PHARMACEUTICALS, INC.; et al., Defendants. Case No. 2:16-cv-5073-MSG [PROPOSED] ORDER AND NOW, this ____day of ___________, 20__, upon consideration of Defendant Reckitt Benckiser Healthcare (UK) Limited’s Motion to Dismiss and any response thereto, it is hereby ORDERED that the Motion is GRANTED and the Plaintiff States’ First Amended Complaint is DISMISSED WITH PREJUDICE. BY THE COURT: _________________________ Mitchell S. Goldberg, J. Case 2:16-cv-05073-MSG Document 141-7 Filed 12/12/16 Page 1 of 1 IN THE UNITED STATES DISTRICT COURT FOR THE EASTERN DISTRICT OF PENNSYLVANIA STATE OF WISCONSIN By Attorney General Brad D. Schimel; et al., Plaintiffs, v. INDIVIOR INC. f/k/a RECKITT BENCKISER PHARMACEUTICALS, INC.; et al., Defendants. Case No. 2:16-cv-5073-MSG CERTIFICATE OF SERVICE I certify that on the date set forth below the foregoing Defendant Reckitt Benckiser Healthcare (UK) Limited’s Motion to Dismiss, Memorandum of Law in Support, Declaration of Benjamin N. Ernst with exhibits, and proposed Order were electronically filed pursuant to the Court’s CM/ECF system, and that the documents are available for downloading and viewing from the CM/ECF system. Notice of this filing will be sent to all counsel of record by operation of the CM/ECF system. I further certify that one exhibit is subject to a pending Motion to Seal Document and that this exhibit has been provided to counsel of record via e-mail. s/ Mark A. Ford Mark A. Ford Date: December 12, 2016 Case 2:16-cv-05073-MSG Document 141-8 Filed 12/12/16 Page 1 of 1