[Federal Register Volume 80, Number 220 (Monday, November 16, 2015)]
[Notices]
[Pages 70822-70825]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-28853]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-1977-N-0356 (Formerly 77N-0240); DESI 1786]


Drugs for Human Use; Drug Efficacy Study Implementation; 
Nitroglycerin Transdermal Systems; Withdrawal of Hearing Request; 
Withdrawal of Applications; Final Resolution of Hearing Requests 
Regarding Transdermal Systems Under Docket

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
that all outstanding hearing requests regarding nitroglycerin drug

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products in transdermal systems under Docket No. FDA-1977-N-0356 
(formerly 77N-0240) (DESI 1786) have been withdrawn. Therefore, 
shipment in interstate commerce of any nitroglycerin drug product in a 
transdermal system identified in this docket, or any identical, 
related, or similar (IRS) product, that is not the subject of an 
approved new drug application (NDA) or abbreviated new drug application 
(ANDA) is unlawful as of the effective date of this notice.

DATES: Effective Date: This notice is effective November 16, 2015.

ADDRESSES: You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to http://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on http://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of 
Dockets Management, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-1977-N-0356 for ``Drugs for Human Use; Drug Efficacy Study 
Implementation; Nitroglycerin Transdermal Systems; Withdrawal of 
Hearing Request; Withdrawal of Applications; Final Resolution of 
Hearing Requests Regarding Transdermal Systems Under Docket.'' Received 
comments will be placed in the docket and, except for those submitted 
as ``Confidential Submissions,'' publicly viewable at http://www.regulations.gov or at the Division of Dockets Management between 9 
a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on http://www.regulations.gov. 
Submit both copies to the Division of Dockets Management. If you do not 
wish your name and contact information to be made publicly available, 
you can provide this information on the cover sheet and not in the body 
of your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: http://www.fda.gov/regulatoryinformation/dockets/default.htm.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to http://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 Division of Dockets Management, 5630 Fishers 
Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Barbara Wise, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 5160, Silver Spring, MD 20993-0002, 301-
796-2089, email: [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    When enacted in 1938, the Federal Food, Drug, and Cosmetic Act (the 
FD&C Act) required that ``new drugs'' (21 U.S.C. 321(p)) be approved 
for safety by FDA before they could legally be sold in interstate 
commerce. Between 1938 and 1962, if a drug obtained approval, FDA 
considered drugs that were IRS (see 21 CFR 310.6(b)(1)) to the approved 
drug to be covered by that approval, and allowed those IRS drugs to be 
marketed without independent approval.
    In 1962, Congress amended the FD&C Act to require that new drugs be 
proven effective for their labeled indications, as well as safe, in 
order to obtain FDA approval. This amendment also required FDA to 
conduct a retrospective evaluation of the effectiveness of the drug 
products that FDA had approved as safe between 1938 and 1962. FDA 
contracted with the National Academy of Science/National Research 
Council (NAS/NRC) to make an initial evaluation of the effectiveness of 
over 3,400 products that had been approved only for safety between 1938 
and 1962. The NAS/NRC reports for these drug products were submitted to 
FDA in the late 1960s and early 1970s. The Agency reviewed and 
reevaluated the reports and published its findings in Federal Register 
notices. FDA's administrative implementation of the NAS/NRC reports was 
called the Drug Efficacy Study Implementation (DESI). DESI covered the 
approximately 3,400 products specifically reviewed by the NAS/NRC, as 
well as the even larger number of IRS products that entered the market 
without FDA approval.
    All drugs reviewed under DESI are ``new drugs'' under the FD&C Act. 
If FDA's final DESI determination classifies a drug product as lacking 
substantial evidence of effectiveness for one or more indications, that 
drug product and those IRS to it may no longer be marketed for such 
indications and are subject to enforcement action as unapproved new 
drugs. If FDA's final DESI determination classifies the drug product as 
effective for one or more of its labeled indications, the drug can be 
marketed for such indications, provided it is the subject of an 
application approved for safety and effectiveness. Sponsors of drug 
products that have been found to be effective for one or more 
indications through the DESI process may rely on FDA's effectiveness

