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Braeburn Inc. v. United States Food and Drug Administration

United States District Court, District of Columbia

July 22, 2019

BRAEBURN INC., Plaintiff,
UNITED STATES FOOD AND DRUG ADMINISTRATION, et al., Defendants, and INDIVIOR INC., Intervenor-Defendant



         Both the plaintiff, Braeburn Inc., and the intervenor-defendant, Indivior Inc., are pharmaceutical companies that manufacture drug products using buprenorphine, a safer alternative to methadone, to treat moderate-to-severe opioid use disorder (“OUD”). All parties recognize the serious national public health problem posed by OUD and the need for effective treatment options for patients with this addiction. Braeburn's product, Brixadi, delivers buprenorphine through an injectable depot that releases buprenorphine over either a weekly or monthly period. In July 2017, Braeburn applied to the Food & Drug Administration (“FDA”) for approval of Brixadi and, on December 21, 2018, received tentative approval for both Brixadi Weekly and Monthly. The critical hitch prompting this lawsuit is that, while Brixadi Weekly could receive final approval once Braeburn submitted proposed labeling to the FDA, Brixadi Monthly was not eligible for final approval until November 30, 2020, upon expiration of a three-year right to exclusivity, under 21 U.S.C. § 355(c)(3)(E)(iii), belonging to Indivior's buprenorphine drug product, Sublocade, which also is an injectable depot that releases buprenorphine over a one-month period.

         Braeburn instituted this action on April 9, 2019 against the FDA and the Department of Health and Human Services, as well as the heads of those agencies in their official capacities, challenging the FDA's determination that Brixadi Monthly cannot be finally approved until Sublocade's three-year exclusivity expires. See generally, Compl., ECF No. 1. Shortly after, Indivior intervened as a defendant. Mot. Intervene, ECF No. 13; see also 1st Min. Order (Apr. 12, 2019) (granting Indivior's motion to intervene).

         Now pending before the Court are cross-motions for summary judgment filed by Braeburn, ECF No. 24, Indivior, ECF No. 26, and the FDA, ECF No. 28. For the reasons explained below, Braeburn's motion is granted and both Indivior's motion and the FDA's motion are denied.[1]

         I. BACKGROUND

         A. Statutory and Regulatory Background

         1. New Drug Applications

         Under the Food, Drug, and Cosmetic Act (“FDCA”), 21 U.S.C. § 301 et seq., new drugs may not be introduced into interstate commerce without the FDA's approval. Id. § 355(a). To obtain FDA approval for a new drug, the drug's sponsor must file an application containing, inter alia, “full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use.” Id. § 355(b)(1)(A). Originally, “all such applications were standalone applications: applications for which the drug's proponent either conducted, or secured a right to reference, all the investigations used to demonstrate the drug's safety and efficacy.” Otsuka Pharm. Co. v. Price (“Otsuka II”), 869 F.3d 987, 989 (D.C. Cir. 2017).

         That changed in 1984 when Congress passed the Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. 98-417, 98 Stat. 1585 (“Hatch-Waxman Amendments”), amending the FDCA to introduce two streamlined paths for the sponsor of a new drug to seek FDA approval. The path utilized by the drugs at issue here, pursuant to § 505(b)(2) of the FDCA, as amended, allows a new-drug sponsor to rely on investigations that were “not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted, ” 21 U.S.C. § 355(b)(2) (codifying § 505(b)(2) of the FDCA), rather than conduct all its own investigations of the new drug's safety and effectiveness. Such an application must meet the remaining requirements codified in § 355(b)(1) and must certify that marketing the new drug would not infringe certain patent protections. Id. § 355(b)(2)(A). These applications may be “submitted for either a change to a previously approved drug or for an entirely new chemical entity, and, in some instances, may describe a drug product with substantial differences from a listed drug.” Administrative Record (“AR”) 412 (sealed).[2]

         2. New Drug Exclusivity

         Permitting new-drug sponsors to rely upon a competitor's safety and efficacy investigations risks free riding. See Otsuka II, 869 F.3d at 990. To forestall that problem, the Hatch-Waxman Amendments also established conditions under which new drugs are entitled to a period of market exclusivity. See Hatch-Waxman Amendments § 103(b). Blending streamlined paths for a new-drug sponsor to obtain FDA approval with exclusivity protections was designed “to balance the need to ‘make available more low cost generic drugs by establishing a generic approval procedure' with new incentives for drug development in the form of exclusivity and patent term extensions.” AR 411 (sealed) (quoting H.R. Rep. No. 98-857, pt. 1, at 14-15 (1984), as reprinted in 1984 U.S.C.C.A.N. 2647-48). Additionally, “[t]hese pathways permit sponsors to rely on what is already known about the previously approved drug, which both allows for speedier market entry than would be possible with a full, standalone 505(b)(1) [new drug application] and leads to increased competition.” AR 411 (sealed); see also Otsuka Pharm. Co. v. Burwell (“Otsuka I”), 302 F.Supp.3d 375, 382 (D.D.C. 2016) (explaining that the Hatch-Waxman Amendments balanced “two competing interests in the pharmaceutical industry: (1) inducing pioneering research and development of new drugs[, ] and (2) enabling competitors to bring low-cost, generic copies of those drugs to market”).

