[Federal Register Volume 83, Number 63 (Monday, April 2, 2018)]
[Notices]
[Pages 13994-14016]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-06537]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2008-N-0549]
Prescription Polyethylene Glycol 3350; Denial of a Hearing and
Order Withdrawing Approval of Abbreviated New Drug Applications
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Commissioner of Food and Drugs (the Commissioner) is
denying requests for a hearing and issuing an order withdrawing
approval of abbreviated new drug applications (ANDAs) for certain
prescription laxatives with the active ingredient polyethylene glycol
3350 (PEG 3350), listed in this document, because the drug products are
misbranded under the Federal Food, Drug, and Cosmetic Act (FD&C Act).
DATES: This order is applicable May 2, 2018.
ADDRESSES: For access to the docket, go to https://www.regulations.gov
and insert the docket number, found in brackets in the heading of this
document, into the ``Search'' box and follow the prompts and/or go to
the Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville,
MD 20852 between 9 a.m. and 4 p.m., Monday through Friday. Publicly
available submissions may be seen in the docket.
FOR FURTHER INFORMATION CONTACT: Julie Finegan, Office of Scientific
Integrity, Office of the Chief Scientist, Food and Drug Administration,
10903 New Hampshire Ave., Bldg. 1, Rm. 4218, Silver Spring, MD 20993-
0002, 301-796-8618.
SUPPLEMENTARY INFORMATION:
I. Background
A. Procedural Background
On February 18, 1999, the U.S. Food and Drug Administration (FDA or
the Agency) approved a new drug application (NDA) submitted by
Braintree Laboratories, Inc., (Braintree) for prescription (or ``Rx'')
PEG 3350 (MiraLAX) (NDA 20-698). Subsequently, FDA approved five ANDAs
for prescription PEG 3350.\1\ On October 6, 2006, FDA approved a new
NDA (NDA 22-015) submitted by Braintree, removing their PEG 3350
laxative drug product from prescription dispensing requirements of
section 503(b) of the FD&C Act (21 U.S.C. 353(b)).\2\
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\1\ The Drug Price Competition and Patent Term Restoration Act
of 1984 (Pub. L. 98-417) (the Hatch-Waxman Amendments) created new
section 505(j) of the FD&C Act, which established the current ANDA
approval process. To obtain approval, an ANDA applicant is not
required to submit evidence to establish the clinical safety and
effectiveness of the drug product; instead, an ANDA relies on FDA's
previous finding that the reference listed drug is safe and
effective. To rely on a previous finding of safety and
effectiveness, an ANDA applicant must demonstrate, among other
things, that the drug product described in an ANDA has the same
active ingredient(s), indications for use, route of administration,
dosage form, strength, and labeling as the reference listed drug
(section 505(j)(2)(A)(i)-(v) and (j)(4) of the FD&C Act). In
addition, the ANDA applicant must submit evidence that its proposed
drug product is bioequivalent to the reference listed drug (section
505(j)(2)(A)(iv) of the FD&C Act).
\2\ On October 10, 2008, Braintree requested that FDA withdraw
approval of the NDA for prescription MiraLAX (NDA 20-698) under 21
CFR 314.150(c) because it had stopped marketing the product. On
February 11, 2009, FDA withdrew approval of the NDA for prescription
MiraLAX in a Federal Register notice (effective March 13, 2009)(74
FR 6896 at 6899 (February 11, 2009)).
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Section 503(b)(1) of the FD&C Act requires that a drug which: (1)
Because
[[Page 13995]]
of its toxicity or other potentiality for harmful effect, or the method
of its use, or the collateral measures necessary to its use, is not
safe for use except under the supervision of a practitioner licensed by
law to administer such drug or (2) is limited by an approved
application under section 505 of the FD&C Act (21 U.S.C. 355) to use
under the professional supervision of a practitioner licensed by law to
administer such drug, be dispensed only upon prescription of a
practitioner licensed to administer such drug. Under section
503(b)(4)(B) of the FD&C Act, a drug, to which the prescription
dispensing provisions of section 503(b)(1) do not apply, shall be
deemed to be misbranded if at any time prior to dispensing, the label
of the drug bears the ``Rx only'' symbol.
Likewise, at section 503(b)(4)(A), drugs that are subject to the
prescription dispensing provisions of section 503(b)(1) must bear the
``Rx only'' symbol; if not, they would be misbranded. These provisions
mean that nonprescription (over-the-counter (OTC)) drugs must not bear
the ``Rx only'' symbol and prescription drugs must bear the ``Rx only''
symbol; otherwise, they each would be misbranded. FDA has long
interpreted these provisions to mean that section 503(b) of the FD&C
Act does not permit the same active ingredient to be simultaneously
marketed in both a prescription drug product and a nonprescription drug
product, unless a meaningful difference exists between the two that
makes the prescription product safe only under the supervision of a
licensed practitioner.\3\
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\3\ In an advanced notice of proposed rulemaking (ANPRM), FDA
previously solicited public comment on the factors that it generally
would consider in determining whether there is a meaningful
difference between prescription and OTC drug products. See ``Drug
Approvals: Circumstances Under Which an Active Ingredient May Be
Simultaneously Marketed in Both a Prescription Drug Product and an
Over-the-Counter Product'' (70 FR 52050, September 1, 2005).
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FDA's regulation at Sec. 310.200 (21 CFR 310.200) sets forth the
procedure for exempting a drug approved for prescription use from the
prescription dispensing requirements of section 503(b)(1)(B) of the
FD&C Act. A drug limited to prescription use under section 503(b)(1)(B)
shall be exempt from the prescription dispensing requirements if FDA
determines that the prescription dispensing requirements are ``not
necessary for the protection of the public health by reason of the
drug's toxicity or other potentiality for harmful effect, or the method
of its use, or the collateral measures necessary to its use, and [FDA]
finds that the drug is safe and effective for use in self-medication as
directed in proposed labeling.'' (See Sec. 310.200(b).) In this
instance, based on studies submitted by the sponsor, FDA determined
that the original prescription MiraLAX product no longer met the
criteria in section 503(b)(1) of the FD&C Act for prescription use.
Therefore, FDA changed MiraLAX's status from prescription to
nonprescription (commonly referred to as an ``Rx to OTC switch''). When
FDA concludes, as it did with MiraLAX, that no prescription indications
remain, FDA describes the Rx to OTC switch as a ``full'' or
``complete'' switch. The Braintree product continued to use the trade
name MiraLAX when it switched from prescription to nonprescription.
Due to this change in MiraLAX's status from prescription to
nonprescription, in an April 20, 2007, letter to the ANDA holders, FDA
noted that the approved ANDAs were based on a reference listed drug
(RLD) with labeling for prescription only use (NDA 20-698) and that
MiraLAX had recently switched from ``Rx-only'' to OTC marketing. FDA
explained that the FD&C Act does not permit both prescription and
nonprescription versions of the same drug product to be marketed at the
same time. The Agency notified the PEG 3350 ANDA holders that their
prescription products, which bear the ``Rx only'' symbol, are
misbranded and may not be lawfully marketed. FDA explained that if the
ANDA holders wished to continue marketing PEG 3350, they may not do so
pursuant to the ANDAs referencing prescription MiraLAX. FDA informed
the ANDA holders that they must file new ANDAs referencing NDA 22-015
and the new ANDAs must include the same OTC labeling as the RLD. FDA
also explained that under section 505(j)(2)(D)(i) of the FD&C Act, the
ANDA holders were not permitted to supplement their ANDAs to reference
NDA 22-015, which was not the RLD identified in their ANDAs. The ANDA
holders did not seek voluntary withdrawal of their applications.
In the Federal Register of October 24, 2008 (73 FR 63491), the
Center for Drug Evaluation and Research (CDER) published a notice of
opportunity for a hearing (NOOH) proposing to withdraw approval of the
ANDAs for drug products containing the active ingredient, PEG 3350,
approved for prescription use. Schwarz Pharma Inc. (Schwarz), ANDA 76-
652; Paddock Laboratories, Inc. (Paddock), ANDA 77-893; Gavis
Pharmaceuticals, LLC (Gavis), ANDA 77-736; and Nexgen Pharma Inc.
(Nexgen), ANDA 77-706 (collectively, the ``ANDA holders''), each
submitted timely requests for a hearing and each submitted evidence in
support of their requests. Teva Pharmaceutical Industries, Ltd., now
Teva Pharmaceuticals USA, (Teva), ANDA 77-445, did not submit a request
for a hearing. Teva's Rx PEG 3350 product has been discontinued. On May
22, 2014, consistent with Sec. 314.200(g)(3) (21 CFR 314.200(g)(3)),
CDER served upon the ANDA holders a proposed order denying their
requests for hearing and withdrawing approvals of their ANDAs and
providing the ANDA holders 60 days to respond with sufficient data,
information, and analysis to demonstrate that there is a genuine and
substantial issue of fact that justifies a hearing. CDER subsequently
extended this 60-day deadline. Breckenridge Pharmaceutical Inc.
(Breckenridge) (ANDA 77-736); Kremer's Urban Pharmaceuticals, Inc.
(Kremer's) (ANDA 76-652); Nexgen; and Paddock submitted objections to
the proposed order. The Commissioner has reviewed the ANDA holders'
objections and is denying their requests for hearing and withdrawing
approval of their ANDAs.
B. The October 24, 2008, NOOH
The NOOH proposed the withdrawal of the PEG 3350 ANDAs on the basis
of the switch of MiraLAX from Rx to OTC. The NOOH noted that the FD&C
Act does not permit both Rx and OTC versions of the same drug product
to be marketed at the same time. Under the FD&C Act, a drug to which
the prescription dispensing requirements do not apply (i.e., an OTC
drug) shall be deemed misbranded if at any time prior to its
dispensing, the label of the product bears the ``Rx only'' symbol. The
NOOH explained that the ANDA products' labels, which bear the ``Rx
only'' symbol, are false or misleading because the same PEG 3350
product was approved for OTC use. The NOOH proposed the withdrawal of
the ANDAs under section 505(e) of the FD&C Act.
The Background section of the NOOH described the original approval
of prescription MiraLAX and the subsequent approval of the OTC product.
The NOOH summarized the two studies that formed the basis for approval
of NDA 20-698, the prescription MiraLAX product for the treatment of
occasional constipation, as follows:
Study 851-6 was a double-blind, parallel trial that
enrolled 151 subjects who were randomized to placebo or MiraLAX 17
grams (g). The treatment lasted 14 days. The primary efficacy endpoint
was bowel movement frequency with success defined as more
[[Page 13996]]
than 3 bowel movements per 7-day period, and failure defined as fewer
than 3 bowel movements per 7-day period, use of a laxative or enema, or
withdrawal from the trial. A total of 133 subjects completed this
study.
Study 851-3 was a single-center, double-blind, triple-
crossover trial that randomized 50 constipated patients to a first
period (10 days) of either 17 or 34 g of MiraLAX therapy. Subsequently,
without a washout interval, subjects were randomized to second or third
periods (also 10 days) of placebo or the alternate MiraLAX dose. The
primary endpoints of efficacy were stool frequency and stool weight.
All 50 patients completed the trial. This study helped to define a
dose-response for MiraLAX.
Table 1--Days to First Bowel Movement MiraLAX Rx Pivotal Studies
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Study Measure Day 1 Day 2 Day 3 Day 4
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851-3......................... Pt w/BM *....... 23 35 42 45
(n=48)........................ %............... 47.9 72.9 87.5 93.8
851-6......................... Pt w/BM......... 28 48 59 63
(n=76)........................ %............... 36.8 63.2 78.9 84.2
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* Pt w/BM = The cumulative number of patients who had at least one bowel movement up to the fourth day of
therapy with 17 g MiraLAX daily.
For both studies, the majority of patients (72.9% and 63.2%, respectively) had at least one bowel movement by
the second day of therapy.
Table 1 illustrates that in both studies submitted to support the
prescription MiraLAX NDA at least one-third of subjects taking 17 g of
MiraLAX had a bowel movement by Day 1 and at least three-fourths had a
bowel movement by Day 3. Based on the results of these studies, a
length of treatment of 2 weeks or less was recommended.
To support approval of the nonprescription application for MiraLAX
for occasional constipation, Braintree submitted three studies
(described in bullets below) evaluating safety and efficacy in adults
(including a subset of elderly subjects) for a period longer than the
previously approved period of up to 14 days of use. Although
nonprescription MiraLAX is indicated for a period of up to 1 week, the
submitted long-term studies supported a determination that the product
would be safe for use in the OTC setting, where repeated purchase and
use may be likely. Subjects who participated in these long-term studies
were constipated, but otherwise healthy, adults with no documented
organic cause for constipation who met protocol-specified modified Rome
Criteria \4\ for constipation. The primary endpoint(s) for these three
studies were all longer term assessments of safety and effectiveness,
not the number of days to first bowel movement.
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\4\ The Rome Criteria is a system developed to classify the
functional gastrointestinal disorders (disorders of the digestive
system in which symptoms cannot be explained by the presence of
structural or tissue abnormality), based on clinical symptoms. Some
examples of these types of disorders include irritable bowel
syndrome, functional dyspepsia, functional constipation, and
functional heartburn. See https://theromefoundation.org/.
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851-CR1: A randomized, double-blind, placebo-controlled,
parallel-group, multicenter study of 304 subjects comparing 6 months of
treatment with MiraLAX 17 g per day to daily treatment with a matched
placebo. Of the patients enrolled in this study 75 (25 percent) were 65
years of age or older. This was an efficacy study in which efficacy was
measured by outcomes of more than 3 satisfactory stools per week and
the occurrence of one or fewer of the following symptoms: Straining in
more than 25 percent of defecations; lumpy or hard stools in more than
25 percent of defecations; or sensation of incomplete evacuation in
more than 25 percent of defecations. More than 80 percent of patients
in this study experienced a bowel movement within 1 to 3 days of
starting therapy.
851-ZCC: An open-label, randomized, parallel-arm,
multicenter study of constipated adult patients randomized to treatment
with either 17 g per day MiraLAX or Zelnorm (tegaserod maleate,
indicated for the short-term treatment of women with irritable bowel
syndrome whose primary bowel symptom is constipation) for 28 days. This
study excluded elderly and male patients because of Zelnorm labeling
restrictions. This study demonstrated that MiraLAX is more effective
than Zelnorm at treating constipation over a 4-week period. Overall,
patients who were having fewer than three bowel movements per week
began having approximately one bowel movement per day by weeks 1 and 2.
851-CR3: An open-label, extended use, multicenter, single-
treatment study of 311 subjects using MiraLAX 17 g per day for 12
months. Of the patients enrolled in this study 117 (38 percent) were 65
years of age or older. This was a 1-year safety study of MiraLAX use,
and no placebo arm was included. Patients treated with MiraLAX for up
to 12 months achieved similar benefits to those previously reported in
shorter studies. According to the self-assessment measure used, 80 to
88 percent of patients (and 84 to 94 percent of elderly patients) rated
themselves successfully treated during the course of the study.
According to CDER, after reviewing the results of these studies,
FDA determined that the three studies provided evidence that
nonprescription MiraLAX could be used by consumers effectively in the
OTC setting, concluding that OTC MiraLAX is efficacious for the vast
majority of users with constipation within 7 days and generally
produces a bowel movement by day 3, and would also be safe if
repeatedly used over time. FDA determined that the criteria in section
503(b)(1) of the FD&C Act were no longer met and that the criteria for
switching prescription MiraLAX to nonprescription status under Sec.
310.200 were met. Thus, the Agency approved MiraLAX as a
nonprescription product for occasional constipation.
As CDER stated in the NOOH, for the prescription and
nonprescription versions of PEG 3350 to be lawfully marketed
simultaneously, there must be some meaningful difference between the
two products (e.g., indication, strength, route of administration,
dosage form, patient population) that makes the prescription product
safe only under the supervision of a practitioner licensed by law. The
NOOH then described the evidence CDER considered in determining that
there is no meaningful difference between the prescription and
nonprescription versions of the PEG 3350 laxative products.
CDER explained that it determined that there is no meaningful
difference between the prescription PEG 3350 ANDA holders' laxative
products and the nonprescription MiraLAX product based upon an
evaluation of the active ingredient, dosage form, strength, route of
administration, indications, and patient population for both versions.
As stated in the NOOH, CDER found that
[[Page 13997]]
the nonprescription and prescription PEG 3350 products are the same.
They have: (1) The same active ingredient, PEG 3350; (2) the same
dosage form, a powder for solution; (3) the same strength, a 17g dose
in 4 to 8 ounces of liquid; (4) the same route of administration, oral;
(5) the same indication, i.e. for patients with occasional
constipation; and (6) the same patient population, patients that are 17
years of age or older. With regard to any differences in the labeling
between the prescription and nonprescription products, CDER concluded
that any differences are non-meaningful and are based upon the Agency's
practice under the OTC drug monograph system of having consistent
labeling for OTC laxative groups. For example, CDER found that the
differences in duration of use between the prescription and
nonprescription products were not meaningful and were related only to
advice from the OTC laxative monograph panel that labeling for a 7-day
duration of use helps to promote safety in case the consumer is
constipated from a serious condition for which he or she should seek
care from a physician. The NOOH noted that the OTC MiraLAX labeling
included the phrase ``relieves occasional constipation'' for
consistency with other OTC products and to avoid consumer confusion
that may result from differences in the indication statement among OTC
laxative products. A comparison of the two products' labels is set
forth in table 2.
