April 20, 2017 ELECTRONIC MAIL Re: Entry No.?Thio ental Sodiuml imposed by that Dear? 1 am writin in res onse to your May 20, 2016, letter on hehall?of the? which responded to the Food and Drug Administration?s (FDA) letter ot'April IS, 2016, settin forth the Agency?s tentative decision regarding the admissibility of Entry Number". That entry consists of 1,000 onc~gram vials ol?a dru roduet labeled as_ ?l?hiopentai Sodium USP), which were offered for importation by on July 24, 2015. ?lms noti?ed FDA that it is importing, the detained drugs for use in administering lethal injection. As we noted in our April 15 letter, for decades, FDA generally exercised enforcement discretion regarding sodium thiopental used for capital punishment purposes. Ref. 7 at 52; see Heckler v. Chaney, 470 US. 821, 835-36 (1985); see also Ref. 1, Ex. 14 at 1-2 (2010 FDA statement explaining that DA was exercising enforcement discretion). In February 201 l, a group of prisoners on death row in Arizona, California, and Tennessee ?led suit challenging release of impo?ed thiopental sodium for use as an anesthetic as part of lethal injection. The plaintiffs argued that FDA acted contrary to law, in an arbitrary and capricious manner, and in abuse of its discretion when the Agency allowed shipments of the misbranded and unapproved new drug thiopental to be imported into the .S. In March 2012, the United States District Court for the District of Columbia granted the plaintiffs? motion for summary judgment. See Beat}! v. FDA, 853 F. Supp. 2d 30 (D.D.C. 2012), (Jf?d inparl, rev in part sub Cook v. 733 F.3d 1 (110 Cir. 2013) The District Court?s March 2012 order, as modi?ed in June 2012, permanently enjoins FDA from ?permitting the entry of, or releasing any future Thiopental sodium is also known as sodium thiopental. In this letter, ?thiopcntal sodium? and ?sodium thiopental? are used interchangeably. 2 To avoid confusion, we have maintained the reference numbers from tentative decision in this ?nal decision. As a result, letter dated April 15, 2016 is listed as Reference 7. Apr1120, 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].? i-gifi'if 1532-2352532 contends that Beaty/Cook was ?\Vlongly decided,? Refbound by the terms of the o1de1 issued by the District Court 111 that case. That o1de1 1equi1es the Agency to refuse admission to import entries of foreign- manufactured sodium thiopental if the sodium thiopental appeals to be an unappioved new d1ug 01 a misbranded drug. See Refs. 4&5. Thetefore, we disagree with contention that FDA has room to exercise disc1etion regarding the foreign-manufactuied sodium thiopental if} wishes to import. We have carefull considered all of the a1 guments and information In the May 20, 2016, letter, as well as previous submissions on behalf of the detained d1 ugs Based on a review of the entire record in this matte1 for the reasons detailed below, we have concluded that the detained d1ugs 1n Entry No - I appea1 to be unapp1oved new d1ugs and m1sb1anded d1ugs within the meaning {1121 U. S. C. 352(1)(l) 355(a). In leaching this conclusion, we reject? assertion in its May 20 lette1 that 3 ?inteipletations amount to a federal ban on use of thiopental sodium for lethal injectionpu1 pose o1 intention to interfere with lawfully conducted capital punishment carried out by lethal injection. As noted below, 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 foreign- manufactured 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 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 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. 331(8). The Act further provides that 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 Act thus does not require FDA to ?nd 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 Act. Continental Seafoods, Inc. v. Schweiker, 674 F.2d 38, 43 (DC. Cir. 1982) (emphasis added); see Goodwin v. United States, 371 F. Supp. 433, 436 (SD. Cal. 1972); see also United States v. Food, 2998 Cases, 64 F.3d 984, 992 (5th Cir. April 20, 2017 Page 3 1995) (FDA ?can pursue the administrative procedures of 381 and simply require reexportation ofthe goods,? even where ?the government lacks the ability to prove a violation of the Act] by a preponderance ofthe evidence?); Sugarmrm v. Forbragd, 267 F. Supp. 817, 824 (ND. Cal. 1967), aff?d, 405 F.2d 1 189 (9th Cir. 1968); March. Group, Inc. v. Shalom, No. 95Civ10082, 1996 US. Dist. LEXIS 4880, *22-23 (S.D.N.Y. 1996) (noting ?the wide discretionary power 1? DA enjoys to determine the factors regarding its decision to grant or refuse admission of imported [fan 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 Sodium USP). On August 5, 2015, US. Customs and Border Protection (CBP) detained the shipment. RefAugust 18, 2015,- through counsel, requested that FDA instruct CBP to lift the detention and let the product proceed to destination. Ref. 1, Ex. 1 1 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 ofit?l)A Action? explaining that lintry- -vas detained and subject to refusal of admission based on the following: the product appeared to be misbranded under 21 U.S.C. 352(t)(1) because its labeling appeared to lack adequate directions for use; the product appeared to be misbrandcd under 21 U.S.C. 352(f)(2) because its labeiing 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 ofthe entry, speci?ed that testimony regarding the admissibility of the entry must be submitted to FDA by September 14,2015. 1d. 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 Refpart of its assertion that ?no deference is due? to ?any of the regulatory or statutory interpretations? in 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 ?appearance? standard does not apply. See Ref. 8 at 8-9. Although we agree with- that some ofthe facts in this matter 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 determination regarding what conditions are suggested in the detained drugs? labeling. April 20, 2017 Page 4 On October 23, 20l5-, 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 personnei. Id. at I. In submitting the written testimonyh also requested that DA transfer the matter to the Director, Ollice of Enlorcement and Import Operations (?0510?) 