83 FR 54598 - Denial of Hearing Request Regarding Proposal To Refuse To Approve a New Drug Application for Oxycodone Hydrochloride Immediate-Release Abuse-Deterrent Formulation, Oral Capsules, 5 Milligrams, 15 Milligrams, and 30 Milligrams; Order Refusing Approval

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 83, Issue 210 (October 30, 2018)

Page Range		54598-54604
FR Document		2018-23710

The Chief Scientist is denying a request for a hearing regarding the proposal by the Center for Drug Evaluation and Research (CDER) of the Food and Drug Administration (FDA or Agency) to refuse to approve a new drug application submitted by Pharmaceutical Manufacturing Research Services, Inc. (PMRS) for oxycodone hydrochloride (HCl) immediate-release (IR) capsules, 5 milligrams (mg), 15 mg, and 30 mg in its present form. The Chief Scientist denies approval.

Federal Register, Volume 83 Issue 210 (Tuesday, October 30, 2018)

[Federal Register Volume 83, Number 210 (Tuesday, October 30, 2018)]
[Notices]
[Pages 54598-54604]
From the Federal Register Online [www.thefederalregister.org]
[FR Doc No: 2018-23710]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-N-0188]

Denial of Hearing Request Regarding Proposal To Refuse To Approve
a New Drug Application for Oxycodone Hydrochloride Immediate-Release
Abuse-Deterrent Formulation, Oral Capsules, 5 Milligrams, 15
Milligrams, and 30 Milligrams; Order Refusing Approval

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Chief Scientist is denying a request for a hearing
regarding the proposal by the Center for Drug Evaluation and Research
(CDER) of the Food and Drug Administration (FDA or Agency) to refuse to
approve a new drug application submitted by Pharmaceutical
Manufacturing Research Services, Inc. (PMRS) for oxycodone
hydrochloride (HCl) immediate-release (IR) capsules, 5 milligrams (mg),
15 mg, and 30 mg in its present form. The Chief Scientist denies
approval.

DATES: The order is applicable October 30, 2018.

FOR FURTHER INFORMATION CONTACT: Nathan R. Sabel, Office of Scientific
Integrity, Food and Drug Administration, 10903 New Hampshire Ave.,
Bldg. 1, Rm. 4206, Silver Spring, MD 20993, 301-796-8588.

SUPPLEMENTARY INFORMATION:

I. Procedural Background

PMRS submitted new drug application (NDA) 209155 for oxycodone HCl
IR capsules, 5 mg, 15 mg, and 30 mg, under section 505(b)(2) of the
Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(b)(2)),
relying in part on the Agency's previous findings of safety and
effectiveness for ROXICODONE (oxycodone HCl IR tablets (NDA 021011))
(Ref. 1).
PMRS's product contains excipients, including a dye blend, that
have solubility in common solvents, including water and ethanol,
similar to the solubility of the active pharmaceutical ingredient
(API). PMRS contends that a solution prepared from its product for
subcutaneous or intravenous injection will look relatively ``impure''
compared to a solution prepared from Roxicodone and will have a dark,
opaque, ``contaminated-looking'' appearance, providing both a ``visual
deterrent'' and a ``chemical deterrent'' to abuse by injection (Refs. 2
and 3).\1\ PMRS provided in vitro data intended to show that a solution
prepared for injection would have these qualities but provided no data
or literature supporting the conclusion that people who inject opioids
would, in fact, be deterred from injecting such a solution (Ref. 2).
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\1\ With respect to the purported ``chemical deterrent'' aspect
of its product, we note that PMRS's claims that its product resists
physical and chemical ``extraction'' appear to rest on a
misunderstanding of how that term is used in the context of abuse-
deterrent opioids. PMRS appears to be using the term ``extraction''
to mean that it is difficult to separate the API from the excipients
in solution, not that it is difficult to prepare a solution that
contains the API. In fact, PMRS's data show that the oxycodone in
its formulation can be readily extracted in commonly available
solvents into a solution physically suitable for injection. These
data show that more of the API could be extracted from oxycodone HCl
IR capsules (approximately 98 percent of the API) than from
ROXICODONE (approximately 90-91 percent) in both small and medium
volume extraction and at ambient and high temperatures (Refs. 1 and
2).
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PMRS also provided in vitro data intended to demonstrate that its
product would be more difficult to grind into particle sizes suitable
for snorting compared to ROXICODONE but provided no data from studies
in human subjects to evaluate the pharmacokinetic or pharmacodynamic
properties of the product following abuse via the nasal route (Ref.
1).\2\ Nonetheless, PMRS proposed labeling for its product representing
that it has abuse-deterrent properties (Ref. 4).
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\2\ While PMRS initially intended for the product to confer
resistance to grinding to particle sizes suitable for snorting (Ref.
7), PMRS has conceded, based on the results of its testing, that the
formulation should not be considered to have this property. See Ref.
2 at 12-13 (``Because of the decrease in particle size distribution
after grinding as the drug product ages, resistance to grinding
cannot be considered as one of the characteristics of [PMRS'
product]'').
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On November 16, 2017, CDER issued a complete response letter to
PMRS under Sec. 314.110(a) (21 CFR 314.110(a)) stating that the NDA
could not be

[[Page 54599]]

approved in its present form, describing the specific deficiencies,
and, where possible, recommending ways PMRS might remedy these
deficiencies (Ref. 5). The deficiencies cited include the following:
(1) The application in its present form is not approvable with the
proposed labeling describing abuse-deterrent properties, for multiple
reasons. In particular, (a) the oxycodone in the formulation can be
readily extracted in commonly available solvents into a solution
suitable for injection; (b) there were insufficient data showing the
presence of excipients (including dye) in the formulation can be
expected to deter abuse by injection; (c) the data submitted were
insufficient to show the product was meaningfully resistant to
manipulation for misuse or abuse; and (d) there were not data
submitted, including data from pharmacokinetic and human abuse
liability studies, fully characterizing the product's abuse potential
by all relevant routes of abuse. Also, the data submitted were not
sufficient to rule out the possibility that the proposed formulation
could result in a greater proportion of abuse by injection of PMRS's
product compared to a conventional oxycodone IR formulation. Abuse by
injection carries greater risk of overdose and transmission of
infectious disease than abuse by other routes.
(2) The safety and purity of the excipients intended (but not
shown) to confer abuse-deterrent properties were not adequately
characterized, either by the intended oral route of use or by expected
routes of abuse, including injection.
(3) An overall evaluation of elemental impurities in the final
formulation and a risk assessment for each heavy metal (taking into
consideration the maximum daily dose) were not provided.
(4) The application did not fully comply with the patent
certification requirements applicable to applications submitted under
section 505(b)(2) of the FD&C Act.
The complete response letter describes additional deficiencies
relating to the chemistry, manufacturing, and controls (CMCs) and
current good manufacturing practice requirements that CDER determined
precluded approval of the application in its present form (Ref. 5). The
complete response letter also noted that satisfactory resolution of
objectionable inspection observations was required before the
application could be approved (Ref. 5).
In response to the complete response letter, on November 17, 2017,
PMRS submitted a request for an opportunity for hearing under Sec.
314.110(b)(3) on whether there are grounds under section 505(d) of the
FD&C Act for denying approval of the NDA.
On February 13, 2018, FDA published a notice of opportunity for a
hearing (NOOH) setting forth CDER's proposal to refuse to approve
PMRS's NDA for oxycodone HCl IR capsules in 5-mg, 15-mg, and 30-mg
strengths (83 FR 6196). The NOOH stated that, for the reasons described
above and others described in the complete response letter, notice is
given to PMRS and to all other interested persons that FDA proposes to
issue an order refusing to approve the NDA because the application
fails to meet the criteria for approval under section 505(d) of the
FD&C Act, including that: (1) PMRS has not provided sufficient data to
show that the product would be safe (section 505(d)(1)); (2) PMRS has
not shown that the methods used in, and the facilities and controls
used for, the manufacture, processing, or packing of the product are
adequate to preserve its identity, strength, quality, and purity
(section 505(d)(3)); and (3) the labeling PMRS proposed for the product
is false or misleading (section 505(d)(7)).
PMRS submitted a request for a hearing on February 15, 2018. PMRS
also submitted data, information, and analysis in support of its
hearing request on April 13, 2018 (April Submission).\3\ CDER submitted
a proposed order on June 13, 2018, and PMRS submitted a Response to
CDER's Proposed Order on August 9, 2018 (August Submission), consistent
with regulations at Sec. 314.200(g)(3) (21 CFR 314.200(g)(3)),
affording the hearing requestor 60 days to respond to a proposed order.
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\3\ Although timely filed, PMRS did not submit the data,
information, and factual analysis in the required format (e.g., the
submission lacks a statement signed by the person responsible for
such submission that it includes in full all studies and information
as required) (Sec. 314.200(d)(3)). The Chief Scientist has
nevertheless reviewed PMRS's April Submission in its entirety.
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II. Statutory and Regulatory Framework Regarding 21 CFR Part 12
Hearings

Under Sec. 12.24(a)(2) (21 CFR 12.24(a)(2)), the Agency reviews a
hearing request to determine whether a hearing has been justified. FDA
has the authority to deny a hearing when it appears from the hearing
request that there are no material disputes of fact. See Costle v.
Pacific Legal Found., 445 U.S. 198, 214 (1980) (a party seeking a
hearing is required to meet a ``threshold burden of tendering evidence
suggesting the need for a hearing''), reh'g denied, 446 U.S. 947
(1980), citing Weinberger v. Hynson, Westcott & Dunning, Inc., 412 U.S.
609, 620-21 (1973); Pineapple Growers Ass'n v. FDA, 673 F.2d 1083,
1085-86 (9th Cir. 1982) (holding that no hearing is necessary unless
``material issues of fact'' have been raised).
In determining whether there are material issues of fact suitable
for a hearing, FDA considers the specific criteria set out in Sec.
12.24(b) and grants a hearing only if the material submitted in support
of the request shows the following: (1) There is a genuine and
substantial factual issue for resolution at a hearing; a hearing will
not be granted on issues of policy or law; \4\ (2) the factual issue
can be resolved by available and specifically identified reliable
evidence; a hearing will not be granted on the basis of mere
allegations or denials or general descriptions of positions and
contentions; (3) the data and information submitted, if established at
a hearing, would be adequate to justify resolution of the factual issue
in the way sought by the requestor; a hearing will be denied if the
Agency concludes that the data and information submitted are
insufficient to justify the factual determination urged, even if
accurate; \5\ (4) resolution of the factual issue in the way sought by
the person is adequate to justify the action requested; a hearing will
not be granted on factual issues that are not determinative with
respect to the action requested (e.g., if the Agency concludes that the
action would be the same even if the factual issue were resolved in the
way sought); \6\ (5) the action requested is