Table 2--Comparison of the Prescription and Nonprescription Labels
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Prescription MiraLAX/ Nonprescription
PEG 3350 MiraLAX
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Indication.................. For the treatment of Relieves occasional
occasional constipation
constipation. (irregularity).
Strength.................... 17g................. 17g.
Route of Administration..... For oral The bottle top is a
administration measuring cap
after dissolution marked to contain
in water. The cap 17g of powder when
on each bottle is filled to the
marked with a indicated line.
measuring line and Stir and dissolve
may be used to in any 4 to 8
measure a single ounces of beverage
MiraLAX dose of 17 (cold, hot, or room
g (about one temperature) then
heaping tablespoon). drink.
Dosage Form................. Powdered form....... Powdered form.
Duration of Use............. This product should Use no more than 7
be used for 2 weeks days. Ask a doctor
or less or as if you need to use
directed by a a laxative for
physician. longer than 1 week.
Effectiveness............... Treatment for 2 to 4 Generally produces a
days may be bowel movement in 1
required to produce to 3 days.
a bowel movement.
Population.................. Adults.............. For adults and
children 17 years
of age and over.
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CDER concluded that, where there is no meaningful difference
between nonprescription MiraLAX and the prescription PEG 3350 products,
the continued marketing of the same PEG 3350 product could result in
the consumer confusion that Congress intended to prevent through
section 503(b)(4)(B) of the FD&C Act. CDER reasoned that the display of
the Rx-only symbol on the ANDA holders' PEG 3350 products rendered the
labeling of those products false or misleading where the same PEG 3350
product was approved for OTC use. Accordingly, CDER concluded that the
labeling of the prescription PEG 3350 products is false and misleading,
and the products are thus misbranded under section 502 of the FD&C Act
(21 U.S.C. 352) because they continue to bear the ``Rx only''
symbol.\5\ CDER thus proposed withdrawal of the ANDAs pursuant to
section 505(e) of the FD&C Act. Under section 505(e), FDA may, after
due notice and an opportunity for a hearing, withdraw the approval of
an application submitted under section 505(j) of the FD&C Act if the
Secretary finds that on the basis of new information before him,
evaluated together with the evidence before him when the application
was approved, the labeling of such drug, based on a fair evaluation of
all material facts, is false or misleading in any particular and was
not corrected within a reasonable time after receipt of written notice
from the Secretary specifying the matter complained of.
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\5\ See section 502(a) of the FD&C Act (deeming a drug to be
misbranded if its labeling is false or misleading in any
particular); see also section 503(b)(4) and Sec. 310.200(d).
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The NOOH informed the PEG 3350 ANDA holders that if they requested
a hearing they would have to present data and information showing that
there is a genuine and substantial issue of fact requiring a hearing.
The NOOH also stated that if it conclusively appeared from the face of
the data, information, and factual analyses submitted in support of a
hearing request that there was no genuine and substantial issue of fact
precluding the withdrawal of the PEG 3350 ANDAs, or if the requests for
a hearing were not made in the required format or with the required
analyses, the Commissioner would enter summary judgment against the
holders of the PEG 3350 ANDAs, making findings and conclusions, and
denying a hearing (73 FR 63491).
II. Statutory and Regulatory Framework Regarding 21 CFR Part 12
Hearings
The specific criteria considered when determining whether a hearing
is justified are set out in Sec. 12.24(b) (21 CFR 12.24(b)). Under
that regulation, a hearing will be granted if the material submitted by
the requester shows, among other things, 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; (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
Commissioner concludes that the data and information submitted are
insufficient to justify the factual determination urged, even if
accurate; (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 Commissioner concludes that the
action would be the same even if the factual issue were resolved in the
way sought); (5) the action requested is 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 notice issuing the final
regulation or the NOOH are met.
[[Page 13998]]
A party seeking a hearing is required to meet a ``threshold burden
of tendering evidence suggesting the need for a hearing.'' (Costle v.
Pacific Legal Found., 445 U.S. 198, 214 (1980), reh'g denied, 446 U.S.
947 (1980) (citing Weinberger v. Hynson, Westcott & Dunning, Inc., 412
U.S. 609, 620-21 (1973).) A party's argument that a hearing is
necessary to ``sharpen the issues'' or to ``fully develop the facts''
does not meet this test. (Georgia Pacific Corp. v. U.S. EPA, 671 F.2d
1235, 1241 (9th Cir. 1982)). If a hearing request fails to identify any
factual evidence that would be the subject of a hearing, FDA will not
provide one (Hynson, 412 U.S. at 620). FDA may deny a hearing and enter
an order withdrawing approval of an application when it appears from
the request for hearing that there is no genuine and substantial issue
of fact. (See Sec. 314.200(g); Hynson, 412 U.S. at 620; John D.
Copanos & Sons, Inc. and Kanasco, Ltd. v. FDA, 854 F.2d 510, 522 (D.C.
Cir. 1988).)
A hearing request must not only contain evidence, but that evidence
should raise a material issue of fact concerning which a meaningful
hearing might be held (Pineapple Growers Ass'n v. FDA, 673 F.2d 1083,
1085-86 (9th Cir. 1982).) When the issues raised in the objection are,
even if true, insufficient to alter the decision, the Agency need not
grant a hearing. (See Dyestuffs & Chemicals, Inc. v. Flemming, 271 F.2d
281, 286 (8th Cir. 1959), cert. denied, 362 U.S. 911 (1960).) A hearing
need not be held to resolve questions of law. (See Citizens for Allegan
County, Inc. v. FPC, 414 F.2d 1125, 1128 (D.C. Cir. 1969); Sun Oil Co.
v. FPC, 256 F.2d 233, 240 (5th Cir. 1958), cert. denied, 358 U.S. 872
(1958).) Mere allegations or conclusory statements are not sufficient
to justify a hearing (Sec. 12.24(b)(2); 39 FR 9750 at 9755, March 13,
1974). In determining whether a hearing is justified, FDA will analyze
the data and information underlying a conclusion by the person
requesting a hearing that a hearing is necessary (39 FR 9750 at 9755;
see also Evers v. General Motors Corp., 770 F.2d 984, 986 (11th Cir.
1985) (It is settled that ``a party may not avoid summary judgment
solely on the basis of an expert's opinion that fails to provide
specific facts from the record to support its conclusory
allegations.''); accord United States v. Various Slot Machines On Guam,
658 F.2d 697, 700 (9th Cir. 1981) (``in the context of a motion for
summary judgment, an expert must back up his opinion with specific
facts''); Merit Motors, Inc. v. Chrysler Corp., 569 F.2d 666, 673 (D.C.
Cir. 1977)).
In summary, a hearing request must present sufficient credible
evidence to raise a genuine and substantial issue of fact and the
evidence presented by the requestor, if established at a hearing, must
be adequate to resolve the issue as requested and to justify the action
requested.
III. Analysis
The Commissioner has reviewed the evidence submitted by the holders
of the PEG 3350 ANDAs and finds that they have not raised a genuine and
substantial issue of fact requiring a hearing under Sec. Sec. 12.24(b)
and 314.200(g), that the legal objections offered are without merit and
cannot justify a hearing, and that summary judgment should be granted
against them. The Commissioner also orders that, under section 505(e)
of the FD&C Act, approval of the PEG 3350 ANDAs, including all related
amendments and supplements, are hereby withdrawn, effective May 2,
2018.
The reasons for the Commissioner's decision are described more
fully below.
A. Hearing Request
As noted, each of the PEG 3350 ANDA holders, except Teva, requested
a hearing and submitted evidence, including information and factual
analyses, as to why FDA should grant a hearing regarding their
requests. As Sec. 12.24(b) makes clear, FDA requires ``specifically
identified reliable evidence'' to grant a hearing. FDA will not grant a
hearing based solely upon ``mere allegations or denials or general
descriptions of positions and contentions.'' Furthermore, courts have
held that ``general and unsupported statements . . . of experts . . .
[that] fail to address the specific problems identified by the FDA . .
. do not create a genuine issue of fact.'' (Copanos, 854 F.2d at 526.)
Similarly, the Supreme Court noted that it was appropriate to withdraw
a drug from the market if the only evidence presented in opposition to
its withdrawal is ``clinical impressions of practicing physicians,'' as
that does not constitute the type of evidence upon which FDA bases its
regulatory decisions. (Hynson, 412 U.S. at 630.)
None of the PEG 3350 ANDA holders submitted data or other
information in support of their requests for a hearing that presents a
genuine and substantial issue of fact that would be determinative with
respect to whether there is some meaningful difference between the
prescription and nonprescription products approved by FDA that makes
the prescription product safe only under the supervision of a licensed
practitioner. Instead, they made numerous assertions and included
anecdotal evidence in the form of declarations from practicing
physicians, published medical literature, and trade publications on
issues that are not material to this proceeding. Much of the
information submitted by the PEG 3350 ANDA holders overlapped, and some
ANDA holders chose to reference other submissions. Nexgen submitted
five declarations from practicing physicians, one news release, and one
document outlining objections to the medical review of NDA 22-015
(nonprescription MiraLAX). Nexgen also submitted a bibliography of
journal articles cited by its medical experts in their declarations.
Paddock submitted a wide variety of documents, including labeling for
different products, published medical literature, letters sent to the
company by FDA, a copy of the NOOH, a copy of the tentative final
monograph (TFM) for OTC laxatives, and various web publications on
constipation and its comorbidities. Paddock also referenced a number of
online resources in its footnotes and cross-referenced three of the
declarations submitted by Nexgen--those of Thomas Quincy Garvey III,
M.D., Paul Erick Hyman, M.D., and Irvin Wechsler, B.Sc Pharm. Schwarz
did not submit any original evidence, but rather chose to incorporate
all of Nexgen's arguments and evidence by reference. Gavis submitted no
evidence in support of its assertions.
The ANDA holders object to the proposed order's treatment of their
evidentiary submissions. They maintain that the proposed order
misapplied the summary judgment standard and misinterpreted FDA
regulations and precedent relevant to summary judgment. Nexgen and
Breckenridge submitted a joint objection to the proposed order in which
they maintain that FDA cannot impose summary judgment where it has not
issued a regulation setting forth the standard on which summary
judgment will be based (Nexgen/Breckenridge Joint Objection (hereafter
Nexgen Objection) at 13-17). Nexgen and Paddock contend that summary
judgment is inappropriate where the term meaningful difference has not
been defined and the determination of meaningful difference is
inherently factual (Paddock Comments at 19; Nexgen Objection at 21-22).
Nexgen complains that FDA applied the concept of material fact so
narrowly that no issue is likely to satisfy those criteria (Nexgen
Objection at 19). Kremers maintains that the proposed order's
application of the summary judgment standard violates due process
[[Page 13999]]
because it holds that FDA will not allow its scientific judgment to be
challenged in an administrative hearing (Kremers Objection at 13-14).
Likewise, Paddock complains that the proposed order impermissibly
assessed the persuasiveness of the evidence, which is more
appropriately done at a hearing (Paddock Objection at 11-12, 15-17).
The ANDA holders argue that FDA erred in rejecting the expert
affidavits because language in the preamble to part 12 (21 CFR part 12)
suggests that expert disagreement is sufficient to create a factual
dispute for which a hearing is needed (Kremer's Objection at 8-10).
They contend that the expert affidavits contain facts and analysis
that, if proven at a hearing, demonstrate meaningful differences
between Rx and OTC PEG 3350 products. They maintain that basing the
hearing denial on the lack of clinical data was improper in this
particular proceeding, where the efficacy of PEG 3350 is not at issue
(Nexgen Objection at 18-19; Kremers Objection at 8-9; Paddock at 13-
14).
The Commissioner has reviewed the evidence presented and finds that
it either fails to address the specific problems identified by FDA and/
or that it does not constitute specifically identified reliable
evidence. In the ANPRM and the NOOH, FDA stated that in determining
whether the same active ingredient can be simultaneously marketed in
prescription and OTC products, FDA would consider whether there is a
meaningful difference between two drug products, such as active
ingredient, dosage form, strength, route of administration,
indications, or patient population that makes the prescription product
safe only under the supervision of a licensed practitioner. Much of the
evidence submitted by the ANDA holders does not warrant granting a
hearing because the evidence is not relevant to the above factors. A
significant portion of the evidence submitted by the ANDA holders in
support of the hearing includes published medical literature and
affidavits summarizing the impressions of practicing physicians
regarding unapproved uses of PEG 3350, such as chronic constipation,
opioid-induced constipation, and use in pediatric patients (see, e.g.,
Waymack Declaration ]] 17-25, 28; Waymack Bibliography 1-2, 5-6, 8-9);
Hyman Declaration ]] 8-23; Hyman Bibliography 1-2, 4, 6-14; Weschler
Declaration ]] 9-14). The indication for both OTC MiraLAX and the
generic prescription PEG 3350 products is occasional constipation.
Neither the prescription products nor OTC MiraLAX are indicated for
treatment of chronic constipation or opioid-induced constipation or for
treatment of pediatric patients. Evidence regarding these unapproved
uses of PEG 3350 is not relevant and does not raise a material issue of
fact regarding the factors FDA set forth in the ANPRM or the NOOH.
The expert statements regarding duration of use likewise fail to
meet the criteria at Sec. 12.24 for granting a hearing. The NOOH
explained that, in previous switches, a drug remained prescription for
one duration of use while becoming OTC for the other duration only when
there was an additional and more fundamental difference between the
products, such as a different indication, dose, duration of therapy,
and/or target population (73 FR 63491 at 63493 n.1), none of which are
present here. The NOOH further explained that the 7-day duration of use
for OTC MiraLAX was based upon the labeling intended for the OTC
audience and to ensure consistent labeling among OTC laxative products.
The ANDA holders did not dispute this. Nevertheless, they made
arguments and submitted affidavits of impressions of practitioners
citing review documents and approved labeling related to duration of
use. The ANDA holders focus on PEG 3350's alleged increased efficacy
after 2 to 4 weeks and maintained efficacy from 4 weeks to up to 6
months of use, based upon the ``or as directed by a physician''
language in the prescription labeling. Also relying upon the ``or as
directed by a physician'' phrase in the prescription labeling, the ANDA
holders contend that such language indicates that prescription MiraLAX
has an unlimited duration of use. They further maintain that OTC
MiraLAX has a maximum duration of use of 7 days.
Prescription PEG 3350 is approved for a duration of use of ``2
weeks or less or as directed by a physician.'' Nonprescription
MiraLAX's labeled duration of use states: ``use no more than 7 days'';
``Stop use and ask a doctor if . . . you need to use a laxative for
longer than 1 week''; and ``do not take more than directed unless
advised by your doctor.'' The labeling of both products states that the
patient may use the product for less than the 7-day or 14-day duration
the ANDA holders cite. In addition, the labeling for both products
explicitly states that the products can be expected to be effective in
producing a bowel movement in less than 7 days,\6\ which is consistent
with the fact that both products are indicated for occasional
constipation and not chronic constipation. Both products' labeling also
acknowledges the discretion of a treating physician to recommend a
duration of use beyond the labeled duration.\7\ For this reason, the
ANDA holders' attempts to show that there is increasing efficacy over
an extended period of time is not determinative of whether there is a
meaningful difference between the prescription and OTC products as
approved by FDA. Moreover, although the PEG ANDA holders complain that
the proposed order improperly relied upon a lack of data, the ANDA
holders raised the issue of comparative efficacy over time based upon a
misplaced reliance on the data from the MiraLAX application and without
submitting supporting data.
---------------------------------------------------------------------------
\6\ The prescription labeling states, ``Treatment for 2 to 4
days may be required to produce a bowel movement.'' The
nonprescription labeling states, ``Generally, produces a bowel
movement in 1 to 3 days.''
\7\ FDA does not seek to interfere with the exercise of the
professional judgment of health care providers in prescribing or
administering, for unapproved uses for individual patients, most
legally marketed medical products.
---------------------------------------------------------------------------
Duration of use alone was not set forth in the ANPRM or the NOOH as
a factor the Agency considers in determining whether there is a
meaningful difference between a prescription product and an OTC
product. Moreover, the NOOH made clear that the duration of use on the
OTC label resulted from the intended audience (consumers) and the need
to maintain consistency with the labeling of other OTC laxative
products, and not from any difference necessitated by science. The
plain language of the labeling provides discretion to patients and
physicians with regard to duration of use. Considering all these
factors, the Commissioner in this proceeding declines to conclude that
duration of use alone, without an additional more fundamental
difference between the products, is sufficient to establish a
meaningful difference. As such, the evidence and affidavits regarding
duration of use do not raise material issues of fact that would be
determinative with respect to this action, and thus do not justify a
hearing. Additional discussion of the meaningful difference standard
and duration of use is found in section III.D.