         One form of exclusivity lies at the crux of the parties' dispute. In full, the relevant provision reads:

If an application submitted under subsection (b) for a drug, which includes an active ingredient (including any ester or salt of the active ingredient) that has been approved in another application approved under subsection (b), is approved after September 24, 1984, and if such application contains reports of new clinical investigations (other than bioavailability studies) essential to the approval of the application and conducted or sponsored by the applicant, the Secretary may not make the approval of an application submitted under subsection (b) for the conditions of approval of such drug in the approved subsection (b) application effective before the expiration of three years from the date of the approval of the application under subsection (b) if the investigations described in clause (A) of subsection (b)(1) and relied upon by the applicant for approval of the application were not conducted by or for the applicant and if the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted.

21 U.S.C. § 355(c)(3)(E)(iii) (italics and underlining added). The italicized portion of the statute is referred to as the “eligibility clause” and the underlined portion as the “bar clause.” See AR 414 (sealed); see also Otsuka I, 302 F.Supp.3d at 392 (adopting this naming convention). By regulations not challenged here, the FDA has expanded on the meaning of certain terms in the eligibility clause, namely: “active ingredient” has been construed to mean “active moiety, ” 21 C.F.R. § 314.108(b)(4)(iii), [3] and “new clinical investigation” has been defined to mean an investigation producing results “which have not been relied on by FDA to demonstrate substantial evidence of effectiveness of a previously approved drug product for any indication or of safety for a new patient population” and which are not duplicative of “the results of another investigation that was relied on by the agency to demonstrate the effectiveness or safety in a new patient population of a previously approved drug product, ” id. § 314.108(a). In sum, then, § 355(c)(3)(E)(iii) “confers exclusivity when a pharmaceutical company obtains approval to market a previously approved active moiety in a new formulation or for new purposes, and doing so requires it to furnish new clinical investigations to the FDA. With regard to the scope of drugs affected by the three-year exclusivity period, the FDA may not approve an abbreviated application for the same ‘conditions of approval of such drug in the [first-in-time] application.'” Otsuka II, 869 F.3d at 990.

         3. Orphan Drug Exclusivity

         A second form of exclusivity-orphan-drug exclusivity (“ODE”)-lurks in the background of this case. In 2017, Congress amended the circumstances under which a drug is entitled to ODE. See FDA Reauthorization Act of 2017 (“FDARA”), Pub. L. 115-52, 131 Stat. 1005. For this case, what spurred those amendments matters as much as the current statute governing ODE and, thus, this section addresses both.

         Before a new-drug sponsor applies for approval under § 355(b), the sponsor may ask the FDA “to designate the drug as a drug for a rare disease or condition.” 21 U.S.C. § 360bb(a)(1). If the FDA finds that the drug under development will treat a rare disease or condition, the FDA shall designate the drug accordingly. Id. Rare diseases and conditions are those affecting “less than 200, 000 persons in the United States” or those for which the treatment drug is not likely to be profitable. Id. § 360bb(a)(2). Drugs that treat diseases or conditions of this sort are known as orphan drugs. Consequently, the designation available under § 360bb is known as orphan-drug designation. By regulation, the FDA requires a drug sponsor seeking orphan-drug designation for “a drug that is otherwise the same drug as an already approved drug” to “present a plausible hypothesis that its drug may be clinically superior to the first drug.” 21 C.F.R. § 316.20(a).

         Orphan-designated drugs receive 7-year exclusivity periods under the conditions set forth in 21 U.S.C. § 360cc. Before Congress passed FDARA in 2017, § 360cc provided, with exceptions not relevant here, that if the FDA:

[A]pproves an application filed pursuant to section 355 of this title . . . for a drug designated under section 360bb of this title for a rare disease or condition, the [FDA] may not approve another application under section 355 of this title . . . for such drug for such disease or condition for a person who is not the holder of such approved application . . . until the expiration of seven years from the date of the approval of the approved application.

