United States Food and Drug Administration Southwest Import District Notice of FDA Action Entry Number: Notice Number: April 21, 2017 6 Filer: Attention: Broker Box: > 5309, Houston Intercontinental Airport, Houston, TX Port of Entry: Carrier: ; Date Received: July 27, 2015 Arrival Date: July 24, 2015 < Importer of Record: Consignee: HOLD DESIGNATED Summary of Current Status of Individual Lines Line ACS/FDA * 1/1 Product Description Quantity Current Status THIOPENTAL-NA STERILE PWDR (LAW ENFORCEMENT ONLY ) 1000 PCS Refuse 04-21-2017 * = Status change since the previous notice. Read carefully the sections which follow for important information regarding these lines. @ = Consignee ID FDA will not request redelivery for examination or sampling, if the products not released by FDA are moved, following USCS conditional release to a localtion within the metropolitan area or to a location approved by the FDA office at the number below. All products in this entry not listed above may proceed without FDA examination. This notice does not constitute assurance the products involved comply with provisions of the Food, Drug, and Cosmetic Act or other related acts, and does not preclude action should the products later be found violative. REFUSAL OF ADMISSION REDELIVERY WITH FDA VERIFICATION REQUESTED Examination of the following products have been made and you have been afforded an opportunity to respond to a notice of detention. Because it appears that the products are not in compliance, you are hereby notified that they are refused admission. FDA 001 Notice of FDA Action Entry Number: Notice Number 6 Page: 2 Line ACS/FDA Product Description 1/1 THIOPENTAL-NA STERILE PWDR (LAW ENFORCEMENT ONLY ) Refused : 1,000 PCS FD&CA Section 502(f)(1), 801(a)(3); MISBRANDING The article appears to lack adequate directions for use. FD&CA Section 505(a), 801(a)(3); UNAPPROVED NEW DRUG The article appears to be a new drug without an approved new drug application. For the District Director of Customs: Rosa L. Santos, Compliance Officer (Region/District) U.S. Food and Drug Administration 4040 N. Central Expressway Suite 300 Dallas, TX 75204 (214) 253-5269 (214) 253-5316 (FAX) ROSA.SANTOS@FDA.HHS.GOV A request has been made to Customs to order redelivery for all the above product(s), in accordance with 19 CFR 141.113, which were conditionally released to you under terms of the entry bond. Failure to redeliver into Customs custody will result in a claim for liquidated damages under the provisions of the entry bond. These products must be exported or destroyed under Customs supervision within 90 days from the date of this notice, or within such additional time as the District Director of Custom specifies. Failure to do so may result in destruction of the products. Distribution of the products may result in their seizure and/or injunction or criminal prosecution of persons responsible for their distribution. You are required to have FDA verify the identification, exportation, or destruction of the above products. Contact the individual listed above to arrange for the required verification. After completion of the exportation or destruction forward the original of the signed CF-7512 or CF3499, along with any other documents required by Customs, and a copy of this notice to: Houston CBP Office 2350 North Sam Houston Pkwy East Suite 1000 Houston/Galveston, TX 77032 In addition forward copies of the signed CF-7512 or CF-3499, and any other records which document export or destruction, to the individual listed above. Notice Prepared For: The District Director, U.S. Food and Drug Administration Notice Prepared By: RLS FDA 002 United States Food and Drug Administration Southwest Import District Notice of FDA Action Entry Number: Notice Number: April 21, 2017 6 Importer: > 5309, Houston Intercontinental Airport, Houston, TX Port of Entry: Carrier: ; Date Received: July 27, 2015 Arrival Date: July 24, 2015 < Filer of Record: Consignee: HOLD DESIGNATED Summary of Current Status of Individual Lines Line ACS/FDA * 1/1 Product Description Quantity Current Status THIOPENTAL-NA STERILE PWDR (LAW ENFORCEMENT ONLY ) 1000 PCS Refuse 04-21-2017 * = Status change since the previous notice. Read carefully the sections which follow for important information regarding these lines. @ = Consignee ID FDA will not request redelivery for examination or sampling, if the products not released by FDA are moved, following USCS conditional release to a localtion within the metropolitan area or to a location approved by the FDA office at the number below. All products in this entry not listed above may proceed without FDA examination. This notice does not constitute assurance the products involved comply with provisions of the Food, Drug, and Cosmetic Act or other related acts, and does not preclude action should the products later be found violative. REFUSAL OF ADMISSION REDELIVERY WITH FDA VERIFICATION REQUESTED Examination of the following products have been made and you have been afforded an opportunity to respond to a notice of detention. Because it appears that the products are not in compliance, you are hereby notified that they are refused admission. FDA 003 Notice of FDA Action Entry Number: Notice Number 6 Page: 2 Line ACS/FDA Product Description 1/1 THIOPENTAL-NA STERILE PWDR (LAW ENFORCEMENT ONLY ) Refused : 1,000 PCS FD&CA Section 502(f)(1), 801(a)(3); MISBRANDING The article appears to lack adequate directions for use. FD&CA Section 505(a), 801(a)(3); UNAPPROVED NEW DRUG The article appears to be a new drug without an approved new drug application. For the District Director of Customs: Rosa L. Santos, Compliance Officer (Region/District) U.S. Food and Drug Administration 4040 N. Central Expressway Suite 300 Dallas, TX 75204 (214) 253-5269 (214) 253-5316 (FAX) ROSA.SANTOS@FDA.HHS.GOV A request has been made to Customs to order redelivery for all the above product(s), in accordance with 19 CFR 141.113, which were conditionally released to you under terms of the entry bond. Failure to redeliver into Customs custody will result in a claim for liquidated damages under the provisions of the entry bond. These products must be exported or destroyed under Customs supervision within 90 days from the date of this notice, or within such additional time as the District Director of Custom specifies. Failure to do so may result in destruction of the products. Distribution of the products may result in their seizure and/or injunction or criminal prosecution of persons responsible for their distribution. You are required to have FDA verify the identification, exportation, or destruction of the above products. Contact the individual listed above to arrange for the required verification. After completion of the exportation or destruction forward the original of the signed CF-7512 or CF3499, along with any other documents required by Customs, and a copy of this notice to: Houston CBP Office 2350 North Sam Houston Pkwy East Suite 1000 Houston/Galveston, TX 77032 In addition forward copies of the signed CF-7512 or CF-3499, and any other records which document export or destruction, to the individual listed above. Notice Prepared For: The District Director, U.S. Food and Drug Administration Notice Prepared By: RLS FDA 004 April 20, 2017 VLA ELECTRONIC MAIL Re: Entry No. /Thio ental Sodiunrl imported by the Dw?= I am writin in res onse to your May 20, 2016, letter on behalf of the which responded to the Food and Drug Administration?s (FDA) letter of April 15, 2016, settin forth the Agency?s tentative decision regarding the admissibility of Entry Number . That entry consists of 1,000 one-gram vials of a dru roduct labeled as Thiopental Sodium USP), which were offered for importation by on July 24, 2015. has noti?ed FDA that it is importing the detained drugs for use n1 administering lethal injection. As we noted in oru? April 15 letter, for decades, FDA generally exercised enforcement discretion regarding sodium thiopental used for capital punishment pmposes. Ref. 7 at 52; see Heck/er v. Chaney, 470 US. 821, 835-36 (1985): see also Ref. 1, Ex. 14 at 1-2 (2010 FDA statement explaining that FDA was exercising enforcement discretion). In February 2011, a group of prisoners on death row in Arizona, California, and Tennessee ?led suit challenging release of imported thiopental sodirun for use as an anesthetic as part of lethal injection. The plaintiffs argued that FDA acted contrary to law, in an arbitrary and capricious marmer, and in abuse of its discretion when the Agency allowed shipments of the misbranded and unapproved new drug thiopental to be imported into the US. In March 2012, the United States District orut for the District of Columbia granted the plaintiffs? motion for surmnary judgnrent. See Bealy v. FDA, 853 F. Supp. 2d 30 (D.D.C. 2012), a??d in part, rev in part sub nom. Cook v. FDA, 733 F.3d 1 (DC . Cir. 2013) The District ourt?s March 2012 order, as modi?ed in June 2012, permanently enjoins FDA from ?permitting the entry of, or releasing any futru?e Thiopental sodirun is also known as sodium thiopental. In this letter, ?thiopental sodium? and ?sodium thiopental? are used interchangeably. 2 To avoid confusion, we have maintained the reference numbers from tentative decision in this final decision. As a result, letter dated April 15, 2016 is listed as Reference 7. FDA 005 April 20, 2017 Page 2 shipments of, foreign manufactured thiopental that appears to be misbranded or in violation of 21 U.S.C. [§] 355 [as an unapproved new drug].” contends that Beaty/Cook was “wrongly decided,” Ref. 8 at 13, but FDA is bound by the terms of the order issued by the District Court in that case. That order requires the Agency to refuse admission to import entries of foreign-manufactured sodium thiopental if the sodium thiopental appears to be an unapproved new drug or a misbranded drug. See Refs. 4&5. Therefore, we disagree with contention that FDA has room to exercise discretion regarding the foreign-manufactured sodium thiopental wishes to import. We have carefully considered all of the arguments and information in the May 20, 2016, letter, as well as previous submissions on behalf of the detained drugs. Based on a review of the entire record in this matter, for the reasons detailed below, we have concluded that the detained drugs in Entry No. appear to be unapproved new drugs and misbranded drugs within the meaning of 21 U.S.C. §§ 352(f)(1) & 355(a). In reaching this conclusion, we reject assertion in its May 20 letter that FDA’s “interpretations amount to a federal ban on use of thiopental sodium for lethal injection.” See Ref. 8 at 10-11. Nor is it FDA’s purpose or intention to interfere with lawfully conducted capital punishment carried out by lethal injection. As noted below, FDA’s determination that the detained drugs cannot be imported under the Beaty/Cook order because they appear to be unapproved new drugs and misbranded drugs has no effect on importation of foreignmanufactured sodium thiopental that has an FDA approval and is properly labeled and, thus, is not in violation of the Federal Food, Drug, and Cosmetic Act (“FD&C Act”). Nor does it require FDA to take action against domestic distribution of sodium thiopental, whether or not it is unapproved or misbranded. I. Background A. Statutory Framework Under the FD&C Act, the Secretary of Health and Human Services may request “samples of food, drugs, devices, tobacco products, and cosmetics which are being imported or offered for import into the United States . . . .” 21 U.S.C. § 381(a). The FD&C Act further provides that “[i]f it appears from the examination of such samples or otherwise that . . . (3) such article is adulterated, misbranded, or in violation of [21 U.S.C. § 355], . . . then such article shall be refused admission, except as provided in” 21 U.S.C. § 381(b). 21 U.S.C. § 381(a)(3) (emphasis added). The FD&C Act thus does not require FDA to find that an article that is offered for importation is actually adulterated, misbranded, or in violation of 21 U.S.C. § 355 in order to refuse admission to that article; rather, the Agency has “broad authority to prohibit import” of any article that “appears” to violate the FD&C Act. Continental Seafoods, Inc. v. Schweiker, 674 F.2d 38, 43 (D.C. Cir. 1982) (emphasis added); see Goodwin v. United States, 371 F. Supp. 433, 436 (S.D. Cal. 1972); see also United States v. Food, 2998 Cases, 64 F.3d 984, 992 (5th Cir. FDA 006 April 20, 2017 Page 3 1995) (FDA “can pursue the administrative procedures of § 381 and simply require reexportation of the goods,” even where “the government lacks the ability to prove a violation of the [FD&C Act] by a preponderance of the evidence.”); Sugarman v. Forbragd, 267 F. Supp. 817, 824 (N.D. Cal. 1967), aff’d, 405 F.2d 1189 (9th Cir. 1968); K&K Merch. Group, Inc. v. Shalala, No. 95Civl0082, 1996 U.S. Dist. LEXIS 4880, *22-23 (S.D.N.Y. 1996) (noting “the wide discretionary power FDA enjoys to determine the factors regarding its decision to grant or refuse admission of imported goods”). 3 If an article is refused admission, it must be exported or destroyed within ninety days. 21 U.S.C. § 381(a). B. The Proceedings On or about July 24, 2015, offered for import 1,000 one-gram vials of a product labeled as (Thiopental Sodium USP). On August 5, 2015, U.S. Customs and Border Protection (CBP) detained the shipment. Ref. 1, Ex. 10 at 1. On August 18, 2015, through counsel, requested that FDA instruct CBP to lift the detention and let the product proceed to destination. Ref. 1, Ex. 11 at 1-2. By letter dated August 24, 2015, FDA denied that request. Ref. 1, Ex. 12. On August 24, 2015, FDA issued a “Notice of FDA Action” explaining that Entry was detained and subject to refusal of admission based on the following: the product appeared to be misbranded under 21 U.S.C. § 352(f)(1) because its labeling appeared to lack adequate directions for use; the product appeared to be misbranded under 21 U.S.C. § 352(f)(2) because its labeling appeared to lack adequate warning against use in a pathological condition or by children where it may be dangerous to health or against an unsafe dose, method, administering duration, application, in manner/form, to protect users; and the product appeared to be a new drug that lacked an approved new drug application as required by 21 U.S.C. § 355. Ref. 1, Ex. 1 at 1-2. The notice, which was sent to as the listed consignee of the entry, specified that testimony regarding the admissibility of the entry must be submitted to FDA by September 14, 2015. Id. at 2. On September 10, 2015, through counsel, requested an extension to respond to the Notice of FDA Action. On the same day, FDA granted an extension until October 23, 2015. See Ref. 1, Ex. 1 at 3. 3 As part of its assertion that “no deference is due” to “any of the regulatory or statutory interpretations” in FDA’s decision, appears to argue that the only questions the Agency is called upon to resolve in this matter are “pure questions of law” to which section 381(a)’s “appearance” standard does not apply. See Ref. 8 at 8-9. Although we agree with that some of the facts in this matter (e.g., that the detained products are drugs and they lack an approved application) are not in dispute, this matter does not present only undisputed facts and purely legal questions. For example, it involves FDA’s determination regarding what conditions are suggested in the detained drugs’ labeling. FDA 007 April 20, 2017 Page 4 011 October 23, 2015, through counsel, submitted written testimony regarding the detained drugs. Ref. 1. The letter explained position that the detained drugs should not be refused admission and requested an in- erson hearing with appropriate FDA personnel. Id. at 1. In submitting the written testimony, also requested that FDA transfer the matter to the Director, Of?ce of Enforcement and Import Operations or his designee, who would serve as the hearing of?cer for this detention. In a telephone discussion on December 10, 2015, FDA counsel informed you that the Agency did not intend to transfer the matter to OEIO. In a subse uent telephone discussion with FDA cormsel 011 February 2, 2016, FDA asked whether? still wanted to present information regarding the detained drugs in person. Subsequently, in a series of phone commrmications on March 11, 2016, you stated that concrured with an approach in which FDA would send a written, tentative decision and provide with the opportrurity to respond before reaching a ?nal decision. The Agency set forth its tentative conclusions in a letter dated April 15, 2016. In that letter, the Agency provided- with the ortlmity to respond to the tentative conclusions, either in writing or in a meeting, and assru'ed that the Agency would take any information provided in response to the April 15 letter into account in reaching a ?nal conclusion regarding the admissibility of the detained diugs. The letter speci?ed that additional testimony regarding the admissibility of the entr must be submitted within 20 calendar days of receipt. Ref. 7 at 15. After receiving the letterpi through counsel, requested an extension to May 20, which FDA granted. See Ref. 9 at 1. responded to tentative conclusions in the May 20 letter, which included ?ve attachments. C. The Detained Drugs Entry No. consists of 1,000 one-gram vials of - (Thiopental Sodirun USP). Ref. 2 at 2. The labels on the Vials of thiopental sodium state: 1 gm Thiopental Sodirun USP Sterile RX 011] manufactru'er and distribution services For law enforcement pmpose only. Mfg. Date: 06/2015 Exp. Date: 05/2017 FDA 008 April 20, 2017 Page 5 Marketed Ref. 3 at 23-24. The label bears no other information. Ref. 1, Ex. 3 at 1. See also Ref. 1 at 2 (?Aside from the information printed on the label . . . there is no additional labeling accompanying the drug specifying information about its properties or uses?). Stickers on the outside of each box of vials repeat the information on the vial label. Ref. 3 at 43. The boxes contain no package inserts, lea?ets, or other materials with directions for use or warnin about the use of the thiopental sodium. An outside box label lists the as the consi ee. Id. at 26-27. In addition to the label listing the certi?cate of anal sis int entr the thiopental sodium states that it is by? Thiopental sodirun is a barbiturate that depresses nervous system ?mction to render a person lmconscious, Ref. 1, Ex. 15 at 3-5 (Goodman and Gihnan?s, The Pharmacological Basis of Therapeutics, 11th ed., at 347-49), which can cause death in a large enough dose. Ref. 1, Ex. 16 at 10 (History of Barbitlu?ates, at 338). As classi?ed among anesthetics, it is an ultrashort- acting agent. Id. Like other anesthetics, its effects vary based on patient-speci?c factors such as weight and age, and its use must be calibrated. Ref. 1, Ex. 15 at 3-5 (Goodman and Gilman?s, at 347-349). In addition, thiopental soditmr can produce allergic reactions in some individuals. 10'. at 6 (Goodman and Gihnan?s, at 350). It is a schedule controlled substance. Ref. 1 at 2; Ref. 1, Ex. 3. ocumentation for Ref. 2 at 4. agrees that the detained thiopental sodium is a drug within the meaning of the Act and does not dispute that the detained drugs are not the subject of an approved new drug application, an approved abbreviated new application, or an effective investigational new drug application. In fact, there are no FDA-approved sodium thiopental products that are crurently being marketed for any use. 5 4 In its initial submission,- acknowledged that the thiopental sodium is a drug, because it is intended to affect the structlu?e and ?mction of the body. Ref. 1 at 5 (discussing 21 U.S.C . 321 1 C) and stating that ?[t]his second de?nition applies here?). Moreover, in the May 20 letterpw repeatedly refers to the detained thiopental sodium as ?detained drugs.? See Ref. 8 assim. Previously, for example, Abbott Laboratories held an NDA (NDA 11-679) for Pentothal Sodilun (thiopental sodium) Suspension. FDA withdrew that NDA in 2001 at Abbott?s request because the drug was no longer marketed. See 66 Fed. Reg. 43017 (Aug. 16, 2001). NDA 11-679 remains listed in Orange Book, meaning that FDA has not determined that Abbott?s thiopental sodium drug product was withdrawn for safety or ef?cacy reasons. Unless FDA makes such a determination, NDA 11-679 can be cited in applications for approval using the abbreviated pathways established in the Act. FDA 009 April 20, 2017 Page 6 is importin the detained drugs for use in administering lethal injection. Ref. 1, Ex. 13 1] 5. Speci?cally, states that in the last decade it has ?executed 182 offenders by administering lethal injection? and ?will continue to execute additional offenders through lethal irrection, on a recurring and continuing basis, for the foreseeable future.? Ref. 8, Attch. E. ?has previously purchased and used thiopental sodium in numerous executions,? I'd; see also Ref. 1, Ex. 13 11 5. ?current execution protocol? mandates use of ientobarbital, see Ref. 8, Attch. however, is ?preparing for a contingency in which may once again utilize thiopental sodium in executions and will do so when necessary if FDA re eases its hold on? the detained drugs. Ref. 8, Attch. RefBound by Judicial Order to Refuse Entry to the Detained Sodium Thio ental If It A ears to be an Una roved New Dru or Misbranded As noted above, the District orut?s March 2012 order, as modi?ed in J1me 2012, permanently enj oins FDA from ?permitting the entry of, or releasing any future shipments of, foreign manufactru?ed thiopental that appears to be misbranded or in Violation of 21 U.S.C . 355 [as an unapproved new drug].? Ref. 4 at 1-2; Ref. 5 at 2. We interpret the order to mean what it says: namely, that FDA is required to refuse entry to thiopental produced abroad when it appears that the thiopental is misbranded or an unapproved new drug. - argues that, even if FDA concludes that the detained drugs appear to be rurapproved new drugs and/ or misbranded (1111 s, the Agency can and should exercise enforcement discretion to admit Entry . Ref. 8 at 13. In particular, - contends that the Beam/Cook decision is distinguishable from the present circumstances because the parties to that case stipulated that the drugs at issue were unapproved new drugs and misbranded. But the question here is not whether this case is similar to Beam/Cook or whether BeaIy/Cook is persuasive authority that FDA should follow. Rather, the question is whether the terms of the Beaty/Cook order cover the circrunstances presented in this case. So long as the import entry at issue is ?foreign manufactru?ed thiopental that appears to be misbranded or in violation of 21 U.S.C. 355,? the District Court?s order constrains enforcement discretion. Similarly, we reject- argument that FDA should have discretion to admit the thiopental because Beam/Cook was (in View) ?wrongly decided.? Ref. 8 at 13. argrunent on this grormd is effectively a collateral attack on the District orut?s order. But the BeaIy/Cook decision camrot be subjected to collateral attack through this proceeding; the order could only be modi?ed through further judicial action. Until the Court lifts or modi?es its order, that order continues to govern review of thiopental import entries. See, GTE Siz'lvania, Inc. v. Consumers Union of the US, 445 US. 375, 386 (1980) (?persons subject to an injunctive order issued by a corut with jru?isdiction are expected to obey that decree until it is modi?ed or reversed . . . Because, as discussed below, we conclude that the thiopental at issue here appears to be a misbranded and unapproved new drug, under the order, FDA is without discretion to FDA 010 April 20, 2017 Page 7 permit entry to the foreign-manufactured sodium thiopental wishes to import. Consistent with the District Court’s order, FDA must refuse entry of this thiopental into the United States. III. The Detained Thiopental Sodium Appears To Be An Unapproved New Drug In the April 15 letter, FDA tentatively concluded that the labeling of the detained thiopental sodium suggests the conditions under which it will be used: for lethal injection. challenges that tentative conclusion on several grounds. First, argues that although FDA may look beyond a product’s labeling to determine “whether an article is a ‘drug’ in the first place . . . based on [its] intended use,” the Agency may consider only statements in a drug’s labeling to determine whether the drug is a “new drug” under 21 U.S.C. § 321(p). See Ref. 8 at 6. Based on this assertion, contends that the Agency’s tentative conclusion that the detained drugs are new drugs is “erroneous” because the Agency reached its conclusion by relying “primarily on information that is not labeling . . . .” See id. (emphasis in original). Second, argues that FDA erred in concluding that the labeling of the detained drugs “suggest[s] any condition of use.” Id. at 7. Third, claims that FDA had “no basis for concluding that the detained drugs are not generally accepted [sic] as safe and effective for any use simply because FDA could not find scientific literature documenting studies with this particular distributor’s product.” See id. at 8. We address each of these arguments below. A. The Meaning of “Conditions . . . Suggested in the Labeling” In this matter, FDA must determine whether a detained drug that is not approved for any use appears to be a “new drug” as defined in 21 U.S.C. § 321(p). Before turning to specific arguments, we begin by addressing the meaning of “suggested” in this inquiry. As discussed in greater detail below, under the FD&C Act, a “drug” is a “new drug” unless, among other things, it is generally recognized among qualified experts as being “safe and effective for use under the conditions prescribed, recommended, or suggested in [its] labeling.” See 21 U.S.C. § 321(p)(1) (emphasis added). In this proceeding, has equated the phrase “prescribed, recommended, or suggested” with the conditions being “stated” or “specified” in the labeling. For example, in the October 23, 2015, letter, argued, “[f]or FDA to establish that a drug is a ‘new drug,’ the agency must demonstrate that the drug is not generally recognized as safe and effective with respect to specific conditions of use stated in the labeling. When no conditions for use are so specified, it is not possible for FDA to establish that a drug is a ‘new drug.’” Ref. 1 at 7 (emphasis added). In its May 20 letter, contends that the “plain meaning of the term ‘suggested’ is ‘proposed.’” Ref. 8 at 7 n.10. The three terms “prescribed,” “recommended,” and “suggested” each must be given an independent, non-superfluous meaning. According to Webster’s New International Dictionary FDA 011 April 20, 2017 Page 8 Second Edition Unabridged (G&C Merriam Co. 1940) 6 (Ref. 10), prescribe means “[t]o lay down authoritatively as a guide, direction, or rule of action” and, as used in medicine, “[t]o direct, designate, or order the use of, as a remedy; as, the doctor prescribed medicine.” Id. at 1 (italics in original). “Recommend” in turn is defined in part as “[t]o commend, or bring forward explicitly, as meriting consideration, acceptance, adoption, election, or the like.” Id. at 2 (emphasis added). By comparison, the first definition of “suggest” is “[t]o put (something) into one’s mind; to arouse or awaken, often by indirect means, the thought or feeling of, the desire for, the temptation to commit, the will to do, or the like; as, plays that harm by suggesting evil; now, often, to propose tentatively; to mention as a hint, a possible explanation or course, etc.; as, to suggest a walk in the country, a moratorium; to suggest that a change of government is necessary.” See Ref. 10 at 3 (italics in original, emphasis added). Thus, “suggest” is not limited to things that are explicitly stated, specified, or proposed, as contends. “Suggested” has a broader meaning, and something can be “suggested” even if only proposed or hinted at indirectly. This broader meaning of “suggested” is confirmed by Congress’s inclusion of “suggested” following “prescribed” and “recommended.” Having already covered conditions of use that are either “prescribed” or “recommended” in the labeling, Congress’s inclusion of “suggested” must mean that it applies to situations where the conditions for use are not “la[id] down authoritatively,” “direct[ed],” or “commend[ed] . . . explicitly.” Thus, because no indications for use are explicitly “prescribed” or “recommended” in the labeling of the detained drugs, it is necessary to consider here what is “suggested” in the drugs’ labeling. B. Statements on the Label of the Detained Sodium Thiopental Suggest Its Use for Lethal Injection contends that FDA may consider only statements in a drug’s labeling 7 in determining whether the drug is a “new drug” under 21 U.S.C. § 321(p). See Ref. 8 at 6. Based on this assertion, argues that the Agency’s tentative conclusion that the detained drugs are new drugs is “erroneous” because the Agency based its conclusion “primarily on information that is not labeling . . . .” See id. (emphasis in original). 8 We disagree. 6 See, e.g., Taniguchi v. Kan Pacific Saipan, Ltd., 566 U.S. 560, 566-67 (2012) (explaining “When a term goes undefined in a statute, we give the term its ordinary meaning,” and considering dictionaries contemporaneous to the regulatory enactment). 7 As used in the FD&C Act, “label” means “a display of written, printed, or graphic matter upon the immediate container of any article . . . .” 21 U.S.C. § 321(k) (emphasis added). “Labeling” means “all labels and other written, printed, or graphic matter” that is either “upon any article or any of its containers or wrappers” or “accompanying such article.” 21 U.S.C. § 321(m). 8 position appears to be that an importer can avoid having a drug that is not approved for any use classified as a “new drug” – and thereby bypass entirely the premarket approval scheme for new drugs mandated by Congress – simply by removing from the drug’s labeling any explicit FDA 012 April 20, 2017 Page 9 Four statements appear on the labels of the detained drugs: “Thiopental Sodium USP,” “Sterile,” “Rx only,” and “For law enforcement purpose only.” Ref. 3 at 23-24; Ref. 1, Ex. 3 at 1. These statements are indisputably “labeling” because the drugs’ labels are part of their “labeling.” 21 U.S.C. § 321(m). Taken together, these four statements suggest the conditions under which this unapproved drug will be used: for lethal injection. “Rx only” makes clear that the detained drugs are prescription drugs, 9 meaning that due to their “toxicity or other potentiality for harmful effect, or the method of [their] use, or the collateral measures necessary to [their] use, [they are] not safe for use except under the supervision of a” licensed practitioner. See, e.g., 21 U.S.C. § 353(b)(1)(A). “Sterile” on the label of this single-glass-vial drug suggests that the drugs are likely to be administered by injection, where sterility is critical. As has acknowledged, there are several well-known uses of thiopental sodium. See Ref. 8 at 7. Currently, one of the best-known uses of thiopental sodium is for lethal injection, most often for anesthesia in multi-drug protocols, but sometimes as the lethal agent itself. 10 Indeed, sodium thiopental has been described as “the key drug in the three drug protocol used in most executions since lethal injection began in 1982,” see Owen Dyer, The Slow description of the purposes for which it is to be used, while at the same time submitting sworn testimony stating unequivocally the purpose for which that very drug will be used. We do not agree that position is correct, but it is not necessary to address it because the labeling of these detained drugs does in fact suggest their conditions of use. 9 In fact, if the detained drugs are not prescription drugs despite being labeled as such, they are misbranded. See 21 U.S.C. § 353(b)(4)(B) (a drug that is not a prescription drug “shall be deemed to be misbranded if at any time prior to dispensing the label of the drug bears the symbol” Rx only). 10 See, e.g., Glossip v. Gross, 135 S. Ct. 2726, 2732 (2015) (“By 2008, at least 30 of the 36 States that used lethal injection employed” a “three-drug protocol” for lethal injection that included sodium thiopental); Baze v. Rees, 553 U.S. 35, 53 (2008) (“Thirty States, as well as the Federal Government, use a series of sodium thiopental, pancuronium bromide, and potassium chloride, in varying amounts.”); Cook, 733 F.3d at 4 (noting that when the complaint was filed in that case, the states in which the plaintiffs had been sentenced to death “and many others executed prisoners by injecting them with a sequence of three drugs” that included sodium thiopental); Death Penalty Information Center, State by State Lethal Injection, http://www.deathpenaltyinfo.org/state-lethal-injection (describing States’ use of thiopental sodium in both three-drug and single-drug protocols); Jennifer Horne, Lethal Injection Drug Shortage, COUNCIL OF STATE GOVERNMENTS E-NEWSLETTER (Feb. 17, 2011), http://www.csg.org/pubs/capitolideas/enews/issue65 4.aspx; Emma Marris, Death-row drug dilemma, NATURE (Jan. 27, 2011) (available at http://www.nature.com/news/2011/110121/ full/news.2011.53.html); Jennifer Sullivan, Killer on Death Row 16 ½ Years is Executed, Seattle Times (Sept. 10, 2010) (available at http://www.seattletimes.com/ seattle-news/killer-on-deathrow-16-years-is-executed). FDA 013 April 20, 2017 Page 10 Deatlz of Lethal Injection, 348 BMJ 2670 (2014), and was used by Texas as part of a three-drug combination for many years. 1 does not dispute that this is a widely-recognized use of the drug, but notes that ?thiopenta sodirun may be used for a variety of different purposes other than lethal injection.? Ref. 8 at 7. In particular,- has asserted that ?[t]he standard reference source for pharmacology indicates that sodium thiopental is a barbitru?ate that produces rmconsciousness and anesthesia? and that ?[t]his effect is well known; the drug has been used for purposes of anesthesia since before the Act] was enacted in 1938.? Ref. 1 at 4 n.2. Because there are possible pmposes for sodium thiopental other than use in lethal injection, - contends ?the drug?s name does not suggest any particular condition of use.? Ref. 8 at 7. But a drug must be for all of the conditions of use suggested in its labeling,12 and, as discussed below, the detained sodium thiopental is not under any conditions of use. In any event, here, the fourth statement on the detained drugs? label??For law enforcement prupose only,? in combination with the name of the drug and other statements, ?suggests? that the drug is for use in lethal injection. - implicitly acknowledges as much when it argues, ?The ?law enforcement purpose only? legend . . . rovides a warnin not to use the product for any medical pmpose . . . Id. (emphasis added). Because, asi notes, the ?law enforcement purpose only? legend conveys that the drugs are not to be used for any ?medical purpose? that is, not for their anesthetic or barbitru'ate effects apart from lethal injection we conclude that the statements on the labels of these unapproved drugs collectively suggest propose or hint at indirectly) use of the detained drugs in lethal injection. As noted in the tentative decision, the Agency?s interpretation of the detained drug?s use is confnmed by! submissions. See, Ref. 8, Attch. at 1 execution protocol crurent requn?es the use of pentobarbital. However . . . consrders alternatives to pentobarbital, including thiopental sodium, as a contingency should find pentobarbital unavailable?); Ref. 8, Attch. at 1 is preparing for a contingency in which may 11 Michael Graczyk, Execution Drug Cost Quadruples for Texas Prisons, USA Today (Aug. 15, 2014) (Texas used ?three-din combination of sodium thiopental, pancuroniurn bromide and potassirun chloride? untilh. stopped production of sodium thiopental) (available at costs/ 141 15595/); eras May Soon Change the Way it Executes Prisoners, Dallas Morning News (Feb. 3, 2011) (sodirun thiopental was ?one of three drugs that Texas uses to administer lethal injections? until it was in shortage) (available at see also Ref. 1, Ex. 13 11 5 ?has previously purchased and used thiopental sodium in numerous executions?). United States v. An Article of Neo-Terramycin Soluble Powder Concentrate, 540 F. Supp. 363, 379 (ND. Tex. 1982) ?nding that a drug is not generally recognized as effective for one or more of the label claims would result in a determination that the product is a new drug, even if it is assruned that it is generally recognized as effective for the remaining label claims?); see also United States v. An Article of Drug. . . Quinaglute, 268 F. Supp. 245, 248-49 (ED. Mo. 1967) FDA 014 April 20, 2017 Page 11 once again utilize thiopental sodium in executions and will do so when necessary if FDA releases its hold on the purchased thiopental sodium that is being detained by FDA.”); Ref. 1, Ex. 13 ¶ 5 (“ has previously purchased and used thiopental sodium in numerous executions before it became commercially unavailable to correctional facilities for such purpose” and “I am attempting to once again utilize thiopental sodium in executions and will do so when necessary if the FDA releases its hold on the purchased thiopental sodium.”); Ref. 1 at 4. We do not agree with contention that the Agency is relying “primarily on information that is not labeling to conclude that [the detained drugs] are ‘new drugs.’” Ref. 8 at 6 (emphasis in original). In particular, points to the tentative conclusion’s citation of two court cases and several articles. FDA did not cite those materials as “labeling” for the detained drugs. Rather, the Agency cited the court cases and articles simply to illustrate that sodium thiopental’s use in lethal injection is well known. See Ref. 7 at 7. Similarly, FDA did not, and does not, rely on supporting affidavits as part of the Agency’s determination of the “new drug” status of the detained drugs. Instead, we simply note that the interpretation of the labeling of the detained drugs as suggesting use of those drugs in lethal injection is “confirmed by” own statements regarding how it plans to use the drugs. C. The FD&C Act’s Definition of “New Drug” If a product is a drug, then, as a matter of law, it is a “new drug” that must be approved by FDA before it can be lawfully distributed in interstate commerce, unless it satisfies two requirements. 13 First, it must be generally recognized among qualified experts as being safe and effective (“GRAS/E”) “for use under the conditions prescribed, recommended, or suggested in the labeling thereof.” 21 U.S.C. §§ 321(p)(1), 331(d), 355. Second, even if a drug has become GRAS/E as a “result of investigations to determine its safety and effectiveness for use under such conditions,” it remains a new drug unless it has been “used to a material extent or for a material time” other than in those investigations. 21 U.S.C. § 321(p)(2). 14 13 The definition of “new drug” also contains a limited exception for grandfathered drugs. See 21 U.S.C. § 321(p)(1) (a drug that does not meet that section’s “generally recognized” standard “shall not be deemed to be a ‘new drug’ if at any time prior to the enactment of [the FD&C Act] it was subject to the Food and Drugs Act of June 30, 1906, as amended, and if at such time its labeling contained the same representations concerning the conditions of its use.”); see also Public Law 87-781, § 107 (reprinted following 21 U.S.C. § 321) (grandfather clause in 1962 Amendments that was not codified). The two grandfather clauses in the FD&C Act have been interpreted very narrowly. See, e.g., United States v. Allan Drug Corp., 357 F.2d 713, 718-19 (10th Cir. 1966) (holding that a drug product “loses the immunity of the Grandfather clause and becomes a new drug” subject to the FDCA’s premarket approval requirements even if there is no more than a “mere change in the labeling after the effective date of the Act”); United States v. Articles of Drug . . . 5,906 Boxes, 745 F.2d 105, 113 (1st Cir. 1984). has not claimed, nor does FDA believe, that these provisions apply to the detained sodium thiopental. 