Other evidence submitted by the ANDA holders consists of expert
statements or impressions of practitioners that challenge FDA's 2006
decision to approve MiraLAX--or, in some instances, any laxative
product--as an OTC product (see, e.g., Garvey Declaration ]] 10-17, 21-
25; Waymack Declaration ]] 9-10, 26-27, 29; Beier Declaration ]] 8, 10-
17; Weschler Declaration ]] 15-17); see also Nexgen
[[Page 14000]]
Comments at 46-48 (contrasting FDA's approval of OTC MiraLAX with a
prior decision to approve OTC Plan B only for individuals 16 years of
age and older); Nexgen Objection at 37-40, 47 (raising arguments
related to a lack of labeling comprehension, self-selection, and actual
use studies and an advisory committee meeting prior to MiraLAX's OTC
approval). Other statements focus on issues such as whether the
clinical trials were adequate to support the efficacy of MiraLAX within
7 days, whether constipation is a self-limiting condition suitable for
treatment with an OTC drug, and whether FDA correctly concluded that
MiraLAX may be used safely for up to 7 days (with certain exceptions
set forth in the OTC label) without the supervision of a licensed
practitioner.
This evidence challenges FDA's decision to approve MiraLAX as an
OTC product. As explained in the Background section, the PEG 3350 ANDAs
were approved based upon FDA's finding that the generic PEG 3350
products have the same active ingredient, indication for use, route of
administration, dosage form, strength, and labeling as, and that they
were bioequivalent, to prescription MiraLAX. The PEG ANDA holders were
not required to submit evidence to establish the safety and efficacy of
their products. Rather, the ANDAs relied upon FDA's prior finding of
MiraLAX's safety and efficacy for approval, which was supported by the
evidence submitted in the previously approved NDA for prescription
MiraLAX (NDA 20-698). Subsequently, FDA approved NDA 22-015 for OTC
MiraLAX, which has the same active ingredient, indication for use,
route of administration, dosage form, and strength as prescription
MiraLAX. The ANDA holders now challenge the decisions made in the
course of the approval of NDA 22-015 and seek a hearing on these
issues. Neither the FD&C Act nor its implementing regulations require
that the ANDA holders be afforded a hearing on FDA's decision to
approve the NDA for OTC MiraLAX, and that issue is not determinative in
this proceeding, which is only to decide whether OTC MiraLAX as already
approved by FDA is meaningfully different from the approved
prescription products. Accordingly, the Commissioner finds that a
hearing on this evidence submitted with regard to these issues is not
warranted. (See Sec. 12.24(b); Hynson, 412 U.S. at 620; Capanos, 854
F.2d at 522, 526).
The Commissioner further concludes that a hearing may be denied in
this proceeding, even in the absence of a regulation setting forth the
standard for determining whether there is a meaningful difference
between prescription and nonprescription products containing the same
active ingredient. This is so because the meaningful difference
standard was set forth in the ANPRM and the NOOH, and the NOOH
discussed in detail the facts and evidence that formed the basis for
CDER's proposed withdrawal of the ANDAs. Where the NOOH provides such
information, precise regulations specifying the type of evidence
necessary to justify a hearing are not required (Capanos, 854 F.2d at
520; cf. American Cyanamid Co. v. FDA, 606 F.2d 1307, 1312-13 (D.D.C.
1979); Hess & Clark, Inc. v. FDA, 495 F.2d 975, 984 (D.C. Cir. 1974)).
Furthermore, the factors set forth in the ANPRM and the NOOH, which FDA
will consider in determining whether there is a meaningful difference
between prescription and nonprescription drug products containing the
same active ingredient (indication, strength, route of administration,
dosage form, patient population), are clearly set forth in the
products' labeling.
As to the complaint that the proposed order ``applied the concept
of `material fact' '' so narrowly that no issue is likely to satisfy
that standard (Nexgen Objection at 17), the ANDA holders' requests for
hearing and objections to the proposed order do not dispute that the
active ingredient, dosage form, strength, route of administration,
indication, and patient population are the same for the original
prescription MiraLAX product approved in NDA 20-698, the prescription
generic PEG 3350 products, and OTC MiraLAX approved in NDA 22-015, as
reflected on the products' labeling. Contrary to their assertions, the
Agency is not construing substantial and genuine issue of fact
narrowly. Rather, any data or information presented by the ANDA holders
purporting to establish facts that do not relate to the factors set
forth in the ANPRM and NOOH is immaterial because those are the factors
that are relevant to determining if there is a meaningful difference
between the products. In addition, the factors the Agency set forth as
relevant to determining a meaningful difference between the products
largely align with those the Agency relied upon in approving the PEG
3350 ANDAs (see 21 U.S.C. 355(j)(2)(A)(i) to (v)). Under these
circumstances, it would be difficult for the ANDA holders to raise a
genuine and substantial issue of fact requiring a hearing. Considering
the relevant issues in this proceeding, the evidence submitted combined
with the mere assertions of fact advanced by the PEG 3350 ANDA holders
is insufficient to raise a genuine and substantial issue of fact
requiring a hearing. The Commissioner therefore denies the PEG 3350
ANDA holders' request for a hearing and is entering summary judgment
(Sec. Sec. 12.24(b)(1) and (2), and 314.200(g)).
B. New Evidence Submitted With the Objections to the Proposed Order
In addition to submitting evidence intended to support its
arguments in its request for hearing, Nexgen's objection to CDER's
proposed order included new evidence and allegations. Nexgen maintains
the new information and allegations raise genuine and substantial
issues of fact requiring a hearing. The new information includes
medical literature describing the use of PEG 3350 for chronic
constipation and for a duration longer than 14 days, and literature
discussing the physician's role in PEG 3350 use. Also included in the
Objection are allegations that FDA was long ``aware'' of the tension
between the safe duration of use period for OTC laxatives and the use
of laxatives for prolonged periods in certain populations with
physician supervision. Nexgen also alleges for the first time that OTC
MiraLAX has a new indication because FDA's approval letter referenced
required pediatric studies for OTC MiraLAX. Nexgen also raises
allegations regarding: additional active ingredients for which FDA has
permitted simultaneous prescription and nonprescription products; the
lack of a labeling comprehension study and advisory committee meeting
prior to approval of OTC MiraLAX; a U.S. Department of Health and Human
Services (HHS) announcement of a grant to study PEG 3350 in the
pediatric population; and the cost of OTC MiraLAX. Nexgen submitted
survey results of physician perceptions of the OTC and prescription
MiraLAX labeling, data on reported adverse events for MiraLAX after the
OTC approval, and data on continued sales of prescription MiraLAX
(Nexgen Objection at 23-43; Nexgen Objection Exhibits 5-7).
Under Sec. 314.200(c), an applicant who wishes to participate in a
hearing shall file the studies on which the person relies to justify a
hearing within 60 days after the date of publication of the notice of
opportunity for hearing. FDA will not consider data or analyses
submitted after that 60-day timeframe when determining whether a
hearing is warranted unless they are derived from well-controlled
studies begun before the
[[Page 14001]]
date of the notice of opportunity for hearing and the results of the
studies were not available within 60 days after the date of publication
of the notice. Under those circumstances, the person requesting a
hearing shall list all studies in progress, the results of which the
person intends later to submit in support of the request for a hearing.
Additionally, such person must submit a copy of the complete protocol,
a list of participating investigators, and a brief status report of the
studies within 60 days of the notice of hearing. Further, FDA may
consider studies submitted outside the 60-day timeframe when the person
requesting a hearing makes a showing of an inadvertent omission and
hardship (Sec. 314.200(c)(1) and (2)).
In the preamble to 21 CFR 130.14, the predecessor to Sec. 314.200,
FDA rejected a comment suggesting that FDA should permit later
submission of material ``not known'' to exist at the time a request for
hearing is due. FDA stated on numerous occasions in the past, persons
requesting a hearing have subsequently supplemented that request with
multiple submissions of data and information culled from the literature
and other sources, all of which were available at the time of the
original request for hearing. This has resulted in lengthy delays while
the newly submitted information has been assessed. In the interest of
administrative efficiency, it is essential that this type of continuous
submission be precluded. Accordingly, the new regulations require that
any submission of existing information be made within the 60-day time
period permitted in the regulations. (39 FR 9750 at 9757.) Likewise, in
the preamble to the predecessor to part 12, FDA stated it would be
impracticable to permit supplementation at any time prior to the
Commissioner's ruling on an objection or request for hearing, for the
Commissioner would then be required to defer his ruling whenever
supplemental material was received. This would seriously disrupt the
process of ruling on objections and requests, would frustrate efforts
of persons to respond in support of denial of a hearing, and could
prolong action indefinitely. (41 FR 51706 at 51707, November 23, 1976.)
In its request for a hearing, Nexgen stated, ``Nexgen is submitting
herein substantial facts and legal analyses controverting FDA's
position, and intends to supplement this information in its `60 day'
submission pursuant to 21 CFR 12.22 and 314.200.'' (Nexgen Comment at
2). Regarding the new information and allegations Nexgen submitted in
its Objection, Nexgen made no attempt to supplement its request for
hearing in a manner that comports with the requirements of Sec.
314.200(c)(2). Nexgen did not show that the information includes data
derived from well-controlled studies that began before the date of the
notice of opportunity for hearing and that the results were not
available within 60 days of the date of publication of the notice.
Nexgen did not list the studies in progress, nor did it submit the
protocols, the participating investigators, or a status report of the
studies. Nexgen made no showing that any of the data or analyses or
cited publications are derived from well-controlled studies. Even if
FDA were to consider information not derived from well-controlled
studies submitted after 60 days, Nexgen made no attempt to inform FDA
that it would be submitting the results of a telephonic survey, adverse
event data, labeling analysis of products for which FDA has permitted
simultaneous prescription and nonprescription marketing, cost data, or
continued sales data for prescription MiraLAX. Additionally, Nexgen did
not show that the new information and allegations submitted in the
Objections were not included in its Request for Hearing due to an
inadvertent omission and hardship. Nexgen's failure to submit this new
evidence in conformance with Sec. 314.200 gives the Commissioner
sufficient reason to decline to review it.
Even if the Commissioner were to consider the submissions in
Nexgen's objection, Nexgen's new information and analyses are not
relevant to the issue of whether there is a meaningful difference
between the prescription and nonprescription versions of MiraLAX
approved by FDA such that PEG 3350 could be marketed simultaneously in
both a prescription and nonprescription MiraLAX product. The data and
analyses submitted by Nexgen, such as the physician survey, studies of
PEG 3350 for chronic constipation, the approval process for OTC
MiraLAX, adverse event reports for MiraLAX, sales data for prescription
MiraLAX, the cost of OTC MiraLAX, and HHS funding to study PEG 3350 in
the pediatric population, are not related to the factors set forth in
the ANPRM and the NOOH as material to determining meaningful
difference. In light of the requirements in Sec. 314.200 for
submitting data and analyses after the 60-day deadline, FDA's rationale
for imposing restrictions on the submission of data and analyses after
60 days, and the lack of relevance of this information, the
Commissioner will not further consider the information Nexgen and
Breckenridge submitted with their objections to the proposed order.
C. Legal Arguments Offered by the ANDA Holders
The ANDA holders have failed to raise a genuine and substantial
issue of fact that requires a hearing, and a hearing will not be
granted on issues of law (Sec. 12.24(b)(1)). In addition, the
Commissioner does not find the arguments advanced by the PEG 3350 ANDA
holders persuasive and is entering summary judgment against them. The
Commissioner will address each argument and assertion made by the PEG
3350 ANDA holders in support of their hearing requests to explain the
finding of summary judgment.
The arguments addressed in section III.C of this order challenge
the statutory and regulatory requirements of the FD&C Act that govern
prescription and nonprescription marketing status, the withdrawal of
approval of a drug application, generic drugs and exclusivity, and FDA
enforcement. The arguments challenge the regulatory requirements of the
Administrative Procedure Act (APA) and FD&C Act with regard to notice
and comment rulemaking. The arguments also challenge the statutory and
regulatory requirements for summary judgment. As such, they are legal
arguments, which do not raise a genuine and substantial issue of fact.
Thus, these arguments cannot form the basis for granting a hearing (see
Sec. Sec. 12.24(b)(1) and 314.200(g)). In addition, these arguments do
not have any legal merit.
1. The Agency's Authority Under Section 503(b)(4)(B) of the FD&C Act
Nexgen, Paddock, and Gavis all submitted arguments regarding the
Agency's authority under section 503(b)(4)(B) of the FD&C Act.
Specifically, they argue that because their ANDAs were approved as
prescription products, they are required to bear the ``Rx only'' symbol
and therefore cannot be deemed misbranded under section 503(b)(4)(B) of
the FD&C Act (Nexgen Comments at 37-39). As the basis for this
argument, they suggest that the provisions in section 503(b)(1)(A) are
independent of those in section 503(b)(1)(B) of the FD&C Act, and a
drug is a prescription drug if it is covered under section
503(b)(1)(B), regardless of whether it is covered under section
503(b)(1)(A) (Nexgen Comments at 38; Gavis Comments at 002; Paddock
Comments at 6). Thus, they contend that once a drug is approved as
prescription under section 503(b)(1)(B) of the FD&C Act, it is
[[Page 14002]]
always prescription and that status cannot be taken away, regardless of
a change from prescription to nonprescription status of the RLD.
Likewise, they argue that the Durham-Humphrey Amendments (Pub. L.
82-215 (1951)) were not intended to address the situation in which a
prescription drug product is forced to change to nonprescription
because a separate NDA for the same active ingredient was approved as a
nonprescription product (Nexgen Comments at 39-40). They further argue
that if Congress intended generic prescription drugs to become
misbranded immediately when their referenced products are approved for
nonprescription use, it should have written that explicitly into the
FD&C Act (Gavis Comments at 003; Paddock Comments at 6; Nexgen Comments
at 39-40).
A basic rule of statutory construction is that ``a statute is to be
read as a whole . . . since the meaning of statutory language, plain or
not, depends on context.'' (King v. St. Vincent's Hosp., 502 U.S. 215,
220 (1991) (citations omitted).) ``A provision that may seem ambiguous
in isolation is often clarified by the remainder of the statutory
scheme . . . .'' (United Savings Ass'n v. Timbers of Inwood Forest
Associates, 484 U.S. 365, 371 (1988) (citations omitted)). In line with
the notion that the statute should be read in a holistic manner,
congressional silence on a particular point does not lend more credence
to one interpretation if much of the evidence would point to another
interpretation. ``An inference drawn from congressional silence
certainly cannot be credited when it is contrary to all other textual
and contextual evidence of congressional intent.'' (See Burns v. United
States, 501 U.S. 129, 136 (1991) (internal citation omitted).) Further,
where Congress does not explicitly include language addressing a
particular situation, it is appropriate for FDA to form an
interpretation of the proper application of the statute based on the
legislative history (see Wilder v. Virginia Hosp. Ass'n, 496 U.S. 498,
515 (1990) (referencing to Senate report for evidence of ``the primary
objective'' of the Boren amendment to the Medicaid law)).
The ANDA holders' argument that once a product is approved as a
prescription product, it is always a prescription product, cannot
withstand a holistic reading of section 503(b) of the FD&C Act. Section
503(b)(3) states that FDA may ``remove drugs subject to section 505 [of
the FD&C Act] from the requirements of [section 503(b)(1)] . . . when
such requirements are not necessary for the protection of the public
health.'' On its face, the statute authorizes the Secretary to exempt a
product from the prescription-dispensing requirements when such
requirements are not necessary for the protection of the public health.
Further, section 503(b)(3) of the FD&C Act references 503(b)(1) in its
entirety and thus applies to drugs that are limited by an application
approved under section 505 of the FD&C Act to prescription use under
section 503(b)(1)(B). FDA set forth this interpretation when it issued
Sec. 310.200 in 1963 (28 FR 6377, June 20, 1963). That regulation
states that any drug limited to prescription use under section
503(b)(1)(B) of the act shall be exempted from prescription dispensing
requirements when the Commissioner finds such requirements are not
necessary for the protection of the public health by reason of the
drug's toxicity or other potentiality for harmful effect, or the method
of its use, or the collateral measures necessary to its use, and he
finds that the drug is safe and effective for use in self-medication as
directed in proposed labeling. (Sec. 310.200(b).) Therefore, the ANDA
holders' general contention that once a product is approved as a
prescription product under section 503(b)(1)(B) of the FD&C Act, it can
never lose its prescription status, is incorrect.
Section 503(b)(4) of the FD&C Act describes when a drug product is
required to bear the ``Rx only'' symbol on its label and when a drug
product may not bear the ``Rx only'' symbol. Under section
503(b)(4)(A), any drug product that is subject to 503(b)(1) ``shall be
deemed misbranded if at any time prior to dispensing the label of the
drug fails to bear . . . the symbol `Rx only'.'' Under section
503(b)(4)(B) of the FD&C Act, any drug product that is not subject to
503(b)(1), i.e., a nonprescription product, shall be deemed to be
misbranded if it bears the ``Rx only'' symbol on its label any time
prior to the dispensing of the drug product. The purpose of section
503(b)(4) of the FD&C Act is to eliminate the marketing of both
prescription and nonprescription versions of the same drug product at
the same time (see Pub. L. 82-215 (1951)).