[[Page 54600]]

not inconsistent with any provision in the FD&C Act or any FDA
regulation; and (6) the requirements in other applicable regulations,
e.g., 21 CFR 10.20, 12.21, 12.22, and 314.200, and in the NOOH are met.
Similarly, Sec. 314.200(g) provides that a person requesting a hearing
``may not rely upon allegations or denials but is required to set forth
specific facts showing that there is a genuine and substantial issue of
fact that requires a hearing with respect to a particular drug product
specified in the request for hearing.''
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\4\ See also Georgia Pacific Corp. v. U.S. EPA, 671 F.2d 1235,
1241 (9th Cir. 1982) (finding that a party's argument that a hearing
is necessary to ``sharpen the issues'' or to ``fully develop the
facts'' is not sufficient to justify a hearing); Citizens for
Allegan County, Inc. v. FPC, 414 F.2d 1125, 1128 (D.C. Cir. 1969)
(finding that ``no evidentiary hearing is required where there is no
dispute on the facts and the agency proceeding involves only a
question of law.''); and Sun Oil Co. v. FPC, 256 F.2d 233, 240 (5th
Cir. 1958), cert. denied, 358 U.S. 872 (1958).
\5\ See also John D. Copanos & Sons, Inc. and Kanasco, Ltd. v.
FDA, 854 F.2d 510, 522 (D.C. Cir. 1988) (``The mere existence of
some alleged factual dispute between the parties will not defeat an
otherwise properly supported motion for summary judgment; the
requirement is that there be no genuine issue of material fact . . .
Only disputes over facts that might affect the outcome of the suit
under the governing law will properly preclude the entry of summary
judgment. Factual disputes that are irrelevant or unnecessary will
not be counted.'') (emphasis in original), quoting Anderson v.
Liberty Lobby, Inc., 477 U.S. 242, 247-248 (1986) and Hynson, 412
U.S. at 620.
\6\ See also Hynson, 412 U.S. at 621 (1973) and Dyestuffs &
Chemicals, Inc. v. Flemming, 271 F.2d 281, 286 (8th Cir. 1959)
(``Where the objections stated and the issues raised thereby are,
even if true, legally insufficient, their effect is a nullity and no
objections have been stated. Congress did not intend the
governmental agencies created by it to perform useless or unfruitful
tasks.''), cert. denied, 362 U.S. 911 (1960).
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III. Analysis

Following review of the administrative record related to this
proceeding, the Chief Scientist \7\ finds that PMRS has not raised a
genuine and substantial issue of fact justifying a hearing regarding
CDER's proposal to refuse to approve the NDA in its present form.\8\ As
further explained below, the Chief Scientist finds that a hearing would
not otherwise be in the public interest. Accordingly, the Chief
Scientist denies PMRS's hearing request under Sec. Sec. 12.24(b) and
314.200(g) and orders approval denied under section 505(d) of the FD&C
Act for PMRS's NDA in its present form.
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\7\ Under FDA Staff Manual Guide 1410.21, the Chief Scientist is
authorized to perform all delegable functions of the Commissioner of
Food and Drugs. (See FDA Staff Manual Guide 1410.21 ] 1.B.7).
\8\ PMRS suggests that it has an absolute statutory right to a
hearing on whether its NDA is approvable under section 505(c)(1)(B)
of the FD&C Act without regard to whether it can satisfy the
criteria for a hearing set forth in FDA's regulations, including the
requirement that a person requesting a hearing must demonstrate with
data and analysis that there is a genuine and substantial issue of
fact that requires a hearing (April Submission at 6-7). PMRS is
incorrect. FDA's duly issued summary judgment procedures have been
consistently upheld and are fully compatible with section
505(c)(1)(B) of the FD&C Act. ``It is well established that the
statutory grant of a public hearing is not absolute'' (Community
Nutrition Inst. v. Young, 773 F.2d 1356, 1364 (D.C. Cir. 1985)). FDA
has the authority to deny a hearing when it appears from the
submission of the party requesting a hearing that no substantial
issue of fact is in dispute (Pineapple Growers Ass'n, 673 F.2d at
1085-86; Hynson, 412 U.S. at 621; Hess & Clark, Inc. v. FDA, 495
F.2d 975, 983 (D.C. Cir. 1974)).
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A. PMRS's Request for a Hearing Is Denied Because No Genuine and
Substantial Issue of Fact Exists Regarding the Lack of Sufficient,
Reliable Evidence Supporting PMRS's Proposed Labeling for Abuse-
Deterrent Properties

Among other bases for proposing to deny PMRS's NDA, the NOOH cites
the requirement that FDA deny approval to applications that propose
labeling that is false or misleading in any particular (see section
505(d)(7) of the FD&C Act; 21 CFR 314.125(b)(6)). On this basis, the
November 16, 2017, complete response letter explained that the NDA in
its current form is not approvable with the proposed labeling
describing abuse-deterrent properties. PMRS proposed labeling that
includes multiple statements that the product has properties that make
it more difficult to manipulate for purposes of abuse and misuse than a
conventional formulation (Ref. 6). These statements include the
assertion that the product ``is formulated with inactive ingredients
that make the capsule more difficult to manipulate for misuse and
abuse'' and that ``the results of this testing demonstrated that [the
product] capsules, in comparison to Roxicodone tablets, have increased
resistance to physical and chemical extraction.'' (Ref. 6).\9\
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\9\ In its latest submission, PMRS appears to propose revising
its NDA labeling to include the statement ``Oxycodone HCl IR ADF
capsules should be prescribed knowing meaningful abuse-deterrent
properties have not been proven,'' among other labeling adjustments
(August Submission at 5). First, PMRS cannot adjust the content of
the NDA that is the subject of this hearing process in the middle of
the process itself. Among other reasons, the question this
proceeding seeks to resolve is not whether PMRS might formulate an
NDA that might address some of the deficiencies cited in the NOOH.
Rather, this process seeks to determine whether the application PMRS
submitted to CDER for review should be denied approval as CDER
proposes. PMRS may not change the substance of that application
during this proceeding. Second, given that the ``ADF'' abbreviation
of the product name PMRS retains in this revised language stands for
``Abuse Deterrent Formulation,'' it is difficult to see how this
change, even if permissible, would remove the concern that is the
primary focus of this order: that PMRS's labeling represents that
its product possesses abuse-deterrent properties when the presence
of such properties is not supported by substantial and reliable
evidence. Consistent with the regulations governing this 21 CFR part
12 proceeding, this order evaluates PMRS's NDA as it was evaluated
by CDER and not as PMRS might seek to modify that application now.
If PMRS wishes to seek Agency review of a different NDA at this
juncture, the appropriate avenue would be to submit a new
application through the standard Agency process.
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Specifically, the complete response letter explained that PMRS
submitted ``[n]o data . . . to support the proposed hypothesis that the
presence of excipients or dye in the solution would create a deterrence
to intravenous abuse'' (Ref. 5). Generally, PMRS's hypothesis is that
commonly used methods of preparing a solution for injection, if applied
to its product, will result in a solution that will look ``visually
unappealing'' compared to a solution prepared from Roxicodone, and will
have a dark, opaque, ``contaminated-looking'' appearance that will
serve as a ``visual deterrent'' to abuse (Ref. 2). PMRS's NDA provided
in vitro data intended to show that a solution prepared for injection
would have such an appearance (Refs. 2 and 3).\10\
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\10\ According to CDER's review, there remain some questions
concerning whether a solution extracted from PMRS's formulation
would consistently have the dark or opaque appearance observed in
PMRS's in vitro data. The appearance of an extracted solution of the
product may vary, depending on the solvent used in extraction and
filtering methods employed by experienced abusers. However, for the
purposes of this order, the Chief Scientist assumes that the
solution extracted from PMRS's formulation appears as a dark, opaque
solution.
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As CDER informed PMRS during the application process, CDER
considered this in vitro data unable to prove that PMRS's hypothesis is
correct that individuals would actually be deterred by the appearance
of a solution prepared from this formulation (Ref. 8). Although a
solution prepared from PMRS's product may appear a certain way based on
the in vitro data provided, PMRS has produced no scientific data or
information to establish that people who inject opioids would be less
likely to do so because of this appearance or based upon knowledge that
the solution contains other components of the drug product in addition
to the API. To demonstrate that this formulation deters abuse, and thus
to support the proposed labeling for abuse-deterrent properties, CDER
asked PMRS to provide evidence sufficient to prove that people who
abuse opioids by injection would be deterred from doing so based on the
solution's appearance.\11\
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\11\ CDER informed PMRS of the need for such evidence prior to
PMRS's submission of the NDA:
``At this time, we are not aware of data that support a
deterrent effect based on the presence of a dye in a formulation
intended to be abuse-deterrent. Provide evidence that supports the
concept that the incorporation of a dye into a formulation imparts
abuse-deterrent effects to that formulation. A hypothetical argument
that the presence of a dye will provide an abuse-deterrent effect is
not sufficient to support labeling.'' (Ref. 8).
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Critically, however, PMRS's NDA and subsequent submissions in this
proceeding contain no such data or information on this critical
question, either from PMRS's studies of its own product or from any
potentially relevant scientific literature. In lieu of scientifically
valid evidence for the proposition that appearance deters abuse, PMRS
simply reiterates how the solution appears. PMRS states, variously,
that the ``dark, significant color is visually unappealing for
potential intravenous abuse'' (Ref. 2); that ``PMRS considers this
visual deterrent effective in classifying drug products as abuse
deterrent'' (id.); that ``[t]he use of an FD&C dye was considered a
deterrent to abuse as it