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determinations, but typically must update their labeling to conform to 
the indication(s) found to be effective by FDA and include any 
additional safety information required by FDA. Those drug products with 
NDAs approved before 1962 for safety therefore require approved 
supplements to their original applications if one or more indications 
are found to be effective under DESI; IRS drug products require an 
approved NDA or ANDA, as appropriate. Furthermore, labeling for drug 
products classified as effective may contain only those indications for 
which the review found the product effective unless the firm marketing 
the product has received an approval for the additional indication(s).

II. Final Resolution of Hearing Requests Regarding Nitroglycerin 
Transdermal Systems Under Docket No. FDA-1977-N-0356 (formerly 77N-
0240); DESI 1786

    In a Federal Register notice published in February 1972, FDA 
announced its evaluation of reports received from NAS/NRC regarding 
certain single-entity coronary vasodilators, including controlled-
release nitroglycerin tablets, for indications relating to the 
management, prophylaxis, and treatment of angina attacks (37 FR 4001, 
February 25, 1972). In a Federal Register notice published in December 
1972, FDA temporarily exempted specified single-entity coronary 
vasodilators covered by DESI from the time limits established for 
completing DESI (37 FR 26623 at 26624, December 14, 1972). The December 
1972 notice did not initially include controlled-release forms of the 
drugs, but a notice published in July 1973 allowed the case-by-case 
addition of controlled-release dosage forms, pending the completion of 
scientific studies that showed a drug was released in a defined manner 
which would permit well-controlled clinical trials to determine 
effectiveness (38 FR 18477, 18478, July 11, 1973; corrected by 38 FR 
19920, July 25, 1973).
    The December 1972 notice was amended again in August 1977, to 
announce the addition of controlled-release forms of specified coronary 
vasodilators, and the availability of guidelines and methods for 
determining the bioavailability of coronary vasodilators (42 FR 43127, 
August 26, 1977). The August 1977 notice specifically added 
nitroglycerin (topical ointment forms, conventional oral forms, and 
controlled release forms) to the list of drugs allowed to remain on the 
market while efficacy studies were conducted (42 FR 43127 at 43128). 
The December 1972 notice was further amended in October 1977, to extend 
the deadlines for submission of data and applications required for the 
coronary vasodilator products, and to announce the availability of 
guidelines for alternative methods of determining bioavailability for 
these products (42 FR 56156, October 21, 1977). Controlled-release 
transdermal nitroglycerin patches were included among the types of 
drugs permitted to remain on the market pending completion of efficacy 
studies based on their similarity to nitroglycerin ointment products 
(58 FR 38129 at 38130, July 15, 1993).
    In July 1993, FDA revoked the temporary exemption for single-entity 
coronary vasodilator products containing nitroglycerin in a transdermal 
delivery system, which had allowed the products to stay on the market 
beyond the time limit scheduled for the implementation of DESI (58 FR 
38129). FDA found the products to be effective for prevention of angina 
pectoris caused by coronary artery disease, and required sponsors to 
submit bioavailability/bioequivalence studies within 1 year (see 58 FR 
38129 at 38130 to 38131). In March 1999, FDA reclassified one NDA and 
five ANDAs for nitroglycerin transdermal systems to lacking substantial 
evidence of effectiveness, based on the sponsors' failure to submit the 
required bioavailability/bioequivalence data (64 FR 14451, March 25, 
1999). In the March 1999 notice, FDA proposed to withdraw approval of 
the applications and offered an opportunity for a hearing on the 
proposal to withdraw the applications.
    In response to the March 1999 notice, Schwarz Pharma, Inc. (Schwarz 
Pharma), now a subsidiary of UCB, S.A., which was the sponsor of two of 
the five ANDAs, and Hercon Laboratories Corp. (Hercon), which was the 
sponsor of the remaining three ANDAs, requested hearings.\1\ G.D. 
Searle & Co., which was the sponsor of the identified NDA, did not 
submit a hearing request.
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    \1\ The March 1999 notice incorrectly referred to Hercon as 
``Hercon Pharmaceutical Company, Inc.''
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    At the request of Hercon, in the Federal Register of March 4, 2005 
(70 FR 10651 at 10656), FDA withdrew approval of Hercon's three ANDAs 
that were the subject of the 1999 notice of opportunity for a hearing. 
On January 10, 2011, FDA sent a letter to Hercon to determine whether 
it remained interested in pursuing its hearing request. On February 9, 
2011, Hercon responded by withdrawing its hearing request. On July 17, 
2002, Schwarz Pharma withdrew its hearing request and requested 
withdrawal of its ANDAs that were the subject of the 1999 notice of 
opportunity for a hearing.
    There are no longer outstanding hearing requests for nitroglycerin 
drug products in transdermal systems under this docket. Therefore, as 
proposed in the March 1999 notice of opportunity for hearing, FDA finds 
that the following applications lack substantial evidence of 
effectiveness and hereby withdraws approval of the applications under 
section 505(e) of the FD&C Act (21 U.S.C. 355): ANDA 88-727, DEPONIT 
(release rate of 0.2 mg of nitroglycerin per hour), held by Schwarz 
Pharma; ANDA 89-022, DEPONIT (release rate of 0.4 mg of nitroglycerin 
per hour), held by Schwarz Pharma; and NDA 20-146, NITRODISC, held by 
G.D. Searle & Co. Shipment in interstate commerce of any nitroglycerin 
drug product in a transdermal system identified in this docket, or any 
IRS product, that is not the subject of an approved NDA or ANDA is 
unlawful as of the effective date of this notice (see DATES). Any 
person who wishes to determine whether a specific product is covered by 
this notice should write to Barbara Wise at the Center for Drug 
Evaluation and Research (see FOR FURTHER INFORMATION CONTACT). Firms 
should be aware that, after the effective date of this notice (see 
DATES), FDA intends to take enforcement action without further notice 
against any firm that manufactures or ships in interstate commerce any 
unapproved product covered by this notice.