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 did not intend to transfer the matter to 01310. In a subsec uent telephone discussion with 1" DA counsel on February 2, 2016, 1? DA asked whetheihstill wanted to present information regarding the detained drugs in person. Suhsequentiy, in a series of phone communications on March l, 2016, you stated tha concurred with an approach in which FDA would send a written, tentative decision and provide with the opportunity to respond before reaching a final decision. The Agency set forth its tentative conclusions in a letter dated April 2016. In that letter, the Agency provided- with the )ortunity to respond to the tentative conclusions, either in writing or in a meeting, and assured that the Agency would take any information provided in response to the April i5 letter into account in reaching a ?nal conclusion regarding the admissibility of the detained drugs. The letter specified 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 letter,* through counsel, requested an extension to May 20, which FDA granted. See Ref. 9 at l. -rcsponded 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 Sodium USP). Ref. 2 at 2. The labels on the vials of thiopental sodium state: 1 gm Thiopental Sodium USP Sterile Rx Only manufacturer and distribution services For law enforcement purpose only. Alpt?lZO, 2017 Page 5 'ke Ref. 3 at 23-24. The label bears no other infonnation. Id; Ref. 1, Ex. 3 at t. See also Ref. 1 at 2 (?Aside from the infonnation printed on the label . . . there is no additional labeling accompanying the drug specifying infonnation about its properties or uses?). Stickers on the outside of each box of vials tepeat the information on the vial label. Ref. 3 at 43 The boxes contain no package inseits, lea?ets, or othei materials with dnections foi use 01 wamins about the use of the thiopental sodium. An outside box label lists the as the con31 cc. Id. at 2627.111 addition to the label listing the ceiti?cate of anal sis int enti ocumentation for the thiopental sodium states that it is ?[111]anufact1ned by" if: Ref_ 2 at 4_ Thiopental sodium is a ba1biturate that depiesses newous system function to rendei a person unconsciouslh Ref(Goodman and Gihnan The Pharmacological Basis offhempemics, ed, at 347- -49), which can cause death in a huge enough dose Ref 1, Ex. l6 at 10 (History oi Baibituiates, at 338). As classi?ed among anesthetics, it is an 111113311611- actiug agent. 10?. 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, at 347-349). In addition, thiOpental sodium can produce allergic reactions in some individuals. Id. at 6 (Goodman and Gihnan?s, at 350). It is a schedule controlled substance. Ref. 1 at 2; Ref. 1, Ex. 3. agrees that the detained thiopental sodium is a ding within the meaning of the Act and does not dispute that the detained dings are not the subject of an approved new chug application, an approved abbreviated new drug application, or an effective investigational new (bug application. In fact, there are no DA?approved sodium thiopental products that are cun?ently being marketed for any use.5 4 In its initial submission, aclmowledged that the thiopental sodium is a (hug, because it is intended to affect the structure and function of the body. Ref. 1 at 5 (discussing 21 U.S.C. 321 . C) and stating that ?[t]his second de?nition applies here?). Moreover, in the May 20 letter, epeatedly refers to the detained thiopental sodium as ?detained drugs. See Ref. 8 assist. Pieviously, fo1 example, Abbott Labomtories held an NBA (NBA 11-679) foz Pentothal Sodium (thiopental sodium) Suspension. FDA withdlew that NDA 1n 2001 at Abbott? 1equest because the drug was no longer marketed. See 66 Fed. Reg. 4301? (Aug. 16, 2001). NDA ll-679 remains listed in Orange Book, meaning that FDA has not detennined that Abbott?s thiopental sodium ding product was withdrawn for safety or ef?cacy reasons. Unless FDA makes such a detennination, NDA 11-679 can be cited in applications for approval using the abbreviated pathways established in the Act. April 20, 2017 Page 6 is importin the detained drugs for use in administering lethal injection. Ref. 1, 1311.13 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 in ection, on a r'ecuuing and continuing basis, for the foreseeable ?tture. Ref. 8, Attch. E. ?has p1eviously purchased and used thiopental sodium in numerous executions,? I'd; see - (1150 Ref. 1 Ex. 13 1] S. "c111'1ent execution protocol? mandates use of entoba1bital, see Ref. 8, Attch. howeve1, is preparing for a contingency in which may once again utilize thiopental sodium 111 executions and will do so when necessary if FDA 1e eases its hold on? the detained (hugs. Ref. 8, Attch. RefBound by Judicial Order to Refuse Entry to the Detained Sodium Thiopental If It Appears to be an Unapproved New Drug or Mishranded As noted above, the District Court?s March 2012 order, as modi?ed in June 2012, permanently enjoins FDA from ?permitting the eutiy 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 (hugjf? Ref. 4 at 12; Ref. 5 at 2. We interpret the order to mean what it says: namely, that FDA is required to refuse entry to thiopeutal produced abroad when it appears that the thiopeutal is misbranded or an tuiapproved new ding. argues that, even if FDA concludes that the detained appear to be unapproved new drugs and/01 iinsbranded dru - s, the Agency can and should exercise . eufo1ce1nent discretion to admit Entry Ref. 8 at 13. In particular, contends that the Beirut/C0011 decision ts distinguishable from the plesent circumstances