[[Page 54601]]

provides a visual deterrent once introduced to aqueous solution''
(id.); that ``the ready solubility of the excipients matching the
solubility profile of the API . . . maximiz[es] deterrence by rendering
[the product] less attractive or rewarding for injection due to the
inability to isolate the API from the inactive ingredients for
injection'' (Ref. 9); and that ``it was very important that excipients
for this formulation have same [solubility] in order to provide a
chemical deterrent for abuse'' (Ref. 2).\12\ Despite these assertions
and the in vitro data related to how the product looks in solution,
PMRS has offered no evidence to establish that opioid-abusers will be
deterred by the color or appearance of a solution prepared from PMRS's
formulation.
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\12\ We note that PMRS provided some data and information
regarding its particular choice of dye blend, arguing that the blend
it selected was ``the most visually deterring'' of the colors
evaluated ``as it resulted in a dark, opaque, `contaminated-looking'
solution'' (Ref. 2 at page 4). As this order discusses, this data
does not constitute sufficient evidence for the proposition that
people who inject opioids can reasonably be expected to be
``visually deterred'' from doing so based on the appearance of the
solution prepared for injection.
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PMRS has also failed to offer evidence to establish its proposed
conclusion related to another deficiency cited in the complete response
letter (Ref. 5), specifically, PMRS's failure to establish that its
product formulation deters abuse by snorting. Despite CDER's requests
that human testing be conducted to establish whether this formulation
deters abuse by snorting (see Refs. 5 and 8), PMRS declined to conduct
such testing or to provide any other information to show that its
product functions to deter abuse by snorting. Without human testing, or
other appropriate data and information, it is not possible to evaluate
whether PMRS's formulation has properties that render it more or less
likely to be snorted.\13\ If the product were in fact less likely to be
snorted, the product could result in shifting the pathway of abuse from
snorting to injection. This shift would increase the product's overall
risks associated with abuse compared to a conventional formulation,
both because abuse by injection of any opioid carries additional risks
particular to that route of abuse (Ref. 10) and because abuse by
injection of PMRS's product in particular carries unknown additional
risks associated with injection of the co-extracted excipients.\14\
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\13\ As previously noted, PMRS intended for its formulation to
confer resistance to grinding (for the purpose of snorting) but
ultimately conceded that the product has not been shown to have this
property. See supra footnote 2.
\14\ In June 2017 FDA sought withdrawal from the market of OPANA
ER (oxymorphone HCl ER tablets (NDA 21610)) based on similar
concerns (Ref. 12). Specifically, FDA requested that OPANA ER be
withdrawn from the market after review of postmarket data showed a
significant shift in the route of abuse from nasal to injection
following the product's reformulation. The reformulated product had
been intended to deter abuse by injection and snorting. Injection
abuse of reformulated OPANA ER has been associated with serious
adverse events, including numerous cases of thrombotic
microangiopathy which are thought to have been related to injection
of the excipients included to deter abuse (Refs. 12 and 13).
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The Chief Scientist concludes that PMRS has not created a genuine
and substantial issue of fact justifying a hearing on this issue. As
CDER informed PMRS during the review process and in the complete
response letter, PMRS has not provided evidence that demonstrate its
product deters abuse. Despite requesting a factual hearing and offering
in vitro data intended to demonstrate how its product looks in
solution, PMRS has not provided sufficient and reliable data or
information that creates a genuine and substantial dispute of fact with
respect to whether the appearance of such a solution deters abuse in
the manner PMRS proposes to describe in its labeling. PMRS may have
submitted evidence to show what the product looks like when prepared
for injection but PMRS has not provided no clinical evidence--or indeed
any evidence--that this appearance will deter abuse as PMRS's NDA
represents in its proposed labeling. In addition, PMRS has failed to
provide sufficient evidence to establish that the product formulation
deters abuse by snorting. As a result, there exists no contested
factual issue with respect to the information available to demonstrate
whether PMRS's formulation possesses abuse-deterrent properties.
Accordingly, the Chief Scientist denies PMRS's request for a factual
hearing on this issue under Sec. Sec. 12.24(b) and 314.200(g) because
there exists no genuine and substantial issue of fact that would
require such a hearing to resolve.

B. PMRS's NDA Proposes Labeling That Is False and Misleading Under
Section 505(d)(7) of the FD&C Act and Is Therefore Appropriately Denied
Approval

Having found that that is no genuine and substantial question of
fact with respect to whether PMRS's proposed labeling is false or
misleading, the Chief Scientist also finds that the Agency must
therefore issue an order refusing to approve PMRS's NDA in its present
form under section 505(d)(7) of the FD&C Act.
FDA makes approval decisions, including decisions regarding the
content of FDA-approved prescription drug labeling, based on a
comprehensive scientific evaluation of the available data and
information, allowing only information for which there is a scientific
basis to be included.\15\ As discussed above, no evidence establishes
the proposition that this formulation has the abuse-deterrent
properties PMRS proposes to include in its product labeling.\16\ The
absence of such evidence in support of PMRS's assertions is
particularly problematic in light of the novel and highly speculative
nature of PMRS's abuse-deterrence hypothesis. It is well understood
that people suffering from opioid use disorder--particularly people who
abuse opioids by injection--routinely take extraordinary risks in
connection with their opioid abuse. The individuals who abuse opioids
by injection are known to be undeterred by such serious risks as
disease transmission (including HIV and hepatitis C) associated with
needle-sharing, injection-site infections, overdose, and even death
(Ref. 10). Certain ``street'' opioids, such as black tar heroin, are
commonly administered by injection despite their contaminated
appearance (Ref. 11) and despite the real risks associated with the
unknown composition and purity of such products (including, but not
limited to, the presence of contaminants).
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\15\ See, e.g., 21 CFR 201.56(a)(1) (providing that the labeling
of prescription drugs must contain a summary of the essential
scientific information needed for the safe and effective use of the
drug), 21 CFR 201.56(a)(2) (providing that the labeling must be
informative and accurate and neither promotional in tone nor false
or misleading in any particular and that labeling must be updated
when new information becomes available that causes the labeling to
become inaccurate, false, or misleading), and 21 CFR 201.56(a)(3)
(providing that labeling must be based whenever possible on data
derived from human experience).
\16\ As noted previously, PMRS's claims that its product resists
physical and chemical ``extraction'' appear to rest on a
misunderstanding of how that term is used in the context of abuse-
deterrent opioids. See supra footnote 1.
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Against this backdrop, PMRS's unsupported assertions and in vitro
data are insufficient to demonstrate that its product formulation will
deter abuse. Given the lack of data establishing the effect of PMRS's
formulation on its risks of abuse compared to a conventional
formulation, the labeling statements PMRS has proposed suggesting that
sufficient and reliable evidence exists and establishes that PMRS's
formulation deters abuse would be false and misleading. Thus, the
proposed labeling

[[Page 54602]]

includes false and misleading statements suggesting that PMRS's product
is expected to be safer than a conventional formulation with respect to
the risks of abuse when this conclusion remains unproven.\17\
Accordingly, the Chief Scientist has determined that PMRS has not
submitted data or information that can support a conclusion that its
product would deter abuse by injection and that PMRS's proposed
labeling is false and misleading under section 505(d)(7) in the absence
of such evidence. As a result, the Chief Scientist accepts CDER's
proposal to refuse approval for PMRS's NDA in its present form.
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\17\ During the review process, PMRS proposed that its labeling
include the following disclaimers: ``Abuse of TRADENAME by
injection, as well as by the oral and nasal routes, is still
possible,'' and ``there is no clinical evidence that TRADENAME has a
reduced abuse liability compared to immediate-release oxycodone''
(Ref. 6). These disclaimers do not render PMRS's other abuse-
deterrent labeling statements any less false and misleading. For
example, the first disclaimer implies that the product has abuse-
deterrent properties, while stating that these properties do not
render the product abuse-proof. The second disclaimer conveys an
assessment of the product's abuse-deterrent properties is not based
on data from human studies but continues to suggest that the product
possesses these (unproven) properties. In the context of the other
labeling PMRS proposes related to abuse-deterrence, these
disclaimers, if anything, render the NDA's proposed labeling even
more misleading.
---------------------------------------------------------------------------

C. PMRS's Legal and Policy Arguments Are Unavailing

Instead of providing data and information addressing the absence of
genuine and substantial issues of fact discussed in the previous
sections, the PMRS's submissions consists largely of legal and policy
objections to FDA's approach to evaluating, labeling, and approving
opioids, as well as requests for the Agency to take specific actions
regarding other drug products premised on PMRS's proposed alternative
policies regarding opioids. These legal and policy arguments do not
raise a genuine and substantial issue of fact justifying a hearing. See
Sec. 12.24(b)(1) (``A hearing will not be granted on issues of policy
or law.'').\18\ Furthermore, a hearing will not be granted on the issue
of whether FDA should take regulatory actions regarding other drug
products which are not the subject of the NOOH.\19\ Accordingly, this
order does not address the merits of FDA's policies regarding abuse-
deterrent opioids or PMRS's objections to those policies, except as
they apply to the question of whether PMRS has raised a genuine and
substantial issue of fact which precludes CDER's proposal to refuse to
approve PMRS's NDA.\20\ Instead, the Chief Scientist's order addresses
only those aspects of the PMRS submissions that are at least
potentially relevant to the question of whether PMRS has submitted
data, information, or analysis that raises a genuine and substantial
issue of fact justifying a hearing on the issue of whether PMRS's
proposed abuse-deterrent labeling claims are false or misleading.
---------------------------------------------------------------------------

\18\ Courts have uniformly recognized that an administrative
hearing need not be held to resolve questions of law or policy (see
Citizens for Allegan County, 414 F.2d 1125 (D.C. Cir. 1969); Sun Oil
Co. v. FPC, 256 F.2d 233, 240 (5th Cir.), cert denied, 358 U.S. 872
(1958)).
\19\ Sec. 314.200(g)(8) (``A request for a hearing, and any
subsequent grant or denial of a hearing, applies only to the drug
products named in [the NOOH]'').
\20\ Similarly, this order does not address PMRS's arguments
that do not go to the specific deficiencies cited in the complete
response letter and the NOOH, such as its argument that its product,
as well as other opioid products, should not bear labeling
consistent with chronic use and instead should only be labeled for
management of acute pain.
---------------------------------------------------------------------------

PMRS argues that CDER incorrectly proposed refusing to approve its
NDA with the proposed abuse-deterrent labeling because CDER applied
what PMRS considers the flawed approach to the evaluation and labeling
of abuse-deterrent products contained in FDA's 2015 guidance for
industry, ``Abuse-Deterrent Opioids--Evaluation and Labeling'' (Ref.
14) (the Guidance). Specifically, PMRS argues that the guidance's
emphasis on premarket studies (i.e., laboratory studies and human
testing) is scientifically invalid and that FDA should only approve
abuse-deterrent formulations with abuse-deterrent labeling claims based
on post-market epidemiological data. PMRS contends that data from
premarket studies of abuse deterrence cannot constitute ``substantial
evidence'' that a product deters abuse and therefore results in abuse-
deterrent labeling claims that are false and misleading (April
Submission at 2-5). PMRS further argues that CDER improperly treated
compliance with the guidance approach as a requirement for approval of
abuse-deterrent labeling, rather than merely as a set of
recommendations, in violation of the Administrative Procedure Act (APA)
(April Submission at 5-7). The Chief Scientist finds these arguments
unconvincing and not relevant to the matter at hand.
First, PMRS makes a policy argument that FDA, by following the
approach described in the Guidance, routinely approves abuse-deterrent
labeling claims that are too strong or overly broad based on premarket
data. But this argument does not raise an issue of fact regarding the
approvability of an NDA for a product bearing a labeling claim that
PMRS characterizes as a ``more appropriately limited claim about abuse
deterrence'' (April Submission at 2). As stated above, PMRS has not
presented data, information, or analysis that support a conclusion that
its product is approvable with its own proposed labeling, rendering the
question of whether ``broader labeling statements'' (April Submission
at 2) should be withheld until supported by post-market epidemiological
data irrelevant for purposes of this order.\21\ Even in its August
submission, PMRS continues to suggest that its product should be
labeled as possessing abuse-deterrent properties, even naming its
product ``ADF'' or Abuse Deterrent Formulation, while simultaneously
arguing that no evidence can demonstrate such properties pre-market
(August Submission at 5).\22\ If PMRS is correct that such properties
cannot be established pre-market, then labeling its product with abuse-
deterrent properties becomes even more transparently false and
misleading. PMRS cannot have it both ways without admitting that their
proposed labeling lacks a scientific basis. Further, even if FDA were
to agree with PMRS that only labeling claims of the type proposed by
PMRS should be approved based on premarket studies, this policy change
would not alter the conclusion that PMRS has not raised a genuine and
substantial issue of fact justifying a hearing regarding CDER's
proposal to refuse to approve PMRS's NDA with the labeling described in
the NDA.\23\
---------------------------------------------------------------------------