III. Discontinued Products

    Firms must notify the Agency of certain product discontinuations in 
writing under section 506C(a) of the FD&C Act (21 U.S.C. 356c). See 
http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm142398.htm. Some 
firms may have previously discontinued manufacturing or distributing 
products covered by this notice without discontinuing the listing as 
required under section 510(j) of the FD&C Act (21 U.S.C. 360(j)). Other 
firms may discontinue manufacturing or distributing listed products in 
response to this notice. All firms are required to electronically 
update the listing of their products under section 510(j) of the FD&C 
Act to reflect discontinuation of unapproved products covered by this 
notice (21 CFR 207.21(b)). Questions on electronic drug listing updates 
should be sent to [email protected]. In addition to the required 
update, firms can also notify the Agency of product discontinuation by 
sending a letter, signed by the firm's chief executive officer and 
fully identifying the

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discontinued product(s), including the product NDC number(s), and 
stating that the manufacturing and/or distribution of the product(s) 
have been discontinued. The letter should be sent electronically to 
Barbara Wise (see FOR FURTHER INFORMATION CONTACT). FDA plans to rely 
on its existing records, including its drug listing records, the 
results of any future inspections, or other available information, when 
it targets violative products for enforcement action.

IV. Reformulated Products

    FDA cautions firms against reformulating products into unapproved 
new drugs and marketing under the same name or substantially the same 
name (including a new name that contains the old name). Reformulated 
products marketed under a name previously identified with a different 
active ingredient or combinations of active ingredients have the 
potential to confuse health care practitioners and harm patients.

    Dated: November 9, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-28853 Filed 11-13-15; 8:45 am]
BILLING CODE 4164-01-P