MEMORANDUM OPINION
BERYL
A. HOWELL, CHIEF JUDGE
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,
...