14 FDA recognizes that health care professionals may choose to use approved drugs for unapproved uses. FDA generally does not regulate the conduct of health care professionals in FDA 015 April 20, 2017 Page 12 1. General Recognition of Safety and Effectiveness General recognition of effectiveness requires a three-pronged showing. First, there must exist a body of evidence that would at least be sufficient to obtain FDA’s approval for the product. See United States v. 50 Boxes More or Less, 909 F.2d 24, 26 (1st Cir. 1990); United States v. 225 Cartons, More or Less, of an Article off Drug … (Fiorinal), 871 F.2d 409, 413 (3d Cir. 1989). As the Supreme Court has explained, “‘general recognition of effectiveness’ requires at least ‘substantial evidence’ of effectiveness for approval of [a new drug application].” Weinberger v. Hynson, Westcott & Dunning, Inc., 412 U.S. 609, 629 (1973); see also United States v. Undetermined Quantities of an Article of Drug (Anucort), 709 F. Supp. 511, 514 n.2 (D.N.J. 1987), aff’d, 857 F.2d 1464 (3d Cir. 1988). The FD&C Act defines “substantial evidence” as evidence consisting of “adequate and well-controlled investigations, including clinical investigations . . . on the basis of which it could fairly and responsibly be concluded by . . . [qualified] experts that the drug will have the effect it purports or is represented to have . . . .” 21 U.S.C. § 355(d); Warner-Lambert Co. v. Heckler, 787 F.2d 147, 151 (3d Cir. 1986). Second, the investigations must be published in the scientific literature so that they are made generally available to the community of qualified experts and are, thereby, subject to peer evaluation, criticism, and review. Weinberger v. Bentex Pharms., Inc., 412 U.S. 645, 652 (1973); United States v. Article of Drug . . . 4,680 Pails, 725 F.2d 976, 987 (5th Cir. 1984); United States v. Undetermined Quantities of Various Articles of Drug . . . Equidantin Nitrofurantoin, 675 F.2d 994, 1001 (8th Cir. 1982); Premo Pharm. Labs., Inc. v. United States, 629 F.2d 795, 803-04 (2d Cir. 1980); United States v. Sene X Eleemosynary Corp. Inc., 479 F. Supp. 970, 977 (S.D. Fla. 1979) (general recognition of safety and effectiveness cannot be established by anecdotal evidence or the fact that a number of physicians throughout the country prescribe the drug); United States v. Undetermined Quantities of Articles of Drug, Street Drug Alternatives, 145 F. Supp. 2d 692, 701 (D. Md. 2001) (absence of literature establishing the safety and efficacy of the product is proof that the requisite general recognition does not exist). Third, there must be a consensus among the qualified experts, based on the adequate and well-controlled published investigations of the product in question, that the product is safe and effective for use under the conditions prescribed, recommended, or suggested in its labeling. See, e.g., Tri-Bio Labs., Inc. v. United States, 836 F.2d 135, 141 (3d Cir. 1987) (“[E]ither the unawareness of the drug product by experts generally or a genuine dispute among qualified experts regarding a drug product’s safety and effectiveness preclude[s] its qualifying for exclusion as ‘generally recognized.’”) (internal quotation omitted); Equidantin, 675 F.2d at 1000-01 (requiring “general consensus of expert opinion in favor of” the drug); Premo Pharm., 629 F.2d at 803 (“genuine dispute among qualified experts regarding a drug product’s safety and effectiveness preclude[s] its qualifying for exclusion as ‘generally recognized.’”); United States v. Article of Drug . . . “Entrol-C Medicated”, 513 F.2d 1127, 1128 (9th Cir. 1975). prescribing or using a legally marketed drug for an unapproved use within the practice of medicine. FDA 016 April 20, 2017 Page 13 A drug product that fails to meet any one of these three conditions is a new drug as a matter of law. See 4,680 Pails, 725 F.2d at 985; United States v. Seven Cardboard Cases . . . Codeine Capsules, 716 F. Supp. 1221, 1223-24 (E.D. Mo. 1989); United States v. 118/100 Tablet Bottles, 662 F. Supp. 511, 513-14 (WD. La. 1987); see also United States v. Articles of Drug . . . Promise ootlipaste, 826 F.2d 564, 569 (7th Cir. 1987). 2. Material Extent or Material Time As noted, even if a drug is it remains a ?new drug? if the dlug has not been used to a ?material extent or for a material time rmder such conditions.? 21 U.S.C . 321(p)(2). See anson, 412 US. at 631 drug cannot transcend ?new diug? status until it has been used ?to a material extent or for a material time??); United States v. Articles of Drug . . . HORMONIN, 498 F. Supp. 424, 432 (D.N.J.) (stating that a drug is a ?new drug? even if recognized as unless it also has been ??used to a material extent or for a material time? lmder non- investigative conditions?), a??d sub nom. Appeal of CarnrickLabs., Inc. 672 F.2d 902 (3d Cir. 1981) and aff?d sub nom. United States v. Articles of Drug, 672 F.2d 904 (3d Cir. 1981). D. The Detained Drugs Appear to Be ?New Drugs? In our April 15 letter, FDA explained that there is no approved new drug application for the detained drugs e. FDA also explained that the detained drugs are not Speci?cally, FDA explained that the Agency?s searches of the ublished scienti?c literatlu?e formd no adequate and well-controlled trials evaluating* (or thiopental sodium for use as part of a lethal injection or, or rat matter, any ot 1er use. FDA therefore tentatively concluded that the detained thiopental sodium is not for use in lethal injection. In its submissions, does not claim that an adequate and well- controlled trials evaluating (or thiopental sodium have been published in the scienti?c literature. Nor does appear to argue that the detained drugs are actually Imder ?y conditions of use. Instead, contends that the Agency should not have limited its search of the ublished scienti?c literatlu'e to studies involving? (0rd) thiopental product. Ref. 8 at 12. We disagree, but, as discussed below, the point is moot both because there are no published adequate and well-controlled trials evaluating any manufactru'er?s sodium thiopental for use in lethal irrection and because there is no evidence in the record that or has marketed (thiopental sodium USP) to a material extent or for a material time. 1. It Was Proper to Focus the ?General Recognition? Analysis on the Detained Dru Product Rather Than Just Its Active In redient As noted,- contends that ?the Tentative Decision has no basis for concluding that the detained drugs are not generally accepted [sic] as safe and effective for any use simply because FDA could not ?nd scienti?c literatru?e docrunenting studies with this particular distributor?s product.? Ref. 8 at 8 (emphasis added). Instead, argues, often establishes general acceptance [sic] of safety and effectiveness respect to active ingredients (whose ?nished dosage forms have speci?c required labeling) and not with respect to ?nished FDA 017 April 20, 2017 Page 14 dosage forms manufactured or distributed by a particular company. See generally 21 C.F.R. §§ 331-358.” Id. We disagree. It is well settled that the FD&C Act’s definitions of “drug” and “new drug” apply to the drug product, 15 not just its active ingredient. United States v. Generix Drug Corp., 460 U.S. 453, 459 (1983). In the Generix case, Generix Drug Corporation argued that it was not required to have approved new drug applications to market generic drug products, because those drug products contained the same active ingredients as FDA-approved pioneer drug products. The Supreme Court determined that a generic drug product – that is, one that contains the “same active ingredients as a previously approved pioneer drug” but different inactive ingredients – is a “new drug” subject to the FD&C Act’s premarket approval requirement. Id. at 455. In reaching that conclusion, the Court held that the “statutory phrase ‘any drug’” in the new drug definition (“any drug . . . [which] is not generally recognized as safe and effective . . . or . . . which has not, otherwise than in [safety and effectiveness] investigations, been used to a material extent or for a material time . . . .”) applies to the “complete drug product,” not just its active ingredient. Id. at 457; see also id. at 459 (“The term ‘drug’ is plainly intended throughout the [FD&C] Act to include entire drug products, complete with active and inactive ingredients.”). Thus, every drug product remains subject to the premarket approval requirement in section 355(a), “until the product (and not merely its active ingredient) no longer falls within the terms of [section 321(p)].” Id. at 461. Because the Generix Court held that the word “drug” in the “new drug” definition refers to an entire finished drug product, including excipients, and not just to the active ingredient, courts generally have held that studies of one drug product are insufficient to support a claim that a similar drug product is GRAS/E. See Premo Pharm., 629 F.2d at 803 (2d Cir. 1980) (“later developed ‘me-too’ products such as Insulase are required to apply for FDA approval for the undisputed reason that a difference in inactive ingredients, as exists here, when combined with the active ingredient, can affect the safety and effectiveness of the drug product. . . . [T]he purpose of the [FD&C] Act is to subject all such drug products not generally recognized as safe and effective (whether or not labelled ‘me-too’ products) to the premarket clearance requirements of the Act.”); United States v. Baxter Healthcare Corp., 712 F. Supp. 1352, 1356 (N.D. Ill. 1989) (“When examining a product to determine whether it is a drug, new or otherwise, the court must look at the product as a whole, ‘complete with active and inactive ingredients.’”) (quoting Generix, 460 U.S. at 459); Undetermined Quantities of an Article of Drug (Anucort), 709 F. Supp. at 515-16 (“the ‘substantial evidence’ requirement” can be satisfied “only by (1) adequate and well-controlled studies of the product Anucort itself or by (2)(a) adequate and well-controlled studies of another drug with the same active ingredients as 15 “Drug product” means “a finished dosage form, for example, tablet, capsule, or solution, that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients.” 21 C.F.R. § 314.3. FDA 018 April 20, 2017 Page 15 Anucort and (b) adequate and well-controlled studies demonstrating that the other drug and Anucort are bioequivalent.”). 16 To determine GRAS/E status for the detained thiopental, the specific drug product (including its active ingredients, excipients, and dosage) would have to be shown to be safe and effective in adequate and well-controlled clinical investigations. Because the relevant question is whether the detained drug products, not just their active ingredients, are GRAS/E for use under the conditions suggested in their labeling, it was appropriate for FDA to search for adequate and well-controlled clinical trials of and thiopental sodium in the published scientific literature. FDA’s searches identified no such studies, nor have any been And, as discussed above, in the absence of such studies, it is not possible for the cited by detained drugs to meet the “general recognition” standard. We do not agree that FDA “often establishes general acceptance [sic] of safety and effectiveness with respect to active ingredients (whose finished dosage forms have specific required labeling) — and not with respect to finished dosage forms manufactured or distributed by a particular company. See generally 21 C.F.R. §§ 331-358.” Ref. 8 at 8. cites a portion, but not the entirety, of the regulations established as part of the over-the counter (OTC) Drug Review, a regulatory system specific to nonprescription drugs. Thus, presents an incomplete picture. In order to be GRAS/E and not misbranded, each individual nonprescription drug product regulated under the OTC Drug Review must comply with the general conditions set forth in 21 C.F.R. Part 330 (and other applicable regulations), as well as with the specific conditions set forth in the applicable OTC drug monograph (the regulations to which refers, i.e., 21 C.F.R. §§ 331-358), which include specific OTC uses of active ingredients, along with other parameters, such as dosage forms, dosage strengths, route of administration, and the associated directions and warnings that must be included in labeling. See generally 21 C.F.R. § 330.14(a); 21 C.F.R. §§ 331-358. As a result, it is the drug product – not its active ingredient(s) alone – which complies with all of these requirements that is GRAS/E for its intended use. FDA has not promulgated any drug monographs that apply to prescription drugs, such as sodium thiopental. 17 Moreover, as discussed, FDA has not identified sufficient evidence to show 16 Likewise, passage of the Hatch-Waxman Amendments to the FD&C Act in 1984, The Drug Price Competition and Patent Term Restoration Act of 1984 (Pub. Law 98-417), provides evidence of congressional intent to subject drugs that share very similar characteristics to the application requirement. Under the Hatch-Waxman Amendments, drugs that are bioequivalent to drugs with approved new drug applications still need approved abbreviated new drug applications. This requirement enables FDA to evaluate active ingredients, inactive ingredients, labeling, chemistry, manufacturing, and controls, and other factors, in addition to bioequivalence, that combine to determine the safety and effectiveness of a finished drug product. FDA 019 April 20, 2017 Page 16 that the detained thiopental sodium drug products are, themselves, GRAS/E for use in lethal injection (or under any other conditions of use). In sum, the GRAS/E status of the detained drugs is not and cannot be established simply by claiming similarity to, or based on data regarding, another drug product, even one with the same active ingredient. It must independently be shown to be safe and effective in adequate and well-controlled clinical investigations, and no such studies have been published regarding the detained sodium thiopental. In any event, even if were correct that the detained sodium thiopental’s GRAS/E status can be determined based on published adequate and well-controlled studies of its active ingredient, the result would be the same. We have searched for published adequate and wellcontrolled studies evaluating the use of the active ingredient sodium thiopental for use in lethal injection, either as a sole agent or in combination with other agents, and no such studies were identified. Thus, it is not possible for sodium thiopental from , ., or any other firm to qualify as GRAS/E for use under the conditions suggested by the detained drugs’ labeling. 2. The Manufacturer of the Detained Drugs Has Failed to Avail Itself of FDA’s Approval Pathways Although the detained drugs are not GRAS/E, there are pathways for a manufacturer to distribute a sodium thiopental product by obtaining FDA approval of a new drug application (NDA). For example, a manufacturer could file either a stand-alone NDA under 21 U.S.C. § 355(b)(1), or use the abbreviated pathway in 21 U.S.C. § 355(b)(2) by relying in part on the FDA finding that a previously approved sodium thiopental product it references (e.g., Abbott’s Pentothal Sodium (thiopental sodium) Suspension NDA 11-679) is safe and effective as evidence in support of its own safety and effectiveness. Such an application would need to support any differences from the listed drug (such as a new dosage form, indication, or new formulation) with appropriate safety and effectiveness information. Likewise, a section 355(b)(2) applicant could submit published literature to FDA for the Agency’s review to help establish safety or efficacy for its requested indication. Yet, the manufacturer of the detained drugs has failed to avail itself of any of FDA’s new drug approval pathways available to it by not submitting a new drug application for the detained drugs for review to the Agency. For example, if a manufacturer avails itself of the section 355(b)(2) abbreviated pathway and receives approval for its sodium thiopental product, the drug would not be an unapproved new drug in violation of 21 U.S.C. § 355. 17 As previously noted, there is no dispute that the detained drugs, which are labeled “Rx only,” are prescription drugs. See Ref. 1, Ex. 3 (showing “Rx only” on the label); Ref. 1 at 4 n.2 (thiopental sodium “easily satisfies the definition of a prescription drug”). FDA 020 April 20, 2017 Page 17 3. The Detained Drugs Have Not Been Used to a Material Extent or for a Material Time As noted, to bypass the FD&C Act’s premarket approval requirement, a drug must also satisfy the “material extent” or “material time” requirement. 21 U.S.C. § 321(p)(2). See Hynson, 412 U.S. at 631; Articles of Drug . . . HORMONIN, 498 F. Supp. at 432. Like the “general recognition” requirement in subsection 321(p)(1), the material extent/time requirement in subsection 321(p)(2) is specific to the drug product, “not merely its active ingredient.” See Generix, 460 U.S. at 461. According to the registration and listing information submitted, the “marketing start date” for the detained drugs was June 5, 2015. Ref. 1 Ex. 2. And, we are aware of only one previous shipment of thiopental drug product to the United States. 18 The detained drugs have not been used to a material extent or a material time, and thus are new drugs within the meaning of 21 U.S.C. § 321(p)(2). See Premo, 629 F.2d at 804 (“although Premo has produced and sold at wholesale some 16,500,000 Insulase tablets (some of which have been seized in Government actions under 21 U.S.C. § 334), there is no evidence that Insulase has been used to a material extent or for any substantial period of time.”). In short, the detained drugs appear to be new drugs for two independent reasons. They are not GRAS/E for use under the conditions suggested in their labeling. And, even if they were GRAS/E under such conditions, they are new drugs because they have not been marketed to a material extent or for a material time. E. The Detained Drugs Appear to Violate Section 355(a) of the FD&C Act The FD&C Act mandates that all new drugs distributed in interstate commerce be approved by FDA or be the subject of an investigational new drug application. 21 U.S.C. §§ 331(d), 355(a). As noted, does not dispute that the detained drugs are not the subject of an approved new drug application, an approved abbreviated new drug application, or an effective investigational new drug application. Therefore, they appear to be unapproved new drugs. IV. The Detained Drugs Appear to Be Misbranded Under 21 U.S.C. § 352(f)(1) In addition to appearing to be an unapproved new drug, the detained sodium thiopental appears to be misbranded because its labeling does not bear adequate directions for use, as required by section 21 U.S.C. § 352(f)(1). 19 18 That shipment was received before the Beaty/Cook order was issued. The Agency tentatively concluded that the detained sodium thiopental also appears to be misbranded because its labeling fails to bear adequate warnings, as required by 21 U.S.C. § 352(f)(2). Because the Agency concludes that the detained drugs appear to be unapproved new drugs and misbranded within the meaning of section 352(f)(1) and because indicated a willingness to add warnings to the detained product, it is not necessary to reach a final 19 FDA 021 April 20, 2017 Page 18 In our April 15 letter, the Agency noted that the thiopental sodium that is attempting to import includes no directions for those who would administer the drug or receive it. Specifically, it lists no recommended dose and offers no instructions for reconstituting the powder inside the vials. Its labeling includes no precautions, contraindications, or warnings, or other information required in prescribing information for health professionals. Instead, it bears little text beyond “[f]or law enforcement purpose only,” “Rx only,” “CIII,” “1 gm,” and manufacturer information. FDA therefore asserted that the labeling provides inadequate directions for a prescription-drug barbiturate that will be administered to humans to produce anesthesia as part of a lethal injection procedure, or, possibly, to be used as the sole drug for lethal injection. contends that the detained thiopental sodium is not misbranded under 21 U.S.C. § 352(f)(1) because it “falls within the exemption established by 21 C.F.R. § 201.125.” Ref. 1 at 3. 20 Section 201.125’s “law enforcement” exemption, however, occurs in the context where otherwise misbranded drugs are not administered to humans. Thus, applying this exception to excuse the absence of adequate directions for use in the labeling of drugs for lethal injection is not supported by the text and the history of the exemption. Section 201.125 states: A drug subject to § 201.100 or § 201.105, shall be exempt from [21 U.S.C. § 352(f)(1) requiring adequate directions for use] if [1] shipped or sold to, or in the possession of, persons regularly and lawfully engaged in instruction in pharmacy, chemistry, or medicine not involving clinical use, or engaged in law enforcement, or in research not involving clinical use, or in chemical analysis, or determination regarding whether the detained drugs are misbranded within the meaning of section 352(f)(2). See Ref. 1 at 6 n.3 (regarding section 352(f)(2), stated “Under FFDCA section 801(b), we further request the opportunity to relabel the detained drug to include the warnings FDA deems adequate.”). 20 interpreted our tentative decision as a contention that a drug needs to meet all of the requirements of section 201.100 (which governs prescription drugs for human use) “to fit within section 201.125” (which includes the law enforcement exemption). Ref. 8 at 2 n.4. Instead, our view is that that the detained thiopental sodium fits within neither exemption from the requirement to bear adequate directions for use. does not dispute the Agency’s tentative conclusion that the detained drugs do not meet the conditions for the exemption from the requirement to bear adequate directions for use in 21 C.F.R. § 201.100. For example, as discussed in FDA’s tentative decision, the label of the drug lacks a “recommended or usual dosage,” and the labeling on or within the drug’s package lacks “adequate information for its use, including indications, effects, dosages, routes, methods, and frequency and duration of administration, and any relevant hazards, contraindications, side effects, and precautions under which practitioners licensed by law to administer the drug can use the drug safely and for the purposes for which it is intended . . . .” See 21 C.F.R. 201.100(c)(1). FDA 022 April 20, 2017 Page 19 physical testing, and is to be used only for such instruction, law enforcement, research, analysis, or testing. 21 C.F.R. § 201.125 (emphases added). Thus, the law enforcement exemption resides within a regulation with a two-part test for each exemption: the drug must be shipped, sold to, or in the possession of people engaged in particular activities, and it must be to be used only for the specific exempted purpose. As an initial matter, as noted in our tentative decision, the law enforcement exemption could not have been intended to apply to lethal injection, because FDA issued the regulation adding the exemption to section 201.125 in 1956, well before any State used lethal injection as a method of execution. See Regulations for the Enforcement of the Federal Food, Drug, and Cosmetic Act; Exemption of Certain Drugs and Devices from Labeling Requirements, 21 Fed. Reg. 2309, 2327 (Apr. 11, 1956) (final rule); Baze, 553 U.S. at 42 (describing the first State use of lethal injection). argues that the absence of the phrase “not involving clinical use” following “law enforcement” reflects a “conscious decision not to apply the qualifier to the law enforcement exemption.” Ref. 8 at 3. Based on this, contends that the “law enforcement” exception extends to use of drugs in lethal injection. Nevertheless, in context, FDA inserted the law enforcement exemption into an existing regulation addressing six other possible uses of drugs, not one of which involves administration to humans: instruction in pharmacy, instruction in chemistry, and instruction in medicine not involving clinical use, research not involving clinical use, chemical analysis, and physical testing. In each category that was likely to have implicated administration of the drug to humans – “instruction in medicine” and “research” – FDA explicitly provided that such use is outside the exemption. In the other categories – including law enforcement – no explicit limitation was specified, but it is implied by the context and the time period when FDA issued these regulations. Thus, FDA believes “law enforcement” should be interpreted in the context of “chemical analysis” and “physical testing”: the Agency did not attach the “not involving clinical use” modifier because “law enforcement” was understood to refer to activities similar to chemical analysis and physical testing. reading of the regulation is also counterintuitive. As we noted in our tentative decision, if the “not involving clinical use” limitation were to be applied only to categories where it was specifically attached, as advocates, the regulation would require “adequate directions” in the labeling for medical school professors administering drugs to humans, but not law enforcement personnel administering drugs to humans. This result cannot be what the Agency intended when adding the “law enforcement” language to section 201.125. also cites to a 2001 dictionary definition to argue that “even if the qualifier [‘not involving clinical use’] could be read into the law enforcement exemption,” the term “clinical use” should be understood to refer to use involving medical treatment of a patient, and thus the law enforcement exemption could still encompass lethal injection. Ref. 8 at 3. As in other FDA regulations, though, “clinical use” in § 201.125 refers to a use involving administration of drugs to humans. See, e.g., 21 C.F.R. § 312.3 (defining “clinical investigation” to mean “any FDA 023 April 20, 2017 Page 20 experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects”). Interpreting the law enforcement exemption as not extending to administration of drugs to humans is supported by the historical context of the regulation’s promulgation. At the time the exemption was added to section 201.125, the Agency was extremely active in investigative law enforcement work related to drug safety. More precisely, FDA promulgated the law enforcement exemption four years after the rest of § 201.125, see 21 Fed. Reg. 2327 (Apr. 11, 1956); Regulations for the Enforcement of the Federal Food, Drug, and Cosmetic Act; Drugs and Devices; Directions For Use; Exemption From Prescription Requirements, 17 Fed. Reg. 6807, 6819-6820 (July 25, 1952) (final rule), and just five months after testifying before Congress about FDA and State efforts on trafficking and misuse of amphetamines and barbiturates, see 21 Fed. Reg. 2327; Traffic In, and Control of, Narcotics, Barbiturates, and Amphetamines, Hearings Before the H. Subcomm. on Ways and Means, 84th Congress 1119-1120, 1123 (1955) (statement of John L. Harvey, FDA Deputy Commissioner, Nov. 17, 1955). dismisses the Agency’s discussion of these historical facts as a “post-hoc rationalization.” Ref. 8 at 3-4. But these sources indicate that the law enforcement exemption was aimed at facilitating the investigative work that the Agency and Congress were focused on at the time, instead of being specifically intended for facilitating shipment of unlabeled drugs to law enforcement officers to administer to people. FDA’s statements in the preamble to the regulation also support the Agency’s interpretation. If FDA had intended the law enforcement exemption as extending to drugs to be administered to humans, it seems implausible that the Agency would have stated that, in the cases where the exemption applied, “the [adequate-directions] labeling requirements are not necessary for the protection of the public health.” 21 Fed. Reg. 2309, 2327. By contrast, the Agency’s preamble statements are entirely consistent with the exempted uses being investigative activities like officer training and undercover buys. There are uses of drugs that could be characterized as part of law enforcement (e.g., court-mandated antipsychotic medication as a condition of supervised release). Interpreting the law enforcement exemption as broadly as advocates would exempt those uses. Likewise, mischaracterizes FDA’s past statements. alleges that the Agency’s 2010 press message document “confirms that the detained drugs fit squarely within the Agency’s 1956 statements regarding the exemption.” However, when FDA spoke of deferring to law enforcement in its 2010 press message document, the Agency was not interpreting the “law enforcement” provision of section 201.125. Ref. 1, Ex. 14. Instead, the Agency noted that it was “exercising enforcement discretion” in the context of drugs being imported for lethal injection, in light of flexibility under Heckler v. Chaney to “prioritiz[e] . . . enforcement resources to most effectively achieve [its] statutory mission.” Id. The two concepts are distinct. In short, the 1956 placement of the law enforcement exemption into section 201.125, a regulation with six other categories of uses that do not involve clinical use of drugs, indicates FDA 024 April 20, 2017 Page 21 that when the Agency added the language, it was not intended to extend the exemption to drugs to be administered to Today, FDA continues to believe that the law enforcement exemption was not intended to extend to drugs to be administered to hrnnans.22 Due to the textual and historical context of this exception, the detained drugs at issue appear to be misbranded. V. Conclusions Are Not in Con?ict with Con ressional Intent and Do Not Lead to Absurd Results offers two additional challenges to interpretation of the Act, based on interpretation of 18 U.S.C. 3596 and a 1937 predecessor, and its contention that decision produces ?absurd results.? We address these issues in turn. A. Interpretations of the New Drug and Misbranding Provisions Are Not in Con?ict with Con ressional Intent argues that the Agency?s interpretations of the new drug and misbranding provisions 0 the Act, as applied to the detained drugs, ?con?ict with congressional intent by restricting State options in implementing capital sentences.? Ref. 8 at 10. In particular, citing two statutes that address federal death sentences, - claims that ?Congress has made clear? that States are to be permitted to devise their own procedru'es for executions ?free of any federal interference.? Id. Because, inHview, interpretations of the Act amormt to a ?federal ban? on the use of so iopental for lethal injections, they impermissibly restrict State options in implementing capital sentences. Id. at 10-11. This argument both misr?eads the cited statutes and overstates the effect of determination regarding the detained drugs. Congress enacted the ?st statute that cites, 18 U.S.C. 3596,23 in 1994. Violent Crime Control and Law Enforcement Act, Pu . L. No. 103-322, 60002, 108 Stat. 1796. This 21 notes (Ref. 8 at 3) that FDA could have changed the text of the regulation when separatmg the drug and device exemptions, but it is not sruprising that FDA did not add or subtract modi?ers in a revision that was simply a recodi?cation into new sections. Subchapter H?Medical Devices: Reorganization and Republication, 41 Fed. Reg. 6896, 6896 (Feb. 13, 1976) 22 Thus, we do not dispute the idea that regulations can sometimes accommodate changing technology, see Ref. 8 at 3, but disagree on the basic scope of the exemption. 23 The statute states in relevant part: In general. A person who has been sentenced to death pursuant to this chapter [18 U.S.C . 3591 et seq.] shall be committed to the custody of the Attorney General rurtil exhaustion of the pr?ocedru?es for appeal of the judgment of conviction and for review of the sentence. When the sentence is to be implemented, the Attorney General shall release the person sentenced to death to the custody of a United States marshal, who shall supervise implementation of the sentence in the manner prescribed by the law of the State in which the sentence is imposed. If the law of FDA 025 April 20, 2017 Page 22 1994 statute states, among other things, that US. Marshals shall supervise a federal death sentence ?in the manner prescribed by the law of the State in which the sentence is imposed.? Id. The law uses language similar to its 1937 predecessor, in which Congress speci?ed that the federal death penalty would be implemented in a manner ?prescribed by the laws of the State within which the sentence is imposed.? The Capital leishment Method Act of 193 7, Pub. L. No. 156, 50 Stat. 304 (1937) (codi?ed at 18 U.S.C. 542 (1937) and subsequently repealed). By contrast, previous federal statutes required execution by hanging. See Crimes Act of 1790, Stat. 112-119 (1790) (?The manner of in?icting the plmishment of death, shall be by hanging the person convicted by the neck until dead?); An Act To odify, Revise, and Amend the Penal Laws of the United States, Pub. L. No. 350, 323, 35 Stat. 1151 (1909) (?The maimer of in?icting the punishment of death shall be by hanging?). Thus, the statutes discussed by- address whether the federal government will apply a state-speci?c method of execution for federal sentences, rather than a 1mifonn federal method. The statutes do not address methods of execution for state-imposed death sentences. has not cited anything in the text or legislative history of either of these statutes to support its contention that Congress aimed to provide unrestricted State options in implementing a death sentence. Likewise, we have not identified any evidence indicating that Congress even considered the 1937 statute when enacting the Act in 1938. Instead, Congressional statements at the time the Capital Plurishment Method Act of 1937 was enacted re?ect a desire to move away from hanging to newer methods of execution employed by states.24 But this does not equate to Congress intending States to develop procedlu?es for implementing capital sentences of any federal interference.? Ref. 8 at 10.25 In any event, there is no con?ict because overstates the scope and consequence of decision regarding the detained drugs. claims that ?interpretations amount to a federal ban on use of thiopental sodium for lethal injection,? Ref. 8 at 10-11, but FDA has not made any determination, one way or the other, about which diugs may be used for lethal the State does not provide for implementation of a sentence of death, the court shall designate another State, the law of which does provide for the implementation of a sentence of death, and the sentence shall be implemented in the latter State in the manner prescribed by such law. 18 U.S.C. 3596(a). 24 See, H. Rep. No. 164, at (1937); S. Rep. No. 690, at (1937). 25 also points to Department of Justice regulations, which were promulgated in an interim period prior to the enactment of 18 U.S.C. 3596. See Ref. 8 at 11 n. 15. Those regulations, 28 .F.R. 26.2 and 26.3, require lethal injection in federal death penalty executions. There is no evidence that the Department of Justice intended this regulation to have any effect on the implementation of state executions. Furthermore, many states have altered their procedures to provide for the use of different drugs. See Deborah W. Denno, Lethal Injection Chaos Post- Baze, 102 Geo. 1331, 1362-66 (2014). FDA 026 April 20, 2017 Page 23 injection. 