[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.
------------------------------------------------------------------------

    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