While considering the Durham-Humphrey Amendments, Congress noted
that retail pharmacists shelved one and the same drug product made by
various manufacturers, but with different labels. Some drug products
bore prescription labeling while the same drug product manufactured by
a different firm bore nonprescription labeling, leading to confusion
for both pharmacists and the public. (See H.R. Rep. No. 82-700, at 3
(1951); S. Rep. No. 82-946, at 2 (1951); 97 Cong. Rec. 9235 (1951); see
also 97 Cong. Rec. 9321 (1951).) Congress stated that the purpose of
the amendments was to change that ``uncertain situation'' into a
``certain situation.'' (See 97 Cong. Rec. 9330 (1951).) The amendments
were also meant to ``relieve retail pharmacists and the public from
burdensome and unnecessary restrictions on the dispensing of drugs that
are safe for use without the supervision of a physician.'' (S. Rep. No.
82-946, at 1-2 (1951); see also 97 Cong. Rec. 9235 (1951).)
If section 503(b)(4) of the FD&C Act were construed the way Nexgen,
Paddock, and Gavis describe, the Durham-Humphrey Amendments would be
rendered meaningless. If a prescription generic drug product were
allowed to remain on the market by virtue of its approval as a
prescription product, which approval was based, among other things, on
its bioequivalence to an RLD, despite that RLD's switch from
prescription to nonprescription, there would be simultaneous marketing
of prescription and nonprescription versions of the same drug product.
This result conflicts with a holistic reading of section 503(b) of the
FD&C Act. Further, this result would negate a central purpose of the
Durham-Humphrey Amendments as set forth in the legislative history:
avoiding confusion for pharmacists and the public.
Additionally, the ANDA holders' argument with respect to Congress's
failure to include specific language in the FD&C Act describing the
exact situation in which the PEG 3350 ANDA holders find themselves is
not persuasive. In the absence of express statutory language, FDA is
permitted to put forth a reasonable interpretation of the statute. The
courts have long held that FDA's interpretation of the FD&C Act governs
as long as it is ``a permissible construction of the statute.'' (See
Chevron, U.S.A., Inc. v. Natural Res. Def. Council, Inc., 467 U.S. 837,
842-44(1984); Novartis Pharm. Corp. v. Leavitt, 435 F.3d 344, 349 (D.C.
Cir. 2006) (``FDA interpretations of the FDCA receive deference''); cf.
Pharmanex v. Shalala, 221 F.3d 1151, 1160 (10th Cir. 2000) (FDA's
interpretation that a ``new drug'' includes active ingredients as well
as finished drug products is entitled to deference); Nat'l Pharm.
Alliance v. Henney, 47 F. Supp. 2d 37, 39-40 (D.D.C. 1999) (because
Congress's use of ``drug'' in section 505 did not clearly speak to the
relevant issue, courts must defer to FDA's interpretation).) As
described above, Congress expressed
[[Page 14003]]
clear concerns about the same products being marketed as both
prescription and nonprescription products and the ensuing confusion for
both pharmacists and the public at large. FDA's interpretation of the
application of the Durham-Humphrey Amendments is not only a permissible
construction of section 503(b) of the FD&C Act when reading that
section as a whole, but a logical interpretation in light of the
legislative history behind the amendments. Additionally, based on those
concerns, Congress could not have intended the interpretation that the
ANDA holders put forth.
Furthermore, the PEG 3350 ANDA holders' interpretation of section
503(b)(4) of the FD&C Act is inconsistent with that held by the United
States Court of Appeals for the Seventh Circuit (Seventh Circuit). The
PEG 3350 ANDA holders were the Defendants-Appellees in a case under
section 43(a)(1)(B) of the Lanham Act (15 U.S.C. 1125(a)(1)(B))
concerning the marketing of generic prescription PEG 3350 products,
which was appealed to the Seventh Circuit after the District Court
dismissed the case pending a decision by FDA regarding the misbranding
of their products (i.e., the publication of this notice). In its
opinion, the Seventh Circuit upheld the lower court's decision and
clearly explained that ``the Food, Drug, and Cosmetic Act does not
permit both by-prescription-only and over-the-counter versions of the
same drug to be sold at the same time.'' (Schering-Plough Healthcare
Products, Inc. v. Schwarz Pharma, Inc., 586 F.3d 500, 505 (7th Cir.
2009) (citing section 503(b)(4) of the FD&C Act).) The Seventh Circuit
also explained that, in light of this provision of the FD&C Act, ``the
FDA is conducting a proceeding to determine whether [the PEG 3350 ANDA
products] are misbranded now that there is an over-the-counter version
of the drug . . . [and] if the FDA determines that they are `the same,'
the result will be that the generic drug can no longer be sold.''
(Id.).
In this case, CDER concluded, and the Commissioner affirms, that
there is not a meaningful difference between the prescription and
nonprescription versions of MiraLAX; i.e., that they are essentially
the ``same.'' And, once a drug product is fully switched from
prescription to nonprescription use, the previous prescription drug
product may no longer be legally marketed as per section 503(b) of the
FD&C Act, as the prescription product would be misbranded under section
503(b)(4)(B). Had Braintree continued to market prescription MiraLAX
following FDA's approval of OTC MiraLAX, the prescription MiraLAX would
have been misbranded. It follows that the PEG 3350 ANDA products that
reference prescription MiraLAX and that were approved based upon a
finding that they met the requirements of section 505(j)(2)(A)(i) to
(v) and (j)(4) of the FD&C Act cannot avoid being misbranded under
section 503(b)(4) and Sec. 310.200(d) simply because they were
initially approved as prescription drugs and continue to be marketed as
prescription products.
2. The Agency's Authority Under Section 505(e) of the FD&C Act
a. False or misleading. Nexgen and Paddock submitted comments
arguing that the prescription version of the labeling is not false or
misleading; therefore, the Agency does not have the authority to
withdraw the product under section 505(e) of the FD&C Act. Nexgen and
Paddock argue that the PEG 3350 labeling is not false or misleading
because it still meets the standards under which it was initially
approved as a prescription drug product referencing NDA 20-698. They
maintain that the approval of their products as prescription drugs did
not depend upon PEG 3350's toxicity or other potentiality for harmful
effect, or the method of its use, or the collateral measures necessary
to its use. Rather, they maintain that their PEG 3350 products are
entitled to prescription status under section 503(b)(1)(B) of the FD&C
Act because the ANDA required that their products be dispensed by
prescription. They also contend that because the NOOH provides no
evidence of new information that would indicate that the labeling is
false or misleading, section 505(e)(3) of the FD&C Act does not apply
(see Nexgen Comments at 41; Paddock Comments at 9-10).
These legal arguments are based upon an incorrect assertion that
the products are not misbranded under section 503(b)(4) of the FD&C
Act. In this instance, neither criterion under 503(b)(1) applies to the
generic PEG 3350 products. FDA previously determined, at the time OTC
MiraLAX was approved, that the supervision of a licensed practitioner
is no longer necessary for the use of MiraLAX and that no prescription
indications remained. After FDA made that determination with regard to
the RLD, the legal status of the RLD as a prescription product and the
medical and scientific basis underlying the approval of both the RLD
and the generic PEG 3350 products as prescription drugs no longer
existed. Where, as here, the legal and scientific underpinnings of the
approval of the generic PEG 3350 products as prescription drugs have
ceased to exist, FDA concludes that section 503(b)(1)(B) of the FD&C
Act no longer applies to those products. This interpretation is
supported by a reading of section 503(b) as a whole and is consistent
with the purpose of the statute as set forth in the legislative
history, as discussed in the above subsection of this order. In
addition, the labeling of the ANDA PEG 3350 products is false or
misleading. By bearing the ``Rx only'' symbol, the labeling implies
that the products can be dispensed safely only with a licensed
practitioner's prescription. Yet, FDA has determined that MiraLAX can
be used safely and effectively in the nonprescription setting and
specifically does not meet the criteria in 503(b)(1) of the FD&C Act.
In section III. D. of this order, FDA has determined that the generic
PEG 3350 products are the same drug product as nonprescription MiraLAX
(i.e., there is no meaningful difference between them) for purposes of
determining whether they are misbranded under section 503(b)(4) of the
FD&C Act. Thus, the contention that the generic prescription labeling
is not false or misleading because the applications were originally
approved as prescription products is without merit.
Because the labeling for the PEG 3350 prescription products is
false or misleading, the Agency has the authority to withdraw approval
of the products under section 505(e)(3) of the FD&C Act. The ``new
information'' in this case is the October 2006 approval of MiraLAX as
an OTC drug, the change in status of MiraLAX from prescription to
nonprescription, and the fact that the PEG 3350 ANDA holders have not
submitted new ANDAs referencing OTC MiraLAX and including the same OTC
labeling as the RLD after receiving written notice from FDA.
Accordingly, the standard for withdrawal in section 505(e)(3) of the
FD&C Act has been met.
b. Written notice. Schwarz submitted comments arguing that the
April 20, 2007, letters are not sufficient ``written notice'' under the
FD&C Act to justify the NOOH. Schwarz argues that because neither the
Secretary, nor anyone with properly delegated authority, provided
written notice to Schwarz, the April 20, 2007, letter does not
constitute an advisory opinion or represent the formal position of FDA.
Further, Schwarz claims that there is no evidence that Schwarz did not
attempt to correct the issues identified in the April 20, 2007, letter.
Because of this, Schwarz contends that FDA has not satisfied the
prerequisites to withdrawal under
[[Page 14004]]
section 505(e)(3) of the FD&C Act and the NOOH is invalid (Schwarz
Comments at 2-3).
This argument is unavailing. Section 505(e) states that the
Secretary may, ``after due notice and opportunity for hearing to the
applicant,'' withdraw approval of a drug application if the Secretary
finds that the labeling of such drug is false or misleading in any
particular and was not corrected within a reasonable time after receipt
of written notice from the Secretary specifying the matter complained
of. Schwarz's assertions regarding the April 20, 2007, letter are
unavailing, as even if the Commissioner were to assume that the Buehler
letter failed to satisfy the requirements of section 505(e), the NOOH
itself also satisfies this requirement.
The NOOH issued in October 2008 proposed the withdrawal of the PEG
3350 ANDAs on the basis of the switch of MiraLAX from Rx to OTC. The
NOOH noted that the FD&C Act does not permit both Rx and OTC versions
of the same drug product to be marketed at the same time. Under the
FD&C Act, a drug to which the prescription dispensing requirements do
not apply (i.e., an OTC drug) shall be deemed misbranded if at any time
prior to its dispensing, the label of the product bears the ``Rx only''
symbol. The NOOH explained that the ANDA products' labels, which bear
the ``Rx only'' symbol, are false or misleading because the same PEG
3350 product was approved for OTC use. Thus the NOOH, which was issued
by the Associate Commissioner for Policy and Planning pursuant to
delegated authority,\8\ also satisfies the requirement in section
505(e) of the FD&C Act that there be written notice specifying the
matter complained of.
---------------------------------------------------------------------------
\8\ The Secretary delegated authority to the Commissioner, with
authority to redelegate, all functions vested in the Secretary under
the FD&C Act, as set forth in the FDA Staff Manual Guide, Volume II,
Number 1410.10 (effective May 18, 2005). Available at: https://web.archive.org/web/20070701125239/http://www.fda.gov:80/smg/1410_10.html (accessed December 15, 2017). At the time the NOOH was
issued, the Commissioner had redelegated the authority to perform
all functions of the Commissioner to certain specified officials
including the Associate Commissioner for Policy and Planning, as set
forth in the FDA Staff Manual Guide, Volume II, Number 1410.21
(effective May 15, 2007). Available at: https://web.archive.org/web/20070705185904/http://www.fda.gov:80/smg/1410_21.html (accessed
December 15, 2017).
---------------------------------------------------------------------------
Contrary to Schwarz's suggestion, there is nothing in the statute
that requires written notice to ``justify'' the NOOH; the statute only
requires written notice as a prerequisite to the withdrawal itself. The
NOOH did not withdraw the applications; it merely initiated this
proceeding during which the applicants were given ample opportunity to
contest the proposed withdrawals. The Commissioner is withdrawing
approval of the applications via this order, and the NOOH serves as
written notice prior to this withdrawal under section 505(e) of the
FD&C Act.\9\
---------------------------------------------------------------------------
\9\ The ANDA holders have received additional notice prior to
this withdrawal order that their products' labeling was false or
misleading, as required by section 505(e) of the FD&C Act. In May
2014, Dr. Janet Woodcock, CDER Director, wrote to the ANDA holders
and attached a copy of the proposed order, which specified CDER's
basis for concluding that the prescription MiraLAX labeling is false
or misleading. The ANDA holders have not corrected the misbranding
within a reasonable time of receiving Dr. Woodcock's letter. In May
2014, Dr. Woodcock had the properly delegated authority to take
regulatory actions for drugs for human use for which approved
applications submitted under section 505 of the FD&C Act are in
effect. See FDA Staff Manual Guide 1410.104 ] 1.A (effective June
12, 2012). Available at: https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/StaffManualGuides/UCM336918.pdf.
---------------------------------------------------------------------------
3. The Agency's Authority Under Hatch-Waxman
Paddock's comments contend that the Hatch-Waxman amendments do not
authorize FDA to withdraw approval of an ANDA for nonsafety or
noneffectiveness reasons. In fact, Paddock argues, by removing the
prescription PEG 3350 products from the market, FDA is effectively
awarding Braintree 6 years of exclusivity for its prescription product,
which contravenes the Hatch-Waxman Amendments in section 505(c) and (j)
of the FD&C Act. Paddock further argues that FDA's award of 3 years of
exclusivity to OTC MiraLAX must have been based on studies in a new
patient population and thus contravenes the proposal to find that there
is not a meaningful difference between the prescription and OTC
products (Paddock Comments at 5-6).
These allegations make incorrect statements about the Agency's
authority under the FD&C Act regarding withdrawal of generic drug
products and granting of market exclusivity. The Hatch-Waxman
Amendments established new section 505(j) of the FD&C Act, which sets
forth the ANDA approval process for generic drugs. The NOOH proposed
withdrawal based upon the second sentence of section 505(e) of the FD&C
Act, which explicitly references section 505(j), and vests the
Secretary with the authority to withdraw an ANDA whenever new
information establishes that ``the labeling of such drug . . . is false
or misleading in any particular.'' The prescription PEG 3350 ANDAs are
misbranded under section 503(b)(4)(B) of the FD&C Act and FDA's
regulations because they are marketed for prescription use at the same
time as a nonprescription product that FDA determines in this order is
not meaningfully different. In this case, the use of the ``Rx only''
symbol on the labeling of the prescription PEG 3350 products is false
or misleading because it implies that the products are required to be
dispensed only with a prescription; whereas FDA has determined that the
same product does not meet the criteria in section 503(b)(1) of the
FD&C Act and can be used safely and effectively in the nonprescription
setting.
FDA did not award Braintree 6 years of exclusivity for its
prescription product. Braintree received 3 years of exclusivity under
section 505(j)(5)(F) of the FD&C Act when the initial approval of
prescription MiraLAX was supported by new clinical studies essential to
its approval conducted by or on behalf of Braintree. It also received 3
years of exclusivity under the same provision when the OTC switch NDA
was approved because Braintree supported its OTC MiraLAX application
with new clinical studies conducted by or on behalf of Braintree that
were essential to its approval. These are two separate awards of
exclusivity earned by Braintree under the criteria set forth in the
FD&C Act. Contrary to Paddock's contention, there were two separate
bases for granting two 3-year periods of exclusivity, as is often the
case when products switch from prescription to nonprescription status.
4. Arguments Regarding the Administrative Procedure Act
a. Notice and comment rulemaking. Paddock argues that the Agency's
withdrawal of the Rx PEG 3350 ANDAs following MiraLAX's switch from Rx
to OTC would violate the APA when MiraLAX's switch was not accomplished
through the notice and comment rulemaking process. Paddock argues that
the Durham-Humphrey Amendments preclude withdrawal of a generic product
based on a change of the RLD to nonprescription status unless the RLD's
prescription status was changed through rulemaking (Paddock Comments at
2-3). Therefore, Paddock contends that because the Agency did not
engage in notice and comment rulemaking to change the status of MiraLAX
from prescription to nonprescription, it does not have the authority to
withdraw approval of the PEG 3350 ANDAs (Paddock Comments at 2-3, 7).
Paddock further argues that the approval of OTC MiraLAX and the later
decision to propose withdrawal of
[[Page 14005]]
the prescription PEG 3350 ANDAs from the market is essentially a
legislative rule issued without notice and comment in violation of the
APA (Paddock Comments at 7-8). In addition, Paddock argues that because
the Agency has never defined how it assesses a meaningful difference,
it is in effect issuing a legislative rule without engaging in notice
and comment rulemaking (Paddock Comments at 19).
These allegations are inaccurate regarding the Agency's authority
under the FD&C Act and the APA, neither of which requires the issuance
of regulations before FDA can determine that a drug no longer meets the
criteria at section 503(b)(1) of the FD&C Act. Paddock seemingly relies
upon section 503(b)(3), which describes one procedure for exempting a
drug from the prescription drug requirements of section 503(b)(1) of
the FD&C Act. Specifically, section 503(b)(3) provides that FDA may, by
regulation, remove a drug from the prescription dispensing requirements
in section 503(b)(1) of the FD&C Act when the prescription status
mandated by its NDA approval is no longer ``necessary for the
protection of the public health.'' FDA has interpreted section 503(b)
of the FD&C Act to allow the Agency to switch a drug product from
prescription to nonprescription by approving an NDA submitted by a
sponsor seeking such a change. In practice, FDA has exercised that
authority and changed the status of numerous products from prescription
to nonprescription through the submission of NDAs.
