[Federal Register Volume 83, Number 210 (Tuesday, October 30, 2018)]
[Notices]
[Pages 54598-54604]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[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.
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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