because the parties to that case stipulated that the drugs at issue were unapproved new drugs and nusbranded. But the question here is not whether this case is similar to Beatv/Cook or whether Bengt/Cook is persuasive authority that FDA should follow. Rather, the question is whether the terms of the Bertn1/C00k order cover the circumstances presented in this case. So long as the import entry at issue is ?foreigi manufactured thiopental that appears to be misbrauded 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/Coot was (in View) ?wrongly decided.? Ref. 8 at 13. argument on this ground 18 effectively a collateral attack on the Dishict Court 3 01".de1 But the React/Cook decision cannot be subjected to collateral attack though this proceeding; the order could only be modi?ed through futther judicial action. Until the Court lifts or modi?es its injunction order, that order continues to govern review of thiopental import entries. Sec, 9.3., GTE Stitvmlio, Inc. v. Consmuers Union of?ze US, 445 US. 375, 386 (1980) (?persons subject to an injunctive order issued by a court with jurisdiction 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 injunction order, is without discretion to Aprrl 20, 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. 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 thioental sodium suggests the conditions unde1 which it will be used: fot lethal injection. challenges that tentative conclusion on several grounds. First, FDA may look beyond a product 3 labeling to determine? ?whethe1 an article 13 a ?drug? in the ?rst place. .based on [its] intended use, ?the Agency may consider only statements in a drug 3 labeling to determine whether the drug is a ?new drug? unde1 21 U. S. C. 321(p). See Ref 8 at 6. Based on this assertion, .ji contends that the Agency?s tentative conclusion that the detained drugs are new d1ugs 1s erroneous ?because the Agency reached its conclusion by relying ?urimarily on information that 1s n_ot labeling. See id. (emphasis in 01 iginal) Second, .f'f'g'izii argues that FDA e1 red in concludin_ that the labeling of the detained drugs ?suggest[s] any condition of use.? Id at 7. Third, 1:525}? 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 ?nd scienti?c 11te1atu1e 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 13 not approved for any use appears to be a ?new drug? as defined 1n 21 U. S. C. 321(p) Before turning to speci?c arguments, we begin by addressing the meaning of ?suggested? 1n this Inquiiy. As discussed in greater detail below, under the Act, a ?drug? is a ?new drug? unless, among other things, it is generally recognized among quali?ed experts as being ?safe and effective for use under the conditions prescribed 1ecommended, or $11 ested in [its] labeling? See 21 U. S. C. 321(p)(1) (emphasis added). In this proceeding, has equated the phrase p1escr1bed recommended, or suggested? with the conditions being ?stated? or ?specified? in the labeling. F01 example, in the October 23, 2015, lette1, argued, ?[fjor FDA to establish that . a drug' 13 a ?new drug,? the agency must demonsnate that the drug 18 not generally recognized as safe and effective with respect to specific conditions of use stated in the labeling. When no conditions for use are sos s,peci?ed it is not possible f01 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 te1m ?suggested? 18 p?r.oposed Ref. 8 at 7 n. 10. The three terms ?prescribed,? ?recommended,? and ?suggested? each must be given an independent, non-super?uous meaning. According to Webster?s New International Dictionary April 20, 2017 Page 8 Second Edition Unabridged Merriam Co. 1940)6 (Ref. 10), prescribe means lay down authoritatively as a guide, direction, or rule of action? and, as used in medicine, 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 ?1th 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 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 mor;atorium to suggest that a change of government is necessary. ?See Ref. 10 at 3 (italics 1n original, emphasis added) Thus, ?suggest? is not limited to things that are explicitly stated, speci?ed, or proposed, as contends. ?Suggested? has a broader meaning, and something can be? ?suggested? even if only proposed 01 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 ?1a[id] down authoritatively,? 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 011 the Label of the Detained Sodium Thiopental Suggest Its Use for Lethal Iniection contends that FDA may c0nside1 only statements in a d1ug? labeling in determining wheth the d1ug IS a ?new drug? under 21 U. S. C. 321(p). See Ref. 8 at 6. Based on this asse1tion argues that the Agency?s tentative conclusion that the detained d1ugs me new d1ugs is? ?"e11oneous? ?because the Agency based its conclusion? ?prima1ily on information that is n_ot labeling . . . See id. (emphasis in original).8 We disagree. 6 See, v. Kan Paci?c Saipan, Ltd, 566 US. 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 Act, ?label? means ?a display of written, printed, or graphic matter m1; 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 an of its containers or wrappers? or ?accompanying such article.? 21 U.S.C. 321(m). 3 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 Ap1?1120, 2017 Page 9 Four statements appear 011 the labels of the detained drugs: ?Thiopental Sodium ?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, 21 U.S.C. ?Sterile? on the label of this singlefglass-vial drug suggests that the drugs are likely to be administered by injection, where sterility is critical. i has acknowledged, thele are several well- known uses of thiopental sodium. See Ref 8 at 7. Curiently, one of the best- known uses of thiopental sodium is fo1 lethal injection, most often fo1 anesthesia in multi- chug 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 Stow 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 ve1y d1 ug will be used. We do not agree thatil position is cor,1ect but it is not necessary to addless it because the labeling of these detained drugs does in fact suggest their conditions of use. 9 In fact, if the detained drugs me not presc1iption 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). 