Further, in the absence of express statutory language requiring
rulemaking, government agencies possess broad discretion in deciding
whether to proceed by general rulemaking or case-by-case adjudication.
(See, e.g., NLRB v. Bell Aerospace, 416 U.S. 267, 293-94 (1974)
(stating that ``the choice made between proceeding by general rule or
by individual, ad hoc litigation is one that lies primarily in the
informed discretion of the administrative agency.'' (internal citation
omitted)); see generally Cellnet Commc'n, Inc. v. FCC, 965 F.2d 1106,
1111 (D.C. Cir. 1992) (reviewing the FCC's refusal to initiate a
rulemaking and stating that ``an agency's refusal to initiate a
rulemaking is evaluated with a deference so broad as to make the
process akin to non-reviewability.'').) While the Agency may proceed
through rulemaking, FDA also has the authority to exempt a drug from
the prescription dispensing requirements without rulemaking. Switching
a product through the NDA holder's submission of an NDA is an example
of the Agency exercising its authority to proceed on a case-by-case
basis.
As noted above, Paddock argues that withdrawal of the PEG 3350
ANDAs in the absence of notice and comment rulemaking constitutes a
legislative rule. Under section 505(e) of the FD&C Act, FDA may
withdraw approval of applications through adjudication, as the Agency
is doing here; therefore, FDA's withdrawal of the PEG 3350 ANDAs does
not constitute a legislative rule. Further, the issue of whether an FDA
action involving an interpretation of the FD&C Act constitutes a
legislative rule has been previously considered. In a matter
challenging FDA's implementation of the pediatric exclusivity
provisions of the Food and Drug Administration Modernization Act of
1997 (FDAMA), one of the arguments maintained that the ``Guidance for
Industry: Qualifying for Pediatric Exclusivity Under Section 505A of
the Federal Food, Drug, and Cosmetic Act'' was a legislative rule that
should have been enacted through notice and comment rulemaking. To
determine whether the rule in that case was legislative or
interpretive, the court used the four-part test from American Mining
Congress v. Mine Safety & Health Admin., 995 F.2d 1106 (D.C. Cir.
1993). The court first asked ``whether in the absence of the rule there
would not be an adequate legislative basis for . . . agency action.''
(Nat'l Pharm. Alliance v. Henney, 47 F. Supp. 2d 37, 41 (D.D.C. 1999).)
The court reasoned that, ``[FDAMA] on its face provides all the
`legislative basis' that is necessary for the agency's action,'' (Id.)
and did not reach the remaining questions. As explained in section
III.C.1 of this order, Congress explicitly added the Durham-Humphrey
Amendments to the FD&C Act to eliminate the marketing of both
prescription and nonprescription versions of the same drug product at
the same time. Thus, as with FDAMA, sections 503 and 505(e) of the FD&C
Act provide the legislative basis for FDA to withdraw the PEG 3350
ANDAs; therefore, FDA's withdrawal action does not constitute a
legislative rule. To the extent that Paddock argues that FDA's
interpretation of meaningful difference, as set forth in the NOOH and
ANPRM, is a legislative rule, applying the American Mining Congress
four-part test again supports that FDA's interpretation does not
constitute a legislative rule. As explained earlier in section I.B of
this order, in the 2005 Federal Register notice referenced above, FDA
explained that the Agency has interpreted the language in section
503(b)(1) and (4) of the FD&C Act to allow marketing of the same active
ingredient in products that are both prescription and nonprescription,
assuming some meaningful difference exists between the two that makes
the prescription product safe only under the supervision of a licensed
practitioner (70 FR 52050 at 52051). FDA noted such a difference could
be, for example, in indication, strength, route of administration, and/
or dosage form. This is a permissible interpretation of the FD&C Act by
FDA (see, e.g., Shalala v. Guernsey Mem'l Hosp., 514 U.S. 87, 110
(1995) (5-4 decision) (O'Connor, J., dissenting)). The interpretation
of ``meaningful difference'' does not require notice and comment
rulemaking because the Durham-Humphrey Amendments provide an adequate
legislative basis on its face to make such an interpretation.
b. Burden of proof. Paddock argues that the Agency also violates
the APA in its application of evidentiary requirements with regard to
summary judgment. Paddock argues that the APA places the burdens of
persuasion and production on the party seeking an order, which in this
case is the Secretary (Paddock Comments at 14). Here, Paddock contends
that the Agency has to present evidence that the labeling of the
prescription PEG 3350 products is false and misleading and that FDA's
action to withdraw the ANDAs is based on new information (Paddock
Comments at 14).
It is inappropriate, Paddock argues, for the Agency to issue a
summary judgment order absent a hearing because the APA only authorizes
a hearing officer to do so, and the Agency should be the party
demonstrating that there is no genuine and substantial issue of fact
(Paddock Comments at 16). If the Agency proceeds as it plans to
according to the NOOH and issues an order for summary judgment, Paddock
argues, it would be acting as prosecutor, judge, and jury, which is not
authorized under the APA (Paddock Comments at 16).
Furthermore, both Nexgen and Paddock request that the Agency make
all of the data from the clinical studies in the nonprescription
MiraLAX NDA (22-015) available to the PEG 3350 ANDA holders (Nexgen
Comments at 40 n. 37; Paddock Comments at 17-19; Nexgen Objection at
76-77). Not doing so, they claim, deprives them of due process because
the data cited in the NOOH is not sufficient to understand the basis
upon which FDA is acting to remove the PEG 3350 ANDAs from the market.
Paddock argues that, under Rule 56(f) of the Federal Rules of Civil
Procedure (FRCP), it has the right to review the protocols and data
[[Page 14006]]
underlying the OTC MiraLAX approval (Paddock Comments at 17-19).
These allegations mischaracterize the Agency's authority to issue
summary judgment orders as set forth under the FD&C Act, its
implementing regulations, and the APA, and as reflected in case law.
The Agency is authorized under section 505(e) of the FD&C Act to
withdraw a drug from the market, after notice and opportunity for a
hearing, if its labeling is false and misleading. In addition, FDA's
regulations set forth a regulatory procedure for withdrawing approval
of drug marketing applications under 505(e) that is designed to provide
due process, including notice and opportunity for a hearing, to
application holders (see Sec. 314.200(a)). FDA's regulations governing
formal evidentiary public hearings set forth the grounds upon which a
hearing may be denied and summary decision granted (see Sec. 12.24).
FDA regulations explicitly require the person requesting a hearing to
show that the criteria in Sec. 12.24(b) for granting a hearing are
met. Likewise, where FDA serves a proposed order denying a hearing, the
burden remains on the person requesting the hearing to respond with
sufficient data, information, and analysis to justify a hearing
(Sec. Sec. 12.24 and 314.200(g)).
In fact, these administrative procedures have been previously
upheld by the Supreme Court (see Hynson, 412 U.S. at 622 (``we find FDA
hearing regulations unexceptionable on any statutory or constitutional
ground.'')). Likewise, the courts have held that summary judgment is
available to FDA if hearing requests fail to raise a genuine and
substantial issue of fact. (See Hynson, 412 U.S. at 621 (``We cannot
impute to Congress the design of requiring, nor does due process
demand, a hearing when it appears conclusively from the applicant's
`pleadings' that the application cannot succeed.''); Hess & Clark, 495
F.2d at 983 (``When the FDA issues a Notice of Opportunity for Hearing,
its summary judgment procedures are available if the requesting party
fails to raise material issues of fact.'').) Contrary to Paddock's
contentions, FDA is authorized to act as the final arbiter on issues of
summary judgment. In issuing the predecessor regulation to Sec.
314.200, FDA rejected comments asserting that an Administrative Law
Judge should determine whether there is an issue of fact justifying a
hearing. FDA noted that the same legal arguments were raised in the
pharmaceutical industry briefs in Hynson and were rejected by the
Supreme Court holding that the present summary judgment procedures met
all statutory and constitutional requirements (39 FR 9750 at 9754). Not
all of the constraints inherent in Rule 56 of the FRCP apply to this
proceeding. (See Smithkline Corp. v. FDA, 587 F.2d 1107, 1119 (D.C.
Cir. 1978) (``The Supreme Court has made clear, however, that, because
these circumstances do not involve the Seventh Amendment right to a
trial by jury, we need not engage in the sharp limitations on summary
judgment required by Rule 56 of the Federal Rules of Civil
Procedure.''); Copanos, 854 F.2d at 518 (``It is well settled that this
provision does not guarantee the applicant a hearing in all
circumstances; the agency may by regulation provide for summary
withdrawal of approvals. . . .'').)
Based on the requirements of the FD&C Act, FDA's regulations, and
the APA, Paddock and the other PEG 3350 ANDA holders have been afforded
an appropriate opportunity to justify a hearing on the factual basis
for the proposed withdrawal of approval for the ANDAs. They have been
given specific instructions as to the type and detail of evidence
required to support a request for hearing. As explained elsewhere in
this order, the ANDA holders' approval relies on FDA's prior safety and
efficacy findings for the RLD. The issue for resolution in this
proceeding is whether there is a meaningful difference between OTC
MiraLAX and the prescription PEG 3350 products as approved by FDA.
Whether or not FDA should have approved MiraLAX Rx or MiraLAX OTC in
the first place is not at issue here. Due process does not require FDA
to provide the underlying data supporting the approval of prescription
or OTC MiraLAX. The Agency is not obligated to provide the PEG 3350
ANDA holders additional or more detailed information with regard to its
issuance of the NOOH.
5. Other Legal Arguments or Claims
Nexgen argues in its request for a hearing that FDA has never taken
enforcement action to require the withdrawal of a prescription drug
product simply because it lacks a meaningful difference from a later-
approved nonprescription drug product (Nexgen Comments at 43). Thus,
they contend that ``FDA has no regulatory standards in place and no
enforcement history to cite as a body of law establishing the
foundation or the basis for its extraordinary proposed withdrawal'' of
the prescription PEG 3350 ANDAs (Nexgen Comments at 43 (emphasis in
original)).\10\
---------------------------------------------------------------------------
\10\ Counsel for Nexgen, Buchanan, Ingersoll & Rooney PC, also
raised this issue in a Citizen Petition to the Agency (unrelated to
the subject of this notice). See Docket No. FDA-2009-P-0589, Citizen
Petition from Edward John Allera, Request to Confirm Dihydrocodeine
Bitartrate as Generally Recognized as Safe and Effective for Use as
a Liquid Antitussive in Prescription Cough/Cold Drug Products, dated
December 1, 2009. The Agency denied the Citizen Petition in its
entirety noting that ``The fact that FDA has not taken enforcement
action against particular products in the past has no bearing on the
lawfulness of the marketing of such products. FDA is not estopped
from enforcing the requirements of the FD&C Act because the Agency
has not previously enforced those requirements with respect to
certain unapproved and violative products.'' (See Response to
Citizen Petition FDA-2009-P-0589, issued March 9, 2012.)
---------------------------------------------------------------------------
This argument does not have any legal merit. It is within FDA's
purview to determine when and what enforcement actions are appropriate
regarding specific drug products, taking into account Agency resources
and public health priorities. Such individual enforcement-related
decisions have no bearing on the lawfulness of the marketing of any
particular product. Even if FDA were enforcing provisions of the FD&C
Act it had not previously, FDA is not estopped from enforcing those
provisions (see Scott Paper Co. v. Marcalus Mfg. Co., 326 U.S. 249, 257
(1945); Donovan v. Daniel Marr & Son, Co., 763 F.2d 477, 484 (1st Cir.
1985); United States v. Undetermined Quantities of Clear Plastic Bags
of an Article of Drug for Veterinary Use, 963 F. Supp. 641, 646-647,
aff'd, No. 97-3467, 1998 U.S. App. LEXIS 9320, at *3-4 (6th Cir. May 4,
1998); United States v. 789 Cases of Latex Surgeons' Gloves, 799 F.
Supp. 1275, 1296-97 (D.P.R. 1992)). Companies marketing drug products
in the United States have the responsibility to ensure that their
products are safe and effective and marketed in compliance with the
law. Any product, including a product that is misbranded under the FD&C
Act, which is being marketed illegally is subject to enforcement action
at any time.\11\
---------------------------------------------------------------------------
\11\ FDA, Guidance for FDA Staff and Industry Marketed
Unapproved Drugs Manual of Compliance Policy Guides 440.100 at 5-6
(2011), available at https://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/ucm074382.htm.
---------------------------------------------------------------------------
Gavis submitted comments arguing that changing their prescription
PEG 3350 product to nonprescription status would open them up to
product liability in many States because they would not have the
benefit of the learned intermediary defense, which exists for
prescription products (Gavis Comments at 005). Nexgen argues for the
first time in its objection that the ANDA holders could be subject to
design defect liability for use beyond 7 days and misbranding charges
for promoting use beyond 7 days. Nexgen also maintains that physicians
may be subject to tort
[[Page 14007]]
liability for instructing patients to use OTC MiraLAX for a duration
longer than 7 days (Nexgen Objection at 77-78).
Potential liability issues are not among the factors FDA considers
in determining whether an active ingredient may be simultaneously
marketed in a prescription and nonprescription product. With regard to
the decision to approve OTC MiraLAX, the Agency does not consider
individual State tort law liability in its decisions regarding the
safety and efficacy of drug products and whether the criteria for
prescription products at section 503(b)(1) of the FD&C Act are met. As
a matter of Federal law, FDA determines when approving an NDA whether a
product meets the criteria for prescription drugs in the FD&C Act at
section 503(b), or whether it can be safely and effectively marketed as
a nonprescription product.
D. Evidence and Arguments Regarding Meaningful Difference Between the
Prescription and Nonprescription PEG 3350 Products
As noted in section III.A, the PEG 3350 ANDA holders submitted
evidence and arguments to support the contention that there is a
meaningful difference between the prescription and nonprescription PEG
3350 products and assert that FDA is incorrect in proposing to withdraw
the prescription version from the market. The evidence and arguments
submitted by the PEG 3350 ANDA holders are further addressed in this
section.
1. Duration of Use
Despite the fact that FDA considered the change of MiraLAX from
prescription to nonprescription to be a ``full'' switch (and MiraLAX is
no longer a RLD eligible to be marketed on a prescription basis),
Nexgen, Gavis, and Paddock all assert that the difference in duration
of use between the prescription and nonprescription versions of the PEG
3350 labeling constitutes a meaningful difference between the two
products.
Table 3--Labeling Regarding Duration of Use for Prescription and
Nonprescription PEG 3350
------------------------------------------------------------------------
Nonprescription
Prescription MiraLAX MiraLAX
------------------------------------------------------------------------
Duration of Use............. This product should Use no more than 7
be used for 2 weeks days. Stop use and
or less or as ask a doctor if you
directed by a need to use a
physician. laxative for longer
than 1 week.
------------------------------------------------------------------------
Nexgen and Gavis both argue that the words ``or as directed by a
physician'' in the prescription MiraLAX labeling can be construed to
mean that the PEG 3350 ANDA prescription products can be prescribed by
a physician for an indefinite period of time or for chronic use;
whereas the wording of the nonprescription MiraLAX labeling implies
that FDA determined that use of PEG 3350 for longer than 7 days is
unsafe for the consumer without supervision of a practitioner licensed
by law (Gavis Comments at 003-004; Nexgen Comments at 6). Thus, they
assert that because the prescription ANDA products are labeled for a
longer duration of use with physician oversight, those products must be
dispensed pursuant to prescription. They argue that because the PEG
3350 ANDAs are approved for prescription use, they should be allowed to
remain on the market for those patients who need physician supervision
(Gavis Comments at 003-004; Nexgen Comments at 8-9).
Furthermore, Nexgen and Gavis assert that the data submitted as
part of the NDA for nonprescription MiraLAX support long-term use of
the product, and withdrawing the prescription PEG 3350 ANDAs from the
market would leave patients without a long-term option (see Gavis
Comments at 004-005). Paddock and Nexgen claim that the data supporting
the application for nonprescription use show that consumers taking PEG
3350 will experience increasing levels of effectiveness between 10 days
and 1 month of use (Paddock Comments at 24; Nexgen Comments at 9;
Nexgen Objection at 49-58). They believe this change in effectiveness
over time is a material difference between the prescription and
nonprescription products and shows that longer-term use with physician
supervision is medically necessary (Nexgen Comments at 12; Paddock
Comments at 20). Furthermore, Nexgen argues that the studies used to
support the nonprescription MiraLAX NDA were conducted in chronically
constipated patients and were designed to evaluate chronic use over the
long term (Nexgen Comments at 14-15; Nexgen Objection at 49-58).
Nexgen also contends that FDA arbitrarily chose 7 days as a
duration of use for the nonprescription MiraLAX product. This duration
of use, Nexgen argues, was not based on FDA's medical judgment, but
instead was a recommended time for OTC laxatives generally (Nexgen
Comments at 7; Nexgen Objection at 56-57). Paddock agrees and claims
that the statements in the NOOH are contrary to the recommendation in
the TFM \12\ on OTC laxatives (50 FR 2124 at 2131, January 15, 1985)),
which states that ``constipation lasting more than 1 week could be a
sign of a more serious condition for which proper diagnosis and
treatment may be warranted. Therefore, the 1-week use limitation
warning will be retained for bulk-forming laxatives as well as all
other OTC laxative drug products,'' which Paddock believes indicates
that the Agency found there to be a significant difference between 1-
and 2-weeks duration of use (Paddock Comments at 22-23). Nexgen
maintains that FDA must address at a hearing why it approved a 7-day
duration of use consistent with the TFM in light of the NDA studies and
literature (Nexgen Objection at 56-57). The ANDA holders' arguments
regarding duration of use are not persuasive.
