Document ID: FDA-1975-N-0336-0121
Agency: fda
Document Type: Notice
Title: Drugs for Human Use; Drug Efficacy Study Implementation; Oral Prescription Drugs Containing an Anticholinergic or Antispasmodic in Combination With a Sedative, and
Single-Entity Antispasmodic Drug Products, in Oral Dosage Form; Withdrawal of Hearing Requests; Final Resolution of Drug Efficacy Study Implementation
Posted Date: 2022-04-25T04:00Z

[Federal Register Volume 87, Number 79 (Monday, April 25, 2022)]
[Notices]
[Pages 24311-24313]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-08740]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-1975-N-0336 (formerly 1975N-0184)]

Drugs for Human Use; Drug Efficacy Study Implementation; Oral 
Prescription Drugs Containing an Anticholinergic or Antispasmodic in 
Combination With a Sedative, and Single-Entity Antispasmodic Drug 
Products, in Oral Dosage Form; Withdrawal of Hearing Requests; Final 
Resolution of Drug Efficacy Study Implementation

AGENCY: Food and Drug Administration, Health and Human Services (HHS).

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
that all outstanding hearing requests regarding drug products 
containing an anticholinergic or antispasmodic in combination with a 
sedative, and single-entity antispasmodic drug products, in oral dosage 
form, under Docket FDA-1975-N-0336 (formerly 75N-0184) (DESI 10837) 
have been withdrawn. Therefore, shipment in interstate commerce of any 
such product identified in Docket FDA-1975-N-0336 covered by DESI 
10837, 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 date of this notice. 
This notice does not affect products covered by DESI 597 under the same 
docket.

DATES: This notice is applicable April 25, 2022.

ADDRESSES: For access to the docket to read background documents or the 
electronic and written/paper comments received, 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 (HFA-305), 5630 
Fishers Lane, Rm. 1061, Rockville, MD 20852. The most relevant 
background documents regarding this matter are available in the docket. 
However, additional background documents are available upon request 
(see FOR FURTHER INFORMATION CONTACT).

FOR FURTHER INFORMATION CONTACT: Jeffrey Trunzo, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 5111,

[[Page 24312]]

Silver Spring, MD 20993-0002, 301-796-2029, email: 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    When enacted in 1938, the Federal Food, Drug, and Cosmetic Act 
(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 Sciences/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 covered by the DESI review 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 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 Oral Prescription 
Drugs Containing an Anticholinergic or Antispasmodic in Combination 
With a Sedative, and Single-Entity Antispasmodic Drug Products, in Oral 
Dosage Form Under Docket No. FDA-1975-N-0336 (Formerly 75N-0184); DESI 
10837