21 U.S.C. § 360cc(a) (2016). The FDA's implementing regulations direct that, “[u]nless FDA previously approved the same drug for the same use or indication, FDA will not approve another sponsor's marketing application for the same drug for the same use or indication before the expiration of 7 years from the date of” the approval of an orphan-designated drug. 21 C.F.R. § 316.31(a). “Same drug, ” is defined to exclude any subsequent drug “shown to be clinically superior to the first drug.” Id. § 316.3(b)(14)(i). The effect of these regulations is that an orphan-designated drug sharing the same use or indication as a previously approved orphan-designated drug will not receive ODE unless shown to be clinically superior to the prior version. Eagle Pharms., Inc. v. Azar, No. 16-cv-790 (TJK), 2018 WL 3838265, at *2 (D.D.C. June 8, 2018). The purpose of these regulations is to undercut “‘evergreening' of [ODE], ” meaning “the possibility of repeating the seven-year exclusivity period . . . .” Id. (citing Orphan Drug Regulations, 78 Fed. Reg. 35, 117, 35, 127 (June 12, 2013)).

         In 2011, the FDA considered the ODE eligibility of a drug product called Gralise. See Depomed, Inc. v. U.S. Dep't of Health & Human Servs., 66 F.Supp.3d 217, 226 (D.D.C. 2014).[4]A year earlier, Gralise had received orphan-drug designation after its sponsor presented a plausible hypothesis that Gralise was clinically superior to an orphan drug already approved to treat the rare disease Gralise that treated. Id. at 225-26. The FDA approved the § 355(b)(2) application for Gralise the next year, but denied Gralise ODE because its sponsor had not subsequently proven that Gralise was clinically superior to the already-approved drug. Id. at 226. Gralise's sponsor then challenged, as contrary to the text of § 360cc(a), the FDA rule that an orphan-designated drug approved for marketing must prove its clinical superiority to the earlier-approved drug before receiving ODE. The Court agreed, ruling that forcing the sponsor of a drug, which already has received orphan designation and is subsequently approved for marketing, to prove its clinical superiority as a condition of ODE contravened the statute. Id. at 229-33. “[T]he plain language of [§ 360cc(a)] means precisely what it says, to wit, when a drug, like Gralise, has obtained both orphan-drug designation and marketing approval, the FDA is precluded from approving any other such drug for seven years from the date of approval.” Id. at 233. Therefore, Gralise was entitled to ODE. Id. at 237.

         Despite Depomed, the FDA announced that the challenged regulation would continue to be applied. Policy on Orphan-Drug Exclusivity; Clarification, 79 Fed. Reg. 76, 888-01 (Dec. 23, 2014). In 2017, Congress passed FDARA, which amended § 360cc to reflect the FDA's regulatory practice. Consequently, under the new version of the statute, if the sponsor of a drug designated under § 360bb seeks ODE, but the drug “is otherwise the same, as determined by the [FDA], as an already approved or licensed drug for ” and treats “the same rare disease or condition as the already approved drug, ” the new drug's sponsor must “demonstrate that such drug is clinically superior to any already approved or licensed drug that is the same drug” as a condition of receiving ODE. 21 U.S.C. § 360cc(c)(1). “Clinically superior” means “that the drug provides a significant therapeutic advantage over and above an already approved or licensed drug in terms of greater efficacy, greater safety, or by providing a major contribution to patient care.” Id. § 360cc(c)(2). Additionally, and relevant here, FDARA's “Rule of Construction” instructs that “[n]othing in the amendments . . . shall affect any determination under . . . (21 U.S.C. 360bb, 360cc) made prior to the date of enactment of the [FDARA].” FDARA § 607(b), 131 Stat. at 1050.

         B. FDA Approval of Drugs to Treat Opioid Use Disorder

         Opioid use is a public health emergency, with millions of Americans misusing prescription opioids, leading to 33, 091 deaths in 2015 alone. AR 162 (sealed). Two million adults have been identified as suffering from OUD, AR 162 (sealed), which “is a chronic, relapsing disease characterized by the repeated, compulsive seeking or use of an opioid despite adverse social, psychological, and physical consequences, ” AR 158 (sealed).

         One effective method of treating OUD is through prescription opioids themselves. AR 163-64 (sealed). Buprenorphine is one such opioid, which operates as a “partial agonist, ” AR 163 (sealed), by attaching to, and activating, a nerve cell's opioid receptor and creating the same effect as an illicit opioid, thereby relieving the urge to use opioids, AR 164 (sealed). A partial agonist such as buprenorphine has effects like a full agonist, but the effects “are understood to reach a ‘ceiling' at moderate doses, beyond which increasing doses of the drug do not produce the increased effect that would result from full opioid agonists.” AR 165 (sealed). A supposed benefit of that ceiling is to “limit its attractiveness as a drug of abuse.” AR 165 (sealed).