---------------------------------------------------------------------------
\12\ See generally 21 CFR part 330 (describing the public
rulemaking process resulting in the establishment of standards (drug
monographs) for an OTC therapeutic drug class).
---------------------------------------------------------------------------
When FDA approved nonprescription MiraLAX, it considered the change
from prescription to nonprescription to be complete, i.e., no
prescription indications remained. As set forth explicitly in the
approved labeling, both the prescription and nonprescription products
are indicated for occasional constipation, not chronic constipation,
and the duration of use must be read in concert with that approved
indication. Thus, FDA did not consider there to be any meaningful
differences between the prescription and nonprescription labeling, and
FDA considered any minor wording changes to simply be due to the
different audiences (i.e., learned intermediary versus lay consumer)
and the difference in setting (i.e., use with a physician's supervision
versus consumer self-directed use).
Although the words ``or as directed by a physician'' in the
prescription ANDA labeling may be interpreted as contemplating extended
use, in the prescription setting a physician would have been involved
in making that determination. Thus, according to the
[[Page 14008]]
labeling, a physician may choose, in his or her discretion as a medical
professional, to prescribe the product for longer than 2 weeks.
Contrary to the arguments posited by the ANDA holders, this recognition
of physician discretion did not change the approved indication to
chronic constipation. In any event, the nonprescription product also
recognizes such discretion, so in that regard the products are the
same, as well. Nonprescription MiraLAX describes a shorter duration of
use and recommends seeing a physician if the patient needs to use a
laxative for longer than 7 days, and, if so, a physician can direct the
OTC consumer to continue using the product for a longer duration.
Although the studies supporting the approval of both the
prescription and nonprescription versions of MiraLAX were of a longer
duration than the duration of use for which the nonprescription product
is labeled, when evaluating nonprescription labeling FDA determines
what it believes to be the appropriate duration of use before
recommending consumers seek assistance from a physician. The studies
themselves are only one aspect of that determination. Furthermore, for
approvals of both prescription and nonprescription products generally,
long-term studies are often used to establish safety of the product.
(See ``Guidance for Industry: Premarketing Risk Assessment,'' available
at https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126958.pdf.) For nonprescription MiraLAX, the purpose of the longer
duration of the studies was to assess the safety of the product for use
in the OTC setting in which the potential exists for consumers to use
the product repeatedly without consulting a physician.
FDA acknowledges that the study designs used in the trials that
supported the change from prescription to nonprescription status were
similar to study designs that could be used to support an indication of
chronic idiopathic constipation, which is a long-term use indication
that FDA would likely consider to be a prescription use. While the
trials conducted to support the approval of MiraLAX as a
nonprescription product were sufficiently long in duration to
potentially have supported an indication for chronic idiopathic
constipation (in addition to occasional constipation), such an
indication was not sought by the sponsor. Because Braintree did not
seek a chronic idiopathic constipation indication as a prescription
product, and the ANDA prescription products were not approved for and
are not labeled for that use, any argument that the studies support
this use, or that their approvals should not be withdrawn because the
product is used off-label, is irrelevant.
In determining whether a complete change from prescription to
nonprescription status was appropriate, FDA found that there was no
evidence in the three studies submitted in the MiraLAX NDA for
nonprescription use that showed a different efficacy or safety profile
in the treated population, compared with the studies that supported the
prescription indication. With regard to the ANDA holders' assertions
that the data supporting the nonprescription use demonstrates increased
efficacy between 14 days and 1 month, the trials for the original
prescription product were not designed to evaluate comparative efficacy
over time. Therefore, there is no evidence from the studies that were
used to support the approval of the prescription indication that
establishes that MiraLAX is most effective when used for more than 7
days as the PEG 3350 ANDA holders claim. As to the longer-term studies
supporting the nonprescription approval, as explained above, FDA
considered the longer-term studies for nonprescription MiraLAX
primarily to provide safety information. Specifically, these studies
confirm that the drug would still be considered safe if a consumer
chose to use it repeatedly before seeking advice from a physician. The
studies cannot be used to support the assertions made by the PEG 3350
ANDA holders that the prescription product is most effective when used
for a longer period of time. As reflected in their respective labeling,
both products were expected to be effective in producing a bowel
movement in less than 7 days, further confirming that there is no
meaningful difference with respect to duration of use.
The ANDA holders also challenge decisions made during the course of
FDA approval of OTC MiraLAX. They maintain that FDA's decision, made at
the time of the OTC approval, to include a 7-day duration of use in the
OTC labeling was arbitrary and was not based on FDA's medical judgment.
As discussed above, the ANDA holders are not entitled to a hearing with
regard to the decision to approve OTC MiraLAX or to decisions related
to the content of the OTC label; those decisions are not at issue in
this proceeding. Based on its studies and analyses submitted to support
the nonprescription MiraLAX NDA, Braintree's proposed nonprescription
labeling contained a 14-day duration of use, like the labeling for the
prescription product. However, FDA, in conducting its own analysis,
determined that the appropriate duration of use for the nonprescription
MiraLAX product was 7 days with an instruction to consult a physician
after that time. FDA determined that the 7-day duration of use was
appropriate for a consumer self-medicating in the nonprescription
setting and concluded that the nonprescription labeling should be
consistent with earlier FDA determinations for other nonprescription
laxatives. FDA issued a TFM for nonprescription laxative products in
1985. In this proposed regulation, the Agency agreed with the advisory
panel regarding duration of use for laxatives in the OTC setting. The
panel had previously stated that the reason for this recommendation is
that a sudden change in bowel habits may be due to serious disease
(e.g., cancer, stricture), and the continued use of a laxative may
delay diagnosis of such conditions. The panel is of the opinion that
the available scientific evidence shows that very few indications
warrant the use of any laxative beyond 1 week, except under the advice
of a physician (40 FR 12902 at 12906, March 21, 1975). In the preamble
to the TFM, FDA stated that ``the [A]gency considers the recommended 1-
week limitation on the use of laxatives to be a necessary warning for
the safe use of these products.'' (50 FR 2124 at 2130). This decision
regarding the appropriate duration of use for laxative products in the
OTC setting was not arbitrary, as the ANDA holders contend, but rather
was based on FDA's scientific judgment regarding laxative products and
its determination regarding how best to protect and promote the health
of consumers using laxatives in the OTC setting. In any event, however,
this decision regarding the OTC label was not based on any meaningful
difference between the prescription and nonprescription products.
Gavis and Nexgen also attempt to fashion an argument out of a
typographical error in the NOOH (Nexgen Comments at 5-6; Gavis Comments
at 003-004). FDA wrote in the NOOH that the prescription indication is
the following: ``This product should be used for 2 weeks or less as
directed by a physician.'' The correct wording of the ANDA prescription
labeling is, ``This product should be used for 2 weeks or less or as
directed by a physician'' (emphasis added to indicate omitted word).
Gavis and Nexgen both argue that FDA's conclusion that there is no
meaningful difference is faulty because they contend that the Agency
relied on the misstated indication for the prescription
[[Page 14009]]
PEG 3350 labeling. The Commissioner acknowledges that FDA
unintentionally omitted the word ``or'' from the description of the
ANDA prescription labeling in the NOOH. No meaning should be ascribed
to this omission. FDA's analysis was based on the actual ANDA
prescription labeling.
Nexgen also argues that the approval of nonprescription MiraLAX was
an ``Initial Marketing of a Drug Product OTC'' and not an ``Rx to OTC
Switch'' under the Center for Drug Evaluation and Research's Manual of
Policies and Procedures (MAPP) 6020.5. Similar to their arguments
described above, Nexgen contends that an ``Rx to OTC switch'' did not
occur because the nonprescription MiraLAX has a different duration of
use from the prescription product, which they suggest points to a
meaningful difference between the two (Nexgen Comments at 16). Further,
Nexgen accuses FDA of making an ``after-the-fact effort to revise or
re-write the actual history relating to the OTC application and its
review, apparently to rationalize its unfounded and unprecedented
proposed enforcement action [withdrawing the PEG 3350 ANDAs]'' (Nexgen
Comments at 17). Nexgen maintains that the switch of MiraLAX from
prescription to nonprescription was not a complete switch because OTC
MiraLAX was approved under a different NDA number, while, for other
products, FDA has effectuated a partial switch with a new NDA and a
complete switch with a supplemental NDA (Nexgen Objection at 44-46).
Nexgen also maintains that the switch was not a complete switch because
Breckenridge's prescription ANDA was approved only a few months prior
to approval of OTC MiraLAX, Nexgen's prescription ANDA was approved 10
days prior to the approval of OTC MiraLAX, and the prescription MiraLAX
NDA was not withdrawn until March 2009 (Nexgen Objection at 46).
These arguments have no validity. Nexgen's characterizations of
FDA's actions are unfounded and incorrect. In assessing whether section
503(b)(4) allows the same active ingredient in products that are both
prescription and nonprescription, FDA considers the products' approved
indication, strength, route of administration, dosage form, and patient
population and not the definitions in MAPP 6020.5 or MAPP processes
that may have been followed prior to the approval. Facts related to the
timing of a generic prescription PEG 3350 approval and the withdrawal
of the prescription NDA likewise are not relevant to those
considerations. While Braintree's NDA for nonprescription MiraLAX has a
different NDA number, the issuance of a new NDA number is an
administrative issue, which is irrelevant to the question of whether
there is a meaningful difference between the prescription and
nonprescription versions. Despite the difference in NDA numbers, FDA
did consider the nonprescription MiraLAX NDA to be an ``Rx to OTC
switch'' according to the MAPP.
In sum, the Commissioner has concluded that that there is not a
meaningful difference between the prescription and nonprescription
products based on the duration of use. The Commissioner does not find
the arguments advanced by the PEG 3350 ANDA holders on this topic
persuasive and is entering summary judgment against them.
2. Difference in Patient Populations
Nexgen, Gavis, and Paddock also submitted comments regarding the
use of PEG 3350 in high-risk populations. They argue that their
prescription approvals should not be withdrawn because, in their
opinion, the supervision of a licensed practitioner is necessary for
the safe and effective use of this drug in high-risk populations
(Nexgen Comments at 26-30). They believe that patients in higher-risk
populations cannot self-diagnose and self-treat their constipation.
Therefore, they argue that the product should be dispensed upon a
prescription and that a physician should be involved in the care of
such patients (Paddock Comments at 24-26).
Furthermore, they do not believe that the nonprescription product
can be used correctly by all of the patients that regularly use PEG
3350 and contend that eliminating the prescription version promotes
self-medication by chronically ill individuals (Nexgen Comments at 47;
Paddock Comments at 20). Specifically, they argue that the studies
submitted to support the approval of MiraLAX for nonprescription use do
not reflect how the product will be used in high-risk populations
because high-risk subjects were excluded from the study population
(Nexgen Comments at 21; Paddock Comments at 24). The studies excluded
children and patients with a history of heart failure, diabetes, kidney
failure, gastrointestinal disease, and surgeries or obstruction.
Paddock argues that these groups represent large segments of the
population who need laxative therapy (Paddock Comments at 24). In
addition, Nexgen, Paddock, and Gavis note that subpopulations like
children and the elderly require close monitoring when using laxatives
and are at risk when taking a nonprescription product (Paddock Comments
at 25; Gavis Comments at 007; Nexgen Comments at 31-33).
Finally, Nexgen notes that FDA failed to consider the needs of
pediatric patients in its analysis. The prescription labeling stated
that ``safety and effectiveness in pediatric patients has not been
established''; whereas, the nonprescription labeling states, ``children
16 years of age or under: ask a doctor.'' Nexgen argues that the
nonprescription labeling fails to consider that a physician's
supervision is required for use in children. Nexgen also conjectures
that by allowing Braintree to defer pediatric studies until 2016, FDA
contemplated use of nonprescription MiraLAX in children (Nexgen
Comments at 7-8).
FDA disagrees with the PEG 3350 ANDA holders' argument that there
should be a prescription version of PEG 3350 available. As an initial
matter, the ANDA holders' allegations regarding potential misuse by
chronically ill individuals are simply a new iteration on their prior
arguments about an off-label use of MiraLAX: Chronic constipation
associated with these chronic illnesses. The data submitted by
Braintree met the statutory and regulatory criteria for changing the
product's status from prescription to nonprescription. In making this
determination, FDA found that the product is safe and effective for use
for self-medication as directed in the proposed nonprescription
labeling. In this instance, and with all other nonprescription drug
products, the labeling describes the patient population for which the
product was found to be safe and effective, and suggests that other
populations, such as children, should consult a physician.
Nonprescription labeling is designed to assist consumers in appropriate
self-selection and use. In addition, the nonprescription labeling is
designed to instruct consumers regarding when they should seek the
advice of a physician. Further, a physician is free to instruct a
patient on how and whether to use a nonprescription product.
FDA disagrees with the contention that nonprescription MiraLAX is
unsafe for use by elderly patients. In fact, the long-term clinical
studies conducted to support the approval of MiraLAX as a
nonprescription product enrolled a significant number of patients aged
65 years or older. In one study, 25 percent of the patients were over
65 years old, and in another study, 38 percent of
[[Page 14010]]
patients were over 65 years old.\13\ The ANDA holders present their
experts' observations related to the risk of MiraLAX use in the elderly
but do not challenge the results of these studies. Furthermore, the
risk information in the prescription labeling on geriatric use (``In
geriatric nursing home patients a higher incidence of diarrhea occurred
at the recommended 17 g dose. If diarrhea occurs MiraLAX should be
discontinued'') is reflected in the risk information in the
nonprescription ``Drug Facts'' label (``When using this product you may
have loose, watery, more frequent stools; Stop use and ask a doctor if
. . . [bullet] you get diarrhea''). Based on available data and
information, FDA determined that the product is safe and effective for
use in geriatric patients without a prescription if used as directed in
the approved labeling and disagrees with Nexgen and Paddock's
contentions that only having a nonprescription version available puts
elderly patients at risk.
---------------------------------------------------------------------------
\13\ Ruyi He, GI Team Leader AP Comments on NDA 22-015, dated
August 14, 2006.
---------------------------------------------------------------------------
With regard to pediatric patients, the approved nonprescription
MiraLAX labeling, like the prescription labeling, indicates that the
product is for those 17 and older and explains that children under 16
should consult with a physician. No randomized, controlled studies were
performed to properly assess the efficacy and safety of nonprescription
MiraLAX in pediatric patients. In the absence of such data, it is
common for nonprescription labeling to include age cutoffs and instruct
consumers to talk to their doctor. Based on a particular patient's
medical condition, a physician can choose to direct him or her on how
to use a nonprescription product.
3. Difference in Labeling
Nexgen and Paddock also argue that removing the prescription PEG
3350 products from the market would deprive physicians of important
information that is included in the prescription labeling but not in
the nonprescription labeling. Nexgen argues that the quality of
information provided in the prescription labeling and package insert is
helpful in treating high-risk patients (Nexgen Comments at 21). Paddock
notes that the package insert more fully discusses the efficacy,
safety, and risk profile of PEG 3350 for long-term use and in high-risk
patients (Paddock Comments at 20). Nexgen maintains that FDA's TFM for
laxative products proposed to require professional labeling for OTC
laxatives (Nexgen Objection at 72). These differences, they argue,
constitute a meaningful difference between the products and require
that prescription PEG 3350 remain on the market.
It is true that prescription labeling contains more detailed
information than is included on nonprescription products (see
Sec. Sec. 201.57 and 201.66 (21 CFR 201.57 and 201.66)). However, when
FDA determines that a product meets the statutory and regulatory
criteria for changing its status from prescription to nonprescription,
the new nonprescription labeling is designed for consumer use as per
Sec. 201.66. Prescription labeling is designed to inform medical
practitioners and thus contains more information than OTC labeling.
Such additional detail would not be appropriate or useful in the OTC
setting. Because FDA considered the change from prescription to
nonprescription status to be a ``full'' switch, the prescription
labeling is no longer appropriate. The fact that the prescription
labeling is more detailed does not establish a meaningful difference
between the prescription and nonprescription versions.
The factors FDA generally considers in determining whether there is
a meaningful difference are indication, strength, route of
administration, population, and dosage form. As the labeling for the
prescription and nonprescription PEG 3350 products shows, they have the
same indication, strength, route of administration, population, and
dosage form. As explained in the NOOH, if FDA were to include the
differences between prescription and nonprescription labeling
requirements as a factor in determining whether there is a meaningful
difference sufficient to allow the same active ingredient to be
marketed in prescription and nonprescription products, FDA would never
be able to exempt a drug product from the prescribing requirements of
section 503(b). This result would be in contravention of the plain
language of section 503 of the FD&C Act and the purpose of Congress in
enacting that provision. Further, Nexgen's contention that FDA proposed
to require professional labeling for nonprescription laxatives in the
TFM for those products fails to establish a meaningful difference
between the prescription and nonprescription PEG 3350 products.\14\
---------------------------------------------------------------------------
\14\ Should a physician wish to access more detailed information
about the efficacy, safety, and risk profile of nonprescription
MiraLAX for long-term use and/or use in high-risk patients, such
information is available in the medical literature.