\21\ For similar reasons, the Chief Scientist does not address
the merits of PMRS's legal argument that application of the approach
described in the Guidance raises concerns under the First Amendment.
PMRS contends that ``[i]t cannot be that an Agency can compel an
applicant to forego a more limited truthful and non-misleading claim
and to instead seek broader labeling claims that an applicant finds
objectionable'' (April Submission at 4, footnote 4). Given that PMRS
has not presented data, information, or analysis that support a
conclusion that its product is approvable with what PMRS
characterizes as more limited claims regarding abuse-deterrence,
PMRS's First Amendment objections to broader labeling claims are not
relevant to this proceeding.
\22\ See supra footnotes 6 and 16.
\23\ We note that the Guidance was developed after considerable
deliberation by the Agency and after thorough consideration of
stakeholder comments expressed at public meetings and submitted to
the docket. If PMRS wants to provide further input on the Guidance,
there is already a mechanism in place for PMRS to do so (see Sec.
10.115(f)). A hearing on CDER's proposal to refuse to approve PMRS's
NDA, however, is not the proper forum for effecting changes to FDA
policy. See Sec. 12.24(b)(1).
---------------------------------------------------------------------------

The Chief Scientist finds PMRS's APA claim similarly irrelevant to
the question of whether a hearing should be granted. PMRS contends
that, by recommending that PMRS follow the

[[Page 54603]]

approach to evaluating abuse-deterrent opioids described in the
Guidance, and by referring to the guidance in the complete response
letter and other documents, CDER ``effectively converted a nonbinding
guidance document into a requirement for abuse-deterrent labeling that
has the force and effect of the law'' (April Submission at 7). But
challenging FDA's recommended approach for study design to measure
abuse-deterrent effectiveness pre-market is immaterial to the proposal
to refuse PMRS's specific NDA because PMRS has provided no evidence--
either of the type FDA recommended or otherwise--that this formulation
deters abuse. As a result and as discussed in the previous section,
PMRS's proposed labeling remains false and misleading because it
represents abuse-deterrent properties for a formulation that has not
been shown to actually possess those properties.
In sum, the Chief Scientist concludes that PMRS has raised no legal
or policy argument that alters the determinations discussed in the
previous sections.

D. A Hearing is not Otherwise in the Public Interest

In its August Submission, PMRS argues that a Part 12 hearing would
be ``otherwise in the public interest'' within the meaning of Sec.
314.200(g)(6) in order to resolve broader policy issues related to
opioid abuse. The Chief Scientist disagrees and finds in her discretion
that a Part 12 hearing on this NDA would not otherwise be in the public
interest.
As discussed above, PMRS's submissions raise arguments relevant to
FDA's regulation of opioid products and to the crisis of opioid abuse,
generally. For example, PMRS argues that the ``emphasis on so-called
abuse-deterrent formulations and labeling in response to the opioid
epidemic has resulted in the market entry of additional misbranded
products'' and that ``[s]uch false and misleading labeling serves only
to confuse prescribers and patients about what the product is and . . .
is not'' (April Submission at 4). In its submissions, PMRS also
requests that FDA take specific regulatory action regarding several
other specific opioid products.
The Agency continues to take a variety of steps to address the
public health crisis created by opioid abuse and the resulting
addiction and death. For example, in May 2017, the Commissioner of Food
and Drugs (the Commissioner) announced the establishment of an Opioid
Policy Steering Committee to explore and develop additional approaches
or strategies FDA could deploy to combat the opioid crisis.\24\ FDA has
also held public hearings on topics relating to opioid abuse, including
to receive stakeholder input on how FDA might, under its Risk
Evaluation and Mitigation Strategy (REMS) authority, improve the safe
use of opioid analgesics by curbing overprescribing to decrease the
occurrence of new addictions and limit misuse and abuse of opioid
analgesics.\25\
---------------------------------------------------------------------------

\24\ See 82 FR 58572 (December 13, 2017).
\25\ Id.
---------------------------------------------------------------------------

The Agency is also working to enhance prescriber and patient
awareness of the safe use of opioids. In 2017, FDA notified holders of
approved applications for IR opioid analgesics of the Agency's
determination that a REMS is necessary for IR opioid analgesics to
ensure that the benefits of these drugs continue to outweigh the risks.
Under this new policy, the IR opioid analgesics that are intended to be
used in the outpatient setting will be subject to the same REMS
requirements as the Extended-Release/Long-Acting opioid analgesics.
In addition, the Agency is undertaking a study to improve its
understanding of prescriber beliefs relating to use of opioid products
with abuse-deterrent properties.\26\ The Agency is evaluating
currently-used nomenclature for such products, including by surveying
doctors to better understand how they perceive these terms and to
assess the clinical understanding that has developed around products
with labeling for abuse-deterrent properties. Further, FDA is
continuously monitoring the safety of approved opioid products based on
post-market information, including through a focus on improving post-
market data collection in this area.
---------------------------------------------------------------------------

\26\ See Scott Gottlieb, M.D., Commissioner of Food and Drugs,
Remarks Delivered Before FDA's Scientific Meeting on Opioids (July
10, 2017), available at https://www.fda.gov/newsevents/speeches/ucm566189.htm.
---------------------------------------------------------------------------

As these examples show, the Agency is working to address the crisis
of opioid addiction and abuse and recognizes the importance of seeking
public comment and participation relevant to FDA's opioid-related
policies. However, the Chief Scientist does not believe that a Part 12
hearing on the approvability of PMRS's NDA is an appropriate forum to
address such concerns and finds in her discretion that such a hearing
would not be in the public interest.

E. Additional Issues Not Decided by This Order

As described above, the Chief Scientist has determined that PMRS
has not raised a genuine and substantial issue of fact that would
warrant a hearing and that PMRS's proposed labeling containing abuse-
deterrent representations would be false and misleading under section
505(d)(7) of the FD&C Act. Although the complete response letter and
NOOH describe additional deficiencies in PMRS's NDA, it is not
necessary to address these issues in this order because, even if
resolved in PMRS's favor, PMRS's NDA would still be refused approval in
its present form under section 505(d)(7) of the FD&C Act.\27\
---------------------------------------------------------------------------

\27\ ``A hearing will be denied if the Commissioner concludes
that the data and information submitted are insufficient to justify
the factual determination urged even if accurate.'' Sec.
12.24(b)(3). Furthermore, ``[a] hearing will not be granted on
factual issues that are not determinative with respect to the action
requested, e.g., if the Commissioner concludes that the action would
be the same even if the factual issue were resolved in the way
sought[.]'' Sec. 12.24(b)(4).
---------------------------------------------------------------------------

IV. Findings and Order

For the reasons described above, the Chief Scientist finds that
PMRS has not raised any genuine and substantial issue of fact that
would justify a hearing (see Sec. Sec. 12.24(b)(1) and 314.200(g)(1)).
Accordingly, PMRS's request for a hearing is denied. The record
conclusively shows that the approval criteria set forth in section
505(d)(7) of the FD&C Act have not been met. Therefore, under section
505(d) of the FD&C Act of the FD&C Act, the Chief Scientist hereby
denies approval to PMRS's NDA in its present form.

V. References

The following references marked with an asterisk (*) are on display
in the Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, and
are available for reviewing by interested persons between 9 a.m. and 4
p.m., Monday through Friday; they are also available electronically at
https://www.regulations.gov. The reference without an asterisk is not
on public display at https://www.regulations.gov because it has
copyright restriction. References without asterisks are available for
viewing only at the Dockets Management Staff. FDA has verified the
website addresses, as of the date this document publishes in the
Federal Register, but websites are subject to change over time.

* 1. Clinical Review, Cross-Discipline Deputy Director Review and
Summary Division Director Review, NDA 209155.
* 2. ``Module 3 Quality, 3.2.P.2.2 Drug Product,'' PMRS Inc., NDA
209155.
* 3. ``Module 2 Common Technical Document Summaries,'' PMRS, NDA
209155.

[[Page 54604]]

* 4. Proposed labeling for oxycodone HCl IR capsules, PMRS, NDA
209155 (Dec. 2017).
* 5. Complete Response letter, NDA 209155 (November 16, 2017).
* 6. ``Filing Communication Responses,'' PMRS, NDA 209155.
* 7. ``Request for Priority Review Designation,'' PMRS, NDA 209155.
* 8. ``Memorandum of Meeting Minutes'' for Type B, Pre-NDA, July 11,
2016 teleconference (August, 8, 2016).
* 9. ``NDA 209155 CMC Information Request 5-25-17,'' PMRS, NDA
209155.
* 10. Centers for Disease Control, ``Integrated Prevention Services
for HIV Infection, Viral Hepatitis, Sexually Transmitted Diseases,
and Tuberculosis for Persons Who Use Drugs Illicitly: Summary
Guidance From the CDC and the U.S. Department of Health and Human
Services,'' Morbidity and Mortality Weekly Report, vol. 61, pp. 1-
40, 2012.
* 11. National Institute on Drug Abuse, ``What is heroin and how is
it used?'', available at https://www.drugabuse.gov/publications/research-reports/heroin/what-heroin (accessed June 13, 2018).
* 12. FDA News Release, ``FDA requests removal of Opana ER for risks
related to abuse'' (June 8, 2017), available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm562401.htm.
13. Hunt, R. et al., ``A Mechanistic Investigation of Thrombotic
Microangiopathy Associated with IV Abuse of Opana ER,'' Blood, Feb.
16, 2017.
* 14. FDA Guidance for Industry ``Abuse-Deterrent Opioids--
Evaluation and Labeling,'' available at https://www.fda.gov/downloads/Drugs/Guidances/UCM334743.pdf.