         1. Early Approval of Buprenorphine Drugs

         The FDA first approved buprenorphine in 1981 as a pain medication. AR 164 (sealed), 404 (sealed). In 1994, Indivior obtained orphan designation for Subutex, a sublingual buprenorphine product, to treat opioid dependence, Defs.' Reply Supp. Cross-Mot. Summ. J. (“Defs.' Reply”) at 23, ECF No. 46; AR 66, and then, in 2002, the FDA approved Indivior's application to market Subutex, AR 164 (sealed), 404 (sealed).[5] Subutex was the first approved use of buprenorphine to treat an opioid-related disease. AR 404 (sealed). Since the first approved uses of buprenorphine as a treatment for OUD, other drugs that deliver a sublingual, daily dose of buprenorphine have been approved. AR 164 (sealed).

         2. Approval of Extended-Release Buprenorphine Drugs to Treat OUD

         Although several drugs that deliver a daily dose of buprenorphine have received FDA approval, these products come with certain risks. “[W]hen a partial agonist displaces a full agonist at the receptor, the relative reduction in receptor activation can produce withdrawal effects, ” such that “[i]ndividuals dependent on full agonists may therefore experience sudden and severe symptoms of withdrawal.” AR 165 (sealed). Additionally, the euphorigenic effects of even a partial agonist like buprenorphine are strong enough to create an illicit market. AR 165 (sealed). Furthermore, unintentionally exposing children to buprenorphine may be harmful. AR 156 (sealed), 165 (sealed), 1221. Separate from risks associated with a partial agonist, daily-dosing delivery systems pose difficulties attendant to requiring that a patient self-administer the drug for an extended period at home. AR 1221. Accordingly, the FDA has encouraged pharmaceutical companies to devise methods of administering buprenorphine that mitigate these risks, specifically promoting “well-tolerated, less burdensome treatments, with reduced liability for abuse, misuse, and overdose.” AR 156 (sealed). (a)Probuphine Probuphine, which the FDA approved in May 2016, is one drug that satisfies some of those criteria. AR 404-06 (sealed). Probuphine is a “6-month subdermal implant for the maintenance treatment of opioid dependence in patients who have achieved and sustained prolonged clinical stability on [8mg per day or less] of a transmucosal buprenorphine-containing product.” AR 404 (sealed).

         (b) Sublocade

         Sublocade is a second drug to treat OUD that mitigates some of the risks associated with daily, self-administered doses of buprenorphine. Sublocade is an injectable depot that “provides sustained plasma levels of buprenorphine sufficient to block the effects of exogenous opioids over a minimum of 28 days and is intended for the treatment of moderate to severe . . . OUD in patients who have undergone treatment initiation and dose-stabilization with a transmucosal buprenorphine-containing product.” AR 12. On May 30, 2017, Indivior filed a new-drug application under § 355(b)(2) for Sublocade, AR 1, which the FDA approved on November 30, 2017, AR 1.

         Two new clinical investigations were essential to Sublocade's approval. AR 420 (sealed). The first tested how well Sublocade inhibited the subjective effects of opioid use. AR 31, 407 (sealed). Before participants in that study were treated with Sublocade, they were treated for up to 14 days on 8mg to 24mg per day of Suboxone, a drug that administers buprenorphine sublingually, to achieve dose stabilization, AR 31, which is the brief process of identifying the dose of buprenorphine needed to mitigate precipitated withdrawal symptoms, AR 65, 407 n.21 (sealed). Participants able to complete the stabilization phase received a 300mg injection of Sublocade on the first and twenty-ninth days of the study. AR 31-33. At different days across the study, participants were injected with either a narcotic or a placebo and asked to measure their “drug liking.” AR 33. This study showed that “drug liking” scores for participants receiving Sublocade were not higher than participants receiving a placebo. AR 33 (sealed). The second investigation tested the efficacy, safety, and tolerability of multiple Sublocade injections over a 24-week period. AR 43. Again, participants started on Suboxone for three days, and then dose adjusted for between four and 11 days. AR 43, 407 (sealed). Participants who managed the stabilization phase (and who were not randomly selected for a placebo) were randomized between a path on which they received a 300mg dose of Sublocade once per month for six months or a path on which they received two monthly doses of 300mg Sublocade, followed by four monthly doses of 100mg Sublocade. AR 43, 407 (sealed). This study showed that Sublocade blocked the effects of opioid use for the entire period between doses. AR 45, 408 (sealed).