1 See, Glosstp v. Gross, 135 S. Ct. 2726, 2732 (2015) (?By 2008, at least 30 ofthe 36 States that used lethal injection employed? a ?three-drug protocol? for lethal injection that included sodium thiopental); Baze v. Rees, 553 US. 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 ?led 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, (describing States? use of thiopental sodium in both three-drug and single?drug protocols); Jennifer Horne, Lethal Injection Drug Shortage, COUNCIL or GOVERNMENTS (Feb. 17, 201 1), 4.aspx; Emma Marris, Death-r0111 drug dilemma, NATURE (Jan. 27, 2011) (available at 1/1 10121/ full/news.201 1.53.11tml); Jennifer Sullivan, Killer on Death Row 16 ?72 Years is Executed, Seattle Times (Sept. 10, 2010) (available at seattle-news/killer-on-death- row-16-years-is-executed). Page 10 Death ofLei?hai Iiyectz'on, 348 2670 (2014), and was used by Texas as part of a three-ding combination f01 many yeais. does not dispute that this 13 a widely-iecognized use of the ding, but notes that ?thiopenta sodium may be used for a variety of diffe1ent puiposes othe1 than lethal injection.? Ref. 8 at 7. In padloular, has asserted that ?[t]he standard reference source for pharmacology indicates that sodium thiopental is a barbiturate that produces lulconscionsness and anesthesia? and that ?[t]his effect is well known; the d111gl1as been used for pinposes of anesthesia since before the Act] was enacted in 1938.? Ref. 1 at 4 n2. Because there are possible purposes for sodium thiopental other than use in lethal injection, contends ?the drug?s name does not suggest any paiticulai condition of useding must be fo1 all of the conditions of use suggested 111 its labeling,12 and, as discussed below, the detained sodium thiopental is not undei any conditions of use. In any event, here the fomth statement on the detained dmgs? label? law e11fo1ce1nent pinpose only,? in combination with the name of the chug and othei statements ?suggests? that the lS fo1 use in lethal injection 3: implicitly aclmowledges as much when it a1',gues ?The ?law enfmcenient pinpose only legend iovides a wanna not to use the pioduct f01 any medical punaose. Id. (emphasis Cadded). Because, asi notes, the ?law enforcement pinpose only? legend conveys that the dings are not to be used for any ?medical puipose? - that is, not for their anesthetic or barbitiu?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 111 the tentative decision, the Agency 3 intelpretation of the detained dmg? 5 use is continued by 33.35.25' submissions See, e. Ref. 8_ Attch at execution pictocol cunent requnes the use ofpentobaibital. Howevei. con31de1s alternatives to pentobaibital, including thiopental sodium, as a contingency should 3.1253" find pentobarbital unavailable?); Ref. 8, Attch. at 1 is piepaiing fo1 a contingency in which nay 11 Michael Graczyk, Execution Drug Cost Quadnq?esfor Texas Prisons, USA Today (Aug. 15, 2014) (Texas used ?three-ding combination of sodium thiopental, pancuroniuni bromide and potassium chlon'de? until Hospira Inc. stopped production of sodium thiopental) (available at lS/texas-execution-ding- costs/141155950; ems Moi? Soon Change the Way it Erecutes Prisoners, Dallas Morning News (Feb. 3, 2011) (sodium 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 5 ?has previously purchased and used thiopental sodium in numerous executions?). Untied States v. .411 Article of Neo- Terramycin Soluble Powder Concentrate, 540 F. Supp. 363, 379 (ND. Tex. 1982) ?nding that a dung is not generally recognized as effective for one or more of the label claims would result in a detennination that the product is a new drug, even if it is assumed that it is generally recognized as effective for the remaining label claims?); see also United States v. An Article of Drug. . . Qtriitag/me, 268 F. Supp. 245, 243-49 (ED. Mo. 1967) Apr1120, 2017 Page 1 1 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 Ref. 1, Ex. l3 11 5 .15 has previously purchased and used thiopental sodium in numerous executions before it became commercially unavailable to correctional facilities for such purpose? and 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 553;ng contention that the Agency 1s relying? ?primarily on information that rs n_ot labeling to conclude that [the detained drugs] are ?new drugs. Ref. 8 at 6 (emphasis 1n original). In particula1, points to the tentative conclusion? 3 citation of two court cases and several articles. FDA d1 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, 1er on ijfg?ifgf supporting affidavits as part of the Agency?s determination of the? new drug? status of the detained d1u.gs Instead, we simply note that the interpretation of the labeling of the detained drugs as suggesting use of those drugs' 1n lethal injection is c?onf1rmed by? own statements 1"ega1ding how it plans to use the d1 ugs C. The Act?s De?nition 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 d1st1 ibuted in interstate commerce, unless it satis?es two 1'equi1'.ements 3 First, it must be generally recognized among quali?ed expe1ts as being safe and effective ?for use under the conditions plescribed, recommended 01' suggested 1n the labeling thereof.? 21 U.S.C. 321(p)(1), 331(d), 355. Second, even ifa drug has become 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. ?3 The definition of ?new drug? also contains a limited exception for grandfathered d1ugs. See 21 U.S.C. 32l(p)(l) (a drug that does not meet that section?s ?generally recognized? standa1d ?shall not be deemed to be a ?new drug? if at any time prior to the enactment of [the 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 Act have been interpreted very narrowly. See, e. 