---------------------------------------------------------------------------
4. Other Active Ingredients Marketed in Prescription and
Nonprescription Drug Products Simultaneously
Nexgen and Paddock do not agree that the examples FDA cited in the
NOOH of active ingredients that are simultaneously marketed in
prescription and nonprescription drugs that FDA considers to be
meaningfully different (ranitidine hydrochloride (HCl), omeprazole, and
ibuprofen) can be distinguished from PEG 3350. In addition, Nexgen and
Paddock identified other examples of active ingredients that are
simultaneously marketed in prescription and nonprescription products
(butenafine HCl, terbinafine HCl, cimetidine, and loperamide) that they
believe are analogous to PEG 3350. They argue that all of the examples
of active ingredients being simultaneously marketed for prescription
and nonprescription uses have less significant differences in
conditions of use than those between the prescription and
nonprescription versions of MiraLAX (Paddock Comments at 2 and 21;
Nexgen Comments at 49-53). Furthermore, Nexgen argues that in the
examples FDA cited in its NOOH, each of the active ingredients has a
prescription version because of a need for continued physician
oversight to treat certain patient populations. In this way, they
contend, those products are analogous to the prescription PEG 3350
products. Thus, they argue that the ANDA PEG 3350 approvals should be
retained to ensure the intervention and supervision of a physician of
certain patients for which physicians commonly prescribe PEG 3350
(geriatric patients, pediatric patients, patients with chronic
constipation) and for whom a serious disease or condition is the cause
of constipation. They argue that, although PEG 3350 is not approved for
chronic use and pediatric patients, FDA must consider that PEG 3350 is
commonly prescribed for these uses (Nexgen Comments at 49-50). Nexgen
also argues that meaningful differences exist between the prescription
and nonprescription labels of MiraLAX and ranitidine products because
the prescription labeling for the prescription MiraLAX and ranitidine
includes information describing dosing in elderly patients, while the
OTC labeling for both products does not (Nexgen Comments at 50).
Nexgen and Paddock's arguments that FDA's determinations regarding
whether there are meaningful differences between the prescription and
nonprescription versions of ranitidine HCl, omeprazole, and
[[Page 14011]]
ibuprofen do not support the conclusion that the prescription PEG 3350
products also have meaningful differences from nonprescription MiraLAX.
Nexgen's and Paddock's meaningful difference arguments largely compare
uses for which the ANDA holders assert PEG 3350 is commonly prescribed,
but for which it is not approved, (e.g., pediatric patients and
patients with chronic constipation) with indications for which
ranitidine HCl, omeprazole, and ibuprofen are approved. Because this
proceeding to withdraw approval of the Rx PEG 3350 products focuses on
whether such products as approved by FDA are meaningfully different
than OTC MiraLAX, such arguments regarding unapproved uses of PEG 3350
are irrelevant in this proceeding. Other arguments are relevant to the
issue of whether any laxative product should be approved OTC (e.g.,
constipation may be caused by a serious underlying condition) and not
relevant to the issue of whether there is a meaningful difference
between the prescription and nonprescription products as approved by
FDA.
The ANDA holders' reliance on FDA's decision to allow simultaneous
prescription and nonprescription marketing of other active ingredients
is misplaced because FDA makes these decisions on a case-by-case basis,
based upon the merits of the individual application before the Agency.
Nevertheless, the Commissioner will address the examples of
simultaneous marketing raised by the ANDA holders. Furthermore, the
permitted simultaneous prescription and nonprescription marketing of
active ingredients, such as butenafine HCl (Mentax Rx and Lotrimin
Ultra), terbinafine HCl (Lamisil), cimetidine, and loperamide are
distinguishable from the prescription PEG 3350 products. Unlike
MiraLAX, the differences in the cited examples are meaningful for the
reasons set forth in this section. Moreover, none of the examples cited
below rely upon duration of use alone to support the simultaneous
marketing of Rx and OTC products. While some of the Rx and OTC products
discussed below do have different durations of use, there is also an
additional, more fundamental difference between the Rx and OTC products
discussed below, such as different indication, patient population, or
dose.
a. Butenafine HCl. The active ingredient, butenafine HCl, is an
antifungal agent for which safety and efficacy have been established
for the topical treatment of a variety of superficial dermal infections
(tinea corporis, tinea cruris (jock itch), interdigital tinea pedis
(athlete's foot), and tinea versicolor (a fungal infection of the skin
resulting in small, discolored patches)) due to susceptible organisms.
FDA considers some of these indications to require the involvement of a
practitioner licensed by law and thus to meet the standard for
requiring a prescription under section 503(b)(1) of the FD&C Act, while
others do not. The active ingredient is marketed with the tradename
Mentax as a prescription product, and with the tradename Lotrimin Ultra
as a nonprescription product. The indications for the active ingredient
butenafine HCl Rx and butenafine HCl OTC are set out in table 4.
Table 4--Differences Between the Prescription and Nonprescription Versions of Drug Products With the Active
Ingredient Butenafine HCl and Butenafine HCl
----------------------------------------------------------------------------------------------------------------
Lotrimin Ultra (butenafine HCl)
Mentax (butenafine HCl) (Rx) (OTC)
----------------------------------------------------------------------------------------------------------------
Indication................................. Indicated for the topical Indicated for the treatment of
treatment of the dermatologic athlete's foot (tinea pedis)
fungal infection, tinea and jock itch (tinea cruris) in
(pityriasis) versicolor due to consumers 12 years and older.
Malassezia furfur (formerly P. Consumers less than 12 years
orbiculare). old are directed to ask a
doctor.
----------------------------------------------------------------------------------------------------------------
Tinea versicolor, the prescription indication, is usually diagnosed
based on a medical history and physical examination. The symptoms may
resemble other skin conditions and require the expertise of a physician
for diagnosis using an ultraviolet light or other professional
diagnostic tools. In contrast, FDA considers the indication for the
treatment of athlete's foot and/or jock itch to be conditions that a
consumer can self-diagnose and self-treat.
Thus, FDA determined that the prescription indication requires the
supervision of a practitioner licensed by law and meets the criteria at
section 503(b)(1) of the FD&C Act, while the nonprescription
indications did not meet the criteria at section 503(b)(1). Thus, the
differences in the indications for the active ingredient, butenafine
HCl creams are meaningful in that the conditions for which they are
indicated require different levels of expertise to diagnose and treat.
b. Terbinafine HCl. The active ingredient terbinafine HCl is an
antifungal agent that is administered either orally or topically. It is
marketed as a prescription product under the tradename Lamisil Gel and
as a nonprescription product under the tradename Lamisil Cream.\15\
Like the last example, the indications for the two products are
different as explained in table 5.
---------------------------------------------------------------------------
\15\ The Rx Gel (NDA 20-846) has been discontinued.
Table 5--Differences Between Prescription Terbinafine HCl and Nonprescription Terbinafine HCl
----------------------------------------------------------------------------------------------------------------
Lamisil DermGel Rx Lamisil Cream OTC
----------------------------------------------------------------------------------------------------------------
Indication................................. For the treatment of tinea For the treatment of athlete's
(pityriasis) versicolor due to foot (tinea pedis), tinea
M. furfur, tinea pedis corporis (ringworm) and jock
(athlete's foot), tinea corporis itch (tinea cruris) in
(ringworm) or tinea cruris (jock consumers 12 years and older.
itch) due to Trichophyton Consumers less than 12 years
rubrum, Trichophyton old are directed to ask a
mentagrophytes, or doctor.
Epidermophyton floccosum.
----------------------------------------------------------------------------------------------------------------
[[Page 14012]]
As noted in table 5, the nonprescription version of Lamisil (cream)
is used for the treatment of athlete's foot (tinea pedis), ringworm
(tinea corporis), and jock itch (tinea cruris)--common conditions a
consumer can self-diagnose and self-treat. The prescription version of
Lamisil is indicated for the treatment of tinea versicolor, which
requires the expertise of a physician to diagnose and treat (as
discussed above). Similar to butenafine HCl discussed in section
III.D.4.a., the differences in the indication of Rx versus OTC
terbinafine HCl are meaningful in that the conditions for which they
are indicated require different levels of expertise to diagnose and
treat (as discussed above).
c. Loperamide. Loperamide is an oral antidiarrheal agent marketed
under the trade name Imodium as a nonprescription product. Loperamide
prolongs the transit time of the intestinal contents. It reduces fecal
volume, increases the viscosity and bulk density, and diminishes the
loss of fluid and electrolytes. Table 6 sets out the differences
between the indication, dosage, and duration of use for loperamide Rx
versus loperamide OTC.
Table 6--Differences Between Loperamide Rx and Loperamide OTC
----------------------------------------------------------------------------------------------------------------
Loperamide Rx (Imodium) 2 Loperamide OTC Loperamide
milligram (mg) capsule (Imodium) 2 mg caplet
----------------------------------------------------------------------------------------------------------------
Indication................................. Indicated for the control and Used for the control of symptoms
symptomatic relief of acute of diarrhea, including
nonspecific diarrhea and chronic travelers' diarrhea.
diarrhea associated with
inflammatory bowel disease. It
is also indicated for reducing
the volume of discharge from
ileostomies.
Dose....................................... The recommended daily dose in The recommended daily dose in
adults should not exceed 16 mg adults and children over 12
(8 capsules). In children, the years of age should not exceed
dosing is based on age and 8 mg (4 capsules) in 24 hours.
weight range. Following the In children, the dosing is
first treatment day, it is based on age and weight range
recommended that subsequent (different from that of the Rx
doses (1 mg/10 kg body weight) labeling).
be administered only after a
loose stool; total daily dosage
should not exceed recommended
dosages for the first day.
Duration of Use............................ There is no specified limit in Patients are directed to stop
the duration of use. use and ask a doctor if
symptoms get worse or diarrhea
lasts for more than 2 days.
----------------------------------------------------------------------------------------------------------------
Prescription loperamide is indicated for the control and
symptomatic relief of acute nonspecific diarrhea and chronic diarrhea
associated with inflammatory bowel disease and for reducing the volume
of discharge from ileostomies. These conditions require the diagnostic
skills and treatment intervention of a physician. In comparison, OTC
loperamide is indicated for the treatment of diarrhea, including
traveler's diarrhea, which can be self-diagnosed and treated. In
addition, the total daily dose is 8 mg for OTC loperamide and 16 mg for
Rx loperamide, and there are differences in dosing for children.
Finally, the OTC version has a recommended duration of use of only 2
days, whereas the Rx version is used to treat chronic conditions for an
unlimited period of time under the supervision of a physician.
The differences between Rx and OTC loperamide are meaningful in
that the conditions for which they are indicated require different
levels of expertise to diagnose and treat. In addition, they are dosed
at different levels.
d. Cimetidine. Cimetidine is an oral H2-receptor
antagonist used mainly for treating acid-related gastrointestinal
disorders. It is marketed as Tagamet. Table 7 sets out the differences
between the dosage, indication, and duration of use for cimetidine Rx
versus cimetidine OTC.
Table 7--Differences Between Cimetidine Rx and Cimetidine OTC
----------------------------------------------------------------------------------------------------------------
Cimetidine Rx Cimetidine OTC
----------------------------------------------------------------------------------------------------------------
Indication................................. Indicated for the treatment of Relief of heartburn associated
acid-related gastrointestinal with acid indigestion and sour
disorders such as stomach; prevention of
gastroesophageal reflux disease heartburn associated with acid
(GERD) and duodenal ulcers. indigestion and sour stomach
brought on by eating or
drinking certain foods and
beverages.
Dosage..................................... 200 mg-1600 mg as adjusted to 200 mg up to 2 times per day as
individual patient needs. needed to relieve heartburn.
Duration of Use............................ 2-3 times per day for 4-12 weeks. No longer than 14 days unless
Indication specific. directed by a physician.
----------------------------------------------------------------------------------------------------------------
The conditions for which cimetidine Rx is indicated require a
physician for diagnosis and treatment; they cannot be self-diagnosed
and are not appropriate for self-treatment. They are also treated at a
significantly higher dose (e.g., 400 to 1600 mg per day for 4 to 8
weeks; 800 mg twice a day for 12 weeks) and at a much longer duration
(up to 12 weeks) than the OTC drug product with the same active
ingredient.
Cimetidine OTC is indicated to relieve or prevent heartburn
associated with acid indigestion and sour stomach that occurs after
eating or drinking certain food or beverages, a condition that patients
can self-diagnose and self-treat. Unlike cimetidine Rx, it is not
indicated to be used on a regular dosing regimen to treat a permanent
medical condition such as GERD or duodenal ulcers. Rather, the OTC
product is used on an ``as needed'' basis to prevent or relieve a
symptom, so consumers could take one or two doses (200 to 400 mg) on a
day they experience heartburn. The OTC labeling limits use to no more
than 2 weeks.
The Rx and OTC versions of cimetidine have meaningful differences
in that the conditions for which they are indicated require different
levels of expertise to diagnose and treat, and they
[[Page 14013]]
have different dosage strengths, durations of use, and indications.
e. Omeprazole. Omeprazole is a proton pump inhibitor used mainly
for treating acid-related gastrointestinal disorders. It is marketed as
PRILOSEC. Table 8 sets out the differences between the dosage,
indication, and duration of use for omeprazole Rx versus omeprazole
OTC.
Table 8--Differences Between Omeprazole Rx and Omeprazole OTC
----------------------------------------------------------------------------------------------------------------
Omeprazole Rx Omeprazole OTC
----------------------------------------------------------------------------------------------------------------
Indication................................. Indicated for the treatment of Indicated for the treatment of
conditions that require profound frequent heartburn occurring 2
inhibition of gastric acid or more days a week.
secretion, such as treatment of
GERD and maintenance of healing
of erosive esophagitis in both
adult and pediatric patients,
and especially the treatment of
hypersecretory conditions.
Dosage..................................... 20 mg-60 mg. Indication specific. 20 mg.
Duration of Use............................ Ranges from once daily for 4 No more than 14 days and not
weeks to an open-ended duration. more often than every 4 months
Indication specific. unless directed by a physician.
----------------------------------------------------------------------------------------------------------------
The conditions for which Rx omeprazole is indicated require the
supervision of a physician for diagnosis and treatment. Depending on
the indication, treatment duration could be months and even years. In
the particular instance of the treatment of symptomatic GERD, the
recommended dose is 20 mg daily for up to 4 weeks and of the treatment
of erosive esophagitis due to acid-mediated GERD, the recommended dose
is 20 mg once daily for 4 to 8 weeks. The Rx version allows titrating
upward to achieve efficacy, especially for pathological hypersecretory
conditions.
On the other hand, omeprazole OTC is approved for the treatment of
frequent heartburn (defined as occurring 2 or more days per week). This
product is to be taken once a day (every 24 hours) every day for 14
days. The product labeling notes that it may take 1 to 4 days for full
effect, although some people may get complete relief of symptoms within
24 hours. The consumer is instructed not to take the drug for more than
14 days or use more than one course every 4 months unless otherwise
directed by a doctor.
The Rx and OTC versions of omeprazole have meaningful differences
in that the conditions for which they are indicated require different
levels of expertise to diagnose and treat, and they have different
durations of use and indications.
f. Ranitidine HCl 150 mg. Ranitidine HCl is a histamine
H2-receptor antagonist that inhibits stomach acid
production. It is marketed as ZANTAC. It comes in a wide variety of
strengths, but the 150 mg strength tablet is the only formulation that
is marketed as both Rx and OTC. Table 9 sets out the differences
between the dosage, indication, and duration of use for 150 mg
ranitidine HCl Rx versus ranitidine OTC.
Table 9--Differences Between Ranitidine HCl Rx and Ranitidine HCl OTC
----------------------------------------------------------------------------------------------------------------
150 mg Ranitidine HCl Rx 150 mg Ranitidine HCl OTC
----------------------------------------------------------------------------------------------------------------
Indication................................. Pediatric patients (1 month to 16 Relieves heartburn associated
years): Treatment of duodenal with acid indigestion and sour
and gastric ulcers, maintenance stomach. Prevents heartburn
of healing of duodenal and associated with acid
gastric ulcers, and treatment of indigestion and sour stomach
GERD and erosive esophagitis. brought on by eating or
Adult patients: Multiple drinking certain foods and
indications related to duodenal beverages.
ulcer, gastric ulcer, GERD,
erosive esophagitis, and
pathological hypersecretory
conditions.
Dosage..................................... Pediatric patients: Dose varies Adults and children 12 years and
based on body weight; dose over:
frequency is one to two times To relieve symptoms, swallow 1
per day, depending on the tablet with a glass of water.
indication. To prevent symptoms, swallow 1
Adult patients: One to four times tablet with a glass of water 30
per day, depending on the to 60 minutes before eating
indication. food or drinking beverages that
cause heartburn. Can be used up
to twice daily (do not take
more than 2 tablets in 24
hours).
Children under 12 years: Ask a
doctor.