         (c) Brixadi

         Brixadi is a third drug that treats OUD while addressing the risks associated with daily, self-administered doses of buprenorphine. Braeburn submitted a § 355(b)(2) application in the summer of 2017 for Brixadi, shortly after Indivior had filed its application for Sublocade. AR 142 (sealed), 152 (sealed). Like Sublocade, Brixadi is an “extended-release formulation of buprenorphine . . . for the treatment of moderate to severe . . . OUD in adults.” AR 152 (sealed). Unlike Sublocade, Brixadi comes in both a weekly and monthly depot version. AR 152 (sealed).[6]

         Braeburn's application for approval of Brixadi relied on three of its own clinical investigations of the drug's safety and effectiveness in both versions. AR 409 (sealed). The first study involved stabilizing participants with an oral opioid for three to seven days, AR 185 (sealed), and then administering Brixadi Weekly for seven weeks, AR 183 (sealed), and showed that 24mg and 32mg doses of Brixadi Weekly inhibit the subjective effects of opioid use, AR 183 (sealed), 409 (sealed). The second study involved participants who were new to buprenorphine treatment, each of whom received a 4mg test dose of buprenorphine, AR 194-196 (sealed), 200 (sealed), 409 (sealed), followed by an injection of Brixadi Weekly, AR 194 (sealed), 199 (sealed), 202 (sealed). After taking the weekly product for 12 weeks, participants transitioned to Brixadi Monthly. AR 194 (sealed), 202 (sealed). This investigation demonstrated that Brixadi “would be appropriate for use from the first patient visit . . . so that no take-home house of sublingual buprenorphine would be necessary in the real-world setting.” AR 194 (sealed). A third study confirmed the safety of Brixadi Weekly and Monthly over an extended period, AR 178 (sealed), 180 (sealed), 225 (sealed), and involved participants, who were both new-to-treatment and transitioning from prior buprenorphine treatment, AR 178-180 (sealed), 225 (sealed), with new-to-treatment patients all starting on Brixadi Weekly, AR 234 (sealed).

         On December 21, 2018, the FDA tentatively approved Braeburn's application for Brixadi. AR 270. Prescribing information included with the tentative approval specified that before taking Brixadi, patients new to buprenorphine should take a 4mg transmucosal test dose to confirm their buprenorphine tolerance without experiencing precipitated withdrawal. AR 278. If the test dose is tolerated, patients may then receive a 16mg dose of Brixadi Weekly, followed three days later by an 8mg dose of the weekly product. AR 278. In the first week of treatment, the patient can receive one more 8mg dose if needed. AR 278-79. After the first week, the patient receives Brixadi Weekly at a volume that matches the total amount of the drug administered in week one. AR 278-79. While new-to-treatment patients may not use Brixadi Monthly, patients already being treated with either a transmucosal buprenorphine product or Brixadi Weekly may transition to one of Brixadi Monthly's doses: 64mg, 96mg, or 128 mg. AR 278-79. Approval for Brixadi Weekly, however, was only tentative pending the FDA's receipt of appropriate labeling from Braeburn, a step Braeburn has not taken, AR 403 (sealed), and approval for Brixadi Monthly was only tentative because that product “is subject to expiration of a period of patent protection and/or exclusivity” and so final approval “may not be granted before the period has expired, ” AR 270.

         3. FDA's Letter Decision Blocking Final Approval of Monthly Brixadi

         The same day that the FDA sent Braeburn the tentative approval letter, the FDA's Center for Drug Evaluation and Research Exclusivity Board issued a letter decision (“Letter Decision”) explaining why Brixadi Monthly was not eligible for final approval. See generally AR 402-36 (sealed). The agency assessed whether Brixadi Monthly was blocked by the three-year exclusivity, under § 355(c)(3)(E)(iii), belonging to Probuphine or Sublocade. AR 403 (sealed). While Probuphine's exclusivity, the FDA decided, did not bar market entry for either Brixadi product, Sublocade's exclusivity, which does not expire until November 30, 2020, prevented final approval of Brixadi Monthly. AR 403 (sealed).

         The Letter Decision explained that the FDA interprets the phrase “for the conditions of approval, ” the operative language in § 355(c)(3)(E)(iii)'s bar clause, to mean that the FDA may not approve any application under § 355(b) for a drug product that shares the exclusivity-eligible drug's “innovation represented by its approved drug product that is supported by new clinical investigations essential to approval.” AR 416 (sealed). Thus, § 355(c)(3)(E)(iii) prevents the FDA from approving a drug application if the applied-for drug shares a quality that the FDA deems another drug sponsor to have innovated and to have obtained approval for in the prior three years. AR 416 (sealed). At the same time, ...

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