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 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 ofDrug. . . 5,906 Boxes, 745 F.2d 105, 13 (lst Cir. 1984). has not claimed, 1101' does FDA believe, that these provisions apply to the detained sodium thiopental. 14 FDA recognizes that health care professionais may choose to use approved drugs for unapproved uses. FDA generally does not regulate the conduct of health care professionals in 1. General Recognition of safetv and Effectiveness General recognition of effectiveness requires a three-pronged showing. Fig, there must exist a body of evidence that would at least be suf?cient to obtain 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 Ofth?ttg (Fiorinat), 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 atso United States v. Undetermined Quantities of an Articte (Anttcort), 709 F. Supp. 511, 514 n.2 (D.N.J. 1987), 857 F.2d 1464 (3d Cir. 1988). The A'ct de?nes ?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. Heckier, 787 F.2d 147, 151 (3d Cir. 1986). Second, the investigations must be published in the scienti?c literature so that they are made generally available to the community of quali?ed 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 ofVarions Articies . . Eqnidantin Nitrofttrantoin, 675 F.2d 994, 1001 (8th Cir. 1982); Premo Pliarm. Labs, Inc. v. United States, 629 F.2d 795, 803?04 (2d Cir. 1980); United States v. Sene Eleetnosynary Corp. Inc, 479 F. Supp. 970, 977 (SD. 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 AIternatives, 145 F. Supp. 2d 692, 701 (D. Md. 2001) (absence of literature establishing the safety and ef?cacy of the product is proof that the requisite general recognition does not exist). M, there must be a consensus among the quali?ed 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, Tri?Bio Labs, Inc. v. United States, 836 F.2d 135, 141 (3d Cir. 1987) the unawareness of the drug product by experts generally or a genuine dispute among quali?ed experts regarding a drug product?s safety and effectiveness preclude[s] its qualifying for exclusion as ?generally recognized?) (internal quotation omitted); eqtidantin, 675 F.2d at 1000-01 (requiring ?general consensus of expert opinion in favor of? the drug); Preino Panama, 629 F.2d at 803 (?genuine dispute among quali?ed 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 ridedicated?, 513 F.2d 1 127, 1128 (9th Cir. 1975). prescribing or using a legally marketed drug for an unapproved use within the practice of medicine. 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. [221, 1223-24 (ED. Mo. 1989); United States v. 118/100 Tablet Bottles, 662 li?. Supp. 5! l, 5I3-l 4 (WJ). La. see also United States v. Articles QfDrag. . . Promise 'lbothpaste, 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 dtug? if the drug has not been used to a ?material extent or fora material time under such conditions.? 2i .S.C. See Hwtson, 412 US. at 63! drug cannot transcend ?new drug? status until it has been used ?to a material extent or for a material timc??); United States v. Articles ofDrug. . . 498 F. Supp. 424, 432 (stating that a drug is a ?new drug? even if recognized as unicss it also has been ?used to a material extent or for a material time? under non- investigative conditions?), sub nom. Appeal Labs, Inc, 672 F.2d 902 (3d Cir. 198]) and alfa? sub nom. United States v. Articles of Drug, 672 F.2d 904 (3d Cir. I98 I). The Detained Drugs Appear to Be ?New Drugs? In our April l5 letter, FDA explained that there is no approved new drug application for the detained drugs FDA also explained that the detained drugs are not Speci?cally, FDA explained that the Agency?s searches ofthe ublished scientific literature found no adequate and well-controlled trials evaluating? thiopental sodium for use as part of a lethal injection or, for that matter, any other use. FDA therefore tentatively concluded that the detained thiopental sodium is not for use in lethal injection. in its submissions oes not claim that an adequate and well- controlled trials cvaluatin thiopental sodium have been published in the scientific literature. Nor does appear to ar ue that the detained drugs are actually under conditions of use. instead, contends that the Agency should not have limited its search of the ublished scienti?c literature to studies invoivang?mspami product. Ref. 8 at .2. we disagree, at, as iscusse ow, tie pomt Is moot 10th because there are no published adequate and well-controlled trials evaluating any manufacturer?s sodium thiopental for use in lethal in'ection and because there is no evidence in the record that? has marketcd- (thiopental sodium USP) to a material extent or fora material time. I. 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 (hugs 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.? Ref. 8 at 8 (emphasis added). [nstead,_argues, often establishes general acceptance [sic] of safety and effectiveness with respect to active ingredients (whose ?nished dosage forms have speci?c required labeling) and not with respect to finished Page 14 dosage forms manufactured or distributed by a particular company. See genera/1y 21 C.F.R. 331-358.? Id. We disagree. It is well settled that the Act?s de?nitions of ?drug? and ?new drug? apply to the drug product, 15 notjust 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 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 de?nition (?