Dated: October 25, 2018.
Denise Hinton,
Chief Scientist.
[FR Doc. 2018-23710 Filed 10-29-18; 8:45 am]
BILLING CODE 4164-01-P

54598 Federal Register / Vol. 83, No. 210 / Tuesday, October 30, 2018 / Notices

or prevents the use of plasma in settings the collections of information in 21 CFR relying in part on the Agency’s previous
where freezers and other support part 814 have been approved under findings of safety and effectiveness for
equipment are unavailable (e.g. OMB control number 0910–0231. ROXICODONE (oxycodone HCl IR
battlefields, remote locations, and other tablets (NDA 021011)) (Ref. 1).
III. Electronic Access PMRS’s product contains excipients,
austere settings) and may lead to
delayed administration. Dried plasma Persons with access to the internet including a dye blend, that have
(such as freeze-dried or spray-dried may obtain the draft guidance at either solubility in common solvents,
plasma) offers the potential to address https://www.fda.gov/BiologicsBlood including water and ethanol, similar to
these challenges by providing a product Vaccines/GuidanceCompliance the solubility of the active
that is stable at ambient temperatures RegulatoryInformation/Guidances/ pharmaceutical ingredient (API). PMRS
and can be rapidly reconstituted and default.htm or https:// contends that a solution prepared from
transfused. www.regulations.gov. its product for subcutaneous or
Recent clinical studies have Dated: October 25, 2018. intravenous injection will look
demonstrated promising efficacy and relatively ‘‘impure’’ compared to a
Leslie Kux,
safety of dried plasma, particularly in solution prepared from Roxicodone and
Associate Commissioner for Policy.
military applications, and dried plasma will have a dark, opaque,
products are available for limited use in [FR Doc. 2018–23637 Filed 10–29–18; 8:45 am]
‘‘contaminated-looking’’ appearance,
Germany, South Africa, and France. BILLING CODE 4164–01–P
providing both a ‘‘visual deterrent’’ and
This guidance is intended to assist a ‘‘chemical deterrent’’ to abuse by
manufacturers, sponsors, and applicants injection (Refs. 2 and 3).1 PMRS
developing dried plasma products DEPARTMENT OF HEALTH AND
provided in vitro data intended to show
intended for transfusion in order to HUMAN SERVICES
that a solution prepared for injection
facilitate the availability of safe and would have these qualities but provided
Food and Drug Administration
effective dried plasma products in the no data or literature supporting the
United States. [Docket No. FDA–2018–N–0188] conclusion that people who inject
This draft guidance is being issued opioids would, in fact, be deterred from
consistent with FDA’s good guidance Denial of Hearing Request Regarding
injecting such a solution (Ref. 2).
practices regulation (21 CFR 10.115). Proposal To Refuse To Approve a New PMRS also provided in vitro data
The draft guidance, when finalized, will Drug Application for Oxycodone intended to demonstrate that its product
represent the current thinking of FDA Hydrochloride Immediate-Release would be more difficult to grind into
on considerations for the development Abuse-Deterrent Formulation, Oral particle sizes suitable for snorting
of dried plasma products intended for Capsules, 5 Milligrams, 15 Milligrams, compared to ROXICODONE but
transfusion. It does not establish any and 30 Milligrams; Order Refusing provided no data from studies in human
rights for any person and is not binding Approval subjects to evaluate the pharmacokinetic
on FDA or the public. You can use an or pharmacodynamic properties of the
AGENCY: Food and Drug Administration,
alternative approach if it satisfies the product following abuse via the nasal
HHS.
requirements of the applicable statutes route (Ref. 1).2 Nonetheless, PMRS
and regulations. This guidance is not ACTION: Notice.
proposed labeling for its product
subject to Executive Order 12866. SUMMARY: The Chief Scientist is denying representing that it has abuse-deterrent
II. Paperwork Reduction Act of 1995 a request for a hearing regarding the properties (Ref. 4).
proposal by the Center for Drug On November 16, 2017, CDER issued
This draft guidance refers to
Evaluation and Research (CDER) of the a complete response letter to PMRS
previously approved collections of
Food and Drug Administration (FDA or under § 314.110(a) (21 CFR 314.110(a))
information subject to review by the
Agency) to refuse to approve a new drug stating that the NDA could not be
Office of Management and Budget
(OMB) under the Paperwork Reduction application submitted by
Act of 1995 (44 U.S.C. 3501–3520). The Pharmaceutical Manufacturing Research 1 With respect to the purported ‘‘chemical

Services, Inc. (PMRS) for oxycodone deterrent’’ aspect of its product, we note that
collections of information in 21 CFR PMRS’s claims that its product resists physical and
part 211 have been approved under hydrochloride (HCl) immediate-release chemical ‘‘extraction’’ appear to rest on a
OMB control number 0910–0139; the (IR) capsules, 5 milligrams (mg), 15 mg, misunderstanding of how that term is used in the
collections of information in 21 CFR and 30 mg in its present form. The Chief context of abuse-deterrent opioids. PMRS appears
Scientist denies approval. to be using the term ‘‘extraction’’ to mean that it is
part 312 have been approved under difficult to separate the API from the excipients in
OMB control number 0910–0014; the DATES: The order is applicable October solution, not that it is difficult to prepare a solution
collections of information in 21 CFR 30, 2018. that contains the API. In fact, PMRS’s data show
that the oxycodone in its formulation can be readily
part 601 have been approved under FOR FURTHER INFORMATION CONTACT: extracted in commonly available solvents into a
OMB control number 0910–0338; the Nathan R. Sabel, Office of Scientific solution physically suitable for injection. These
collections of information in 21 CFR Integrity, Food and Drug data show that more of the API could be extracted
part 610 have been approved under Administration, 10903 New Hampshire from oxycodone HCl IR capsules (approximately 98
percent of the API) than from ROXICODONE
OMB control numbers 0910–0116, Ave., Bldg. 1, Rm. 4206, Silver Spring, (approximately 90–91 percent) in both small and
0910–0139, and 0910–0338; the MD 20993, 301–796–8588. medium volume extraction and at ambient and high
collections of information in 21 CFR SUPPLEMENTARY INFORMATION: temperatures (Refs. 1 and 2).
2 While PMRS initially intended for the product
part 630 have been approved under
khammond on DSK30JT082PROD with NOTICES

OMB control number 0910–0116; the I. Procedural Background to confer resistance to grinding to particle sizes
suitable for snorting (Ref. 7), PMRS has conceded,
collections of information in 21 CFR PMRS submitted new drug based on the results of its testing, that the
part 640 have been approved under application (NDA) 209155 for formulation should not be considered to have this
OMB control number 0910–0116; the oxycodone HCl IR capsules, 5 mg, 15 property. See Ref. 2 at 12–13 (‘‘Because of the
decrease in particle size distribution after grinding
collections of information in 21 CFR mg, and 30 mg, under section 505(b)(2) as the drug product ages, resistance to grinding
part 812 have been approved under of the Federal Food, Drug, and Cosmetic cannot be considered as one of the characteristics
OMB control number 0910–0078; and Act (FD&C Act) (21 U.S.C. 355(b)(2)), of [PMRS’ product]’’).

VerDate Sep<11>2014 17:34 Oct 29, 2018 Jkt 247001 PO 00000 Frm 00033 Fmt 4703 Sfmt 4703 E:\FR\FM\30OCN1.SGM 30OCN1

Federal Register / Vol. 83, No. 210 / Tuesday, October 30, 2018 / Notices 54599

approved in its present form, describing for hearing under § 314.110(b)(3) on v. Hynson, Westcott & Dunning, Inc.,
the specific deficiencies, and, where whether there are grounds under section 412 U.S. 609, 620–21 (1973); Pineapple
possible, recommending ways PMRS 505(d) of the FD&C Act for denying Growers Ass’n v. FDA, 673 F.2d 1083,
might remedy these deficiencies (Ref. 5). approval of the NDA. 1085–86 (9th Cir. 1982) (holding that no
The deficiencies cited include the On February 13, 2018, FDA published hearing is necessary unless ‘‘material
following: a notice of opportunity for a hearing issues of fact’’ have been raised).
(1) The application in its present form (NOOH) setting forth CDER’s proposal In determining whether there are
is not approvable with the proposed to refuse to approve PMRS’s NDA for material issues of fact suitable for a
labeling describing abuse-deterrent oxycodone HCl IR capsules in 5-mg, 15- hearing, FDA considers the specific
properties, for multiple reasons. In mg, and 30-mg strengths (83 FR 6196). criteria set out in § 12.24(b) and grants
particular, (a) the oxycodone in the The NOOH stated that, for the reasons a hearing only if the material submitted
formulation can be readily extracted in described above and others described in in support of the request shows the
commonly available solvents into a the complete response letter, notice is following: (1) There is a genuine and
solution suitable for injection; (b) there given to PMRS and to all other substantial factual issue for resolution at
were insufficient data showing the interested persons that FDA proposes to a hearing; a hearing will not be granted
presence of excipients (including dye) issue an order refusing to approve the on issues of policy or law; 4 (2) the
in the formulation can be expected to NDA because the application fails to factual issue can be resolved by
deter abuse by injection; (c) the data meet the criteria for approval under available and specifically identified
submitted were insufficient to show the section 505(d) of the FD&C Act, reliable evidence; a hearing will not be
product was meaningfully resistant to including that: (1) PMRS has not granted on the basis of mere allegations
manipulation for misuse or abuse; and provided sufficient data to show that the or denials or general descriptions of
(d) there were not data submitted, product would be safe (section positions and contentions; (3) the data
including data from pharmacokinetic 505(d)(1)); (2) PMRS has not shown that and information submitted, if
and human abuse liability studies, fully the methods used in, and the facilities established at a hearing, would be
characterizing the product’s abuse and controls used for, the manufacture, adequate to justify resolution of the
potential by all relevant routes of abuse. processing, or packing of the product factual issue in the way sought by the
Also, the data submitted were not are adequate to preserve its identity, requestor; a hearing will be denied if the
sufficient to rule out the possibility that strength, quality, and purity (section Agency concludes that the data and
the proposed formulation could result 505(d)(3)); and (3) the labeling PMRS information submitted are insufficient
in a greater proportion of abuse by proposed for the product is false or to justify the factual determination
injection of PMRS’s product compared misleading (section 505(d)(7)). urged, even if accurate; 5 (4) resolution
to a conventional oxycodone IR PMRS submitted a request for a of the factual issue in the way sought by
formulation. Abuse by injection carries hearing on February 15, 2018. PMRS the person is adequate to justify the
greater risk of overdose and also submitted data, information, and action requested; a hearing will not be
transmission of infectious disease than analysis in support of its hearing request granted on factual issues that are not
abuse by other routes. on April 13, 2018 (April Submission).3 determinative with respect to the action
(2) The safety and purity of the CDER submitted a proposed order on requested (e.g., if the Agency concludes
excipients intended (but not shown) to June 13, 2018, and PMRS submitted a that the action would be the same even
confer abuse-deterrent properties were Response to CDER’s Proposed Order on if the factual issue were resolved in the
not adequately characterized, either by August 9, 2018 (August Submission), way sought); 6 (5) the action requested is
the intended oral route of use or by consistent with regulations at
expected routes of abuse, including § 314.200(g)(3) (21 CFR 314.200(g)(3)), 4 See also Georgia Pacific Corp. v. U.S. EPA, 671

injection. affording the hearing requestor 60 days F.2d 1235, 1241 (9th Cir. 1982) (finding that a
(3) An overall evaluation of elemental party’s argument that a hearing is necessary to
to respond to a proposed order. ‘‘sharpen the issues’’ or to ‘‘fully develop the facts’’
impurities in the final formulation and is not sufficient to justify a hearing); Citizens for
a risk assessment for each heavy metal II. Statutory and Regulatory Allegan County, Inc. v. FPC, 414 F.2d 1125, 1128
(taking into consideration the maximum Framework Regarding 21 CFR Part 12 (D.C. Cir. 1969) (finding that ‘‘no evidentiary
daily dose) were not provided. Hearings hearing is required where there is no dispute on the
facts and the agency proceeding involves only a
(4) The application did not fully Under § 12.24(a)(2) (21 CFR question of law.’’); and Sun Oil Co. v. FPC, 256 F.2d
comply with the patent certification 12.24(a)(2)), the Agency reviews a 233, 240 (5th Cir. 1958), cert. denied, 358 U.S. 872
requirements applicable to applications hearing request to determine whether a (1958).
submitted under section 505(b)(2) of the hearing has been justified. FDA has the
5 See also John D. Copanos & Sons, Inc. and