26 Instead, FDA has applied the FD&C Act to conclude that the particular drugs seeks to import cannot be imported under the Beaty/Cook order. Moreover, the supposed result about which complains follows directly from the Beaty/Cook order. To the extent objects to that result, the proper course is to seek approval by FDA, relief from Congress or the court that issued the Beaty/Cook order – or use a drug that has been lawfully imported. FDA cannot flout a court order at request. For all of these reasons, we do not agree that FDA’s interpretations of the FD&C Act conflict with congressional intent. B. FDA’s Interpretations Do Not Lead to Absurd Results also contends that FDA’s interpretations should be rejected because they lead to absurd results. Ref. 8 at 12. In particular, points to FDA’s tentative conclusions that GRAS/E status, including for use in lethal injection, must be based on adequate and wellcontrolled clinical trials, and that the detained drugs cannot qualify for the law enforcement exemption. Id. In statutory interpretation, “absurdity is a high bar.” Stovic v. R.R. Ret. Bd., 826 F.3d 500, 505 (D.C. Cir. 2016). As the Supreme Court has stated, it applies where the plain language of a statute “would produce an absurd and unjust result which Congress could not have intended.” Griffin v. Oceanic Contractors, Inc., 458 U.S. 564, 574 (1982). Thus, an outcome is not absurd merely because it might be unlikely, surprising, or difficult to achieve. Here, it is not absurd to suggest that the FD&C Act requires a drug to be shown to be safe and effective for use under the conditions suggested in its labeling. There are numerous situations where it is difficult to design appropriate clinical trials, such as testing a treatment for anthrax infection or plague. In such cases, FDA regulations may allow flexibility, or trials may differ from what scientists generally envision, but FDA’s statutory mandate remains the same. absurdity point also fails to grapple with the total absence of scientific research evaluating the safety or efficacy of the detained drugs for any use. In short, has not shown that FDA’s position leads to absurd results. At one time, FDA exercised enforcement discretion with respect to thiopental imports, thus avoiding questions about how to assess the safety and effectiveness of thiopental for lethal injection, or whether the thiopental was or was not approved. FDA is now subject to the Court’s order in Beaty/Cook with respect to importation of foreign-manufactured sodium thiopental that 26 We also note that FDA’s determination that the detained drugs cannot be imported under the Beaty/Cook order because they are unapproved new drugs and misbranded drugs has no effect on importation of foreign-manufactured sodium thiopental that is not in violation of the FD&C Act, for example if a foreign manufacturer obtains FDA approval of a new drug application or abbreviated new drug application. Nor does it require FDA to take action against domestic distribution of sodium thiopental, whether or not it is unapproved or misbranded. See Heckler, 470 U.S. at 838. FDA 027 April 20, 2017 Page 24 is unapproved or misbranded. As a result, FDA has conducted its established inquiry to determine whether the detained sodium thiopental is for use under the conditions suggested in its labeling, leading to the conclusion that the drug is not for use in lethal injection and to determine whether the manufacturer of the detained drugs holds an FDA approval of such drugs, which it does not. As discussed in greater detail above, we also reject- contention that requiring a drug to comply with section 352(f)(l) produces absurd results when it is being shipped to law enforcement for use, in lethal injection. We fail to see how requiring a drug to bear labeling explaining, for example, how it should be reconstituted, the appropriate dose, or descriptions of proper methods of administration is inconsistent with the Act. VI. Conclusion For the reasons set forth above, we have determined that the thiopental sodium appears to be an unapproved new drug and misbranded. Based on the order issued in the Beaty/Cook case, FDA must refuse admission to the detained drugs. Beaty, 853 F. Supp. 2d 30, afd in part, rev in part sub nom. Cook, 733 F.3d 1. -has requested that we ?retain custody of the detained drugs under conditions that preserve their integrity pending completion of any judicial review,? or ?con?rm that -will be given 90 clays to export the dru to the original foreign distributor,? to hold ready for re- importation if a court rulesirfavor. Ref. 8, Attch. at 1-2. We con?rm that, because we are refusing admission has ninety days from the date of notice of refusal to export or destroy the drugs, consistent with applicable regulations. See, 21 U.S.C. 381(a). Sincerel A4?m5 End/4L ?ue?f/W QM Todd W. Cato Director, Southwest Import District Of?ce FDA 028 April 20, 2017 Page 25 References: Reference 1: Release Request for Thiopental Sodium on Behalf of the , October 23, 2015 Exhibit 1: FDA Notices of Action ... Exhibit 3: Label ... Exhibit 10: CBP Detention Notice Exhibit 11: Request for Delivery of Imported Sodium Thiopental Exhibit 12: FDA Response to Request for Delivery Exhibit 13: Affidavit Exhibit 14: FDA Statement regarding Sodium Thiopental Exhibit 15: Excerpt from Goodman & Gilman’s The Pharmacological Basis of Therapeutics Exhibit 16: History of Barbiturates ... Reference 2: Entry Documentation, Reference 3: Photos of Detained Thiopental Sodium Reference 4: Order issued in Beaty v. FDA, March 27, 2012 Reference 5: Order issued in Beaty v. FDA, June 22, 2012 Reference 6: Letter from FDA to , June 23, 2015 Reference 7: Tentative Decision to , April 15, 2016 Reference 8: Response to April 15, 2016 Tentative Decision on Behalf of the , May 20, 2016 Attachment A: Documents Pertaining to Federal Execution Protocol Attachment B: Labeling for Beaty/Cook Drugs Attachment C: Affidavit Attachment D: Affidavit Attachment E: Affidavit FDA 029 April 20, 2017 Page 26 Reference 9: Email from FDA to , April 29, 2016 Reference 10: Webster’s New International Dictionary Second Edition Unabridged (G&C Merriam Co. 1940) FDA 030 REFERENCE 1 To: Cc: Subject: Request for Release Date: Friday, October 23, 2015 4: 13 PM Attachments Hello Ms. Santos. I hope you are having a good Friday. Please ?nd our request for release of the thiopental sodium detained by FDA and detained by Customs at FDA's request under the above referenced entry number. An authorization letter is included with the attached letter. We request FDA to release the goods immediately and to instruct CBP to lift that aieni?s detention to permit immediate delivery to the Alternatively, we request FDA to grant an in-person hearing with the appropriate FDA personnel, lift the deten Ion, and release the goods within 30 days from receipt of this submission. Further, I respectfully request this case be transferred to Douglas Stearn, Director, Of?ce of Enforcement and Imports, or his designee in ORA Headquarters, who will become the Hearing Of?cer for this detention. Please inform me who the new Hearing Of?cer will be and the time and place for additional testimony to be given. Thank you and best regards NOTICE: This e-mail may contain information that is privileged or othenNise con?dential. It is intended solely for the holder of the e- mail address to which it has been intended, and should not be disseminated, distributed, copied or forwarded to any other persons. It is not intended for transmission to, or receipt by, any other person. If you have received this e-mail in error, please delete it without copying or forwarding it, and notify us of the error by reply e-mail so that our address records can be corrected. IRS CIRCULAR 230 DISCLOSURE: To ensure compliance with requirements imposed by the IRS, we inform you that any US. tax advice contained in this communication (including any attachments) is not intended or written to be used, and cannot be used, for the purpose of avoiding penalties under the Internal Revenue Code or (ii) promoting, marketing or recommending to another party any transaction or matter addressed herein. Please do not hesitate to contact me, however, if you have any questions regarding this matter. FDA 032 COMMERCIAL CONFIDENTIAL COMM UNI CA I I 0N October 23, 2015 Via Electronic Mail: rosa. santosaifda. hits. gov: Rosa L. Santos, Compliance Of?cer US. Food and Drug Administration 4040 N. Central Expressway Suite 300 Dallas. TX 75204 Re: Release Request for (Customs N0. hioiental Sodium on Behalf of the Dear Ms. Santos: We are making this submission, as cormsel for the in response to the notice of detention issued by FDA on August 24, 2015 and attached as Ex bit 1. As indicated in the notice of detention, and as required by 21 .F.R. 1.94, has a right to introduce testimony regarding the detained entry as owner and consignee of the imported goods. This submission includes written testimony. We also request the opportmrity to have an in-person hearing with appropriate FDA personnel regarding the matters discussed herein. Background The detained entry at issue consists of Vials of the drug thiopental sodium (also known as sodium thiopental or sodium entothal . The drug was manufactured and labeled at an FDA- registered facility in . Ex. 2. The drug is listed with FDA. Ex. 2. 1 This document contains commercial con?dential and proprietary information. Certain words and/or numbers contained in in this document are exempted from disclosure under the Freedom of Information Act pursuant to Title 19 CPR. because the information represents ?trade secrets and commercial or financial information obtained from any person which is privileged or con?dential.? Title 19 CFR 103.31a provides that certain advance electronic information that is required for inbound air. rail. truck. or vessel cargo under various provisions of the Customs Regulations is "per se exempt from disclosure? under 19 FR This information includes. for example. the foreign airport of origination. cargo description. quantity. and weight. shippers? name and address. and consignee's name and address for air shipments (and similar information for other shipments). Because the electronic version of this information is exempt from disclosure. the written version of this information provided 011 the actual entries and entry documents are also ?per se exempt? from disclosure. Title 19 FR 103.31 provides that importers can request that shippers? and consignees? names and addresses 011 manifests can be protected from disclosure. This demonstrates this same information is con?dential if it is found on entries and entry documents. In addition. Customs and Border Protection FOI Of?ce interprets the exemptions so broadly that that Office considers the entire entry to be ?business cormnercial information.? See e. Memorandum of Understanding Between the US Department of the Treasruy US. Customs Service and The US. Department of Health and Human Services Food and Drug Administration. MOU 225-91-4003. at II.8. (available at Rosa L. Santos, Compliance Of?cer Customs Entry N1mrber_ Re: Release Request for Thiopental Sodium on Behalf of October 23 2015 Page 2 of 9 Each vial of the drug bears a label identifying it as Thiopental Sodirun and bearing the legend: ?For law enforcement pmpose only.? Ex. 3. There are no statements in the label addressing conditions of use. Aside ??om the information printed on the label (discussed herein), there is no additional labeling accompanying the diug specifying information about its properties or uses. The only documentation accompanying the includes cormnercial and customs documentation identifying the name and quantity of the drug. Ex. 4. The customs declaration (Form 3461 line 20) reiterates that the drug is for ?law enforcement only.? Ex. 5. The label for each vial of the drug includes a legend (indicating that the is a schedule controlled substance). Ex. 3. - is registered with the Drug Enforcement Administration (DEA) as an importer of this drug. Ex. 6. Detentions by Customs and FDA On June 8, 2015, ?led a Controlled Substance Import Declaration (DEA Form 236), as re 11ired 21 FR. 5 1312, with DEA. Ex. 7. This Declaration included a signed statement by explaining that - proposed importation of sodium thiopental was intended for law enforcement pruposes. After a number of communications between DEA and- DEA issued a written response on July 13. 2015 stating that DEA would notify US. Customs and Border Protection (C BP) and FDA of the upcoming importation. According to DEA, FDA had contacted DEA and asserted that (1) the thiopental appeared to be misbranded or in violation of 21 U.S.C. 355 (New Drug Provision), and (2) it was illegal to import thiopental. Ex. 8. At that time, FDA had not examined the imported thiopental sodirun. In fact, the diugs had not yet even been shipped to the United States. On July 24, 2015. the private label distributor shipped 1000 vials of the drug thiopental sodium, which arrived the same day. Through its Customs Broker- ?led with CBP Entry for Immediate Delivery. Ex. 5. FDA reviewed the Entry, examined and Therefore.- claims on behalf of its supplier. manufacturer. shippers. ?lers and other parties in its supply chain. all entry information and entry docrunents. to be ?exempt from disclosure" under FOIA. express claim of exemption applies similarly to all information in this submission. Prior to FDA or CBP ma 1g any response to any request by any person other than or its counsel for any information under FOIA or under FDA or CBP regulations governing disclosure. expressl asserts these exemptions and requests FDA and/or CBP supply the request(s) and any proposed response for to review and redact. See 21 .F.R. 20.61. Rosa L. Santos, Compliance Of?cer Customs Entry Nrunber_ Re: Release Request for Thiopental Sodium on Behalf of October 23, 2015 Page 3 of 9 detained the goods by July 29, 2015. Ex. 9. FDA alleged that the goods appeared to be a new drug without an approved new drug application. FDA rescinded the detention the next day without stating any reason. CBP then detained the shipment 011 August 5, 2015, refusing to allow the goods to travel to destination. The detention notice indicated that the goods were detained at the request of FDA . . for FDA [admissibility] and ?uther analysis?. Ex. 10. - did not receive notice of the detention until after August 16, 2015. 011 August 18, - submitted a letter to FDA and BP requesting that FDA instruct BP to lift the detention and permit the goods to proceed to destination under - basic importation bond, as is normally permitted in the coru?se of commercial import transactions. The request included a certification by- promising that it would not use the thiopental sodium unless and until pending detention of the goods is resolved. Ex. 11. FDA denied this request on August 24. letter provided no reasons for its denial. Ex. 12. 011 August 24, 2015, FDA issued a new notice of detention. Ex. 1. The FDA notice of detention alleged that the detained shipment of thiopental sodium appears to: (1) ?lack adequate directions for use? (21 U.S.C. 381(a)(3) and 352(f)(1) (Misbranding)); (2) ?lack adequate warning against use in pathological condition or by children where it may be dangerous to health or against an unsafe dose, method, administering dlu?ation, application, in manner/form, to protect users? (21 U.S.C. 38l(a)(3) and 352(t)(2) (Misbranding)); and (3) ?be a new drug without an approved new drug application? 21 U.S.C. 381(a)(3) and 355(a) (Unapproved New Drug). We explain below why the detained shipment does not (and therefore does not appear to) violate the provisions cited in the notice. We therefore respectfully request FDA to lift the detention and release the goods. I. The Detained Drug Does Not Violate Statutory Requirements Governing Adequate Directions for Use The detained drug does not violate statutory requirements governing adequate directions for use. FDA has promulgated a number of regulatory exemptions from the statutory requirement, set forth in FFDCA section 502(f)(1), that a drug must bear adequate directions for use. The imported drug falls within the exemption established by 21 .F.R. 201.125 (entitled ?Drugs for use in teaching, law enforcement, research, and analysis?). The pertinent part of the section 201.125 exemption applies to a drug that is ?shipped or sold to, or in the possession of, persons . . . engaged in law enforcementused only for . . . law enforcement.? Rosa L. Santos, Compliance Of?cer Customs Entry Nlunber_ Re: Release Request for Thioperrtal Sodium on Behalf of October 23, 2015 Page 4 of 9 As the attached commercial and customs docrunentation demonstrates, the detained drug was both shipped and sold to Ex. 4. also has requested possession of the drug (and would be possessing the ug now if FDA a not denied that request). Ex. 12. When FDA discussed lethal injection in the 2011 policy statement attached in Ex. 14, the agency acknowledged that ?state De artments of Correction? are engaged in ?law enforcement.? The attached af?davit 0* that- is a law enforcement agency. Ex. 13. The detained drug also is to be used only for law enforcement. The restrictive legend on the label (?For law enforcement pmpose only?) makes that clear. In addition, before the detention occrured, - reaf?rmed (in the DEA Form 236) that the dru would only be used for law enforcement pruposes. Ex. 7. The attached af?davit of elaborates that the speci?c law enforcement prupose is to effectuate lawfully-imposed capital sentences through lethal injection. Ex 13. Capital punislnnent is an ?aspect of the law enforcement process.? Bell v. Lynaugh, 858 F.2d 978, 986 (5th Cir. 1988) (Jones, ., concruring). See also Baze v. Rees, 533 US. 35, 61 (2008) (States may enact laws specifying the ?sanction? of capital prurishrnent, which is a means to enforce?? a State?s laws) (citation omitted) (plurality opinion of Roberts, II. The Detained Drug Does Not Violate Statutory Requirements Governing Adequate Warnings for Users The detained ding also does not violate statutory requirements governing adequate warnings for users. The pertinent statutory provision is FFDCA section 502(f)(2), which states that a drug is misbranded ?[u]nless its labeling bears . . . such adequate warnings against use in those pathological conditions or by children where its use may be dangerous to health, or against rmsafe dosage or methods or dlu?ation of administration or application, in such marmer and form, as are necessary for the protection of users.? The ?users? to be protected by these ?necessary? and ?adequate? warnings are patients who take drugs for medicinal pmposes. The purpose of section 502(f)(2) is to provide warnings to patients as they take their own drugs. FDA therefore generally has imposed this warning requirement with regard to non-prescription drugs, because 2 For the section 201.125 exemption to apply. a drug also must fall within the de?nition of a prescription drug. In pertinent part. FFDCA section 503(b)(1) de?nes a prescription drug as one ?intended for use by man which . . . because of its toxicity or other potentiality for harmful effect. or the method of its use. or the collateral measures necessary to its use. is not safe for use except under the supenision of a practitioner licensed by law to administer such drug.? 21 U.S.C. The standard reference source for pharmacology indicates that sodirun thiopental is a barbiturate that produces unconsciousness and anesthesia. Goodman Gilman '5 The Phannaco/ogica/ Basis of Therapeutics. at 347-49 (1 ed. 2006) (attached as Ex. 15). This effect is well known: the drug has been used for purposes of anesthesia since before the FFDCA was enacted in 1938. Ex. 16 at 333. The drug easily satis?es the de?nition of a prescription drug: it is hard to imagine FDA suggesting that a drug that produces unconsciousness and anesthesia is a non-prescription drug. It therefore is not surprising that the Physicians? Desk Reference has included a listing for a different manufacturer?s thiopental sodium as a prescription drug. Ex. 17. Rosa L. Santos, Compliance Of?cer Customs Entry Nrunber_ Re: Release Request for Thiopental Sodium on Behalf of October? 23, 2015 Page 5 of 9 patients may take such drugs without the bene?t of any warnings a physician could provide. See, 47 Fed. Reg. 30012, 30016 (July 9, 1982) (?Section 502(t)(2) . . . states, in part, that any drug marketed OTC must bear in labeling such adequate warnings as are necessary for the protection of users?). Section requirement to warn patient ?users? as they self-administer drugs parallels section ?adequate directions for use? requirement. Congress enacted both of these statutory subsections together, in the original 1938 Act, and the language of both has remained unchanged since that time. The two provisions are tied together, with the ?rst addressing (affnmative) directions and the other addressing (prohibitive) warnings. FDA has consistently interpreted the ?adequate directions? requirement of section 502(f)(1) as applying only to ?use? by lay patients as they take their own drugs. See 21 .F.R. 201.5 (defming adequate directions for use as ?directions rurder which the layman can use a drug?). The directions for lay patient users required by section 502(f)(1) complement the warnings to lay patient users required by section 502(f)(2). Here there will be no lay patient ?users? taking the detained drugs. This is a circumstance in which the imported substance is a drug that will not be used for medicinal pmposes at all. It is well established that ?the word ?drug? is a term of art for the purposes of the Act, encompassing far more than the strict medical de?nition of that word.? United States v. Bacto-Unidisk, 394 US. 784, 793 (1969). The de?nitions of the term ?drug? set forth in the FFDCA do not require that it must be ?intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man.? 21 U.S.C. To the contrary, a substance may be a drug simply because it is not a food and is ?intended to affect the structure or any function of the body of man.? Id. This second defmition applies here. There are two alternate ways for FDA to conclude that the detained drug does not violate the warning requirement of section 502(f)(2). First, FDA can properly conclude that no ?warnings are necessary for the protection of users? here because there are no patient ?users? within the meaning of the statute. There also will be no self-administration of a drug. As explained above, the prupose of section 502(f)(2) is to guide lay patient users as they take their own drugs. Here the drug is being used for a law enforcement purpose (where it will not be self-administered) and not for a medicinal prupose that would require patient warnings. Such warnings are not any more ?necessary? for this law enforcement plupose than they would be for the other categories of drugs covered by 21 .F.R. 210.125 (which also do not involve patient use) drugs used only for ?research not involving clinical use, or in chemical analysis, or physical testing.? Sections 502(f)(1) and 502(f)(2) have different mechanisms for addressing situations in which their requirements are not ?necessary? to protect patients. Under section 502(f)(1), the default rule is that adequate directions for use must be provided; if such directions are ?not necessary for the protection of the public health,? FDA must promulgate a regulatory exemption from the default rule. 21 U.S.C. 352(1). By contrast, there is no default warning requirement (or exemption process) under section 502(f)(2). If section 502(f)(2) warnings are not ?necessary Rosa L. Santos, Compliance Of?cer Customs Entry Nrunber_ Re: Release Request for Thiopental Sodium on Behalf of October? 23, 2015 Page 6 of 9 for the protection of users,? no warnings are required in the ?rst place. Here the conclusion that section 502(f)(2) warnings are not ?necessary? for the detained thiopental sodium draws support ?'om decision that section 502(f)(1) directions for use are not ?necessary.? When FDA promulgated the law enforcement exemption (21 .F.R. ?201.125) in 1956, Commissioner Larrick made a speci?c ?nding that the labeling requirements of section 502(f)(1) are ?not necessary for the protection of the public health? when a drug is ?shipped, sold, or in the possession of persons engaged in law-enforcement.? 21 Fed. Reg. 2309, 2327 (Apr. 11, 1956). The same is true for section 502(f)(2) warnings, which are not ?necessary? when drugs will only be shipped or sold to, or? possessed by, law enforcement personnel and not lay patient ?user's.? Second, in the alternative, FDA can properly conclude that the label for the detained drug contains a warning that is ?adequate? Within the meaning of section 502(f)(2). FDA has not promulgated any speci?c warning requirements for thiopental sodirun (although it has done so for other drugs as noted above). Therefore the only potential application of section 502(f)(2) is the general obligation that any warnings that are ?necessary? for the protection of ?users? must be ?adequate.? FDA has not established that the detained drug?s labeling fails to meet this ?adequacy? standard. It is important to rurder?stand that - has tight controls in place that would prevent diversion of the detained drug ??om its law enforcement prupose to a situation in which it could reach a lay patient ?user.? The detained drug is a controlled substance and will be stored under secru?ity requirements imposed and monitored by the DEA. See Ex. 13. But even in the very rmlikely event such a diversion did occru?, the ?law enforcement prupose only? legend on the label would suf?ce as a warning that is fully adequate to inform any potential patient ?users? (or for that matter any healthcare professionals treating such patients) that the patients should not use the drug for any prupose (with any dosage or with any method or dru?ation of administration or application). FDA has previously recognized that an analogous legend serves as an adequate warning against patient use. See, EX. 18 at 8 (?research use only? labeling on in vitro diagnostic products ?is meant to serve as a warning, to prevent such products from being used in clinical diagnosis, patient management, or an investigation that is not exempt ?'om 21 FR part 812?). Here FDA has not demonstrated that the ?law enforcement prupose only? legend is not an ?adequate? warning under section 3 If FDA were to conclude that warnings under section 502(f)(2) are necessary. and that the ?law enforcement use only? legend is an inadequate warning. we request the agency to provide a supporting rationale that includes the warnings FDA deems adequate. Under FFDCA section 801(b). we further request the opportunity to relabel the detained drug to include the warnings FDA adequate. Rosa L. Santos, Compliance Of?cer Customs Entry Nrunber_ Re: Release Request for Thiopental Sodium on Behalf of October 23, 2015 Page 7 of 9 The Detained Drug Does Not Violate Statutory Provisions Reguiring FDA Approval for New Drugs The detained drug also does not violate statutory provisions requiring FDA approval for new drugs. FFDCA section 505(a) prohibits introduction of a ?new drug? into interstate commerce without an approved New Drug Application (NDA) or Abbreviated New Drug Application (ANDA). This requirement does not apply to the detained drug, because it does not ?t within the statutory de?nition of a ?new drug.? In pertinent part, the FFDCA de?nes a ?new drug? as a drug not generally recognized among quali?ed experts as ?safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof. . . 21 U.S.C. 321(p)(l). ?Conditions of use? are therapeutic requirements, recommendations, or suggestions. The labeling of the detained drug does not prescribe, recommend, or suggest any conditions of use. Ex. 3. For FDA to establish that a drug is a ?new drug,? the agency must demonstrate that the drug is not generally recognized as safe and effective with respect to speci?c conditions of use stated in the labeling. When no conditions of use are so speci?ed, it is not possible for FDA to establish that a drug is a ?new drug.? Because there is no basis for concluding that the detained drug is a ?new drug,? section 505(a) does not prohibit its distribution without a NDA or ANDA.4 When FDA wishes to initiate an enforcement action involving an unapproved drug that does not have conditions of use speci?ed in the labeling, the agency typically claims that the drug lacks ?adequate directions for use? (and therefore is misbranded) under FFDCA section 502(f)(1). This enforcement theory has been colloquially known as a ?back door? rurapproved drug charge, applicable when there is no ?new drug? and therefore no Violation of section 505(a). Here, however, 21 .F.R. 201.125 exempts the detained thiopental sodirun ??om the ?adequate directions for use? requirement as explained above. In essence, the detained drug is in a regulatory postru?e very similar to that of a prescription chemical, used in pharmacy compounding, that meets the exemption from ?adequate directions for use? applicable to ?prescription chemicals and other prescription components.? See 21 .F.R. ?201.120. As a drug component, the prescription chemical falls within the FFDCA de?nition of a ?drug.? See 21 U.S.C. But the prescription chemical is not an rmapproved new drug (prohibited by section 505(a)) even though the chemical lacks an approved NDA or ANDA. The chemical does not meet the statutory de?nition of ?new drug,? because its 4 The FFDCA also de?nes a ?new drug? as a drug that has become generally recognized as safe and effective for use under the conditions prescribed. recommended. or suggested in the labeling (based on investigations under ?such conditions?) but which has not. otherwise than in ?such investigations.? been used to a material extent or for a material time under ?such conditions.? This de?nition obviously is also tied to conditions of use speci?ed in the labeling. Without any conditions of use speci?ed in the labeling. it is not possible for FDA to establish that a drug ?ts within this de?nition of a ?new drug." Rosa L. Santos. Compliance Of?cer Customs Entry Number Re: Release Request for Thiopental Sodium on Behalf of? October 23. 2015 Page 8 of 9 labeling does not specify any conditions of use. The applicable exemption regulation (21 .F.R. con?rms that the prescription chemical is not itself a ?new drug.? by referring to the possibility that a ?new drug? may be compormded from the chemical. 21 .F.R. Instead of specifying conditions of use. the chemical?s labeling contains the legend ?For prescription comporurding.? Complying with that requirement and the other provisions of section 201.120 makes it lawful to distribute the unapproved prescription chemical. just as it is lawful to distribute the detained drug lurder the law enforcement exemption established by 21 C.F.R. 201.125. We therefore request FDA to release the goods and to instruct CBP to lift that agenc ?s detention to permit irmnediate delivery to - Alternatively. we request FDA to grant an in-person hearing with appropriate FDA personnel. li? the detention. and release the goods within 30 days from receipt of this submission. a: a: If have ani iuestion regardini the above. please do not hesitate to contact me at - Sincerel . cc: Capt. Domenic Veneziano. Director. Division of Import Operations. FDA Douglas Steam. Director. Of?ce of Enforcement and 1111 0113. FDA . o-C ormsel to i Enclosures: Exhibit 1: FDA Notices of Action Exhibit 2: Distributor and Manufactru?er Registrations Drug Listings Exhibit 3: Thiopental Label Exhibit 4: Airway Bill and Invoice Exhibit 5: BP 3461 Exhibit 6: TDC DEA License Exhibit 7: TDC DEA Form 236 Exhibit 8: DEA Letter to Rosa L. Santos Compliance Of?cer Customs Entry Number Re: Release Request for Thiopental Sodium on Behalf of October 23: 2015 Page 9 of9 Exhibit 9: Withdrawn FDA Detention Exhibit 10: CBP Detention Notice Exhibit 11: Request for Delivery of Imported Sodium Thiopental Exhibit 12: FDA Response to Request for Delivery Exhibit 13: Af?davit of? Exhibit 14: FDA Policy Statement regarding Sodium Thiopental Exhibit 15: Exceipt from Goodman Gilman?s The Pharmacological Basis of Therapeutics Exhibit 16: History of Barbiturates Exhibit 17: Physicians? Desk Reference Exhibit 18: FDA Guidance Distribution of In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only 15:58 93643?6994 DGCHUNTSUILLE PAGE 82f82 July 27, 20.15 To Whom it May Concern: RE: FDA, DEA and .S. CBP matters Please be advised we, the_ have authorized the law ?lm of?to engage the .8. Food and Drug Administration (FDA), the Drug Enforcement Agency, and the Bureau of Customs and Border Protection (CBP) respecting all issves related to the manufacture, distribution, exportation, and importation of FDA~regulated products. In order to assist us in our matters we authorize '011. to discuss our FDA, and related issues, ?lings, and records with and the other attome 's at the firm. j. their Regulatory Advisers, their Regulatory Specialistg or their aralecrals. The ?rm?s telephone number 15 If yen have any questions regarding this authorization, please do not hesitate to contact me at Sincerel Exhibit 1 FDA 043 United States Food and Drug Administration Southwest Import District Notice of FDA Action Entry Number: Notice Number: August 24, 2015 3 Importer: > Port of Entry: 5309, Houston Intercontinental Airport, Houston, TX Carrier: ; Date Received: July 27, 2015 Arrival Date: July 24, 2015 < Filer of Record: Consignee: HOLD DESIGNATED Summary of Current Status of Individual Lines Line ACS/FDA * 001/001 Product Description Quantity Current Status THIOPENTAL-NA STERILE PWDR (LAW ENFORCEMENT ONLY ) 1000 PCS Detained 08-24-2015 * = Status change since the previous notice. Read carefully the sections which follow for important information regarding these lines. @ = Consignee ID FDA will not request redelivery for examination or sampling, if the products not released by FDA are moved, following USCS conditional release to a localtion within the metropolitan area or to a location approved by the FDA office at the number below. All products in this entry not listed above may proceed without FDA examination. This notice does not constitute assurance the products involved comply with provisions of the Food, Drug, and Cosmetic Act or other related acts, and does not preclude action should the products later be found violative. DETENTION The following products are subject to refusal pursuant to the Federal Food Drug and Cosmetic Act (FD&CA), Public Health Service Act (PHSA),or other related acts in that they appear to be adulterated, misbranded or otherwise in violation as indicated below: FDA 044 Notice of FDA Action Entry Number: Notice Number 3 Page: 2 Line ACS/FDA Product Description Respond By 001/001 THIOPENTAL-NA STERILE PWDR (LAW ENFORCEMENT ONLY ) September 14, 2015 FD&CA Section 502(f)(1), 801(a)(3); MISBRANDING The article appears to lack adequate directions for use. FD&CA Section 502(f)(2), 801(a)(3); MISBRANDING It appears to lack adequate warning against use in a pathological condition or by children where it may be dangerous to health or against an unsafe dose, method, administering duration, application, in manner/form, to protect users. FD&CA Section 505(a), 801(a)(3); UNAPPROVED NEW DRUG The article appears to be a new drug without an approved new drug application. Please direct your response to: Rosa L. Santos, Compliance Officer (Region/District) U.S. Food and Drug Administration 4040 N. Central Expressway Suite 300 Dallas, TX 75204 (214) 253-5269 (214) 253-5316 (FAX) ROSA.SANTOS@FDA.HHS.GOV You have the right to provide oral or written testimony, to the Food & Drug Administration, regarding the admissibility of the article(s) or the manner in which the article(s) can be brought into compliance. This testimony must be provided to FDA on or before the dates shown above. Notice Prepared For: The District Director, U.S. Food and Drug Administration Notice Prepared By: RLS FDA 045 United States Food and Drug Administration Southwest Import District Notice of FDA Action Entry Number: Notice Number: 4 September 11, 2015 Filer: Attention: Broker Box: > 5309, Houston Intercontinental Airport, Houston, TX Port of Entry: Carrier: ; Date Received: July 27, 2015 Arrival Date: July 24, 2015 < Importer of Record: Consignee: HOLD DESIGNATED Summary of Current Status of Individual Lines Line ACS/FDA * 001/001 Product Description Quantity Current Status THIOPENTAL-NA STERILE PWDR (LAW ENFORCEMENT ONLY ) 1000 PCS Extension granted 09-102015 * = Status change since the previous notice. Read carefully the sections which follow for important information regarding these lines. @ = Consignee ID FDA will not request redelivery for examination or sampling, if the products not released by FDA are moved, following USCS conditional release to a localtion within the metropolitan area or to a location approved by the FDA office at the number below. All products in this entry not listed above may proceed without FDA examination. This notice does not constitute assurance the products involved comply with provisions of the Food, Drug, and Cosmetic Act or other related acts, and does not preclude action should the products later be found violative. EXTENSION REQUEST GRANTED Line ACS/FDA Product Description Respond By 001/001 THIOPENTAL-NA STERILE PWDR (LAW ENFORCEMENT ONLY ) October 23, 2015 Rosa L. Santos, Compliance Officer (Region/District) (214) 253-5269 (214) 253-5316 (FAX) FDA 046 Notice of FDA Action Entry Number: U.S. Food and Drug Administration 4040 N. Central Expressway Suite 300 Dallas, TX 75204 Notice Number 4 Page: 2 ROSA.SANTOS@FDA.HHS.GOV This extension is granted until the dates shown above. Notice Prepared For: The District Director, U.S. Food and Drug Administration Notice Prepared By: ARM FDA 047 Exhibit 2 FDA 048 10/10/2015 Drug Establishments Current Registration Site U.S. Food and Drug Administration Protecting and Promoting Your Health Drug Establishments Current Registration Site Search Results for   Download data (downloadExcel.cfm) Firm Name  Facility  Establishment Identifier Data Universal  Numbering System Number Address Expiration Date 12/31/2015 « ‹ 1 › » Data Current through: October 09, 2015 Return to Drug Firm Annual Registration Status Home Page (default.cfm) http://www.accessdata.fda.gov/scripts/cder/drls/getDRLS.cfm FDA 049 1/1 Pragmatic Structured Product Labeling Editor XForms") Copyright 2010 Pragmatic Data LLC. All rights reserved. Template Load Template 1 Load File Save Save In Reset Validate IHeaderI lData Elementsl IContent Of Labeling ISPL Viewl XML View I I Helpl Thiopental Sodium USP Sterile Rx Only/C111 For law enforcement purpose only. l- thiopcntal sodium powder Product Information Product Type BULK INGREDIENT Item Code (Source) Route ofAdministntion NOT APPLICABLE Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength THIOPENTAL SODIUM (UNII: 49Y44QZL70) (THIOPENTAL - THIOPENTAL 100 in 100 Packaging Item Code Package Description Marketing Start Date Marketing End Date 1? FDA 050 Marketing Information Marketing Category Application Number or Monograph Citation bulk ingredient Labeler  Marketing Start Date Marketing End Date 06/05/2015   Establishment Name Address ID/FEI Business Operations Revised: 6/2015  For help, click the "Help" tab. Refer to the FDA SPL XForms web page for troubleshooting help and other advisories. For any remaining unanswered questions email may be sent to spl@fda.hhs.gov and spl@pragmaticdata.com. Copyright (c) 2010­2012 Pragmatic Data LLC. All rights reserved. Government Restricted Rights Legend:The Pragmatic XForms SPL product is restricted computer software under the provisions of FAR 52.227­14 with Alternate III under the contract HHSF223200950194P and FAR 52.227­19under the contract HHSF223201110180C Pragmatic Data LLC grants to the FDA a perpetual non­ exclusive and non­transferable license to use the product and to permit the public to use the product through websites operated by the FDA. Any other rights regarding the use duplication or disclosure of this computer software according to FAR 52 227­14 Alternate III (d) shall be specified as follows: The FDA may distribute the product to the public through a redistributable file delivered by Pragmatic Data to the FDA for this purpose. The license to redistribute this file shall be granted only to the FDA and is not transferable and not assignable to other parties. Pragmatic Data grants to the public receiving this file from the FDA a perpetual non­exclusive and non­transferable limited license to use the product at no charge. "Use" of the product shall mean to manually encode SPL content for data submissions to the FDA but not to make the product available to others and not to embed it into larger works or web sites. Under the restricted rights in data clause Pragmatic Data reserves the right to modify the software and reserves all rights of redistribution of so modified software. FDA 051 10/10/2015 Drug Establishments Current Registration Site U.S. Food and Drug Administration Protecting and Promoting Your Health Drug Establishments Current Registration Site Search Results for? Facility Data Universal Establishment Numbering Firm Name Identi?er System Number Address Expiration Date 12/31/2015 Data Current through: October 09, 2015 Return to Dru Firm Annual Re istration Status Home Pa default.cfm FDA 052 1/1 Pragmatic Structured Product labeling Editor XForms") Copyright 2010 Pragmatic Data LLC. All rights reserved. Template Load Template Load File Save Save In Reset Validate lHeaderI lData Elementsl lContent Of Labeling ISPL Viewl View I I Helpl Thiopental Sodium USP Sterile Rx For law enforcement purpose only. l- thiopcntal sodium powder Product Information Product Type BULK INGREDIENT Item Code (Source) Route ofAdministntion NOT APPLICABLE Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength THIOPENTAL SODIUM (UNII: 49Y44QZL70) - UNIIJISZSM7NA3) THIOPENTAL 100 in 100 Packaging Item Code Package Description Marketing Start Date Marketing End Date FDA 053 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date bulk ingredient Labeler  Marketing End Date 06/05/2015   Establishment Name Address ID/FEI Business Operations Revised: 6/2015  For help, click the "Help" tab. Refer to the FDA SPL XForms web page for troubleshooting help and other advisories. For any remaining unanswered questions email may be sent to spl@fda.hhs.gov and spl@pragmaticdata.com. Copyright (c) 2010­2012 Pragmatic Data LLC. All rights reserved. Government Restricted Rights Legend:The Pragmatic XForms SPL product is restricted computer software under the provisions of FAR 52.227­14 with Alternate III under the contract HHSF223200950194P and FAR 52.227­19under the contract HHSF223201110180C Pragmatic Data LLC grants to the FDA a perpetual non­ exclusive and non­transferable license to use the product and to permit the public to use the product through websites operated by the FDA. Any other rights regarding the use duplication or disclosure of this computer software according to FAR 52 227­14 Alternate III (d) shall be specified as follows: The FDA may distribute the product to the public through a redistributable file delivered by Pragmatic Data to the FDA for this purpose. The license to redistribute this file shall be granted only to the FDA and is not transferable and not assignable to other parties. Pragmatic Data grants to the public receiving this file from the FDA a perpetual non­exclusive and non­transferable limited license to use the product at no charge. "Use" of the product shall mean to manually encode SPL content for data submissions to the FDA but not to make the product available to others and not to embed it into larger works or web sites. Under the restricted rights in data clause Pragmatic Data reserves the right to modify the software and reserves all rights of redistribution of so modified software. FDA 054 Exhibit 3 FDA 055 . FDA 056 Exhibit 4 FDA 057 JUL-27-2016 11 :56 P.002 Value Given For Custom Purpose: 25000 USD CUSTOM INVOICE I INVOICE N08: I EXPORTERS IOATE I l_s ll i. 04/07/2015 i I Buyers Order I DEA Number: Phone Number: CARRIAGE BY PLACE OF RECEIPT OF PRE COUNTRY OF COUNTRY OF FINAL 1 CARRIER ORIGIN DESTINATION . - 2 USA. VESSEL FLIGHT WI- LOADING NO PORT or HEAL DESTINATION DISCHARGE Huntsville, Texas DESCRIPTION MARKS 8: NO KIND QUAIJTITY AMOUT AMOUNT OF PACKAGE CONTAINER NO.