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,? notjust its active ingredient. Id. at 457; see also id. at 459 (?The term ?drug? is plainly intended throughout the 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 Id. at 461. Because the Generix Court held that the word ?drug? in the ?new drug? de?nition refers to an entire finished drug product, including excipients, and notjust 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 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 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 (Amrcorr), 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 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 CPR. 314.3. Apr1l20, '20 1.7- Page 15 Anucort and adequate and1 well- controlled studies demonstrating that the othet drug and Anucort ale bioequivalent. To determine status for the detained thiopental, the speci?c 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, notjust their active ingredients are fo1 use unde1 the conditions suggested in their labelin- it was a 10 date for FDA to sea1ch 1?01 adequate and '3 well- contlolled clinical t1ials thiopental sodium 1n the published scienti?c lite1".atu1e FDA 5 searches 1dent1?ed no such studies, nor have any been i-i-lfi And, as discussed above, In the absence of such studies, it is not possible f01 the detained drugs to meet the gene1al recognition? standaid. We do not agree that FDA ?often establishes general acceptance [sic] of safety and effectiveness with 1espect to active ingredients (whose ?nished dosage f01ms have speci?c required labeling) w- and not with 1espect to ?nished dosage forms manufactured o1 distributed by a particulal company. See gene1 ally 21 C. F. 331 -358 Ref 8 at 8 cites a portion, but not the entirety, of the legulations established as pa1t of the ove1 -the counte1 (OTC) Ding Review, a 1eguiatory system speci?c to nonpresciiption d1ugs. Thus, presents an incomplete picture. In order to be and not misblanded, each individual nonprescription diug product iegulated under the OTC D1ug Review must comply with the gene1al conditions set forth in 21 C. F. R. Part 330 (and 0the1 applicable legulations), as well as with the specific conditions set fo1th1n the applicable OTC d1 ug monograph (the 1egulati0ns to which refers, i 21 C. F. R. 331 ?,358) which include speci?c OTC uses of active ingredients, along with other pa1ameters, such as dosage fo11n,s dosage route of administration, and the associated directions and warnings that must be included in labeling. See generally 21 C.F.R. 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 for its intended use. FDA has not promulgated any drug monographs that apply to prescription drugs, such as sodium thiopental.? Moreover, as discussed, FDA has not identi?ed suf?cient evidence to show 16 Likewise, passage of the Hatch-Waxman Amendments to the 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 ?nished drug product. Page 16 that the detained thiopental sodium drug products are, themselves, for use in lethal injection (or under any other conditions of use). In sum, the 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 conect that the detained sodium thiopental? 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 well? controlled studies evaluating the use of the active ingredient sodium thiopental for use in lethal injection, eithe1 as a sole agent 01 in combination with other agents, and no such studies were 1dent1fied Thus, it is not possible for sodium thiopental f1om ,01 any othe1 1? 1m to qualify as for use unde1 the cond1t1ons suggested by the detained drugs? labeling. 2. The Manufacturer of the Detained Drugs Has Failed to Avail Itself of Approval Pathwavs Although the detained drugs are not 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)(l), 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 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 ef?cacy for its requested indication. Yet, the manufacturer of the detained drugs has failed to avail itself of any of 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 I12 (thiopental sodium ?easily satis?es the definition of a prescription drug?). Aprll 20, Page 17 3. The Detained Drugs Have Not Been Used to a Material Extent or for a Material Time As noted, to bypass the Act?s premarket approval requirement, a drug must also satisfy the ?material extent? or ?material time? requirement. 21 U.S.C. 32l(p)(2). See Hynson, 412 US. at 631;Arricies ofDrug. . . 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 speci?c to the drug product, ?not merely its active ingredient.? See Generix, 460 US. at 461. Accmding to the registration and listing information I. 1i: start date? for the detai ed 11111 was June 5,2015 Ref. 1 Ex. 2. And, we a1e awa1e of only one p1evious shipment of q? thiopental d1ug product to the United States. 13 The detained drugs have not been used to a mate1ial extent 01 a mate1 1al time, and thus are new d1ugs within the meaning of 21 U. S. C. 321(p)(2). See P161110, 629 F. 2d at 804 (?although P1emo 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?). submitted, the ?ma1keting In short, the detained drugs appear to be new drugs for two independent reasons. They are not for use under the conditions suggested in their labeling. And, even if they were 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 Act The Act mandates that all new drugs distributed in interstate commerce be app1oved by FDA or be the sub'ect of an investigational new chug application. 21 S. C. 331(d), 355(a). As noted, . does not dispute that the detained d1ugs me not the subject of an approved new d1ug application, an apploved abbleviated new drug application, 01 an effective investigational new drug application. Thelef01e, they appear to be unapp1oved new d1ugs. IV. The Detained Drugs Appear to Be Misbranded Under 21 U.S.C. In addition to appearing to be an unapploved new drug, the detained sodium thiopental appeals to be misbtanded because its labeling does not bear adequate ditections f01 use, as 1equired by section 21 U. s. C. ?9 13 That shipment was received before the Beauty/Cook order was issued. 19 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. 