Duration of Use............................ Indication specific. For most Stop use and ask a doctor if
indications, duration is open- your heartburn continues or
ended. worsens or if you need to take
this product for more than 14
days.
----------------------------------------------------------------------------------------------------------------
OTC ranitidine HCl is indicated for conditions that the patient may
self-diagnose and self-treat and because of the ability to self-
diagnose and self-treat, the dosing is on an ``as needed'' basis to
prevent or relieve a symptom. For example, a consumer could take one or
two doses (150 to 300 mg) on a day they experience heartburn. The OTC
product limits time for which a consumer should use the product without
consulting a doctor. In addition, the OTC product is only approved for
use in adults and children 12 and over.
On the other hand, Rx ranitidine HCl is indicated for the treatment
of more serious acid- related gastrointestinal disorders such as GERD
and duodenal ulcers, which require a physician to diagnose. These
conditions are chronic and require treatment over an extended period of
time under the supervision of a physician. Further, the Rx ranitidine
HCl is approved for use in children as young as 1 month old. Nexgen
acknowledges that Rx ranitidine HCl remains approved because, among
other reasons, it is indicated for much more severe medical conditions
than the OTC ranitidine HCl (Nexgen Comments at
[[Page 14014]]
50). Nevertheless, Nexgen argues that the labeling for prescription PEG
3350 and ranitidine addresses use in elderly patients, which does not
appear in the OTC labeling. Such labeling differences result from the
differences in the labeling requirements for prescription (Sec.
201.57) and OTC (Sec. 201.66) products. Such differences were not set
forth in the ANPRM or the NOOH for this proceeding as a factor that FDA
would consider in determining that there is a meaningful difference
such that the same active ingredient could be marketed in both a
prescription and nonprescription product. Unlike OTC MiraLAX and Rx PEG
3350, the Rx and OTC versions of 150 mg ranitidine HCl have meaningful
differences in that the conditions for which they are indicated require
different levels of expertise to diagnose and treat, and they have
different indications, durations of use, dosages, and indicated patient
populations.
g. Ibuprofen. Ibuprofen is a nonsteroidal anti-inflammatory drug
used as an analgesic for relief of symptoms of, including but not
limited to, arthritis, fever, inflammation, and dysmenorrhea. Ibuprofen
is marketed under multiple brand names, including ADVIL and MOTRIN, and
comes in multiple dosage forms. Tables 10a and 10b set out the
differences in indication, dosing, and duration of use of the 100 mg/5
mL suspension for Rx versus OTC use and the meaningful differences in
the 400 mg Rx tablet and the 200 mg OTC tablet.
Table 10a--Differences Between Ibuprofen Suspension Rx and Ibuprofen Suspension OTC
----------------------------------------------------------------------------------------------------------------
Ibuprofen 100 mg/5 mL suspension Ibuprofen 100 mg/5 mL suspension
Rx OTC
----------------------------------------------------------------------------------------------------------------
Indication................................. Pediatric Patients: For reduction Pediatric Patients (age 2-11):
of fever in patients aged 6 Relieves minor aches and pains
months up to 2 years of age. For due to the common cold, flu,
relief of mild to moderate pain sore throat, headache, and
in patients aged 6 months up to toothache. Reduces fever (stop
2 years of age. For relief of use and ask a doctor if: Fever
signs and symptoms of juvenile or pain gets worse or lasts
arthritis. more than 3 days)
Adult Patients: For treatment of
primary dysmenorrhea. For relief
of the signs and symptoms of
rheumatoid arthritis and
osteoarthritis.
Dosage..................................... Pediatric Patients: Doses vary The dosage depends on the
depending on the condition being child's age and weight. An
treated, but the recommended attached dosing chart informs
maximum daily dose in treating the consumer how large of a
any of the conditions is 40mg/kg. dose the child should receive.
Adult Patients: The dose of
ibuprofen oral suspension should
be tailored to each patient, and
may be lowered or raised from
the suggested doses depending on
the severity of symptoms either
at time of initiating drug
therapy or as the patient
responds or fails to respond.
Duration of use............................ Ranges from as necessary to an No more than 3 days unless
open-ended daily dosage. directed by a doctor.
----------------------------------------------------------------------------------------------------------------
Table 10b--Differences Between Ibuprofen Tablet Rx and Ibuprofen Tablet OTC
----------------------------------------------------------------------------------------------------------------
Ibuprofen 400 mg tablet Rx Ibuprofen 200 mg tablet OTC
----------------------------------------------------------------------------------------------------------------
Indication................................. Indicated for relief of the signs Indicated for the temporary
and symptoms of rheumatoid relief of minor aches and pains
arthritis and osteoarthritis, due to: Headache, minor pain of
relief of mild to moderate pain, arthritis, backache, menstrual
and treatment of primary cramps, muscular aches,
dysmenorrhea. toothache, and the common cold.
Indicated to temporarily reduce
fever.
Dosage..................................... Patients should use the lowest Adults and children 12 years and
effective dose for the shortest older, take one caplet every 4
duration consistent with patient to 6 hours while symptoms
treatment goals. After observing persist. If pain does not
the response to initial therapy, respond to one caplet, two
the dose and frequency should be caplets may be used. Do not
adjusted to suit an individual exceed six caplets in 24 hours,
patient's needs. Do not exceed unless directed by a doctor.
3200 mg total daily dose.
Rheumatoid arthritis and
osteoarthritis suggested dosage:
1200 mg-3200 mg daily.
Mild to moderate pain suggested
dosage: 400 mg every 4 to 6
hours as necessary for relief of
pain.
Dysmenorrhea suggested dosage:
400 mg every 4 hours as
necessary for relief of pain.
Duration of use............................ Shortest duration consistent with Stop and ask a doctor if pain
individual patient treatment gets worse or lasts more than
goals. 10 days, or fever gets worse or
lasts more than 3 days.
----------------------------------------------------------------------------------------------------------------
Both Rx ibuprofen forms allow for high doses to treat rheumatoid
arthritis and juvenile arthritis, as well as other chronic conditions.
The ibuprofen Rx suspension also allows for titration of doses to treat
pain of varying severity in adults who cannot swallow pills and for
pediatric patients depending on the severity of the symptoms. Neither
Rx ibuprofen form limits the duration of use in patients. The labeled
instructions to titrate the dosage and use the product for an unlimited
duration support the necessity of physician oversight with both Rx
ibuprofen forms.
On the other hand, the ibuprofen OTC suspension product has fixed
age and weight range dosing divisions, does not exceed 15 mg/kg per
dose, does not allow for dose titration, and limits use to 3 days. The
ibuprofen OTC tablet label recommends a maximum daily dose of 1200 mg,
whereas the ibuprofen
[[Page 14015]]
Rx tablet allowed for up to 3200 mg daily, for certain conditions. The
ibuprofen OTC tablet also limits use to 3 or 10 days, for certain
conditions. Finally, both OTC ibuprofen forms are indicated for less
severe and non-chronic conditions. Because the ibuprofen 100 mg/5 mL
suspension Rx and OTC products and the ibuprofen Rx and OTC tablet
products differ in the indications, dosage, and durations of use
depending upon the indication, they are meaningfully different.
Unlike the meaningful differences in the examples provided in
section III.D.4, and for the reasons discussed in other parts of this
section, FDA does not consider there to be a meaningful difference
between the prescription PEG 3350 products and the nonprescription
MiraLAX product. The Commissioner finds that the meaningful differences
between the other active ingredients that are marketed in drug products
that are both prescription and nonprescription products described in
section III.D.4 are distinguishable from the nonmeaningful differences
between the prescription PEG 3350 products and the nonprescription
MiraLAX product. The examples cited by the PEG 3350 ANDA holders
significantly differ in one or more of their indications, dosage, or
target population. In addition to these differences, some also have a
different duration of therapy. All of these drugs were initially
approved as prescription products, and then subsequently the active
ingredients were also approved for use in a nonprescription product for
different indications, or sometimes a subset of, the prescription
indications--unlike MiraLAX where no different prescription indications
remain. By definition, prescription products are approved for use for
indications for which consumers cannot self-diagnose or self-treat,
thus requiring the supervision of a licensed practitioner, i.e., the
prescription standard in section 503(b) of the FD&C Act is met. In the
case of nonprescription MiraLAX, it is not indicated for any conditions
that consumers cannot self-diagnose or self-treat, and thus does not
meet the standard in section 503(b) of the FD&C Act.
5. Other Objections
Other objections raised by the PEG 3350 ANDA holders regarding
their contention that there is a meaningful difference between the
prescription PEG 3350 products and nonprescription MiraLAX include
those related to the wording of the indication, the exclusivity granted
to Braintree, and the cost of OTC MiraLAX.
Gavis and Nexgen argue that the prescription ANDA PEG 3350 labeling
states that the product is for the ``treatment'' of occasional
constipation; whereas, nonprescription MiraLAX is for ``reliev[ing]''
occasional constipation. Gavis contends that nonprescription MiraLAX
``relieves'' constipation, rather than treating it, which is a
meaningful difference requiring the prescription product to remain on
the market (Gavis Comments at 006; Nexgen Objection at 66). Nexgen
notes that ``treats'' and ``relieves'' may not be used interchangeably
under FDA's regulation for OTC drug products at 21 CFR 330.1(i) (Nexgen
Objection at 66). The NOOH explained that the approved OTC MiraLAX
labeling uses the word ``relieves'' to ensure consistency with other
OTC monograph laxative products. As noted, FDA, in considering whether
there is a meaningful difference, compares the active ingredient,
dosage form, strength, route of administration, indications, and
patient population. In this case, because both the OTC and Rx products
are indicated for occasional constipation, the different terms
``relieves'' and ``treats'' do not constitute a meaningful difference.
Paddock also argues that granting Braintree 3 years of exclusivity
under section 505(j)(5)(F) of the FD&C Act indicates that there are
meaningful differences between the prescription PEG 3350 labeling and
the nonprescription MiraLAX labeling because the clinical data
submitted to support nonprescription MiraLAX was in different
populations (Paddock Comments at 2). In Paddock's opinion, 3-year
exclusivity would only be authorized if the data were the result of
``new clinical investigations,'' which would indicate that
nonprescription MiraLAX is different from the prescription PEG 3350
products (Paddock Comments at 6). It is true that Braintree conducted
new clinical investigations to support its NDA for nonprescription
MiraLAX. However, contrary to Paddock's contentions, the basis of
approval for the prescription product consisted of two studies, 851-3
and 851-6, which demonstrated that at least one-third of subjects
taking 17 g of MiraLAX per day have a bowel movement by Day 1, and at
least three-fourths have a first bowel movement by Day 3. The three
studies submitted in the nonprescription NDA, studies 851-CR1, 851-ZCC,
and 851-CR3, did not show a different efficacy or safety profile in the
treated populations when compared with the studies submitted in support
of the prescription NDA (851-3 and 851-6). The three studies submitted
with the nonprescription NDA simply provided evidence that
nonprescription MiraLAX would be safe if used repeatedly over time in
an OTC setting. As noted in section III.C.3, Braintree earned 3 years
of exclusivity for the new clinical studies it conducted that supported
approval of its OTC switch NDA. In the Commissioner's opinion, the fact
that clinical data was necessary to provide assurance that
nonprescription availability of the product was safe does not, in and
of itself, support the contention that the product is meaningfully
different from the previously approved prescription product. Sponsors
of nonprescription drug products frequently perform additional studies
that FDA concludes are essential to support a change from prescription
to nonprescription status, such as actual use studies, for which they
may receive exclusivity (if the statutory criteria for exclusivity are
met).
Paddock also notes that removing the prescription PEG 3350 products
from the market will nearly triple the cost of the product for the
average insured patient (Paddock Comments at 2). Paddock maintains that
this predicted cost increase is because consumers with insurance may
pay less out of pocket for prescription drugs than for nonprescription
drugs, and the exclusivity granted to Braintree for the nonprescription
product would create a monopoly if all competing prescription products
were withdrawn from the market (Paddock Comments at 30). Paddock and
Nexgen argue that withdrawal of approval for prescription PEG 3350
products will reduce the availability of the products due to the
absence of Medicaid and health insurance coverage (Nexgen Comments at
43; Paddock Comments at 30; Nexgen Objection at 41). Nexgen challenges
FDA's conclusion in the draft order that cost is not a relevant
consideration in this proceeding (Nexgen Objection at 42).
These arguments are irrelevant. In this instance, the prescription
PEG 3350 products may no longer be lawfully marketed. In the ANPRM and
NOOH, FDA set forth the factors it generally considers in determining
whether the same active ingredient may be marketed in a prescription
and nonprescription product: Issues related to the cost of drug
products are not a relevant consideration.
Nexgen maintains that FDA should stay the withdrawal of the ANDAs
pending the finalization of the TFM for OTC laxatives and FDA issuing a
response on a pending citizen petition
[[Page 14016]]
submitted by Nexgen (Nexgen Objection at 78-82). According to Nexgen,
its pending citizen petition requests that FDA find that the
prescription MiraLAX NDA was not withdrawn for reasons of safety and
efficacy and to declare Nexgen's prescription ANDA as the new RLD drug
for prescription PEG 3350 products (Objection at 79). It is not
necessary to finalize the TFM for OTC laxatives or to respond to
Nexgen's pending citizen petition prior to the withdrawal of the ANDAs.
As discussed elsewhere in this order, the OTC MiraLAX labeling is
consistent with the TFM for OTC laxatives with respect to the use of
the phrase ``relieves'' versus ``treats'' and the instruction to ``use
no more than 7 days'' and ``Stop use and ask a doctor if . . . you need
to use a laxative for longer than 1 week.'' However, this labeling does
not change the factors relevant to determining whether there is a
meaningful difference between the prescription and nonprescription PEG
3350 products. If an order is entered withdrawing the approval of the
ANDAs, the issues raised in the citizen petition will be moot.
Nexgen complains that FDA largely based its draft proposed order on
a January 2013 letter from Merck rather than more carefully reviewing
and responding to each argument raised by the ANDA holders, rendering
the order suspect (Nexgen Objection at 75-76). In fact, both the Merck
letter and the draft proposed order were written in response to the
issues and evidence submitted by the ANDA holders. The draft proposed
order provided a lengthy analysis addressing the arguments and evidence
submitted by the ANDA holders. The fact that the draft proposed order
ultimately reached the same conclusion urged by the NDA holder (and the
result proposed by CDER in the NOOH) does not render that order
``suspect.''
In sum, the Commissioner believes that the change in prescription
to nonprescription status was a complete switch. In addition, the
Commissioner concludes that there is not a meaningful difference
between the prescription and nonprescription products approved by FDA
based on the arguments discussed in this section. The Commissioner
finds that the ANDA holders have failed to raise a genuine and
substantial issue of fact regarding a meaningful difference between
prescription and nonprescription MiraLAX that requires a hearing. The
Commissioner does not find the arguments advanced by the PEG 3350 ANDA
holders on the topics discussed in this section persuasive and is
entering summary judgment against them.
IV. Findings and Order
Based upon the above, the Commissioner finds that the PEG 3350 ANDA
holders have failed to raise a genuine and substantial issue of fact
requiring a hearing in their responses to the NOOH. A hearing,
therefore, is not required under Sec. 12.24(b). The PEG 3350 ANDA
holders did not submit any specifically identified reliable evidence
demonstrating that a hearing is necessary. Other evidence submitted was
not material to the issues in this proceeding. Even if the Commissioner
were to accept these factual assertions as having some weight, such
evidence does not present a sufficient area of disagreement to require
an evidentiary hearing. Rather, the evidence is ``so one-sided that
[FDA] must prevail as a matter of law.'' (See Anderson v. Liberty
Lobby, Inc., 477 U.S. 242, 252 (1986).)
In addition to finding that the ANDA holders have failed to raise a
genuine and substantial issue of fact that requires a hearing, the
Commissioner does not find the arguments advanced by the PEG 3350 ANDA
holders persuasive and is entering summary judgment against them under
Sec. 314.200(g). There is no meaningful difference between the ANDA
holders' PEG 3350 products and OTC MiraLAX. The labeling of the ANDA
holders' PEG 3350 products is false and misleading because it bears the
``Rx only'' symbol when FDA has determined in approving OTC MiraLAX
that the drug can be used safely and effectively in the nonprescription
setting and does not meet the criteria for a prescription drug in
503(b)(1) of the FD&C Act. This false and misleading labeling was not
corrected within a reasonable time after receipt of written notice from
FDA. Therefore, under section 505(e) of the FD&C Act and under
authority delegated to the Commissioner, the PEG 3350 ANDA holders'
requests for a hearing are denied.
It is ordered, that pursuant to section 505(e) of the FD&C Act (21
U.S.C. 355(e)), that approval of the following ANDAs: ANDA 76-652 held
by Kremers Urban Pharmaceuticals, Inc.; ANDA 77-736 held by
Breckenridge Pharmaceutical, Inc.; ANDA 77-706 held by Nexgen Pharma,
Inc. (formerly known as Anabolic Laboratories, Inc.); ANDA 77-893 held
by Paddock Laboratories, LLC.; and ANDA 77-445 held by Teva
Pharmaceutical, USA; and all amendments and supplements to them, be and
hereby are withdrawn, effective May 2, 2018.
Dated: March 22, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-06537 Filed 3-30-18; 8:45 am]
BILLING CODE 4164-01-P