    In a Federal Register notice published on June 22, 1971 (36 FR 
11875) (1971 Federal Register notice), FDA announced its evaluation of 
reports received from NAS/NRC under DESI 10837, regarding 
anticholinergic drug products containing the following active 
ingredients: Prochlorperazine maleate and isopropamide iodide; 
oxyphencyclimine hydrochloride and meprobamate; oxyphencyclimine 
hydrochloride and hydroxyzine hydrochloride; tridihexethyl chloride and 
meprobamate; and propantheline bromide and thiopropazate hydrochloride. 
The drugs were found to be possibly effective as adjunctive therapy in 
peptic ulcer and in the irritable bowel syndrome (irritable colon, 
spastic colon, mucous colitis, functional gastrointestinal disorders); 
functional diarrhea; drug induced diarrhea; ulcerative colitis, and 
urinary bladder spasm, and urethral spasm (i.e., smooth muscle spasm). 
In addition, oxyphencyclimine and meprobamate preparations were found 
to be possibly effective for dysmenorrhea. These drugs were found to 
lack substantial evidence of effectiveness for their other labeled 
indications.
    In a Federal Register notice published November 11, 1975 (40 FR 
52644) (1975 Federal Register notice), the Agency explained that 
several of the products listed in the 1971 Federal Register notice may 
remain on the market while clinical studies were being conducted to 
determine their efficacy for the indications rated as ``possibly 
effective,'' because they were widely used in the treatment of peptic 
ulcer disease and functional bowel syndrome and were perceived as 
important and useful tools of therapy by many gastroenterologists and 
general practitioners (40 FR 52644 at 52648). In addition to the 
products from the 1971 Federal Register notice, the 1975 Federal 
Register notice included several products, among them Librax Capsules, 
NDA 12-750, containing clidinium bromide and chlordiazepoxide, now 
manufactured by Bausch Health Companies, Inc. (Bausch), that had been 
the subject of safety-only applications approved before 1962 and that 
had not been reviewed by NAS/NRC. Librax Capsules was included in the 
1975 Federal Register notice notwithstanding the Stipulation for 
Dismissal in Hoffman-La Roche, Inc. v. Richardson, et. al., Civil 
Action 11-73 (D.N.J. August 2, 1973), discussed below. The 1975 Federal 
Register notice set forth a timetable for conducting clinical efficacy 
studies for drug products subject to the notice. In a Federal Register 
notice published June 20, 1978 (43 FR 26490) (1978 Federal Register 
notice), FDA announced a change in its previous policy for testing and 
marketing of the drugs that were subject of the November 11, 1975, 
notice (e.g., Librax), including an extension of deadline for 
completion of the studies for 1 year.
    In a Federal Register notice published January 16, 1981(46 FR 3977) 
(1981 Federal Register notice), FDA announced its evaluation of study 
reports received in response to the 1975 Federal Register notice. FDA 
concluded that there was a lack of substantial evidence demonstrating 
the effectiveness of the drugs listed in the 1975 notice, proposed to 
withdraw approval of the new drug applications, and offered an 
opportunity for hearing to manufacturers of the drugs listed in the 
notice, as well as to the manufacturers of IRS products.
    As set forth in a Federal Register notice published July 24, 2012 
(77 FR 43337) (2012 Federal Register notice), several companies 
submitted timely hearing requests in response to the 1981 Federal 
Register notice, but the only such request that had not been withdrawn 
as of July 2012, was the request regarding Librax Capsules, filed by 
Roche Laboratories, manufacturer of Librax Capsules in 1981 (77 FR 
43337 at 43341). In response to the 2012 Federal Register notice, 
Valeant Pharmaceuticals North America LLC (now Bausch) affirmed the 
hearing request regarding Librax Capsules by letter dated August 22, 
2012.
    On May 23, 2016, FDA posted a Notice to Docket 1975-N-0336,

[[Page 24313]]

explaining that Librax is not subject to review under DESI because a 
new drug application for Librax was approved by the Agency on September 
1, 1966, and at that time the Agency determined that Librax was safe 
and effective for the indications set forth in its labeling, 
(consistent with the Stipulation for Dismissal in Hoffman-La Roche, 
Inc. v. Richardson, et al., Civil Action 11-73 (D.N.J. August 2, 
1973)). On June 2, 2016, Valeant responded by withdrawing its hearing 
request.
    There are no longer outstanding hearing requests pertaining to drug 
products containing an anticholinergic or antispasmodic in combination 
with a sedative, and single-entity antispasmodic drug products, in oral 
dosage form under Docket No. FDA-1975-N-0336, DESI 10837. Shipment in 
interstate commerce of any drug product identified in this docket under 
DESI 10837, or any IRS product, that is not the subject of an approved 
NDA or ANDA is unlawful as of the applicable date of this notice (see 
DATES). Any person who wishes to determine whether a specific product 
is covered by this notice should write to Jeffrey Trunzo (see FOR 
FURTHER INFORMATION CONTACT). Firms should be aware that, after the 
applicable 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 
https://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 510(j) of the FD&C Act to 
reflect discontinuation of unapproved products covered by this notice 
(21 CFR 207.57(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 discontinued product(s), including the product National 
Drug Code (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 Jeffrey Trunzo (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 identifies 
violative products for enforcement action.

IV. Reformulated Products

    FDA cautions firms against reformulating products 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 
healthcare practitioners and harm patients.

    Dated: April 20, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-08740 Filed 4-22-22; 8:45 am]
BILLING CODE 4164-01-P