- per unit Thiopentn Sodium USP [gm Vial Vials 25 25000 25000 I I Declaration: SIGNATURE We declare that this invoice shows the aetual prim?: or?the DATE i goods I Described and that all the particulars am We and correct FDA 058 JUL-27-2016 11:56 P.003 Air' Waymu ?m 9 Imam-(Ilall'uu m-u' I nu~ Ill..ll." In: ill :m Ivl D-?n ?1 'Nt- Ll! Mv gun.? il'l'll Ll? II 1 QNIMHY t?lhl??ln :?Rr ill! "m ANO t?ul rum-w Hr [mm vamp-1 - "n?!il 745 W. I M'Hml?nmrr 'nr Al II \ll?A?lN 34' \tl'llu' . Llr?ilf?luj? I. r' 1 My I hall 1. . u" ..r,ml I .?uluu 1.- FREI MT PREPAI - -. - PRIORITY Jul-?lm nun-r: .n1H.. rum] [1-5qu I . . :4 .muln) "lmwatlnn ?v I .r ?In1n? JIIDALLAS Worm: To: .. . . :Jum n: Iqu'. .. .- - . .. ?(Junk ?my. l-ul ?Inn 55. - - l' Wmuh! L. Mini I CONTENTS: CHEMICALS . lion HAZARIZOUS 03 27.0 a; 27x 426/- 1150 .1 ems 30x22x35t 3 12: um; 3' I ?my: Lollw" umm Lam-mu ?5037' me 250/?03c 1oo/ws'mx V'Illmhu ti AWC 100/413 455/? In . Jim". '1 4' 'I-muf shun-du? '?vrl-c? l' 1? MW Inc-1 un'm'pmwm 70/- awe-"ma quad?? ?vlu"' tud' d::?hbofl ?ver-To: art! In In nth-tJ? a,,1.t.ng? h, ?noun-"a 'u 'hu ?ml-tau Luann-.1 .- ..- 705/- 00 -fuv'. -. f?uv Tu??mwz-t- LIAN-H- 12777/- 9/7/15 gun?gykm?uw} Nam ?ku Dan! LP II . ll" Qatar: at (murmur low ?ow 1 (mama. In: Can" I ?In uni? 4+ lint-Immu- FDA 059 TOTAL P.003 Exhibit 5 FDA 060 BOX: D97-ll7 DEPARTMENT OF HOMELAND SECURITY US. Customs and Border Protection DELIVERY 19 CFR 1423, 14216,14222, 14224 Form Approved OMB No. 1651-0024 AMS CARRIER TEAM 041 ABI CERTIFIED 1 . ARRIVAL DATE 2. ELECTED ENTRY DATE 3. ENTRY TYPE 4. ENTRY NUMBER 072415 01 5. PORT 6. SINGLE TRANS. BOND 7. FILE NUMBER 5309 8. CONSIGNEE NUMBER l9, IMPORTER NUMBER 1% i i CODE 15. VESSEL CODEINAME I 14. LOCATION OF 16. US. PORT OF UNLADING 5501 17. MANIFEST NUMBER 18. GO. NUMBER 19. TOTAL VALUE 25000 20. DESCRIPTION OF MERCHANDISE THIOPENTIAL-NA STERILE PWDR (LAW ENFORCEMENT ONLY 21. AWB CODE 22. NO. 23. MANIFEST QUANTITY 24. HS. NUMBER OF ORIGIN 25. COUNTRY 26. MANUFACTURER NO. I 3 CTNS 27. CERTIFICATION 28. CBP USE ONLY I hereby make application for entry/immediate delivery. I certify that the above Information is accurate the bond is suf?cient, valid and current, and that all reqUIrements of 19 CFR Part 142 have been met. OTHER AGENCY ACTION REQUIRED, NAMELY: SIGNATURE OF APPLICANT FI DATE CBP EXAMINATION REQUIRED 07/29/15 I: ENTRY REJECTED, BECAUSE: 29. BROKER OR OTHER GOVT. AGENCY USE 02 FDA HOLD 07/27/15 14 FDA DOCUMENTS REQUIRED 07/27/15 02 FDA HOLD 07/28/15 14 FDA DOCUMENTS REQUIRED 07/28/15 04 FDA 07/29/15 01 FDA EXAM 07/29/15 DELIVERY AUTHORIZED: SIGNATURE DATE PAPERWORK REDUCTION ACT STATEMENT: An agency may not conduct or sponsor an information collection and a person is not required to respond to this information unless it displays a current valid OMB control number and an expiration date. The control number for this collection is 1651-0024111e estimated average time to complete this application is 15 minutes. If you have any comments regarding the burden estimate you can write to US. Customs and Border Protection, Of?ce of Regulations and Rulings, 799 9th Street, NW, Washington DC 20229. RM 061 CBP Form 3461 (10/09) Exhibit 6 FDA 062 DEA REGISTRATION ms REGISTRATION . FEE. NUMBER EXPIRES mm FEE EXEMPT SCHEDULES ISSUE DATE 01-21?2015 CONTROLLED SUBSTANCE REGISTRATION CERTIFICATE UNITED STATES DEPARTMENT OF JUSTICE DRUG ENFORCEMENT ADMINISTRATION SectIons 304 and 1008 (21 USC 824 and 958) of the ConIroIled Substances Act of 1970. as amended. provide that the Attorney General may revoke or suspend a registration to mamfacture. distribute. dispel-me, Import or export a controled substance. THIS CERTIFICATE IS NOT TRANSFEMBLE 0N CHANGE OF OWNERSHIP. CONTROL. LOCATION, OR BUSINESS ACTIVITY. AND IT IS NOT VALID AFTER THE EXPIRATION DATE. WASHINGTON D. C. 20537 CONTROLLED SUBSTANCE REGISTRATION CERTIFICATE UNITED STATES DEPARTMENT OF JUSTICE DRUG ENFORCEMENT ADMINISTRATION WASHINGTON DC. 20537 DEA THIS REGISTRATION FEE NMER PAD 11-30?201 5 FEE EXEMPT SCIEDULES BUSINESS ACTIWTY ISSUE DATE . IMPORTER 01-21-2015 3N, Farm 055223 {4am AND IT IS NOT VALID AFTER THE EXPIRATION DATE. I5 I. ?Ijl' t1 304%; 1008 (21 use 324 95?Tof the ControIIed SIIBSIB pea. Act of ?197 Sgn?amended. provide the may revoke or suspend a reg?n?atton t9 mnufacture. dispense import or eXport a whitened substance THIS CERTIFICATE IS NOT TRANSFERABLE 0N CHANGE WSHIP. CONTROL. LOCATION. OR BUSINESS ACTIVITY, DEA REGISTRATION THIS REGISTRATION FEE CONTROLLED CHEMICAL -. NUMBER REGISTRATION CERTIFICATE I STATES DEPARTMENT OF JUSTICE FEE EXEMPT DRUG ENFORCEMENT ADMINISTRATION WASHINGTON DC 20537 ISSUE DATE . 01?21 -201 5 . 3N 15% . Sections 304 and 1008(21 use 324 and 9.58)de Contro?ed SubstanmAd ?1970 as amended pIOv'Ide that the A?omey Geneva! may revoke or suspend a to manufactwa. distribute. dispeme. import or export a conuo?ed substam THIS CERTIFICATE Is NOT TRANSFERABLE 0N CHANGE OF CONTROL. LOCATION, OR AND IT Is NOT VALID AFTER THE EXPIRATION SCHEDMS REQUESTING MOMMATIONS TO YOUR . REGISTRATION To mum a change toyour registered name. address. the drug schedule or me drug codes you handle. please 15'; I. ?gs? 1'31" . $13.1 [July I II MES I am 1, when our web site at or 2 can ourcustomerSetvioe COMO: at 14800} 882-9539 - or 3. submlt you chmg?s) in w??ngto 0mg Enforcement Box 28083 Washington. DC 20083 See Title 21 Code Of Federal ReguIaIlons. Sedlon 1301.51 for comma - Form DEA-2231511 (M07) . FDA 064 Exhibit 7 FDA 065 TX002 US. Department of Justice Drug Enforcement Administration CONTROLLED SUBSTANCES IMPORT EXPORT DECLARATION (Read Instructions on reverse before completing) OMB APPROVAL No. 1117-0009 EXPIRATION DATE: 9/30/2016 See reverse for Privacy Act 1. . . U.S. CUSTOMS CHECK IMPORT DECLARATION Nonnarcotic Substances In Schedules IV, CERTIFICATION ONE . Nonnarcotic Substances In Schedules IL, and and all substances in Date Of Departure/Arrival EXPORT DECLARA ION Schedule (Name and Address) BROKER OR FORWARDING AGENT, USED (Name and Date of Certification Address) DEA NO Signature of Customs Official :0 2 CONTROL Eo TO BE IMPORTED OR EXPORTED DEA Transaction ID 2a. NAME AND QUANTITY OF DRUG OR PREPARATION (Enter names as shown on labels; numbers and sizes of packages; strength of tablets, capsules, etc, CSA Drug Code I 2b CONTROLLED SUBSTANCE CONTENT OF DRUG 0R PREPARATION expressed as acid, base or alkaloid. (Enter names of controlled substances contained in the drug, 2c. DATE AND ACTUAL QUANTITY (Completed by registrant at time of and NDC Number) compound, or preparation) transaction) Thiopental Thiopental 1,000 vials 1,000 vials lshipment 914.1 mg vial 993.6 mg powder I vial (Thiopental Sodium) 914.1 mg powder/ vial (Thiopental) NDC Number: 914100 mg shipment 914.1 shipment of Thiopental l- 3a. FOREIGN (for US. import) DOMESTIC (for US. export) PORT OF EXP RT AN ROX.DEPART RE DATE June 19, 2015 4a. MODE OF NAME OF VESSEL (if known) Air Freight 2015 5. NAME AND ADDRESS OF FOREIGN 3b. FOREIGN (for us. export) DOMESTIC (for us. Import) PORT OF IMPORTATION AND APPROX. ARRIVAL DATE George Bush Intercontinental Houston Airport (IAH) - June 23. 4b. NAME OF ALL INTERMEDIATE CARRIERS I hereby certify that the substancels) listed :n Section 2 are to be Imported (conform to 21 5.. C. ?952(b)) Exported (conform to 21 C. 953(e)) and are intended for :1 Medical, Scientific, or I Otherlegitimate uses (attach explanation for other 'egitimate use). CI The above named substances are to be Re-Exportec (Attach documentation per Title 21, CFR 1312.27) to (list countries): lfthe form is being used as an "Export Declaration", attach documentation that the consignee is authorized under the laws and regulations Of the country ofdestination to receive the controlled substances If the controlled substances are being re- exported from the ?rst c0untry to second countries, attach documentation that the consignee in the country of ultimate destination is authorized under the laws and regulations of that country to receive the controlled substances A TH . A NP DATE June 8, 2015 i DEA FORM-236 cow 3 FDA 066 TXUOZ Explanation for the Legitimate l'se ofThiopental Being Imported l'nder 21 [his product IS being imponed lor use b\ ?law 'cs with tedcral statuttm and regulatorx \xill not use this tm aetixities other than law en tbreement activities. __Junc 8. 20] 5_ Date FDA 067 Exhibit 8 FDA 068 U. S. Department of Justice Drug Administration 3 870] Spring?cld. irginia -31?2 JUL 1 3 2015 Hour- 'l?his is confirmation ol? prcvious co111111unicatio11s with Associatc ?Attorucx? on lunc 18 2015 and lunc 24 2015 regarding proposcd importation of sodium thiopcntal.. \ouk111m Drug Administration (1)1 A s1 0 .-\11111i11istration (I DA) that sodium thiopcntal import is an drug product in lnitcd Statcs and it appcars to he nushrandcd or in Violation oill 355. According to l5l)A. is no approvcd application for sodium thiopcntal. and it is illcgal to import an unapprovcd nc\\ drug into l'nitcd Statcs. [11 light ol?thc information providcd by the l?l)A and the? submittcd DliA (?ontrollcd Substanccs Import."lixport Dcclaration. l-?orm 33(1. tiic DEA noti?ed the Customs Bordcr and Protcction and FDA ol?thc potcntial illcgal importation 111' sodium thiopcntal. 11? you haVc an} 1111cstions rcgarding this mattcr. plcasc contact Catli} (iallagth (?hicll chulatory Scction at 202-307-7194. )scl pt .\ssista11t \dministrator ()ll col FDA 069 Exhibit 9 FDA 070 United States Food and Drug Administration Southwest import District Notice of FDA Action Entry Number: Notice Number: 2 July 29. 2015 Filer: Attention: Broker Box: Port of Entry: 5309, Houston intercontinental Airport. Houston, TX Carrier: Date Received: July 27. 2015 Arrival Date: July 24. 2015 importer of Record: Consignee: HOLD DESIGNATED Summary of Current Status of individual Lines . Prod?? Description 001/001 THIOPENTAL-NA STERILE PWDR 1000 PCS Detained 07-29-2015 (LAW ENFORCEMENT ONLY) Status change since the previous notice. Read carefully the sections which follow for important information regarding these lines. Consignee iD FDA will not request redelivery for examination or sampling. if the products not released by FDA are moved, following USCS conditional release to a localtion within the metropolitan area or to a location approved by the FDA of?ce at the number below. All products in this entry not listed above may proceed without FDA examination. This notice does not constitute assurance the products involved comply with provisions of the Food. Drug, and Cosmetic Act or other related acts, and does not preclude action should the products later be found violative. DETENTION The following products are subject to refusal pursuant to the Federal Food Drug and Cosmetic Act Public Health Service Act other related acts in that they appear to be adulterated. misbranded or otherwise in violation as indicated below: .. ..?i?duci.9.??.50?9?19i1.. . FDA 071 Notice of FDA Action Notice Number 2 Entry Numberr? Page: 2 001/001 STERILE PWDR August 18, 2015 (LAW ENFORCEMENT ONLY Section 505(a), 801(a)(3); UNAPPROVED NEW DRUG The article appears to be a new drug without an approved new drug application. Please direct your response to: Rosa L. Santos, Compliance Of?cer (Region/District) (214)253-3339 FAX U.S. Food and Drug Administration 130?ng 4040 N. Central Expressway Surte 300 Dallas. TX 75204 You have the right to provide oral or written testimony. to the Food Drug Administration, regarding the admissibility of the article(s) or the manner in which the article(s) can be brought into compliance. This testimony must be provided to FDA on or before the dates shown above. Notice Prepared For: The District Director. US. Food and Drug Administration Notice Prepared By: AO FDA 072 Exhibit 10 FDA 073 23 50 Sam Houston Pkwy E. Ste. 1000 - - - 7" Detention Number: 15- 016 Houston. US. Customs and Border Protection NOTICE OF DETEN ow Port Code: 5309 Port Name; Houston Location of Merchandise: Date of Detention 8/5/2015 Entry number: Importer Importer Number?? Reason for Detention: Detain for FDA addmissibility and further analysis Estimated length of Detention 30 Days Tests or inquiries to be Conducted Additional Information/Action Requested of Importer. Reouested By SCBPO Fischer Date of Rednest' 8/4/2015 Detaining Of?cer: SCBPO Fischer Supervisory Approval By: SCBPO Fischer Customs Pomt of Contact; SCBPO Fischer Phone Number (281) 443-4350 (this detention may be released only by the Team or by the inspector who initiated -t Before releasing this merchandise contac the detaining of?cer) Additiooal Remarks Extension of Detention Period Until' Extension Authorized by Dispositon Disposition Date: Shipitionts may be detained for up to 30 days, unless statutory or irileragency agreements mandates that a longer period of time. is requned or the.- inlpo??l/bl?oker requests a longer detention period through the Port Director 8 Customs and Border Protection is providing lnfonnatlon appearing on, and, subject to bonding roQulrements, unredacted samples of. products and their packaging and labels. or photographs of such products. packaging. and labels that bear or ot a mark suspected of being counterfeit of a mark you have recorded With CBP. The Information that you are receiving may be protected by the Trade Secrets Act and may only be used to assist CBP its infringment determination AGREEMENT TO REDELIVER If merchandise is release conditionally from Customs custody to the principle before all required evidence is produced, before its quantity and value are determined. the principle agrees to reds-liver timely. on deitiarid by Customs. the merchandise released it it fails to comply with the laws or regulations governing admission into the United States (Section 113.52rd)i1i Customs Regulations FDA 074 Exhibit 11 FDA 075 CONFIDENTIAL OMAIE CIAL UNI A I 0N August 18. 2015 Via Email: douglas.stearn?fda?hsgov; steven. scotieldga. cbg. dlzs. gov Douglas Steam Director Office of Enforcement and Import Operations US. Food and Drug Administration 12420 Parklawn Drive Rockville, MD 20857 Re: Request for Delivery of Imported Sodium hiopental to Destination Dear Mr. Steam. We represent Please see attached authorization letter. Presently the Customs Service Port at the Bush International Air 011 in Houston has detained our client?s shipment of thioperrtal sodium entry number (entered July 27, 2015). Neither we nor oru' client?s broker has received the CBP Detention Notice explaining the reason for the detention now over 15 days since arrival. According to the Detention Notice, CBP is detaining the goods at the request of FDA. Therefore, we request that FDA instruct BP to lift the detention and permit the goods to proceed to destination under the importer's basic importation bond as is ordinary in the coru'se of commercial import transactions. needs to receive the goods at destination to complete the transaction for the goods. To that end, has declared in writing that upon receipt of the goods at destination it will not use the product unless and until pending detention of the good is resolved. See attached. If you have an uestions regarding the foregoing. please feel free to contact me or my Associate. phone or email at Senior Cc: MATERIAL 0R MIDAZOLAM 5! [8-30 vears ?int-w? SD (percent redixtionv 31-653 vcars The drug is a yellowish, hygroscopic powder. stabilized with sodium carbonate as buffer (60 mpg/u of Tlrio- pental Sodium). Educational Resources [laxtier Pharmaceutical Products Inc o??ers a wrde riinge of educational materials free of charge to physicians, nurse- 6-t 0 6.3 2 04 anestlit-tists. nurses and hos ital ham:- 3 5 1.9 3.1 0?6 SUPPLIED cists. They are available from Baxter so]; rcpteiienta- lfil'i?l I 'l'liiopontalSodium fOl' USP. II OVEII- ?we; of b) ?'nlinu w; Baxter Products Inc{Olbwii 95 Spring Street, New Prm'idence. NJ 07974. or hv culling . . t53?l (649.) is? talile abovrl mom 262-3784. .- 6.9 I. l) 5,9 0.6 Syringe Kits and ln?ecllm Kilo ore :ndividually packaged. mlun - 4.9 0.9 Store product prior to :it controlled room tem- (lt?i'H tit'rzituri- 15" (59?46?l?) :olui +9 0.5 Store reconstituted solution in it cool place and use within . 2-1 houm ol' mixing. Administer only clout solution [Murmm USP) decreases the doses of nt-u VECURONIUM BROMIDE lhing agents required (see PRECAUTIONS. fin). for Injection FDA only I For informntion an over-the-counter drugs, consult PDR For Nonprescription Drugs. intentina: of anesthesia with in?ow rates of re. the alveolar cont-r ntrzition of desllurnne I within 10" of the Inflzill'd tariff-titration considered rare are italicized. bigcminy, abnormal electrocardiogram, myocardial ischi-niio. Agitation. dizziness. Asthma dyspiiea, hypoxia ONSHIP UNKNOWN: Incidence less than I in 3 or more patients. regardless of 31 i: Fever Hemorrhage. myocardial infarct. Iutrition: Increased creatitune phospholunose . System: Myalgiu. doses: Prunlls IONS for information regarding pediatric ant hypertlicrmia. logs: 'h'nneicnt elevations in glucose and count may occur on with use of other anes- IAND DEPENDENCE [rug abuse liability. and dependence associ- (dea?urune. have not been :8 Invades-go. or suspected overdosage. take actions: discontinue administration of SU ?urane. USP). maintain ii patent airway. ini- or controlled ventilation With oxygen. and iuale cardiovascular function I) ADMINISTRATION W80 (des?urane. USP) from a vaporizer signed and designated for use with desllu- i ration of general anestliesin must lie on the patient's response (see INDIVIDUAL- DOSE). The following two tables provide :potency based upon one and drug interaction edaninately ASA physical status DESFIURANE (IRAN 31) (percent atmospheres! .3 9-100.10.? 5 75:08 3 9.8.arot'crnwivrr pairs (using up-anddown method response! thandiaupmcs ih'urenac the amounts of SU- urane. USP) required to produce anesthesia. unable is hand on st. idies of dnig interaction W) Elm-dunno. WITH OR MIDAZOLAM in" reconstitution with an appropriate diluent. is admin- Injection I'Cils2 2530-0101 I to ml. 2.5 10019-25389 2540-0101 '2 5 100 ml. 2.5 10019-26297 2550-010! 5 200 ml. 25 10019-25588 Syringe Km contuin 1 via! of'flliopcntal Sodium for anectTn, use 1 vial cross Sodium Chloride Injection USP- i sterile syringe and needle. Injection Kits contain 1 Via] of Thiopontal Sodium for Injection USP, 1 of Sterile Water for Injection. sterile transfer spikes. SAFETY AND HANDLING Occupational Caution: There is no specd?ic work exposure limit established for SUPKANEO (des?uranc, USPI. How- ever, the National Institute for Occupational Safety and Health Administration has recommended on 8-hr. time- weighu-d average limit of2 for halogenated anesthetic agents in general (0.5 when coupled with exposure to D. Th2? predicted o?'ecta of acute overexposure by inhalation of SUPRANEthesIlurnnc. USI?anlude headache dizziness or (in extreme casc5) unconsciousness There are no documented udverse effects of chronic expo- sure to halogenated anesthetic vapors (Waste Anesthetic Cases or in the workplace Although results of some epidemiological studies suggest it link between exposure to halogenated and int reased health problems (particularly spontaneous abortion). the relationship is not conclusive. Since expOsure to WAGS is one possible factor in the ?ndings for these studies. Operating room personnel. and pregnant women in pnrticulnr. should minimize. citpo- I sure. Precautions include adequate general ventilation in the operating room. the use of a well-designated and well- maintained scavenging system. worlt practices to minimize leaks and spills while the anesthetic agent is in use. and routine equipment maintenance to minimize lenks. STORAGE Store at room temperature. (ST-86W. SU- PRANlillo ldeiitluriinc. USP) has been demonstrated to be stable for the period defined by the expiration dating on the label. Ra only BAXTER Mfd. and Mktd. by nlfilintoii nf Baxter Healthcare Corporation Deer?eld. IL 60015 USA Revised: June 1998 For Pruduct Inquiry I 800 ANA DRUG ?00447~05 THIOPENTAL SODIUM I?d-d! am] For Injection. USP DESCRIPTION 'I'hiopental Sodium for Injection. is thiobzirbiturate, the sulfur analogue of sodium pcntobarbitnl The drug is prepared as a sterile lyophilized powder and, istered by the intravenous route. Thiopental Sodium. USP chemically designnted sodium and has the fol? DESCRIPTION Vecuromum Bromide for is nondepolnnung nou- romuaculur blocking agent of Intermediate duration, chem- ically decignated as piperidinium. I-IQB. 3a. 5a. 160. 178m. 17 1-methyl-. bromide Tho structural formula is. Its molecular formula is CuH?wBquo? with molecular weight 637.74. Vecuronium Bromide for Injection is supplied as a sterile nonpyrogenic Irt't'lc-drlt'd bull'cred cake of very ?ne micro- scopic particles for intravenous tmection only Each 10 ml. vial contains: Vercuronium Bromide 10 mg. (Iitnc Acid 20.75 mg. Sodium Phosphate Dibasic 16.25 rug: Mun- nitol (to adjust tonicityi 97 mg. pH is ndjusted with sodium hydroxide and/or phosphoric and if necessary pH 3.5?1.5. Each 20 ml, Vial contains? Vcciironiurn Bromide 20 mg; Cit- n'c Acid Aiihydroua 41.5 mg; Sodium Phosphate Dihaaic An- hydrous 32 5 mg. Monnitnl (to adjust tonicity) 194 mg. pH is adjusted with sodium liydrninde and/or phosphoric acid if necessary pH: 3.5-4 5. When reoonatitutcd with Bacteriov static Water for Injection. USP. CONTAINS 0 9% NH BEN- ZYI. ALCOHOL WHICH IS NOT FOR USE IN NEW- BORNS. HOW SUPPLIED Vecumnium Bromide for Injection is supplied as follows: NOC Packaging Vial Number Con?guration Size 10019-481 OI Vecuronium Bromide for 10 ml. Injection IO mi: (diluent not supplied) Shelf pack carton of I. II.) individual vials. 1.0019482-02 Vecuronium Bromide for 20 mL Iniection 20 mg (diluent not supplied) Shelf carton of 10 individual vials. lowing structural formula- I .. 0? ?i/w Cf'i cm (i The drug is a yellowuh. hygroscopic Miler. stabilized with HEAR SD (percent sodium carbonate as a buffer (60 trig/g of Thin- pental Sodiuml. HOW SUPPLIED 'l'hiopt-ntal Sadium for lnjt't?llon. USP, (Lyophilited) is avail- able as follows [See table above] ?30 33m 31:6? r9355(465i) l51?2tl 3moi (Moreno, decreases the doses of neu- - agents (see PRECAUTIONS. nlenance of mu sllu-sin with in?ow rates of the alieolar concentration of deaflurime . be 01 inspired concuilration. . re 1 in thirnuuokinctics section 1 Syringe Kits and Injection Kits are individually packaged. Store product prior to recon-titutiun nt controlled room tem- perature Store reconstituted SolJlIV-ll in a cool place and use within Store at controlled room temperature 15'-3o'c - PROTECT FROM LIGHT. EDUCATIONAL MAYERIAL Educational Resources Boater Pharmaceutical Products Inc offers a wide range of educational materials free of charge to physicians. nurse- past-anesthesia nurses and hospital pharma- cists They nre available from Baxter PPI anlcs representa- tives or by writing to' Baxter Pharmaceutical Products Inc. 95 Spring Street. New Providence. NJ 07974. or by calling (8001 262-3784. 24 hours of mixing. Administer only clear solution. VECUROMUM BROMIDE Ior Injection It only THIS DRUG $110110 88 ADMINISTERBD BY ADE- QUATELY TRAINED INDIVIDUALS FAMII IAR - iurnne. NDC 10019-641-24. is pack- - bottles containing 240 ml. desdu~ WITH ITS ACTIONS. CHARACTERISTICS. AND HAZ- ARDS FDA 133 For information on ovor-thc-counu-r drugs. consult '08 For Nonprescription Drugs. Consult 2 001 supplements and future edltlons lor revisions Exhibit 18 FDA 134 Distribution of In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only Guidance for Industry and Food and Drug Administration Staff Document issued on: November 25, 2013 The draft of this document was issued on June 1, 2011. For questions regarding this document contact Elizabeth Mansfield, by phone at (301) 796-4664, or by email at elizabeth.mansfield@fda.hhs.gov. For questions relating to devices regulated by CBER, contact the Office of Communications, Outreach and Development, CBER at 301-827-1800 or 800-835-4709. U.S. Department of Health and Human Services Food and Drug Administration Center for Devices and Radiological Health Office of In Vitro Diagnostic Device Evaluation and Safety Center for Biologics Evaluation and Research FDA 135 Contains Non-binding Recommendations Preface Public Comment You may submit written comments and suggestions at any time for Agency consideration to the Division of Dockets Management, Food and Drug Administration, 5630 Fishers Lane, rm. 1061, (HFA-305), Rockville, MD, 20852. Submit electronic comments to http://www.regulations.gov. Identify all comments with the docket number 2011-D-0305. Comments may not be acted upon by the Agency until the document is next revised or updated. Additional Copies Additional copies are available from the Internet at: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/uc m[insert specific number].htm or http://www.fda.gov/cber/guidelines.htm. You may also send an e-mail request to dsmica@fda.hhs.gov to receive an electronic copy of the guidance or send a fax request to 301-847-8149 to receive a hard copy. Please use the document number 1723 to identify the guidance you are requesting. Or, contact: Office of Communication, Outreach and Development, HFM-40 Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448 Internet: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/de fault.htm Tel: 800-835-4709 or 301-827-1800 E-mail: ocod@fda.hhs.gov 2 FDA 136 Contains Non-binding Recommendations Table of Contents I. INTRODUCTION.......................................................................................................................................4 II. REGULATORY REQUIREMENTS FOR RESEARCH USE ONLY AND INVESTIGATIONAL USE ONLY IVD PRODUCTS ..................................................................................................................5 III. RESEARCH USE ONLY AND INVESTIGATIONAL USE ONLY IN VITRO DIAGNOSTIC PRODUCTS ...............................................................................................................................................7 A. RESEARCH USE ONLY IN VITRO DIAGNOSTIC PRODUCTS .....................................................................7 B. INVESTIGATIONAL USE ONLY IN VITRO DIAGNOSTIC PRODUCTS ........................................................7 IV. APPROPRIATE LABELING AND DISTRIBUTION PRACTICES FOR RUO AND IUO PRODUCTS ...............................................................................................................................................8 A. LABELING OF RUO AND IUO IVD PRODUCTS .......................................................................................8 1. 2. Research Use Only Labeling .................................................................................. 8 Investigational Use Only Labeling ......................................................................... 8 B. DISTRIBUTION PRACTICES THAT ARE INCONSISTENT WITH RUO/IUO DESIGNATIONS ......................9 1. Instructions for use for an IVD product labeled RUO or IUO ............................. 10 2. Validation and verification of clinical diagnostic testing using IVD products labeled RUO or IUO ....................................................................................................... 10 C. OTHER RELEVANT PRACTICES ............................................................................................................. 11 1. 2. Use of a “certification program” .......................................................................... 11 Software labeled RUO or IUO ............................................................................. 11 V. FDA’S COMPLIANCE APPROACH..................................................................................................... 11 3 FDA 137 Contains Non-binding Recommendations Distribution of In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only Guidance for Industry and Food and Drug Administration Staff This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. I. Introduction FDA is issuing this guidance document to provide the current thinking of the Center for Devices and Radiological Health (CDRH) and the Center for Biologics Evaluation and Research (CBER) on when in vitro diagnostic (IVD) products 1 are properly labeled “for research use only” (RUO) or “for investigational use only” (IUO) 2. FDA is concerned that the distribution of unapproved and uncleared IVD products labeled RUO or IUO, but intended for purposes other than research or investigation (for example, for clinical diagnostic use 3), has led, in some cases, to the clinical diagnostic use of products with unproven performance characteristics, and with manufacturing controls that are 1 “In vitro diagnostic products are those reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body. These products are devices as defined in section 201(h) of the Federal Food, Drug, and Cosmetic Act (the act), and may also be biological products subject to section 351 of the Public Health Service Act.” Title 21, Code of Federal Regulations (CFR), section 809.3(a). 2 This guidance is only intended to apply to IVD products that have not been approved, cleared or licensed for any use, and it is not intended to address off-label uses of any approved, cleared or licensed products. 3 Throughout this guidance document, references to “clinical diagnostic use” and “use in clinical diagnosis” include use in making medical treatment decisions. 4 FDA 138 Contains Non-binding Recommendations inadequate to ensure consistent manufacturing of the finished product. Use of such tests for clinical diagnostic purposes may mislead healthcare providers and cause serious adverse health consequences to patients, who are not aware that they are being diagnosed with or treated based on the results of tests with research or investigational products. FDA is issuing this guidance to clarify the requirements applicable to RUO and IUO IVD products, including that RUO and IUO labeling must be consistent with the manufacturer’s intended use of the device. FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. II. Regulatory Requirements for Research Use Only and Investigational Use Only IVD products Section 520(g) of the FD&C Act, 21 U.S.C. 360j(g), provides for the exemption of devices intended for investigational use from certain requirements of the Act if such devices comply with the procedures and conditions prescribed by that section and by regulation. For example, devices intended for investigational use that meet applicable requirements may be exempted from premarket notification and premarket approval requirements of sections 510, 515, 520(g)(2)(A) of the Act (21 U.S.C. 360, 360e, 21 U.S.C. 360j(g)(2)(A)); see also 21 CFR 812.1(a). A product’s intended use refers to the “objective intent” of those responsible for labeling the product. 4 Intent is determined by such persons’ expressions or may be shown by the circumstances surrounding the distribution of the article. 5 Device Investigations Subject to IDE Regulation FDA's investigational device exemption (IDE) regulation is found at 21 CFR part 812. Under 21 CFR 812.5, investigational devices must bear a label that states the following: "CAUTION--Investigational device. Limited by Federal (or United States) law to investigational use." The labeling may not represent that the device is safe or effective for the purposes for which it is being investigated. 21 CFR 812.5(b). The IDE regulation also prohibits certain conduct by sponsors and investigators pertaining to the investigation and distribution of investigational devices, among other practices. See 21 CFR 812.7. Device Investigations Exempt from IDE Regulation Investigations of diagnostic devices that meet the criteria at section 812.2(c)(3) are exempt from the regulations at 21 CFR 812, with the exception of section 812.119. The criteria at section 812.2(c)(3) include specifying that testing: 4 5 See, 21 CFR 801.4 See, id. 5 FDA 139 Contains Non-binding Recommendations • • • • be non-invasive, not require an invasive sampling procedure that presents a significant risk, not by design or intention introduce energy into a subject, and not be used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure. The criteria in section 812.2(c)(3) also include compliance with labeling requirements section CFR 809.10(c), which exempts shipments and other deliveries of IVDs from certain labeling requirements if either (1) the device complies with part 812, or (2) the investigation is not subject to part 812 and one of the following conditions is met: (i) For a product in the laboratory research phase of development, and not represented as an effective in vitro diagnostic product, all labeling bears the statement, prominently placed: "For Research Use Only. Not for use in diagnostic procedures.'' (ii) For a product being shipped or delivered for product testing prior to full commercial marketing (for example, for use on specimens derived from humans to compare the usefulness of the product with other products or procedures which are in current use or recognized as useful), all labeling bears the statement, prominently placed: "For Investigational Use Only. The performance characteristics of this product have not been established.'' For purposes of this guidance document, "labeled RUO" refers to IVD products labeled in accordance with section 809.10(c)(2)(i); "labeled IUO" refers to IVD products labeled in accordance with section 809.10(c)(2)(ii) unless otherwise specified. Examples of products that meet the criteria for these designations are provided in Section III. Because these products are exempt from most regulatory controls, it is important that they are not distributed for clinical diagnostic uses. Mere placement of an RUO or IUO label on an IVD product does not render the device exempt from otherwise applicable clearance, approval, or other requirements. FDA may determine that the device is intended for use in clinical diagnosis based on other evidence, including how the device is marketed. In general, if evidence shows that an IVD product is inappropriately labeled RUO or IUO, and that the product does not qualify for an investigational device exemption under 520(g) of the Act, and is not cleared, approved, or 510(k)-exempt, the device would be misbranded under sections 502(a) and 502(o) of the Act, 21 U.S.C. 352(a), 352(o), and adulterated under section 501(f) of the Act, 21 U.S.C. 351(f). 6 FDA 140 Contains Non-binding Recommendations III. Research Use Only and Investigational Use Only In Vitro Diagnostic Products Both RUO and IUO products are IVD products currently under development and not approved for clinical diagnostic use. Because they are being shipped for investigations pertaining to product development and not clinical use, these products are exempt from most regulatory controls including IDE regulation. The term RUO refers to devices that are in the laboratory phase of development. The term IUO refers to devices that are in the product testing phase of development. A. Research Use Only In Vitro Diagnostic Products An RUO product is an IVD product that is in the laboratory research phase of development and is being shipped or delivered for an investigation that is not subject to part 812. During the research phase of development, the focus of manufacturer-initiated studies is typically to evaluate design, limited-scale performance, and issues such as usability of the test. Some examples of products FDA would consider to be in this research phase include: • Tests that are in development to identify test kit methodology, necessary components, and analytes to be measured. • Instrumentation, software, or other electrical/mechanical components under development to determine correct settings, subcomponents, subassemblies, basic operational characteristics, and possible use methods. • Reagents under development to determine production methods, purification levels, packaging needs, shelf life, storage conditions, etc. FDA also recognizes that there are certain products, such as instruments, systems, and reagents that are labeled for research use only and intended for use in the conduct of nonclinical laboratory research with goals other than the development of a commercial IVD product, i.e., these products are used to carry out research and are not themselves the object of the research. These include products intended for use in discovering and developing medical knowledge related to human disease and conditions. For example, instruments and reagents intended for use in research attempting to isolate a gene linked with a particular disease may be labeled for research use only when such instruments and reagents are not intended to produce results for clinical use. B. Investigational Use Only In Vitro Diagnostic Products An IUO product is an IVD product that is being shipped or delivered for product testing that is not subject to 21 CFR part 812 (with the exception of §812.119, Disqualification of clinical investigator) prior to full commercial marketing (for example, for testing of specimens derived from humans to compare the usefulness of the product with other products or procedures which are in current use or recognized as useful). Examples of IVD products under investigation that FDA considers to fall in this category include those that are being 7 FDA 141 Contains Non-binding Recommendations evaluated in comparison studies that use archived or fresh specimens to determine performance characteristics. IV. Appropriate Labeling and Distribution Practices for RUO and IUO Products A. Labeling of RUO and IUO IVD Products 1. Research Use Only Labeling With respect to IVD products that are appropriately labeled RUO, the RUO labeling is meant to serve as a warning, to prevent such products from being used in clinical diagnosis, patient management, or an investigation that is not exempt from 21 CFR part 812. In general, IVD products that are intended for clinical diagnosis or patient management must be labeled “For In vitro diagnostic use” 6 and be in compliance with all relevant regulations for In vitro diagnostic devices. An IVD product should not be labeled RUO if it is intended for use in a clinical investigation subject to 21 CFR part 812 or for clinical diagnostic use outside an investigation (for example, in clinical diagnosis for standard medical practice). FDA would consider such an IVD product to be misbranded under section 502(a) of the Act, 21 U.S.C. 352(a), if it were labeled “For Research Use Only” or otherwise labeled solely for research use, because such labeling would be false or misleading. 2. Investigational Use Only Labeling Similarly, with respect to IVD products that are appropriately labeled IUO, the IUO labeling is meant to serve as a warning that products so labeled should not be used in clinical diagnosis, patient management, or an investigation that is not exempt from 21 CFR part 812. An IVD product should not be labeled IUO if it is intended for non-investigational purposes, such as in clinical diagnostic use outside of an investigation. FDA would consider such an IVD product to be misbranded under section 502(a) of the Act, 21 U.S.C. 352(a), if it was labeled with the statement: "For Investigational Use Only" or “Investigational device.” 7 6 21 CFR 809.10(a)(4). Alternatively, some IVD products may be appropriately labeled as analyte specific reagents (see 21 CFR 864.4020 and 21 CFR 809.10(e)(1)(x) or (xi), or as general purpose reagents (see 21 CFR 864.4010 and 21 CFR 809.10(d)(1)(iv)). 7 IVD products intended for investigational use in a manner that is not consistent with an exempted investigation (see 21 CFR 812.2(c) for a description of exempted investigations) must comply with the Investigational Device Exemption (IDE) requirements in 21 CFR part 812 in order to be exempt from many requirements otherwise applicable to medical devices. Instead of being labeled IUO, they must be labeled 8 FDA 142 Contains Non-binding Recommendations B. Distribution Practices that are Inconsistent with RUO/IUO Designations A product’s intended use refers to the “objective intent” of those legally responsible for labeling the product 8, which may be determined by looking at the totality of circumstances surrounding the distribution of the article. 