FD&C Act. Kanasco, Ltd. v. FDA, 854 F.2d 510, 522 (D.C. Cir.
authority to deny a hearing when it 1988) (‘‘The mere existence of some alleged factual
The complete response letter appears from the hearing request that dispute between the parties will not defeat an
describes additional deficiencies there are no material disputes of fact. otherwise properly supported motion for summary
relating to the chemistry, See Costle v. Pacific Legal Found., 445 judgment; the requirement is that there be no
manufacturing, and controls (CMCs) and genuine issue of material fact . . . Only disputes
U.S. 198, 214 (1980) (a party seeking a over facts that might affect the outcome of the suit
current good manufacturing practice hearing is required to meet a ‘‘threshold under the governing law will properly preclude the
requirements that CDER determined burden of tendering evidence suggesting entry of summary judgment. Factual disputes that
precluded approval of the application in the need for a hearing’’), reh’g denied, are irrelevant or unnecessary will not be counted.’’)
its present form (Ref. 5). The complete (emphasis in original), quoting Anderson v. Liberty
446 U.S. 947 (1980), citing Weinberger Lobby, Inc., 477 U.S. 242, 247–248 (1986) and
khammond on DSK30JT082PROD with NOTICES

response letter also noted that Hynson, 412 U.S. at 620.
satisfactory resolution of objectionable 3 Although timely filed, PMRS did not submit the 6 See also Hynson, 412 U.S. at 621 (1973) and
inspection observations was required data, information, and factual analysis in the Dyestuffs & Chemicals, Inc. v. Flemming, 271 F.2d
before the application could be required format (e.g., the submission lacks a 281, 286 (8th Cir. 1959) (‘‘Where the objections
approved (Ref. 5). statement signed by the person responsible for such stated and the issues raised thereby are, even if true,
submission that it includes in full all studies and legally insufficient, their effect is a nullity and no
In response to the complete response information as required) (§ 314.200(d)(3)). The Chief objections have been stated. Congress did not
letter, on November 17, 2017, PMRS Scientist has nevertheless reviewed PMRS’s April intend the governmental agencies created by it to
submitted a request for an opportunity Submission in its entirety. Continued

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54600 Federal Register / Vol. 83, No. 210 / Tuesday, October 30, 2018 / Notices

not inconsistent with any provision in is false or misleading in any particular abuse (Ref. 2). PMRS’s NDA provided in
the FD&C Act or any FDA regulation; (see section 505(d)(7) of the FD&C Act; vitro data intended to show that a
and (6) the requirements in other 21 CFR 314.125(b)(6)). On this basis, the solution prepared for injection would
applicable regulations, e.g., 21 CFR November 16, 2017, complete response have such an appearance (Refs. 2 and
10.20, 12.21, 12.22, and 314.200, and in letter explained that the NDA in its 3).10
the NOOH are met. Similarly, current form is not approvable with the As CDER informed PMRS during the
§ 314.200(g) provides that a person proposed labeling describing abuse- application process, CDER considered
requesting a hearing ‘‘may not rely upon deterrent properties. PMRS proposed this in vitro data unable to prove that
allegations or denials but is required to labeling that includes multiple PMRS’s hypothesis is correct that
set forth specific facts showing that statements that the product has individuals would actually be deterred
there is a genuine and substantial issue properties that make it more difficult to by the appearance of a solution
of fact that requires a hearing with manipulate for purposes of abuse and prepared from this formulation (Ref. 8).
respect to a particular drug product misuse than a conventional formulation Although a solution prepared from
specified in the request for hearing.’’ (Ref. 6). These statements include the PMRS’s product may appear a certain
assertion that the product ‘‘is way based on the in vitro data provided,
III. Analysis formulated with inactive ingredients PMRS has produced no scientific data
Following review of the that make the capsule more difficult to or information to establish that people
administrative record related to this manipulate for misuse and abuse’’ and who inject opioids would be less likely
proceeding, the Chief Scientist 7 finds that ‘‘the results of this testing to do so because of this appearance or
that PMRS has not raised a genuine and demonstrated that [the product] based upon knowledge that the solution
substantial issue of fact justifying a capsules, in comparison to Roxicodone contains other components of the drug
hearing regarding CDER’s proposal to tablets, have increased resistance to product in addition to the API. To
refuse to approve the NDA in its present physical and chemical extraction.’’ (Ref. demonstrate that this formulation deters
form.8 As further explained below, the 6).9 abuse, and thus to support the proposed
Chief Scientist finds that a hearing Specifically, the complete response labeling for abuse-deterrent properties,
would not otherwise be in the public letter explained that PMRS submitted CDER asked PMRS to provide evidence
interest. Accordingly, the Chief Scientist ‘‘[n]o data . . . to support the proposed sufficient to prove that people who
denies PMRS’s hearing request under hypothesis that the presence of abuse opioids by injection would be
§§ 12.24(b) and 314.200(g) and orders excipients or dye in the solution would deterred from doing so based on the
approval denied under section 505(d) of create a deterrence to intravenous solution’s appearance.11
the FD&C Act for PMRS’s NDA in its abuse’’ (Ref. 5). Generally, PMRS’s Critically, however, PMRS’s NDA and
present form. hypothesis is that commonly used subsequent submissions in this
methods of preparing a solution for proceeding contain no such data or
A. PMRS’s Request for a Hearing Is information on this critical question,
injection, if applied to its product, will
Denied Because No Genuine and either from PMRS’s studies of its own
result in a solution that will look
Substantial Issue of Fact Exists product or from any potentially relevant
‘‘visually unappealing’’ compared to a
Regarding the Lack of Sufficient, scientific literature. In lieu of
solution prepared from Roxicodone, and
Reliable Evidence Supporting PMRS’s scientifically valid evidence for the
will have a dark, opaque,
Proposed Labeling for Abuse-Deterrent proposition that appearance deters
‘‘contaminated-looking’’ appearance
Properties abuse, PMRS simply reiterates how the
that will serve as a ‘‘visual deterrent’’ to
Among other bases for proposing to solution appears. PMRS states,
deny PMRS’s NDA, the NOOH cites the 9 In its latest submission, PMRS appears to variously, that the ‘‘dark, significant
requirement that FDA deny approval to propose revising its NDA labeling to include the color is visually unappealing for
applications that propose labeling that statement ‘‘Oxycodone HCl IR ADF capsules should potential intravenous abuse’’ (Ref. 2);
be prescribed knowing meaningful abuse-deterrent that ‘‘PMRS considers this visual
properties have not been proven,’’ among other
perform useless or unfruitful tasks.’’), cert. denied, labeling adjustments (August Submission at 5). deterrent effective in classifying drug
362 U.S. 911 (1960). First, PMRS cannot adjust the content of the NDA products as abuse deterrent’’ (id.); that
7 Under FDA Staff Manual Guide 1410.21, the
that is the subject of this hearing process in the ‘‘[t]he use of an FD&C dye was
Chief Scientist is authorized to perform all middle of the process itself. Among other reasons,
delegable functions of the Commissioner of Food
considered a deterrent to abuse as it
the question this proceeding seeks to resolve is not
and Drugs. (See FDA Staff Manual Guide 1410.21 whether PMRS might formulate an NDA that might
10 According to CDER’s review, there remain
¶ 1.B.7). address some of the deficiencies cited in the NOOH.
8 PMRS suggests that it has an absolute statutory Rather, this process seeks to determine whether the some questions concerning whether a solution
right to a hearing on whether its NDA is approvable application PMRS submitted to CDER for review extracted from PMRS’s formulation would
under section 505(c)(1)(B) of the FD&C Act without should be denied approval as CDER proposes. consistently have the dark or opaque appearance
regard to whether it can satisfy the criteria for a PMRS may not change the substance of that observed in PMRS’s in vitro data. The appearance
hearing set forth in FDA’s regulations, including the application during this proceeding. Second, given of an extracted solution of the product may vary,
requirement that a person requesting a hearing must that the ‘‘ADF’’ abbreviation of the product name depending on the solvent used in extraction and
demonstrate with data and analysis that there is a PMRS retains in this revised language stands for filtering methods employed by experienced abusers.
genuine and substantial issue of fact that requires ‘‘Abuse Deterrent Formulation,’’ it is difficult to see However, for the purposes of this order, the Chief
a hearing (April Submission at 6–7). PMRS is how this change, even if permissible, would remove Scientist assumes that the solution extracted from
incorrect. FDA’s duly issued summary judgment the concern that is the primary focus of this order: PMRS’s formulation appears as a dark, opaque
procedures have been consistently upheld and are that PMRS’s labeling represents that its product solution.
11 CDER informed PMRS of the need for such
fully compatible with section 505(c)(1)(B) of the possesses abuse-deterrent properties when the
FD&C Act. ‘‘It is well established that the statutory presence of such properties is not supported by evidence prior to PMRS’s submission of the NDA:
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grant of a public hearing is not absolute’’ substantial and reliable evidence. Consistent with ‘‘At this time, we are not aware of data that
(Community Nutrition Inst. v. Young, 773 F.2d the regulations governing this 21 CFR part 12 support a deterrent effect based on the presence of
1356, 1364 (D.C. Cir. 1985)). FDA has the authority proceeding, this order evaluates PMRS’s NDA as it a dye in a formulation intended to be abuse-
to deny a hearing when it appears from the was evaluated by CDER and not as PMRS might deterrent. Provide evidence that supports the
submission of the party requesting a hearing that no seek to modify that application now. If PMRS concept that the incorporation of a dye into a
substantial issue of fact is in dispute (Pineapple wishes to seek Agency review of a different NDA formulation imparts abuse-deterrent effects to that
Growers Ass’n, 673 F.2d at 1085–86; Hynson, 412 at this juncture, the appropriate avenue would be formulation. A hypothetical argument that the
U.S. at 621; Hess & Clark, Inc. v. FDA, 495 F.2d 975, to submit a new application through the standard presence of a dye will provide an abuse-deterrent
983 (D.C. Cir. 1974)). Agency process. effect is not sufficient to support labeling.’’ (Ref. 8).