352(t)(2). Because the Agency concludes that the detained d1ugs appeal 11napp1oved new d1ugs and misbranded within the meaning of section 352(f)(1) and because willingness to add wa1nings to the detained product, it is not necessaly to reach a final April 20, 207 Page 18 In our April 15 letter, the Agency noted that the thiopental sodium that attempting to import includes no diiections f01 those who would administe1 the drug 01 receive it. Speci?cally, it lists no recommended dose and offers no 1nst1uct10ns 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 ?[t]or law enforcement purpose only,? ?Rx only,? ?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 misb1anded under 21 C. 352(t)(1) because it ?falls within the exemption established by 21 C. F. R. 201.125.? Ref. 1 at 3.20 Section 201.125 ?3 ?law enforcement? exemption, however, occu1s 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 shipped 01' sold to, or in the possession of. persons regularly and lawfully engaged in instruction in pharmacy, chemistry, 01' medicine not involving clinical use, or engaged in law enforcement, or in research not involving clinical use, or in chemical analysis, or dete1mination regarding whether the detained drugs are misb1anded within the meaning of section Ref. 1 at 6 n. 3 (regarding section 352(1)(2), gii-i?i: stated ?Unde1 FFDCA section 801(1)), we further request the opp01tunity to relabel the detained drug to include the wa1nin_s FDA deems adequate. interpreted our tentative decision as a contention that a d1 ug needs to meet all of the requirements of section 201. 100 (which governs presm 1pt10n d1ugs 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 ?ts within neither exemption from the requirement to bear adequate directions for use i i 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 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. Aprll? 20, 2017 I I 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 speci?c 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) (?nal rule); 3026, 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? re?ects a ?conscious decision not to apply the quali?er to the law enforcement exemption.? Ref. 8 at 3. Based on this, 3 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 53:; 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 dictionaly de?nition to argue that ?even if the quali?er [?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, 21 C.F.R. 312.3 (de?ning ?clinical investigation? to mean ?any Apirl 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) (?nal rule), and just five months after testifying before Congress about FDA and State efforts on traf?cking and misuse of amphetamines and barbiturates, see 21 Fed. Reg. 2327; T1 of In and Com? 0! of Narcotics Barbifmafes and Amphetamines Hearings Before the H. Subcomm. on Ways and Means, 84th Congress 1119-1120,1123 (1955) (statement of John L. Harvey, FDA Deputy Commissione1,Nov. 17, 1955) dismisses the Agency 5 discussion of these historical facts as a ?po-st -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 of?cers to administer to people. 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 [adequatehdirections] 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 court-mandated medication as a condition of supervised release). Interpreting the law enforcement exemption as broadly as advocates would exempt those uses. Agency 3 2010 p1ess message document? ?confirms that the detained drugs fit squarely within the Agency 3 1956 statements regarding the exemption.? Howeve1, when FDA spoke of deferring to law enforcement in its 2010 press message document, the Agency was n_ot 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 ?exibility 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 Page 21 that when the Agency added the language it was not intended to extend the exemption to drugs to be administeied to humans.21 Today, FDA continues to believe that the law2 enforcement exemption was not intended to extend to to be administeied to humans.22 Due to the textual and historical context of this exception, the detained (11'1th at issue appear to be misbranded. V. Conclusions Are Not in Con?ict with Congressional Intent and Do Not Lead to Absurd Results . . . offers two additional challenges to inte1p1etation of the Act, based inteipi'etation of 18 U. S. 3596 and a 1937 p1edecesso1, and its contention that decision p1"0duces"ab3111d We address these 1ssnes in tum. A. Interpretations of the New Drug and Misbranding Provisions Are Not in Con?ict with Congressional Intent argues that the Agency 3 interpretations of the new ding and misbianding provisions 0 the Act, as applied to the detained dnigs,? ?con?ict with congiessional intent by restiicting State options in implementing capital sentences.? Ref. 8 at 10.111 paiticnlai, citing two statutes that addiess fedeial death sentences, claims that ?Congress has made clear? that States ate to be pennitted to devise theii own procedtnes ?01 executions ?nee of any fedeial Id. Because in View, FDA 5 i11te1p1etations of the Act amount to a?fedeial ban? on the use 01 so 111111 1iopental for lethal injections, they iinpennissibly 1est1ict State options in implementing capital sentences. Id. at 10-11. This a1 gument both misreads the cited statutes and overstates the effect of determination regarding the detained drags. cites, 18 U.S.C. 3596.23 in 1994. Violent Congress enacted the first statute that . L. No. 103-322, 60002, 108 Stat. l796. This Crime Control and Law Enforcement Act, Pu notes (Ref. 8 at 3) that FDA could have changed the text of the regulation when sepai ating the drug and device exemptions, but it is not stupiising that FDA did not add 01 subtract modi?eis 111 a revision that was simply a tecodi?cation into new sections. tin?