9 Overt expressions by the manufacturer, such as those present in labeling and advertising, may be sufficient to show determine that an IVD product is in appropriately labeled RUO or IUO, when such expressions demonstrate that the device is actually intended for clinical use despite the RUO or IUO labeling. Other evidence of the intended use of a product could include the design of the product, other statements by the manufacturer about the device, and how the device is sold and distributed by or on behalf of the manufacturer. The following are examples of evidence of intended uses that, depending on the totality of the circumstances surrounding the distribution of the article, would appear to conflict with RUO or IUO labeling: • Written or verbal statements in any labeling, advertising, or promotion of the IVD product by or on behalf of the manufacturer, including any performance claims, instructions for clinical interpretation, clinical information, product names, or descriptors that claim or suggest that the IVD product may be used for any clinical diagnostic use, including a clinical investigation subject to part 812. This may include workshops or presentations that describe clinical uses of products labeled RUO or IUO that do not include appropriate statements and warnings about the research or investigational nature of the products; • Written or verbal statements in any labeling, advertising, or promotion of the IVD product by or on behalf of the manufacturer that suggest that clinical laboratories can validate the test through their own procedures and subsequently offer it for clinical diagnostic use as a laboratory developed test. • • Solicitation of business from clinical laboratories; for example, a manufacturer who produces only products labeled RUO whose sales force makes routine calls to clinical laboratories that do not perform research or clinical studies may be viewed as demonstrating its intent that its products be used for clinical purposes. Provision of certain types of specialized technical support 10 (e.g., assistance in performing clinical validation) to clinical laboratories. “CAUTION—Investigational device. Limited by Federal (or United States) law to investigational use.” 21 CFR 812.5. 8 For the purposes of this guidance document, the term “manufacturer” 21 CFR 806.2(g) is taken as synonymous with “persons legally responsible for the labeling of devices” 21 CFR 801.4. The term “manufacturer” is used as a convenience throughout the guidance. 9 See 21 CFR 801.4. 10 Note: FDA is not referring here to generic maintenance support or software updates for an RUO or IUO IVD product. 9 FDA 143 Contains Non-binding Recommendations Other practices, though not themselves in conflict with RUO or IUO labeling, may support a finding of a conflicting intended use when accompanied by behavior described above. For example, when there is a past history of distribution of a product intended for clinical diagnostic use as an analyte specific reagent (ASR), and the product is now labeled as RUO or IUO, without any change in distribution practices such as advertising to and solicitation of business from clinical laboratories, the “new” RUO/IUO labeling is likely to be inconsistent with the intended use of the manufacturer. Other practices may or may not indicate an intended use that is consistent with RUO/IUO labeling, depending on the context. For example: 1. Instructions for use for an IVD product labeled RUO or IUO FDA may consider all labeling for the product, including the content of the instructions for use and descriptive language in package inserts provided with the product as evidence of intended use. In certain circumstances, such as when the use of an IVD product labeled for research use only is limited to use in the conduct of laboratory research that is unrelated to the development of IVDs, providing instructions for correctly using the product in a research manner (for example, mixing proportions, incubation times, storage conditions, etc.) would be considered to be consistent with research use only labeling. However, inclusion of clinical interpretive information, discussion of clinical significance, or other indications of clinical applicability included with any IVD products labeled for research use only would suggest that such products are not intended for research use only, but rather that they are intended for non-research clinical diagnostic purposes. FDA would consider the provision of such information as evidence of an intended use that would appear to conflict with research use only labeling, and requires compliance with all applicable device requirements under the FD&C Act. FDA believes that those products that are being distributed for use in the research phase of IVD development may be unlikely to need instructions for use, as such products are still in their formative stages, and provision of instructions for using such products may not always be necessary. If basic instructions for use are needed in order to properly configure or use the device in the research phase of development, provision of these may be viewed as consistent with RUO labeling. For IVD products labeled IUO that are the subject of a clinical investigation by a sponsor other than the manufacturer, it is acceptable (and perhaps necessary) for the manufacturer to provide instructions for use to the sponsor of the study using the format described in 21 CFR 809.10(b). 2. Validation and verification of clinical diagnostic testing using IVD products labeled RUO or IUO FDA views the activities of a manufacturer that aid the clinical laboratory in validation 10 FDA 144 Contains Non-binding Recommendations or verification of a test that incorporates RUO or IUO labeled IVD products as evidence of the manufacturer’s intended use. If the manufacturer of an IVD product labeled RUO or IUO were to assist in the validation or verification of the performance of a test for clinical diagnostic use that uses its RUO or IUO labeled IVD, that assistance would be considered to be evidence of a non-research or non-investigational intended use. FDA would consider such evidence along with the totality of the circumstances. In contrast, the manufacturer of an appropriately labeled RUO or IUO device may provide support services such as general repair or maintenance, and general nondiagnostic use-specific technical support, because, in general, these would not constitute evidence of a non-research or non-investigational intended use. FDA recommends that manufacturers assess the totality of the circumstances surrounding the sale and distribution of their RUO and IUO labeled IVD products to ensure that they are not engaging in practices that conflict with their labeling. C. Other Relevant Practices 1. Use of a “certification program” The totality of the circumstances surrounding the distribution and use of an RUO or IUO product should be considered when assessing its intended use. User certification programs, where users certify that they will not use RUO/IUO products in a manner inconsistent with the labeling, would be viewed as one factor to consider when assessing these circumstances. However, the existence of a certification program alone would not relieve manufacturers from their responsibilities to ensure that their labeling and distribution practices for RUO/IUO products are consistent with the product’s RUO/IUO label. 2. Software labeled RUO or IUO Software that is a stand-alone IVD product, or a component of or an accessory to another IVD product, which is labeled for research or investigational use only, may be distributed for research or investigational use to entities conducting research or investigations with the software. V. FDA’s Compliance Approach Manufacturers must comply with all applicable requirements under the FD&C Act and FDA regulations for those IVD products that are intended for use in clinical diagnostic applications. For devices that are not used in research or investigation, these requirements generally include registration of the manufacturer and listing of the device(s), compliance with current Good Manufacturing Practices, and reporting of adverse events, among other general controls. There are also specific requirements for various device types, for example, 11 FDA 145 Contains Non-binding Recommendations analyte specific reagents. See 21 CFR 809.10(e), 809.30, & 864.4020. While some IVD products, including some analyte specific reagents, are exempt from premarket notification, other products require premarket clearance or approval. Where the appropriate regulatory pathway is unclear, manufacturers are encouraged to discuss the matter with FDA. When determining whether non-compliance with statutory and regulatory requirements warrant a regulatory and/or enforcement action, FDA intends to consider the totality of the circumstances concerning a manufacturer’s sale and distribution of a product labeled as RUO or IUO. In general, if evidence shows that an IVD product is inappropriately labeled RUO or IUO, and that the product does not qualify for an investigational device exemption under 520(g) of the Act, and is not cleared, approved, or 510(k)-exempt, the device would be misbranded under sections 502(a) and 502(o) of the Act, 21 U.S.C. 352(a), 352(o), and adulterated under section 501(f) of the Act, 21 U.S.C. 351(f). 12 FDA 146 REFERENCE 2 (BF r1 US Customs and Border Protection DELIVERY CHI hit-i 1?15 577-?: 27. 28? CBP USE ONLY N'Htl 1- i . 12-th :21 Ar.? "naive 2.. . vti 3' tnli 1 3. I-fV?i I'i?i} It} at?! t't'tl'?tl' ?i in ,x v-su? I: i .v nilth? unl- ltz'-? i-m- 1.. HM a. ;.mill;- ih- hum-I- wi?lrl' tn ?In wit; (Lah- ill? :m'ru! an .lu-I I'l ?tu: (Latin-qr. Hi: Nit-'H. .H'Iti IN EM at [it v? .x'Iv'f ?t (JEEP FUHH 346.1 FDA 148 Iii"! o1 . i- "25? 1'15 15.! l' nmi?ri-ik comm DEA Rumhuxii iaf?ai 5' 2 ?3 33? I RH. 12Ilii (Ar) . H?isms . . . 2"qu cw?w 1m ?rm, . tuf- 3 "l'hin'K-ni: ?smihzm 131?v'alur {kin-n Yen ?'uut?vm Purpmc: 5mm 3mm zux lhigi iirnuim .{iui-nv {11? ?1.1qu ?lmy Hi 2m. 3251M FDA 149 likplanatiun for (he Legitimate Ilse nf?l'hiopcnlal Being [?nder 21 95, This pruduut i? buing imporicd 101? my Ihc 'l?hc pmduu?; complics \?x?ilh \?mlulnl?)' am will not use thix product {or nclivitics than lav. :mi?s ilics. rcgu uur} I ha activities. ,lgmc ($2015 Druc FDA 150 QUAI m' CONTROL DEPARTMENT CERTIFICATE OF ANALYSIS FINISHED PRODUCT Product Name Generic Name Manufactured by: I Nap C- 13:: for 36 Mfg. Date. 05/ Exp. Date. 0 . Date Sampled. Batch Size. Qty Sampled. 40 Sampled my. 1 Release Date. 24/ Specification 1,151.13 12:3. .33ch AR. No 5. l4". TF 333? E?Lil . 8.2.ch Ne. ?3 lg: Vlliir" nowc'cs 335.1313 I: I whiz-.- paw ll". mimic-3: If; ass; wait; IIlIe-d glass. mals?. Lie-N?: Slug-4533 be "1.1m IL: (I. umplz l?rI'S TE: - 3 4 1.: Q?u'u Li 11.. Image I: I: (3113313' {I'Itfl? arias: shim? :3 t2": ??nals?: cam: :5 lb wear 3.3233351353 I?Iat?: I.u E7135: 13:; 5:30 MC ?1 ., If.? an ww?v'l: .3 .11 the 33;: Jams 31:: .0 T3333. ammucms 3r 3:01:39 frugmil clear New (9350973362 standard solution >3 5355- E: m: Xill . NU. Ichr: thaw, 1 (3 EU mi: 19893333.?. 3 SEEING be stews": 4 "Mc . 2 Mg.? [Dunn Nu] 3.1) ?73' . aforw cliur 1 EIP -5 I II .30. mg; 1-Analyzed by . Checked by Manager) Sign Dab: I If a . FDA 151 I I 'Air Waybiil i i I i. 5! 'fzini.? 1hr; ,I'iiI? I?vi-l .Im (Imam-?II; Ir Luv-(2 tits: (fame "l {2211? nururrx? iE _ ?Ni" it?? iiEfi?I E, FLII II- v?mr?nto. PAHHEI..l"-"Tgi . ?fiNi?: -4 - .3- I. I [Iiiimri" I II tux: live. :i I. zr'm I i! I ?man I hereby certiiy that the conients of this consignment an: . . fullv and accurately described above by proper shipping name and me classi?ed pal. kaqed T: . .. . marked. and labeled. and in pIopqrr condition for carnage by air according to appiimbie governmental regulations,luREFERENCE 3 5 5 1 A 3mm .md 3 n: mp: Air Wavhill rim original: and have the. same vaiidity . r, ?if gag )3 (105er Um! Ingram m9. rli'; upted In apparent good order and condition 1? a; In ted) Mr cult" IU [Ht UOIQDITIUNS OF CONTRACT ON THE HFII ERSE ALL UOUUS MA i BI: CAIIHIEU BY ANY OTHER MEANS INCLUDING ROAD OR ANY OTHER UNLESS SPECIFIC CONTRARY INSTRUCTIONS ARE GIVEN HEREON BY THE AND SHIPPEH AGREES THAT THE SHIPMENT MAY 1 '1 BE CARRIED VIA INTERMEDIATE STOPPING PLACES WHICH THE CARRIER DEEMS APPROPRIATE THE ATTENTION IS DRAWN TO THE NOTICE CONCERNING CARRIERS LIMITATION OF LIABILITY. Shipper may increase such limitation oi IiabiIity by . :Iaciuririg a higher valuu for carriage and paying supplemental chatge iI H?g?l? 67/211 EM 7/3 . Raiorenoe Number Optional Shippinginionnatlon I Declared Value for Carriage muggy .. 1. :55 7/28/2015 RES 3 FDA 156 7/28/2015 RES 7 FDA 160 7/28/2015 RES 11 FDA 164 . 3" DFW Grusaswl 27 KG 0 IL 7/28/2015 RES 17 1-25 1.174 - IO 0 IL to ?Ly-v a I ?(Wm?m . 7/28/2015 RES 22 8 7 1 A ?Babe; mm w? .b It. 7/28/2015 RES 29 FDA 182 7/28/2015 RES 32 FDA 185 FDA 189 98 SEIEI - 0 9 1 A 3mm mu FDA 192 09 $38 FDA 203 TUTM. PIECES TOTAL WEIGHT ?9 SSH FDA 210 89 FDA 216 REFERENCE 4 Case lzll-cv-OO289-RJL Document 24 Filed 03/27/12 Page 1 of 2 UNITED STATES DISTRICT COURT FOR THE DISTRICT OF COLUMBIA DONALD EDWARD BEATY, et (11., Plaintiffs, v. Civil Case No. 11-289 (RJL) FOOD AND DRUG ADMINISTRATION, and US. DEPARTMENT OF HEALTH AND HUMAN SERVICES, and KATHLEEN SEBELIUS, in her of?cial capacity as Secretary of the US Department of Health and Human Services, and MARGARET A. HAMBURG, M.D., in her of?cial capacity as Commissioner of Food and Drugs, Defendants. ORDER (March 2 i, 2012) For the reasons set forth in the Memorandum Opinion entered thial day of March, 2012, it is hereby ORDERED that plaintiffs? Motion for Summary Judgment and Declaratory Relief on Counts I and is and it is further ORDERED that the defendants? Motion to Dismiss and/or for Summary Judgment is and it is further 1 FDA 218 Case Document 24 Filed 03/27/12 Page 2 of 2 DECLARED, pursuant to 28 U.S.C. 2201(a), that 1. the foreign manufactured thiopental (or ?thiopental?) imported by the importing States Arizona, California, South Carolina, Georgia, and Tennessee) is a misbranded drug and an unapproved new drug within the meaning of the and 2. as such, this thiOpental cannot lawfully be introduced or delivered for introduction into interstate commerce or lawfully be imported into the United States; and 3. defendants? recent actions allowing such thiopental to enter the United States were each contrary to law, arbitrary, capricious, and an abuse of discretion under the and, in particular, 4. defendants? January 4, 2011 announcement that they will allow future shipments of such thiopental to enter the United States is contrary to law, arbitrary, capricious, and an abuse of discretion under the accordingly IT IS HEREBY ORDERED that the FDA: 1. immediately notify any and all state correctional departments which it has reason to believe are still in possession of any foreign manufactured thiopental that the use of such drug is prohibited by law and that, that thiopental must be returned immediately to the and 2. be permanently enjoined from permitting the entry of, or releasing any future shipments of, foreign manufactured thiopental into interstate commerce; and IT IS FURTHER ORDERED that the parties are hereby directed to meet and confer to determine whether further litigation is necessary, or proper, with respect to the remaining count in this Complaint. SO ORDERED. 7W RICHARUEON United States District Judge 2 FDA 219 REFERENCE 5 Case Document 29 Filed 06/22/12 Page 1 of 2 IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF COLUMBIA Donald Edward BEATY, Daniel Wayne COOK, Eric J. KING, Brett Patrick PENSINGER, and Stephen Michael WEST, Civil Action No. 1:11-cv-00289 (RJL) Plaintiffs, ECF Case V. FOOD AND DRUG ADMINISTRATION, UNITED STATES DEPARTMENT OF HEALTH AND HUMAN SERVICES, Kathleen SEBELIUS, and I Mar aret A. HAMBURG, M.D., 3 JUN 2 2 2012 Defendants. Clerk. US District Bankruptcy Courts forthe District of Columbia 211213.13 Upon consideration of the Unopposed Motion to Dismiss Count II, Enter inal Judgment, and Make Certain Modi?cations to the Court?s Injunction ?led by Plaintiffs in the above- captioned matter, it is this '32, day of 2 2012, ORDERED, that the Motion is GRANTED, and it is further, ORDERED, pursuant to Federal Rule of Civil Procedure 41(a)(2) that Count II of Plaintiffs? First Amended Complaint is dismissed without prejudice; and it is further, ORDERED, that the sentence of the Order dated March 27, 2012 (Dkt. No. 24), stating that FDA is ?permanently enjoined from permitting the entry of, or releasing any future shipments of, foreign manufactured thiopental into interstate commerce? is hereby modi?ed to read, ?permanently enjoined from permitting the entry of, or releasing any future shipments of, foreign manufactured thiopental that appears to be misbranded or in violation of 21 U.S.C. 355,? and it is further, FDA 221 Case Document 29 Filed 06/22/12 Page 2 of 2 ORDERED, pursuant to Federal Rule of Civil Procedure 54(b) that the Clerk shall enter ?nal judgment disposing of this action in its entirety. a t. Hon. RicharWeon United States istrict Court Judge 2 - FDA 222 REFERENCE 6 VI (P51): 0 DEPARTMENT OF HEALTH AND SERVICES Public Health Service Food and Drug Administration Rockville MD 20857 June 23. 2015 RE: Importation of Sodium Thiopental Dear? I would like to thank you for the information you provided in the conversation yesterday with Domenic Veneziano and myself regarding the potential importation of sodium thiopental into the United States. You told us that you represented several state overnments seeking to import sodium thiopental as well as serving as the US. agent of the manufactru?er of a sodirmr thiopental product. You informed us that you and your clients believe that sodium thiopental can be legally imported into the United States despite the lack of FDA approval for such a product and previous court decisions. You asked about the possibility of the product proceeding to destination under bond prior to disposition. We cannot give you any assurance that the product will proceed to destination rmder bond. You fruther stated that if the products are released under bond, your clients would not make use of sodirun thiopental unless and until such products are admitted into the United States. You also noted that you do not represent the State of Nebraska. As I mentioned to you, should this product be offered for entry, FDA would conduct its review and, if detained, it would go through the normal detention and hearing process. I request that you provide advance noti?cation to FDA of any upcoming sodirun thiopental shipments to ensure such shipments are properly reviewed for admissibility into the United States. I would also ask that you provide us with a complete list of the parties you represent related to the potential importation of this product. I would also like to reiterate that the United States District omt for the District of permanently enjoined FDA from permitting the entry of, or releasing any future shipments of, foreign manufactured sodium thiopental that appears to be misbranded or an rmapproved FDA 224 new drug in violation of 21 U.S.C. § 355. As we have explained, there is no FDA approved application for sodium thiopental. Sincerely, Douglas Stearn Director Office of Enforcement and Import Operations U.S. Food and Drug Administration Telephone: (301) 796-3668 FDA 225 REFERENCE 7 Public Health Service Food and Drug Administration DEPARTMENT OF HEALTH & HUMAN SERVICES Southwest Imports District 4040 N. Central Expy., Suite 300 Dallas, TX 75204 April 15, 2016 VIA ELECTRONIC MAIL Re: Dear Entry No. imported by the /Thiopental Sodium 1 : On July 24, 2015, the 1,000 one-gram vials of a product labeled as assigned Entry Number offered for import (Thiopental Sodium USP). This entry was As detailed below, although we have not yet reached a final decision on the admissibility of this entry, we have tentatively determined that the thiopental sodium in Entry No. appears to be in violation of 21 U.S.C. § 355(a) and appears to be misbranded under 21 U.S.C. § 352(f)(1) & (2). The thiopental sodium is a “drug” within the meaning of 21 U.S.C. § 321(g)(1)(C) because it is intended to affect the structure or function of the body. The thiopental sodium appears to violate 21 U.S.C. § 355 because it appears to be a “new drug” within the meaning of 21 U.S.C. § 321(p), it is not the subject of an approved application under 21 U.S.C. § 355(b) or (j), and there is no exemption in effect under 21 U.S.C. § 355(i). In addition, the thiopental sodium appears to be misbranded under 21 U.S.C. § 352(f)(1), because its labeling appears to lack adequate directions for use, and it does not appear to be exempt from that requirement under the law enforcement exemption in 21 C.F.R. § 201.125. The thiopental sodium also appears to be misbranded under 21 U.S.C. § 352(f)(2), because its labeling appears to lack adequate warnings. As discussed below, we are providing you with the opportunity to respond to these tentative conclusions before reaching a final determination on the status of the detained product. 1 Thiopental sodium is also known as thiopental, thiopentone, sodium thiopental, and sodium pentothal. FDA 227 April 15, 2016 Page 2 We are thus providing you a period of time when you can submit further information, whether in writing or in person, relevant to the admissibility of the entry. We will consider any additional information you provide in reaching a final conclusion regarding the admissibility of the product. This letter specifies the bases upon which we have tentatively determined that the thiopental sodium appears to be in violation of the Federal Food, Drug, and Cosmetic Act (“FD&C Act”), 21 U.S.C. §§ 352(f)(1), 352(f)(2) & 355, and, therefore, subject to refusal of admission. This letter also explains the relevance of a recent court order to this shipment. I. Background A. Statutory Framework Under the FD&C Act, the Secretary of Health and Human Services may request “samples of food, drugs, devices, tobacco products, and cosmetics which are being imported or offered for import into the United States . . . .” 21 U.S.C. § 381(a). The FD&C Act further provides that “[i]f it appears from the examination of such samples or otherwise that . . . (3) such article is adulterated, misbranded, or in violation of [21 U.S.C. § 355], . . . then such article shall be refused admission, except as provided in” 21 U.S.C. § 381(b). 21 U.S.C. § 381(a)(3) (emphasis added). The FD&C Act thus does not require FDA to find that an article that is offered for importation is actually adulterated, misbranded, or in violation of 21 U.S.C. § 355 in order to refuse admission to that article; rather, the Agency has “broad authority to prohibit import” of any article that “appears” to violate the FD&C Act. Continental Seafoods, Inc. v. Schweiker, 674 F.2d 38, 43 (D.C. Cir. 1982) (emphasis added); see Goodwin v. United States, 371 F. Supp. 433,436 (S.D. Cal. 1972); see also United States v. Food, 2998 Cases, 64 F.3d 984, 992 (5th Cir. 1995) (FDA “can pursue the administrative procedures of § 381 and simply require reexportation of the goods,” even where “the government lacks the ability to prove a violation of the [FD&C Act] by a preponderance of the evidence.”); Sugarman v. Forbragd, 267 F. Supp. 817, 824 (N.D. Cal. 1967), aff’d, 405 F.2d 1189 (9th Cir. 1968); K&K Merch. Group, Inc. v. Shalala, No. 95Civl0082, 1996 U.S. Dist. LEXIS 4880, *22-23 (S.D.N.Y. 1996) (noting “the wide discretionary power FDA enjoys to determine the factors regarding its decision to grant or refuse admission of imported goods”). If an article is refused admission, it must be exported or destroyed within ninety days. 21 U.S.C. § 381(a). FDA 228 April 15, 2016 Page 3 B. The Proceedings As noted, on or about July 24, 2015, offered for import 1,000 one-gram vials of a product labeled as (Thiopental Sodium USP). On August 5, 2015, U.S. Customs and Border Protection (CBP) detained this shipment of thiopental sodium. Ref. 1, Ex. 10 at 1. On August 18, 2015, you, as counsel for requested that FDA instruct CBP to lift the detention and let the product proceed to destination. Ref. 1, Ex. 11 at 1-2. By letter dated August 24, 2015, FDA denied that request. Ref. 1, Ex. 12. On August 24, 2015, FDA issued a “Notice of FDA Action” explaining that Entry was detained and subject to refusal of admission based on the following: the product appeared to be misbranded under 21 U.S.C. § 352(f)(1) because its labeling appeared to lack adequate directions for use; the product appeared to be misbranded under 21 U.S.C. § 352(f)(2) because its labeling appeared to lack adequate warning against use in a pathological condition or by children where it may be dangerous to health or against an unsafe dose, method, administering duration, application, in manner/form, to protect users; and the product appeared to be a new drug that lacked an approved new drug application as required by 21 U.S.C. § 355. Ref. 1, Ex. 1 at 1-2. The notice, which was sent to as the listed consignee of the entry, specified that testimony regarding the admissibility of the entry must be submitted to FDA by September 14, 2015. Ref. 1 Ex. 1 at 2. On September 10, 2015, as counsel for you requested an extension to respond to the Notice of FDA Action. On the same day, FDA granted an extension until October 23, 2015. See Ref. 1, Ex. 1 at 3. On October 23, 2015, on behalf of you submitted written testimony regarding the detained product. Ref. 1. Your letter provided information regarding why you believe the product should not be refused admission, and you requested an in-person hearing with appropriate FDA personnel. Ref. 1 at 1. In submitting the written testimony, you also requested that FDA transfer the matter to the Director, Office of Enforcement and Import Operations (“OEIO”) or his designee, who would serve as the hearing officer for this detention. In a telephone discussion on December 10, 2015, FDA counsel informed you that the Agency intended to follow its typical practice of having staff in the District Office determine admissibility, rather than transferring the matter to OEIO. In a subsequent telephone discussion with FDA counsel on February 2, 2016, FDA asked whether still wanted to present information regarding the detained product in person. Subsequently, in a series of phone communications on March 11, 2016, you stated that concurred with an approach in which FDA would send a written, tentative decision to you and provide ADC with the opportunity to respond before reaching a final decision. FDA 229 April 15, 2016 Page 4 Our tentative conclusion that the thiopental sodium appears to violate 21 U.S.C. §§ 352(f)(1), 352(f)(2), and 355 is based on a review of the entire record in this matter, including the label, labeling, and packaging for the thiopental sodium and the information you submitted on October 23, 2015. C. The Detained Product Entry No. consists of 1,000 one-gram vials of (Thiopental Sodium USP). Ref. 2 at 2. The labels on the vials of thiopental sodium state: 1 gm Thiopental Sodium USP Sterile Rx Only CIII manufacturer and distribution services For law enforcement purpose only. Made in Code No: Batch No.: Mfg. Date: 06/2015 Exp. Date: 05/2017 Marketed by: Ref. 3 at 23-24. The label bears no other information. Ref. 3 at 23-24; Ref. 1, Ex. 3 at 1. See also Ref. 1 at 2 (“Aside from the information printed on the label . . ., there is no additional labeling information accompanying the drug specifying information about its properties or uses.”). The sticker on the outside of a box of vials repeats the information on the vial label. Ref. 3 at 43. The boxes contain no package inserts, leaflets, or other materials with directions for use or warnings about the use of the thiopental sodium. An outside box label lists the as the consignee. Ref. 3 at 26-27. In addition to the label listing FDA 230 April 15, 2016 Page 5 “ manufacturer and distribution services,” the certificate of analysis in the entry documentation for the thiopental sodium states that it is “[m]anufactured by” “ ” Ref. 2 at 4. Thiopental sodium is a barbiturate that depresses nervous system function to render a man or woman unconscious, Ref. 1, Ex. 13 at 3-5 (Goodman and Gilman’s, The Pharmacological Basis of Therapeutics, 11th ed., p. 347-349), which can cause death in a large enough dose. Ref. 1, Ex. 16 at 10 (History of Barbiturates, p. 338). As classified among anesthetics, it is an ultrashort-acting agent. Ref. 1, Ex. 16 at 10 (History of Barbiturates, p. 338). Like other anesthetics, its effects vary based on patient-specific factors such as weight and age, and its use must be calibrated. Ref. 1, Ex. 15 at 3-5 (Goodman and Gilman’s, p. 347-349). In addition, thiopental sodium can produce allergic reactions in some individuals. Ref. 1, Ex. 15 at 6 (Goodman and Gilman’s, p. 350). It is a schedule III controlled substance. Ref. 1 at 2; Ref. 1 Ex. 3. There are currently no FDA-approved applications in effect for the thiopental sodium. The detained product is also not the subject of an effective IND application. D. The District Court’s Order For decades, FDA generally exercised enforcement discretion regarding thiopental sodium used for capital punishment purposes. See Heckler v. Chaney, 470 U.S. 821, 835-36 (1985). See also Ref. 1, Ex. 14 at 1-2 (2010 FDA statement explaining that FDA was exercising enforcement discretion and choosing to continue to defer to law enforcement as a policy matter). In February 2011, a group of prisoners on death row in Arizona, California, and Tennessee filed suit challenging FDA’s release of imported thiopental sodium for use as an anesthetic as part of lethal injection. In March 2012, the U.S. District Court for the District of Columbia granted the plaintiffs’ motion for summary judgment. See Beaty v. FDA, 853 F. Supp. 2d 30 (D.D.C. 2012), aff’d in part, rev’d in part sub nom. Cook v. FDA, 733 F.3d 1 (D.C. Cir. 2013). The District Court’s March 2012 Order, as modified in June 2012, permanently enjoins FDA from “permitting the entry of, or releasing any future shipments of, foreign manufactured thiopental that appears to be misbranded or in violation of 21 U.S.C. [§] 355 [as an unapproved new drug].” Ref. 4 at 1-2; Ref. 5 at 2. On June 23, 2015, FDA sent you a letter after telephone discussions regarding the potential importation of thiopental sodium into the United States. Ref. 6. The letter explained that you told FDA that you represented several state governments seeking to import thiopental sodium and were also serving as the U.S. agent of , the manufacturer of a thiopental sodium product. Ref. 6 at 1. Among other things, FDA’s letter reiterated that the FDA 231 April 15, 2016 Page 6 District Court permanently enjoined FDA from permitting the entry of, or releasing any future shipments of, foreign-manufactured thiopental sodium that appears to be misbranded or an unapproved new drug. Ref. 6 at 1. The letter also reiterated that there was no FDA-approved application for thiopental sodium. Ref. 6 at 2. II. The Detained Thiopental Sodium Appears To Be An Unapproved New Drug acknowledges that the thiopental sodium is a drug, because it is intended to affect the structure and function of the body. Ref. 1 at 5 (discussing 21 U.S.C. § 321(g)(1)(C) and stating that “[t]his second definition applies here”). also admits that its purpose for obtaining the detained thiopental sodium is to “utilize thiopental sodium in executions.” Ref. 1, Ex. 13 ¶ 5. Nevertheless, as set forth in your October 23 letter, argues that the thiopental sodium “does not fit within the statutory definition of a ‘new drug,’” because its labeling “does not prescribe, recommend, or suggest any conditions of use.” Ref. 1 at 7. In particular, asserts that “[w]hen no conditions of use are so specified, it is not possible for FDA to establish that a drug is a ‘new drug.’” Ref. 1 at 7. concludes that it is therefore legal to distribute the drug even in the absence of an approved NDA or ANDA. Ref. 1 at 7. For the reasons discussed below, we believe the detained thiopental sodium’s labeling does “suggest[]” conditions of use. See 21 U.S.C. § 321(p)(1) (defining “new drug”). Those conditions of use are as part of a lethal injection. It appears the drug is not generally recognized as safe and effective under those conditions of use, or under any other conditions of use. Therefore, we tentatively conclude that it appears to be an unapproved new drug. A. The Detained Thiopental Sodium’s Labeling Suggests the Conditions Under Which It Will Be Used: For Lethal Injection As discussed, does not dispute that the detained thiopental sodium is a drug. If a product is a drug, then, as a matter of law, it is a “new drug” unless it is generally recognized among qualified experts as being “safe and effective under the conditions prescribed, recommended, or suggested in its labeling.” 21 U.S.C. § 321(p)(1). The labeling of the detained thiopental sodium suggests the conditions under which it will be used: as a lethal injection drug. 2 The label states “Thiopental Sodium USP,” “Sterile,” “Rx only,” and “[f]or law enforcement purpose only.” Ref. 3 at 23-24; Ref. 1, Ex. 3 at 1. In addition, an outside box label lists the as the consignee. 2 The labeling of a drug includes its container label. 21 U.S.C. § 321(m). FDA 232 April 15, 2016 Page 7 Ref. 3 at 26-27. 3 Those elements alone suggest the drug’s use. Moreover, thiopental sodium is a well-known death penalty drug used for anesthesia in multi-drug protocols or, sometimes, as the lethal agent itself. See, e.g., Baze v. Rees, 553 U.S. 35, 44 (2008); Death Penalty Information Center, State by State Lethal Injection, DEATHPENALTYINFO.ORG, http://www.deathpenaltyinfo.org/state-lethal-injection (last visited Apr. 10, 2016) (describing states’ use of thiopental sodium in both three-drug and single-drug protocols); Emma Marris, Death-row drug dilemma, NATURE (27 Jan. 2011), http://www.nature.com/news/2011/110121/full/news.2011.53.html. notes that “[t]he standard reference source for pharmacology indicates that thiopental sodium is a barbiturate that produces unconsciousness and anesthesia.” Ref. 1 at 4 n.2. states further that “[t]his effect is well known; the drug has been used for purposes of anesthesia since before the [FD&C Act] was enacted in 1938.” Ref. 1 at 4 n.2. The use suggested by the information in the drug’s labeling is confirmed by submission. For example, the declaration submitted as Exhibit 13 states: has purchased the thiopental sodium currently being detained by the FDA. has previously purchased and used thiopental sodium in numerous executions before it became commercially unavailable to correctional facilities for such purpose. In order to resume use of thiopental sodium for executions, no legislative or regulatory action is necessary. My responsibilities to determine the lethal injection procedure include the discretionary decision to determine which substance or substances to use. As part of my statutory duty to ensure that lawful capital sentences are carried out via lethal injection, I am attempting to once again utilize thiopental sodium in executions and will do so when necessary if the FDA releases its hold on the purchased thiopental sodium. Ref. 1 at Ex. 13 ¶ 5 (emphasis added). The October 23 letter underscores the point, stating that “the specific law enforcement purpose [of the thiopental sodium] is to effectuate lawfullyimposed capital sentences through lethal injection.” Ref. 1 at 4. 4 3 The consignee field in the import entry forms confirms that the shipment is destined for Ref. 2 at 1. 4 We note that the execution procedures that you submitted on October 23, 2015 do not describe execution procedure with respect to thiopental sodium. Ref. 1, Ex. 13, Ex. A. Instead, those procedures, dated July 2012, describe use of pentobarbital. Ref. 1, Ex. 13, Ex. A at 8-10. We understand that the thiopental sodium would be used either as the anesthetic in a multi-drug protocol, as Texas has used it in the past, see, e.g., Jennifer Horne, Lethal Injection Drug Shortage, COUNCIL OF STATE GOVERNMENTS E-NEWSLETTER (Feb. 17, 2011), http://www.csg.org/pubs/capitolideas/enews/issue65 4.aspx (discussing thiopental sodium as “an anesthetic that is part of the three-drug cocktail used in lethal injections” and stating that Texas had enough of the drug to execute two death-row inmates), or in a single-drug protocol, FDA 233 April 15, 2016 Page 8 In sum, the labeling of the thiopental sodium plainly suggests the conditions under which the drug will be used. 5 The conditions suggested in the labeling are to affect nervous system function of an inmate as part of an execution. B. The Detained Thiopental Sodium Is Not Generally Recognized As Safe and Effective for Any Use As discussed, if a product is a drug, then, as a matter of law, it is a “new drug” that must be approved by FDA before it can be lawfully distributed in interstate commerce, unless its composition is such that it is generally recognized among qualified experts as being “safe and effective under the conditions prescribed, recommended, or suggested in its labeling.” 21 U.S.C. §§ 321(p)(1), 331(d), 355. General recognition of a drug as safe and effective must rest on a consensus among qualified experts based on adequate and well-controlled clinical trials that are published in the scientific and medical literature. See, e.g., Weinberger v. Hynson, Westcott & Dunning, Inc., 412 U.S. 609, 629 (1973); Weinberger v. Bentex Pharm., Inc., 412 U.S. 645, 652 (1973); United States v. Article of Drug . . . 4,680 Pails, 725 F.2d 976, 987 (5th Cir. 1984); United States v. Undetermined Quantities . . . Equidantin, 675 F.2d 994, 1000-01 (8th Cir. 1982); Premo Pharm. Labs., Inc. v. United States, 629 F.2d 795, 803-04 (2d Cir. 1980) Here, the “conditions . . . suggested in the labeling” of the detained thiopental sodium are use as part of a lethal injection. Under those conditions, we have tentatively determined that it appears that the drug is not generally recognized as safe and effective. For example, there are no adequate and well-controlled trials evaluating thiopental sodium for use as part of a lethal injection that have been published in the scientific literature. Thus, it appears the detained thiopental sodium is not generally recognized as safe and effective for use in lethal injection. See Tri-Bio Labs., Inc. v. United States, 836 F.2d 135, 141 (3d Cir. 1987) (“[E]ither the unawareness of the drug product by experts generally or a genuine dispute among qualified experts regarding a drug product’s safety and effectiveness preclude[s] its qualifying for exclusion as ‘generally recognized.’”) (internal quotation omitted). as utilized in other states. See, e.g., Jennifer Sullivan, Killer on death row 16½ years is executed, THE SEATTLE TIMES (Sept. 10, 2010) (describing a 2010 Washington execution using thiopental sodium alone). 