Prescription Polyethylene Glycol 3350; Denial of a Hearing and Order Withdrawing Approval of Abbreviated New Drug Applications, 13994-14016 [2018-06537]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[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