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 pinsuant to this chapter [18 U.S.C. 3591 et seq.] shall be committed to the custody of the Attomey General until exhaustion of the procedures 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 supeivise implementation of the sentence in the manner prescribed by the law of the State in which the sentence is imposed. If the law of 1111112017" Page 22 1994 statute states, among other things, that U.S. 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 Punishment Method Act of 1937, 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 mamrer of in?icting the punislnnent 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 manner of in?icting the punislnnent of death shall be by 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 uniform 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 um'estricted 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 Punishment Method Act of 1937 was enacted re?ect a desire to move away from hanging to newei methods of execution employed by states 24 But this does not equate to Congress intending States to develop rocedtnes 101 implementing capital sentences ?ties of any federal inteifeience Ref. 8 at 10.5 In any event, the1e IS no con?ict because 'overstates the scope and consequence of FDA 3 decision 1ega1ding the detained dings. claims that ?intetpletations amount to a fede1al ban on use of thiopental sodium for lethal injection, Ref. 8 at 10-11, but FDA has not made any detennination, one way 01 the other, about which dings may be used for lethal the State does not provide for implementation of a sentence of death, the court shall designate anothet State, the law of which does provide for the implementation of a sentence of death, and the sentence shall be implemented 111 the latte1 State in the mannei p1esc1ibed by such law. 18 U.S.C. 3596(a). 2? See, H. Rep. No. 164, at 1 (1937); 8. Rep. No. 690, at 1 (1937). 25 also points to Department of Justice regulations, which were promulgated in an interim peno prior to the enactment of 18 U.S.C. 3596. See Ref. 8 at 11 11.15. These regulations, 28 C.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. Ftiithetmore, many states have altered their procedures to provide for the use of different d1ugs. See Deborah W. Denno, Lethal Injection Chaos Postw Baze, 102 Geo. LJ. 1331, 1362-66 (2014). Apia-120', 2017 Page 23 injection.26 Instead, FDA has applied the Act to conclude that the paiticular drugs- seeks to import cannot be imported under the Beefy/Cook order. Moreover, the supposed result about which. complains follows directly from the Beauty/Cook order. To the extent objects to that 1?,esult the proper couise is to seek approval by FDA, relief from Congress or the court that issued the Beauty/Cook order or use a drug that has been lawfully imported. FDA cannot ?out a court orde1 at 1equest. For all of these reasons, we do not agree that interpretations of the Act con?ict with congressional intent. B. Interpretations Do Not Lead to Absurd Results 35-2} also contends that internretations should be rejected because they lead to absurd results Ref 8 at 12. In particulal, points to tentative conclusions that status, including for use in lethal injection, must be based on adequate and well- controlled clinical tiials, and that the detained diugs cannot qualify for the law enforcement exemption. Id. In statutory interpretation, ?absurdity is a high bar.? Stevie v. R.R. Ref. Bd., 826 F.3d 500, 505 (DC. 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.? Grif?n 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 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 dif?cult to design appropriate clinical trials, such as testing a treatment for anthrax infection or plague. In such cases, FDA legulations may allow flexibility, or tiials may differ f1 om what scientists genelally envision, but 3 statutory mandate remains the same. absuidity point also fails to grapple with the total absence of scienti?c 1"esea1ch evaluating the safety or ef?cacy of the detained dings f01 any use. In slioit, has not shown that position leads to absurd 1esults. 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 new subject to the Court?s order in Badly/Cook with respect to importation of foreign-manufactured sodium thiopental that 7?6 We also note that 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 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. 119011122701 I 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 drags 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. We 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. Bean), 853 F. Supp. 2d 30, a??d fnpart, rev?a? in par! sub nom. Cook, 733 F.3d 1. has requested that we ?retain custody of the detained drugs under conditions that the? integrity Pending COmPIetion of any judicial review,? or ?con?rm tha will be given 90 days to export the - to the original foreign distributor,? to hold ready for re- importation if a court rules 111 favor. Ref. 8, Attch. E, at 1-2. We confirm 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 11.8.0. 381(a). Sincerel 414,, We; proofs 1M Todd W. Cato Director, Southwest Import District Of?ce i2, . .. .. . Page 25 References Reference 1: Release Request for Thiopental Sodium on Behalf of the {2.31; 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: Af?davit 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 Beary v. FDA, March 27, 2012 Reference 5: Order issued in Beary v. FDA, June 22, 2012 Reference 6: Letter from FDA to 3 June 23, 2015 Reference 7: Tentative Decision to April 15, 2016 Reference 8: Response to April 15, 2016 Tentative Decision on Behalf of the lj . May 20, 2016 i: 3 Attachment A: Documents Pertaining to Federal Execution Protocol Attachment B: Labeling for Beafy/Cook Drugs Attachment C: Affidavit Attachment D: Af?davit Attachment E: Af?davit Page 26 Reference 10: Webster?s New International Dictionary Second Edition Unabridged Merriam C0. 1940)