5 You argue that the thiopental sodium is analogous to prescription chemicals used in pharmacy compounding, which must bear a legend, and which, you argue, “d[o] not meet the statutory definition of ‘new drug,’ because [the chemicals’] labeling does not specify any conditions of use.” Ref. 1 at 7-8. (emphasis in original). This comparison is inapt because, among other things, it ignores the fact that the detained thiopental sodium has conditions for use suggested in its labeling. Moreover, as discussed in Section I.A., a product is subject to refusal of admission if it appears to be a new drug that is not approved in violation of 21 U.S.C. § 355. FDA 234 April 15, 2016 Page 9 argues that “[w]hen no conditions of use are . . . specified” in the labeling, “it is not possible for FDA to establish that a drug is a ‘new drug.’” Ref. 1 at 7. This argument is beside the point because, as discussed above, we tentatively conclude that there are conditions for use suggested in the labeling for the detained product. In any event, this argument is not persuasive. There are no adequate and well-controlled trials published in the scientific literature that evaluate thiopental sodium for any use, and therefore thiopental sodium cannot qualify as generally recognized as safe and effective for any use. Moreover, the detained thiopental sodium is not the subject of an approved new drug application, an approved abbreviated new drug application, or an effective investigational new drug application. Therefore, we tentatively conclude that it appears to be an unapproved new drug. III. The Detained Thiopental Sodium Appears to Be Misbranded Under 21 U.S.C. § 352(f)(1) We tentatively conclude that, in addition to appearing to be an unapproved new drug, the thiopental sodium appears to be misbranded because its labeling does not bear adequate directions for use. The thiopental sodium that is attempting to import includes no directions for those who would administer the drug or receive it. It lists no recommended dose, and it includes no instructions for reconstituting the powder inside the vials. It includes no precautions, contraindications, or warnings, or other information required in prescribing information for health professionals. Instead, it bears little text beyond “[f]or law enforcement purpose only,” “Rx only,” “CIII,” “1 gm,” and manufacturer information. That text provides inadequate directions for a prescription-drug barbiturate that will be administered to humans to produce anesthesia as part of a lethal injection procedure, or, possibly, to be used as the sole drug for lethal injection. argues that the thiopental sodium is exempt from the statutory requirement to bear adequate directions for use under 21 C.F.R. § 201.125, entitled “Drugs for use in teaching, law enforcement, research, and analysis.” Ref. 1 at 3. However, the law enforcement exemption within 21 C.F.R. § 201.125 does not apply here, for the reasons discussed below. FDA 235 April 15, 2016 Page 10 A. The Detained Thiopental Sodium’s Labeling Does Not Bear Adequate Directions for Use Under section 502(f)(1) of the FD&C Act, 21 U.S.C. § 352(f)(1), a drug is deemed to be misbranded unless its labeling bears adequate directions for its use. “Adequate directions for use” means “directions under which the layman can use a drug safely and for the purposes for which it is intended.” 21 C.F.R. § 201.5; United States v. Articles of Drug (Rucker Pharmacal), 625 F.2d 665, 671-75 (5th Cir. 1980). The detained thiopental sodium is a prescription drug, as reflected by the “Rx Only” on its label. Ref. 1, Ex. 3 at 1. recognizes in its October 23 letter that the detained product merits the classification: “[t]he drug easily satisfies the definition of a prescription drug; it is hard to imagine FDA suggesting that a drug that produces unconsciousness and anesthesia is a non-prescription drug.” Ref. 1 at 4 n.2. 6 A prescription drug is, by definition, “not safe for use except under the supervision of a practitioner licensed by law to administer such drug.” 21 U.S.C. § 353(b)(1)(A). As a result, it is impossible to provide “adequate directions for [lay] use” for prescription drugs, and they are “presumptively misbranded.” United States v. Regenerative Scis., LLC, 741 F.3d 1314, 1324 (D.C. Cir. 2014). To avoid being misbranded, a prescription drug must qualify for an exemption from the adequate directions for use requirement. Rucker Pharmacal, 625 F.2d at 673. One such exemption is the exemption in 21 C.F.R. § 201.100, for prescription drugs for human use. To qualify for that exemption, if the prescription drug is a new drug, it must bear the “labeling authorized by the approved new drug application . . . .” 21 C.F.R. § 201.100(c)(2). Because the detained thiopental sodium is an unapproved new drug, for the reasons discussed above, we tentatively conclude that it cannot qualify for the exemption in section 201.100. Even if the detained product were not an unapproved new drug, it does not bear the label or labeling required to qualify for the exemption in section 201.100. As a starting point, the label of a prescription drug must provide the recommended or usual dosage and the route of administration (such as “intravenous bolus,” “sublingual,” or “parenteral”), under 21 C.F.R. §§ 201.100(b)(2) and (3), but here the label does not include that information. In addition, the labeling must include sufficient information to enable licensed practitioners to “use the drug safely and for the purposes for which it is intended,” under 21 C.F.R. §§ 201.100(c)(1) and (d)(1). Thus, the labeling must include a package insert with comprehensive information for 6 Indeed, a previous thiopental sodium product for injection, marketed through January 2011, was a prescription drug. FDA 236 April 15, 2016 Page 11 health professionals in enumerated categories. 21 C.F.R. § 201.100(d)(3) (referencing the requirements of §§ 201.56 and 201.57 for newer-format prescription drug labeling and § 201.80 for older-format labeling). These categories range from “Indications and Usage,” 21 C.F.R. §§ 201.56(d)(1), 201.80(c), and “Dosage and Administration,” 21 C.F.R. §§ 201.56(d)(1), 201.80(j), to “Precautions,” which can address “any special care to be exercised by the practitioner for safe and effective use of the drug.” 21 C.F.R. §§ 201.57(c)(6)(ii), 201.80(f). Here, we tentatively conclude that the thiopental sodium seeks to import appears to bear inadequate labeling. The package includes no prescribing information and thus lacks the detailed information required by law for health professionals (e.g. dosing information and precautions). See 21 C.F.R. §§ 201.100(c), 201.100(d), 201.56, 201.57, 201.80. Like other drugs that bear essentially no directions for use, the thiopental sodium appears to be misbranded. See, e.g., Colgrove v. United States, 176 F.2d 614, 616 (9th Cir. 1949) (directions for use are inadequate if there is an omission of directions for use for all conditions for which a drug is recommended or suggested in advertising matter sponsored by the manufacturer or distributor). In summary, we tentatively conclude that it appears the thiopental sodium fails to meet the labeling requirements for a prescription drug for human use, and thus it appears to be misbranded under 21 U.S.C. § 352(f)(1). The law enforcement exemption does not exempt the thiopental sodium shipments at issue here from the adequate directions for use requirement, for reasons discussed below. B. FDA’s Law Enforcement Exemption Does Not Extend to Drugs for Lethal Injection, but Instead Covers Investigative Purposes that Do Not Involve Clinical Use asserts that the detained thiopental sodium is not misbranded under 21 U.S.C. § 352(f)(1) because it “falls within the exemption established by 21 C.F.R. § 201.125,” which “applies to a drug that is ‘shipped or sold to, or in the possession of, persons . . . engaged in law enforcement, . . . and is to be used only for . . . law enforcement.’” Ref. 1 at 3. We do not dispute that use of a drug in lethal injection is use for a law enforcement purpose in one sense of that term. However, the text of 21 C.F.R. § 201.125, its history, and its regulatory framework demonstrate that FDA’s law enforcement exemption does not extend to drugs for lethal injection. The regulation in full states that: A drug subject to § 201.100 or § 201.105, shall be exempt from section 502(f)(1) of the act if [1] shipped or sold to, or in the possession of, persons regularly and lawfully engaged in instruction in pharmacy, chemistry, or medicine not involving clinical use, or engaged in law enforcement, or in research not involving clinical FDA 237 April 15, 2016 Page 12 use, or in chemical analysis, or physical testing, and [2] is to be used only for such instruction, law enforcement, research, analysis, or testing. 21 C.F.R. § 201.125 (emphases added). When FDA promulgated the law enforcement exemption in 1956, no state utilized lethal injection. Baze, 553 U.S. at 42. At the time, the most common method of execution in the United States was the electric chair. Id. See also John West, All the Ways America has Chosen to Execute People Since 1776, Quartz (Feb. 22, 2015), http://qz.com/346332/all-the-waysamerica-has-chosen-to-execute-people-since-1776/ (compiling data from the Death Penalty Information Center and the Inter-University Consortium for Political and Social Research). No state would employ lethal injection in an execution until 1982, in Texas. Deborah W. Denno, Getting to Death: Are Executions Constitutional?, 82 Iowa L. Rev. 319, 375 (1997). Thus, the regulation could not have been intended to apply to drugs for lethal injection. When FDA promulgated the exemption, it did not give an extensive rationale. Instead, the Agency stated that its normal labeling requirements were unnecessary for the protection of the public health in the circumstances to which the exemption applied. More precisely, FDA’s special Federal Register finding stated: Notice, and public procedure are not necessary prerequisites to the promulgation of this order . . . since [1] the exemption granted applies only to drugs and devices shipped, sold, or in the possession of persons engaged in law-enforcement and in such cases the labeling requirements are not necessary for the protection of the public health, [2] since the amendment relaxes existing requirements; and [3] since it would be against public interest to delay providing for the amendment. Regulations for the Enforcement of the Federal Food, Drug, and Cosmetic Act; Exemption of Certain Drugs and Devices from Labeling Requirements, 21 Fed. Reg. 2309, 2327 (Apr. 11, 1956) (emphasis added) (final rule). The preambles to 21 C.F.R. § 201.125 do not state the specific law enforcement uses that FDA envisioned exempting. See 21 Fed. Reg. 2327 (1956 special finding); 17 Fed. Reg. 68196820 (1952 final rule); Drugs and Devices: Directions for Use; Drugs for Prescription Dispensing, 17 Fed. Reg. 1079, 1130-1133 (1952) (proposed rule). However, FDA was intimately involved in the investigation of illegal distribution of narcotics, barbiturates, and amphetamines at the time the Agency promulgated the exemption. See Wallace F. Janssen, FDA Historian, The Story of the Laws Behind the Labels, http://www.fda.gov/AboutFDA/WhatWeDo/History/Overviews/ucm056044.htm (last accessed Jan. 26, 2016) (discussing undercover sales by FDA inspectors and the Agency’s 1940’s efforts to prosecute dealers of barbiturates and amphetamines sold without prescriptions, before the FDA 238 April 15, 2016 Page 13 creation of the Drug Enforcement Agency). In 1955, the Deputy Commissioner of Food and Drugs went before Congress to express concern over misuse of amphetamines and barbiturates and offer suggestions for additional federal regulation of production and distribution of the drugs. Traffic In, and Control of, Narcotics, Barbiturates, and Amphetamines, Hearings Before the H. Subcomm. on Ways and Means, 84th Congress 1119-1120, 1123 (1955) (statement of John L. Harvey, FDA Deputy Commissioner, Nov. 17, 1955). In his statement, the FDA Deputy Commissioner described himself as a “food and drug law enforcement officer” and discussed efforts by “State enforcement officers” who found themselves underequipped in terms of manpower and laws. Id. at 1120. Thus, investigative law enforcement actions related to prescription drugs were a focus of FDA and the public immediately before FDA promulgated the law enforcement exemption in section 201.125. See id. In short, the historical context of the exemption indicates that the law enforcement exemption encompasses law enforcement purposes related to investigative work, rather than drugs for lethal injection. In greater detail, the law enforcement exemption can encompass law enforcement purposes like controlled buys and officer training. For example, a violative drug could be “sold to” an undercover agent “engaged in law enforcement” and “used only for . . . [the] law enforcement” purpose of proving the seller’s illegal activity. See 21 C.F.R. § 201.125. Similarly, the law enforcement exemption could extend to uses like forensic testing. Alternatively, the exemption could facilitate instruction of officers on the look and feel of particular drug products. In all of these cases, adequate directions for use would be unnecessary for the protection of public health, because the drugs would not be intended for uses involving administration to humans. Looking to the regulation as a whole, we tentatively conclude that section 201.125 exempts drugs from the requirement that their labeling bear adequate directions for use only where those drugs are not for clinical use. The regulation’s seven categories are: (1) instruction in pharmacy not involving clinical use, (2) instruction in chemistry not involving clinical use, (3) instruction in medicine not involving clinical use, (4) law enforcement, (5) research not involving clinical use, (6) chemical analysis, and (7) physical testing. In this context, “clinical use” conveys uses involving administration of drugs to humans (or animals, for animal drugs). See, e.g., 21 C.F.R. § 312.3 (defining “clinical investigation” to mean “any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects”). Where clinical use might be expected, such as with “instruction in medicine” or with “research,” FDA explicitly stated that the exemption did not extend to those uses. 21 C.F.R. § 201.125. Although FDA did not attach the same modifier, “not involving clinical use,” to “law enforcement,” the agency very likely did not anticipate clinical use of drugs pursuant to this exemption. It took the same approach for chemical analysis and physical testing. If the “clinical use” limitation applied only to categories (1)-(3), and (5), the regulation would require substantive labeling for medical school professors administering drugs to humans, but not law enforcement personnel, which FDA 239 April 15, 2016 Page 14 could not have been what FDA intended. Like “chemical analysis” and “physical testing,” the “law enforcement” within section 201.125 does not encompass clinical uses involving administration of drugs to humans. In fact, an earlier, 1952 version of what was then 21 C.F.R. § 1.106(m) included only the six categories from “instruction in pharmacy . . . not involving clinical use” to “physical testing,” without “law enforcement.” Regulations for the Enforcement of the Federal Food, Drug, and Cosmetic Act; Drugs and Devices; Directions For Use; Exemption From Prescription Requirements, 17 Fed. Reg. 6807, 6819-6820 (Jul. 25, 1952) (final rule). Thus, FDA specifically inserted the law enforcement exception into a regulation with six other categories of uses that do not involve administration of drugs to humans. See id. In summary, we tentatively conclude that section 201.125 does not apply to the detained thiopental sodium for use in lethal injection. Because it appears its labeling fails to bear adequate directions for use and it is not exempt from that requirement, we tentatively conclude that the detained thiopental sodium appears to be misbranded under 21 U.S.C. § 352(f)(1). IV. The Detained Thiopental Sodium Also Appears to Be Misbranded Because It Lacks Adequate Warnings We tentatively conclude that the thiopental sodium also appears to be misbranded because its labeling fails to bear adequate warnings. See 21 U.S.C. § 352(f)(2). argues that no warnings are necessary for the thiopental sodium, because the purpose of section 502(f)(2) of the FD&C Act is to provide warnings to lay patient users “as they take their own drugs” for medicinal purposes, and there are no patient “users” within the meaning of section 502(f)(2) here. Ref. 1 at 5. In the alternative, argues that FDA has not established that the “law enforcement purpose only” legend is not an “adequate” warning under section 502(f)(2). Ref. 1 at 6. We disagree with both of these arguments. A. Drugs Must Bear Necessary Warnings Section 502(f)(2) of the FD&C Act, 21 U.S.C. § 352(f)(2), requires drug labeling to bear “such adequate warnings against use in those pathological conditions or by children where its use may be dangerous to health, or against unsafe dosage or methods or duration of administration or application, in such manner and form, as are necessary for the protection of users.” argues that “the purpose of section 502(f)(2) is to guide lay patient users as they take their own drugs.” Ref. 1 at 5. However, FDA has required warnings clearly intended for medical professionals, in addition to laypeople, pursuant to section 502(f)(2) and its implementing regulations. See, e.g., Requirements on Content and Format of Labeling for Human Prescription Drug and Biological FDA 240 April 15, 2016 Page 15 Products, 71 Fed. Reg. 3922, 3964 (final rule) (citing 502(f) and quoting the language of 502(f)(2) in the discussion of legal authority for the Physician Labeling Rule, which governs prescribing information for health professionals). Indeed, FDA regulations promulgated pursuant to sections 502(f)(1) and 502(f)(2) require detailed drug labeling for health professionals that features a full section of warnings and precautions, as well as sections for contraindications and adverse reactions. 21 C.F.R. §§ 201.56(d); 201.57(c)(6), (c)(5), (c)(7) (requirements for newer-format labeling). See also 21 C.F.R. § 201.80 (requirements for olderformat labeling). These warnings serve a critical function. They inform medical professionals about specific possible risks in administering a drug, including the risk that a drug will be ineffective for its intended use. In short, contrary to assertion that section 502(f)(2) warnings are only necessary for circumstances involving lay patient users, Ref. 1 at 5, the requirements of 502(f)(2) are indeed relevant here. B. “For Law Enforcement Purpose Only” Is Not An Adequate Warning We disagree that “for law enforcement purpose only” is an adequate warning and, as discussed, tentatively conclude that the thiopental sodium appears to be misbranded because it appears that its labeling fails to bear adequate warnings. We recognize that requested an opportunity to relabel the thiopental sodium to include the warnings FDA deems adequate. Ref. 1 at 6 n.3. It is responsibility to include adequate warnings, and it is not FDA’s role to specify in this context what warnings would suffice. Moreover, even if addressed the lack of adequate warnings, if FDA determines that the detained product appears to be an unapproved new drug under section 505(a) or a misbranded drug under section 502(f)(1), the product would still be subject to refusal of admission. V. Conclusion For the reasons set forth above, we tentatively conclude that the thiopental sodium appears to be an unapproved new drug and misbranded. As discussed above, initially requested a meeting with the Agency to discuss this import entry, but later agreed it would be more productive to first review the Agency’s tentative conclusions. We are therefore providing you with the opportunity to respond to the tentative conclusions expressed herein, either in writing or in a meeting with the Agency. If you prefer a meeting, please contact us as soon as possible so that we can identify possible dates for the meeting. If you prefer to respond in writing, please respond to this letter within 20 calendar days of receipt. We will take any information you provide in response to this letter into account in reaching a final conclusion regarding the admissibility of this product. Please note that if FDA reaches a final conclusion FDA 241 April 15, 2016 Page 16 that the detained product appears to be in violation of the FD&C Act for any of the reasons discussed in this letter, the Agency must refuse admission to the product pursuant to the orders issued in Beaty, 853 F. Supp. 2d 30, aff’d in part, rev’d in part sub nom. Cook, 733 F.3d 1. Sincerely, Rosa L. Santos Compliance Officer Dallas District Office FDA 242 April 15, 2016 Page 17 References: Reference 1: Release Request for Thiopental Sodium on Behalf of the , October 23, 2015 Exhibit 1: FDA Notices of Action ... Exhibit 3: Thiopental Label ... Exhibit 10: CBP Detention Notice Exhibit 11: Request for Delivery of Imported Sodium Thiopental Exhibit 12: FDA Response to Request for Delivery Exhibit 13: Affidavit Exhibit 14: FDA Statement regarding Sodium Thiopental Exhibit 15: Excerpt from Goodman & Gilman’s The Pharmacological Basis of Therapeutics Exhibit 16: History of Barbiturates ... Reference 2: Entry Documentation, Reference 3: Photos of Detained Thiopental Sodium Reference 4: Beaty Cook Order, March 27, 2012 Reference 5: Beaty Cook Order, June 22, 2012, Modifying Order Reference 6: FDA Letter on Sodium Thiopental Importation, June 23, 2015 FDA 243 REFERENCE 8 From: To: Cc: Subject: Date: Attachments: Detained Thiopental Sodium/Entry No. Friday, May 20, 2016 3:50:54 PM A Hello Ms. Santos I am writing as counsel for the? providing the attached submission (with ?ve attachments) in response to the Tentative Decision that you sent to me on April 15, 2016. I would appreciate it if you would confirm receipt via return email. Best regards NOTICE: This e-mail may contain information that is privileged or otherwise con?dential. It is intended solely for the holder of the e- mail address to which it has been intended, and should not be disseminated, distributed, copied or fomarded to any other persons. It is not intended for transmission to, or receipt by, any other person. If you have received this e-mail in error, please delete it without copying or forwarding it, and notify us of the error by reply e-mail so that our address records can be corrected. IRS CIRCULAR 230 DISCLOSURE: To ensure compliance with requirements imposed by the IRS, we inform you that any US. tax advice contained in this communication (including any attachments) is not intended or written to be used, and cannot be used, for the purpose of avoiding penalties under the Internal Revenue Code or (ii) promoting, marketing or recommending to another party any transaction or matter addressed herein. Please do not hesitate to contact me, however, if you have any questions regarding this matter. FDA 245 COMMERCIAL CONFIDENTIAL COMM UNIC A HON May 20. 2016 Via Electronic Mail: Rosa L. Santos, Compliance Of?cer US. Food and Drug Administration 4040 N. Central Expressway Suite 300 Dallas, TX 75204 Re: Release Request for hiogental Sodium 012 Behalt of Dear Ms. Santos: We are making this submission. as cormsel for the - in response to the April 15. 2016 Tentative Decision concerning the detained drugs identi?ed above. We appreciate the opportlmity to provide additional information before a ?nal decision is made regarding admissibility of the detained drugs.l As explained below, we respectfully submit that all of the Tentative Decision?s conclusions regarding the claimed violations of FFDCA sections 505. 502(f)(1) and 502(f)(2) (21 U.S.C. 355, 352(f)(1) and 352(f)(2)) are incorrect. The Tentative Decision?s conclusion that the detained drugs must be refused admission into domestic cormnerce under FFDC A section 801(a) (21 U.S.C. 381(a)) also is incorrect. In the interest of ef?ciency, we are objecting to the Tentative Decision?s conclusions without restating all of the information and argument previously submitted to you on October 23. 2015 (which is incorporated herein by reference).2 We hereby preserve all issues and arguments stated in 01u? prior submission even if not restated here. 0111' failure to respond to a speci?c point in the 1 Based on the April 15, 2016 Tentative Decision we understand that the District Director has designated you as the of?cial to act on his behalf in making the fmal decision whether the detained drugs are in compliance with the Federal Food. Drug. and Cosmetic Act (FFDC A) and the fmal decision whether to refuse the entry. 21 .F.R. 1.94. Please advise us immediately if that is not correct. 7 In the discussion below, citations to Attachments are to the documents that accompany this submission and citations to Exhibits are to those ?led with our original October 23. 2015 submission, including our supplemental submission on May 13. 2016. Rosa L. Santos. Compliance Of?cer May 20. 2016 Page 2 of 15 Tentative Decision is not a concession that the point is correct or a waiver of any objection to that point.3 I. The Detained Drugs Do Not Violate Statutory Requirements Governing Adequate Directions for Use The detained drugs do not violate the requirement for adequate directions for use established by FFDCA section 502(f)(1) (21 U.S.C. The law enforcement exemption set forth in 21 CPR. 201.125 exempts the detained drugs from the ?adequate directions for use? requirement. 4 First, the Tentative Decision does not dispute that lethal injection drugs are acquired and used as part of a law enforcement function. The exemption?s plain language Imambiguously covers lethal injection because that is an aspect of law enforcement. The Tentative Decision therefore acknowledges that, at least ?in one sense of? the term, lethal injection is a law enforcement Tentative Decision at 11. Second, the Tentative Decision erroneously construes the exemption?s text as limited to law enforcement ?not involving clinical use.? The text states a list of persons who may receive, purchase, or possess drugs rmder the exemption. The list is separated by commas that demarcate the differing categories of persons who may receive, pru?chase, or possess exempt drugs. Some of the descriptions contain the quali?er ?not involving clinical use? and others do not. In a series such as this, including the qualifier in some cases and excluding it in others re?ects a conscious decision to omit the qualifier where it does not appear.5 3 This submission and related Attachments contain material that is exempt from disclosure rmder Freedom of Information Act exemptions 4, 6 and If the agency receives a FOIA request for this submission and/or related Attachments we request the opportrmity to object and propose redactions before the material is publicly released. 4 The Tentative Decision discusses both the prescription drug exemption of 21 .F.R. 201.100 and the law enforcement exemption of 21 .F.R. 201.125. In section 201 . 125, the phrase ?subject to 201.100? means a prescription drug as de?ned in the statute (21 U.S.C . not a ding that meets all of the requirements of section 201.100. The exemptions set forth in sections 201.100 and 201.125 are independent of each other. A need not comply with one exemption to fit within the other. If a needed to meet all of the requirements of section 201.100 to fit within section 201.125, section 201 . 125 would serve no purpose, because the drug would already be exempt ??om the requirement for ?adequate directions for use.? 5 Under the ?rule of the last antecedent,? the Tentative Decision is wrong in suggesting that the ?not involving clinical use? modi?er applies to the categories relating to ?pharmacy? and Rosa L. Santos. Compliance Of?cer May 20. 2016 Page 3 of 15 That conclusion draws support from the original version of the regulation, which addressed both drugs and devices and did not include the law enforcement exemption. 20 Fed. Reg. 9525, 9534 (Dec. 20, 1955). When FDA amended the regulation to add the law enforcement exemption, the agency inserted the new exemption between two others that contained the ?not for clinical use? quali?er but omitted the quali?er from the law enforcement exemption. 21 Fed. Reg. 2326, 2327 (Apr. 11, 1956). That omission re?ects a conscious decision not to apply the quali?er to the law enforcement exemption. FDA did not change that decision when it later amended the regulation to separate the device exemption into a different regulation. The operative language of the device law enforcement exemption is identical to the operative language of the law enforcement exemption. Compare 21 .F.R. 801.125 with 21 .F.R. 201.125. In the alternative, even if the quali?er could be read into the law enforcement exemption, the detained diugs would ?t within the exemption. The plain meaning of the term ?clinical use? is use involving medical treatment of a patient. See, Random House Webster?s Unabridged Dictionary (2001) (de?ning ?clinical? as ?concerned with or based on actual observation of and treatment of disease in patients rather than experimentation or theory?). The detained drugs are not for a clinical use within the plain meaning of that term. Third, the Tentative Decision erroneously concludes that the law enforcement exemption is limited to applications that existed, or could have been envisioned by the agency, at the time FDA fn?st promulgated the exemption. Nrunerous corut decisions hold that broadly drafted regulations are not limited to applications that existed, or could have been envisioned by an agency, at the time it promulgated a regulation. See, Oregon Paralyzed Veterans of America v. Regal Cinemas, 339 F.3d 1126, 1133 (9th Cir. 2003). That ?exibility is critically important rmder the FFDC A, where it is often the case that regulations embrace technologies or practices that did not exist at the time the regulations were promulgated. If it were otherwise, the FDA regulatory scheme would be set in stone, rmable to adapt to ever-changing developments in critical therapies. Here the broad and general term ?law enforcement? easily encompasses law enforcement practices that did not exist at the time FDA fn?st promulgated the exemption. Furthermore, there is nothing in the contemporaneous regulatory materials from 1956 indicating that FDA intended to limit the scope of the exemption in that manner (or intended to limit the exemption to ?controlled buys? or of?cer training) as asserted in the Tentative ?chemistry.? See, e. Barnhart v. Thomas, 540 US. 20, 26 (2003). But even if that were not the case, the ?pharmacy,? ?chemistry,? and ?medicine? categories are joined together differently than the law enforcement exemption, which is completely independent of the other categories on the list. Rosa L. Santos. Compliance Of?cer May 20. 2016 Page 4 of 15 Decision. The Tentative Decision?s analysis of the history of law enforcement, including lethal injection and ?controlled buys,? is an inapplicable post-hoc rationalization that does not control the meaning of a regulation promulgated sixty years ago. inn/1y, to the extent that actual contemporaneous statements about the exemption itself are considered which they need not be those statements strongly support application of the exemption to the detained drugs. At the time FDA promulgated the exemption in 1956, the agency determined that otherwise-applicable ?adequate directions for use? requirements ?are not necessary for the protection of the public health? when law enforcement is involved. Tentative Decision at 12; 21 Fed. Reg. at 2327. That determination was the essential premise of the exemption, because without the determination there would be no statutory authority to grant the exemption. 21 U.S.C. 352(f) (conditioning exemptions to section 502(f)(1) on a determination that adequate directions for use are ?not necessary for the protection of the public health?). In the 2010/2011 policy statement attached as Exhibit 14 to our October 2015 submission, FDA recognized both that lethal injection is a ?law enforcement? function and that the agency has no ?public health? justi?cation for restricting distribution or use of lethal injection drugs. policy statement that the detained drugs fit squarely within the agency?s 1956 statements regarding the exemption. II. The Detained Drugs Do Not Violate Statutory Requirements Governing Adeguate Warnings for Users The detained drugs also do not violate the statutory provision requiring ?necessary? and ?adequate? warnings for ?users? (FFDCA section 502(f)(2) (21 U.S.C. This provision is imambiguous, and its plain meaning establishes that there is no statutory violation here. irst, the Tentative Decision does not deny the straightforward conclusion that patients are the ?users? to be protected by these ?necessary? and ?adequate? warnings. Even assruning arguendo that FDA had authority rmder section 502(t)(2) to issue such warnings to physicians as well as patients, the patient is the party to be protected by any warnings.6 The Tentative 6 The Tentative Decision does not deny that FDA generally relies on section 502(f)(2) to provide warnings directly to patients for purposes of self-administration of non-prescription drugs. The Tentative Decision also does not deny that FDA generally relies on (exemptions from) section 502(t)(1) to provide warnings to physicians for the protection of patients. See, e. 21 .F.R. 201.100. While the Tentative Decision argues that warnings under section 502(f)(2) may go to physicians rather than directly to patients, the Tentative Decision cites to a Federal Register reference that does not prove the point. Tentative Decision at 14-15. That reference cites generically to section 502(t), which could just as easily be a reference to section 502(f)(1) as a reference to 502(f)(2). The Tentative Decision also cites to a nrunber of regulations, but Rosa L. Santos. Compliance Of?cer May 20. 2016 Page 5 of 15 Decision does not deny that there are no patient ?users? here. Because there are no ?usersobvrous that no warnings are ?necessary for the protection of users.? Second, in the alternative, the ?law enforcement pmpose only? legend is an adequate warning, for the reasons explained in mm original submission. The Tentative Decision is not supportable because it does not give any rationale for why that legend allegedly is an inadequate warning. The Detained Drugs Do Not Violate Statutory Provisions Reguiring FDA Approval for New Drugs The detained drugs also do not violate statutory provisions requiring FDA approval for new drugs rurder FFDCA section 505 (21 U.S.C. 355). The Tentative Decision does not establish that the detained drugs are ?new drugs,? because it does not establish that any conditions of use are ?prescribed, recommended, or suggested in [their] labeling.? 21 U.S.C. 321(p)(1). As a result, it is not possible to determine whether the detained drugs are generally recognized as they do not prove the point either, given that they are incorporated by reference into the prescription drug labeling regulation promulgated as an exemption to section 502(f)(1). See 21 C.F.R. (citing 21 C.F.R. 210.56, 201.57, 201.80). 7 Even if FDA were able to support the untenable suggestion that death-row prisoners are ?users? within the meaning of the statute, no warnings would be ?necessary? to protect them. There certainly is no basis for warnings ?against use in those pathological conditions or by children where [a drug?s] use may be dangerous to health.? No treatment of a pathological condition is at issue here, and children may not receive lethal injection because it is unconstitutional to execute them. Roper v. Simmons, 543 US. 551 (2005). There also is no basis for warnings addressing the ?dosage or methods or dru'ation of administration or application? that are ?necessary for the protection of? death-row prisoners. No warnings are ?necessary? to ?protect? them, because lethal injection carries out a lawfully-imposed capital sentence lmder which the law requires that a prisoner will not be protected from the consequences of a capital crime. Fruthennore, the applicable state statute requires execution through lethal injection. Texas Code Crim. Proc. 43.14. As the lawful means to implement that requirement, Texas implements execution protocols that control every aspect of the dosage, methods, administration and application of any drug used for lethal injection. See Ex. 13. If the protocol is changed to authorize use of thiopental sodilun, the same tight restrictions would apply, leaving no pinpose for any warning addressing dosage, methods, administration or application. Attachment D. Put another way, even if a warning suggested a dosage, method, administration or application different than the protocol, it would violate state law to deviate from the protocol, rendering the warning meaningless and therefore not ?necessary.? Id. In addition, a warning would not be ?necessary? if it simply restated the same dosage, method, administration or application as that required by the protocol. Rosa L. Santos. Compliance Of?cer May 20. 2016 Page 6 of 15 ?safe and effective for use? rurder those conditions. 107.8 Because FDA has not established that there is a ?new drug,? 21 U.S.C. 355 does not require marketing approval. Determining a diug?s ?new diug? status based solely on statements in its labeling is a fundamental foundation of drug approval regime. A diug may be ?generally recognized as safe and effective? for some uses but not for others. See, 21 .F.R. Labeling statements identify the uses for which approval is required (absent general recognition of safety and effectiveness for that use or an exemption from approval requirements). The approval standard accordingly parallels the ?new drug? standard. FDA bases approval on adequate and well-controlled investigations of the drug?s effectiveness ?under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.? 21 U.S.C. 355(d). When it approves a drug, FDA determines that it is safe and effective ?for use rmder the conditions, prescribed, recommended, or suggested in the proposed labeling thereof.? See 21 U.S.C. 355(d)(1), Once FDA approves a drug, the agency polices compliance under numerous enforcement provisions speci?cally tied to statements in labeling. Those provisions include the two misbranding provisions addressed in the Tentative Decision. 21 U.S.C. 352(t)(1), In stark contrast, determining whether an article is a ?diug? in the ?rst place is based on the intended use of the product, which the agency can establish from information outside the labeling. That is because the statute does not limit the ?drug? determination to the labeling the way it does for the ?new drug? determination. Compare 21 U.S.C. 321(g) with 21 U.S.C. 321(p). FDA therefore has stated that there can be a drug that is not a new drug even though it ?would be a new drug if its labeling bore representations for its intended uses.? 21 .F.R. 201.115. In other words, a drug is not a new drug if the labeling bears no representations for its intended uses.9 Based on the foregoing principles, the Tentative Decision is erroneous. First, even though the ?new ding? determination is limited to statements in the detained drugs? labeling, the Tentative Decision relies primarily on information that is not labeling to conclude that they are ?new drugs.? Tentative Decision at 7. The cited court case and internet articles, and - prior submission and exhibits, are not labeling, among other things because they are not ?upon? the dings (or their containers or wrappers) and do not ?accompany? the drugs. 21 U.S.C. 8 The Tentative Decision misquotes the statute, omitting the phrase ?for use.? Tentative Decision at 8. 9 The ?intended use? de?nition set forth in 21 .F.R. 201.128 also extends beyond the labeling. But that definition addresses the scope of exemptions from the ?adequate directions for use? requirement and is not relevant to the ?new ding? determination. Rosa L. Santos. Compliance Of?cer May 20. 2016 Page 7 of 15 321(m). Information outside of the labeling that documents an intended use for the drugs is not a condition of use ?suggested in the labeling.? The Tentative Decision?s analysis therefore con?icts with the plain and unambiguous meaning of the statute. 