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54602 Federal Register / Vol. 83, No. 210 / Tuesday, October 30, 2018 / Notices

includes false and misleading abuse-deterrent opioids or PMRS’s for a product bearing a labeling claim
statements suggesting that PMRS’s objections to those policies, except as that PMRS characterizes as a ‘‘more
product is expected to be safer than a they apply to the question of whether appropriately limited claim about abuse
conventional formulation with respect PMRS has raised a genuine and deterrence’’ (April Submission at 2). As
to the risks of abuse when this substantial issue of fact which precludes stated above, PMRS has not presented
conclusion remains unproven.17 CDER’s proposal to refuse to approve data, information, or analysis that
Accordingly, the Chief Scientist has PMRS’s NDA.20 Instead, the Chief support a conclusion that its product is
determined that PMRS has not Scientist’s order addresses only those approvable with its own proposed
submitted data or information that can aspects of the PMRS submissions that labeling, rendering the question of
support a conclusion that its product are at least potentially relevant to the whether ‘‘broader labeling statements’’
would deter abuse by injection and that question of whether PMRS has (April Submission at 2) should be
PMRS’s proposed labeling is false and submitted data, information, or analysis withheld until supported by post-
misleading under section 505(d)(7) in that raises a genuine and substantial market epidemiological data irrelevant
the absence of such evidence. As a issue of fact justifying a hearing on the for purposes of this order.21 Even in its
result, the Chief Scientist accepts issue of whether PMRS’s proposed August submission, PMRS continues to
CDER’s proposal to refuse approval for abuse-deterrent labeling claims are false suggest that its product should be
PMRS’s NDA in its present form. or misleading. labeled as possessing abuse-deterrent
PMRS argues that CDER incorrectly properties, even naming its product
C. PMRS’s Legal and Policy Arguments proposed refusing to approve its NDA ‘‘ADF’’ or Abuse Deterrent Formulation,
Are Unavailing with the proposed abuse-deterrent while simultaneously arguing that no
Instead of providing data and labeling because CDER applied what evidence can demonstrate such
information addressing the absence of PMRS considers the flawed approach to properties pre-market (August
genuine and substantial issues of fact the evaluation and labeling of abuse- Submission at 5).22 If PMRS is correct
discussed in the previous sections, the deterrent products contained in FDA’s that such properties cannot be
PMRS’s submissions consists largely of 2015 guidance for industry, ‘‘Abuse- established pre-market, then labeling its
legal and policy objections to FDA’s Deterrent Opioids—Evaluation and product with abuse-deterrent properties
approach to evaluating, labeling, and Labeling’’ (Ref. 14) (the Guidance). becomes even more transparently false
approving opioids, as well as requests Specifically, PMRS argues that the and misleading. PMRS cannot have it
for the Agency to take specific actions guidance’s emphasis on premarket both ways without admitting that their
regarding other drug products premised studies (i.e., laboratory studies and proposed labeling lacks a scientific
on PMRS’s proposed alternative policies human testing) is scientifically invalid basis. Further, even if FDA were to agree
regarding opioids. These legal and and that FDA should only approve with PMRS that only labeling claims of
policy arguments do not raise a genuine abuse-deterrent formulations with the type proposed by PMRS should be
and substantial issue of fact justifying a abuse-deterrent labeling claims based on approved based on premarket studies,
hearing. See § 12.24(b)(1) (‘‘A hearing post-market epidemiological data. this policy change would not alter the
will not be granted on issues of policy PMRS contends that data from conclusion that PMRS has not raised a
or law.’’).18 Furthermore, a hearing will premarket studies of abuse deterrence genuine and substantial issue of fact
not be granted on the issue of whether cannot constitute ‘‘substantial justifying a hearing regarding CDER’s
FDA should take regulatory actions evidence’’ that a product deters abuse proposal to refuse to approve PMRS’s
regarding other drug products which are and therefore results in abuse-deterrent NDA with the labeling described in the
not the subject of the NOOH.19 labeling claims that are false and NDA.23
Accordingly, this order does not address misleading (April Submission at 2–5). The Chief Scientist finds PMRS’s APA
the merits of FDA’s policies regarding PMRS further argues that CDER claim similarly irrelevant to the
improperly treated compliance with the question of whether a hearing should be
17 During the review process, PMRS proposed that guidance approach as a requirement for granted. PMRS contends that, by
its labeling include the following disclaimers: approval of abuse-deterrent labeling, recommending that PMRS follow the
‘‘Abuse of TRADENAME by injection, as well as by rather than merely as a set of
the oral and nasal routes, is still possible,’’ and 21 For similar reasons, the Chief Scientist does not
‘‘there is no clinical evidence that TRADENAME recommendations, in violation of the
address the merits of PMRS’s legal argument that
has a reduced abuse liability compared to Administrative Procedure Act (APA) application of the approach described in the
immediate-release oxycodone’’ (Ref. 6). These (April Submission at 5–7). The Chief Guidance raises concerns under the First
disclaimers do not render PMRS’s other abuse- Scientist finds these arguments Amendment. PMRS contends that ‘‘[i]t cannot be
deterrent labeling statements any less false and that an Agency can compel an applicant to forego
misleading. For example, the first disclaimer unconvincing and not relevant to the a more limited truthful and non-misleading claim
implies that the product has abuse-deterrent matter at hand. and to instead seek broader labeling claims that an
properties, while stating that these properties do First, PMRS makes a policy argument applicant finds objectionable’’ (April Submission at
not render the product abuse-proof. The second that FDA, by following the approach 4, footnote 4). Given that PMRS has not presented
disclaimer conveys an assessment of the product’s data, information, or analysis that support a
abuse-deterrent properties is not based on data from described in the Guidance, routinely
conclusion that its product is approvable with what
human studies but continues to suggest that the approves abuse-deterrent labeling PMRS characterizes as more limited claims
product possesses these (unproven) properties. In claims that are too strong or overly regarding abuse-deterrence, PMRS’s First
the context of the other labeling PMRS proposes broad based on premarket data. But this Amendment objections to broader labeling claims
related to abuse-deterrence, these disclaimers, if are not relevant to this proceeding.
anything, render the NDA’s proposed labeling even argument does not raise an issue of fact 22 See supra footnotes 6 and 16.
more misleading. regarding the approvability of an NDA 23 We note that the Guidance was developed after
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18 Courts have uniformly recognized that an
considerable deliberation by the Agency and after
administrative hearing need not be held to resolve 20 Similarly, this order does not address PMRS’s thorough consideration of stakeholder comments
questions of law or policy (see Citizens for Allegan arguments that do not go to the specific deficiencies expressed at public meetings and submitted to the
County, 414 F.2d 1125 (D.C. Cir. 1969); Sun Oil Co. cited in the complete response letter and the docket. If PMRS wants to provide further input on
v. FPC, 256 F.2d 233, 240 (5th Cir.), cert denied, NOOH, such as its argument that its product, as the Guidance, there is already a mechanism in place
358 U.S. 872 (1958)). well as other opioid products, should not bear for PMRS to do so (see § 10.115(f)). A hearing on
19 § 314.200(g)(8) (‘‘A request for a hearing, and labeling consistent with chronic use and instead CDER’s proposal to refuse to approve PMRS’s NDA,
any subsequent grant or denial of a hearing, applies should only be labeled for management of acute however, is not the proper forum for effecting
only to the drug products named in [the NOOH]’’). pain. changes to FDA policy. See § 12.24(b)(1).

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Federal Register / Vol. 83, No. 210 / Tuesday, October 30, 2018 / Notices 54603

approach to evaluating abuse-deterrent the opioid crisis.24 FDA has also held hearing and that PMRS’s proposed
opioids described in the Guidance, and public hearings on topics relating to labeling containing abuse-deterrent
by referring to the guidance in the opioid abuse, including to receive representations would be false and
complete response letter and other stakeholder input on how FDA might, misleading under section 505(d)(7) of
documents, CDER ‘‘effectively under its Risk Evaluation and Mitigation the FD&C Act. Although the complete
converted a nonbinding guidance Strategy (REMS) authority, improve the response letter and NOOH describe
document into a requirement for abuse- safe use of opioid analgesics by curbing additional deficiencies in PMRS’s NDA,
deterrent labeling that has the force and overprescribing to decrease the it is not necessary to address these
effect of the law’’ (April Submission at occurrence of new addictions and limit issues in this order because, even if
7). But challenging FDA’s recommended misuse and abuse of opioid analgesics.25 resolved in PMRS’s favor, PMRS’s NDA
approach for study design to measure The Agency is also working to would still be refused approval in its
abuse-deterrent effectiveness pre-market enhance prescriber and patient present form under section 505(d)(7) of
is immaterial to the proposal to refuse awareness of the safe use of opioids. In the FD&C Act.27
PMRS’s specific NDA because PMRS 2017, FDA notified holders of approved
has provided no evidence—either of the applications for IR opioid analgesics of IV. Findings and Order
type FDA recommended or otherwise— the Agency’s determination that a REMS For the reasons described above, the
that this formulation deters abuse. As a is necessary for IR opioid analgesics to Chief Scientist finds that PMRS has not
result and as discussed in the previous ensure that the benefits of these drugs raised any genuine and substantial issue
section, PMRS’s proposed labeling continue to outweigh the risks. Under of fact that would justify a hearing (see
remains false and misleading because it this new policy, the IR opioid analgesics §§ 12.24(b)(1) and 314.200(g)(1)).
represents abuse-deterrent properties for that are intended to be used in the Accordingly, PMRS’s request for a
a formulation that has not been shown outpatient setting will be subject to the hearing is denied. The record
to actually possess those properties. same REMS requirements as the conclusively shows that the approval
In sum, the Chief Scientist concludes Extended-Release/Long-Acting opioid criteria set forth in section 505(d)(7) of
that PMRS has raised no legal or policy analgesics. the FD&C Act have not been met.
argument that alters the determinations In addition, the Agency is Therefore, under section 505(d) of the
discussed in the previous sections. undertaking a study to improve its FD&C Act of the FD&C Act, the Chief
understanding of prescriber beliefs Scientist hereby denies approval to
D. A Hearing is not Otherwise in the relating to use of opioid products with
Public Interest PMRS’s NDA in its present form.
abuse-deterrent properties.26 The
In its August Submission, PMRS Agency is evaluating currently-used V. References
argues that a Part 12 hearing would be nomenclature for such products, The following references marked with
‘‘otherwise in the public interest’’ including by surveying doctors to better an asterisk (*) are on display in the
within the meaning of § 314.200(g)(6) in understand how they perceive these Dockets Management Staff (HFA–305),
order to resolve broader policy issues terms and to assess the clinical Food and Drug Administration, 5630
related to opioid abuse. The Chief understanding that has developed Fishers Lane, Rm. 1061, Rockville, MD
Scientist disagrees and finds in her around products with labeling for 20852, and are available for reviewing
discretion that a Part 12 hearing on this abuse-deterrent properties. Further, by interested persons between 9 a.m.
NDA would not otherwise be in the FDA is continuously monitoring the and 4 p.m., Monday through Friday;
public interest. safety of approved opioid products they are also available electronically at
As discussed above, PMRS’s based on post-market information, https://www.regulations.gov. The
submissions raise arguments relevant to including through a focus on improving reference without an asterisk is not on
FDA’s regulation of opioid products and post-market data collection in this area. public display at https://
to the crisis of opioid abuse, generally. As these examples show, the Agency www.regulations.gov because it has
For example, PMRS argues that the is working to address the crisis of opioid copyright restriction. References
‘‘emphasis on so-called abuse-deterrent addiction and abuse and recognizes the without asterisks are available for
formulations and labeling in response to importance of seeking public comment viewing only at the Dockets
the opioid epidemic has resulted in the and participation relevant to FDA’s Management Staff. FDA has verified the
market entry of additional misbranded opioid-related policies. However, the website addresses, as of the date this
products’’ and that ‘‘[s]uch false and Chief Scientist does not believe that a document publishes in the Federal
misleading labeling serves only to Part 12 hearing on the approvability of Register, but websites are subject to
confuse prescribers and patients about PMRS’s NDA is an appropriate forum to change over time.
what the product is and . . . is not’’ address such concerns and finds in her
(April Submission at 4). In its * 1. Clinical Review, Cross-Discipline Deputy
discretion that such a hearing would not Director Review and Summary Division
submissions, PMRS also requests that be in the public interest. Director Review, NDA 209155.
FDA take specific regulatory action * 2. ‘‘Module 3 Quality, 3.2.P.2.2 Drug
regarding several other specific opioid E. Additional Issues Not Decided by
Product,’’ PMRS Inc., NDA 209155.
products. This Order * 3. ‘‘Module 2 Common Technical
The Agency continues to take a As described above, the Chief Document Summaries,’’ PMRS, NDA
variety of steps to address the public Scientist has determined that PMRS has 209155.
health crisis created by opioid abuse not raised a genuine and substantial
27 ‘‘A hearing will be denied if the Commissioner
and the resulting addiction and death. issue of fact that would warrant a
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concludes that the data and information submitted
For example, in May 2017, the are insufficient to justify the factual determination
Commissioner of Food and Drugs (the 24 See 82 FR 58572 (December 13, 2017). urged even if accurate.’’ § 12.24(b)(3). Furthermore,
Commissioner) announced the 25 Id.
‘‘[a] hearing will not be granted on factual issues
26 See Scott Gottlieb, M.D., Commissioner of Food that are not determinative with respect to the action
establishment of an Opioid Policy
and Drugs, Remarks Delivered Before FDA’s requested, e.g., if the Commissioner concludes that
Steering Committee to explore and Scientific Meeting on Opioids (July 10, 2017), the action would be the same even if the factual
develop additional approaches or available at https://www.fda.gov/newsevents/ issue were resolved in the way sought[.]’’
strategies FDA could deploy to combat speeches/ucm566189.htm. § 12.24(b)(4).