10 Second, the de?ciencies in the Tentative Decision?s statutory construction become clear if one considers its logical extension to the drug approval process. As explained above, the ?new drug? defmition and the drug approval standard use the identical statutory phrase: ?conditions of use prescribed, recommended, or suggested in the labeling? (or ?proposed labeling?). If that phrase were stretched to include information outside the labeling, the scope of a new drug approval would extend beyond conditions of use speci?cally stated in the approved labeling. We are con?dent that FDA interprets its new drug approvals as limited in scope to conditions of use speci?cally stated within the four corners of the approved labeling. We also are con?dent that FDA does not interpret its new drug approvals to authorize additional conditions of use that may be intended and even possible to document with evidence outside the labeling if the approved labeling does not expressly state those additional conditions of use. The very same limitation to the few corners of the labeling applies when the agency determines whether a drug is a ?new drug? (which will be subject to the integrally related approval requirements). Third, the Tentative Decision is wrong in claiming that statements in the labeling itself suggest any condition of use. The Tentative Decision is frmdamentally de?cient because it lists certain statements and simply asserts that they suggest a condition of use (without providing any supporting rationale). Tentative Decision at 6-7. In addition, as a matter of law there is no basis for concluding that the label statements ?Thiopental Sodium ?Sterile,? ?Rx only,? and ?[t]or law enforcement pmpose only? suggest conditions of use. As the Tentative Decision acknowledges, thiopental sodium may be used for a variety of different pmposes other than lethal injection. Accordingly, the drug?s name does not suggest any particular condition of use. There is no basis whatsoever for concluding that the terms ?sterile? and ?Rx only? suggest any particular condition of use. The ?law enforcement purpose only? legend simply invokes a regulatory exemption, and (rmder? our alternative argrunent) provides a warning not to use the product for any medical pmpose, but does not suggest a speci?c condition of use for which the agency could assess general recognition of safety and effectiveness. 10 In 21 U.S.C. 321(p), the plain meaning of the term ?suggested? is ?proposed.? See, Random House Webster?s Unabridged Dictionary (defming ?suggest? as ?to mention or introduce (an idea, proposition, plan, etc.) for consideration or possible action?). The Tentative Decision does not argue that the labeling proposes any condition of use. Furthermore, even if a broader de?nition of the term ?suggested? were applied, a condition of use must be suggested ?in? the labeling, not outside the labeling, to be a basis for a ?new drug? determination. Rosa L. Santos. Compliance Of?cer May 20. 2016 Page 8 of 15 Fourth, as a matter of law there also is no basis for concluding that a shipping box address sticker (containing - address) suggests a condition of use in the labeling. Assuming arguendo that the address sticker falls within the statutory de?nition of ?labeling,?11 an address does not suggest a condition of use. Otherwise a drug?s condition of use would change every time it was shipped to a new recipient. Fluthermore, the speci?c shipping sticker addressed in the Tentative Decision does not suggest that the drugs will be used for lethal injection simply because they are being sent to - - facilities use drugs for many purposes having nothing to do with lethal injection. Numerous drugs are used for medical treatment in infnmaries located in prisons administered by- Attachment C. inal/y. the Tentative Decision has no basis for concluding that the detained drugs are not generally accepted as safe and effective for any use simply because FDA could not ?nd scienti?c literature docrunenting studies with this particular distributor?s product. There is no basis for asserting that proof of general acceptance of safety and effectiveness must include scienti?c studies of a particular manufacturer?s or distributor?s version of a drug. To the contrary, FDA often establishes general acceptance of safety and effectiveness with respect to active ingredients (whose ?nished dosage forms have speci?c required labeling) and not with respect to ?nished dosage forms manufactured or distributed by a particular company. See generally 21 .F.R. 331-358. IV. The ?Appearance? Standard of FFDCA Section 8011a} Does Not Change the Foregoing Analysis The Tentative Decision relies repeatedly on the ?appearance? standard of FFDCA section 801(a) (21 U.S.C . 381(a)) to argue that deference should be given to its regulatory and statutory interpretations. Section 801(a) is referring to a factual or evidentiary determination when it uses the phrase it appears from the examination of such samples or otherwise.? The court decisions cited in the Tentative Decision address the ?appearance? standard in that factual or evidentiary context. In the present matter, the agency is not called on to resolve disputed facts or evidence. Instead, the agency is called on to address pru?e questions of law presented by the regulations and statutes discussed above. The Tentative Decision erroneously fails to distinguish between factual or evidentiary determinations (addressed by the cited case law) and resolution of the pine questions of law at issue here. 11 We contest the proposition that a shipping box address sticker that simply lists the recipient (without more) is labeling at all. There must be ?written, printed, or graphic matter? for there to be labeling. The most natural reading of that phrase requires a more substantive statement about a drug than an address where the product will be shipped. Rosa L. Santos. Compliance Of?cer May 20. 2016 Page 9 of 15 There are well-developed and generally-applicable legal doctrines governing the circrunstances under which a corut will, and will not, defer to an agency?s interpretation of its own governing statute or regulations (and if so what the degree of deference should be). See, United States v. Mead Corp, 533 US. 218 (2001); Christopher v. SmithK/ine Beecham Corp., 132 S. Ct. 2156 (2012). The case law cited in the Tentative Decision does not hold that the ?appearance? language of section 801(a) changes these generally-applicable deference doctrines when FDA interprets statutes and regulations in the context of a decision regarding admissibility of an import. Accordingly, even assuming arguendo that that the ?appearance? standard could be applied to a pine legal question, there is no basis for asserting that the ?appearance? standard establishes a different degree of deference than these generally-applicable doctrines require. Under these generally-applicable doctrines, there is no basis for deferring to any of the regulatory or statutory interpretations in the Tentative Decision (even assuming the interpretations were the basis for the ?nal decision on the admissibility of the entry). For example, as explained above the language of the law enforcement exemption in 21 .F.R. 201.125 is unambiguous, and its plain meaning easily embraces lethal injection. 12 Under these circumstances, the plain meaning of the regulation controls; the case law requiring deference to an agency?s interpretation of its own regulations under other circumstances does not require deference here. Other reasons that no deference is due include, but are not limited to, the fact that regulatory interpretation is a novel one evidently developed in anticipation of litigation, the fact that interpretation is a post-hoe rationalization, and the fact that the interpretation lacks the formality and pr'ecedential effect needed to be properly accorded deference. The statutory interpretations (of 21 U.S.C. 352(t)(1), 352(f)(2) and 355) also are not entitled to deference rmder the generally-applicable doctrines described above. If the Tentative Decision is ?nalized as is and the entry refused, the refusal decision would not be the type of agency action subject to the two-part doctrine announced in Chevron USA. Inc. v. Natural Resources Defense Council, Inc., 467 US. 837 (1984). Instead, the refusal decision would only be entitled to ?respect according to its persuasiveness.? Mead, 533 US. at 221. And we respectfully submit that the Tentative Decision?s statutory interpretations are not persuasive as explained above. Even assuming arguendo that the interpretations were subject to a two-part Chevron analysis, they should be rejected at Chevron step I, because the language of the 12 The Ian lage of 21 .F.R. 201.120 also is unambiguous, and its plain meaning supports interpretation. Compare October 23, 2015 Submission at 7-8 with Tentative Decision at 8 n5. Rosa L. Santos. Compliance Of?cer May 20. 2016 Page 10 of 15 statutory provisions is unambiguous, and the interpretations do not square with the plain meaning of those provisions. V. The Tentative Decision?s Statutory and Regulatory Interpretations Con?ict With Congressional Intent bv Restricting State Options in Implementing Capital Sentences Congress has made clear that it intends the states to develop their own varying procedm?es for implementing capital sentences of any federal interference). Although a number of different federal statutes allow for capital punishment for speci?ed crimes, Congress has not imposed a 1mifonn federal death sentence protocol. Congress has determined that the federal ?shall supervise implementation of the [capital] sentence in the manner prescribed by the State in which the sentence is imposed.? 18 U.S.C. ?3596(a). The congressional deference to state-law procedures is so substantial that a federal capital sentence cannot be imposed at all in a state where the death penalty is illegal imder state law; lmder those circrunstances the prisoner must be transferred to a second state, where the federal execution will proceed in accordance with the second state?s procedlu?es. Id. (?If the law of the State does not provide for implementation of a sentence of death, the corut shall designate another State, the law of which does provide for implementation of a sentence of death, and the sentence shall be implemented in the latter State in the manner prescribed by such The current statute requiring deference to state law is a newer version of a substantially similar one that Congress enacted in 1937 (the year before Congress enacted the FFDCA). Act of J1me 19, 1937, 50 Stat. 304 (originally codi?ed at 18 U.S.C. ?542; recodi?ed at 18 U.S.C. ?3566 (1948); repealed 1984).14 The Tentative Decision?s statutory and regulatory interpretations con?ict with congressional intent by restricting state options in implementing capital sentences. Under those interpretations, it would be lmlawful under federal law to use thiopental sodium (from any soru?ce) for lethal injection. In other words, those interpretations amormt to a federal ban on use of thiopental 13 The federal government also may rely on state facilities and personnel to impose the sentence. 18 U.S.C. 3597(a). 14? The 1937 statute (50 Stat. 304) provided as follows: ?The manner of in?icting the punishment of death shall be the manner prescribed by the laws of the State within which the sentence is imposed. The United States marshal charged with the execution of the sentence may use available State or local facilities and the services of an appropriate State or local of?cial or employ some other person for such plupose, and pay the cost thereof in an amormt approved by the Attorney General. If the laws of the State within which sentence is imposed make no provision for the in?iction of the penalty of death, then the court shall designate some other State in which such sentence shall be executed in the manner prescribed by the laws thereof.? Rosa L. Santos. Compliance Of?cer May 20. 2016 Page 11 of 15 sodium for lethal injection. A federal ban would con?ict with Congress?s intent not to interfere with - discretion to establish and modify its own state-law protocol, which speci?cally designates the drug or drugs chosen by - to be used for lethal injection. While - execution protocol crurently does not require use of thiopental sodium, - considers thiopental sodium to be a contingency should ?nd the crurently-authorized drug (pentobar?bital) rmavailable. Ex. 13; Attachment D.1 In order to determine congressional intent properly, it is necessary to construe the broad FFDCA provisions at issue (enacted in 1938) together with 50 Stat. 304 (enacted the year before) and 18 U.S.C. 3596 (enacted in 1994). That is because several statutes addressing the same subject matter should be construed harmoniously if possible. In addition, 50 Stat. 304 provides signi?cant context for the congressional intent rurderlying the FFDCA provisions at issue, which Congress enacted only one year later; indeed the very same 75th Congress enacted both statutes. Furthermore, construing the FF DC A provisions harmoniously with 18 U.S.C. 3596 (which is a more speci?c and later-enacted statute) is fully consistent with the Supreme Court?s decision in FDA v. Brown Williamson Tobacco Corp, 529 US. 120 (2000). In that case, the Court recognized that the implications of a statute may be altered by the implications of a later statute,?? that ?[t]his is particularly so where the scope of the earlier statute is broad but the subsequent statutes more speci?cally address the topic at hand,? and that speci?c policy embodied in a later federal statute should control . . . construction of the [earlier] statute, even though it ha[s] not been expressly amended.?? FDA v. Brown Williamson Tobacco Corp, 529 US. 120, 143 (2000) (citations omitted). the FFDCA together with these other 15 Congress recodi?ed 50 Stat. 304 most recently at 18 U.S.C. 3566 (1948). Congress then repealed that statute in 1984. Dining the ten-year gap before Congress enacted 18 U.S.C . 3596, the Department of Justice relied on other statutory authority and promulgated regulations governing capital pimishment procediu?es. See 28 .F.R. pt. 26. It appears that these procedures may continue to apply to a limited number of federal crimes outside the scope of 18 U.S.C. 3596. These Department of Justice regulations state that unless a corut orders otherwise, a capital sentence will be implemented intravenous injection of a lethal substance or substances in a quantity suf?cient to cause death, such substance or substances to be determined by the Director of the Federal Bureau of Prisons . . . 28 .F.R. 26.3. Under the authority of these regulations, the Bru'eau of Prisons has adopted a federal protocol requiring use of thiopental sodium for lethal injection. lurent unavailability of thiopental sodirun has forced the Biu'eau of Prisons to consider changing its protocol. Attachment A. An FDA ban on thiopental sodirun would con?ict with congressional intent in the authorizing statutes for the Department of Justice regulations, because a ban would impinge upon the Bm?eau of Prisons? discretion to choose which drugs to use for lethal injection (for sentences subject to the regulations). Rosa L. Santos. Compliance Of?cer May 20. 2016 Page 12 of 15 statutes requires a construction permitting use of thiopental sodium for lethal injection if a state- law procedure authorizes or requires it. 16 VI. The Tentative Decision?s Statutory and Regulatog Interpretations Lead to Absurd Results The Tentative Decision?s statutory and regulatory interpretations also should be rejected because they lead to absurd results. These include the following: the conclusion that the statute requires FDA to determine whether the detained drugs are generally recognized as safe and effective for lethal injection, based on any ?adequate and well-controlled clinical trials evaluating [the distributor?s] thiopental sodium for use as part of a lethal injection that have been published in the scienti?c literatru?e.? Tentative Decision at 6, 8. the conclusion that lethal injection drugs require adequate directions for lay users of the drugs and do not fall within an exemption to that requirement that applies when such directions are not necessary for the protection of the public health because lethal injection constitutes a ?clinical use? of a drug. Tentative Decision at 9, 13. the conclusion that lethal injection drugs must include warnings where their ?use may be dangerous to health,? or where there are ?misafe dosage or methods or dru?ation of administration or application.? Tentative Decision at 14. Conclusions as outlandish as these signify that the Tentative Decision?s interpretations do not re?ect congressional intent. Cf. Heckler v. Chaney, 470 US. 821, 827 (1985) (referring to ?the implausible result that the FDA is required to exercise its enforcement power to wane that States only use drugs that are ?safe and effective? for hrunan execution?). It is well established that a statutory interpretation that leads to absru?d results must be rejected. See, e. Pub. Citizen v. US. Dep ?t of Justice, 491 US. 440, 454-55 (1989). 16 The Supreme ourt?s decision in Brown Williamson applies with particular force to the Tentative Decision?s interpretation of the term ?new drug.? In Brown Williamson, the Supreme orut reviewed an FDA interpretation of the ?device? de?nition that would result in a ban of cigarettes. Even though nicotine ?t within the literal de?nition of the term ?drug? (see 529 US. at 162), the Supreme Court held that cigarettes are not drug delivery ?devices,? because if they were they would necessarily be banned as lursafe. Banning cigarettes would con?ict with the congressional intent expressed in subsequent statutes permitting tobacco use. 529 US. at 143-44. Similarly, in the present matter, interpreting the term ?new drug? to apply to the detained thiopental sodirun would result in a ban of that drug for lethal injection p1uposes, contrary to the congressional intent (expressed in the other statutes precluding federal interference with state-law execution procedru?es). Rosa L. Santos. Compliance Of?cer May 20. 2016 Page 13 of 15 VII. FDA Has Enforcement Discretion to Admit the Detained Drugs Even if it Were to Conclude That the Drugs Violate the Statute FDA has enforcement discretion to admit the detained diugs into domestic commerce even if it were to conclude that the drugs Violate the statute. In connection with that issue, the Tentative Decision cites to the District Court?s decision in Beat)? v. FDA, 853 F. Supp. 2d 30 (D.D.C. 2012) and the DC. Circuit?s decision in the same case (Cook v. FDA, 733 F.3d 1 (DC. Cir. 2013)). We respectfully submit that Beaty/Cook does not control the agency?s disposition of the detained drugs. First, Beary/Cook is distinguishable. The parties in that case stipulated that the drugs at issue were rmapproved new dings that violated FFDC A section 505(a). See Beary, 853 F. Supp. 2d at 34 n2. In addition, the facts rmderlying the stipulation are entirely different than those presented here. The Beam/Cook drugs contained labeling stating specific medical uses (concerning general anesthesia, convulsions and intracranial pressru?e). See Attachment (Griffm Decl. Ex. 19 at 5- 8). The parties evidently agreed that there was no general acceptance of safety and effectiveness for the uses stated in the labeling. And there was no FDA approval for the uses stated in the labeling. The only other violations addressed by Beaty/Cook are misbranding violations unrelated to FFDCA section 502(f)(1) or 502(f)(2). The Beaty/Cook parties again stipulated to these violations (which were failure to list the dings under FFDCA section 502(0) and failru?e to include an ?Rx only? label legend under FFDCA section See Bemfv, 853 F. Supp. 2d at 34 n2; Cook, 733 F.3d at 3. These violations are irrelevant here. As established in cm original submission and exhibits, the detained drugs were properly listed, and an ?Rx only? legend does appear on the label. Second, we respectfully submit that Beaty and Cook are wrongly decided with respect to their rulings depriving the agency of discretion to make a particularized decision admitting into domestic commerce, rather than refusing, a speci?c entry of violative imported drugs. FDA does have enforcement discretion to admit the speci?c entry of detained drugs at issue here even if it were to conclude that they violate the statute. In that regard, we incorporate by reference the arglunents in the portions of the government?s D.C . Circuit briefs in Cook that address or support FDA discretion to make particular import admissibility decisions about speci?c entries (to the extent that those argrunents are not inconsistent with- arguments in this matter). We recognize that FDA crurently feels compelled to respect the Beaty/Cook decision regarding enforcement discretion, and we present these argrunents here to preserve them for possible later judicial resolution if necessary. - is not precluded from relitigating the enforcement discretion issue because it was not a party in Beary/Cook. While FDA was a party Rosa L. Santos. Compliance Of?cer May 20. 2016 Page 14 of 15 in Beatv/Cook. the agency may relitigate the enforcement discretion issue with a different party in a different Circuit. See, e. Unitea1 States v. Mendoza. 464 US. 154. 160-62 (1984) (rejecting application of nonmutual collateral estoppel against the government); Johnson v. US. RR. Retirement Bd.. 969 F.2d 1082, 1093 (DC. Cir. 1992) (describing doctrine of intercircuit non-acquiescence). We therefore request FDA to make a ?nal decision to release the detained diugs and instruct Customs and Border Protection to implement that decision by lifting that agency?s detention, to permit immediate delivery to - If FDA makes a ?nal decision refusing admission of the detained dings. - requests the agency to retain custody of the diugs under conditions that protect against any degradation to the quality, potency. identity or ef?cacy of the drugs pending completion of any judicial review of the refusal action. Alternatively, if FDA were to refuse the entry but deny the request to retain custody, - invokes its statutory right to be given a minimum of 90 days to export the drugs to the original foreign distributor (who would hold them ready for re-importation if a corut were to rule that their admission into domestic commerce is lawful). See 21 U.S.C. 381(21): Attachment E. If you have any questions regarding the discussion set forth above. please do not hesitate to Sincerely, cc: Capt. Domenic Veneziano, Director, Division of Import Operations. FDA D011 las Steam, Director. Of?ce of Enforcement and Imports, FDA assesses to Rosa L. Santos. Compliance Of?cer May 20. 2016 Page 15 of 15 Enclosures: Attachment A: Attachment B: Attachment C: Attachment D: Attachment E: Documents Peltaining to Federal Execution Protocol Labeling for Bean/Cook Af?davit of? Af?davit of? Af?davit of? ATTACHMENT A FDA 261 Case Document 286 Filed 05124111 Page 1 of 4 USCA Case #:12-5020 Document #1432911 Wed: 041252013 Page 261 of 296 JAMES ROANE, .IR., e_t V. ERIC H. HOLDER, JR., e_t 31,, UNITED STATES DISTRICT COURT FOR THE DISTRICT OF COLUMBIA Plaintiffs, Civil Action No. Defendants. THE JOINT MOTION FOR AN ORDER ESTABLISHING A DEADLINE FOR DEFENDANTS TO SUPPLEMENT DISCOVERY, IF APPROPRIATE, AND TO EXTEND DEADLINE FOR FILING MOTION TO REOPEN DISCOVERY For the reasons stated herein, Plaintiffs and Defendants jointly and respectfully move the Court for an Order establishing a deadline for Defendants to supplement their discovery responses, if determined appropriate, and extending Plaintiffs? deadline for ?ling a motion to reopen discovery, as stated herein. Good cause exists to grant this motion: 1. On April 14, 201 1, Plaintiffs advised the Court that Defendants had publicly announced that they not have any reserves of sodium thiopental for lethal injections.? Since sodium thiopental is one of the chemicals speci?ed by the Defendants? lethal injection protocol, Plaintiffs? noted that this circumstance may require the Defendants to modify the protocol, which in turn may require additional discovery. On April 14, 201 l, the Court ordered that the parties meet and confer regarding the need for Defendants to supplement discovery, and the need to reopen discovery; that the parties jointly file a status report on this subject by April 29, 2011; and that Plaintiffs file, by no later than May 13, 2011, a motion to reopen discovery. On May 3, 2011, after considering the Parties? Joint Status Report Regarding Supplementation of Discovery (Doc. 281), this Court ordered that Defendants supplement their discovery responses by no later than May 9, 201 l. JAZST FDA 262 Case Document 286 Filed 05124111 Page 2 of 4 USCA Case #12?5020 Document #:1432911 Fi-?ed: 041269013 Page 262 Defendants filed an unopposed request to extend the time to complete their supplementation of discovery as ordered by the Court until May 16, 2011 (Dec. 283). Plaintiffs agreed to that extension on the condition that Defendants would agree to an extension of time for Plaintiffs to file a motion to reopen discovery until May 27', 2011. Defendants so agreed. On May 9, 2011 and May 16, 201 l, Defendants produced supplemental responses to Plaintiffs? written discovery requests, based on the current lethal injection protocol. Defendants? position is that they have complied with the Court?s May 3, 201 1 Order based on the current protocol but that, as explained below, they might have to supplement their discovery depending on whether the Bureau of Prisons modifies the lethal injection protocolcounsel for Defendants wrote to counsel for Plaintiffs, stating that, ?[t]he Federal Bureau of Prisons is currently considering a revision to its lethal injection protocol;? and is ?likely" to make a ?nal determination ?by this summer? as to whether to modify the protocol. Counsel for Defendants therefore proposed that the parties move for a continuance of the schedule for brie?ng the issue of additional discovery ?until the Bureau makes its determination but no later than July 29, 2011." Defendants also recommended that the parties postpone two of the remaining three depositions of Plaintiffs? experts until the Bureau decides whether, and if so, how to modify the lethal injection protocol. The parties subsequently agreed to postpone the remaining three depositions until the Bureau of Prisons makes its determination regarding the lethal injection protocol. 6. The parties cannot determine what, if any, additional discovery may be required, until the Bureau of Prisons determines whether to modify its protocol and, if it does decide to modify the protocol, until the protocol is so modified. For the foregoing reasons, the parties jointly and request that the Court issue an order providing that Defendants shall supplement their discovery responses by July 29, 2011, if appropriate, and extending until August 26, 20] l, the deadline for Plaintiffs to make any motion for additional discovery. In the event that Defendants have not made a decision by July 29, 2011, as to whether to modify the protocol, the parties will meet and confer prior to that date, and submit a joint status report to the Court on or before that date. JA258 FDA 263 Case Document 286 Filed 0524.11 Page 3 of 4 USCA Case #12-5020 fsi' Paul F. Enzinna Paul F. Enzinna (DC Bar No. 421819) Brown Rudnick, LLP 601 l3?h Street, NW. Suite 600 Washington, DC 20005 Counsel/"or Plaintiff James H. Renae, Jr. Stephen A. Northup Troutman Sanders, LLP 1001 Haxall Point Richmond, VA 23219 Frederick R. Gerson Robinson Gerson, P.C. 7102 Three Chopt Road Richmond, VA 23226 Counsel for Piainti?Rz?chard Timon Matthew Herrington Owen Bonheimer Jody Cummings Steptoe Johnson, LLP 1330 Connecticut Avenue NW Washington, DC 20036 Counsel for PIaint?Orfando Hail William Lawler B. Codd Vinson Elkins, LLP 1455 Avenue NW Washington, DC 200044008 Counselfor Webster Document #1432911 Fiied: 0110262013 Page 263 of 296 Rcspect?slly submitted, RONALD C. MACHEN JR. United States Attorney RUDOLPH CONTRERAS Chief, Civil Division [sf Beverlv M. Russell Beverly M. Russell (DC Bar No. 45425?) United States Attorney?s Of?ce for the District of Columbia, Civil Division 555 Fourth Street, NW. Washington, DC. 20530 Ph: 202-307?0492 J's! Robert .1. Erickson Robert J. Erickson, (DC Bar No. 220731) Principal Deputy Chief Criminal Appellate Section U. S. Department of Justice 950 Avenue, NW, Room 1515 Washington, DC 20530 Ph: 202614-2841 Comrselfor Defendants A259 FDA 264 Case Document 286 Filed 05124111 Page 4 of 4 USCA Case 1112-5020 Document #1432911 Filed: 04126f2013 Page 264 of 296 Barbara Hartung 700 E. Main Street Suite 1600 Richmond, VA 23219 Edward E. Seher Thorsen Scher, LLP 3810 Augusta Avenue Richmond, VA 23230 Donald Salaman Skadden 1440 New York Avenue, NW Washington, DC 20005 Counsel for Plaintif??forey Johnson Joshua Christopher Toll King Spalding, LLP 1700 Avenue NW Washington, DC 20006 Margaret O?Donnell PO. Box 4815 Frankfort, KY 40604 CounselfOr Plaintg'ff/liirhony Battle JA26O FDA 265 Case Document 319 Filed 04l01l13 Page 1 of 2 USCA Case #126020 Documer." t-?t432911 Filed: 04l28/2013 Page 295 of 296 UNITED STATES DISTRICT COURT FOR THE DISTRICT OF COLUMBIA JAMES H. ROANE, JR., et al Plaintiffs, Civil Action No. 05-2337 ERIC H. HOLDER, JR., et al., Defendants. STATUS REPORT Pursuant to the Court '3 July 29, Minute Order, Defendants are providing this status report on the Bureau of Prisons' ("Bureau") revisions of the Lethal Injection Protocol used to effectuate federal death sentences. The Department ofJustice and the Bureau of Prisons are continuing to assess matters as relates to revision or amendment of the Bureau's lethal injection protocol due to the unavailability of sodium thiopental used in the current protocol. Howevert the assessment is ongoing and no final determinations have been made as to speci?c changes to the protocol. As ordered by the Count on November 3, 20! l, Defendants will continue to ?le reports on the status of the revisions. Date: April 1, 2013 JA291 FDA 266 Case Document 319 Filed 04!01113 Page 2 of 2 USCA Case #12?5020 Document #1432911 Filed: 04l26l2013 Of Counsel: Rick Winter Respectfully Submitted, RONALD C. MACHEN JR. D.C. BAR 447889 United States Attorney for the District of Columbia DANIEL F. VAN HORN DJC. BAR 924092 Civil Chief By: J's! BENTON G. PETERSON, BAR it 1029849 Assistant United States Attorney US. Attorney?s Of?ce 555 4th Street, NW. - Civil Division Washington, DC. 20530 (202) 514-7233 E's! Robert J. Erickson Eben ROBERT J. ERICKSON. D.C. Bar# 220731 Principal Deputy Chief Criminal Appellate Section U. S. DEPARTMENT OF JUSTICE 950 Avenue, NW, Room 1515 Washington, DC 20530 Ph: (202) 514-2841 Federal Bureau of Prisons A292 FDA 267 Page 296 of 296 Case Document 361 Filed Page 1 of 2 UNITED STATES DISTRICT COURT FOR THE DISTRICT OF COLUMBIA JAMES H. ROANE, JR., et al Plaintiffs, Civil Action No. 05-2337 ERIC H. HOLDER, JR, et al., Defendants. STATUS REPORT Pursuant to the Court '5 July 29. 20] 3 Minute Order. Defendants are providing this status report on the Bureau of Prisons' ("Bureau") revisions of the Lethal Injection Protocol used to effectuate federal death sentences. The Department of Justice and the Bureau are currently engaged in a review ot'the protocol. This assessment is ongoing, and no final determinations have been made as to speci?c changes to the protocol. As ordered by the Court on November 3., 20] l, Defendants will continue to ?le reports on the status of the revisions. Date: April I. 2016 FDA 268 Case Document 361 Filed 04i01/16 Page 2 of 2 Of Counsel: Rick Winter Federal Bureau of Prisons By: Reapectfully submitted, CHANNING D. PHILLIP, D.C. Bar 5793 United States Attorney for the District of Columbia DANIEL F. VAN HORN D.C. BAR 924092 Civil Chief is! BENTON G. PETERSON, BAR 1029349 Assistant United States Attorney US. Attorney?s Office 555 4th Street, N.W. - Civil Division Washington, DC. 20530 (202) 252-2534 FDA 269 Case Document 364 Filed 04l18J16 Page 1 of 8 UNITED STATES DISTRICT COURT FOR THE DISTRICT OF COLUMBIA JAMES H. ROANE, JR., et al. Plaintiffs, vs. Civil Action No. 05-2337 Defendants. JOINT STATUS REPORT The Parties respectfully submit this Joint Status Report pursuant to the Court's Order of Ap?l8,2016. The Plaintiffs in this action1 are individuals sentenced to death under federal statutes that provide for capitai punishment, but which do not specify the method by which such punishment shall be carried out. The United States Department of Justice has promulgated regulations that call for federal death sentences to be imposed by lethal injection. See 28 CPR. Part 26 (1993}. Those regulations, however, do not specify the chemical agents to be used in carrying out such punishment, or the method by which those agents shall be administered. At the time these actions were filed, the Defendants had authored a ?Lethal Injection Protocol? specifying that capital punishment would be carried out using three drugs sodium thiopental, pancuronium 1 This action was originally filed by Plaintiffs Roane, Tipton, and Johnson. On January 29, 2007, the Parties stipulated to the intervention of Plaintiff Webster, and on April 27, 2007, the Parties stipulated to the intervention of Plaintiffs Battle and Hall. Plaintiff Paul moved to intervene on October 6, 2009. The Court denied that motion on July 1, 2010. On March 21, 2014, the U.S. Court of Appeals for the District of Columbia Circuit reversed and remanded, and Paul?s motion to intervene was granted on March 24, 2014. FDA 270 Case Document 364 Filed 04118106 Page 2 of 8 bromide, and potassium chloride and specifying the manner and method by which those agents would be administered. The original complaint in this action was filed on December 6, 2005, alleging that the Lethal Injection Protocol violates the Plaintiffs? Fifth Amendment rights to Due Process, their Eighth Amendment rights to be free from cruel and unusual punishment, and the Administrative Procedure Act, 5 U.S.C. 551 et seq. On February 24, 2006, the Hon. Ellen S. Huvelle entered an order staying the litigation and enjoining the Defendants from carrying out the execution of any Plaintiff. On June 30, 2006, the Hon. Richard W. Roberts entered an order lifting the stay on litigation, and continuing in effect the injunction against Plaintiffs? executions. The Plaintiffs filed an Amended Complaint on July 10, 2006. On February 21, 2007, Judge Richard Roberts granted Plaintiff Webster?s Motion for a Preliminary Injunction enjoining his execution and, on June 11, 2007 entered similar injunctions for Plaintiffs Battle and Hall. The Parties conducted extensive fact discovery. The Defendants provided the Plaintiffs with written discovery concerning the promulgation and implementation of the Lethal Injection Protocol, and the Plaintiffs deposed the Defendants, the persons involved in creating the Lethal Injection Protocol, and the individuals charged with administering the Lethal Injection Protocol. However, in March 2011, the Department oflustice announced that it is no longer able to obtain the sodium thiopental necessary to carry out the Protocol, in the absence of which, all parties agree, the Lethal Injection Protocol can not be carried out. As a result, Defendants informed the Court and the Plaintiffs that the Lethal Injection Protocol is being reviewed. Much of the discovery taken to date concerns the nature and properties of the specific chemicals used in the original Lethal Injection Protocol, at least one of which is no longer FDA 271 Case Document 364 Filed 04118116 Page 3 of 8 available. The discovery taken to date also addresses the methods by which the chemicals used in the original Lethal Injection Protocol would be administered, and the qualifications of, and training provided to, the individuals who would administer them. The Parties do not seek any action by the Court at this time. For the Plaintiffs: Paul F. Enzinna Bar No. 421819] Law Office of Paul F. Enzinna, LLC 5425 Wisconsin Ave, Ste. 600 Chevy Chase, MD 20815 240.113.4500 paul@enzinnalaw.com Counsel for PlaintiffJames H. Roane, Jr. RICHARD AMBROW (DC. Bar No. 1002831) Troutman Sanders, LLP 401 9th Street, NW, Suite 1000 Washington, DC 20004-2134 (202} 274-2983 STEPHEN A. NORTHUP (D.C. Bar. No. 54587) Troutman Sanders LLP 1001 Haxall Point, P.O. Box 1122 Richmond, VA 23218-1122 (804} 697-1240 For the Defendants: CHANNING D. PHILLIPS D.C. BAR fl 415793 United States Attorney for the District of Columbia DANIEL F. VAN HORN D.C. BAR it 924092 Civil Chief Br: ISI BENTON G. PETERSON, BAR it 1029849 Assistant United States Attorney,r U.S. Attorney?s Office 555 4th Street, N.W. - Civil Division Washington, DC. 20530 (202] 252-2534 benton.peterson@usdoj.gov FDA 272 Case Document 364 FREDERICK GERSON FG Law 536 Granite Avenue Richmond, VA 23226 804.428.1121 fred@fgattornev.com Counsel for Piointiff Richard Tipton is} DONALD P. SALZMAN (DC Bar No. 479775} Skadden Arps Slate Meagher 8t Flom LLP 1440 New York Avenue, NW Washington, DC 20005 Telephone: [202} 371-7983 E-mail: Salzman@skadden.com Counsel for Piointiff Corey Johnson is} JOSHUA C. TOLL (D.C. Bar No. 463073} King 8; Spalding LLP 1700 Avenue, NW Washington, DC 20006 (202} 737-0500 MARGARET PO. Box 4815 Frankfort, KY 40604 (502) 320?1837 Counsel for in tervenor-Pioin tiff Anthony Bottle William E. Lawler, WILLIAM E. LAWLER, D.C. Bar No. 398951 8: ELKINS LLP. 2200 Avenue, N.W. Suite 500 West Washington, D.C. 20037?1701 (202) 639-6500 wlawler@velaw.com Counsel for In tervenor-Ploin tiff Bruce Webster FDA 273 Filed 04l'18116 Page 4 of Case Document 364 Filed O4I18I16 Page 5 of 8 Matthew J. Herrington Steptoe 8: Johnson, LLP 1300 Connecticut Avenue NW Washington, DC 20036 202.429.8164 mherrington@steptoe.com Counsel for lntervenor-Plofntiff Orlando Holt GARY E. PROCTOR GARY E. PROCTOR, LLC 3 E. Mulberry Street Baltimore, MD 21202 (410} 444-1500 Fax: {866} 230-4455 Email: gaweproctor@gmail.com ROBE RT L. MCGLASSON MCGLASSON 84 ASSOCIATES, PC 1024 Clairemont Avenue Decatur, GA 30030 (404} 314-7664 Fax: {404) 879-0005 Email: SEAN D. PUBLIC INTEREST LITIGATION CLINIC 6155 Oak Suite Kansas City, MO 64113 (816} 35342795 Fax: (316) 363?2799 Email: dplc@dolclinic.com Counsel for in tervenor-Ploin tiff Jeffrey Poul FDA 274 Case Document 364 Filed 04J18f16 Page 6 of 8 CERTIFICATE OF SERVICE I certify that on April 18, 2016, a copy of the foregoing Parties' Joint Status Report was filed using the system, which will then send notification of such filing to all counsel of record. f5! Paul F. Enzinna Law Office of Paul F. Enzinna 5425 Wisconsin Avenue, Ste. 600 Chevy Chase, MD 20815 240.718.4500 paul@enzinnalaw.com Counsel for Plaintiff James H. Roane. Jr. FDA 275 ATTACHMENT FDA 276 Case Document 12-2 Filed 0321111 Page 1 of 83 IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF COLUMBIA Donald Edward BEATY, Daniel Wayne COOK, Eric J. KING, Brett Patrick PENSINGER, and Stephen Michael WEST, Civil Action No. 1:11-cv-00289 (RJL) Plaintiff?s, ECF Case v. FOOD AND DRUG ADMINISTRATION, UNITED STATES DEPARTMENT OF HEALTH AND HUMAN SERVICES, Kathleen SEBELIUS, and Margaret A. HAMBURG, M.D., Defendants. I I DECLARATION OF SEAN C. GRIFFIN I, Sean C. GriFI'm, declare as follows in support of Plaintiffs? Motion for Summary Judgment in the above-captioned action: I. I am over the age ofeightcen years and am a licensed attorney in good standing in the State of Virginia and the District ot?Columbia. I am a member of the bar of this Court and have appeared as counsel on behalf of Plaintiffs in the above-captioned action. 2. Attached as Exhibit I to this declaration is a true and carrect copy ol?thc Food and Drug Administration?s August 4, 2004 response to a citizen petition filed by the City of Springfield, Massachusetts, Document No. FDA-2003-P-0238-00I0 on 3. Attached as Exhibit 2 to this declaration is a true and correct com! of memorandum in support of its motion to dismiss in Vermont v. Leavitt, Case No. 04-206 in the United States District Court for the District of Vermont. I ofB FDA 277 Case Document 12?2 Filed 03f21f11 Page 2 of 83 4. Attached as Exhibit 3 to this declaration is a true and correct copy of reply memorandum in support ofits motion to dismiss in Vermont v. Leavitt. 5. Attached as Exhibit 4 to this declaration is a true and correct copy of the August I, I979 opinion ofthe United States District Court for the District of Nevada in United States v. Articles ofDrug. . . Labeled in Port . . . Beulhanasia as reported by the Food, Drug, and Cosmetic Law Reporter. 6. Attached as Exhibit 5 to this declaration is a true and cerrect copy ofa chain of emails sent by Murray Lumpkin, Deputy Commissioner, International Programs, FDA, and Tom Smith, Head, Export Control Organisation, UK. Department for Business, Innovation and Skills between November [6 and November I8, 2010. 7. Attached as Exhibit 6 to this declaration is a true and correct copy of pages taken from the United States Pharmacopeia The National Formulary. 8. Attached as Exhibit 7 to this declaration is a true and correct copy ofthe packaging of the sodium thiopental (?thiopental?) sold by Dream Pharma, Ltd. (?Dream?) to the Georgia Department of Corrections as produced by the GDC in January 201 l. 9. Attached as Exhibit 8 to this declaration is a true and correct copy of a patient information leaflet for the thiopental obtained by the Tennessee Department of Corrections in October 2010, as produced by the TDC in January 20l i. It). Attached as Exhibit 9 to this declaration is a true and correct copy of the vial and packaging of the lhiopental sold by Dream to the California Department of Rehabilitation and Corrections as produced by the CDRC in January 201 l. 2 of8 FDA 278 Case Document 12?2 Filed 031121111 Page 3 of 83 1 1. Attached as Exhibit 10 to this declaration is a true and correct copy of a citizen petition submitted to FDA by the City of Spring?eld, Massachusetts in October 2003, Document No. FDA-2003-P-023 3?0002 on 12. Attached as Exhibit 1 1 to this declaration is a true and correct copy of a citizen petition submitted to FDA by the State of Vermont in August 2004, Document No. 0233-0005 on 13. Attached as Exhibit 12 to this declaration is a true and correct copy of August 4, 2004 response to a citizen petition ?led by the State of Vermont, Document No. FDA- 2003-P-0233-001 on l4. Attached as Exhibit 13 to this declaration is a true and correct copy of the customs entry form for entry number I 12-7818637-8, as produced by FDA in January 201 1. 15. Attached as Exhibit 14 to this declaration is a true and correct copy of an email sent by Rebecca Asente, Compliance Officer in New Orleans District Of?ce on June 30, 2010, as produced by FDA in January 201 1. Attached as Exhibit 15 to this declaration is a true and correct copy ofa chain of emails dated from June 30 to July 6, 2010, as produced by the GDC in January 201 1. Attached as Exhibit 16 to this declaration is a true and correct copy of a Notice of FDA Action dated July 16, 2010, as produced by FDA in January 201 1. 18. Attached as Exhibit 17 to this declaration is a true and correct copy of a fax sent by the GDC on August 10, 2010, as produced by FDA in February 201 1. 3of8 FDA 279 Case Document 12-2 Filed 03t21t11 Page 4 of 83 Attached as Exhibit 18 to this declaration is a true and correct copy ofa Notice of FDA Action dated August 13, 2010, as produced by FDA in January 201 l. 20. Attached as Exhibit 19 to this declaration is a true and correct copy of the customs entry form for entry number 1 12-89929?9?0, as produced by FDA in January 201 1. 21. Attached as Exhibit 20 to this declaration is a true and correct copy of a Notice of FDA Action dated September 22, 2010, as produced by FDA in January 201 1. 22. Attached as Exhibit 2 to this declaration is a true and correct copy ofa Notice of FDA Action dated September 28, 2010, as produced by FDA in January 201 l. 23. Attached as Exhibit 22 to this declaration is a true and correct copy ofa fax sent by the Arkansas Department of Correction as produced by FDA in February 201 1. 24. Attached as Exhibit 23 to this declaration is a true and correct copy of an email dated September 28, 2010, from Charles Flanagan of the Arizona Department of Corrections to John McAuliffe ofthe CDRC, as produced by the CDRC in January 20 I. 25. Attached as Exhibit 24 to this declaration is a true and correct copy of a fax from the ADC to Dream dated September 23, 2010, as produced by FDA in February 201 1. 26. Attached as Exhibit 25 to this declaration is a true and correct copy of a letter from the ADC to FDA dated September 24, 2010, as produced by FDA in February 201 l. Attached as Exhibit 26 to this declaration is a true and correct copy of a chain of emails dated from September 24 to September 27, 2010, as produced by FDA in February 201 l. 4of3 FDA 280 Case Document 12-2 Filed 03/21/11 Page 5 of 83 28. Attached as Exhibit 27 to this declaration is a true and correct copy ofa chain of emails dated from September 24 to September 27, 2010, along with three documents attached to the ?nal email on September 27, 2010, as produced by FDA in February 201 l. 29. Attached as Exhibit 28 to this declaration is a true and correct copy of the customs entry form for entry number 574-0250322- as produced by the ADC in December 2010. 30. Attached as Exhibit 29 to this declaration is a true and correct copy ofa Notice of FDA Action dated September 29, 2010, as produced by the ADC in December 2010. 3 I. Attached as Exhibit 30 to this declaration is a true and correct copy of a timeline produced by the CDRC in January 201 1. 32. Attached as Exhibit 31 to this declaration is a true and correct copy ofa chain of emails dated between August 19 and 20, 2010, as produced by the CDRC in January 201 l. 33. Attached as Exhibit 32 to this declaration is a true and correct copy ofa chain of emails dated August 4, 2010, as produced by the CDRC in January 201 I. 34. Attached as Exhibit 33 to this declaration is a true and correct copy ofa chain of emails dated September 29, as produced by the CDRC in January 201 l. 35. Attached as Exhibit 34 to this declaration is a true and correct copy oFa chain of emails dated September 29, as produced by the CDRC in December 2010. 36. Attached as Exhibit 35 to this declaration is a true and correct copy of a pair of memoranda dated October 1, 2010, as produced by the CDRC in January 201 1. Soft? FDA 281 Case Document 12?2 Filed 031121111 Page 6 01?83 Attached as Exhibit 36 to this declaration is a true and correct copy of a sales agreement dated September 30, 2010, as produced by the TDC in January 201 l. 38. Attached as Exhibit 3? to this declaration is a true and correct copy of the customs entry form for entry number I 12-9247186-3, as produced by FDA in January 201 I. 39. Attached as Exhibit 33 to this declaration is a true and correct copy of a document dated October 26, 2010, as produced by the TDC in January 201 I. 40. Attached as Exhibit 39 to this declaration is a true and correct copy of the customs entry form for entry number I 12-9938358-2, as produced by FDA in January 201 1. Attached as Exhibit 40 to this declaration is are three different copies ofa chain of emails dated November 30, 2010, between FDA and CDRC officials. The ?rst version is a true and correct copy of the version produced by FDA in January 201 I. The second version is a true and correct copy of the version produced by FDA in February 201 I. The third version is a true and correct copy of the version produced by the CDRC in February 201 I. 42. Attached as Exhibit 41 to this declaration is a true and correct copy of an email sent by the CDRC to FDA on December 9, 2010, as produced by FDA in February 201 l. 43. Attached as Exhibit 42 to this declaration is a true and correct copy ofa letter from the CDRC to FDA on December 9, 2010, as produced by FDA in February 201 I. 44. Attached as Exhibit 43 to this declaration is a true and correct copy ofa chain of emails dated December 9, 2010, as produced by FDA in February 201 I. 60f3 FDA 282 Case Document 12-2 Filed 03l21/11 Page 7? of 83 45. Attached as Exhibit 44 to this declaration is a true and correct copy ofa chain of emails dated between December 9 and 20, 20l0, as produced by FDA in February 20 l. 46. Attached as Exhibit 45 to this declaration is a true and correct copy of a Notice of FDA Action dated January 6, 2010, as produced by FDA in January 201 1. Attached as Exhibit 46 to this declaration is a true and correct copy oFa chain of emails between FDA and CDRC, dated between December 9, 2010, and January 7, 201 I, as produced by FDA in February 2011. 48. Attached as Exhibit 47 to this declaration is a true and correct copy of a letter from FDA to CDRC dated January 7, 201 l, as produced by FDA in January 201 l. 49. Attached as Exhibit 48 to this declaration is a true and correct copy of a letter from the South Carolina Department of Corrections to customs, as produced by FDA in February 201 l. 50. Attached as Exhibit 49 to this declaration is a true and correct copy of the customs entry form for entry number 1 12-9673446-4, as produced by FDA in January 201 1. Si. Attached as Exhibit 50 to this declaration is a true and correct copy ofa Notice of FDA Action dated November 8, 2010, as produced by FDA in January 201 1. 52. Attached as Exhibit 5] to this declaration is a true and correct copy ofa collection of emails between FDA and the SCDC, dated from December l, 20 IO, through January 5, 20l O, as produced by FDA in January and February 201 1. 70f8 FDA 283 Case Document 12-2 Filed 03f21l11 Page 8 of 83 53. Attached as Exhibit 52 to this declaration is a true and correct wpy ofa Notice of FDA Action dated January 6, 201 1, as produced by FDA in January 2011. 54. Attached as Exhibit 5 3 to this declaration is a true and correct copy of a letter from FDA to the SCDC dated January 7, 2011, as produced by FDA in January 201 l. 55. Attached as Exhibit 54 to this declaration is a true and correct cOpy of a chain of emails dated between September 24 and 27, 2010, as produced by FDA in February 2011. 56. Attached as Exhibit 55 to this declaration is a true and correct copy of a collection of documents related to Archimedes Pharma UK Limited and Link Pharmaceuticals Limited, which were obtained from the litigation ?le of Blankenship v. Owens in the United States District Court for the Northern District of Georgia, Atlanta Division. Attached as Exhibit 56 to this declaration is a true and correct copy of the Dec. 19, 1980 citizen petition at issue in the Heckler v. Chaney litigation. I declare under penalty of perjury that the foregoing is true and cerrect. Sea?c. orimn (DC as No. 499537) SIDLEY AUSTIN LLP 1501 Street, NW. Washington, DC 20005 (202) 736-8000 Executed on March 21, 201 1. Washington, DC BofS FDA 284 Case Document 12-3 Filed 03l21fll Page 34 of 65 IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF COLUMBIA Denald Edward BEATY, Daniel Wayne COOK, Eric J. KING, Brett Patrick PENSINGER, and Stephen Michael WEST, Civil Action No. (RJ L) Plaintiffs, ECF Case v. FOOD AND DRUG ADMINISTRATION, UNITED STATES DEPARTMENT OF HEALTH AND HUMAN SERVICES, Kathleen SEBELIUS, and Margaret A. HAMBURG, M.D., Defendants. Exhibit 19 t0 the Declaration of Sean C. Grif?n FDA 285 Farm DEPARTMENT OF THE TREASURY UNITED SWES CUSIUMS SERVICE 0MB "at 1515-0030 ENTRYIIMMEDIATE DELIVERY CERTIFIED (4) - AIR EXPRESS b) (4) TEL - l?ri? GFFI 142.33, 142316? 143.22, I. MENTAL ME 1 mm: :1 ENTFW 0005114111113 4. ENTRY 091710 1m?? 112-3092979-0 5. FORT a- SINGLE TRANS. new I F. FILE NUMBER 2095 a. OOMSIGNEE NUMBER 9. IMPORTER NUWER (4) IL 0F 9500100 NAME. an. CONEIGHEE MAI-IE (4) (4) 12. 001mm 000E l3. 14. 100mm 0F I (4) (4) 15. VESSEL GODEMME 16. L15. mm as uumma IT. mm NUMBER 13. 0.0. NUMBER 111 Tom mue b) (4 2095 20. CIF TOTAL 02358486234 688760418241 PHARMACEUTICALS THIDPENTAL UHWB 21 MAMFEST CILIANTTW I 24. H5. NWBEFI 2'5 COUNTRY ID. CODE [41 DF OFIGIN GB 76L0N CERTIFICATIW I hereby make apph?catlon [or anlm?mmadlala dallvary. 100an mm The above Infamallon is naturals. the band In su?iciant, valid. and cummt, and that all mqulmmam at 19 Pan 142 have been met. (7X0) 211 00510115 USE ONLY OTHER AGENCY ACTION FTEOUIPIEQ NAMELYE PHONE HO. DATE 03} (4) 09/20/10 CUSTOMS EXAMINATION REQUIRED. 29. BROKER OTHER GOVT. AGENCY USE 110 (?ad l9 ENTRY BECAUSE: DELIVERY AUTHORIZED: Paperwork Raduotlnn not "mine: This Infomatlon I: naeded 10 dalermlna the 0! Import: Into the Unllad States and t0 provide the necessary Inlurmallun fur the examination of the cargo and In the llahlliljr for payment of duties and Your ammo is necessary. Customs Form 00/20/10 17:50:54 110(4) - FDA286 Case Document 12-3 Filed 03121111 Page 36 of 65 Dream Pharma Ltd. 1?6 Horn Lane. Acton. London. W3 Tel: 026 8992 WOOD Fax: 020 3992 3mm E-Maii: info@dreamoharme.oom invoice Details Number: ZEGEINV Dale-E 1 77?09-20 10 Address: Delivenr Address: . VAT no: Currene?oop - Pounds sten?g Purchase lCinder: Heading: PHARMACEUTICALS NOT RESTRICTED Order Details NatneiDescription I Quantity Total Thiopentsl Injection . powder for reconstitution. thiopontai sodium. 500- (4) mg vial packs of 25's i if Batch N0: AW6022 EXP: 05(14 i Statement Details Goods Tutaiz(b) i Subtotal: Kb) (4) 1 Discount r? mm VAT (World Zero)@ i Previous Balance: i insmance: mm. Total: lb) (4) - Pounds sterling Payment Method Prepayment Thank You Ship_pi_ng Details Packing: i Gross Weight {Kym i one box Net weinht mm {Ln Tariff: Carrier: (b (4 13 A Declarations: Matt - .- . .r We certify that this invoice is true and correct. If. If}. a - Fax: 020 3992 7001 Damage. shortage or leakage must be noti?ed in inning to ourselves will'Iil'I 3 days. Non-Delivery within 14 days. Goods remain the property oi Dream Pnarrna Ltd. Until to? payment has been teooiveo. Sonia-oi In our standard conditions orseie. EEOE Company Registration Number1?)? VAT No. (W (4) Director: M. Page 1 of1 FDA 287 Case Document 12-3 Filed 03121111 Page 37 0f 65 ENTRY NUMBER: 112 9992979 0 PAGE: 1 NBR 03(4) INVOICE 09/20/2010 LINE CONSOL. WORKSHEET 05 55 PM ITEMS MARKED 1 0/0- GB LINE VALUE- GBP TARIFF QTY REPORT FDA288 Case Document 12-3 Filed 0321111 Page 38 0f 65 ENTRY NUMBER: 112 3992979 0 PAGE: 1 NBR INVOICE 09/20/2010 SKIPPER DREAM PHARMA LTD 05 55 PM ITEM MARKED REFERENCE INVOICE ITEM TARIFF COUNTRY VALUE-GBP MARK NUMBER OF ORIG. RATE OF DUTY 1 1 GB Q: (2) (ALL END OF REPORT Ht FDA 289 Case Document 12-3 Filed-03i21l11 Page 39 of 65 ?aoio 12:37 From: To: (bf: 174:; . Thiopcniai injection - electronic Medicines Compendium - print fri ndiy Archimedes Pharma UK 250 South Unit Way, Green Park, Reading, R62 6Ut?5, Fax: +44 (0)116 93!. 5056 . notoro you centaet this company: often several companies will market medicines with the some new: ingredient. Please check that this is the correct before contacting them. EM Summary of Product Che ractorIstlos last updated on the OSIOSIZDM b) (4) Thiopental injection 1. NAME OF THE MEDICINAL PRODUCT Thlopental Injection EP 2. QUALITLTIVE AND CDMPOSITIDN Thlopentei Sodium BP Enemy 3. PHARMACEUTICAL FORM Freon-dried Dowder for solution for Injection In a trial. 4. CLIHIEAL 4.1 Therapeutic indications 1 . Thinner-tat I: used for tho induction or general anaesthesia and is alone used as on to provide hypnosis dunno balanced anaesthesia with other anaesthetic agents. Includlno analgesics and made relauants. . 2. Thlenontal is also used as an mm for control of convulsive disorders of various aetiology. Including those caused by local anaesthetics. 3. Thlepental has now been used to reduce the intramnlal pressure In patients with Increased Introcranlal pressure, If ventilation ls provided. [Ideology and method of Intravenous injectlon. Thlooental inlectlon EIP Is adminlsterod intravenously normally as a 2.5% w/v (500mg In 20ml) soiunon. On occasions It may be administered as 5% solution {soon-lg In 10ml). The Intravenous Injection preparation should be used after reconstitution of the sterile powder with Water for In?ation: usually to produce a 2.5% wiv solution and this should no discarded after seven hours. Use In anaesthesia Hormel dosage for tho Induction of anaesthesia ls loot-no to 150mg injected over to to 15 seconds. if n?cc?l?' a repeat dose of mama to 15mm: may be given after one minute. No I'll-ted dosage recommendations for the inn-avenous Injection can be given. since the dosage will need to be carefullyI adjusted according to the patients response. Factors such as age, sex, end weight or the patlent shouid be taken Into consideration. T'hlopontol sodium readied effective concentrations In the brain within 30 seconds and anusthesio Is normally produced within one minute of on Intravenous dose. 20-09-10 FDA 290 Caz-c: Document I-ii'Ed Udell'll Pa 40 0f 65 12:37 Freon: Thiopentel initiation - electronic Medicines Compendium - print Friendly Page 2 ?1?4 Adult mama to 150m Intravenoosly over 10 to 15 seconds. normally- as a 2.5% wiv solution. A repeat dose or teams to ?ame may be given alter one minute. The Intravenous injection should be given slowly and the amounts given titrated against the par-36M? Million? to minimise the risk or respiratorv depression or the possibility of overdosaqe. The average dose for an adult of trans is roughly 200mg to 300mg (Edits to minis of a 2.5% wiv solution) with a maximum of 500mm Children 2 to 7mm bodeeight. intravenously over to to 15 seconds. normally as a 2.5% wiiv solution. Alrepeat dose of 2 to ?nalist; may be given after one minute. The dose is 2 to 7mg!? based on the patient 5 response. The dose for children should not exceed 'a'mg?tq. ere-war Smaller adult doses are advisable. tree in convulsive states ?JSmo to 125mm {3mis to or a 2.5% solution) should be given as soon as possible after the convulsion begins. Further doses may be resulted to control convulsions followine the use of a local anaesthetic. Other regimens. such as the use or rectal diateparn. mav be used to control convulsive states. ?so In neurological patients with raised Jamar-ta! pressure Intermittent bolus injections of 1,5 to limping of bodyweloht may be given to reduce elevations of lob-acranlal pressure if controlled ventilation is provided. 4.3 Contraindications ls contraindicated in respiratory obstruction, acute asthma, severe shock and mvotonlca. Administration of any barbiturate is contraindicated in Care Should also be exercised with severe cardiovascular diseases, severe respiratory diseases and hypertension of varlous aetloiogv. Patients with hypersensitivity reactions to barbiturates. 4.4 Special inventions and precautions for use Special care is needed In administerine titlopontal to patients with the following condidonsn hvpovoiaemia, severe haemorrhape, burns. dehydration. severe anaemia. cardiovascular disease. status asthmotlcus. severe liver disease. mvasthenla gravis and muscular adrenocortical insufficiency {even when controlled by cortisone). cacheuia and severe toxaomla. raised intracranlal pressure, raised blood urea. raised plasma potassium. metabolic disorders e.o. thvrotoxicosis. mvaoedema, diabetes. Thiopentai may precipitate acute clrculotonlr failure in patients with cardiovascular disease. particuiadv i constrictive Thlopcntal can cause respiratory depression and a reduction In cardiac output. Headache is also reported with the use or barbitumte anaesthetics. Reduced doses are recommended in she-alt, dehydration. severe anaemia. hyperitalaemla. tmaemia, myxoodema or other metabolic disorders. Thlopental sodium is metabolised primarily by the liver so doses should be reduced in patients with hepatic impairment. Reduced doses are also indicated in the elderly and In medic ocument.aspx?documentid- i 4338dtcomp. .. 20-09- I FDA 291 Case ?Document 12-3 Filed'03i21i11 Page 4I"of"65 eo-sEP-eeie 12:37 From: To (4) Thiopental Injection - electronic Medicines Compendium - print friendly - Page 3 of 4 patients who have been premeditated with narcotic analgesics. T'hiopental has been shown to Interact with suiphai'urazole. Reduced Initial doses may be required to achieve adequate anaesthesia. but repeat doses may also be necessary to maintain anaesthesia. increased doses may be necessary in patients who have either an habituation or addiction to alcohol or drops or abuse. Under these circumstances it is recommended that supplementary analgesic agents are Acclduntal lntra-arterial injection of thiopcrital causes seyere arterial spasm and an intense burning pain around the Injection site. In the case or accidental intro-arterial Injection of thlopentai the needle should be left In-sltu so that an Injection of on antispasmodlc, such as papaverlne or prllocalne hydrochloride may be elven. Anticoagulant therapy may also be started to reduce the risk of thrombosis. Thlopontal injection should be used with caution in patients With adrenocortical ?51""de c" "it? lntracranial pressiire. 4.5 Intonation with other medicinal products and other forms of interaction Thlopontal has been shown to Interact with suiphafurazole. It should be noted that thlopentai will interact with beta-blockers and calcium antagonists causing a fall In blood pressure. The sedative properties or and analolytics may be potentlated by thiopentai. 4.s Pregnancy and lactation Thlopcntal readily crosses the placental barrier and also appears in breast milk. Therefore. breast-feeding should be temporarily suspended or brass: milk expressed before the Induction of anaesthesia. it has been shown that thiopental can be used without adverse effects during pregnancy although the total dose should not exceed 250mg. However. when considering use of thiopentai the clinician should only use the drug when the expected bene?ts outweigh any potential risks. Effects on ability to drive and use machines Post-operative vertigo, dlsorionoation and sedation may be prolonged and out-patients given tl?ilonentei should therefore be advised not to drive or use machinery. especially within the ?rst 14 to 36 hours. 4.5 undesirable enacts L?w?s?al Bpa?m may occur, together with coughing or sneezing. during the induction procedure. For this reason It is not advised to use thistlental alone ior pororal endoscopy. causes local tissue necrosis and severe pain. This can be relieved by application of an ice pool: and local injection of hydrocorrlcone. The 5% wiv solution is hypertonic and may cause pain on Injection and thrombophlebitis. Allergic reactions. skin reactions and hypersensitivity have been rarely reported. Bronthosposm. respiratory depression and myocardial depression or cardiac may occur. Overdose Overdosago produces acute respiratoryr depression. hypotenslon, circulatory failure and apnoea. Treatment must be artificial ventilation, lowering of the patients head and infusion of plasma volume expanders. 5. PROPERTIES 5.1 Pharmaeodynamic properties Thlopentai is a short-acting substituted barbiturate that Is more lipid soluble than other groups of barbiturates. The drug reversibly depresses the activity ofali tissues. The CNS Is partlcuiariy sensitive and aginally a general anaesthesia can be achieved with without significant effects on peripheral U65. 43 3 20-094 ii FDA 292 Case Document Paw-17-42 01? 12:33 From: Toi (bl p.414 Thlopcntal injection - electronic Medicines Corn pendiurn - print Friondiy Page 4 of 4 Thloponral acts through the CNS with particular activity In the mecencophalie reticular activating sysoern. Tho bamlturatoo oxor't tli?'oront effects on synaptic transmis?on, mostly those depondent on Golan. Autonomic ganglia of tho poripherai nervous system are also depressed. 5.1 Paarmneeiilnetlc punctual! Following Intravenous administration. unconsciwsnoas occvro within 30 second: and will be continued for 20 to on minutes after a single dose. Rapid uptako occurs: to most vascular areas or the brain followed by redistribution into other tissues. Thiopental is strongly bound to plasma protein, which impairs excretion through the kidney. ?10 Mllb??t? aro um?? imitative anti are then curated. ?I?hiopental, thoroioro, whilst having a short duration of action, may have a long elimination phase. 5.3 Preclinical safety data There art: no pro-clinical date of relevance to the prescribar which are additional to that included in other sections of the Summary of Product Chem-mom. E. PHARMACEUTICAL PARTICULARS . 15.1 List of enclolento None 5.2 lncompa?hiiltios Solutions or thiooental Injection have a pH of 10 to :1 ?not are strongly alkaline in order to maintain stability. Solutions are incompatible with acid, acidic salts and solutions sum as pethiolne, morphine and pmmetheaino 48 months. 6.4 special prucautlol?m for aterane no not store above Store intonation? solution tie-ohm to on: 'm an million out. use within 7 hours. Use once following reconstitution and discard any residue. Nature and contents or oontainor 20ml Type clear glass vials with 20mm bromyloutyl caoutchouc sliiconltoo rubbor oloSuroe. Pack site: 25 trials per pack. I o.a one" life 6.6 Special precautions for disposal and other handling Not applicable. 1. MARKETING AIJTHORISAWON HOLDER Link Pharmaceutloalc Limited. Bishop-t Wealri House. Albion Way. Homharn, Wes: Sussex RH 1.2 tail-l. UK B. MARKETING AUTHORISATIGN NUMBERS) PL 12406f?014 3 April 1999 ?no. BATE BF OF THE TEXT January 2003 1 1. Legal Category I I 9. DATE OF FIRST aumomsauoumlmewaa on THE anti-tomsio'rtou POM I umonlospit 'PdocumontidI-i 20-094 0 FDA 293 Case Document 123 Filed 03l21l11 Page 43 of 65 I (4) Manifest report 51'4"" HETFF genFDA 294 Case Document 12-3 Filed 03I21I11 Page 44 of 65 LOCATION HEM NEW INTERNATIONAL AIRBILL ENTRY 112-89929795?0 (4) FDA 295 ATTACHMENT FDA 296 STATIC 0 TEXAS COUNTY OF Before me, the undersigned authority, personally appeared_, who, being by me duly sworn. deposed as follows: My name is 1 am over 2] years ofage. ofsound mind. capable of making this af?davit, and personally acquainted with the facts stated herein. 1 am currently employed as the and have held that position since Prior to that was the I held from and prior to that, I was the from . My office is located in - owns 1 l3 Controlled Substance Registration Certi?cates from the Drug Enforcement Administration. for use at 109 facilities that rovide housing and medical care to almost 148.000 offenders in the state of Texas. Each facility has an intirmary to provide medical care and medication to the offenders housed at that location. The state of 'l?exas spent approximately $45 million in fiscal year 2015 on pharmaceuticals for use by the offender population housed in the l09 facilities. The pharmaceutiez-tls include controlled substances to be used as prescribed by physicians. ?l"urther aftiant sayeth not." med notarv ublie on this th AND BEFORE the undersi 5/ .. '3 day ol .;0l6. NOTARY STATE OF TEXAS FDA 297 ATTACHMENT FDA 298 STATE OF TEXAS C01 WALKER Belore me. the undersigned authority, personally appeared who, being by me duly sworn. deposed as follows: My name is? I am over 2l years of age, ot sound mind capable 01 making this affidavit and )ersonall ac uainted wi n. I am currently employed as the and have held that position a )osition I held fron Prior to that was the and prior to that was the located in My of?ce is 'l?he execution protocol controlling lethal injection procedures requires strict adherence by all involved in the execution process. The protocol provides the details ol?the execution process, including the handling, transport, preparation. and administration ofdrugs. execution protocol currently requires the use ol'pentobarbital. l-lowever, in order to ensure ability to carry out its statutory mandate, onsiders alternatives to pcntobarbital, including tltiopental sodiumt as a contingency should find pentobarbital unavailable. If-ereated a new execution protocol involving thiopcntal sodium, the process would continue to be strictly controlled by the protocol and opportunities for discretionary use ot?tlte drug would be unavailable and prohibited. "Further al'liant sayetlt not." ublic, on tltisthe 27de SWORN AND BEFORE Mli, the undersigned notar or .2016. mm" NOTARY PUBLIC STATE OF TEXAS MY COMM. EXP. 07-23-2017 FDA 299 ATTACHMENT FDA 300 OF TEXAS COUNTY OF WALKER Before me. the undersigned authority, personally appeared? who, being by me duly sworn, deposed as follows: My name is I am over 21 years ofagc, ofsound mind. capable ofmaking this affidavit. and personally acquainted with the facts slated herein. 1 am currently employed as the and have held that position since . Prior to that I was the a )osition I held from and prior to that, was the from . My office is located in During the past ten years, -has executed 182 offenders by administering lethal injection. It. is likely that-will continue to execute additional offenders through lethal injection, on a recurring and continuing basis, for the foreseeable future. 'l'here currently are 244 offenders who have received a capital sentence in-and who are awaiting execution through lethal injection. Eight offenders are scheduled to be executed in the remainder of2016. Based on the average number of scheduled executions in the last ?ve years, more than 20 will receive execution dates next year and subsequent years thereafter. Unless a court intervenes, these offenders will be executed through lethal injection, as directed in their capital sentences. Because it is likely that-will continue to execute additional offenders on a recurring and continuing basis for the foreseeable future,-needs a continuing and recurring supply of drugs to be used for lethal injection. -has previously purchased and used thiopental sodium in numerous executions. - is preparing for a contingency in which -may once again utilize thiopental sodium in executions and will do so when necessary releases its hold on the purchased thiopental sodium that is being detained by FDA. For the reasons stated in - two submissions to FDA in this matter. has concluded that it is lawful to import the thiopental sodium entry current] being detained by FDA. Because there are currently no domestic manufacturers of that to continue importing thiopental sodium from the same foreign source. and with the same labeling, as the entry that FDA is currently detaining. Based on actions thus far as well as applicable import procedures-has a reasonable expectation that when it imports future shipments ofthiopental sodium from the same source and with the same labeling, will take the same actions taken on the detained entry, based on the same legal analysis, unless a court intervenes. lf FDA were to refuse admission into domestic commerce of the drugs currently being detained,-currently intends to seek judicial review ofthat action. -has requested FDA to retain custody of the detained drugs under conditions that preserve their integrity pending Page 1 of2 FDA 301 completion ofany judicial review. i1~ refuses the entry but denies the request to retain custody,_has requested to confirm that -will be I,iven 90 days to export the drugs to the original foreign distributor. Under those circumstancesi will request the foreign distributor to hold the drugs outside the United States pending the conclusion ol'judicial review and (assuming a l?z-ivorable court ruling) re-import the very same drugs. ?l?urther al?tiant sayeth not." SW I TO St BEFORE. MP, the undersiuned notarv ublic, on this the day of . 2016. NOTARY PUBUC STATE OF TEXAS MY COMM. EXP. 07-23-2017 Page 2 of 2 FDA 302 REFERENCE 9 From: To: Subject: Date: Santos, Rosa L RE: Extension Request re Entry Thursday, April 28, 2016 4:33:00 PM Good Afternoon ;   The extension was granted until May 20, 2016.   Thanks,     Rosa Linda Santos Compliance Officer 4040 N. Central Expressway Suite 300 Dallas, Texas 75204 214-253-5269 Phone 214-253-5316 Fax rosa.santos@fda.hhs.gov     From: Sent: Thursday, April 28, 2016 1:13 PM To: Santos, Rosa L Cc: Subject: Extension Request re Entry   Hi Rosa Linda   The  is requesting a short extension of time, to and including May 20, 2016, to respond in writing to the tentative determination attached to your April 18, 2016 email.  I would appreciate it if you would please let me know via return email if a deadline of May 20 is acceptable.   Thanks and best regards.    NOTICE: This e-mail may contain information that is privileged or otherwise confidential. It is intended solely for the holder of the e-mail address to which it has been intended, and should not be disseminated, distributed, copied or forwarded to any other persons. It is not intended for transmission to, or receipt by, any other person. If you have received this e-mail in error, please delete it without copying or forwarding it, and notify us of the error by reply e- FDA 304 mail so that our address records can be corrected. IRS CIRCULAR 230 DISCLOSURE: To ensure compliance with requirements imposed by the RS. we inform you that any US. tax advice contained in this communication (including any attaclmrents) is not intended or written to be used. and cannot be used. for the purpose of avoiding penalties under the Internal Revenue Code or (ii) promoting. marketing or recommending to another party any transaction or matter addressed herein. Please do not hesitate to contact me. however. if you have any questions regarding this matter. On Monday, April 18, 2016, Santos, Rosa wrote: Good Morning, Please see attached letter. Thanks. Rosa Linda Santos Compliance Of?cer 4040 N. Central Expressway Suite 300 Dallas, Texas 75204 214-253-5269 Phone 214-253-5316 Fax NOTICE: This e-mail may contain information that is privileged or othenrvise con?dential. It is intended solely for the holder of the e- mail address to which it has been intended, and should not be disseminated, distributed, copied or forwarded to any other persons. It is not intended for transmission to, or receipt by, any other person. If you have received this e-mail in error, please delete it without copying or forwarding it, and notify us of the error by reply e-mail so that our address records can be corrected. IRS CIRCULAR 230 DISCLOSURE: To ensure compliance with requirements imposed by the IRS, we inform you that any US. tax advice contained in this communication (including any attachments) is not intended or written to be used, and cannot be used, for the purpose of avoiding penalties under the Internal Revenue Code or (ii) promoting, marketing or recommending to another party any transaction or matter addressed herein. Please do not hesitate to contact me, however, if you have any questions regarding this matter. FDA 305 REFERENCE 10 WW 1 3? FDA 307 NEW INTERNATIONAL DICTIONARY OFTHE ENGLISH LANGUAGE Slam-uh mutton UNKBRIDGED .3: i. :3 . 5'5. v. I l. .3 5?3 FDA 308 ?11:st- cove- mly 1n terian i'oithe formed iarated inctive :1 took I the i8 w1th ?d Pres- 5 South In doc- ofthe Amermate Vtenan 1899; Inght IY con- mr hold Reaction . preface, pr a?lu'UIl?lc 5" .1317 ?mti?l'VT I Prescribe? (preoskrib?), Lskribd'); .50 praescnbere, Praescri um fr Wm, before berg: to_ write. See 3011132,] 'a?lgitiv'g- Obs. a To describe in adyance' to foretell writing. To before or in from- 2. T0 lay down authoritatively as a guide, 0 rule of action; to impose as a peremptory order; to direct; ordain; as, to regular hours of study 3. To keep within limits or bounds; to restrain; to com Now Rare. ?Prescribed her [the poet?s Muse?s] - 3. and prun?d her tender Wing." 30?? . 4. Law. To outlaw or invalidate by prescription. 5. Med. To direct, designate or order the use of, as a remedy; as, the doctor prescribed qmmne. --, Intranm?tz?ve: 1. To give directions; to dictate. A forwardness to prescribe to their opinions. M. 2. Law. a To claim a title to _a thing. by right of tion. To become by prescription mvahd or unenforce- able; as, certain rights prescribe 1n twenty years. 3. Med. To write or give medical prescriptions. Syn. Limit control, order, guides pre-scribe' prascrip'tion etc. Erron. vars. of PBOSCRIBE, PROSCRIPTION, etc. Obs. pro-scrib?er n. One who . (pr??'oskript?; prE?sk?p?t}, adj- pram-rp- (us, Dast part. of praescribere; . F. pr . . Pur- 50111319.]. Ordamed or appointed by authonty; prescribed: e?skr escri um: .- - t. 'Yzhat whi 'is rescribzg; as: :?Direcnon; rule; acre 0 . (pron. A medical Drescdp?m- n. 0? 5?33? pi sitibiei b?l ad [Cf -eprort- 3 bleJ . epending on, orpderived frog), mum; be prescribed; subject to prescription. MMp'tion (4114311). ER, fr. L. In in; urrer, mmaiption 611qu . '4 . pgaeocn?bere. 1. A gr d?qtatma; thing prescribed; direction; preempt. 3 Mlzfiwttifn; Obug. gt aRmemcme. . om LW- .3 A plea, or clause, placed at the limiting the scope of the . ?vx w-nzassg, (In n. One who recommences. recon (rek o?mend?), give in Charmindarej 1. 1?0 commit; to mend. go, 0 001181811; to entrust; now usually com- Recommended by the brethren unto the grace of God. Acts xv. 40. 0 praisegnow specif., to make a commendatory state- ment concerning (a person or thing); as, his professors will In; recommend 1t. .0 commend, or bring forward explicitly, as menting consrderation, acceptance, adoption, election, or the hke; to present as one?s advice? one?s choice or as having one?s approval or support; to offer or suggest with favoring re - resentatlons; as, to recommend a newcomer to one?s frien a efendent to the mercy of the court, the appomtment 0 rown to the postmastership. To make acceptable; to attract favor to; as, his manners recommended him. 5. To advise? counsel. ?He recommended that the whole disposition .the camp should be changed.? W. I I To make a recommendation. rec?om-mend' n. RECOMMENDATION. Colloq. re?-com-mend? v. t. See an, 2. ad]. That may be commended or recommended. (-bn'm rec?om-mend?a-ble-ness, n. rec/om-mend - rob! a v. rec?oh?i-?menoda?tion n. recommen- datio; cf. F. recommandatzonJ 1. Act of recommending. 2. State of being recommended; esteem; favor. Obs. . 3. Something which recommends or. commends; as, his only recommendation rs his personality; spent, a state- ment letter, or the hire, declanng what one recommends or expressing commendation; as, the mayor would make no recommendations; 3. candidate supphed recom- ons. . zeadghing, course of procedure, or the hke, recommended. or, esp. Bret, ~ter-I) ?f1- 1 Serving to recommend, commend, or attrac fedorable attention; as, letters recommendatory; recom- manda' tor features. . . 2 O?ere as a recommendation; advrsory 1n nature, as, ?gdn?h?nlh? . 1"?er inm. 151" 2 14.1..uraualulh or 1,1111] nlmiously sweet; saccharine; hit-"1. 10 l111w?1111e1l; as 11 sawing] smil 1: 1111mm: r, manner, or 3. Fund of sugar or sweet Ullimm; as, S1 1ccl1arine. Ant. Sour, acid bitter- :l smnt?lh-IW sng' ar y, 11., pl. 4111111130 iz). Asuuar factory; a110,! aeuul' camp su'gent (s?'jE?ntj, adj. L. suqens, ?mite, Pres. 0' sugere to suck Z.ool uctorml. ??10 maimed su-ges'cent [1.11111 ereto?ck+3o Hilluous; HS, ~escent.] Of, pertaining to, or adapted or,auc DI: "?monds sug gest' (su?jEst'; sit-5651'; 143; 277). ?01; "4 suggestufs, past part. of wagon" to ?ipu under, furnis sun est sub un der ?u aerttoafd was to bring. See JEST. Transitive:1 0 ??ag into one ?s mind; to arouse or awak 1on, 0 ton is). means, the thought or feeling of, the desireior,:on1n tion to commit, the will to do, or thei i kc; as, I ?fig: trees (Euca- harm by suggesting evil; now, often to propoaetonu to mention as a hint, a possible exp anation or mum: as, to suggest a walk 1n the country, a moratorium; to lug- aest that a change of government 13 necessary. Why dost thou then suggest to me distrust? Mata-ta. 2. Of things, to call or bring to mind by wayof process, as a train of thought or the association 0 to lead f:naturalli or logically to the thought etc., of; as, smo suggests ?re; the images i3" ?x roso? ?suggest the beauty of contemplation; as an incentive, motive, inspiration, or rea eaon f?ot ?rt the crude success of? ?Waverley? suggested to Scott contiga'lna ies of novel-griting. lb 11 onvenience next suggest: ow airs. .. 3. To say or advance by way of a succestion. 4. To affect by means of hypnotic suazeation. Feetish leaves ing in which ., a shed 1n maple sugar 1; process of mug of nelgh- malre merry. ped rough - 5. Obs. a To seduce; to prompt to evil; to to t. What Eve, what serpent, hath mauled thee?? To bias mentally by a suggestion. . 4.. hear, usually I To make or advance a I Ii 6! gestionr to tempt; to arouse ideas, 6:th 1f, A bill tion, insinuation,e etc. 4 and usually Syn. -- Prompt, ,lifnsp'llte; imply. ?ii. 1 -- sun set itael 0 enter into 9 mind Fonoidal; as, entertained or accepted. 9? . no 3?13 8030,11. A sussestion. Obs. 1 4 ,3 ?gm-11w, See an. lumen. .01. ?me Re. Sp. ar?mo/ lo r?er. - 4* as" "4 444' 4.111: aunt. 1- manor, a; d: ?(Md-ally u. 8.0 machinG. 11:11, ?11009); Maori-?aw .