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54604 Federal Register / Vol. 83, No. 210 / Tuesday, October 30, 2018 / Notices

* 4. Proposed labeling for oxycodone HCl IR advisory-committees/nursing/ DEPARTMENT OF HEALTH AND
capsules, PMRS, NDA 209155 (Dec. index.html. HUMAN SERVICES
2017).
* 5. Complete Response letter, NDA 209155 DATES: November 19, 2018, 8:30 a.m.– National Institutes of Health
(November 16, 2017). 4:15 p.m. ET.
* 6. ‘‘Filing Communication Responses,’’ ADDRESSES: This meeting will be held Government-Owned Inventions;
PMRS, NDA 209155. by teleconference and webinar. The Availability for Licensing
* 7. ‘‘Request for Priority Review
Designation,’’ PMRS, NDA 209155.
conference call-in number is 1–888–
455–0640; passcode: HRSA COUNCIL. AGENCY: National Institutes of Health,
* 8. ‘‘Memorandum of Meeting Minutes’’ for HHS.
Type B, Pre-NDA, July 11, 2016 The webinar link is https://
teleconference (August, 8, 2016). hrsa.connectsolutions.com/nacnep/. ACTION: Notice.
* 9. ‘‘NDA 209155 CMC Information Request FOR FURTHER INFORMATION CONTACT:
5–25–17,’’ PMRS, NDA 209155. Tracy L. Gray, MBA, MS, RN, Division SUMMARY: The invention listed below is
* 10. Centers for Disease Control, ‘‘Integrated
of Nursing and Public Health, Bureau of jointly owned by an agency of the U.S.
Prevention Services for HIV Infection, Government with Pontificia
Viral Hepatitis, Sexually Transmitted Health Workforce, HRSA, 5600 Fishers
Lane, 11N112, Rockville, Maryland Universidad Catolica de Chile and is
Diseases, and Tuberculosis for Persons available for licensing to achieve
Who Use Drugs Illicitly: Summary 20857; 301–443–3346; or DScott1@
hrsa.gov. expeditious commercialization of
Guidance From the CDC and the U.S.
Department of Health and Human
results of federally-funded research and
Services,’’ Morbidity and Mortality
SUPPLEMENTARY INFORMATION: NACNEP development. Foreign patent
Weekly Report, vol. 61, pp. 1–40, 2012. provides advice and recommendations applications are filed on selected
* 11. National Institute on Drug Abuse, to the Secretary of Health and Human inventions to extend market coverage
‘‘What is heroin and how is it used?’’, Services (Secretary) and the U.S. for companies and may also be available
available at https://www.drugabuse.gov/ Congress on policy matters arising in for licensing.
publications/research-reports/heroin/ the administration of Title VIII of the FOR FURTHER INFORMATION CONTACT:
what-heroin (accessed June 13, 2018). Public Health Service (PHS) Act, as
* 12. FDA News Release, ‘‘FDA requests Licensing information and copies of the
amended, including the range of issues U.S. patent application listed below
removal of Opana ER for risks related to relating to nurse supply, education, and
abuse’’ (June 8, 2017), available at may be obtained by communicating
https://www.fda.gov/NewsEvents/
practice improvements. NACNEP with Ami Gadhia, JD, LL.M., CLP,
Newsroom/PressAnnouncements/ provides an annual report to the Technology Transfer and Patenting
ucm562401.htm. Secretary and Congress describing the Specialist, National Center for
13. Hunt, R. et al., ‘‘A Mechanistic activities of NACNEP, including Advancing Translational Sciences, NIH,
Investigation of Thrombotic findings and recommendations made by 9800 Medical Center Drive, Rockville,
Microangiopathy Associated with IV NACNEP concerning the activities
Abuse of Opana ER,’’ Blood, Feb. 16,
MD 20850, Phone: 301–217–6098, or
under this title. email ami.gadhia@nih.gov. A signed
2017. During the November 19, 2018,
* 14. FDA Guidance for Industry ‘‘Abuse- Confidential Disclosure Agreement will
meeting, NACNEP will continue be required to receive copies of
Deterrent Opioids—Evaluation and
Labeling,’’ available at https:// discussing areas where nursing can take unpublished patent applications.
www.fda.gov/downloads/Drugs/ the lead in the transition of the health
SUPPLEMENTARY INFORMATION:
Guidances/UCM334743.pdf. care system to value-based care through
improvements to nurse education and Technology description follows.
Dated: October 25, 2018. c-Abl Tyrosine Kinase Inhibitory
practice, to advance the development of
Denise Hinton, Compounds and Methods of
its 15th Report. In addition, the
Chief Scientist. members will discuss strategic priorities Manufacture and Use
[FR Doc. 2018–23710 Filed 10–29–18; 8:45 am] and future directions for the Council Description of Technology
BILLING CODE 4164–01–P and discuss possible topics for its 16th
Report. Agenda items are subject to The invention includes compounds
change as priorities dictate. Refer to the that inhibit c-Abl tyrosine kinase, and
DEPARTMENT OF HEALTH AND NACNEP website for any updated methods of making them which include
HUMAN SERVICES information concerning the meeting. administering (i) a therapeutically
Members of the public will have the effective amount of the compound or a
Health Resources and Services stereoisomer, tautomer,
Administration opportunity to provide comments.
Public participants may submit written pharmaceutically acceptable salt,
statements in advance of the scheduled solvate, or prodrug thereof; or (ii) a
Meeting of the National Advisory therapeutically effective amount of the
Council on Nurse Education and meeting. Oral comments will be
honored in the order they are requested pharmaceutical compositions to a
Practice patient with the disease which involves
and may be limited as time allows.
AGENCY: Health Resources and Services Requests to make oral comments or c-Abl tyrosine kinase, including the
Administration (HRSA), Department of provide written statements to NACNEP overexpression of it. In some
Health and Human Services (HHS). should be sent to Ms. Tracy L. Gray, embodiments, the compound inhibits c-
ACTION: Notice. Designated Federal Official, using the Abl tyrosine kinase by binding to an
allosteric site of the c-Abl tyrosine
khammond on DSK30JT082PROD with NOTICES

contact information above at least 3
SUMMARY: The National Advisory business days prior to the meeting. kinase. In some embodiments, the
Council on Nurse Education and compound binds to a myristate pocket
Practice (NACNEP or the Council) has Amy P. McNulty, of the c-Abl tyrosine kinase.
scheduled a public meeting. Information Acting Director, Division of the Executive This technology is available for
about NACNEP and the agenda for this Secretariat. licensing for commercial development
meeting can be found on the NACNEP [FR Doc. 2018–23685 Filed 10–29–18; 8:45 am] in accordance with 35 U.S.C. 209 and 37
website at https://www.hrsa.gov/ BILLING CODE 4165–15–P CFR part 404, as well as for further

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Document Created: 2018-10-30 00:43:26
Document Modified: 2018-10-30 00:43:26

Category		Regulatory Information
Collection		Federal Register
sudoc Class		AE 2.7: GS 4.107: AE 2.106:
Publisher		Office of the Federal Register, National Archives and Records Administration
Section		Notices
Action		Notice.
Dates		The order is applicable October 30, 2018.
Contact		Nathan R. Sabel, Office of Scientific Integrity, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 1, Rm. 4206, Silver Spring, MD 20993, 301-796-8588.
FR Citation		83 FR 54598

83 FR 54598 - Denial of Hearing Request Regarding Proposal To Refuse To Approve a New Drug Application for Oxycodone Hydrochloride Immediate-Release Abuse-Deterrent Formulation, Oral Capsules, 5 Milligrams, 15 Milligrams, and 30 Milligrams; Order Refusing Approval

DEPARTMENT OF HEALTH AND HUMAN SERVICESFood and Drug Administration

Federal Register Volume 83, Issue 210 (October 30, 2018)

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration